TREA

PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO

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Information

  • Patent Application
  • 20170156320
  • Publication Number
    20170156320
  • Date Filed
    February 22, 2017
    7 years ago
  • Date Published
    June 08, 2017
    7 years ago
Information
Abstract
This document discloses molecules having the following formula (“Formula One”):
Description
FIELD OF THE DISCLOSURE

The invention disclosed in this document is related to the field of processes to produce molecules that are useful as pesticides (e.g., acaricides, insecticides, molluscicides, and nematicides), such molecules, and processes of using such molecules to control pests.


BACKGROUND OF THE DISCLOSURE

Pests cause millions of human deaths around the world each year. Furthermore, there are more than ten thousand species of pests that cause losses in agriculture. The world-wide agricultural losses amount to billions of U.S. dollars each year.


Termites cause damage to all kinds of private and public structures. The world-wide termite damage losses amount to billions of U.S. dollars each year.


Stored food pests eat and adulterate stored food. The world-wide stored food losses amount to billions of U.S. dollars each year, but more importantly, deprive people of needed food.


There is an acute need for new pesticides. Certain pests are developing resistance to pesticides in current use. Hundreds of pest species are resistant to one or more pesticides. The development of resistance to some of the older pesticides, such as DDT, the carbamates, and the organophosphates, is well known. But resistance has even developed to some of the newer pesticides, for example, imidacloprid.


Therefore, for many reasons, including the above reasons, a need exists for new pesticides.


DEFINITIONS

The examples given in the definitions are generally non-exhaustive and must not be construed as limiting the invention disclosed in this document. It is understood that a substituent should comply with chemical bonding rules and steric compatibility constraints in relation to the particular molecule to which it is attached.


“Alkenyl” means an acyclic, unsaturated (at least one carbon-carbon double bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, vinyl, allyl, butenyl, pentenyl, and hexenyl.


“Alkenyloxy” means an alkenyl further consisting of a carbon-oxygen single bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy.


“Alkoxy” means an alkyl further consisting of a carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy.


“Alkyl” means an acyclic, saturated, branched or unbranched, substituent consisting of carbon and hydrogen, for example, methyl, ethyl, (C3)alkyl which represents n-propyl and isopropyl), (C4)alkyl which represents n-butyl, sec-butyl, isobutyl, and tert-butyl.


“Alkynyl” means an acyclic, unsaturated (at least one carbon-carbon triple bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, ethynyl, propargyl, butynyl, and pentynyl.


“Alkynyloxy” means an alkynyl further consisting of a carbon-oxygen single bond, for example, pentynyloxy, hexynyloxy, heptynyloxy, and octynyloxy.


“Aryl” means a cyclic, aromatic substituent consisting of hydrogen and carbon, for example, phenyl, naphthyl, and biphenyl.


“(Cx-Cy)” where the subscripts “x” and “y” are integers such as 1, 2, or 3, means the range of carbon atoms for a substituent—for example, (C1-C4)alkyl means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, each individually.


“Cycloalkenyl” means a monocyclic or polycyclic, unsaturated (at least one carbon-carbon double bond) substituent consisting of carbon and hydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.


“Cycloalkenyloxy” means a cycloalkenyl further consisting of a carbon-oxygen single bond, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.


“Cycloalkyl” means a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.


“Cycloalkoxy” means a cycloalkyl further consisting of a carbon-oxygen single bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norbornyloxy, and bicyclo[2.2.2]octyloxy.


“Halo” means fluoro, chloro, bromo, and iodo.


“Haloalkoxy” means an alkoxy further consisting of, from one to the maximum possible number of identical or different, halos, for example, fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy, trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, and pentafluoroethoxy.


“Haloalkyl” means an alkyl further consisting of, from one to the maximum possible number of, identical or different, halos, for example, fluoromethyl, trifluoromethyl, 2,2-difluoropropyl, chloromethyl, trichloromethyl, and 1,1,2,2-tetrafluoroethyl.


“Heterocyclyl” means a cyclic substituent that may be fully saturated, partially unsaturated, or fully unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfur, or oxygen. In the case of sulfur, that atom can be in other oxidation states such as a sulfoxide and sulfone. Examples of aromatic heterocyclyls include, but are not limited to, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl, triazinyl, and triazolyl. Examples of fully saturated heterocyclyls include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydropyranyl. Examples of partially unsaturated heterocyclyls include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 4,5-dihydro-oxazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-isoxazolyl, and 2,3-dihydro-[1,3,4]-oxadiazolyl.


Additional examples include the following




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DETAILED DESCRIPTION OF THE DISCLOSURE

This document discloses molecules having the following formula (“Formula One”):




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wherein:

    • (a) R1 is selected from
      • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
      • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
      • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
      • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
    • (b) R2 is selected from
      • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
      • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
      • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
      • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
    • (c) R3 is selected from
      • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
      • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
      • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
      • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
    • (d) R4 is selected from
      • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
      • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
      • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
      • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
    • (e) R5 is selected from
      • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
      • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
      • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
      • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;
    • (f) R6 is a (C1-C8)haloalkyl;
    • (g) R7 is selected from H, F, Cl, Br, I, OH, (C1-C8)alkoxy, and halo(C1-C8)alkoxy;
    • (h) R8 is selected from H, (C1-C8)alkyl, halo(C1-C8)alkyl, OR14, and N(R14)(R15);
    • (i) R9 is selected from H, F, Cl, Br, I, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, OR14, and N(R14)(R15);
    • (j) R10 is selected from
      • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, cyclo(C3-C6)alkyl, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), NR14R15, C(═O)H, C(═O)N(R14)(R15), CN(R14)(R15)(═NOH), (C═O)O(C1-C8)alkyl, (C═O)OH, heterocyclyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl, (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from OH, (C1-C8)alkoxy, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, NR14R15, and
      • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from (C1-C8)alkoxy, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, and N(R14)(R15);
    • (k) R11 is C(═X5)N(H)((C0-C8)alkyl)N(R11a)(C(═X5)N(H)(R11b))
      • wherein each X5 is independently selected from O or S, and
      • wherein each R11a is independently selected from H, (C1-C8)alkyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl, cyclo(C3-C8)alkyl, substituted cyclo(C3-C8)alkyl,
      • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, OC(═O)H, OH, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, OS(O)2aryl, N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C5)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, wherein each said substituted heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), C(═O)(C1-C8)alkyl, C(═O)(C3-C6)cycloalkyl, S(═O)2(C1-C8)alkyl, NR14R15, and oxo, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo,
      • wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • wherein said substituted cyclo(C3-C8)alkyl, has one or more substituents selected from CN and NO2
    • wherein each R11b is independently selected from (C1-C8)alkyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl, cyclo(C3-C8)alkyl, substituted cyclo(C3-C8)alkyl,
      • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, OC(═O)H, OH, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, OS(O)2aryl, N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, wherein each said substituted heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), C(═O)(C1-C8)alkyl, C(═O)(C3-C6)cycloalkyl, S(═O)2(C1-C8)alkyl, NR14R15, and oxo, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo,
      • wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
      • wherein said substituted cyclo(C3-C8)alkyl, has one or more substituents selected from CN and NO2;
    • (l) R12 is selected from (v), H, F, Cl, Br, I, CN, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, and cyclo(C3-C6)alkyl;
    • (m) R13 is selected from (v), H, F, Cl, Br, I, CN, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, and halo(C1-C8)alkoxy;
    • (n) each R14 is independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl), (C1-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C1-C8)alkyl-C(═O)N(R16)(R17), C(═O)(C1-C8)alkyl, C(═O)(halo(C1-C8)alkyl), C(═O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(═O)O(C1-C8)alkyl, C(═O)H wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
      • wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
      • wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
      • wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C5)alkoxy, (C3-C6)cycloalkyl S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), heterocyclyl, C(═O)(C1-C8)alkyl, C(═O)O(C1-C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2);
    • (o) each R15 is independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl), (C1-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C1-C8)alkyl-C(═O)N(R16)(R17), C(═O)(C1-C8)alkyl, C(═O)(halo(C1-C8)alkyl), C(═O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(═O)O(C1-C8)alkyl, C(═O)H
      • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
      • wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
      • wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
      • wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, (C3-C6)cycloalkyl S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), heterocyclyl, C(═O)(C1-C8)alkyl, C(═O)O(C1-C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2);
    • (p) each R16 is independently selected from H, (C1-C8)alkyl, substituted-(C1-C8)alkyl, halo(C1-C8)alkyl, substituted-halo(C1-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl
      • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
      • wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
      • wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
      • wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo;
    • (q) each R17 is independently selected from H, (C1-C8)alkyl, substituted-(C1-C8)alkyl, halo(C1-C8)alkyl, substituted-halo(C1-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl
      • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
      • wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
      • wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
      • wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo;
    • (r) X1 is selected from N and CR12;
    • (s) X2 is selected from N, CR9, and CR13;
    • (t) X3 is selected from N and CR9; and
    • (v) R12 and R13 together form a linkage containing 3 to 4 atoms selected from C, N, O, and S, wherein said linkage connects back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, wherein said linkage has at least one substituent X4 wherein X4 is selected from R14, N(R14)(R15), N(R14)(C(═O)R14), N(R14)(C(═S)R14), N(R14)(C(═O)N(R14)(R14)), N(R14)(C(═S)N(R14)(R14)), N(R14)(C(═O)N(R14)((C2-C8)alkenyl)), N(R14)(C(═S)N(R14)((C2-C8)alkenyl)), wherein each R14 is independently selected.


In another embodiment of this invention R1 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.


In another embodiment of this invention R2 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.


In another embodiment of this invention R3 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.


In another embodiment of this invention R4 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.


In another embodiment of this invention R5 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.


In another embodiment of this invention R2 and R4 are selected from F, Cl, Br, I, CN, and NO2 and R1, R3, and R5 are H.


In another embodiment of this invention R2, R3, and R4 are selected from F, Cl, Br, I, CN, and NO2 and R1, and R5 are H.


In another embodiment of this invention R2, R3, and R4 are independently selected from F and Cl and R1 and R5 are H.


In another embodiment of this invention R1 is selected from Cl and H.


In another embodiment of this invention R2 is selected from CF3, CH3, Cl, F, and H.


In another embodiment of this invention R3 is selected from OCH3, CH3, F, Cl, or H.


In another embodiment of this invention R4 is selected from CF3, CH3, Cl, F, and H.


In another embodiment of this invention R5 is selected from F, Cl, and H.


In another embodiment of this invention R6 may be selected from any combination of one or more of the following—halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl.


In another embodiment of this invention R6 is trifluoromethyl.


In another embodiment of this invention R7 may be selected from any combination of one or more of the following—H, F, Cl, Br, and I.


In another embodiment of this invention R7 is selected from H, OCH3, and OH.


In another embodiment of this invention R8 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl.


In another embodiment of this invention R8 is selected from CH3 and H.


In another embodiment of this invention R9 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.


In another embodiment of this invention R10 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, halo(C8)alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.


In another embodiment of this invention R10 may be selected from any combination of one or more of the following—H, Cl, Br, CH3, and CF3.


In another embodiment of this invention R10 is selected from Br, C(═NOH)NH2, C(═O)H, C(═O)NH2, C(═O)OCH2CH3, C(═O)OH, CF3, CH2CH3, CH2OH, CH3, Cl, CN, F, H, NH2, NHC(═O)H, NHCH3, NO2, OCH3, OCHF2, and pyridyl.


In another embodiment of this invention R11 is selected from C(═O)N(H)N(CH3)(C(═O)N(H)(CH2CH3)), C(═O)N(H)N(CH3)(C(═O)N(H)(CH2CF3)), C(═O)N(H)N(CH3)(C(═S)N(H)(CH2CH3)), C(═O)N(H)N(CH3)(C(═S)N(H)(CH2CF3)), C(═O)N(H)CH2CH2N(CH3)(C(═O)N(H)(CH2CH3)), and C(═O)N(H) CH2CH2N(CH3)(C(═S)N(H)(CH2CF3)).


In another embodiment of this invention R12 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.


In another embodiment of this invention R12 is selected from CH3, and H.


In another embodiment of this invention R13 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.


In another embodiment of this invention R13 is selected from CH3, Cl and H.


In another embodiment of this invention R12-R13 are a hydrocarbyl linkage containing CH═CHCH═CH.


In another embodiment of this invention R14 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O—(C3)alkyl-aryl, O—(C4)alkyl-aryl, O—(C5)alkyl-aryl, O—(C6)alkyl-aryl, O—(C7)alkyl-aryl, O—(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O—(C3)alkyl-(substituted-aryl), O—(C4)alkyl-(substituted-aryl), O—(C5)alkyl-(substituted-aryl), O—(C6)alkyl-(substituted-aryl), O—(C7)alkyl-(substituted-aryl), O—(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O—(C3)alkyl-heterocyclyl, O—(C4)alkyl-heterocyclyl, O—(C5)alkyl-heterocyclyl, O—(C6)alkyl-heterocyclyl, O—(C7)alkyl-heterocyclyl, O—(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O—(C3)alkyl-(substituted-heterocyclyl), O—(C4)alkyl-(substituted-heterocyclyl), O—(C5)alkyl-(substituted-heterocyclyl), O—(C6)alkyl-(substituted-heterocyclyl), O—(C7)alkyl-(substituted-heterocyclyl), O—(C8)alkyl-(substituted-heterocyclyl), methyl-C(═O)N(R16)(R17), ethyl-C(═O)N(R16)(R17), (C3)alkyl-C(═O)N(R16)(R17), (C4)alkyl-C(═O)N(R16)(R17), (C5)alkyl-C(═O)N(R16)(R17), (C6)alkyl-C(═O)N(R16)(R17), (C7)alkyl-C(═O)N(R16)(R17), and (C8)alkyl-C(═O)N(R16)(R17).


In another embodiment of this invention R14 may be selected from any combination of one or more of the following—H, CH3, CH2CF3, CH2-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2-phenyl, CH2-pyridyl, thietanyl-dioxide, CH2-halothiazolyl, C((CH3)2)-pyridyl, N(H)(halophenyl), CH2-pyrimidinyl, CH2-tetrahydrofuranyl, CH2-furanyl, O—CH2-halopyridyl, and CH2C(═O)N(H)(CH2CF3).


In another embodiment of this invention R15 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O—(C3)alkyl-aryl, O—(C4)alkyl-aryl, O—(C5)alkyl-aryl, O—(C6)alkyl-aryl, O—(C7)alkyl-aryl, O—(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O—(C3)alkyl-(substituted-aryl), O—(C4)alkyl-(substituted-aryl), O—(C5)alkyl-(substituted-aryl), O—(C6)alkyl-(substituted-aryl), O—(C7)alkyl-(substituted-aryl), O—(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O—(C3)alkyl-heterocyclyl, O—(C4)alkyl-heterocyclyl, O—(C5)alkyl-heterocyclyl, O—(C6)alkyl-heterocyclyl, O—(C7)alkyl-heterocyclyl, O—(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O—(C3)alkyl-(substituted-heterocyclyl), O—(C4)alkyl-(substituted-heterocyclyl), O—(C5)alkyl-(substituted-heterocyclyl), O—(C6)alkyl-(substituted-heterocyclyl), O—(C7)alkyl-(substituted-heterocyclyl), O—(C8)alkyl-(substituted-heterocyclyl), methyl-C(═O)N(R16)(R17), ethyl-C(═O)N(R16)(R17), (C3)alkyl-C(═O)N(R16)(R17), (C4)alkyl-C(═O)N(R16)(R17), (C5)alkyl-C(═O)N(R16)(R17), (C6)alkyl-C(═O)N(R16)(R17), (C7)alkyl-C(═O)N(R16)(R17), and (C8)alkyl-C(═O)N(R16)(R17).


In another embodiment of this invention R15 may be selected from any combination of one or more of the following—H, CH3, CH2CF3, CH2-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2-phenyl, CH2-pyridyl, thietanyl-dioxide, CH2-halothiazolyl, C((CH3)2)-pyridyl, N(H)(halophenyl), CH2-pyrimidinyl, CH2-tetrahydrofuranyl, CH2-furanyl, O—CH2-halopyridyl, and CH2C(═O)N(H)(CH2CF3).


In another embodiment of this invention R16 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O—(C3)alkyl-aryl, O—(C4)alkyl-aryl, O—(C5)alkyl-aryl, O—(C6)alkyl-aryl, O—(C7)alkyl-aryl, O—(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O—(C3)alkyl-(substituted-aryl), O—(C4)alkyl-(substituted-aryl), O—(C5)alkyl-(substituted-aryl), O—(C6)alkyl-(substituted-aryl), O—(C7)alkyl-(substituted-aryl), O—(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O—(C3)alkyl-heterocyclyl, O—(C4)alkyl-heterocyclyl, O—(C5)alkyl-heterocyclyl, O—(C6)alkyl-heterocyclyl, O—(C7)alkyl-heterocyclyl, O—(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O—(C3)alkyl-(substituted-heterocyclyl), O—(C4)alkyl-(substituted-heterocyclyl), O—(C5)alkyl-(substituted-heterocyclyl), O—(C6)alkyl-(substituted-heterocyclyl), O—(C7)alkyl-(substituted-heterocyclyl), and O—(C8)alkyl-(substituted-heterocyclyl).


In another embodiment of this invention R16 may be selected from any combination of one or more of the following—H, CH2CF3, cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.


In another embodiment of this invention R17 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O—(C3)alkyl-aryl, O—(C4)alkyl-aryl, O—(C5)alkyl-aryl, O—(C6)alkyl-aryl, O—(C7)alkyl-aryl, O—(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O—(C3)alkyl-(substituted-aryl), O—(C4)alkyl-(substituted-aryl), O—(C5)alkyl-(substituted-aryl), O—(C6)alkyl-(substituted-aryl), O—(C7)alkyl-(substituted-aryl), O—(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O—(C3)alkyl-heterocyclyl, O—(C4)alkyl-heterocyclyl, O—(C5)alkyl-heterocyclyl, O—(C6)alkyl-heterocyclyl, O—(C7)alkyl-heterocyclyl, O—(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O—(C3)alkyl-(substituted-heterocyclyl), O—(C4)alkyl-(substituted-heterocyclyl), O—(C5)alkyl-(substituted-heterocyclyl), O—(C6)alkyl-(substituted-heterocyclyl), O—(C7)alkyl-(substituted-heterocyclyl), and O—(C8)alkyl-(substituted-heterocyclyl).


In another embodiment of this invention R17 may be selected from any combination of one or more of the following—H, CH2CF3, cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.


In another embodiment of this invention X1 is CR12, X2 is CR13, and X3 is CR9.


In another embodiment of this invention a heterocyclyl has preferably about 6 to 10 atoms in the ring structure, more preferably, 6 to 8 atoms.


The molecules of Formula One will generally have a molecular mass of about 100 Daltons to about 1200 Daltons. However, it is generally preferred if the molecular mass is from about 120 Daltons to about 900 Daltons, and it is even more generally preferred if the molecular mass is from about 140 Daltons to about 600 Daltons.


The benzyl alcohol of Formula IV, wherein R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, can be synthesized in two ways. One way, disclosed in step a of Scheme I, is by treatment of the ketone of Formula II, wherein R1, R2, R3, R4, R5, and R6 are as previously disclosed, with a reducing agent, such as sodium borohydride (NaBH4), under basic conditions, such as aqueous sodium hydroxide (NaOH), in a polar protic solvent, such as methyl alcohol (MeOH) at 0° C. Alternatively, an aldehyde of Formula III, wherein R1, R2, R3, R4, R5, and R7 are as previously disclosed, is allowed to react with trifluorotrimethylsilane in the presence of a catalytic amount of tetrabutylammonium fluoride in a polar aprotic solvent, such as tetrahydrofuran (THF), as in step b of Scheme I. The compound of Formula IV can be transformed into the compound of Formula V, wherein Y is selected from Br, Cl or I, and R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, by reaction with a halogenating reagent, such as N-bromosuccinimide and triethyl phosphite in a non-reactive solvent, such as dichloromethane (CH2Cl2) at reflux temperature to provide Y═Br, or such as thionyl chloride and pyridine in a hydrocarbon solvent, such as toluene at reflux temperature to provide Y═Cl, as in step c of Scheme I.




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Formation of the styrene coupling partners can be accomplished as in Schemes II, III IV and V.


In Scheme II, a vinylbenzoic acid of Formula VI, wherein R11 is (C═O)OH and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, can be converted in two steps to the vinylbenzamide of Formula VIIa, wherein R11 is (C═O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, and X are as previously disclosed. As in step d of Scheme II, the benzoic acid of Formula VI is treated with oxalyl chloride in the presence of a catalytic amount of DMF in a non-reactive solvent such as CH2Cl2 to form the acid chloride, which is subsequently allowed to react with an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, in the presence of a base, such as triethylamine (TEA), in a polar aprotic solvent, such as THF, to provide the vinyl benzamide of Formula VIIa, wherein R11 is (C═O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, as in step e of Scheme II.




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In Schemes III and IV, a halobenzoic acid of Formula VIII, wherein R18 is Br or I, R11 is (C═O)OH and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed can be converted to a vinylbenzoic acid ester of Formula VIIb1 or Formula VIIb2, wherein R18 is Br or I, R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. In step f of Scheme III, the halobenzoic acid of Formula VIII, wherein R18 is Br, is treated with a base, such as n-butyllithium (n-BuLi), and DMF in a polar, aprotic solvent, such as THF, at a temperature of about −78° C. The resulting formyl benzoic acid is allowed to react with an acid, such as sulfuric acid (H2SO4), in the presence of an alcohol, such as ethyl alcohol (EtOH), as in step g, to provide the formyl benzoic acid ethyl ester of Formula IX, wherein R11 is (C═O)O(C1-C6 alkyl), and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The vinyl benzoic acid ester of Formula VIIb1 is accessed via reaction of the compounds of Formula IX, with a base, such as potassium carbonate (K2CO3), and methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, at ambient temperature, as in step h of Scheme III.




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In step i of Scheme IV, the halobenzoic acid of Formula VIII, wherein R18 is Br, R11 is (C═O)OH, and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, is treated with di-tert-butyl dicarbonate in the presence of a base, such as TEA and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) in a polar aprotic solvent, such as THF, at ambient temperature. The resulting benzoic acid tert-butyl ester is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such a tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4), and a base, such as K2CO3, in a non-reactive solvent such as toluene at reflux temperature, as in step j, to provide the vinyl benzoic acid ester of Formula VIIb2, wherein R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.




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In step k of Scheme V, the vinyl benzoic acid ester of Formula VIIb2, wherein R10 is Br, R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R12, R13, X1, X2, and X3 are as previously defined, can be further transformed into the corresponding vinyl benzoic acid ester of Formula VIIb3, wherein R10 is CN, R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with copper(I) cyanide (CuCN) in a polar aprotic solvent, such as DMF, at 140° C.




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Coupling of the compounds of Formula V with the compounds of Formula VIIa, VIIb1, VIIb2 and VIIb3 can be accomplished as in Schemes VI, VII, and VIII. In step l of Scheme VI, a compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzamide of Formula VIIa, wherein R11 is (C═O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of copper(I) chloride (CuCl) and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.




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In step l of Scheme VII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoic acid ester of Formula VIIb1, wherein R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the compounds of Formula Xa, wherein R11 is (C═O)O(C1-C6 alkyl), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula Xa are then converted to the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, by either a two-step process as disclosed in steps m and n or in one step as disclosed in step o. In step m of Scheme VII, the ester of Formula Xa is saponified to the corresponding acid under acidic conditions, such as about 11 Normal (N) hydrochloric acid (HCl), in a polar aprotic solvent, such as 1,4-dioxane, at about 100° C. The acid can subsequently be coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed using peptide coupling reagents, such as 1-hydroxybenzotriazole (HOBt), N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), 1-hydroxy-7-azabenzotriazole (HOAt), or O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) in the presence of a base, such as N,N-diisopropylethylamine (DIPEA) or DMAP to give the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed. Alternatively, the ester of Formula Xa is allowed to react with an amine (HN(R14)(R15)) in the presence of a solution of trimethylaluminum in toluene in a non-reactive solvent, such as CH2Cl2, at ambient temperature, as in step o of Scheme VII, to access the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.




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In step l of Scheme VIII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoic acid ester of Formula VIIb2 or VIIb3, wherein R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the compounds of Formula Xb, wherein R11 is (C═O)OH, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed. The compounds of Formula Xb are then converted to the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, in one step as disclosed in step n. In step n of Scheme VIII, the acid of Formula Xb can be coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, using peptide coupling reagents, such as 1-hydroxybenzotriazole (HOBt), N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), 1-hydroxy-7-azabenzotriazole (HOAt), or O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) in the presence of a base, such as DIPEA or DMAP to give the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.




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In step j of Scheme IX, the halobenzoketone of Formula VIIIb, wherein R18 is Br, R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered cyclic ring, and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a non-reactive solvent such as toluene at reflux temperature, to provide the vinyl benzoketone of Formula VIIb4, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed.




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In step l of Scheme X, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoketone of Formula VIIb4 as previously disclosed, wherein R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the compounds of Formula Xc, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula Xc are then converted to the molecules of Formula Xd, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxime [(C═N)(OH)] substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, in step. In step p of Scheme X, the ketone of Formula Xc is allowed to react with hydroxylamine hydrochloride in the presence of sodium acetate and in a polar protic solvent, such as EtOH, at a temperature of about 78° C., to give the molecules of Formula Xd as previously disclosed.




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The compounds of Formula Xc are also converted to the molecules of Formula Xe, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an amine substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, as demonstrated in step q of Scheme XI. The ketone of Formula Xc is allowed to react with ammonium acetate in the presence of sodium cyanoborohydride and in a polar protic solvent, such as MEOH, at a temperature of about 65° C., to give the molecules of Formula Xe.




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The compounds of Formula Xe are converted to the molecules of Formula One, wherein R10 and R11 together form a linkage as previously disclosed in (u), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously, in one step as disclosed in steps r or s. In step r of Scheme XII, the amine of Formula Xe is allowed to react with an isocyanate in a polar, aprotic solvent such as diethyl ether at ambient temperature to provide the molecules of Formula One as previously disclosed. In step s of Scheme XII, the amine of Formula Xe is coupled to an acid with HOBt.H2O and EDC.HCl in the presence of a base, such as DIPEA, in a non-reactive solvent, such as CH2Cl2, to give the molecules of Formula One, as previously disclosed.




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In step t of Scheme XIII, the vinyl benzyl chloride of Formula XIa, wherein R11 is —CH2Cl and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be transformed into the corresponding phthalimide-protected benzyl amine of Formula XIIa, wherein R11 is CH2N(Phthalimide), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 70° C.




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In step u of Scheme XIV, the 4-methylbenzonitrile of Formula XIIIa, wherein R11 is CH3 and R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be transformed into the corresponding benzyl bromide of Formula XIVa, wherein R11 is CH2Br and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a non-reactive solvent, such as carbon tetrachloride at 77° C. The nitrile group (CN) of Formula XIVa can be reduced to the corresponding aldehyde of Formula XVa, wherein R11 is CH2Br and R9, R10, R12, R13, X1, X2, and X3 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0° C., followed by quenching with 1.0 M hydrochloric acid (HCl) as in step v of Scheme XIV. The compound of Formula XVa can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIa, wherein R11 is CH2N(Phthalimide) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60° C. as in step t of Scheme XIV. In step w of Scheme XIV, the aldehyde of Formula XVIa can be converted to the olefin of Formula XIIb, wherein R11 is CH2N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the presence of a base, such as K2CO3, at ambient temperature.




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The aldehyde of Formula XVa, wherein R11 is CH2Br and R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be reacted with a nucleophile, such as 2-aminopyridine, in a polar aprotic solvent, such as N,N-dimethylacetamide (DMA), in the presence of a base, such as K2CO3, at ambient temperature to provide the compound of Formula XVII, wherein R11 is CH2NH(2-pyridine) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, as in step x of Scheme XV. In step w of Scheme XV, the compound of Formula XVII can be converted to the olefin of Formula XVIII, wherein R11 is CH2NH(2-pyridine) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.




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In a two-step, one-pot reaction as in steps y and z of Scheme XVI, the compound of Formula XIX can be reacted with the compounds of Formula XX, wherein R10 and R11 are Cl, X1 is N, and R9, R13, X2, and X3 are as previously disclosed, in the presence of a base, such as sodium hydride (NaH), and a polar aprotic solvent, such as DMF, at ambient temperature to provide the compounds of Formula XXI, wherein R10 is Cl, R11 is (CH)NH2CO2CH2CH3, X1 is N, and R9, R13, X2, and X3 are as previously defined.


Hydrolysis and decarboxylation of the compounds of Formula XXI can be accomplished by reaction under acidic conditions, such as with 3 N HCl, at reflux temperature, to afford the compounds of Formula XXII, wherein R10 is Cl, R11 is CH2NH2.HCl, X1 is N, and R9, R13, X2, and X3 are as previously disclosed, as in step aa in Scheme XVI. The compounds of Formula XXII can be further transformed to the corresponding phthalimide-protected benzyl amines of Formula XXIIIa, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R9, R13, X1, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in the presence of a base, such as TEA, and an aprotic solvent, such as toluene, at reflux temperature as in step ab of Scheme XVI. The bromide of Formula XXIIIa can be converted to the olefin of Formula XIIc, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R8, R9, R13, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a non-reactive solvent such as toluene at reflux temperature, as in step ac of Scheme XVI.




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In step u of Scheme XVII, the 4-methylnaphthonitrile of Formula XIIIb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH3, and R12, R13, X1 and X2 are as previously defined, can be transformed into the corresponding naphthyl bromide of Formula XIVb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2Br, and R12, R13, X1 and X2 are as previously disclosed, by reaction with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a non-reactive solvent, such as carbon tetrachloride at 77° C. The nitrile group (CN) of Formula XIVb can be reduced to the corresponding aldehyde of Formula XVb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if desired a non-aromatic ring), R11 is CH2Br, and R12, R13, X1 and X2 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0° C., followed by quenching with 1.0 M HCl as in step v of Scheme XVII. The compound of Formula XVb can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(Phthalimide), and R12, R13, X1 and X2 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60° C. as in step t of Scheme XVII. In step w of Scheme XVII, the aldehyde of Formula XVIb can be converted to the olefin of Formula XIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(Phthalimide), and R8, R12, R13, X1 and X2 are as previously disclosed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the presence of a base, such as K2CO3, at ambient temperature.




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The compound of Formula XXIV, wherein R11 is NHNH2.HCl and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, can be transformed into the corresponding phthalimide-protected hydrazine of Formula XXV, wherein R11 is NHN(Phthalimide) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in glacial acetic acid at reflux temperature as in step ad of Scheme XVIII. The bromide of Formula XXV can be converted to the olefin of Formula XIIe, wherein R11 is NHN(Phthalimide) and R8, R9, R10, R13, X1, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a polar aprotic solvent such as 1,2-dimethoxyethane at 150° C. under microwave conditions, as in step ae of Scheme XVIII.




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In step af of Scheme XIX, the compound of Formula XXVI, wherein R11 is B(OH)2, and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react with 2-hydroxyisoindoline-1,3-dione in the presence of CuCl and pyridine in a solvent, such as 1,2-dichlorobenzene, at ambient temperature to provide the compound of Formula XIIf, wherein R11 is ON(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.




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In step l of Scheme XX, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIa, wherein R11 is CH2N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIa, wherein R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIa is removed as in step ag of Scheme XX by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIa, wherein R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIa can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by acylation with an anhydride, such as acetic anhydride, and a base, such as TEA, in a non-reactive solvent such as CH2Cl2 at 0° C. as in step ah1 of Scheme XX.




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In step l of Scheme XXI, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIb, wherein R11 is CH2N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIb, wherein R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIb is removed as in step ag of Scheme XXI by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIb, wherein R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as DMF, as in step ah2a of Scheme XXI.


In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═S)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a thioacid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as DMF, as in step ah2 of Scheme XXI.


In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, in two steps. The first step (step ah3a of Scheme XXI) involves reaction with an aldehyde in a polar protic solvent such as MeOH, followed by reaction with sodium borohydride. The second step (step ah3b of Scheme XXI) involves acylation with an acid chloride, such as cyclopropylcarbonyl chloride, and a base, such as TEA, in a non-reactive solvent such as CH2Cl2 at ambient temperature of Scheme XXI.


In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an isocyanate (step ai1 of Scheme XXI) or a carbamoyl chloride (step ai2 of Scheme XXI) in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0° C.


In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═S)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an isothiocyanate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0° C., as in steps aj of Scheme XXI.


In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a dicarbonate, such as di-tert-butyl dicarbonate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at ambient temperature, as in steps ak of Scheme XXI.


In yet another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)(C═O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a chlorooxalic acid ester, such as 2-chloro-2-oxoacetate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0° C., as in steps al of Scheme XXI.




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In step l of Scheme XXII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIc, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R8, R9, R12, R13, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIc, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIc is removed as in step ag of Scheme XXII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIc, wherein R10 is Cl, R11 is CH2NH2, X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIc can be transformed into the compounds of Formula One, wherein R10 is Cl, R11 is CH2N(C═O)(R14), X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXII.




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In step l of Scheme XXIII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if desired a non-aromatic ring), R11 is CH2N(Phthalimide) and R8, R9, R12, R13, X1 and X2 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIId is removed as in step ag of Scheme XXIII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed. The compounds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXIII.


In another embodiment, the compounds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(C═O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1 and X2 are as previously disclosed, by reaction with an isocyanate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0° C. as in step ai1 of Scheme XXIII.




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In step l of Scheme XXIV, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIe, wherein R11 is NHN(Phthalimide) and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIe, wherein R11 is NHN(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIe is removed as in step ag of Scheme XXIV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIe, wherein R11 is NHNH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIe can be transformed into the compounds of Formula One, wherein R11 is NHN(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXIV.




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In step l of Scheme XXV, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIf, wherein R11 is ON(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIf, wherein R11 is ON(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIf is removed as in step ag of Scheme XXV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIf, wherein R11 is ONH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIf can be transformed into the compounds of Formula One, wherein R11 is ON(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXV.




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In step l of Scheme XXVI, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XVIII, wherein R11 is CH2NH(2-pyridine) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula One, wherein R11 is CH2NH(2-pyridine), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.


The compounds of Formula One can be further elaborated by standard methods. For example, when R11 contains a thioether, the thioether can be oxidized to the sulfone by treatment with oxone in the presence of an acetone:water mixture at ambient temperature. When R11 contains an oxalate ester, the compound of Formula One can be transformed into the corresponding oxalamide by reaction with an amine hydrochloride and a solution of trimethylaluminum in toluene in a non-reactive solvent such as CH2Cl2.




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In Scheme XXVII, a fluorobenzaldehyde of Formula XXIX, wherein R10, X1, X2, and X3 are as previously disclosed can be converted to a (1,2,4-triazol-1-yl)benzaldehyde of Formula XXX, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R10, X1, X2, and X3 are as previously disclosed by reaction with a substituted or unsubstituted 1,2,4-triazole in the presence of a base, such as potassium carbonate, in a solvent such as DMF as in step aj. In step ak, the (1,2,4-triazol-1-yl)benzaldehyde of Formula XXX is converted to a (1,2,4-triazol-1-yl)vinyl benzene of Formula XXXIa wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R10, X1, X2, and X3 are as previously disclosed by reaction with triphenyl phosphonium bromide in the presence of a base, such as potassium carbonate, in an aprotic solvent, such as 1,4-dioxane.




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In Scheme XXVIII, a bromofluorobenzene of Formula XXXII, wherein R10, X1, X2, and X3 are as previously disclosed can be converted to a (1,2,4-triazol-1-yl)vinylbenzene of Formula XXXIb, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R10, X1, X2, and X3 are as previously disclosed in two steps. In step al, the bromofluorobenzene is reacted with a substituted or unsubstituted 1,2,4-triazole in the presence of a base, such as potassium carbonate, in a solvent such as DMF to generate the (1,2,4-triazol-1-yl)bromobenzene. In step cl, the (1,2,4-triazol-1-yl)bromobenzene is reacted with vinyl boronic anhydride pyridine complex in the presence of a catalyst, such as Pd (PPh3)4, and a base, such as potassium carbonate in a solvent such as toluene.




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Coupling of the compounds of Formula V with compounds of Formula XXXIa and XXXIb can be accomplished as in Schemes XXIX. In step l, a compound of Formula V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and a vinylbenzene of Formula XXXIa or XXXIb, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R9, R10, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the molecules of Formula One, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed.




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In Scheme XXX, compounds of Formula XXXIII wherein R11 is a 3-nitro-1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed can be converted to compounds of Formula One, wherein R11 is a 3-amido-1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed by a two-step process. In step am, the 3-nitro-1,2,4-triazol-1-yl group is reduced to a 3-amino-1,2,4-triazol-1-yl group in the presence of zinc dust and ammonium chloride in a protic solvent, such as MeOH. In step an, the 3-amino-1,2,4-triazol-1-yl group is acylated with an acid chloride, such as cyclopropylcarbonyl chloride or acetyl chloride, in the presence of a base, such as TEA, in a solvent such as CH2Cl2.




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In step ao of Scheme XXXI, a bromophenyl methyl ketone of Formula XXXIV wherein R10, X1, X2, and X3 are as previously disclosed is converted to an phenyl methyl ketone of the Formula XXXV wherein R11 is a 1,2,4-triazol-1-yl group, and R10, X1, X2, and X3 are as previously disclosed by treatment with 1,2,4-triazole in the presence of a base, such as cesium carbonate, and a catalyst, such as copper iodide, in a solvent, such as DMF. In step ap, the 1,2,4-triazolylacetophenone of Formula XXXV is converted to the trimethylsilyl enol ether of Formula XXXVI by treatment with trimethylsilyl triflluoromethanesulfonate in the presence of a base, such as TEA, in an aprotic solvent, such as CH2Cl2. In step aq, the silyl enol ether is reacted with a compound of Formula V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene at a temperature of about 180° C. to generate a ketone of the Formula XXXVII, wherein R11 is a 1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R10, X1, X2, and X3 are as previously disclosed. In step ar, the ketone of the Formula XXXVII is treated with methylmagnesium bromide in an aprotic solvent, such as THF to generate the tertiary alcohol. The tertiary alcohol then undergoes an elimination reaction when treated with a catalytic amount of p-toluenesulfonic acid in a solvent, such as toluene, when heated to a temperature to allow azeotropic removal of water to produce compounds of Formula One wherein R11 is a 1,2,4-triazol-1-yl group, R8 is methyl, and R1, R2, R3, R4, R5, R6, R7, R10, X1, X2, and X3 are as previously disclosed, as in step as.




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In Scheme XXXII, a compound of Formula XXXVIII, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered cyclic ring, and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula One, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an alkylamine substituent with the ring carbon atoms form a 5- or 6-membered cyclic ring and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by treatment with an alkylamine, such as 3,3,3-trifluoropropylamine, in the presence of a reducing agent, such as sodium cyanoborohydride, in a solvent, such as DCE.




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In Scheme XXXIII, a compound of Formula XXXIX, wherein X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula XL, wherein X1, X2, and X3 are as previously disclosed, by treatment with a reducing agent, such as sodium cyanoborohydride, in a solvent, such as acetic acid, as in step au. In step av, the nitrogen atom is protected with a tert-butyloxycarbonyl (BOC) group by reaction with di-tert-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile. The bromide of Formula XL can be converted to the olefin of Formula XLI, wherein R8, X1, X2 and X3 are as previously disclosed, by reaction with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl2(dppf), and a base, such as K2CO3, in a polar aprotic solvent such as DMSO at 100° C., as in step aw.




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In Scheme XXXIV, a compound of Formula XXXIX, wherein X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula XLII, wherein X1, X2, and X3 are as previously disclosed in two steps. In step ax, the olefin is formed by treatment of the bromide with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl2, and a ligand, such as triphenylphosphine, and a base, such as Cs2CO3, in a solvent mixture such as THF/H2O. In step ay, the nitrogen atom is protected with a tert-butyloxycarbonyl (BOC) group by reaction with di-tert-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile.




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In step l of Scheme XXXV, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XLI or XLII, wherein R8, X1, X2 and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 150° C. to provide the corresponding compounds of Formula XLIIIa or XLIIIb, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed.




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In Scheme XXXVI, a compound of Formula XLIIIa, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula XLIV, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed by treatment with trifluoroacetic acid, in a solvent such as CH2Cl2, as in step az. Compounds of the Formula XLIV can then be transformed into compounds of the Formula XLV wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, in two steps. In step ba, the indoline is treated with sodium nitrite (NaNO2), in an acid, such as concentrated HCl, at a temperature around 5° C., to form the nitrosoindole. In step bb, the nitrosoindole is reacted with ammonium chloride in the presence of zinc powder in a protic solvent, such as MeOH. In step be, compounds of the Formula XLV are transformed into compounds of the Formula XLVI, wherein X4 is N(R14)(C(═O)R14) and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by treatment with and acid, such as 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl.




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In Scheme XXXVII, a compound of Formula XLIIIb, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed is converted to an indole of Formula XLVII, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed by treatment with trifluoroacetic acid, in a solvent such as CH2Cl2, as in step bd. Compounds of the Formula XLVII can be transformed into compounds of the Formula XLVIII wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by reaction with 4-nitrophenyl-2-((tert-butoxycarbonyl)amino)acetate in the presence of potassium fluoride and a crown ether, such as 18-crown-6-ether, in a solvent, such as acetonitrile, as in step be. Compounds of the Formula XLVIII can be transformed into compounds of the Formula XLIX, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed in two steps. In step bf, the Boc group is removed by treatment with trifluoroacetic acid, in a solvent such as CH2Cl2. In step bg, the amine is treated with 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2.




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In Scheme XXXVIII, a compound of Formula L, wherein X1, X2, and X3 are as previously disclosed is converted to a compound of the Formula LI, wherein X1, X2, and X3 are as previously disclosed by treatment with copper (II) sulfate pentahydrate and Zn powder in a base, such as sodium hydroxide as in step bh. Compounds of the Formula LI can be transformed into compounds of the Formula LII wherein X1, X2, and X3 are as previously disclosed, by reaction with hydrazine, in a solvent such as water, at a temperature around 95° C., as in step bi. In step bj, the olefin of the Formula LIII wherein X1, X2, and X3 are as previously disclosed is formed by treatment of the bromide with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl2(dppf), and a base, such as K2CO3, in a solvent mixture such as DMSO. Compounds of the Formula LIV, wherein X1, X2, and X3 are as previously disclosed, can be formed from compounds of the Formula LIII by reaction with ethyl bromoacetate, in the presence of a base, such as Cs2CO3, in a solvent, such as DMF.




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In step l of Scheme XXXIX, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compound of Formula LIV, wherein R8, X1, X2 and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compound of Formula LV, wherein RI, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed. The compound of Formula LV can be further transformed into a compound of the Formula LVI, wherein RI, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, in two steps. In step bl, the ester is hydrolyzed to the acid in the presence of HCl and acetic acid, at a temperature of about 100° C. In step bm, the acid is treated with an amine, such as 2,2,2-trifluoroethylamine, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2.




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In step bn of Scheme XL, carboxylic acids of the Formula LVII, wherein R11 is C(═O)OH and R8, R10, X1, X2, and X3 are as previously disclosed and compounds of the Formula V, wherein Y is Br and R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as N-methyl pyrrolidine, at a temperature of about 150° C. to afford compounds of Formula LVIII, wherein R11 is (C═O)OH and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, and X3 are as previously disclosed. Compounds of the Formula LVIII can be further transformed to the corresponding benzamides of Formula LIX, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, and X3 are as previously disclosed, by treatment with an amine, such as 2-amino-N-(2,2,2-trifluoroethyl)acetamide, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step bo.




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EXAMPLES

The examples are for illustration purposes and are not to be construed as limiting the invention disclosed in this document to only the embodiments disclosed in these examples.


Starting materials, reagents, and solvents that were obtained from commercial sources were used without further purification. Anhydrous solvents were purchased as Sure/Seal™ from Aldrich and were used as received. Melting points were obtained on a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated Melting Point System from Stanford Research Systems and are uncorrected. Molecules are given their known names, named according to naming programs within ISIS Draw, ChemDraw, or ACD Name Pro. If such programs are unable to name a molecule, the molecule is named using conventional naming rules. 1H NMR spectral data are in ppm (δ) and were recorded at 300, 400, or 600 MHz, and 13C NMR spectral data are in ppm (δ) and were recorded at 75, 100, or 150 MHz, unless otherwise stated.


Example 1: Preparation of 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (AI1)



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Step 1 Method A. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (AI2)

To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (procured from Rieke Metals, UK; 5.0 grams (g), 20.5 millimoles (mmol)) in MeOH (100 mL) at 0° C. were added sodium borohydride (NaBH4; 3.33 g, 92.5 mL) and 1 Normal (N) aqueous sodium hydroxide solution (NaOH; 10 mL). The reaction mixture was warmed to 25° C. and stirred for 2 hours (h). After the reaction was deemed complete by thin layer chromatography (TLC), saturated (satd) aqueous (aq) ammonium chloride (NH4Cl) solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was diluted with diethyl ether (Et2O) and washed with water (H2O; 3×50 mL). The organic layer was dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure to afford the title compound as a liquid (4.0 g, 79%): 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 3H), 5.00 (m, 2H), 2.74 (s, 1H); ESIMS m/z 242.97 ([M−H]−).


Step 1 Method B. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (AI2)

To a stirred solution of 3,5-dichlorobenzaldehyde (10 g, 57 mmol) in THF (250 mL) were added trifluoromethyltrimethylsilane (9.79 g, 69.2 mmol) and a catalytic amount of tetrabutylammonium fluoride (TBAF). The reaction mixture was stirred at 25° C. for 8 h. After the reaction was deemed complete by TLC, the reaction mixture was diluted with 3 N hydrochloric acid (HCl) and then was stirred for 16 h. The reaction mixture was diluted with H2O and was extracted with ethyl acetate (EtOAc; 3×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (8.41 g, 60%).


The following compounds were made in accordance with the procedures disclosed in Step 1 Method B of Example 1 above.


2,2,2-Trifluoro-1-(3,4,5-trichlorophenyl)ethanol (AI3)



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The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m/z 278 ([M+H]+); IR (thin film) 3420, 1133, 718 cm−1.


1-(3,5-Dichloro-4-fluorophenyl)-2,2,2-trifluoroethanol (AI4)



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The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m/z 262 ([M+H]+); IR (thin film) 3420, 1133, 718 cm−1.


1-(3,4-Dichlorophenyl)-2,2,2-trifluoroethanol (AI5)



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The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H), 2.60 (s, 1H); EIMS m/z 244 ([M]+).


1-(3,5-Dibromophenyl)-2,2,2-trifluoroethanol



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The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.58 (s, 2H), 5.08-5.02 (m, 1H), 4.42 (bs, 1H); EIMS m/z 333.7 ([M]+); IR (thin film) 3417, 2966, 1128, 531 cm−1.


1-(4-Bromo-3,5-dichlorophenyl)-2,2,2-trifluoroethanol



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The product was isolated as a colorless liquid: 1H NMR (300 MHz, DMSO-d6) δ 7.75 (s, 2H), 7.24 (d, J=6.0 Hz, 1H), 5.34-5.29 (m, 1H); EIMS m/z 321.88 ([M]+); IR (thin film) 3420, 1706, 1267, 804, 679 cm−1.


1-(3,5-Dibromo-4-chlorophenyl)-2,2,2-trifluoroethanol



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The product was isolated as a pale yellow gum: 1H NMR (300 MHz, DMSO-d6) δ 7.89 (s, 2H), 7.20 (d, J=6.0 Hz, 1H) 5.34-5.30 (m, 1H); EIMS m/z 366.0 ([M]+).


Step 2. 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (AI1)

To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol (4.0 g, 16.3 mmol) in CH2Cl2 (50 mL), were added N-bromosuccinimide (NBS; 2.9 g, 16.3 mmol) and triphenyl phosphite (5.06 g, 16.3 mmol), and the resultant reaction mixture was heated at reflux for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and was concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 100% pentane) afforded the title compound as a liquid (2.0 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 3H), 5.00 (m, 1H); EIMS m/z 306 ([M]+).


The following compounds were made in accordance with the procedures disclosed in Step 2 of Example 1.


5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (AI6)



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The product was isolated as a colorless oil (300 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 2H), 5.00 (m, 1H); EIMS m/z 340.00 ([M]+).


5-(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (AI7)



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The product was isolated as a colorless oil (320 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 2H), 5.00 (m, 2H); EIMS m/z 324.00 ([M]+).


4-(1-Bromo-2,2,2-trifluoroethyl)-1,2-dichlorobenzene (AI8)



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The product was isolated as a colorless oil (300 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H); EIMS m/z 306.00 ([M]+).


1,3-Dibromo-5-(l-bromo-2,2,2-trifluoroethyl)benzene



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The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.59 (s, 2H), 5.04-4.97 (m, 1H); EIMS m/z 394.6 ([M]+); IR (thin film) 1114, 535 cm−1.


2-Bromo-5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichlorobenzene



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The title molecule was isolated as a colorless liquid: 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 2H), 6.27-6.21 (m, 1H); EIMS m/z 383.9 ([M]+); IR (thin film) 2924, 1114, 749, 534 cm−1. 1,3-Dibromo-5-(1-bromo-2,2,2-trifluoroethyl)-2-chlorobenzene




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The title molecule was isolated as a pale yellow liquid: 1H NMR (300 MHz, DMSO-d6) δ 7.97 (s, 2H), 6.27-6.19 (m, 1H); EIMS m/z 428.0 ([M]+).


Example 2: Preparation of N-Methyl-4-vinylbenzamide (AI9)



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Step 1. 4-Vinylbenzoyl chloride (AI10)

To a stirred solution of 4-vinylbenzoic acid (1 g, 6.75 mmol) in CH2Cl2 (20 mL) at 0° C. were added a catalytic amount of DMF and oxalyl chloride (1.27 g, 10.12 mmol) dropwise over a period of 15 minutes (min). The reaction mixture was stirred at 25° C. for 6 h. After the reaction was deemed complete by TLC, the reaction mixture was concentrated under reduced pressure to give the crude acid chloride.


Step 2. N-Methyl-4-vinylbenzamide (AI9)

To 1 M N-methylamine in THF (13.5 mL, 13.5 mmol) at 0° C. were added TEA (1.34 mL, 10.12 mmol) and the acid chloride from Step 1 above in THF (10 mL), and the reaction mixture was stirred at 25° C. for 3 h. After the reaction was deemed complete by TLC, the reaction mixture was quenched with water and then was extracted with EtOAc (3×). The combined EtOAc layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (650 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (br s, 1H), 5.82 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H); ESIMS m/z 161.95 ([M+H]+).


The following compounds were made in accordance with the procedures disclosed in accordance with Example 2.


N,N-Dimethyl-4-vinylbenzamide (AI11)



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The product was isolated as an off-white solid (650 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 4H), 6.71 (m, 1H), 5.80 (d, J=17.6 Hz, 1H), 5.31 (d, J=10.8 Hz, 1H), 3.05 (s, 3H), 3.00 (s, 3H); ESIMS m/z 176.01 ([M+H]+).


N-(2,2,3-Trifluoromethyl)-4-vinylbenzamide (AI12)



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The product was isolated as an off-white solid (900 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (br s, 1H), 5.82 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 4.19 (m, 2H); ESIMS m/z 230.06 ([M+H]+).


Morpholino(4-vinylphenyl)methanone (AI13)



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The product was isolated as a white solid (850 mg, 60%): ESIMS m/z 218.12 ([M+H]+).


Example 3: Preparation of Ethyl 2-methyl-4-vinylbenzoate (AI14)



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Step 1. 4-Formyl-2-methylbenzoic acid (AI15)

To a stirred solution of 4-bromo-2-methylbenzoic acid (10 g, 46.4 mmol) in dry THF (360 mL) at −78° C. was added n-BuLi (1.6 M solution in hexane; 58.17 mL, 93.0 mmol) and DMF (8 mL). The reaction mixture was stirred at −78° C. for 1 h then was warmed to 25° C. and stirred for 1 h. The reaction mixture was quenched with 1 N HCl solution and extracted with EtOAc. The combined EtOAc extracts were washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The residue was washed with n-hexane to afford the title compound as a solid (3.0 g, 40%): mp 196-198° C.; 1H NMR (400 MHz, DMSO-d6) δ 13.32 (br s, 1H), 10.05 (s, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 2.61 (s, 3H); ESIMS m/z 163.00 ([M−H]−).


Step 2. Ethyl 4-formyl-2-methylbenzoate (AI16)

To a stirred solution of 4-formyl-2-methylbenzoic acid (3 g, 18.2 mmol) in ethyl alcohol (EtOH; 30 mL) was added sulfuric acid (H2SO4, ×M; 2 mL), and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with H2O. The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a solid (2.8 g, 80%): 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).


Step 3. Ethyl 2-methyl-4-vinylbenzoate (AI14)

To a stirred solution of ethyl 4-formyl-2-methylbenzoate (2.8 g, 4 mmol) in 1,4-dioxane (20 mL) were added potassium carbonate (K2CO3; 3.01 g, 21.87 mmol) and methyltriphenyl phosphonium bromide (7.8 g, 21.87 mmol) at 25° C. Then the reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 25-30% EtOAc in n-Hexane) to afford the title compound as a solid (2.0 g, 72%): 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 1H), 7.27 (m, 2H), 6.68 (dd, J=17.6, 10.8 Hz, 1H), 5.84 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 4.39 (m, 2H), 2.60 (s, 3H), 1.40 (m, 3H); ESIMS m/z 191.10 ([M−H]−); IR (thin film) 2980, 1716, 1257 cm−1.


Example 4: Preparation of tert-Butyl 2-chloro-4-vinylbenzoate (AI17)



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Step 1. tert-Butyl 4-bromo-2-chlorobenzoate (AI18)

To a stirred solution of 4-bromo-2-chlorobenzoic acid (5 g, 21.37 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate (25.5 g, 25.58 mmol), TEA (3.2 g, 31.98 mmol) and DMAP (0.78 g, 6.398 mmol), and the reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with EtOAc and washed with H2O. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 2-3% EtOAc in n-hexane) to afford the title compound as a liquid (3.2 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.62 (m, 2H), 7.44 (d, J=8.4 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 290.10 ([M+H]+); IR (thin film) 1728 cm−1.


The following compounds were made in accordance with the procedures disclosed in Step 1 of Example 4.


tert-Butyl 2-bromo-4-iodobenzoate (AI19)



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The product was isolated as a colorless oil (1.2 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 382.10 ([M+H]+); IR (thin film) 1727 cm−1.


tert-Butyl 4-bromo-2-(trifluoromethyl)benzoate (AI20)



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The product was isolated as a colorless oil (1 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 1.57 (s, 9H); ESIMS m/z 324.10 ([M+H]+); IR (thin film) 1725 cm−1.


Step 2. tert-Butyl 2-chloro-4-vinylbenzoate (AI17)

To a stirred solution of tert-butyl 4-bromo-2-chlorobenzoate (1.6 g, 5.50 mmol) in toluene (20 mL) was added tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4; (0.31 mg, 0.27 mmol), K2CO3 (2.27 g, 16.5 mmol) and vinylboronic anhydride pyridine complex (2.0 g, 8.3 mmol) and the reaction mixture was heated to reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 5-6% EtOAc in n-hexane) afforded the title compound as a liquid (0.6 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.1 Hz, 1H), 7.44 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz, 1H), 5.85 (d, J=17.6 Hz, 1H), 5.40 (d, J=10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 238.95 ([M+H]+); IR (thin film) 2931, 1725, 1134 cm−1.


The following compounds were made in accordance with the procedures disclosed in Step 2 of Example 4.


tert-Butyl 2-bromo-4-vinylbenzoate (AI21)



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The product was isolated as a colorless oil (1 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.68 (m, 2H), 7.36 (d, J=8.0 Hz, 1H), 6.68 (dd, J=17.6, 10.8 Hz, 1H), 5.84 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 282.10 ([M+H]+); IR (thin film) 2978, 1724, 1130 cm−1.


tert-Butyl 2-(trifluoromethyl)-4-vinylbenzoate (AI22)



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The product was isolated as a colorless oil (1.2 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=6.4 Hz, 2H), 7.59 (d, J=7.6 Hz, 1H), 6.77 (dd, J=17.6, 10.8 Hz, 1H), 5.89 (d, J=17.6 Hz, 1H), 5.44 (d, J=10.8 Hz, 1H), 1.58 (s, 9H); ESIMS m/z 272.20 ([M+H]+); IR (thin film) 2982, 1727, 1159 cm−1.


Example 5: Preparation of tert-Butyl 2-cyano-4-vinylbenzoate (AI23)



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To a stirred solution of tert-butyl 2-bromo-4-vinylbenzoate (0.5 g, 1.77 mmol) in DMF (20 mL) was added copper(I) cyanide (CuCN; 0.23 g, 2.65 mmol), and the reaction mixture was heated at 140° C. for 3 h. The reaction mixture was cooled to 25° C., diluted with H2O, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 15% EtOAc in n-hexane) to afford the title compound as a white solid (0.3 g, 72%): mp 51-53° C.; 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.77 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.93 (d, J=17.6 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 229.84 ([M+H]+); IR (thin film) 2370, 1709, 1142 cm−1.


Example 6: Preparation of Ethyl 2-bromo-4-iodobenzoate (AI46)



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To a stirred solution of 4-iodo-2-bromobenzoic acid (5 g, 15.29 mmol) in ethyl alcohol (EtOH; 100 mL) was added sulfuric acid (H2SO4; 5 mL), and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc (2×100 mL) and washed with H2O (100 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the compound as a pale yellow solid (5 g, 92%): 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=1.2 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).


The following compounds were made in accordance with the procedures disclosed in Example 6.


Ethyl 4-bromo-2-chlorobenzoate (AI47)



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The title compound was isolated as an off-white solid (2.0 g, 80%): 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=1.2 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 4.65 (q, J=7.2 Hz, 2H), 1.56 (t, J=7.2 Hz, 3H).


Ethyl 4-bromo-2-methylbenzoate (AI48)



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The title compound was isolated as a pale yellow liquid (3.0 g, 83%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.40 (t, J=7.2 Hz, 3H) ESIMS m/z 229.11 ([M+H]+); IR (thin film) 1725 cm−1.


Ethyl 4-bromo-2-fluorolbenzoate (AI49)



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The title compound was isolated as a colorless liquid (9.0 g, 79%): 1H NMR (400 MHz, DMSO-d6) δ 7.84 (t, J=8.4 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 4.34 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); ESIMS m/z 246.99 ([M+H]+), IR (thin film) 1734 cm−1.


Example 7: Preparation of Ethyl 4-bromo-2-ethylbenzoate (AI50)



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To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol) in THF (16 mL), was added 1.0 M ethyl magnesium bromide in THF (32 mL, 32.0 mmol) dropwise at 0° C. and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched with 2 N HCl and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude 4-bromo-2-ethylbenzoic acid as a colorless liquid that was used in the next step without purification (0.4 g): 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 1H), 7.47 (m, 1H), 7.43 (m, 1H), 2.95 (q, J=4.0 Hz, 2H), 1.32 (t, J=4.0 Hz, 3H); ESIMS m/z 228.97 ([M+H]+).


The title compound was synthesized from 4-bromo-2-ethylbenzoic acid in accordance to the procedure in Example 6, isolated as a colorless liquid (0.15 g, 68%): 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J=8.4 Hz, 1H), 7.47 (m, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.06 (q, J=7.6 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H); ESIMS m/z 226.96 ([M−H]−); IR (thin film) 3443, 1686, 568 cm−1.


Example 8: Preparation of Ethyl 2-bromo-4-vinylbenzoate (AI51)



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To a stirred solution of ethyl 2-bromo-4-iodobenzoate (5 g, 14.3 mmol) in THF/water (100 mL, 9:1) was added potassium vinyltrifluoroborate (1.89 g, 14.3 mmol), Cs2CO3 (18.27 g, 56.07 mmol) and triphenylphosphine (0.22 g, 0.85 mmol) and the reaction mixture was degassed with argon for 20 min, then charged with PdCl2 (0.05 g, 0.28 mmol). The reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to ambient temperature and filtered through a celite bed and washed with ethyl acetate. The filtrate was again extracted with ethyl acetate and the combined organic layers washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (2 g, 56%): 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=8.4 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.42 (d, J=11.2 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=3.6 Hz, 3H); ESIMS m/z 255.18 ([M+H]+); IR (thin film) 1729 cm−1.


The following compounds were made in accordance with the procedures disclosed in Example 8.


Ethyl 2-methyl-4-vinylbenzoate (AI52)



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The title compound was isolated as a colorless liquid (0.8 g, 80%): 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.27 (m, 2H), 6.79 (dd, J=17.6, 10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.42 (d, J=11.2 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 191.10 ([M+H]+); IR (thin film) 1717, 1257 cm−1.


Ethyl 2-fluoro-4-vinylbenzoate (AI53)



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The title compound was isolated as a pale yellow liquid (2.0 g, 50%): 1H NMR (400 MHz, DMSO-d6) δ 7.87 (t, J=8.0 Hz, 1H), 7.51 (d, J=16.0 Hz, 1H), 7.48 (d, J=16.0 Hz, 1H), 6.82 (dd, J=17.6, 10.8 Hz, 1H), 6.09 (d, J=17.6 Hz, 1H), 5.50 (d, J=10.8 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H); ESIMS m/z 195.19 ([M+H]+); IR (thin film) 1728 cm−1.


Example 9: Preparation of Ethyl 2-chloro-4-vinylbenzoate (AI54)



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To a stirred solution of ethyl 2-chloro-4-bromobenzoate (2 g, 7.63 mmol) in dimethylsulfoxide (20 mL) was added potassium vinyltrifluoroborate (3.06 g, 22.9 mmol) and potassium carbonate (3.16 g, 22.9 mmol). The reaction mixture was degassed with argon for 30 min. Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.27 g, 0.38 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×50 mL), washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the compound as brown gummy material (1.1 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.70 (dd, J=17.6, 11.2 Hz, 1H), 5.87 (d, J=17.6 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 211.22 ([M+H]+); IR (thin film) 1729, 886 cm−1.


The following compounds were made in accordance with the procedures disclosed in Example 9.


Ethyl 2-ethyl-4-vinylbenzoate (AI55)



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The title compound was isolated as a color less liquid (1.0 g, 66%): 1H NMR (300 MHz, CDCl3) δ 7.85 (m, 1H), 7.29 (m, 2H), 6.76 (d, J=10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.36 (d, J=10.5 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 3.10 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H); ESIMS m/z 205.26 ([M+H]+); IR (thin film) 1720, 1607, 1263 cm−1.


Methyl 2-methoxy-4-vinylbenzoate (AI56)



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The title compound was isolated as a pale yellow liquid (1.2 g, 75%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.04 (d, J=1.2 Hz, 1H), 6.97 (s, 1H), 6.74 (dd, J=11.2, 11.2 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.39 (d, J=17.6 Hz, 1H) 3.93 (s, 3H), 3.91 (s, 3H). ESIMS m/z 193.18 ([M+H]+); IR (thin film) 1732 cm−1.


Example 10: Preparation of (E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (AI24)



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To a stirred solution of ethyl 2-methyl-4-vinylbenzoate (2.0 g, 10.5 mmol) in 1,2-dichlorobenzene (25 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (6.44 g, 21.0 mmol), copper(I) chloride (CuCl; 208 mg, 21 mmol) and 2,2bipyridyl (0.65 g, 4.1 mmol). The reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; eluting with 25-30% EtOAc in petroleum ether) afforded the title compound as a solid (1.7 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=8.0 Hz, 1H), 7.37 (m, 1H), 7.27-7.24 (m, 4H), 6.59 (d, J=16.0 Hz, 1H), 6.59 (dd, J=16.0, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.08 (m, 1H), 2.62 (s, 3H), 1.42 (t, J=7.2 Hz, 3H); ESIMS m/z 415.06 ([M−H]−); IR (thin film) 1717, 1255, 1114 cm−1.


Compounds AI25, AI57-AI68 and AC1-AC5 (Table 1) were made in accordance with the procedures disclosed in Example 10.


(E)-Ethyl 4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)-benzoic acid (AI25)



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The product was isolated as a pale brown gummy liquid (500 mg, 40%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.71 (m, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.42 (s, 2H), 6.70 (d, J=16.0 Hz, 1H), 6.57 (dd, J=16.0, 8.0 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.19 (m, 1H), 1.40 (t, J=7.6 Hz, 3H); ESIMS m/z 502.99 ([M−H]−); IR (thin film) 1730, 1201, 1120, 749 cm−1.


(E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluorobenzoate (AI57)



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1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.26 (s, 3H), 7.21 (d, J=8.4 Hz, 1H), 7.16 (d, J=11.6 Hz, 1H), 6.59 (d, J=16.0 Hz, 1H), 6.47 (dd, J=, 16.0, 8.0 Hz, 1H), 4.41 (q, J=6.8 Hz, 2H), 4.18 (m, 1H), 1.41 (t, J=6.8 Hz, 3H); ESIMS m/z 419.33 ([M−H]−); IR (thin film) 1723, 1115, 802 cm−1.


(E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-bromobenzoate (AI58)



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1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.38 (m, 2H), 7.26 (m, 2H), 6.56 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 7.6 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.39 (m, 1H), 1.42 (t, J=7.2 Hz, 3H); ESIMS m/z 481.22 ([M−H]−); IR (thin film) 1727, 1114, 801, 685 cm−1.


(E)-Ethyl 2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoate (AI59)



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1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.40 (s, 2H), 7.36 (d, J=1.6 Hz, 1H), 6.56 (d, J=16.0 Hz, 1H), 6.44 (dd, J=16.0, 7.6 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=6.8 Hz, 3H); ESIMS m/z 514.74 ([M−H]−); IR (thin film) 1726, 1115, 808, 620 cm−1.


(E)-Ethyl 2-methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoate (AI60)



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The title compound was isolated as a light brown gummy material: 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.8 Hz, 1H), 7.34 (d, J=6.0 Hz, 2H), 7.25 (d, J=7.2 Hz, 2H), 6.59 (d, J=16.0 Hz, 1H), 6.42 (dd, J=16.0, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J=7.2 Hz, 3H).


(E)-Ethyl 2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoate (AI61)



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1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=8.0 Hz, 1H), 7.46 (d, J=1.6 Hz, 1H), 7.40 (s, 2H), 7.31 (d, J=1.6 Hz, 1H), 6.57 (d, J=16.0 Hz, 1H), 6.44 (dd, J=16.0 Hz, 8.0 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=6.8 Hz, 3H); ESIMS m/z 470.73 ([M−H]−); IR (thin film) 1726, 1115, 809, 3072 cm−1.


(E)-Ethyl 4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzoate (AI62)



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The title compound was isolated as a pale brown liquid (1.0 g, 46.3%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.41 (s, 2H) 6.65 (d, J=16.0 Hz, 1H), 6.49 (dd, J=16.0, 8.0 Hz, 1H), 4.42 (q, J=7.6 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=7.6 Hz, 3H); ESIMS m/z 502.99 ([M−H]−); IR (thin film) 1730, 1202, 1120, 750 cm−1.


(E)-Ethyl 2-chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI63)



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1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=6.0 Hz, 1H), 7.46 (d, J=1.8 Hz, 2H), 7.34 (m, 1H), 7.24 (m, 1H), 6.57 (d, J=16.2 Hz, 1H), 6.45 (dd, J=16.2, 7.2 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 4.13 (m, 1H), 1.41 (t, J=7.2 Hz, 3H); ESIMS m/z 455.0 ([M+H]+); IR (thin film) 1728, 1115, 817 cm−1.


(E)-Ethyl 2-fluoro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI64)



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1H NMR (400 MHz, CDCl3) δ 7.93 (t, J=7.6 Hz, 1H), 7.34 (d, J=5.6 Hz, 2H), 7.21 (d, J=8.0 Hz, 1H), 7.16 (d, J=11.6 Hz, 1H), 6.59 (d, J=16.0 Hz, 1H), 6.49 (dd, J=16.0, 7.6 Hz, 1H), 4.42 (q, J=7.6 Hz, 2H), 4.13 (m, 1H), 1.41 (t, J=7.6 Hz, 3H); ESIMS m/z 436.81 ([M−H]−); IR (thin film) 1725 cm−1.


(E)-Ethyl 2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI65)



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1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.36 (m, 3H), 6.56 (d, J=15.6 Hz, 1H), 6.44 (dd, J=15.6, 8.0 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 4.10 (m, 1H), 1.42 (t, J=6.8 Hz, 3H); ESIMS m/z 498.74 ([M−H]−); IR (thin film) 1726, 1114, 820, 623 cm−1.


(E)-Ethyl 2-methyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI66)



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The title compound was isolated as a brown semi-solid: 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.8 Hz, 1H), 7.34 (d, J=6.0 Hz, 2H), 7.25 (d, J=7.2 Hz, 2H), 6.59 (d, J=16.0 Hz, 1H), 6.42 (dd, J=16.0 Hz, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); ESIMS m/z 432.90 ([M−H]−); IR (thin film) 1715 cm−1.


(E)-Methyl 2-methoxy-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI67)



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1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8.4 Hz, 1H), 7.35 (d, J=6.0 Hz, 2H), 7.03 (d, J=1.2 Hz, 1H), 6.92 (s, 1H), 6.59 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.0 Hz, 1H), 4.13 (m, 1H), 3.93 (s, 3H), 3.88 (s, 3H); ESIMS m/z 437.29 ([M+H]+); IR (thin film) 1724 cm−1.


(E)-Ethyl 2-ethyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI68)



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1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.0 Hz, 1H), 7.35 (d, J=9.6 Hz, 2H), 7.26 (m, 1H), 7.24 (m, 1H), 6.60 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.14 (m, 1H), 3.01 (q, J=7.6 Hz 2H), 1.41 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H); ESIMS m/z 447.05 ([M−H]−); IR (thin film) 1715, 1115, 817 cm−1.


Example 11: Preparation of (E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI32)



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To a stirred solution of (E)-ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (1.7 g, 4.0 mmol) in 1,4-dioxane (10 mL) was added 11 N HCl (30 mL), and the reaction mixture was heated at 100° C. for 48 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with H2O and extracted with chloroform (CHCl3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure, and the crude compound was washed with n-hexane to afford the title compound as a white solid (0.7 g, 50%): mp 142-143° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.66 (s, 3H), 7.52-7.44 (m, 2H), 6.89 (dd, J=16.0, 8.0 Hz, 1H), 6.78-6.74 (d, J=16.0 Hz, 1H), 4.84 (m, 1H), 2.50 (s, 3H); ESIMS m/z 387.05 ([M−H]−); IR (thin film) 3448, 1701, 1109, 777 cm−1.


The following compounds were made in accordance with the procedures disclosed in Example 11.


(E)-2-Methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI26)



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The product was isolated as a pale brown gummy liquid (1 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68 (d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz, 1H), 4.16 (m, 1H), 2.50 (s, 3H); ESIMS m/z 422.67 ([M−H]−).


(E)-2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI27)



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The product was isolated as an off-white semi-solid (1 g, 45%): 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.4 Hz, 1H), 7.50 (m, 1H), 7.40 (s, 1H), 7.36 (m, 2H), 6.59 (d, J=15.6 Hz, 1H), 6.48 (dd, J=15.6, 7.6 Hz, 1H), 4.14 (m, 1H); ESIMS m/z 442.72 ([M−H]−); IR (thin film) 3472, 1704, 1113, 808 cm−1.


(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI28)



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The product was isolated as a brown solid (1 g, 45%): mp 70-71° C.; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.40 (m, 3H), 6.58 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 4.14 (m, 1H); ESIMS m/z 484.75 ([M−H]−); IR (thin film) 3468, 1700 cm−1.


(E)-2-Cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI29)



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The product was isolated as an off-white solid (500 mg, 45%): mp 100-101° C.; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.65 (br s, 1H), 7.42 (s, 2H), 6.73 (d, J=16.0 Hz, 1H), 6.58 (dd, J=16.0, 8.0 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 431.93 ([M−H]−).


E)-4-(3-(3,4-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI30)



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The product was isolated as a pale brown liquid (500 mg, 46%): 1H NMR (400 MHz, CDCl3) δ 8.03 (m, 1H), 7.49 (m, 2H), 7.29 (m, 1H), 7.22 (m, 2H), 6.73 (d, J=16.0 Hz, 1H), 6.58 (dd, J=16.0, 7.8 Hz, 1H), 4.16 (m, 1H), 2.64 (s, 3H); ESIMS m/z 386.84 ([M−H]−); IR (thin film) 3428, 1690, 1113, 780 cm−1.


(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI31)



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The product was isolated as a white solid (500 mg, 50%): mp 91-93° C.; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.0 Hz, 1H), 7.35 (d, J=5.6 Hz, 1H), 7.30 (m, 3H), 6.61 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.65 (s, 3H); ESIMS m/z 406.87 ([M−H]−).


(E)-4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzoic acid (AI33)



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The product was isolated as a white solid (500 mg, 45%): mp 142-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68 (d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz, 1H), 4.16 (m, 1H); ESIMS m/z 474.87 ([M−H]−).


(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI69)



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The title compound was isolated as a brown solid (0.8 g, 28%): 1H NMR (400 MHz, CDCl3) δ 13.42 (br, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.94 (m, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.65 (m, 1H), 7.06 (dd, J=15.9, 9.0 Hz, 1H), 6.80 (d, J=15.9 Hz, 1H), 4.91 (m, 1H); ESIMS m/z 484.75 ([M−H]−); IR (thin film) 3469, 1700 cm−1.


(E)-2-Bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluo robut-1-enyl)benzoic acid (AI70)



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The title compound was isolated as a yellow liquid (0.3 g, crude): 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=8.1 Hz, 1H), 7.67 (s, 1H), 7.34 (m, 3H), 6.56 (d, J=15.9 Hz, 1H), 6.45 (dd, J=15.9, 7.6 Hz, 1H), 4.43 (m, 1H); ESIMS m/z 471.0 ([M−H]−).


(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-ethylbenzoic acid (AI71)



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The title compound was isolated as a brown gummy material (0.2 g, crude): 1H NMR (300 MHz, DMSO-d6) δ 12.5 (br, 1H), 7.85 (d, J=6.3 Hz, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.52 (m, 2H), 6.96 (dd, J=8.7, 8.7 Hz, 1H), 6.78 (d, J=15.6 Hz, 1H), 4.80 (m, 1H), 4.06 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H); ESIMS m/z 419.06 ([M−H]−).


(E)-2-Chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (AI72)



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The title compound was isolated as a yellow liquid (0.7 g, 95%): 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=6.0 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.41 (s, 3H), 6.57 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 8.0 Hz, 1H), 4.16 (m, 1H); ESIMS m/z 455.0 ([M+H]+); IR (thin film) 1728, 1115, 817 cm−1.


(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI73)



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The title compound was isolated as a light brown gummy material (0.7 g, 38%): mp 91-93° C.; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.0 Hz, 1H), 7.35 (d, J=5.6 Hz, 1H), 7.30 (m, 3H), 6.10 (d, J=16.0 Hz, 1H), 6.46 (dd, J=16.0, 8.0 Hz, 1H), 4.03 (m, 1H), 2.65 (s, 3H); ESIMS m/z 406.87 ([M−H]−).


(E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluorobenzoic acid (AI74)



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The title compound was isolated as a light brown liquid (0.3 g, crude): ESIMS m/z 393.15 ([M−H]−).


(E)-2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (AI75)



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The title compound was isolated as a light brown liquid (0.35 g, crude): ESIMS m/z 451.91 ([M−H]−).


Prophetically, compounds AI34, AI36-AI41, AI44-AI45 (Table 1) could be made in accordance with the procedures disclosed in Example 10, or Examples 10 and 11.


Example 12: Preparation of (E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methyl-N-(2,2,2-trifluoroethyl)benzamide (AC6)



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To a stirred solution of (E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid in DMF was added 2,2,2-trifluoroethylamine, 1-hydroxybenzotriazole hydrate (HOBt.H2O), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) and DIPEA, and the reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with hexane:EtOAc afforded a white semi-solid (110 mg, 50%): 1H NMR (400 MHz, CDCl3) 7.40 (m, 2H), 7.26 (m, 3H), 6.56 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 5.82 (br s, 1H), 4.08 (m, 3H), 2.52 (s, 3H); ESIMS m/z 468.40 ([M−H]−); IR (thin film) 1657, 1113, 804 cm−1.


Compounds AC7-AC38, AC40-AC58, AC110-AC112, AC117, and AC118 (Table 1) were made in accordance with the procedures disclosed in Example 12.


Example 13: Preparation of 4-((E)-3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methyl-N-((pyrimidin-5-yl)methyl)benzamide (AC39)



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To a stirred solution of (pyrimidin-5-yl)methanamine (0.15 g, 1.43 mmol) in CH2Cl2 (10 mL) was added drop wise trimethylaluminum (2 M solution in toluene; 0.71 mL, 1.43 mmol), and the reaction mixture was stirred at 25° C. for 30 min. A solution of ethyl 4-((E)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (0.3 g, 0.71 mmol) in CH2Cl2 was added drop wise to the reaction mixture at 25° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound (0.18 g, 55%): mp 141-144° C.;



1H (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.79 (s, 2H), 7.37 (m, 2H), 7.23 (m, 2H), 7.21 (m, 1H), 6.57 (d, J=16.0 Hz, 1H), 6.40 (dd, J=16.0, 7.6 Hz 1H), 6.21 (m, 1H), 4.65 (s, 2H), 4.11 (m, 1H), 2.46 (s, 3H); ESIMS m/z 477.83 ([M−H]−).


Example 14: Preparation of (E)-2-Chloro-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC64)



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To a stirred solution of glycine amide (0.15 g, 0.58 mmol) in CH2Cl2 (5 mL) was added trimethylaluminum (2 M solution in toluene; 1.45 mL, 2.91 mmol) dropwise, and the reaction mixture was stirred at 28° C. for 30 min. A solution of (E)-ethyl 2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoate (0.3 g, 0.58 mmol) in CH2Cl2 (5 mL) was added drop wise to the reaction mixture at 28° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 1N HCl solution (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound as yellow solid (0.15 g, 50%): mp 83-85° C.; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 2H), 7.36 (d, J=6.8 Hz, 1H), 7.05 (t, J=5.2 Hz, 1H), 6.70 (t, J=5.2 Hz, 1H), 6.57 (d, J=15.6 Hz, 1H), 6.44 (dd, J=15.6, 8.0 Hz, 1H), 4.23 (d, J=5.6 Hz, 2H), 4.15 (m, 1H), 4.01 (m, 2H); ESIMS m/z 580.72 ([M−H]−).


Compounds AC59-AC75 (Table 1) were made in accordance with the procedures disclosed in Example 14.


Example 15: Preparation of (E)-2-Bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (AC79)



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To a stirred solution of (E)-2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (300 mg, 0.638 mmol) in CH2Cl2 (5.0 mL) was added 2-amino-N-(2,2,2-trifluoroethyl)acetamide (172. mg, 0.638 mmol) followed by benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (364.5 mg, 0.701 mmol) and DIPEA (0.32 mL, 1.914 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 40% ethyl acetate/petroleum ether) afforded the title compound as an off-white solid (121 mg, 31%): 1H NMR (400 MHz, CDCl3) δ 8.69 (t, J=6.0 Hz, 1H), 8.58 (t, J=6.0 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J=6.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.0 (m, 1H), 6.76 (d, J=15.6 Hz, 1H), 4.83 (t, J=8.0 Hz, 1H), 3.98 (m, 4H); ESIMS m/z 610.97 ([M+H]+); IR (thin film) 3303, 1658, 1166, 817 cm−1.


Compounds AC76-AC80, AC96-AC102, and AC113 (Table 1) were made in accordance with the procedures disclosed in Example 15.


Example 16: Preparation of (E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(1,1-dioxidothietan-3-yl)-2-fluorobenzamide (AC83)



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To a stirred solution of (E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluoro-N-(thietan-3-yl)benzamide (100 mg, 0.2159 mmol) in acetone/water (1:1, 5.0 mL) was added oxone (266 mg, 0.4319 mmol) and the resultant reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) afforded the title compound as an off white solid (70.0 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 8.07 (t, J=8.4 Hz, 1H), 7.39 (t, J=1.6 Hz, 1H), 7.31 (d, J=1.2 Hz, 1H), 7.26 (m, 2H), 7.23 (m, 2H), 7.19 (d, J=1.6 Hz, 1H), 6.60 (d, J=16.8 Hz, 1H), 6.49 (dd, J=16.8, 7.6 Hz, 1H), 4.90 (m, 1H), 4.64 (m, 2H), 4.14 (m, 2H); ESIMS m/z 493.83 ([M−H]−); IR (thin film) 1527, 1113, 801, 1167, 1321 cm−1.


Compounds AC81-AC87 (Table 1) were made in accordance with the procedures disclosed in Example 16.


Example 17: Preparation of (E)-N-((5-Cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methylbenzamide (AC89)



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A solution of (E)-N-(2-(2-(cyclopropanecarbonyl)hydrazinyl)-2-oxoethyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide (200 mg, 0.379 mmol) in POCl3 (2.0 mL) was stirred at ambient temperature for 10 min, then the resultant reaction mixture was heated to 50° C. for 1 h. The reaction mixture was quenched with ice water at 0° C. and extracted with ethyl acetate. The combined ethyl acetate layer was washed with saturated NaHCO3 solution and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 50% ethyl acetate/pet ether) afforded the title compound as a light brown gummy material (70.0 mg, 36%): 1H NMR (400 MHz, CDCl3) δ 7.43 (m, 2H), 7.27 (m, 2H), 7.23 (m, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.41 (dd, J=16.0, 7.6 Hz, 1H), 4.79 (d, J=5.6 Hz, 2H), 4.14 (m, 1H), 2.48 (s, 3H), 2.18 (m, 1H), 1.16 (m, 4H); ESIMS m/z 509.89 ([M+H]+); IR (thin film) 1666, 1166, 1112, 800 cm−1.


Example 18: Preparation of (E)-2-Bromo-N-(2-thioxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzothioamide (AC90)



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To a stirred solution of (E)-2-bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (400 mg, 0.638 mmol) in 5 mL of THF at ambient temperature was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) (336 mg, 0.830 mmol) in one portion. The resulting reaction mixture was stirred for 18 h. TLC showed the reaction was not complete, therefore additional Lawesson's reagent (168 mg, 0.415 mmol) was added and reaction stirred for 48 h. After the reaction was deemed complete by TLC, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 230-400 mesh; eluting with 20% EtOAc in hexanes) afforded the title compound as a yellow glassy oil (188 mg, 44.7%): 1H NMR (400 MHz, CDCl3) δ 8.34 (m, 1H), 8.27 (m, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.40 (s, 2H), 7.36 (dd, J=8.2, 1.7 Hz, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.38 (dd, J=15.9, 7.9 Hz, 1H), 4.89 (d, J=8.4, 5.5 Hz, 2H), 4.48 (qd, J=9.0, 6.0 Hz, 2H), 4.11 (m, 1H); ESIMS m/z 656.9 ([M−H]−).


Example 19: Preparation of (E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenylthioamido)-N-(2,2,2-trifluoroethyl)acetamide (AC91)



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To a stirred solution of (E)-2-bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (400 mg, 0.638 mmol) in 5 mL of THF at ambient temperature was added Lawesson's reagent (64.5 mg, 0.160 mmol) in one portion. The resulting reaction mixture was stirred for 18 h, after which time, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 230-400 mesh; eluting with 20% EtOAc in hexanes) afforded the title compounds as a yellow oil (18.5 mg, 4.51%): 1H NMR (400 MHz, CDCl3) δ 8.18 (t, J=5.0 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.40 (s, 2H), 7.34 (dd, J=8.1, 1.6 Hz, 1H), 6.52 (m, 2H), 6.37 (dd, J=15.9, 7.9 Hz, 1H), 4.54 (d, J=4.9 Hz, 2H), 4.12 (m, 1H), 3.99 (qd, J=8.9, 6.5 Hz, 2H); ESIMS m/z 640.9 ([M−H]−).


The following compound was made in accordance with the procedures disclosed in Example 19.


(E)-2-Bromo-N-(2-thioxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC92)



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The product was isolated as a colorless oil (17.9 mg, 4.36%): 1H NMR (400 MHz, CDCl3) δ 9.16 (d, J=6.1 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.41 (m, 3H), 7.21 (t, J=5.6 Hz, 1H), 6.55 (d, J=15.9 Hz, 1H), 6.41 (dd, J=15.9, 7.8 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 4.45 (qd, J=9.0, 6.0 Hz, 2H), 4.12 (q, J=7.2 Hz, 1H); ESIMS m/z 640.9 ([M−H]−).


Example 106: Preparation of Ethyl (Z) 2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoate (AI76)



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The title compound was made in accordance with the procedure disclosed in Example 88 and was isolated as a yellow viscous oil (416 mg, 23%): 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8.0 Hz, 1H), 7.40 (d, J=1.7 Hz, 1H), 7.35 (s, 2H), 7.12 (dd, J=8.0, 1.7 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.23-5.91 (m, 1H), 4.42 (q, J=7.1 Hz, 2H), 4.33-4.10 (m, 1H), 1.42 (t, J=7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −69.34 (d, J=8.3 Hz); EIMS m/z 514.10 ([M]−); IR (thin film) 2983, 1727, 1247, 1204, 1116 cm−1.


Example 107: Preparation of (Z)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (AI77)



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To a stirred solution of (Z)-ethyl 2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoate (360 mg, 0.70 mmol) in CH3CN (1.0 mL) was added iodotrimethylsilane (0.28 mL, 2.8 mmol). The reaction mixture was heated to reflux for 20 h, allowed to cool to ambient temperature and partitioned between CH2Cl2 and aq. 10% Na2S2O3. Organic phase was washed once with aq. 10% Na2S2O3 and dried over MgSO4 and concentrated in vacuo. Passing the material through a silica plug with 10% EtOAc in hexanes, followed by 20% MeOH in CH2Cl2) as the eluting solvents afforded the title compound as a yellow foam (143 mg, 42%): mp 54-64° C.; 1H NMR (400 MHz, CDCl3) δ 11.36 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.30 (s, 2H), 7.14 (d, J=7.9 Hz, 1H), 6.85 (d, J=11.4 Hz, 1H), 6.15 (t, J=10.9 Hz, 1H), 4.36-4.09 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −69.30.


Example 108: Preparation of (Z)-2-Bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC95)



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To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50° C. oil bath for 1.5 h, treated with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aq. 5% NaHSO4 (2×) and once with sat. NaCl (1×). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61° C.: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −69.31, −72.3; EIMS m/z 626.9 ([M+1]+).


Example 109a: Preparation of (E)-2-Bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC114)



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(E)-tert-Butyl 4-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)piperidine-1-carboxylate (0.75 g, 1.11 mmol) was added to dioxane HCl (10 mL) at 0° C. and was stirred for 18 h. The reaction mixture was concentrated under reduced pressure and triturated with diethylether to afford the compound as a light brown solid (0.6 g, 88%).


Example 109b: Preparation of (E)-N-(1-Acetylpiperidin-4-yl)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC103)



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To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in CH2Cl2 (10.0 mL) was added TEA (0.046 mL, 0.35 mmol) and stirred for 10 min. Then acetyl chloride (0.014, 0.18 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution and brine solution. The combined CH2Cl2 layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was washed with 5% diethyl ether/n-pentane to afford the title compound as a white solid (0.054 g, 50%).


Example 110: Preparation of (E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-(1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)benzamide (AC104)



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To a stirred solution of 3,3,3-trifluoropropanoic acid (0.02 g, 0.16 mmol) in CH2Cl2 (10.0 mL), (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), PYBOP (0.09 g, 0.17 mmol), and DIPEA (0.06 g, 0.48 mmol) were added at ambient temperature. The reaction mixture was stirred at ambient temperature for 5 h. The reaction mixture was diluted with CH2Cl2. The combined CH2Cl2 layer was washed with 3N HCl and saturated NaHCO3 solution, the separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% MeOH in CH2Cl2) to afford the title compound as an off white gummy material (0.035 g, 29.%).


Example 111: Preparation of (E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide (AC105)



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To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in THF (5.0 mL) was added TEA (0.06 mL, 0.64 mmol) and stirred for 10 min. Then 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.03, 0.16 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a brown solid (0.05 g, 44%).


Example 112: Preparation of (E)-2-Bromo-N-(1-methylpiperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC106)



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A solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), formaldehyde (30% in water) (0.1 mL, 0.16 mmol) and acetic acid (0.01 mL) in MeOH (5.0 mL) was stirred at ambient temperature for 30 min. After that NaBH3CN (0.01 g, 0.16 mmol) was added at 0° C. and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to obtain residue which was diluted with ethyl acetate and washed with saturated aq. NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether/pentane to afford the title compound as a pale yellow gummy material (0.06 g, 59%).


Example 113: Preparation of ((E)-2-Bromo-N-(1-(cyanomethyl)piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC107)



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To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-bromoacetonitrile (0.07, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.125 g, 46.8%).


Example 114: Preparation of (E)-2-Bromo-N-(1-(oxetan-3-yl)piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC108)



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A solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.2 g, 0.35 mmol), oxetan-3-one (0.027 g, 0.38 mmol) and acetic acid (0.01 mL) in MeOH (5.0 mL) was stirred at ambient temperature for 30 min. After that NaBH3CN (0.022 g, 0.35 mmol) was added at 0° C. slowly lot wise over the period of 10 min and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to obtain a residue which was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether/pentane to afford the title compound as an off-white solid (0.05 g, 23%).


Example 115: Preparation of (E)-2-Bromo-N-(1-(2-hydroxyethyl)piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC109)



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To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-chloroethanol (0.05, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.09 g, 34%).


Example 116: Preparation of (E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamido)acetic acid (AI78)



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To a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)acetate (440 mg, 0.734 mmol) in CH2Cl2 (36.0 ml), was added TFA (4.0 mL) and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain residue which was washed with n-pentane to afford the title compound as an off-white solid (310 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 13.0 (s, 1H), 8.75 (t, J=5.7 Hz, 1H), 7.93 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 6.96 (dd, J=15.3, 9.3 Hz, 1H), 6.78 (d, J=15.3 Hz, 1H), 4.83 (m, 1H), 3.90 (d, J=5.7 Hz, 2H); ESIMS m/z 543.61 ([M+H]+); IR (thin film) 3429, 1635, 1114, 772 cm−1.


Example 117: Preparation of (E)-N-((6-Chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methylbenzothioamide (AC115)



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To the stirred solution of (E)-N-((6-chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide (0.06 g, 0.117 mmol) in toluene (3 mL) was added Lawesson's reagent (0.14 g, 0.351 mmol) and the reaction was irradiated at 100° C. for 1 h, then cooled to ambient temperature and concentrated under reduced pressure to provide crude compound. The crude product was purified by preparative HPLC to afford the product as yellow color solid (0.03 g, 49%).


Example 118: Preparation of (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-2-(trifluoromethoxy)benzamide (AC116)



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Step 1. 2-(Trifluoromethoxy)-4-vinylbenzoic acid (AI79)

To a stirred solution of 4-bromo-2-(trifluoromethoxy)benzoic acid (1 g, 3.67 mmol) in DMSO (20 mL) was added potassium vinyltrifluoroborate (1.47 g, 11.02 mmol) and potassium carbonate (1.52 g, 11.02 mmol). The reaction mixture was degassed with argon for 30 min. Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.13 g, 0.18 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×50 mL), washed with brine, and dried over Na2SO4. Concentration under reduced pressure furnished the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.4 g, 47%): 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=8.1 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.35 (s, 1H), 6.78 (dd, J=17.4.1, 11.1 Hz, 1H), 5.92 (d, J=17.4 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H); ESIMS m/z 232.97 ([M+H]+).


Step 2. (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trifluoromethoxy)benzoic acid (AI80)

To a stirred solution of 2-(trifluoromethoxy)-4-vinylbenzoic acid (0.356 g, 1.53 mmol) in 1N methyl pyrrolidine (5.0 mL) was added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichloro 4-fluorobenzene (1.0 g, 3.07 mmol), copper(I) chloride (CuCl; 0.03 g, 0.307 mmol) and 2,2 bipyridyl (0.095 g, 0.614 mmol). The reaction mixture was stirred at 150° C. for 1 h. After the reaction was complete by TLC, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.3 g, 21%): 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.0 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.35 (s, 3H), 6.63 (d, J=16.0 Hz, 1H), 6.50 (dd, J=16.0, 8.0 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 474.81 ([M−H]−).


Step 3. (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-2-(trifluoromethoxy)benzamide (AC116)

A mixture of (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trifluoromethoxy)benzoic acid (0.25 g, 0.52 mmol), 2-amino-N-(2,2,2-trifluoroethyl)acetamide (0.158 g, 0.62 mmol), PyBOP (0.40 g, 0.78 mmol) and DIPEA (0.134 g, 1.04 mmol) in CH2Cl2 (10.0 mL) were stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 20% ethyl acetate/pet ether) afforded the title compound as a pale yellow gummy material (0.15 g, 47%).


The following molecules were made in accordance with the procedures disclosed in Example 118, Step 2:


(E)-4-(3-(3,5-Dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid



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The title molecule was isolated as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 13.5 (bs, 1H), 8.03 (s, 1H), 7.95-7.85 (m, 4H), 7.81 (d, J=7.8 Hz, 1H), 7.14 (dd, J=15.6, 9.6 Hz, 1H), 6.90 (d, J=15.9 Hz, 1H), 4.86-4.79 (m, 1H); ESIMS m/z 528.82 ([M−H]+); IR (thin film) 3437, 1707, 1153, 555 cm−1.


(E)-4-(3-(3,5-Dibromo-4-chlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid



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Isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ, 13.36 (bs, 1H) 8.05 (s, 2H), 7.95 (d, J=8.1 Hz, 1H), 7.87-7.67 (m, 2H), 7.14 (dd, J=9.0, 15.6 Hz, 1H), 6.96 (d, J=15.6 Hz, 1H), 4.88-4.82 (m, 1H); ESIMS m/z 564.58 ([M+H]+).


(E)-4-(3-(4-Bromo-3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid



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Isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.6 (bs, 1H) 8.03 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.88 (s, 2H), 7.81 (d, J=8.1 Hz, 1H), 7.13 (dd, J=16.2, 7.5 Hz, 1H), 6.91 (d, J=15.9 Hz, 1H), 4.89-4.83 (m, 1H); ESIMS m/z 532.0 ([M+H]+).


(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid



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The title molecule was isolated as an off white solid: mp 140-143° C.; 1H NMR (400 MHz, DMSO) δ13.60 (bs, 1H), 8.02 (s, 1H), 7.94-7.90 (m, 1H), 7.88-7.86 (m, 2H), 7.81-7.79 (m, 1H), 7.12 (dd, J=15.6, 8.8 Hz, 1H), 6.89 (d, J=15.6 Hz, 1H), 4.86-4.81 (m, 2H); ESIMS m/z 458.88 ([M−H]−).


Example 20: Preparation of 5-Vinyl-2,3-dihydro-1H-inden-1-one (BI1)



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To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.7 mmol) in toluene were added vinylboronic anhydride pyridine complex (8.55 g, 35.54 mmol), Pd(PPh3)4 (0.1 g, 0.094 mmol), K2CO3 (22.88 g, 165.83 mmol). The resultant reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with H2O and brine. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) afforded the title compound as a solid (1.8 g, 48%): 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=7.2 Hz, 1H), 7.49 (br s, 1H), 7.44 (d, J=7.2 Hz, 1H), 6.82 (m, 1H), 5.90 (d, J=7.4 Hz, 1H), 5.42 (d, J=6.4 Hz, 1H), 3.20 (m, 2H), 2.70 (m, 2H); ESIMS m/z 159.06 ([M+H]−).


The following compound was made in accordance with the procedures disclosed in Example 20.


6-Vinyl-3,4-dihydronaphthalen-1(2H)-one (BI2)



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The product was isolated as an off-white solid (5 g, 48%): 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=8.4 Hz, 1H), 7.48 (m, 2H), 6.82 (m, 1H), 6.02 (d, J=7.4 Hz, 1H), 5.44 (d, J=6.4 Hz, 1H), 2.95 (m, 2H), 2.60 (m, 2H), 2.00 (m, 2H); ESIMS m/z 173.14 ([M−H]−); IR (thin film) 1681 cm−1.


Example 21: Preparation of (E)-5-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-one (BI3



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5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (4 g, 11.7 mmol), 5-vinyl-2,3-dihydro-1H-inden-1-one (0.92 g, 5.8 mmol), CuCl (0.115 g, 1.171 mmol) and 2,2-bipyridyl (0.053 g, 0.34 mmol) in 1,2-dichlorobenzene (25 mL) were heated at 180° C. for 16 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) to afford the title compound as a liquid (1.28 g, 25%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.4 Hz, 1H), 7.52 (m, 3H), 6.68 (d, J=7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m/z 419.14 ([M+H]−); IR (thin film) 1708.94, 1113.60, 807.77 cm−1.


The following compound was made in accordance with the procedures disclosed in Example 21.


(E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2,3-dihydro-1H-inden-1-one (BI4)



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The product was isolated as a brown semi-solid (1.2 g, 16%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.4 Hz, 1H), 7.54 (m, 3H), 7.30 (s, 1H), 6.68 (d, J=7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m/z 400.84 ([M−H]−); IR (thin film) 815, 1113, 1709 cm−1.


(E)-6-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-one (BI5)



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The product was isolated as a pale yellow semi solid (1.2 g, 30%): 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.0 Hz, 1H), 7.42 (s, 2H), 7.35 (m, 1H), 7.24 (m, 2H), 6.62 (d, J=16 Hz, 1H), 6.46 (m, 1H), 4.18 (m, 1H), 2.95 (m, 2H), 2.65 (m, 2H), 2.19 (m, 2H); ESIMS m/z 432.94 ([M−H]−); IR (thin film) 1680, 1113, 808 cm−1.


Example 22: Preparation of (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-fluoro-2,3-dihydro-1H-inden-1-one (BI6)



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To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one (0.5 g, 1.24 mmol) in acetonitrile (20 mL), was added Selectfluor® (0.52 g, 1.48 mmol) and the reaction was heated to reflux temperature for 16 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and diluted with CH2Cl2. The solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) to afford the title compound as a pale yellow semi solid (0.1 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.80 (m, 1H), 7.48 (m, 2H), 7.32 (m, 2H), 6.65 (d, J=16.0 Hz, 1H), 6.54 (dd, J=16.0, 8.0 Hz, 1H), 5.38 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.32 (m, 1H); ESIMS m/z 419.06 ([M−H]−); IR (thin film) 1728, 1114, 817 cm−1.


Example 23: Preparation of (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-inden-1-amine (BC10)



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To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one (0.15 g, 0.35 mmol) in DCE (10 mL), was added trifluoropropyl amine (0.048 g, 0.42 mmol) and sodium cyanoborohydride (0.055 g, 0.875 mmol) in cooling and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCE, was washed with water and brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether) to afford the title compound as a colorless gummy material (0.042 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.38-7.20 (m, 5H), 6.62 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 5.83 (br, 1H), 5.52 (m, 1H), 4.12 (m, 1H), 3.02 (m, 3H), 2.82 (m, 1H), 2.50 (m, 2H), 1.82 (m, 1H), 1.42 (m, 1H); ESIMS m/z 497.98 ([M−H]−); IR (thin film) 3027, 1654, 815 cm−1.


Example 24: Preparation of 6-((E)-4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-one oxime (BI5a)



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To a stirred solution of ((E)-6-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-one (0.4 g, 0.92 mmol) in EtOH (50 mL) were added hydroxylamine hydrochloride (0.128 g, 1.85 mmol) and sodium acetate (0.23 g, 2.77 mmol), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether). The title compound was isolated as a solid (0.3 g, 73%): mp 155-158° C.; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.41 (s, 2H), 7.24 (m, 1H), 7.17 (m, 1H), 6.57 (d, J=16 Hz, 1H), 6.46 (dd, J=16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.82 (m, 4H), 2.04 (m, 2H); ESIMS m/z 445.95 ([M−H]−).


Example 25: Preparation of (E)-5-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (BI5b)



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To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-one (1 g, 2.39 mmol) in MEOH (10 mL) were added ammonium acetate (1.84 g, 23.9 mmol) and sodium cyanoborohydride (NaCNBH3; 0.44 g, 7.17 mmol) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O and extracted with EtOAc. The combined organic extracts were washed with H2O and saturated aqueous sodium bicarbonate (satd aq NaHCO3) solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (500 mg, crude): 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 2H), 7.40 (s, 1H), 7.30 (s, 2H), 6.71 (s, 2H), 4.78 (m, 1H), 4.2 (m, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 1.60 (m, 2H); ESIMS m/z 419.02 ([M+H]+); IR (thin film) 2924, 1552, 1112, 807 cm−1.


The following compound was made in accordance with the procedures disclosed in Example 25.


(E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2,3-dihydro-1H-inden-1-amine (BI7)



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The product was isolated as a light brown gummy material, taken as such to the next step (0.15 g, crude compound): ESIMS m/z 401.97 ([M−H]−).


(E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-fluoro-2,3-dihydro-1H-inden-1-amine (BI8)



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The product was isolated as a light brown gummy material, taken as such to the next step (0.15 g, crude compound): ESIMS m/z 420.15 ([M−H]−).


(E)-6-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-1,2,3,4-tetrahydronaphthalen-1-amine (BI9)



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The product was isolated as a pale yellow liquid (500 mg crude).


Example 26: Preparation of (E)-1-Methyl-3-(5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-but-1-enyl)-2,3-dihydro-1H-inden-1-yl)thiourea (BC1)



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To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (0.1 g, 0.23 mmol) in Et2O (5 mL) was added methylisothiocyanate (0.026 g, 0.35 mmol), and the mixture was stirred for 2 h at 25° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SiO2, 20% EtOAc in petroleum ether). The title compound was isolated as a liquid (65 mg, 50%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 7.25-7.18 (m, 3H), 6.58 (d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.4 Hz, 1H), 5.91-5.70 (br, 2H), 4.05 (m, 1H), 3.05-2.80 (m, 6H), 2.70 (m, 1H), 1.81 (m, 1H); ESIMS m/z 492.17 ([M+H]+); IR (thin film) 3211, 1569, 1113, 806 cm−1.


Compounds BC2-BC3 in Table 1 were made in accordance with the procedures disclosed in Example 26.


Example 27: Preparation of (E)-3,3,3-Trifluoro-N-(5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-yl)propanamide (BC4)



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To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (0.1 g, 0.23 mmol) in CH2Cl2 (10 mL) were added trifluoropropionic acid (0.044 g, 0.34 mmol), EDC.HCl (0.038 g, 0.35 mmol), HOBt.H2O (0.07 g, 0.46 mmol) and DIPEA (0.074 g, 0.57 mmol), and the reaction mixture was stirred for 16 h at 25° C. The reaction mixture was diluted with CH2Cl2 and washed with H2O. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, 15% EtOAc in petroleum ether) to afford the title compound as a liquid (65 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 7.25-7.20 (m, 3H), 6.34 (d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.0 Hz, 1H), 5.81 (br, 1H), 5.48 (m, 1H), 4.10 (m, 1H), 3.10 (m, 2H), 2.86-3.07 (m, 2H), 2.86 (m, 1H), 1.81 (m, 1H); ESIMS m/z 529.02 ([M+H]+); IR (thin film) 3283, 1652, 1241, 811 cm−1.


Compounds BC5-BC9, BC11 in Table 1 were made in accordance with the procedures disclosed in Example 27.


Example 28: Preparation of tert-Butyl 5-vinylindoline-1-carboxylate (BI10)



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Step 1. 5-Bromo-indoline (BI11): To 5-Bromo-1H-indole (2.5 g, 12.82 mmol) in acetic acid (10.0 mL), NaCNBH3 (2.38 g, 38.46 mmol) was added portion wise at 10° C. over the period of 20 min. After that the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated NaHCO3, water and brine solution. The combined ether layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound as a pale yellow semi-solid (1.8 g, 71%).


Step 2. tert-Butyl-5-bromoindoline-1-carboxylate (BI12)

To a stirred solution of 5-bromo-indoline (3.0 g, 15 mmol) in acetonitrile (100 ml), was added DMAP (0.185 g, 1.522 mmol) and di-tert-butyl dicarbonate (3.98 g, 18.3 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was concentrated on reduced pressure to obtain a residue which was diluted with diethyl ether and washed with water and brine solution (2×). The combined ether layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as an off-white solid, which was used in the next step without further purification (3.0 g).


Step 3. tert-Butyl-5-vinylindoline-1-carboxylate (BI10)

A stirred solution of tert-butyl-5-bromoindoline-1-carboxylate (2.0 g, 6.73 mmol), potassium vinyl trifluoroborate (2.6 g, 20.20 mmol) and K2CO3 (2.78 g, 20.2 mmol) in DMSO (50.0 mL) was degassed with argon for 20 min at ambient temperature. PdCl2(dppf) (0.49 g, 0.67 mmol) was added at ambient temperature, then the reaction mixture was heated to 100° C. for 3 h. The reaction mixture was cooled to ambient temperature and filtered through a celite bed under vacuum and washed with diethyl ether. The reaction mixture was extracted with diethyl ether. The combined diethyl ether layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% ethyl acetate/petroleum ether) to afford the title compound as an off-white solid (1.2 g, 73%): Mp 85.5-88.6° C.; 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 3H), 6.69 (dd, J=17.4, 10.8 Hz, 1H), 5.64 (d, J=10.5 Hz, 1H), 5.13 (d, J=10.5 Hz, 1H), 4.00 (t, J=9.0 Hz, 2H), 3.10 (t, J=9.0 Hz, 2H), 1.55 (bs, 9H).


Example 29: Preparation of (E)-tert-Butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indoline-1-carboxylate (BI13)



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To a stirred solution of tert-butyl-5-vinylindoline-1-carboxylate (1.28 g, 5.23 mmol) in1,2-dichlorobenzene (10.0 mL), was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (3.4 g, 10 mmol), CuCl (103 mg, 1.05 mmol) and 2,2-bipyridyl (0.326 g, 2.092 mmol) and the resultant reaction mixture was degassed with argon for 30 min and heated to 150° C. for 1 h. The reaction mixture was cooled to ambient temperature and filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as a pale yellow gummy solid (0.3 g, 61%): 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=6.0 Hz, 2H), 7.22 (s, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.21 (dd, J=16.0, 7.6 Hz, 1H), 4.07 (m, 3H), 3.10 (t, J=8.4 Hz, 2H), 1.55 (s, 9H); ESIMS m/z 433.79 ([M−H]−); IR (thin film) 1168, 858 cm−1.


Example 30: Preparation of (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1-amine (BI14)



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Step 1. (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline (BI15)

To a stirred solution of (E)-tert-butyl-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-carboxylate (0.2 g, 0.4 mmol) in CH2Cl2 (10.0 mL) was added TFA (0.6 mL) and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2, washed with saturated aq NaHCO3, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a light brown gummy material which was used in the next step without further purification (0.12 g): 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=6.4 Hz, 2H), 7.21 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.49 (d, J=15.6 Hz, 1H), 6.21 (dd, J=15.6, 8.4 Hz, 1H), 4.07 (m, 1H), 3.61 (t, J=8.4 Hz, 2H), 3.05 (t, J=8.4 Hz, 2H); ESIMS m/z 389.89 ([M+H]+); IR (thin film) 3385, 1112, 816 cm−1.


Step 2. 5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-nitrosoindoline (BI16)

To (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline (0.2 g, 0.5 mmol) in concentrated HCl (5.0 ml) at 5° C., was added slowly NaNO2 in water and the reaction was allowed to stir at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2, and the CH2Cl2 layer washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a pale yellow solid that was used in the next step without further purification (0.2 g): 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.4 Hz, 1H), 7.39 (m, 4H), 6.61 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.4 Hz, 1H), 4.07 (m, 3H), 3.23 (t, J=8.4 Hz, 2H); ESIMS m/z 418.82 ([M+H]+); IR (thin film) 1488, 1112, 860 cm−1.


Step 3. (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1-amine (BI14)

To (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-nitrosoindoline (0.1 g, 0.2 mmol) in MeOH(10.0 mL) was added zinc powder (77.5 mg) and NH4Cl (36.9 mg, 0.69 mmol) in water (2.0 mL). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with CH2Cl2 and the CH2Cl2 layer was washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.08 g): ESIMS m/z 404.86 ([M+H]+).


Example 31: Preparation of (E)-N-(5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1-yl)-3,3,3-trifluoropropanamide (BC12)



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To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-amine (0.1 g, 0.247 mmol) in CH2Cl2 (10.0 ml) was added 3,3,3-trifluoropropanoic acid (0.038 g, 0.297 mmol), PyBOP (0.192 g, 0.370 mmol) and DIPEA (0.047 g, 0.370 mmol) and the reaction was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2, and the separated CH2Cl2 layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.12 g, 33%): 1H NMR (400 MHz, CDCl3) δ 7.32, (d, J=6.0 Hz, 2H) 7.28 (m, 1H), 7.20 (d, J=8.0, 1H), 7.14 (d, J=8.8, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); ESIMS m/z 514.86 ([M+H]+); IR (thin film) 3428, 1112, 857 cm−1.


Example 32: Preparation of tert-Butyl-5-vinyl-1H-indole-1-carboxylate (BI17)



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Step 1. 5-Vinyl-1H-indole (BI18)

A mixture of 5-bromo-1H-indole (2.5 g, 12.82 mmol), potassium vinyltrifluoroborate (2.57 g, 19.2 mmol), Cs2CO3 (12.53 g, 38.46 mmol) and triphenylphosphine (201 mg, 0.769 mmol) in THF/water (9:1, 75 ml) was degassed with argon for 20 min, then charged with PdCl2 (45.3 mg, 0.256 mmol). The reaction mixture was heated to reflux for 16 h, then cooled to ambient temperature, filtered through celite bed and washed with ethyl acetate. The filtrate was again extracted with ethyl acetate, and the combined organic layer washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (1.5 g, 83%): 1H NMR (400 MHz, CDCl3) δ 8.20 (br, 1H), 7.68 (s, 1H), 7.45 (s, 2H), 7.21 (m, 1H), 6.90 (dd, J=16.0, 10.8 Hz, 1H), 6.55 (m, 1H), 5.75 (d, J=10.5 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H); ESIMS m/z 142.05 ([M−H]−).


Step 2. tert-Butyl-5-vinyl-1H-indole-1-carboxylate (BI17)

To a stirred solution of 5-vinyl-1H-indole (0.7 g, 4.89 mmol) in acetonitrile (20 ml) was added DMAP (59.65 mg, 0.489 mmol) and di-tert-butyl dicarbonate (1.38 g, 6.36 mmol), and the reaction was stirred at ambient temperature for 3 h. The reaction mixture was concentrated under reduced pressure to obtain a residue which was diluted with CH2Cl2 and washed with water and brine solution. The combined CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as an off-white semi-solid (0.7 g, 59%): 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.0 Hz, 1H), 7.60 (s, 2H), 7.30 (d, J=8.4 Hz, 1H), 7.21 (m, 1H), 6.90 (dd, J=16.0, 10.8 Hz, 1H), 6.59 (s, 1H), 5.75 (d, J=10.5 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 242.10 ([M−H]−); IR (thin film) 1630 cm−1.


Example 33: Preparation of (E)-tert-Butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indole-1-carboxylate (BI19)



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To a stirred solution of tert-butyl 5-vinyl-1H-indole-1-carboxylate (0.65 g, 2.67 mmol), in 1,2-dichlorobenzene (10.0 mL) was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (1.74 g, 5.37 mmol), CuCl (53 mg, 0.537 mmol) and 2,2-bipyridyl (167 mg, 1.07 mmol). The resultant reaction mixture was degassed with argon for 30 min and heated to 150° C. for 2 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.25 g, 10%): 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J=16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 1.65 (s, 9H); ESIMS m/z 485.91 ([M−H]−); IR (thin film) 1165, 854 cm−1.


Example 34: Preparation of (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indole (BI20)



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To a stirred solution of (E)-tert-butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indole-1-carboxylate (0.2 g, 0.40 mmol) in CH2Cl2 (10.0 mL) was added TFA (70 mg, 0.61 mmol) and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown solid (0.2 g, 97%): mp 132.9-138.8° C.; 1H NMR (400 MHz, CDCl3) δ 11.19 (br, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J=16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.82 (m, 1H); ESIMS m/z 387.98 ([M+H]+).


Example 35: Preparation of 4-Nitrophenyl 2-((tert-butoxycarbonyl)amino)acetate (BI21)



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To a stirred solution of 4-nitrophenol (1.0 g, 7.19 mmol) in CH2Cl2 (20.0 mL) was added N-Boc glycine (1.38 g, 7.91 mmol) and EDC HCl (2.05 g, 10.785 mmol) and the reaction was stirred at ambient temperature for 24 h. The reaction mixture was diluted with CH2Cl2 and washed with water and saturated brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown gummy material that was used in the next step without further purification (1.1 g): 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=9.2 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 5.07 (br, 1H), 4.20 (s, 2H), 1.47 (s, 9H); ESIMS m/z 296.27 ([M+H]+).


Example 36: Preparation of (E)-tert-Butyl (2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)carbamate (BI22)



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To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indole (0.1 g, 0.258 mmol) in acetonitrile (5.0 mL) was added 4-nitrophenyl 2-(tert-butoxycarbonylamino) acetate (0.114 g, 0.387 mmol), potassium fluoride (0.03 g, 0.516 mmol), 18-crown-6-ether (0.075 g, 0.283 mmol) and DIPEA (0.0332 g, 0.258 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was concentrated to obtain a residue which was diluted with CH2Cl2 and washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a light brown gummy material which was used in the next step without further purification (0.1 g): ESIMS m/z 545.23 ([M+H]+).


Example 37: Preparation of (E)-N-(2-(5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)-3,3,3-trifluoropropanamide (BC13)



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Step 1. (E)-2-Amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)ethanone (BI23)

To a stirred solution of (E)-tert-butyl 2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)-2-oxoethylcarbamate (0.05 g, 0.09 mmol) in CH2Cl2 (5.0 mL) was added TFA (0.01 mL) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound which was used in the next step without further purification (50 mg).


Step 2. (E)-N-(2-(5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)-3,3,3-trifluoropropanamide (BC13)

To a stirred solution of (E)-2-amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl) ethanone (0.04 g, 0.09 mmol) in CH2Cl2 (5.0 ml) was added 3,3,3-trifluoropropanoic acid (17.5 mg, 0.136 mmol), PyBOP (70 mg, 0.135 mmol) and DIPEA (29 mg, 0.225 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2, and the CH2Cl2 layer was washed with water and saturated brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2, 100-200 mesh; 10% ethyl acetate/petroleum ether) to afford the title compound as an off-white solid (30 mg, 60%): mp 121-126° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (br, 1H), 7.59 (s, 1H), 7.45 (m, 4H), 6.72 (d, J=3.6 Hz, 3H), 6.39 (m, 1H), 4.71 (t, J=7.2 Hz, 2H), 4.15 (m, 1H), 3.51 (m, 1H), 3.28 (m, 1H); ESIMS m/z 553.06 ([M−H]−).


Example 38: Preparation of Ethyl 2-(1-oxo-6-vinylphthalazin-2(1H)-yl)acetate (BI24)



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Step 1. 5-Bromo-3-hydroxyisoindoline-1-one (BI25)

A mixture of Zn powder (1.73 g, 26.154 mmol), copper (II) sulfate pentahydrate (0.02 g, 0.08 mmol) and 2M aq NaOH (27 mL) were cooled to 0° C. 5-Bromoisoindoline-1,3-dione (5 g, 22 mmol) was added at the same temperature over the period of 30 min. The reaction mixture was stirred at 0° C. for 30 min and 3 h at ambient temperature. The reaction mixture was filtered and the filtrate was neutralized with concentrated HCl. The reaction mixture was diluted with ethanol and extracted with ethyl acetate. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a brown solid, which was used in the next step without further purification (1.3 g): mp 258-261° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (br, 1H), 7.81 (m, 2H), 7.69 (m, 1H), 6.44 (m, 1H), 5.88 (d, J=9.3 Hz, 1H); ESIMS m/z 225.83 ([M−H]−); IR (thin film) 1684, 3246, 606 cm−1.


Step 2. 6-Bromophthalazine-1(2H)-one (BI26)

To a stirred solution of 5-bromo-3-hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g, 8.80 mmol) and heated to 95° C. for 5 h. The reaction mixture was cooled to ambient temperature, filtered and washed with diethyl ether and pentane (1:1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).


Step 3. 6-Vinylphthalazine-1(2H)-one (BI27)

A solution of 6-bromophthalazine-1(2H)-one (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and K2CO3 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at ambient temperature. PdCl2(dppf) (0.04 g, 0.055 mmol) was added at ambient temperature, and the reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to ambient temperature and filtered through celite bed under vacuum and washed with ethyl acetate. The reaction mixture was extracted with ethyl acetate and the combined ethyl acetate layer dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 50% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.12 g, 63%): 1H NMR (400 MHz, DMSO-d6) δ 13.61 (br, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, J=10.8 Hz, 1H); ESIMS m/z 172.93 ([M+H]+); IR (thin film) 1748, 1655, 3241 cm−1.


Step 4. Ethyl-2-(1-oxo-6-vinylphthalazine-2(1H)-yl acetate (BI24)

To a stirred solution of 6-vinylphthalazine-1(2H)-one (0.5 g, 2.90 mmol) in DMF (5.0 mL) was added Cs2CO3 (0.94 g, 2.90 mmol) and the reaction was stirred for 10 min. Ethyl bromoacetate (0.48 g, 2.90 mmol) was added to the reaction mixture at ambient temperature and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and brine solution (2×). The separated ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 25% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.34 g, 45%): 1H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.24 (m, 1H), 8.04 (m, 2H), 7.01 (m, 1H), 6.17 (d, J=2.1 Hz, 1H), 5.56 (d, J=10.8 Hz, 1H), 4.92 (s, 2H), 4.19 (m, 2H), 1.23 (m, 3H). ESIMS m/z 259.10 ([M+H]+); IR (thin film) 1750, 1660 cm−1.


Example 39: Preparation of (E)-Ethyl 2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1-oxophthalazin-2(1H)-yl)acetate (BI28)



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To a stirred solution of ethyl-2-(1-oxo-6-vinylphthalazine-2(1H)-yl acetate (0.07 g, 0.27 mmol) in 1,2-dichlorobenzene (1.0 mL) was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2fluorobenzene (0.17 g, 0.54 mmol), CuCl (0.005 g, 0.05 mmol) and 2,2-bipyridyl (0.016 g, 0.10 mmol) and the resultant reaction mixture was degassed with argon for 30 min and heated to 180° C. for 12 h. The reaction mixture was cooled to ambient temperature and filtered and the filtrated was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 10-15% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (40 mg, 29%): 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=8.4 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.65 (s, 1H), 7.37 (d, J=6.3 Hz, 2H), 6.76 (d, J=16.0 Hz, 1H), 6.59 (dd, J=16.0, 8.0 Hz, 1H), 4.96 (s, 2H), 4.29 (m, 3H), 1.31 (t, J=7.2 Hz, 3H); ESIMS m/z 503.0 ([M+H]+); IR (thin film) 1660, 1114, 817 cm−1.


Example 40: Preparation of (E)-2-(6-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1-oxophthalazin-2(1H)-yl)acetic acid (BI29)



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A solution of (E)-ethyl-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl) acetate (0.04 g, 0.07 mmol) in HCl (0.5 mL) and acetic acid (0.5 mL) was heated to 100° C. for 3 h. The solvent was removed under reduced pressure and the residue diluted with water. The aqueous layer was extracted with ethyl acetate and the separated ethyl acetate layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was triturated with diethyl ether-pentane mixture to afford the title compound as a brown solid (0.03 g): 1H NMR (400 MHz, DMSO-d6) δ 13.0 (br s, 1H), 8.43 (m, 1H), 8.23 (d, J=8.1 Hz, 1H), 8.14 (m, 2H), 7.91 (m, 2H), 7.16 (dd, J=16.0, 8.0 Hz, 1H), 6.99 (d, J=16.0 Hz, 1H), 4.96 (m, 3H); ESIMS m/z 473.0 ([M−H]−); IR (thin film) 1629, 1168, 817 cm−1.


Example 41: Preparation of (E)-2-(6-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1-oxophthalazin-2(1H)-yl)-N-(2,2,2-trifluoroethyl)acetamide (BC14)



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To a stirred solution of (E)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl)acetic acid (0.15 g, 0.31 mmol) in CH2Cl2 (20.0 ml) was added 2,2,2-trifluoroethanamine (0.03 g, 0.31 mmol), PyBOP (0.17 g, 0.34 mmol) and DIPEA (0.15 ml, 0.93 mmol) at ambient temperature, and the reaction was stirred for 18 h. The reaction mixture was diluted with CH2Cl2 and washed with 3N HCl (2×20 mL), NaHCO3 (2×20 mL) and brine solution (2×). The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.11 g): mp 172-175° C.; 1H NMR (400 MHz, CDCl3) δ 8.83 (t, J=6.6 Hz, 1H), 8.42 (t, J=14.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (t, J=6.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.16-7.07 (m, 1H), 7.01-6.93 (m, 1H), 4.96-4.81 (m, 3H), 4.00-3.88 (m, 2H); ESIMS m/z 554.0 ([M−H]−).


Example 42: Preparation of 2-(4-Vinylbenzyl)isoindoline-1,3-dione (CI1)



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To a stirred solution of 1-(chloromethyl)-4-vinylbenzene (10 g, 66 mmol) in DMF (100 mL) was added potassium phthalimide (13.3 g, 72.1 mmol), and the resultant reaction mixture was heated at 70° C. for 16 h. The reaction mixture was diluted with H2O and extracted with CHCl3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Recrystallization from MEOH afforded the title compound as an off-white solid (8 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.83 (m, 2H), 7.71 (m, 2H), 7.39 (m, 4H), 6.65 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.21 (d, J=10.8 Hz, 1H), 4.82 (s, 2H); GCMS m/z 263.2 ([M]+); IR (thin film) 3420, 1133, 718 cm−1.


Example 43: Preparation of (E)-2-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI2)



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Using the procedure of Example 10 with 2-(4-vinylbenzyl)isoindoline-1,3-dione and 1-(1-bromoethyl)-3,5-dichlorobenzene as the starting materials, the title compound was isolated as an off-white solid (0.3 g, 40-50%): mp 142-145° C.; 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 7.74 (m, 2H), 7.42 (m, 2H), 7.36 (m, 3H), 7.27 (m, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m/z 488.17 ([M−H]−).


The following compound was made in accordance with the procedures disclosed in Example 43.


(E)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI3)



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The title compound was isolated as an off white solid (0.3 g, 56%): mp 145-146° C.; 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 7.74 (m, 2H), 7.42-7.31 (m, 6H), 6.58 (d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m/z 522.2 ([M−H]−); IR (thin film) 1716, 1110, 712 cm−1.


Prophetically, compounds CI4-CI5 (Table 1) could be made in accordance with the procedures disclosed in Example 43.


Example 44: Preparation of (E)-(4-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (CI6)



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To a stirred solution of (E)-2-(4-(3-(3,5-dichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3-dione (1.2 g, 2.45 mmol) in EtOH was added hydrazine hydrate (0.61 g, 12 mmol), and the resultant reaction mixture was heated at 90° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the crude title compound as a gummy liquid (0.9 g) which was used without further purification.


The following compounds were made in accordance with the procedures disclosed in Example 44.


(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)methanamine (CI7)



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The title compound was isolated and used without further purification.


Prophetically, compounds CI8-CI9 (Table 1) could be made in accordance with the procedures disclosed in Example 44.


Example 45: Preparation of 4-(Bromomethyl)-3-chlorobenzonitrile (CI10)



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To a stirred solution of 3-chloro-4-methylbenzonitrile (5 g, 25.4 mmol) in carbon tetrachloride (CCl4; 50 mL) under an argon atmosphere was added NBS (5.16 g, 29 mmol), and the mixture was degassed for 30 min. To this was added azobisisobutyronitrile (AIBN; 0.3 g, 1.8 mmol), and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, washed with H2O, and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (4.8 g, 68%): mp 87-88° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.59 (s, 2H), 4.60 (s, 2H); ESIMS m/z 229.77 ([M+H]+); IR (thin film) 2235, 752, 621 cm−1.


The following compounds were made in accordance with the procedures disclosed in Example 45.


4-(Bromomethyl)-3-(trifluoromethyl)benzonitrile (CI11)



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The title compound was isolated as an off-white gummy material (5 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 4.62 (s, 2H); ESIMS m/z 262.11 ([M−H]−); IR (thin film) 2236, 1132, 617 cm−1. 3-Bromo-4-(bromomethyl)benzonitrile (CI12)




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The title compound was isolated as an off-white solid (5 g, 67%): mp 82-83° C.; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.61 (m, 2H), 4.62 (s, 2H); EIMS m/z 272.90; IR (thin film) 2229, 618 cm−1.


4-(Bromomethyl)-3-fluorobenzonitrile (CI13)



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The title compound was isolated as an off-white solid (2 g, 60%): mp 79-81° C.; 1H NMR (400 MHz, CDCl3) δ 7.54 (t, J=8.0 Hz, 1H), 7.48 (dd, J=8.0 Hz, 8.0, 1H), 7.38 (dd, J=5 Hz, 1H), 4.5 (s, 2H); EIMS m/z 215.


Example 46: Preparation of 4-(Bromomethyl)-3-chlorobenzaldehyde (CI14)



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To a stirred solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0° C. was added dropwise diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 23.9 mL), and the reaction mixture was stirred at 0° C. for 1 h. 10 M HCl in H2O (5 mL) was added until the reaction mixture turned to a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 80%): mp 64-66° C.; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.92 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); ESIMS m/z 232.78 ([M+H]+).


The following compounds were made in accordance with the procedures disclosed in Example 46.


4-(Bromomethyl)-3-(trifluoromethyl)benzaldehyde (CI15)



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The title compound was isolated as a pale yellow low-melting solid (5 g, 60%): 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.19 (s, 1H), 8.09 (m, 1H), 7.81 (m, 1H), 4.61 (s, 2H); ESIMS m/z 265.04 ([M−H]−); IR (thin film) 1709, 1126, 649 cm−1.


3-Bromo-4-(bromomethyl)benzaldehyde (CI16)



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The title compound was isolated as a pale yellow solid (5 g, 62%): mp 94-95° C.; 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 8.05 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); EIMS m/z 275.90.


4-(Bromomethyl)-3-fluorobenzaldehyde (CI17)



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The title compound was isolated as an off-white solid (5 g, 61%): mp 43-45° C.; 1H NMR (400 MHz, CDCl3) δ 9.1 (s, 1H), 7.54 (t, J=8 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.38 (d, J=5 Hz, 1H), 4.5 (s, 2H); EIMS m/z 216.


Example 47: Preparation of 3-Chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (CI18)



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To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (3.8 g, 14 mmol) in DMF (40 mL) was added potassium phthalimide (3.54 g, 19.14 mmol), and the mixture was heated at 60° C. for 6 h. The reaction mixture was cooled to ambient temperature and diluted with H2O (100 mL). The solid obtained was separated by filtration and dried under vacuum to afford the title compound as a white solid (2.8 g, 60%): mp 123-126° C.; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s, 2H); ESIMS m/z 298.03 ([M−H]−).


The following compounds were made in accordance with the procedures disclosed in Example 47.


4-((1,3-Dioxoisoindolin-2-yl)-3-(trifluoromethyl)benzaldehyde (CI19)



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The title compound was isolated as an off white solid (1 g, 62%): mp 142-143° C.; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.15 (s, 1H), 7.91 (m, 2H), 7.80 (m, 3H), 7.27 (m, 1H), 5.19 (s, 2H); ESIMS m/z 332.03 ([M−H]−).


3-Bromo-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (CI20)



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The title compound was isolated as an off-white solid (0.5 g, 64%): mp 159-161° C.; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s, 2H); ESIMS m/z 314.00 ([M−CHO]−).


4-((1,3-Dioxoisoindolin-2-yl)-3-fluorobenzaldehyde (CI21)



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The title compound was isolated as a white solid (2 g, 60%): mp 154-156° C.; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.9 (m, 2H), 7.75 (m, 2H), 7.6 (m, 2H), 7.5 (t, J=7.6 Hz, 1H), 5.05 (s, 2H); EIMS m/z 283.1.


Example 48: Preparation of 2-(2-Chloro-4-vinylbenzyl)isoindoline-1,3-dione (CI22)



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To a stirred solution of 3-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (2.8 g, 8.2 mmol) in 1,4-dioxane (30 mL) were added K2CO3 (1.68 g, 12.24 mmol) and methyl triphenyl phosphonium bromide (4.37 g, 12.24 mmol) at ambient temperature. Then the resultant reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as a white solid (1.94 g, 70%): mp 141-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.70 (m, 2H), 7.41 (m, 1H), 7.21 (m, 2H), 6.71 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.23 (d, J=10.8 Hz, 1H), 4.92 (s, 2H); ESIMS m/z 298.10 ([M−H]−).


The following compounds were made in accordance with the procedures disclosed in Example 48.


2-(2-(Trifluoromethyl)-4-vinylbenzyl)isoindoline-1,3-dione (CI23)



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The title compound was isolated as a light brown solid (0.5 g, 60%): mp 134-135° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.71 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.65 (m, 1H), 5.80 (d, J=17.8 Hz, 1H), 5.19 (d, J=10.8 Hz, 1H), 5.09 (s, 2H); ESIMS m/z 332.10 ([M+H]+).


2-(2-Bromo-4-vinylbenzyl)isoindoline-1,3-dione (CI24)



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The title compound was isolated as an off white solid (0.5 g, 62%): mp 126-128° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.62 (s, 1H), 7.21 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.62 (m, 1H), 5.72 (d, J=17.8 Hz, 1H), 5.15 (d, J=10.8 Hz, 1H), 4.95 (s, 2H); EIMS m/z 341.10.


2-(2-Fluoro-4-vinylbenzyl)isoindoline-1,3-dione (CI25)



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The title compound was isolated as a white solid (0.5 g, 61%): mp 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.72 (m, 2H), 7.25 (m, 1H), 7.11 (m, 2H), 6.63 (m, 1H), 5.80 (d, J=17.6 Hz, 1H), 5.28 (d, J=10.8 Hz, 1H), 4.92 (s, 2H); EIMS m/z 282.08.


Example 49: Preparation of (E)-2-(2-Chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI26)



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To a stirred solution of 2-(2-chloro-4-vinylbenzyl)isoindoline-1,3-dione (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (3.48 g, 11.36 mmol), CuCl (112 mg, 1.13 mmol) and 2,2-bipyridyl (0.35 g). The resultant reaction mixture was degassed with argon for 30 min and then was stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in n-hexane) to afford the title compound as solid (1.3 g, 50%): mp 141-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 2H), 7.24 (m, 2H), 7.20 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.10 (m, 1H); ESIMS m/z 524.07 ([M+H]+).


The following compounds were made in accordance with the procedures disclosed in Example 49.


(E)-2-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI27)



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The title compound was isolated as a pale white solid (0.2 g, 55%): mp 128-129° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 3H), 7.22 (m, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H); ESIMS m/z 557.99 ([M+H]+).


(E)-2-(2-Chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI28)



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The title compound was isolated as an off white solid (0.2 g, 54%): mp 177-180° C.; 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 2H), 7.77 (m, 2H), 7.42 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.21 (m, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H); ESIMS m/z 540.08 ([M−H]−); IR (thin film) 1716 cm−1.


(E)-2-(2-Chloro-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI29)



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The title compound was isolated as an off-white solid (0.2 g, 59%): 1H NMR (400 MHz, CDCl3) δ 7.89 (m, 2H), 7.76 (m, 2H), 7.47 (m, 3H), 7.21 (m, 3H), 6.50 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 7.6 Hz, 1H), 4.97 (s, 2H), 4.11 (m, 1H); ESIMS m/z 522.27 ([M−H]−); IR (thin film) 3064, 1717, 1111, 715 cm−1.


(E)-2-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)-benzyl)isoindoline-1,3-dione (CI30)



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The title compound was isolated as an off-white solid (0.2 g, 54%): mp 141-142° C.; 1H NMR (400 MHz, CDCl3) 7.94 (m, 2H), 7.80 (m, 2H), 7.69 (s, 1H), 7.44 (m, 1H), 7.38 (m, 1H), 7.24 (m, 2H), 7.19 (m, 1H), 6.60 (d, J=16.0 Hz, 1H), 6.39 (dd, J=16.0, 7.6 Hz, 1H), 5.10 (s, 2H), 4.11 (m, 1H); ESIMS m/z 556.00 ([M−H]−).


(E)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)-benzyl)isoindoline-1,3-dione (CI31)



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The title compound was isolated as an off-white solid (0.2 g, 56%): mp 130-132° C.; 1H NMR (400 MHz, CDCl3) δ 7.94 (m, 2H), 7.80 (m, 2H), 7.69 (s, 1H), 7.44 (m, 3H), 7.19 (m, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 7.6 Hz, 1H), 5.10 (s, 2H), 4.12 (m, 1H); ESIMS m/z 589.57 ([M−2H]−).


(E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3-dione (CI32)



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The title compound was isolated as a pale yellow solid (0.2 g, 55%): mp 160-162° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.62 (s, 1H), 7.39 (s, 2H), 7.24 (m, 1H), 7.16 (m, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 4.98 (s, 2H), 4.12 (m, 1H); ESIMS m/z 599.78 ([M−H]−).


(E)-2-(2-Fluoro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3-dione (CI33)



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The title compound was isolated as an off-white solid (0.2 g, 55%): mp 72-74° C.; 1H NMR (400 MHz, CDCl3) δ 7.88 (m, 2H), 7.74 (m, 2H), 7.38 (s, 2H), 7.34 (m, 1H), 7.18 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 4.91 (s, 2H), 4.08 (m, 1H); ESIMS m/z 539.89 ([M−H]−); IR (thin film) 1773 cm−1.


Prophetically, compounds CI34-CI41 (Table 1) could be made in accordance with the procedures disclosed in Example 49.


Example 50: Preparation of (E)-(2-Chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (CI42)



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To a stirred solution of (E)-2-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (0.4 g, 0.76 mmol) in EtOH was added hydrazine hydrate (0.38 g, 7.6 mmol), and the resultant reaction mixture was heated at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a gummy liquid (0.3 g), which was carried on to the next step without further purification.


The following compounds were made in accordance with the procedures disclosed in Example 50.


(E)-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine (CI43)



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The product obtained in this reaction was carried on to the next step without further purification.


(E)-(2-Chloro-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-methanamine (CI44)



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The product obtained in this reaction was carried on to the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=8.4 Hz, 2H), 7.39 (m, 2H), 7.23 (m, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 7.6 Hz, 1H), 4.12 (m, 1H), 3.90 (s, 2H); ESIMS m/z 391.90 ([M−H]−); IR (thin film) 3370, 3280, 1111, 817 cm−1.


(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)-phenyl)methanamine (CI45)



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The title compound was isolated as a gummy material. The product obtained in this reaction was carried on to the next step without further purification.


(E)-(2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-methanamine (CI46)



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The title compound was isolated as a gummy material: The product obtained in this reaction was carried on to the next step without further purification.


(E)-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine (CI47)



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The title compound was isolated as a gummy material. The product obtained in this reaction was carried on to the next step without further purification.


(E)-(2-Fluoro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine (CI48)



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The title compound was isolated as a gummy material: 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 7.33 (t, J=7.6 Hz, 1H), 7.13 (m, 2H), 6.56 (d, J=16.0 Hz, 1H), 6.33 (dd, J=16.0, 7.6 Hz, 1H), 4.08 (m, 1H), 3.90 (s, 2H); ESIMS m/z 413.84 ([M+H]+); IR (thin film) 3368, 3274, 1114, 808 cm−1.


Prophetically, compounds CI49-CI57 (Table 1) could be made in accordance with the procedures disclosed in Example 50.


Example 51: Preparation of 3-Chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde (CI58)



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To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (2 g, 9 mmol) in N,N-dimethylacetamide (DMA; 20 mL) was added K2CO3 (2.36 g, 17.16 mmol) and 2-aminopyridine (0.84 g, 8.58 mmol), and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as off-white solid (1.05 g, 50%): mp 122-123° C.; 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.72 (d, J=4.8 Hz, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.4 (m, 1H), 6.64 (d, J=3.9 Hz, 1H), 6.38 (d, J=6.3 Hz, 1H), 5.04 (br s, 1H), 4.71 (s, 2H); ESIMS m/z 246.97 ([M+H]+).


Example 52: Preparation of N-(2-Chloro-4-vinylbenzyl)pyridin-2-amine (CI59)



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To a stirred solution of 3-chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde (1 g, 4. mmol) in 1,4-dioxane (20 mL) were added K2CO3 (0.84 g, 6.09 mmol) and methyl triphenyl phosphonium bromide (2.17 g, 6.09 mmol) at ambient temperature. Then the resultant reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 10% EtOAc in n-Hexane) to afford the title compound as a white solid (0.5 g, 50%): mp 119-121° C.; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.42-7.40 (m, 3H), 7.26 (s, 1H), 6.66 (m, 2H), 6.36 (d, J=6.3 Hz, 1H), 5.75 (d, J=13.2 Hz, 1H), 4.92 (br s, 1H), 4.60 (s, 2H); ESIMS m/z 245.05 ([M+H]+).


Example 53: Preparation of Ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (CI60)



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Ethyl 2-(diphenylmethyleneamino)acetate (10.2 g, 38.2 mmol) was added to sodium hydride (NaH; 3.18 g, 133.52 mmol) in DMF (50 mL) at 0° C., and the mixture was stirred for 30 min. To this was added 5-bromo-2,3-dichloropyridine (12.9 g, 57.23 mmol), and the reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was quenched with 2 N HCl solution and then stirred for 4 h at ambient temperature. The mixture was extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as a liquid (1.3 g, 20%): 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.89 (s, 1H), 5.09 (s1H), 4.23 (m, 2H), 2.27 (br s, 2H), 1.26 (m, 3H); ESIMS m/z 293.05 ([M+H]+); IR (thin film) 3381, 3306, 1742, 759, 523 cm−1.


Example 54: Preparation of (5-Bromo-3-chloropyridin-2-yl)methanamine hydrochloride (CI61)



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A stirred solution of ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (0.5 g, 1.7 mmol) in 3 N HCl (25 mL) was heated at reflux for 4 h. The reaction mixture was washed with diethyl ether and H2O. The combined ether layer was concentrated under reduced pressure to afford the title compound as an off-white solid (400 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.70 (br s, 2H), 8.45 (s, 1H), 4.56 (m, 2H); ESIMS m/z 221.15 ([M+H]+).


Example 55: Preparation of 2-((5-Bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (CI62)



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To a stirred solution of (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride (0.3 g, 1.4 mmol) in toluene (40 mL) was added TEA (0.41 g, 4.08 mmol) and phthalic anhydride (0.24 g, 1.63 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a white solid (0.25 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.45 (s, 1H), 7.88 (m, 2H), 7.74 (m, 2H), 4.56 (m, 2H); ESIMS m/z 349 ([M−H]−); IR (thin film) 3307, 1665, 1114, 813 cm−1.


Example 56: Preparation of 2-((3-Chloro-5-vinylpyridin-2-yl)methyl)isoindoline-1,3-dione (CI63)



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To a stirred solution of 2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (0.23 g, 0.65 mmol) in toluene (10 mL) were added Pd(PPh3)4(3.7 mg, 0.003 mmol), K2CO3 (0.269 g, 1.95 mmol) and vinyl boronic anhydride pyridine complex (0.78 g, 3.28 mmol), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as an off-white solid (0.2 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.72 (m, 1H), 6.63 (m, 1H), 5.79 (d, J=16.0 Hz, 1H), 5.39 (d, J=16.0 Hz, 1H), 5.12 (s, 2H); ESIMS m/z 299.20 ([M+H]+).


Example 57: Preparation of (E)-2-((3-Chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichloro-phenyl)but-1-en-1-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (CI64)



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To a stirred solution of 2-((3-chloro-5-vinylpyridin-2-yl)methyl)isoindoline-1,3-dione (0.35 g, 1.17 mmol) in 1,2-dichlorobenzene (10 mL) were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.8 g, 2.3 mmol), CuCl (23 mg, 0.12 mmol), 2,2-bipyridyl (0.073 g, 0.234 mmol), and the reaction mixture was heated at 180° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a liquid (0.4 g, 50%): mp 79-82° C.; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.36 (s, 2H), 6.51 (d, J=15.6 Hz, 1H), 6.32 (dd, J=15.6, 8.0 Hz, 1H), 5.30 (s, 2H), 4.13 (m, 1H); ESIMS m/z 559 ([M+H]+).


Example 58: Preparation of (E)-(3-Chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methanamine (CI65)



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To a stirred solution of (E)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (200 mg, 0.358 mmol) in EtOH (5 mL) was added hydrazine hydrate (89.6 mg, 1.79 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2. The organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (100 mg). The product obtained in this reaction was carried on to the next step without further purification.


Example 59: Preparation of 4-(Bromomethyl)-1-naphthonitrile (CI66)



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To a stirred solution of 4-methyl-1-naphthonitrile (5 g, 30 mmol) in CCl4 (50 mL) under argon atmosphere was added NBS (6.06 g, 34.09 mmol), and the reaction mixture was degassed for 30 min. AIBN (0.3 g, 2.1 mmol) was added, and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, diluted with H2O and extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 52%): mp 131-133° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (m, 1H), 8.24 (m, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.78 (m, 2H), 7.62 (d, J=8.0 Hz, 1H), 4.95 (s, 2H); ESIMS m/z 245.92 ([M+H]+); IR (thin film) 2217 cm−1.


Example 60: Preparation of 4-(Bromomethyl)-1-naphthaldehyde (CI67)



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To a stirred solution of 4-(bromomethyl)-1-naphthonitrile (8 g, 33 mmol) in toluene (100 mL) at 0° C. was added dropwise DIBAL-H (1.0 M solution in toluene; 43 mL), and the reaction mixture was stirred at 0° C. for 1 h. 3 N HCl in H2O (50 mL) was added to the mixture until it became a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in petroleum ether) afforded the title compound as a white solid (7 g, 88%): mp 115-116° C.; 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 9.35 (m, 1H), 8.22 (m, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.75 (m, 3H), 4.95 (s, 2H); ESIMS m/z 248.88 ([M+H]+).


Example 61: Preparation of 4-((1,3-Dioxoisoindolin-2-yl)methyl)-1-naphthaldehyde (CI68)



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To a stirred solution of 4-(bromomethyl)-1-naphthaldehyde (7 g, 28. mmol) in DMF (100 mL) was added potassium phthalimide (7.3 g, 39.5 mmol), and the mixture was heated at 85° C. for 2 h. The reaction mixture was cooled to ambient temperature and diluted with H2O (100 mL). The obtained solid was separated by filtration and dried under vacuum to afford the title compound as a white solid (8.8 g, 98%): mp 190-192° C.; 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.25 (m, 1H), 8.41 (m, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.95 (m, 4H), 7.80 (m, 4H), 7.61 (m, 4H), 5.39 (s, 2H); ESIMS m/z 316.09 ([M+H]+); IR (thin film) 1708 cm−1.


Example 62: Preparation of 2-((4-Vinylnaphthalen-1-yl)methyl) isoindoline-1,3-dione (CI69)



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To a stirred solution of 4-((1,3-dioxoisoindolin-2-yl)methyl)-1-naphthaldehyde (9 g, 28.5 mmol) in 1,4-dioxane (100 mL) were added K2CO3 (6 g, 42.8 mmol) and methyl triphenyl phosphonium bromide (15.3 g, 35.7 mmol) at ambient temperature. The reaction mixture was heated at 100° C. for 14 h and then was cooled to ambient temperature. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (6 g, 67%): mp 146-147° C.; 1H NMR (400 MHz, CDCl3) δ 8.35 (m, 2H), 7.95 (m, 4H), 7.65 (m, 4H), 7.39 (m, 1H), 5.81 (m, 1H), 5.45 (m, 1H), 5.21 (s, 2H); ESIMS m/z 314.13 ([M+H]+).


Example 63: Preparation of (E)-2-((4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione (CI70)



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To a stirred solution of 2-((4-vinylnaphthalen-1-yl)methyl)isoindoline-1,3-dione (1.5 g, 4.79 mmol) in 1,2-dichlorobenzene (15 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,4,5-trichlorobenzene (3.2 g, 9.5 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (0.149 g, 0.95 mmol), and the resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 14 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (1.5 g, 56%): mp 158-160° C.; 1H NMR (400 MHz, CDCl3) δ 8.40 (m, 1H), 7.89 (m, 2H), 7.74 (m, 2H), 7.64 (m, 2H), 7.58 (m, 2H), 7.46 (s, 2H), 7.36 (m, 2H), 6.31 (m, 1H), 5.30 (s, 2H), 4.21 (m, 1H); ESIMS m/z 572.08 ([M−H]−).


Example 64: Preparation of (E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (CI71)



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To a stirred solution of (E)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione (0.4 g, 0.7 mmol) in EtOH was added hydrazine hydrate (0.18 g, 3.5 mmol), and the resultant reaction mixture was heated at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, and the solution was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The title compound was isolated as a gummy liquid (150 mg, 50%). The product obtained in this reaction was carried on to the next step without further purification.


Example 65: Preparation of 2-((4-Bromophenyl)amino)isoindoline-1,3-dione (CI72)



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To a stirred solution of (4-bromophenyl)hydrazine hydrochloride (0.5 g, 2.2 mmol) in glacial acetic acid (8 mL) was added phthalic anhydride (0.398 g, 2.690 mmol), and the reaction mixture was stirred at 130° C. for 1 h under a nitrogen atmosphere. The reaction mixture was quenched with satd aq. NaHCO3 solution and filtered to give a solid. Purification by column chromatography (SiO2, 0-10% EtOAc in petroleum ether) afforded the title compound as a solid (60 mg, 84%): mp 205-206° C.; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.99 (m, 4H), 7.32 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H); ESIMS m/z 314.95 ([M−H]−).


Example 66: Preparation of 2-((4-Vinylphenyl)amino)isoindoline-1,3-dione (CI73)



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To a solution of 2-(4-bromophenylamino)isoindoline-1,3-dione (2 g, 6. mmol) in 1,2-dimethoxyethane (20 mL) and H2O (4 mL) were added vinyl boronic anhydride pyridine complex (4.57 g, 18.98 mmol) and K2CO3 (1.3 g, 9.5 mmol) followed by Pd(PPh3)4(0.219 g, 0.189 mmol). The resultant reaction mixture was heated at 150° C. in a microwave for 30 min and then was concentrated under reduced pressure. Purification by column chromatography (SiO2, 15% EtOAc in petroleum ether) afforded the title compound as a solid (200 mg, 13%): mp 174-176° C.; 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.94 (m, 4H), 7.29 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 6.61 (m, 1H), 5.61 (d, J=17.6 Hz, 1H), 5.05 (d, J=11.2 Hz, 1H); ESIMS m/z 263.18 ([M−H]−).


Example 67: Preparation of (E)-2-((4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)amino)isoindoline-1,3-dione (CI74)



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To a stirred solution of 2-(4-vinylphenylamino)isoindoline-1,3-dione (0.3 g, 1.1 mmol) in 1,2-dichlorobenzene (5 mL) were added CuCl (0.022 g, 0.273 mmol), 2,2-bipyridyl (0.07 g, 0.46 mmol) and 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.77 g, 2.27 mmol). The reaction mixture was degassed with argon for 30 min and was heated at 180° C. for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 0-30% EtOAc in petroleum ether) to afford the title compound as a solid (450 mg, 75%): mp 187-189° C.; 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.96 (m, 4H), 7.82 (s, 2H), 7.37 (d, J=8.8 Hz, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.61 (m, 2H), 6.58 (m, 1H), 4.59 (m, 1H); ESIMS m/z 523.05 ([M−H]−).


Example 68: Preparation of (E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydrazine (CI75)



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To a stirred solution of (E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenylamino)isoindoline-1,3-dione (0.16 g, 0.31 mmol) in EtOH (5 mL), was added hydrazine hydrate (0.076 g, 1.52 mmol), and the reaction mixture was heated at 85° C. for 1 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a solid (0.08 g, 66%) which was carried on to the next step without further purification.


Example 69: Preparation of 2-(4-Vinylphenoxy)isoindoline-1,3-dione (CI76)



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To a stirred solution of 4-vinylphenylboronic acid (2 g, 13 mmol), 2-hydroxyisoindoline-1,3-dione (3.63 g, 24.53 mmol), and CuCl (1.214 g 12.26 mmol) in 1,2-dichloroethane (50 mL) was added pyridine (1.065 g, 13.48 mmol), and the resultant reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was diluted with H2O and extracted with CHCl3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (2 g, 63%): mp 129-131° C.; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=2.0 Hz, 2H), 7.82 (d, J=3.2 Hz, 2H), 7.38 (d, J=2.0 Hz, 2H), 7.14 (d, J=2.0 Hz, 2H), 6.70 (m, 1H), 5.83 (d, J=16.0 Hz, 1H), 5.22 (d, J=10.8 Hz, 1H); ESIMS m/z 266.12 ([M+H]+).


Example 70: Preparation of (E)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenoxy)isoindoline-1,3-dione (CI77)



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To a stirred solution of 2-(4-vinylphenoxy)isoindoline-1,3-dione (0.3 g, 1.1 mmol) in 1,2-dichlorobenzene (10 mL) was added 1-(1-bromoethyl)-3,4,5-trichlorobenzene (769 mg, 2.26 mmol), CuCl (22 mg, 0.22 mmol) and 2,2-bipyridyl (35 mg, 0.44 mmol), and the resultant reaction mixture was degassed with argon for 30 min and heated to 180° C. for 24 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in petroleum ether) to afford the title compound as a solid (0.29 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 1H), 7.62 (m, 2H), 7.50 (m, 1H), 7.40 (s, 2H), 7.12 (s, 1H), 6.90 (m, 2H), 6.60 (m, 2H), 6.20 (m, 1H), 4.08 (m, 1H); ESIMS m/z 524.09 ([M−H]−).


Example 71: Preparation of (E)-O-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydroxylamine (CI78)



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To a stirred solution of (E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenoxy)isoindoline-1,3-dione (0.2 g, 0.4 mmol) in EtOH was added hydrazine hydrate (0.1 g, 1.9 mmol), and the resultant reaction mixture was heated at 90° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2. washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a gummy liquid (0.08 g, 53%): 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 6.98 (s, 1H), 6.82 (s, 2H), 6.48 (m, 1H), 6.20 (m, 1H), 5.02 (s, 1H), 4.08 (m, 1H); ESIMS m/z 394.94 ([M−H]−).


Example 72: Preparation of (E)-N-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)benzyl)acetamide (CC1)



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To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.3 g, 0.8 mmol) in CH2Cl2 (10 mL) was added acetic anhydride (0.12 mL, 1.14 mmol), and TEA (0.217 mL, 1.52 mmol), and the resultant reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% ethyl acetate in hexane) afforded the title compound as an off-white solid (0.2 g, 60%) mp 107-109° C.; 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 5.75 (br s, 1H), 4.46 (d, J=6 Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H); ESIMS m/z 402.00 ([M+H]+).


Compounds CC2-CC6 in Table 1 were made in accordance with the procedures disclosed in Example 72. In addition, compound DC56 in Table 1 was made from compound DC55 in accordance with the procedures disclosed in Example 72.


Example 73: Preparation of (E)-N-(2-Chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)acetamide (CC7)



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To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.3 g, 0.8 mmol) in DMF (5 mL) was added 2,2,2-trifluoropropanoic acid (97 mg, 0.76 mmol), HOBt.H2O (174 mg, 1.14 mmol) and EDC.HCl (217 mg, 1.14 mmol) and DIPEA (196 mg, 1.52 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; ethyl acetate in hexane (30-50% afforded the title compound as an off-white solid (0.2 g, 60%): mp 127-128° C.; 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 4H), 7.24 (m, 2H), 6.53 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 5.86 (br s, 1H), 4.51 (d, J=6.0 Hz, 2H), 4.05 (m, 1H), 2.02 (s, 3H); ESIMS m/z 436.03 ([M+H]+).


Compounds CC8-CC28 in Table 1 were made in accordance with the procedures disclosed in Example 73.


Example 74: Preparation of (E)-N-(Pyridin-2-ylmethyl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide (CC29)



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Step 1: (E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)methanamine

(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)phenyl)methanamine (0.46 g, 1 mmol) was dissolved in MEOH (3 mL). To this was added pyridine-2-carbaldehyde (0.107 g, 1 mmol). The reaction mixture was stirred for 1 h. After 1 h, NaBH4 (0.076 g, 2 mmol) was added and left at ambient temperature for 3 h. The reaction mixture was concentrated to give an oily residue. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a pale yellow liquid (0.22 g, 40%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.8 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 4.02 (s, 2H), 3.96 (s, 2H); ESIMS m/z 552.95 ([M+H]+); IR (thin film) 3338, 1114, 808 cm−1.


Step 2: (E)-N-(Pyridin-2-ylmethyl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide

(E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzyl)methanamine (0.27 g, 0.05 mmol) was taken up in CH2Cl2 (3 mL). To this was added TEA (0.14 mL, 0.1 mmol). The reaction mixture was stirred for 10 min. After 10 min, the reaction mixture was cooled to 0° C., and cyclopropylcarbonyl chloride (0.08 mL, 0.075 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h and then was washed with H2O and satd aq NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated to obtain pale yellow gummy material (0.15 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.6 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 5.02 (s, 1H), 4.8 (s, 1H), 4.8 (d, J=10 Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H); ESIMS m/z 620.86 ([M−H]−); IR (thin film) 1645, 1115, 808 cm−1.


Example 75: Preparation of (E)-N-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3-(methylsulfonyl)propanamide (CC30)



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(E)-N-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3-(methylthio)propanamide (0.15 g, 0.28 mmol) was treated with oxone (0.175 g, 0.569 mmol) in 1:1 acetone:water (20 mL) for 4 h at ambient temperature. The acetone was evaporated to obtain a white solid (0.095 g, 60%): mp 101-104° C.; 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 4H), 7.24 (m, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 6.12 (br s, 1H), 4.53 (m, 2H), 4.10 (m, 1H), 3.42 (m, 2H), 2.91 (s, 3H), 2.78 (m, 2H); ESIMS m/z 559.75 ([M−H]−).


Example 76: Preparation of (E)-1-(2-Chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)-3-ethylurea (CC31)



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To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and ethylisocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.141 g, 60%): mp 177-178° C.; 1H NMR (400 MHz, CDCl3) δ 7.58 (m, 2H), 7.41 (m, 3H), 7.24 (m, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 4.70 (br s, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); ESIMS m/z 463 ([M−H]−).


Compounds CC32-CC35 in Table 1 were made in accordance with the procedures disclosed in Example 76.


Example 77: Preparation of (E)-3-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-1,1-dimethylurea (CC36)



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To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and N,N-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M−H]−); IR (thin film) 3350, 1705, 1114, 808 cm−1.


Example 78: Preparation of (E)-1-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3-ethylthiourea (CC37)



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To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and ethyl isothicyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.14 g, 60%): mp 88-91° C.; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=8 Hz, 1H), 7.41 (d, J=7.2 Hz, 2H), 7.26 (m, 2H), 6.50 (d, J=16 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 6.0 (br s, 1H), 5.73 (br s, 1H), 4.80 (br s, 2H), 4.09 (m, 1H), 1.23 (m, 3H); ESIMS m/z 515.01 ([M+H]+).


Compound CC38 in Table 1 was made in accordance with the procedures disclosed in Example 78.


Example 79: Preparation of (E)-tert-Butyl (2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)-3-ethylurea (CC39)



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To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and di-tert-butyl dicarbonate (0.163 mL, 0.75 mmol), and the reaction mixture was stirred for 4 h at ambient temperature. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 10-20% EtOAc in hexane) afforded the title compound as a white solid (0.147 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 1.53 (s, 9H); ESIMS m/z 526.09 ([M−H]−); IR (thin film) 3350, 1705, 1114, 808 cm−1.


Compound CC40 in Table 1 was made in accordance with the procedures disclosed in Example 79.


Example 80: Preparation of (E)-Methyl 2-((2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)amino)-2-oxoacetate (CC41)



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To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in hexane) afforded the title compound as a solid (0.12 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.60 (d, J=4.4 Hz, 2H), 4.18 (m, 1H), 3.85 (s, 3H); ESIMS m/z 512.22 ([M−H]−); IR (thin film) 1740, 1701, 1114, 808 cm−1.


Example 81: Preparation of (E)-N1-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-N2-(2,2,2-trifluoroethyl)oxalamide (CC42)



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To a stirred solution of 2,2,2-trifluoroethylamine hydrochloride (0.1 g, 0.77 mmol) in CH2Cl2(10 mL) was added dropwise trimethylaluminum (2 M solution in toluene; 0.39 mL, 0.77 mmol), and the reaction mixture was stirred at 25° C. for 30 min. A solution of (E)-methyl 2-((2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-2-oxoacetate (0.2 g, 0.38 mmol) in CH2Cl2(5 mL) was added dropwise to the reaction mixture at 25° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; 20%-40% EtOAc in n-hexane) to afford the title compound (0.13 g, 60%): mp 161-163° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.45 (br s, 2H), 7.90 (s, 2H), 7.75 (s, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 6.93 (m, 1H), 6.75 (m, 1H), 4.80 (m, 1H), 4.40 (s, 2H), 3.90 (s, 2H); ESIMS m/z 578.96 ([M−H]−).


Example 82: Preparation of (E)-N-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)pyridin-2-amine (CC43)



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To a stirred solution of N-(2-chloro-4-vinylbenzyl)pyridin-2-amine (0.3 g, 1.22 mmol) in 1,2-dichlorobenzene (5 mL) were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.83 g, 2.44 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (76 mg, 0.48 mmol). The resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as an off-white solid (0.2 g, 35%): mp 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=4.0 Hz, 1H), 7.40 (m, 5H), 7.22 (m, 1H), 6.61 (m, 2H), 6.35 (m, 2H), 4.94 (br s, 1H), 4.61 (d, J=6.4 Hz, 2H), 4.11 (m, 1H); ESIMS m/z 505.39 ([M+H]+).


Example 83: Preparation of (E)-N-((3-Chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-but-1-en-1-yl)pyridin-2-yl)methyl)-3,3,3-trifluoropropanamide (CC44)



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To a stirred solution of (E)-(3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methanamine (0.1 g, 0.2 mmol) in CH2Cl2 (5 mL) were added 3,3,3-trifluoropropanoic acid (45 mg, 0.350 mmol), EDC.HCl (67 mg, 0.350 mmol), HOBt.H2O (71 mg, 0.467 mmol) and DIPEA (60.2 mg, 0.467 mmol), and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2 and washed with H2O. The combined CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) afforded the title compound as a pale yellow liquid (30 mg, 35%): 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.77 (s, 1H), 7.47 (br s, 1H), 7.40 (s, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 8.0 Hz, 1H), 4.68 (d, J=4.0 Hz, 2H), 4.14 (m, 1H), 3.24 (q, J=10.8 Hz, 2H); ESIMS m/z 536.88 ([M−H]−); IR (thin film) 3320, 1674, 1114, 808.


Compound CC45 in Table 1 was made in accordance with the procedures disclosed in Example 83.


Example 84: Preparation of (E)-3,3,3-Trifluoro-N-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)propanamide (CC46)



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To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2Cl2 (8 mL) were added 3,3,3-trifluoropropanoic acid (0.032 g, 0.24 mmol), HOBt.H2O (52 mg, 0.33 mmol), EDC.HCl (0.065 g, 0.33 mmol) and DIPEA (0.044 g, 0.45 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc (3×30 mL). The combined EtOAc layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as a gummy material (60 mg, 50%): mp 151-153° C.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 1H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (m, 1H), 6.42 (m, 1H), 5.92 (br s, 1H), 4.92 (m, 2H), 4.24 (m, 1H), 3.12 (m, 2H); ESIMS m/z 554.04 ([M−H]−).


Compounds CC47-CC48 in Table 1 were made in accordance with the procedures disclosed in Example 84.


Example 85: Preparation of (E)-1-Ethyl-3-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)urea (CC49)



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To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2Cl2 at 0° C. were added TEA (0.064 mL, 0.44 mmol) and ethylisocyanate (0.023 mL, 0.33 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30% EtOAc in hexane) afforded the title compound as a solid (0.07 g, 60%): mp 84-87° C.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 1H), 7.98 (m, 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 4.6 (br s, 1H), 4.24 (m, 1H), 3.21 (m, 2H), 1.2 (t, J=4.6 Hz, 3H); ESIMS m/z 515.33 ([M+H]+).


Example 86: Preparation of (E)-N′-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)cyclopropanecarbohydrazide (CC50)



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To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydrazine (0.1 g, 0.3 mmol) in CH2Cl2 (10 mL) was added DIPEA (65 mg, 0.51 mmol), HOBt.H2O (59 mg, 0.38 mmol), EDC.HCl (73 mg, 0.38 mmol) and cyclopropanecarbonyl chloride (0.024 g, 0.28 mmol), and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with satd aq NaHCO3 solution and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 5-25% EtOAc in petroleum ether) afforded the title compound as a solid (65 mg, 55%): mp 138-140° C.; 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 7.90 (s, 1H), 7.84 (s, 2H), 7.34 (d, J=8.4 Hz, 2H), 6.65 (d, J=15.6 Hz, 1H), 6.61 (m, 1H), 6.57 (s, 1H), 6.48 (dd, J=15.6, 8.8 Hz, 1H), 4.74 (m, 1H), 1.64 (m, 1H), 0.75 (m, 4H); ESIMS m/z 461.32 ([M−H]−).


Compound CC51 in Table 1 was made in accordance with the procedures disclosed in Example 86.


Example 87: Preparation of (E)-N-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenoxy)cyclopropanecarboxamide (CC52)



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To a stirred solution of (E)-O-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydroxylamine (0.15 g, 0.38 mmol) in CH2Cl2 (5 mL) was added EDC.HCl (0.109 g, 0.569 mmol), HOBt.H2O (0.087 g, 0.569 mmol), DIPEA (0.097 g, 0.758 mmol) and cyclopropanecarboxylic acid (0.049 g, 0.569 mmol). The resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O and extracted with CHCl3 (35 mL) The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 20% EtOAc in hexane) afforded the title compound as a brown liquid (0.06 g, 34%): 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.85 (m, 1H), 6.45 (m, 1H), 6.65 (m, 1H), 6.20 (m, 1H), 5.55 (s, 1H), 4.08 (m, 1H), 1.90 (m, 1H), 1.30-1.10 (m, 4H); ESIMS m/z 464.87 ([M−H]−).


Compound CC53 in Table 1 was made in accordance with the procedures disclosed in Example 87.


Example 88: Preparation of (Z)-3,3,3-Trifluoro-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)propanamide (CC54)



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A silicon borate vial was charged with (E)-3,3,3-trifluoro-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)propanamide (133 mg, 0.269 mmol) and dimethyl sulfoxide (DMSO; 10 mL). The mixture was placed within 0.6 to 1 meter (m) of a bank of eight 115 watt Sylvania FR48T12/350BL/VHO/180 Fluorescent Tube Black Lights and four 115 watt Sylvania (daylight) F48T12/D/VHO Straight T12 Fluorescent Tube Lights for 72 h. The mixture was concentrated in vacuo and purified by reverse phase chromatography to give the title compound as a colorless oil (11 mg, 8%): 1H NMR (300 MHz, CDCl3) δ 7.28 (s, 2H), 7.25 (m, 2H), 7.10 (d, J=8.0 Hz, 2H), 6.89 (d, J=11.4 Hz, 1H), 6.07 (br s, 1H), 6.01 (m, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.34 (m, 1H), 3.12 (q, J=7.5 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 162.44, 137.20, 135.38, 135.23, 134.82, 134.68, 131.71, 129.00, 128.80, 128.69, 128.10, 127.96, 122.63, 76.70, 47.33 (q, J=28 Hz), 43.59, 42.12 (q, J=30 Hz); ESIMS m/z 504 ([M+H]+).


Compounds DC46, AC93. AC94 in Table 1 were made in accordance with the procedures disclosed in Example 88.


Example 89: Preparation of 1-(1-Bromo-2,2,2-trifluoroethyl)-3-chlorobenzene (DI2)



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The title compound was synthesized in two steps via 1-(3-chlorophenyl)-2,2,2-trifluoroethanol (DI1, prepared as in Step 1, Method B in Example 1); isolated as a colorless viscous oil (1.5 g, 75%): 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.42-7.35 (m, 3H), 5.02 (m, 1H), 2.65 (br s, 1H)) and Step 2 in Example 1 and isolated (0.14 g, 22%): 1H NMR (400 MHz, CDCl3) δ 7.50 (br s, 1H), 7.42-7.35 (m, 3H), 5.07 (m, 1H).


The following compounds were made in accordance with the procedures disclosed in Example 89.


(1-Bromo-2,2,2-trifluoroethyl)benzene (DI4)



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2,2,2-Trifluoro-1-phenylethanol (DI3) was isolated (10 g, 80%): 1H NMR (300 MHz, CDCl3) δ 7.48 (m, 2H), 7.40 (m, 3H), 5.02 (m, 1H), 2.65 (d, J=7.1 Hz, 1H). The title compound (DI4) was isolated as a liquid (8.0 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.50 (m, 2H), 7.40 (m, 3H), 5.00 (q, J=7.5 Hz, 1H).


1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dimethylbenzene (DI20)



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1-(3,5-Dimethylphenyl)-2,2,2-trifluoroethanol (DI19) was isolated an off white solid: 1H NMR (400 MHz, CDCl3) δ 7.05 (s, 2H), 7.02 (s, 1H), 4.95 (m, 1H), 2.32 (s, 6H); ESIMS m/z 204 ([M]−). The title compound (DI20) was isolated (3.0 g, 51%).


1-(1-Bromo-2,2,2-trifluoroethyl)-2,4-dichlorobenzene (DI22)



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1-(2,4-Dichlorophenyl)-2,2,2-trifluoroethanol (DI21) was isolated as an off white powder (5.3 g, 61%): mp 49-51° C.; 1H NMR (400 MHz, CDCl3) δ 7.62-7.66 (d, 1H), 7.42-7.44 (d, 1H), 7.32-7.36 (d, 1H), 5.6 (m, 1H), 2.7 (s, 1H); ESIMS m/z 244 ([M]+). The title compound (DI22) was isolated (3.2 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.62-7.72 (m, 1H), 7.4-7.42 (m, 1H), 7.3-7.38 (m, 1H), 5.7-5.8 (m, 1H).


1-(1-Bromo-2,2,2-trifluoroethyl)-2,3-dichlorobenzene (DI24)



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1-(2,3-Dichlorophenyl)-2,2,2-trifluoroethanol (DI23) was isolated as a pale yellow oil (5.2 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.62-7.64 (d, 1H), 7.52-7.54 (m, 1H), 7.29-7.33 (t, 1H), 5.6-5.76 (m, 1H), 2.7 (s, 1H); ESIMS m/z 243.9 ([M]+). The title compound (DI24) was isolated as an oil (8.7 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.62-7.71 (m, 1H), 7.44-7.52 (m, 1H), 7.27-7.3 (s, 1H), 5.81-5.91 (m, 1H).


2-(1-Bromo-2,2,2-trifluoroethyl)-1,4-dichlorobenzene (DI26)



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1-(2,5-Dichlorophenyl)-2,2,2-trifluoroethanol (DI25) was isolated as a yellow oil (4.1 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.68-7.7 (s, 1H), 7.3-7.37 (m, 2H), 5.51-5.6 (m, 1H), 2.7 (s, 1H); ESIMS m/z 244 ([M]+)). The title compound (DI26) was isolated (3.0 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.7-7.78 (m, 1H), 7.3-7.4 (m, 2H), 5.7-5.8 (m, 1H).


1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-bis(trifluoromethyl)benzene (DI28)



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1-(3,5-Bis(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (DI27) was isolated (3.8 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.98 (m, 3H), 5.25 (m, 1H), 3.2 (br, 1H); ESIMS m/z 312.2 ([M]+). The title compound (DI28) was prepared and carried on crude.


1-(1-Bromo-2,2,2-trifluoroethyl)-2,3,5-trichlorobenzene (DI30)



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2,2,2-Trifluoro-1-(2,3,5-trichlorophenyl)ethanol (DI29) was isolated as a white solid (4.0 g, 60%): mp 113-115° C.; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 1H), 7.50 (d, 1H), 5.60-5.70 (m, 1H), 2.75 (s, 1H); ESIMS m/z 278.0 ([M+]). The title compound (DI30) was isolated (2.9 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.70 (d, 1H), 7.50 (d, 1H), 5.72-5.82 (m, 1H).


1-(1-Bromo-2,2,2-trifluoroethyl)-3-chloro-5-(trifluoromethyl)benzene (DI32)



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1-(3-Chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (DI31) was isolated as a pale yellow oil (2.0 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 3H), 5.08 (m, 1H), 2.81 (s, 1H); ESIMS m/z 278.1 ([M]+). The title compound (DI32) was isolated oil (2.0 g, 40%): ESIMS m/z 342 ([M]+).


5-(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-methoxybenzene (DI34)



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1-(3,5-Dichloro-4-methoxyphenyl)-2,2,2-trifluoroethanol (DI33) was isolated as an off white solid (0.8 g, 60%); mp 92-95° C.: 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 2H), 5.00 (m, 1H), 3.89 (s, 3H), 2.64 (m, 1H); ESIMS m/z 274 ([M]+). The title compound (DI34) was isolated as a colorless liquid (0.6 g, 57%).


Example 90: Preparation of 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-difluorobenzene (DI36)



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The title compound was synthesized in two steps via 1-(3,5-difluorophenyl)-2,2,2-trifluoroethanol (DI35, prepared as in Step 1, Method A in Example 1; isolated as a colorless oil (0.2 g, 75%): 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 2H), 6.88 (m, 1H), 5.06 (m, 1H), 2.66 (s, 1H); ESIMS m/z 212 ([M]+) and Step 2 in Example 1 and isolated (3.2 g, 50%); 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 2H), 6.86 (m, 1H), 5.03 (q, J=7.4 Hz, 1H).


The following compounds were made in accordance with the procedures disclosed in Example 90.


1-(1-Bromo-2,2,2-trifluoroethyl)-4-chlorobenzene (DI38)



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1-(4-Chlorophenyl)-2,2,2-trifluoroethanol (DI37) was isolated as a colorless oil (5.0 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.44-7.38 (m, 4H), 5.05 (m, 1H), 2.55 (s, 1H); ESIMS m/z 210 ([M]+). The title compound (DI38) was isolated (3.0 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 5.10 (q, J=7.2 Hz, 1H).


1-(1-Bromo-2,2,2-trifluoroethyl)-4-methoxybenzene (DI40)



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2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol (DI39) was isolated as a pale yellow liquid: 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.8 Hz, 2H), 6.95 (m, J=8.8 Hz, 2H), 5.00 (m, 1H), 3.82 (s, 3H), 2.44 (s, 1H); ESIMS m/z 206.1 ([M]+). The title compound (DI40) was isolated (3.8 g, 62%).


1-(1-Bromo-2,2,2-trifluoroethyl)-4-fluorobenzene (DI42)



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2,2,2-Trifluoro-1-(4-fluorophenyl)ethanol (DI41) was isolated as a colorless oil (5 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.48-7.45 (m, 2H), 7.13-7.07 (m, 2H), 5.06 (m, 1H), 2.53 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI42) was prepared and carried on as crude intermediate.


1-(1-Bromo-2,2,2-trifluoroethyl)-4-methylbenzene (DI44)



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2,2,2-Trifluoro-1-(p-tolyl)ethanol (DI43) was isolated as colorless oil (5.0 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 5.02 (m, 1H), 2.46 (m, 1H), 2.37 (s, 3H); ESIMS m/z 190 ([M]+). The title compound (DI44) was isolated (3.0 g, 45%).


1-(1-Bromo-2,2,2-trifluoroethyl)-3-fluorobenzene (DI46)



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2,2,2-Trifluoro-1-(3-fluorophenyl)ethanol (DI45) was isolated as a colorless viscous oil (2.8 g, 93%): 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 1H), 7.25 (m, 2H), 7.14 (m, 1H), 5.06 (m, 1H), 2.60 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI46) was isolated (2.0 g, 61%).


1-(1-Bromo-2,2,2-trifluoroethyl)-2-fluorobenzene (DI48)



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2,2,2-Trifluoro-1-(2-fluorophenyl)ethanol (DI47) was isolated as a colorless oil (2.5 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 1H), 7.43 (m, 1H), 7.24 (m, 1H), 7.13 (m, 1H), 5.42 (m, 1H), 2.65 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI48) was isolated (2.0 g, 61%): 1H NMR (400 MHz, CDCl3) δ 7.61 (m, 1H), 7.40 (m, 1H), 7.23 (m, 1H), 7.10 (m, 1H), 5.40 (m, 1H); GCMS m/z 255 ([M−H]−).


Example 91: Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5)



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To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).


The following compound was made in accordance with the procedures disclosed in Example 91.


5-Formyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI49)



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The title compound was isolated (2.8 g, 60%); 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.98 (s, 1H), 8.35 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H), 8.07 (d, 1H); IR (thin film) 3433, 3120, 1702, 1599, 1510 cm−1.


2-Chloro-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI50)



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The title compound was isolated as an off white solid (3.0 g, 40%): mp 149-151° C.; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.74 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.90 (m, 2H); ESIMS m/z 208.10 ([M+H]+).


5-Methyl-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI51)



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The title compound was isolated as a white solid (0.5 g, 74%): mp 109-111° C.; 1H NMR (400 MHz, D6-DMSO) δ 10.06 (s, 1H), 9.00 (s, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.92 (d, J=9.2 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H), 2.30 (s, 3H); ESIMS m/z 188.13 ([M+H]+).


Example 92: Preparation of 5-Formyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)benzonitrile (DI52)



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To a stirring solution of 2-fluoro-5-formylbenzonitrile (0.5 g, 3.3 mmol) in DMF (25 mL) were added K2CO3 (0.68 g, 4.95 mmol) and 3-nitro-1,2,4 triazole (0.45 g, 4.2 mmol) and the resultant reaction mixture was stirred at ambient temperature for 14 h. After completion of reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and concentrated under reduced pressure to afforded the title compound as a pale yellow solid (0.36 g, 45%): mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.61 (s, 1H), 8.69 (s, 1H), 8.45 (d, J=9.3 Hz, 1H), 8.23 (d, J=9.3 Hz, 1H); ESIMS m/z 242.3 ([M−H]−); IR (thin film) 2238, 1705, 1551, 1314 cm−1.


Example 93: Preparation of 4-(3-Methyl-1H-1,2,4-triazol-1-yl)benzaldehyde (DI53)



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To a stirring solution of 4-fluorobenzaldehyde (5.0 g, 40.32 mmol) in DMF (50 mL), were added K2CO3 (3.34 g, 40.32 mmol) and 3-methyl-1,2,4-trizole (3.34 g, 40.32 mmol) and the resultant reaction mixture was stirred at ambient temperature for 4 h. After completion of the reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc (3×). The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and concentrated under reduced pressure to afforded the title compound as a white solid (4.1 g, 60%): mp 125-128° C.; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.76 (s, 1H), 8.02 (d, 2H), 7.85 (d, 2H), 2.50 (s, 3H); ESIMS m/z 188.04 ([M+H]+).


The following compound was made in accordance with the procedures disclosed in Example 93.


4-(1H-1,2,4-triazol-1-yl)-3-(trifluoromethyl)benzaldehyde (DI54)



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The title compound was isolated as white solid (1.05 g, 60%): mp 81-83° C.; 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 8.25 (d, J=7.2 Hz, 1H), 8.18 (s, 1H), 7.79 (d, J=7.2 Hz, 1H); ESIMS m/z 241.0 ([M]+).


4-(3-Nitro-1H-1,2,4-triazol-1-yl)benzaldehyde (DI55)



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The title compound was isolated as pale yellow solid (0.10 g, 23%): mp 159-161° C.; 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.89 (s, 1H), 8.15 (m, 2H), 8.00 (m, 2H); ESIMS m/z 217.11 ([M−H]−).


3-Bromo-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI56)



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The title compound was isolated as white solid (3.2 g, 51%): mp 126-128° C.; 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.69 (s, 1H), 8.27 (M, 1H, 8.18 (s, 1H) 7.99 (d, J=9.2 Hz, 1H), 7.76 (d, J=9.2 Hz, 1H); ESIMS m/z 250.9 ([M]+).


5-Formyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (DI57)



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The title compound was isolated as white solid (0.13 g, 30%): mp 147-149° C.; 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.89 (s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.24 (dd, J=8.6, 1.3 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 2.54 (s, 3H); ESIMS m/z 213.09 ([M+H]+); IR (thin film) 2239, 1697 cm−1.


3-Nitro-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI58)



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The title compound was isolated as pale yellow solid (3.0 g, 60%): mp 116-118° C.; 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.26 (d, J=6.9 Hz, 1H), 8.16 (s, 1H), 7.83 (d, J=6.9 Hz, 1H); ESIMS m/z 219.00 ([M+H]+).


Example 94: Preparation of 1-(4-Vinylphenyl)-1H-1,2,4-triazole (DI59)



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To a stirred solution of 4-[1,2,4]triazol-1-yl-benzaldehyde (9.0 g, 52 mmol) in 1,4-dioxane (100 mL), were added K2CO3 (10.76 g, 78 mmol) and methyl triphenyl phosphonium bromide (22.2 g, 62.4 mmol) at room temperature. The resultant reaction mixture was heated to 70° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afforded the title compound as a white solid (5.6 g, 63%): ESIMS m/z 172.09 ([M+H]+).


The following compound was made in accordance with the procedures disclosed in Example 94.


1-(2-Methyl-4-vinylphenyl)-1H-1,2,4-triazole (DI60)



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The title compound was isolated as an off white solid (1.5 g, 76%): 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.11 (s, 1H), 7.35 (m, 2H), 7.27 (d, J=8.7 Hz, 1H), 6.74 (m, 1H), 5.82 (d, J=17.3 Hz, 1H), 5.36 (d, J=10.0 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 186.14 ([M+H]+).


2-(1H-1,2,4-Triazol-1-yl)-5-vinylbenzonitrile (DI61)



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The title compound was isolated as an off-white solid (1.40 g, 71%): mp 126-129° C.; 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.18 (s, 1H), 7.82-7.84 (m, 1H), 7.72-7.80 (m, 2H), 6.70-6.80 (dd, J=17.6, 10.8 Hz, 1H), 5.90-5.95 (d, J=17.6 Hz, 1H), 5.50-5.70 (d, J=10.8 Hz, 1H); ESIMS m/z 197.03 ([M+H]+).


Example 95: Preparation of 2-(3-Nitro-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI62)



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To a stirred solution of 5-formyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)benzonitrile (0.36 g, 1.49 mmol) in 1,4-dioxane (25 mL), were added K2CO3 (0.3 g, 2.2 mmol) and methyl triphenyl phosphonium bromide (0.63 g, 1.79 mmol). The resultant reaction mixture was heated to 100° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afford the title compound as a solid (0.25 g, 70%): mp 103-105° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.34 (m, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 6.87 (m, 1H), 6.20 (d, J=15.7 Hz, 1H), 5.56 (d, J=11.8 Hz, 1H); ESIMS m/z 240.27 ([M−H]−); IR (thin film) 2240, 1514, 1312 cm−1.


The following compound was made in accordance with the procedures disclosed in Example 95.


1-(3-Chloro-4-vinylphenyl)-1H-1,2,4-triazole (DI63)



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The title compound was isolated as an off-white solid (2.3 g, 80%): mp 134-137° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.10 (m, 1H), 5.80 (d, J=17.2 Hz, 1H), 5.47 (d, J=12.4 Hz, 1H); ESIMS m/z 206.04 ([M+H]+.


3-Methyl-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI64)



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The title compound was isolated as a white solid (0.6 g, 60%): mp 109-111° C.; 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.40-7.60 (m, 4H), 6.70-7.00 (dd, J=17.6, 10.8 Hz, 1H), 5.80 (d, J=17.6 Hz, 1H), 5.30 (d, J=17.6 Hz, 1H), 2.50 (s, 3H); ESIMS m/z 186.20 ([M+H]+).


1-(2-(Trifluoromethyl)-4-vinylphenyl)-1H-1,2,4-triazole (DI65)



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The title compound was isolated as a colorless oil (0.6 g, 60%): 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 6.70-6.90 (dd, J=17.6, 10.8 Hz, 1H), 5.90-6.00 (d, J=17.6 Hz, 1H), 5.50-5.80 (d, J=10.8 Hz 1H); ESIMS m/z 240.16 ([M+H]+).


3-Nitro-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI66)



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The title compound was isolated as a pale yellow solid (61 mg, 20%): mp 137-139° C.; 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.68 (d, J=7.7 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 6.77 (dd, J=17.7, 10.8, 1H), 5.87 (d, J=17.7 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H); ESIMS m/z 217.28 ([M+H]+).


1-(2-Bromo-4-vinylphenyl)-1H-1,2,4-triazole (DI67)



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The title compound was isolated as a white solid (1.2 g, 40%): mp 75-77° C.; 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.12 (s, 1H), 7.75 (s, 1H) 7.42 (s, 2H), 6.70 (m, 1H), 5.83 (d, J=18 Hz, 1H), 5.42 (d, J=12 Hz, 1H); ESIMS m/z 249.1 ([M]+).


2-(3-Methyl-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI68)



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The title compound was isolated as an off-white solid (0.6 g, 60%): mp 96-97° C.; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.80 (s, 1H), 7.74 (m, 2H), 6.73 (dd, J=17.6 Hz, 10.8 Hz, 1H), 5.88 (d, J=17.6 Hz, 1H), 5.49 (d, J=10.8 Hz, 1H), 2.52 (s, 3H); ESIMS m/z 211.10 ([M+H]+); IR (thin film) 2229 cm−1.


1-(2-Nitro-4-vinylphenyl)-1H-1,2,4-triazole (DI69)



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The title compound was isolated as a yellow solid (1.78 g, 60%): mp 102-104° C.; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.72-7.76 (d, J=8.0 Hz, 1H), 7.52-7.56 (d, J=17.6 Hz, 1H), 6.70-6.82 (dd, J=17.6, 10.8 Hz, 1H), 5.85-6.00 (d, J=17.6 Hz, 1H), 5.50-5.60 (d, J=10.8, Hz 1H); ESIMS m/z 217.0 ([M+H]+).


Example 96: Preparation of 3-Methyl-2-(1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI70)



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Step 1. 5-Bromo-2-fluoro-3-methylbenzaldehyde

To a stirred solution of di-isopropyl amine (4.01 g, 39.88 mmol) in THF (20 mL) was added n-butyl lithium (1.6 M in hexane) (19.9 mL, 31.91 mmol) at −78° C. slowly dropwise over the period of 10 min, the reaction mixture was stirred at −78° C. for 30 min. A solution of 4-bromo-1-fluoro-2-methylbenzene (5.0 g, 26.6 mmol) in THF (30.0 mL) was added at −78° C., and the reaction mixture was stirred for 1 h at the same temperature. DMF (5.0 mL) was added and stirred at −78° C. for another 30 min. The reaction was monitored by TLC; then the reaction mixture was quenched with 1N HCl solution (aq) at 0° C. The aqueous layer was extracted with diethyl ether, washed with water and saturated brine solution. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 5% ethyl acetate/pet ether) to afford the title compound as a white solid (3.6 g, 64%); mp 48-50° C.: 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (dd, J=17.6, 10.8 Hz, 1H), 5.52 (d, J=17.6 Hz, 1H), 2.21 (s, 3H); ESIMS m/z 211.35 ([M−H]−).


Step 2. ((E)-5-Bromo-2-fluoro-3-methylbenzaldehyde oxime

To a stirred solution of 5-bromo-2-fluoro-3-methylbenzaldehyde (3.5 g, 16.2 mmol) in ethanol (50.0 mL) were added sodium acetate (2.0 g, 24.3 mmol) and hydroxylamine hydrochloride (1.69 g, 24.3 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated on rotavapour to obtain crude compound, which was washed with water filtered and dried under vacuum to afford the title compound as a white solid: mp 126-127° C.; 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 232.10 ([M+H]+).


Step 3. 5-Bromo-2-fluoro-3-methylbenzonitrile

A stirred solution of (E)-5-bromo-2-fluoro-3-methylbenzaldehyde oxime (0.5 g, 2.2 mmol) in acetic anhydride (5.0 mL) was heated to reflux for 18 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound as a light brown gummy material (0.4 g, crude): ESIMS m/z 213.82 ([M+H]+).


Step 4. 5-Bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI71)

To a stirred solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) was added potassium carbonate (1.95 g, 14.14 mmol) followed by 1H-1,2,4-triazole (0.811 g, 9.433 mmol) at ambient temperature. The reaction mixture was heated to 140° C. for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) to afford the title compound as a pink solid (0.6 g, 49%): 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.23 (s, 1H), 7.91 (d, J=2.4 Hz, 2H), 2.21 (s, 3H), ESIMS m/z 262.57 ([M+H]+); IR (thin film) 2231, 554 cm−1.


Step 5. 3-Methyl-2-(1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI70)

A mixture of 5-bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.6 g, 2.3 mmol), potassium carbonate (0.95 g, 6.87 mmol), vinyl boronic anhydride (0.82 g, 3.43 mmol) and triphenylphosphine (0.13 g, 0.114 mmol) in toluene (20.0 mL) were stirred and degassed with argon for 30 min. The reaction mixture was heated to reflux for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound that was purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) to afford the title compound as a pink solid (0.25 g, 52%): 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (d, J=17.6, 1H), 5.52 (d, J=10.8 Hz, 1H), 2.21 (s, 3H), ESIMS m/z 211.35 ([M+H]+); IR (thin film) 2236, 1511 cm−1.


The following compound was made in accordance with the procedures disclosed in Steps 4 and 5 of Example 96.


1-(2-Fluoro-4-vinylphenyl)-1H-1,2,4-triazole (DI72)



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1-(4-Bromo-2-fluorophenyl)-1H-1,2,4-triazole (DI73) was isolated as a pale yellow solid (3.0 g, 75%): mp 113-116° C.; 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.13 (m, 2H), 7.50 (m, 1H), 7.21 (m, 1H); ESIMS m/z 241.93 ([M]+). The title compound (DI72) was isolated as a yellow solid (1.0 g, 71%): mp 67-70° C.; 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.13 (s, 1H), 7.94 (m, 1H), 7.41 (m, 1H), 7.24 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.81 (d, J=17.6 Hz, 1H), 5.37 (d, J=10.8 Hz, 1H); ESIMS m/z 190.00 ([M+H]+).


Example 119: Preparation of 1-(1-(4-Vinylphenyl)-1H-1,2,4-triazol-5-yl)ethanone (DI78)



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To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min. To this N-methoxy-N-methyl acetamide in THF (0.66 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×50 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (280 mg, 23%): mp 97-98° C.; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.50 (d, 2H), 7.38 (d, 2H), 6.68 (dd, 1H), 5.85 (d, 1H), 5.38 (d, 1H), 2.75 (s, 3H); ESIMS m/z 214.14 ([M+H]+).


Example 120: Preparation of Cyclopropyl(1-(4-vinylphenyl)-1H-1,2,4-triazol-5-yl)methanone (DI79)



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To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min. To this N-methoxy N-methylcyclopropoxide in THF (0.82 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (420 mg, 30%): mp 90-91° C.; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 6.75 (dd, J=16.3, 10.7 Hz, 1H), 5.81 (d, J=16.3 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 3.22 (m, 1H), 1.27 (m, 2H), 1.18 (m, 2H); ESIMS m/z 240.18 ([M+H]+); IR (thin film) 2922, 1630 cm−1.


Example 121: Preparation of 5-(Methylthio)-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI80)



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To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 50 mL of THF, was added n-BuLi (0.41 g, 6.4 mmol) at −78° C. and stirred for 30 min. To this dimethyldisulfide in THF (0.6 g, 6.43 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (0.6 g, 48%): mp 68-70° C.; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.05 (m, 4H), 6.75 (dd, J=16.4, 10.7 Hz, 1H), 5.81 (d, J=16.4 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 2.73 (s, 3H); ESIMS m/z 218.09 ([M+H]+).


Example 122: Preparation of 5-Methyl-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI81)



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To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (0.5 g, 2.9 mmol) in 10 mL of THF, was added n-BuLi (0.22 g, 3.5 mmol) at −78° C. and stirred for 30 min. To this methyl iodide in THF (0.50 g, 3.5 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) afford the title compound as a pale brown liquid (250 mg, 46%): 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.55 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 2H), 6.76 (dd, J=18, 11 Hz, 1H), 5.83 (d, J=18 Hz, 1H), 5.38 (d, J=11 Hz, 1H), 2.55 (s, 3H); ESIMS m/z 186.13 ([M+H]+); IR (thin film) 1517, 1386, 1182, 847 cm−1.


Example 97: Preparation of (E)-1-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-1H-1,2,4-triazole (DC1)



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To a stirred solution of 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichloro-benzene (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL), were added 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (2.22 g, 13.0 mmol), CuCl (64 mg, 0.65 mmol) and 2,2-bipyridyl (0.2 g, 1.3 mmol). The resultant reaction mixture was degassed with argon for 30 min, then stirred at 180° C. for 24 h. After completion of reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the filtrate concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (0.8 g, 32%): mp 93-97° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.38 (t, J=1.8 Hz, 1H), 7.29 (s, 2H), 6.62 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.2 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 398.05 ([M+H]+).


Compounds DC2-DC37, DC44, DC45, DC47-49, DC50, DC51, DC54, DC58, DC60, DC62, and DC63-DC67 in Table 1 were made in accordance with the procedures disclosed in Example 97.


Example 98: Preparation of (E)-2-(3-Nitro-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzonitrile (DC40)



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To a stirred solution of 2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (0.9 g, 3.7 mmol) in 1,2-dichlorobenzene (10 mL), were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (2.5 g, 7.5 mmol), CuCl (73 mg, 0.74 mmol) and 2,2-bipyridyl (0.23 g, 1.49 mmol) and the resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 14 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh, 25-30% EtOAc in Pet ether) afforded the title compound as an off white solid (0.9 g, 50%): mp 70-73° C.; 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 1H), 7.88 (m, 3H), 7.44 (s, 2H), 6.67 (d, J=16.0 Hz, 1H), 6.56 (dd, J=16.0, 7.6 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 436.11 ([M−2H]−).


Example 99: Preparation of (E)-2-(3-Amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzonitrile (DC41)



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To a stirred solution of (E)-2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.6 g, 1.2 mmol) in MeOH (10 mL), were added Zn dust (0.39 g, 5.98 mmol) and sat. aq NH4Cl solution (5 mL) and the resultant reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction (TLC), the reaction mass was concentrated under reduced pressure. The reaction mass was diluted with CH2Cl2, filtered through a celite bed, and the obtained filtrate concentrated under reduced pressure to afford the title compound as a solid (0.5 g, 89%): mp 72-75° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.26 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.77 (d, J=8.4 Hz, 1H), 6.42 (dd, J=15.6, 9.2 Hz, 1H), 6.83 (d, J=15.6 Hz, 1H), 5.87 (s, 2H), 4.89 (m, 1H); ESIMS m/z 469.95 ([M−H]−).


Compound DC38 in Table 1 was made in accordance with the procedures disclosed in Example 99. Also, compound DC55 in Table 1 was made from compound DC54 in accordance with the procedures disclosed in Example 99, with the exception of using ammonium formate in place of ammonium chloride.


Example 100: Preparation of (E)-N-(1-(2-Cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-1H-1,2,4-triazol-3-yl)-N-(cyclopropanecarbonyl)cyclopropanecarboxamide (DC42)



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To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.1 g, 0.21 mmol) in CH2Cl2 at ambient temperature, was added cyclopropylcarbonyl chloride (0.045 g, 0.42 mmol) and the reaction mixture was stirred for 2 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by preparative HPLC afforded the title compound as a solid (0.09 g, 79%): mp 104-107° C.; 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 2H), 7.83 (s, 1H), 7.80 (m, 2H), 7.42 (s, 2H), 6.65 (d, J=16.4 Hz, 1H), 6.51 (dd, J=7.6, 8.0 Hz, 1H), 4.17 (m, 1H), 2.16 (m, 2H), 1.25 (m, 4H), 1.00 (m, 4H); ESIMS m/z 609.98 ([M+H]+); IR (thin film) 2234, 1714, 1114, 807 cm−1.


Example 101: Preparation of (E)-N-(1-(2-Cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-1H-1,2,4-triazol-3-yl)cyclopropanecarboxamide (DC43)



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To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.15 g, 0.31 mmol) in CH2Cl2 at 0° C., were added TEA (0.1 g, 1 mmol) and cyclopropylcarbonyl chloride (0.04 g, 0.38 mmol) and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2 and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by column chromatography (SiO2, 100-200 mesh) afforded the title compound as a solid (66 mg, 34%): mp 109-112° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.94 (br s, 1H), 8.36 (s, 1H), 8.08 (m, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.13 (dd, J=15.6, 9.2 Hz, 1H), 6.87 (d, J=15.6 Hz, 1H), 4.92 (m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H); ESIMS m/z 540.04 ([M+H]+); IR (thin film) 3233, 2233, 1699, 1114, 807 cm−1.


Compound DC39 in Table 1 was made in accordance with the procedures disclosed in Example 101.


Example 102: Preparation of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone (DI74)



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To a stirred solution of 4-bromoacetophenone (10 g, 50 mmol) in DMF (100 mL), were added 1,2,4-triazole (5 g, 75 mmol), Cs2CO3 (32.6 g, 100.5 mmol) and CuI (1.4 g, 10.1 mmol) and the resultant reaction mixture was refluxed for 48 h. After completion of the reaction (by TLC), the reaction mixture was cooled to ambient temperature and diluted with water (200 mL) and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure. Purification by washing with diethyl ether afforded the title compound as a solid (5 g, 96%): 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.16, (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.6 Hz, 2H), 2.66 (s, 3H); ESIMS m/z 186.02 ([M−H]−).


Example 103: Preparation of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one (DI75)



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Step 1. 1-(4-(1-(trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole (DI76)

To a stirred solution of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone (4.5 g, 24.0 mmol) in CH2Cl2 at 0° C., were added TEA (3.7 g, 36.1 mmol) and trimethylsilyl trifluoromethanesulfonate (8 g, 36 mmol) and the resultant reaction mixture was stirred for 1 h. The reaction mixture was quenched with a mixture of sat aq sodium bicarbonate solution and ether. The ether layer and was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (5.5 g) which was taken directly to next step.


Step 2. 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one (DI75)

To a stirred solution of 1-(4-(1-(trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole (6 g, 23 mmol) and 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichlorobenzene (7.1 g, 34.7 mmol) in 1,2-dichlorobenzene (30 mL) was degassed with argon. To this CuCl (0.23 g, 2.31 mmol) and 2,2-bipyridyl (0.73 g, 4.63 mmol) was added to the above reaction mixture and the resultant reaction mixture was heated to 180° C. for 18 h. After completion of the reaction (by TLC), the reaction mixture was absorbed onto silica gel and purified by column chromatography (SiO2; 10% EtOAc in petroleum ether) to afford title compound as a solid (3 g, 31%): 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.15 (s, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.33 (m, 1H), 7.30 (m, 2H), 4.20 (m, 1H), 3.63 (m, 2H); ESIMS m/z 412.14 ([M−H]−).


Example 104: Preparation of 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5-trifluoropentan-2-ol (DI77)



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To a solution of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one (300 mg, 0.726 mmol) in THF cooled to 0° C. was added methylmagnesium bromide (450 mg, 5 mmol) drop wise. The reaction was stirred for 3 h at 0° C., then the reaction mixture was quenched with sat aq NH4Cl solution and extracted with ethyl acetate. The combined EtOAc layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (100 mg, 32%): 1H NMR (400 MHz, CDCl3) δ two diastereoisomers 8.58 (s, 1H, minor), 8.48 (s, 1H, major), 8.13 (s, 1H, minor), 8.09 (s, 1H, major), 7.70 (d, J=9.0 Hz, 2H, minor), 7.53 (d, J=9.0 Hz, 2H, minor), 7.40 (d, J=9.0 Hz, 2H, major), 7.31 (m, 1H, minor), 7.27 (d, J=9.0 Hz, 2H, major), 7.20 (m, 2H, minor), 7.01 (m, 1H, major), 6.75 (m, 2H, major), 350 (m, 1H), 2.50 (m, 2H), 1.56 (s, 3H, major), 1.54 (s, 3H, minor); ESIMS m/z 430.05 ([M+H]+).


Example 105: Preparation of (E)-1-(4-(4-(3,5-Dichlorophenyl)-5,5,5-trifluoropent-2-en-2-yl)phenyl)-1H-1,2,4-triazole (DC68)



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To a solution of 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5-trifluoropentan-2-ol (100 mg, 0.233 mmol) in toluene was added a catalytic amount of p-toluenesulfonic acid (PTSA) and the water was removed by azeotropic distillation over the course of 12 h. The reaction mixture was cooled to room temperature and dissolved in ethyl acetate. The solution was washed with sat aq NaHCO3 solution and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (30 mg, 31%).


Example 123: Preparation of (E)-5-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzaldehyde (DC52)



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To a stirred solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.3 g, 0.71 mmol) in toluene (10 mL) at −78° C. was added dropwise diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 0.85 mL), and the reaction mixture was stirred at −78° C. for 20 min. The reaction mixture was quenched with the addition of 1 N HCl solution, then the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/Pet ether) to afford the title compound as a yellow oil.


Compound DC53 in Table 1 was made in accordance with the procedures disclosed in Example 123.


Example 124: Preparation of (E)-5-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-methyl-2-(1H-1,2,4-triazol-1-yl)aniline (DC57)



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To a stirred solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)aniline (0.3 g, 0.7 mmol) in CH2Cl2 (10 mL) was added TEA (0.155 mL, 1.09 mmol) and methyl iodide (0.124 g, 0.873 mmol). The reaction was stirred at ambient temperature for 18 h. The CH2Cl2 layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/Pet ether) to afford the title compound as a yellow semi-solid (0.07 g, 70%).


Example 125: Preparation of (E)-5-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzoic acid (DC61)



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A solution of (E)-ethyl 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzoate (0.2 g, 0.4 mmol) in 6 N HCl (10 mL) was stirred at 100° C. for 18 h. The reaction was cooled to ambient temperature, resulting in a white solid precipitate. The precipitate was filtered to afford the title compound as a white solid (0.12 g, 60%).


Example 126: Preparation of (Z)-5-((E)-3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N′-hydroxy-2-(1H-1,2,4-triazol-1-yl)benzimidamide (DC59)



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A solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.3 g, 0.71 mmol), sodium acetate (0.087 g, 1.065 mmol) and hydroxylammonium chloride (0.072 g, 1.065 mmol) in 9:1 ethanol/water mixture (10 mL) was stirred at 70° C. for 8 h. The reaction was cooled to ambient temperature, and the ethanol was evaporated. The residue was dissolved in water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off white solid.


Example 127: Preparation of (E)-1-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluoro-3-methoxybut-1-en-1-yl)phenyl)-1H-1,2,4-triazole (DC70)



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Step 1. (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one

To a solution of 1-(3,5-dichlorophenyl)ethanone (0.5 g, 2.6 mmol) in ethanol (20 mL) was added 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (0.46 g, 2.65 mmol) and the reaction was cooled to 0° C. Sodium hydroxide (0.22 g, 5.29 mmol) in water (10 mL) was then added and the reaction was allowed to stir for 2 h at 0° C. The reaction was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (0.149 g, 17%); ESIMS m/z 430.05 ([M+H]+) 344.08


Step 2. (E)-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2-(3,5-dichlorophenyl)-1,1,1-trifluorobut-3-en-2-ol (DC69)

To a solution of (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one (1 g, 3 mmol) in THF (150 mL) was added trifluoromethyltrimethylsilane (0.517 g, 3.644 mmol) and tetra-n-butylammonium fluoride (TBAF) (1.0 M, 1 mL) at 0° C. The reaction was slowly warmed to ambient temperature and allowed to stir for 2 h. The reaction was then cooled to 0° C. and 5 M HCl solution was added and the reaction was stirred for an additional 4 h at ambient temperature. The reaction was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 25% EtOAc/hexanes) to afford the title compound as an off-white solid (0.3 g, 25%).


Step 3. (E)-1-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluoro-3-methoxybut-1-en-1-yl)phenyl)-1H-1,2,4-triazole (DC70)

To a solution of (E)-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2-(3,5-dichlorophenyl)-1,1,1-trifluorobut-3-en-2-ol (0.15 g, 0.36 mmol) in THF (5 mL) was added NaH (60%, 10 mg, 0.44 mmol) at 0° C. The reaction was allowed to stir at 0° C. for 30 min, then methyl iodide (61 mg, 0.44 mmol) was added slowly and the reaction was warmed to ambient temperature and allowed to stir for 4 h. The reaction was quenched with aq NH4Cl solution and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (55 mg, 35%).


Prophetic Example F1: Preparation of (E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoyl)-N-ethyl-1-methylhydrazinecarboxamide (F1)



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Prophetically, (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid can be reacted with N-ethyl-1-methylhydrazinecarboxamide in the presence of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl) and DMAP to furnish the title molecule (Org. Lett. 2004, 6, 929-931).


Example 128: Preparation of (E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoyl)-N-(2,2,2-trifluoroethyl)hydrazinecarboxamide (F7)



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Step 1. tert-Butyl 2-((2,2,2-trifluoroethyl)carbamoyl)hydrazinecarboxylate

To a stirred solution of tert-butyl hydrazinecarboxylate (1.0 g, 8 mmol) in anhydrous benzene (10.0 mL) was added 1,1,1-trifluoro-2-isocyanatoethane (1.06 g, 8 mmol) neat via syringe to give a gelatin like mixture. Anhydrous THF was added to give a clear solution which was stirred for 10 minutes, after which time the reaction mixture was evaporated to afford the title compound as a white solid (1.62 g, 79%): 1H NMR (400 MHz, CDCl3) δ 6.63 (s, 1H), 6.40 (d, J=2.2 Hz, 1H), 5.84 (s, 1H), 3.88 (qd, J=9.0, 6.6 Hz, 2H), 1.48 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −73.20. This material is used without further purification.


Step 2. N-(2,2,2-Trifluoroethyl)hydrazinecarboxamide hydrochloride

To a stirred solution of tert-butyl 2-((2,2,2-trifluoroethyl)carbamoyl)hydrazinecarboxylate (1.62 g, 6.30 mmol) in anhydrous dioxane (10.0 mL) was added HCl (4M in dioxane, 2-3 mL). The reaction mixture was stirred at ambient temperature for 18 h, then heated at reflux for 2-3 h. The reaction mixture was allowed to cool to ambient temperature and then evaporated to afford the title compound as a white solid (1.33 g, 109%): 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 3H), 9.25 (s, 1H), 7.72 (t, J=6.5 Hz, 1H), 3.91 (qd, J=9.7, 6.5 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −71.41; ESIMS m/z 156 ([M−H]−). This material is used without further purification.


Step 3. (E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoyl)-N-(2,2,2-trifluoroethyl)hydrazinecarboxamide

To a solution containing (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (120 mg, 0.246 mmol), 1,2-dichloroethane (DCE) (5 mL) was added sequentially EDC.HCl (70.6 mg, 0.368 mmol), N-(2,2,2-trifluoroethyl)hydrazinecarboxamide hydrochloride (52.3 mg, 0.270 mmol) and DMAP (63.0 mg, 0.516 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2, washed with 0.1N HCl then with aqueous NaHCO3, dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography afford the title compound as a glassy oil (40 mg, 26%): 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.65 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.51 (d, J=6.4 Hz, 1H), 7.40 (s, 3H), 6.54 (d, J=15.8 Hz, 1H), 6.42 (dd, J=16.0, 7.7 Hz, 1H), 5.95 (s, 1H), 4.10 (s, 1H), 3.91 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −68.56, −73.02; ESIMS m/z 627.9 ([M+H]+).


Example 129: Preparation of (E)-1-Isopropyl-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzoyl)-N-(2,2,2-trifluoroethyl)hydrazinecarboxamide (FA3)



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DIPEA (0.32 ml, 1.88 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (263 mg, 0.69 mmol) and 1-amino-1-isopropyl-3-(2,2,2-trifluoroethyl)urea hydrochloride (178 mg, 0.75 mmol) were added to a stirred solution of 2-(trifluoromethyl)-4-[(E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl]benzoic acid (300 mg, 0.63 mmol) in DMF (2 mL) at ambient temperature and the reaction mixture was stirred for 4 h. Water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine followed by water, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica, eluting with 20% EtOAc in petroleum ether to afford the title compound as a brown gum (135 mg, 29%).


Example 130: Preparation of 1-Isopropyl-N-(2,2,2-trifluoroethyl)hydrazinecarboxamide hydrochloride



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Step 1. tert-Butyl 2-isopropyl-2-(2,2,2trifluoroethylcarbamoyl)hydrazine carboxylate

2,2,2-Trifluoroethanamine (284 mg, 2.87 mmol), TEA (0.8 ml, 5.74 mmol)) in CH2Cl2 (6 mL) were added to the solution of triphosgene (298 mg, 1 mmol) in CH2Cl2 (8 mL) at −40° C. and the reaction mixture was stirred for 30 min. tert-Butyl N-(isopropylamino)carbamate (JOC, 2013, 78, 3541-3552) (500 mg, 2.87 mmol) in CH2Cl2 (4 mL) was then added to the reaction mixture at −40° C. and stirred at ambient temperature—overnight. Water was added to the reaction mixture and it was extracted with CH2Cl2. The organic layer wad washed with brine, dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (580 mg, crude): mp 90-94° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.70 (bs, 1H), 6.81 (t, J=6.3, 1H), 3.89-3.80 (m, 2H), 3.11-3.08 (m, 1H), 1.40 (s, 9H), 0.97 (d, J=6.0 Hz, 6H); ESIMS m/z 241.9 ([M-tert-Butyl]+).


The following compounds were made in accordance with the procedures disclosed in Steps 1 of Example 130.


Benzyl-2-methyl-2-(2,2,2-trifluoroethylcarbamoyl)hydrazinecarboxylate



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The title compound was isolated as a colorless gum (8.0 g, 20%): 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.41 (m, 6H), 5.11 (s, 2H), 3.85-3.73 (m, 2H), 2.95 (s, 3H); IR (thin film) 3332, 2960, 1735, 1161, 742 cm−1.


Benzyl 2-((2,2-difluoroethyl)carbamoyl)-2-methylhydrazinecarboxylate



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The title compound was isolated as a brown solid: mp 79-82° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.39 (bs, 1H), 7.38-7.35 (m, 5H), 6.10-5.75 (m, 1H), 5.72 (bs, 1H), 5.10 (s, 2H), 3.41-3.36 (m, 2H), 2.94 (s, 3H).


Benzyl 2-methyl-2-((3,3,3-trifluoropropyl)carbamoyl)hydrazinecarboxylate



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The title compound was isolated as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 9.46 (bs, 1H), 7.37-7.30 (m, 5H), 5.10 (s, 2H), 4.50 (bs, 1H), 3.31-3.19 (m, 2H), 2.92 (s, 3H), 2.38-2.33 (m, 2H); ESIMS m/z 320.3 ([M+H]+); IR (thin film) 3415, 1647, 1267, 1143, 742, 514 cm−1.


Step 2. 1-Isopropyl-N-(2,2,2-trifluoroethyl)hydrazinecarboxamide hydrochloride

—HCl (4 M in dioxane, 10 mL) was added to a stirred solution of tert-butyl N-[isopropyl(2,2,2-trifluoroethylcarbamoyl)amino]carbamate (530 mg, 1.77 mmol) in 1,4-dioxane (5 mL) at 0° C. and the reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated and the residue was washed with pentane to afford the title compound as a pale yellow solid. (360 mg, crude): 1H NMR (300 MHz, DMSO-d6) δ 11.2 (bs, 2H), 9.81 (s, 1H), 6.98 (t, J=6.3 Hz, 1H), 3.90-3.80 (m, 2H), 3.07-3.03 (m, 1H), 1.18 (d, J=6.6 Hz, 6H); 13C NMR (300 MHz, DMSO-d6) δ 157.06, 126.90, 52.25, 45.33, 17.49; 19F NMR (300 MHz, DMSO-d6) δ −71.52; ESIMS m/z 200.0 ([M−HCl]+).


Example 131: Preparation of 1-Methyl-N-(2,2,2-trifluoroethyl)hydrazinecarboxamide hydrochloride



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Pd—C(10%, 0.88 g, 8.24 mmol) was added portion wise to a stirred solution of benzyl N-(2,2,2-trifluoroethylcarbamoylamino)carbamate (8.0 g, 27.47 mmol) in MeOH (80 mL) and the reaction mixture was stirred an under hydrogen atmosphere (30 psi) at ambient temperature for 12 h. The reaction mixture was filtered through Celite® and washed with MeOH. The filtrate was concentrated—and the residue was dissolved in—1,4-dioxane (20 mL) and HCl (4 M in 1,4-dioxane, 10 mL) was added under stirring. After stirring at ambient temperature for 3 h the volatiles were evaporated under vacuum and the residue was washed with EtOAc. The precipitated solid was dried under vacuum to afford the title compound as a white solid (3 g, 50%): 1H NMR (300 MHz, DMSO-d6) δ 9.88 (bs, 2H), 7.99 (bs, 1H), 3.94-3.82 (m, 2H), 3.12 (s, 3H); 19F NMR (300 MHz, DMSO-d6) δ −71.11; ESIMS m/z 171.2 ([M−HCl]+); IR (thin film) 3243, 1679, 1565, 1157, 648 cm−1.


The following compounds were made in accordance with the procedures disclosed in of Example 131 without subsequent treatment with HCl.


N-(2,2-Difluoroethyl)-1-methylhydrazinecarboxamide



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The title compound was isolated as a pale yellow solid: mp 81-84° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.00 (t, J=6.3 Hz, 1H), 6.14-5.74 (m, 1H), 4.52 (bs, 2H), 3.46-3.32 (m, 2H), 2.95 (s, 3H); EIMS m/z 153.2 ([M]+).


1-Methyl-N-(3,3,3-trifluoropropyl)hydrazinecarboxamide



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The title compound was isolated as a yellow semi solid: 1H NMR (300 MHz, DMSO-d6) δ 6.93 (bs, 1H), 4.40 (bs, 2H), 3.25-3.02 (m, 2H), 2.91 (s, 3H), 2.87-2.56 (m, 2H); EIMS m/z 185.2 ([M]+); IR (thin film) 3409, 1652, 1530, 1144, 763, 552 cm−1.


Example 132: Preparation of 3,5-Dibromo-4-chlorobenzaldehyde



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Step 1. Methyl 4-amino-3,5-dibromobenzoate

conc. H2SO4 (1.35 mL, 25.48 mmol) was added dropwise to a stirred solution of 4-amino-3,5-dibromobenzoic acid (5.0 g, 16.99 mmol) in MeOH (50 mL) at ambient temperature and the reaction mixture was then stirred at 80° C. for 8 h. The reaction mixture was allowed to cool to ambient temperature, volatiles were evaporated and ice-water was added to the residue and extracted with EtOAc. The organic layer was washed with aqueous NaHCO3 solution followed by brine and water, dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (5.0 g, 95%): 1H NMR (300 MHz, DMSO-d6) δ 7.91 (s, 2H), 6.20 (bs, 2H), 3.78 (s, 3H); ESIMS m/z 307.0 ([M]+); IR (thin film) 3312, 2953, 1726, 595 cm−1.


Step 2. Methyl 3,5-dibromo-4-chlorobenzoate

CuCl2 (2.82 g, 21.0 mmol) in MeCN (30 mL) was stirred at 80° C. for 30 min. -tert-Butylnitrite (2.7 mL, 23 mmol) was then added dropwise at the same temperature and the mixture was stirred for another 10 min. Methyl 4-amino-3,5-dibromobenzoate (5.0 g, 16 mmol) in MeCN (30 mL) was added dropwise to the reaction mixture and stirred at 80° C. for 30 min. The reaction mixture was allowed to cool to ambient temperature and aqueous ammonia solution (20 mL) was added to the reaction mixture and extracted with petroleum ether. The organic layer was washed with brine followed by water, dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (4.5 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 2H), 3.94 (s, 3H); ESIMS m/z 326 ([M]+); IR (thin film) 1732, 746 cm−1.


Step 3. (3,5-Dibromo-4-chlorophenyl)methanol

NaBH4 (1.53 g, 40.65 mmol) was added portionwise to a stirred solution of methyl 3,5-dibromo-4-chlorobenzoate (4.45 g, 13.6 mmol) in MeOH (50 mL) at 0° C. The reaction mixture was then stirred at ambient temperature for 8 h. The volatiles were evaporated and the residue was diluted with CH2Cl2 and washed with brine followed by water. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (3.3 g, 80%): 1H NMR (300 MHz, DMSO-d6) δ 7.71 (s, 2H), 5.49 (bs, 1H), 4.48 (d, J=4.5 Hz, 2H); ESIMS m/z 297.9 ([M]+); IR (thin film) 3460, 747, 534 cm−1.


Step 4. 3,5-Dibromo-4-chlorobenzaldehyde

Pyridinium chlorochormate (PCC, 3.44 g, 15.9 mmol) was added in one portion to a stirred solution of (3,5-dibromo-4-chlorophenyl)methanol (3.2 g, 11.0 mmol) in CHCl3 (40 mL) at ambient temperature and the reaction mixture was stirred—overnight. The reaction mixture was filtered through Celite®, the Celite® pad was washed with CHCl3 and the filtrate was concentrated to afford the title compound as an off white solid (2.0 g, 62%): mp 110-113° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.27 (s, 2H); ESIMS m/z 297.0 ([M]+).


Example 133: Preparation of 4-Bromo-3,5-dichlorobenzaldehyde



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Step 1. Methyl 4-amino-3, 5-dichlorobenzoate

conc. H2SO4 (2.5 mL, 97.04 mmol) was added drop wise to a stirred solution of 4-amino-3,5-dichlorobenzoic acid (10.0 g, 48.54 mmol) in MeOH (150 mL) at 0° C. and the reaction mixture was then stirred at 80° C. for 8 h. The volatiles were evaporated; ice-water was added to the residue and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound as a white solid (7.5 g, 70%): 1H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 2H), 3.96 (s, 3H); ESIMS m/z 282 ([M]+); IR (KBr): 1733, 762, 514 cm−1.


Step 2. Methyl 4-bromo-3,5-dichlorobenzoate

CuBr2 (7.5 g, 34.08 mmol) in MeCN (50 mL) was stirred at 80° C. for 30 min. -tert-Butylnitrite (6.5 mL, 54.55 mmol) was added dropwise at the same temperature and the mixture was stirred for another 10 min. Methyl 4-amino-3,5-dichlorobenzoate in MeCN (30 mL) was added dropwise to the reaction mixture at stirred at 80° C. for 30 min. The reaction mixture was allowed to cool to ambient temperature and aqueous ammonia solution (20 mL) was added and extracted with petroleum ether. The organic layer was washed with brine followed by water, dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (7.5 g, 77%): 1H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 2H), 3.94 (s, 3H); ESIMS m/z 282 ([M]+); IR (thin film) 1733, 762, 514 cm−1.


Step 3. (4-Bromo-3,5-dichlorophenyl)methanol

DIBAL-H (1M in toluene, 66 mL, and 66.0 mmol) was added dropwise to a stirred solution of methyl 4-bromo-3, 5-dichlorobenzoate (7.5 g, 26.0 mmol) in THF (50 mL) at −78° C. The reaction mixture was allowed to warm toward ambient temperature and stirred for 6 h. The reaction mixture was poured into ice-water and extracted with CH2Cl2. The organic layer was washed with brine followed by water, dried (Na2SO4), filtered and concentrated to afford 6.0 g of a mixture of (4-bromo-3,5-dichlorophenyl)methanol and 4-bromo-3,5-dichlorobenzaldehyde—as an off white solid which was taken to next step without purification.


Step 4. 4-Bromo-3, 5-dichlorobenzaldehyde

PCC (7.5 g, 35.16 mmol) was added in one portion to a stirred solution—containing a mixture of (4-bromo-3,5-dichlorophenyl)methanol and 4-bromo-3,5-dichlorobenzaldehyde (6.0 g) in CHCl3 (40 mL) at ambient temperature and the reaction mixture was stirred overnight. The reaction mixture was filtered through celite. The celite pad was washed with CHCl3. The filtrate was concentrated to afford the title compound as an off white solid (3.5 g, 67%): mp 125-128° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.10 (s, 2H); ESIMS m/z 252 ([M]+).


Example 134: Preparation of (E)-N-(2-Aminoethyl)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide



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Step 1. (E)-tert-Butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)ethylcarbamate

PyBOP (420 mg, 0.82 mmol) and DIPEA (0.410 mL, 2.46 mmol) were added to a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (400 mg, 0.82 mmol) and tert-butyl 2-aminoethylcarbamate (130 mg, 0.82 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred at ambient temperature for 18 h. Water was added to the reaction mixture which was then extracted with CH2Cl2 (25 mL). The organic layer was washed with 2N HCl followed by a saturated aqueous NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 40% EtOAc in petroleum ether to afford the title compound as a brown solid (200 mg, 39%): 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J=5.2 Hz, 1H), 7.91-7.89 (m, 3H), 7.58 (d, J=6.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 6.99 (dd, J=15.6, 9.2 Hz, 1H), 6.84 (t, J=6.0 Hz, 1H), 6.76 (t, J=15.6 Hz, 1H), 4.84-4.80 (m, 1H), 3.24-3.20 (m, 2H), 3.11-3.08 (m, 2H), 1.30 (s, 9H); ESIMS m/z 628.80 ([M+H]+); IR (thin film) 3365, 1701, 1167, 699, 555 cm−1.


Step 2. (E)-N-(2-Aminoethyl)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide

TFA (0.5 mL) was added to a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)ethylcarbamate (200 mg, 0.31 mmol) in CH2Cl2 (10 mL) at 0° C. and the reaction mixture was then stirred at ambient temperature for 18 h. The volatiles were evaporated under reduced pressure; water was added to the residue and the mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 1-5% MeOH in CH2Cl2 to afford the title compound as a brown solid (50 mg, 31%): 1H NMR (400 MHz, DMSO-d6) δ 8.56 (bs, 1H), 7.70 (bs, 2H), 7.94-7.91 (m, 3H), 7.62-7.59 (m, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.00 (dd, J=15.6, 9.2 Hz, 1H), 6.77 (d, J=15.6 Hz, 1H), 4.84-4.81 (m, 1H), 3.46-3.41 (m, 2H), 2.95-2.92 (m, 2H); ESIMS m/z 528.72 ([M+H]+); IR (thin film) 3435, 1671, 1113, 722, 555 cm−1.


Example 135: Preparation of (E)-N-(2-Aminoethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (FA10)



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To a solution of (E)-N-(2-aminoethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (0.2 g, 0.385 mmol) in CH2Cl2 (4 ml) under a nitrogen atmosphere and cooled in an ice bath was added triphosgene (228 mg, 0.770 mmol) and triethylamine (0.445 mL, 3.19 mmol). The mixture was stirred at ambient temperature for 1.5 h, then was treated with 2,2,2-trifluoroethanamine (0.248 mL, 3.01 mmol). After stirring for 18 h at ambient temperature, the mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were concentrated in vacuo and the resulting crude oil was purified by column chromatography on silica eluting with EtOAc and hexanes—to afford the title compound as a viscous yellow/green oil (50 mg, 20%).


The following prophetic molecules could be made in accordance with the procedures disclosed in Prophetic Example F1:













Compound



Number
Structure







F1


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F2


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F3


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F4


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F5


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F6


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F7


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F8


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F9


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F10


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F11


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F12


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F13


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F14


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F15


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F16


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F17


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F18


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F19


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F20


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F21


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F22


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F23


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F24


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F25


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F26


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F27


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F28


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F29


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F30


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F31


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F32


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F33


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F34


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F35


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F36


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F37


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F38


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F39


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F40


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The following prophetic molecules could be made in accordance with the procedures disclosed in this application:




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Compound












Number
R1
R2
R3
R4
R6
R8
R10
R11a
X5
R11b







F41
F
F
F
H
CF3
H
Br
CH3
O
CH2CH3


F42
F
F
F
H
CF3
H
Cl
CH3
O
CH2CH3


F43
F
F
F
H
CF3
H
CF3
CH3
O
CH2CH3


F44
F
F
F
H
CF3
H
CH3
CH3
O
CH2CH3


F45
F
F
F
H
CF3
H
Br
CH3
S
CH2CH3


F46
F
F
F
H
CF3
H
Cl
CH3
S
CH2CH3


F47
F
F
F
H
CF3
H
CF3
CH3
S
CH2CH3


F48
F
F
F
H
CF3
H
CH3
CH3
S
CH2CH3


F49
F
F
F
H
CF3
H
Br
H
O
CH2CH3


F50
F
F
F
H
CF3
H
Cl
H
O
CH2CH3


F51
F
F
F
H
CF3
H
CF3
H
O
CH2CH3


F52
F
F
F
H
CF3
H
CH3
H
O
CH2CH3


F53
F
F
F
H
CF3
H
Br
H
S
CH2CH3


F54
F
F
F
H
CF3
H
Cl
H
S
CH2CH3


F55
F
F
F
H
CF3
H
CF3
H
S
CH2CH3


F56
F
F
F
H
CF3
H
CH3
H
S
CH2CH3


F57
F
F
F
H
CF3
CF3
Br
H
O
CH2CF3


F58
F
F
F
H
CF3
CF3
Cl
H
O
CH2CF3


F59
F
F
F
H
CF3
CF3
CF3
H
O
CH2CF3


F60
F
F
F
H
CF3
CF3
CH3
H
O
CH2CF3


F61
F
F
F
H
CF2CF3
H
Br
H
O
CH2CF3


F62
F
F
F
H
CF2CF3
H
Cl
H
O
CH2CF3


F63
F
F
F
H
CF2CF3
H
CF3
H
O
CH2CF3


F64
F
F
F
H
CF2CF3
H
CH3
H
O
CH2CF3


F65
F
F
F
H
CF3
H
Br
H
O
CH2CF3


F66
F
F
F
H
CF3
H
Cl
H
O
CH2CF3


F67
F
F
F
H
CF3
H
CF3
H
O
CH2CF3


F68
F
F
F
H
CF3
H
CH3
H
O
CH2CF3


F69
F
F
F
H
CF3
H
Br
H
S
CH2CF3


F70
F
F
F
H
CF3
H
Cl
H
S
CH2CF3


F71
F
F
F
H
CF3
H
CF3
H
S
CH2CF3


F72
F
F
F
H
CF3
H
CH3
H
S
CH2CF3


F73
Cl
Cl
H
Cl
CF3
H
Br
CH3
O
CH2CH3


F74
Cl
Cl
H
Cl
CF3
H
Cl
CH3
O
CH2CH3


F75
Cl
Cl
H
Cl
CF3
H
CF3
CH3
O
CH2CH3


F76
Cl
Cl
H
Cl
CF3
H
CH3
CH3
O
CH2CH3


F77
Cl
Cl
H
Cl
CF3
H
Br
CH3
S
CH2CH3


F78
Cl
Cl
H
Cl
CF3
H
Cl
CH3
S
CH2CH3


F79
Cl
Cl
H
Cl
CF3
H
CF3
CH3
S
CH2CH3


F80
Cl
Cl
H
Cl
CF3
H
CH3
CH3
S
CH2CH3


F81
Cl
Cl
H
Cl
CF3
H
Br
H
O
CH2CH3


F82
Cl
Cl
H
Cl
CF3
H
Cl
H
O
CH2CH3


F83
Cl
Cl
H
Cl
CF3
H
CF3
H
O
CH2CH3


F84
Cl
Cl
H
Cl
CF3
H
CH3
H
O
CH2CH3


F85
Cl
Cl
H
Cl
CF3
H
Br
H
S
CH2CH3


F86
Cl
Cl
H
Cl
CF3
H
Cl
H
S
CH2CH3


F87
Cl
Cl
H
Cl
CF3
H
CF3
H
S
CH2CH3


F88
Cl
Cl
H
Cl
CF3
H
CH3
H
S
CH2CH3


F89
Cl
Cl
H
Cl
CF3
CF3
Br
H
O
CH2CF3


F90
Cl
Cl
H
Cl
CF3
CF3
Cl
H
O
CH2CF3


F91
Cl
Cl
H
Cl
CF3
CF3
CF3
H
O
CH2CF3


F92
Cl
Cl
H
Cl
CF3
CF3
CH3
H
O
CH2CF3


F93
Cl
Cl
H
Cl
CF2CF3
H
Br
H
O
CH2CF3


F94
Cl
Cl
H
Cl
CF2CF3
H
Cl
H
O
CH2CF3


F95
Cl
Cl
H
Cl
CF2CF3
H
CF3
H
O
CH2CF3


F96
Cl
Cl
H
Cl
CF2CF3
H
CH3
H
O
CH2CF3


F97
Cl
Cl
H
Cl
CF3
H
Br
H
O
CH2CF3


F98
Cl
Cl
H
Cl
CF3
H
Cl
H
O
CH2CF3


F99
Cl
Cl
H
Cl
CF3
H
CF3
H
O
CH2CF3


F100
Cl
Cl
H
Cl
CF3
H
CH3
H
O
CH2CF3


F101
Cl
Cl
H
Cl
CF3
H
Br
H
S
CH2CF3


F102
Cl
Cl
H
Cl
CF3
H
Cl
H
S
CH2CF3


F103
Cl
Cl
H
Cl
CF3
H
CF3
H
S
CH2CF3


F104
Cl
Cl
H
Cl
CF3
H
CH3
H
S
CH2CF3


F105
H
H
H
OCF3
CF3
H
Br
CH3
O
CH2CH3


F106
H
H
H
OCF3
CF3
H
Cl
CH3
O
CH2CH3


F107
H
H
H
OCF3
CF3
H
CF3
CH3
O
CH2CH3


F108
H
H
H
OCF3
CF3
H
CH3
CH3
O
CH2CH3


F109
H
H
H
OCF3
CF3
H
Br
CH3
S
CH2CH3


F110
H
H
H
OCF3
CF3
H
Cl
CH3
S
CH2CH3


F111
H
H
H
OCF3
CF3
H
CF3
CH3
S
CH2CH3


F112
H
H
H
OCF3
CF3
H
CH3
CH3
S
CH2CH3


F113
H
H
H
OCF3
CF3
H
Br
H
O
CH2CH3


F114
H
H
H
OCF3
CF3
H
Cl
H
O
CH2CH3


F115
H
H
H
OCF3
CF3
H
CF3
H
O
CH2CH3


F116
H
H
H
OCF3
CF3
H
CH3
H
O
CH2CH3


F117
H
H
H
OCF3
CF3
H
Br
H
S
CH2CH3


F118
H
H
H
OCF3
CF3
H
Cl
H
S
CH2CH3


F119
H
H
H
OCF3
CF3
H
CF3
H
S
CH2CH3


F120
H
H
H
OCF3
CF3
H
CH3
H
S
CH2CH3


F121
H
H
H
OCF3
CF3
CF3
Br
H
O
CH2CF3


F122
H
H
H
OCF3
CF3
CF3
Cl
H
O
CH2CF3


F123
H
H
H
OCF3
CF3
CF3
CF3
H
O
CH2CF3


F124
H
H
H
OCF3
CF3
CF3
CH3
H
O
CH2CF3


F125
H
H
H
OCF3
CF2CF3
H
Br
H
O
CH2CF3


F126
H
H
H
OCF3
CF2CF3
H
Cl
H
O
CH2CF3


F127
H
H
H
OCF3
CF2CF3
H
CF3
H
O
CH2CF3


F128
H
H
H
OCF3
CF2CF3
H
CH3
H
O
CH2CF3


F129
H
H
H
OCF3
CF3
H
Br
H
O
CH2CF3


F130
H
H
H
OCF3
CF3
H
Cl
H
O
CH2CF3


F131
H
H
H
OCF3
CF3
H
CF3
H
O
CH2CF3


F132
H
H
H
OCF3
CF3
H
CH3
H
O
CH2CF3


F133
H
H
H
OCF3
CF3
H
Br
H
S
CH2CF3


F134
H
H
H
OCF3
CF3
H
Cl
H
S
CH2CF3


F135
H
H
H
OCF3
CF3
H
CF3
H
S
CH2CF3


F136
H
H
H
OCF3
CF3
H
CH3
H
S
CH2CF3


F137
H
F
H
Br
CF3
H
Br
CH3
O
CH2CH3


F138
H
F
H
Br
CF3
H
Cl
CH3
O
CH2CH3


F139
H
F
H
Br
CF3
H
CF3
CH3
O
CH2CH3


F140
H
F
H
Br
CF3
H
CH3
CH3
O
CH2CH3


F141
H
F
H
Br
CF3
H
Br
CH3
S
CH2CH3


F142
H
F
H
Br
CF3
H
Cl
CH3
S
CH2CH3


F143
H
F
H
Br
CF3
H
CF3
CH3
S
CH2CH3


F144
H
F
H
Br
CF3
H
CH3
CH3
S
CH2CH3


F145
H
F
H
Br
CF3
H
Br
H
O
CH2CH3


F146
H
F
H
Br
CF3
H
Cl
H
O
CH2CH3


F147
H
F
H
Br
CF3
H
CF3
H
O
CH2CH3


F148
H
F
H
Br
CF3
H
CH3
H
O
CH2CH3


F149
H
F
H
Br
CF3
H
Br
H
S
CH2CH3


F150
H
F
H
Br
CF3
H
Cl
H
S
CH2CH3


F151
H
F
H
Br
CF3
H
CF3
H
S
CH2CH3


F152
H
F
H
Br
CF3
H
CH3
H
S
CH2CH3


F153
H
F
H
Br
CF3
CF3
Br
H
O
CH2CF3


F154
H
F
H
Br
CF3
CF3
Cl
H
O
CH2CF3


F155
H
F
H
Br
CF3
CF3
CF3
H
O
CH2CF3


F156
H
F
H
Br
CF3
CF3
CH3
H
O
CH2CF3


F157
H
F
H
Br
CF2CF3
H
Br
H
O
CH2CF3


F158
H
F
H
Br
CF2CF3
H
Cl
H
O
CH2CF3


F159
H
F
H
Br
CF2CF3
H
CF3
H
O
CH2CF3


F160
H
F
H
Br
CF2CF3
H
CH3
H
O
CH2CF3


F161
H
F
H
Br
CF3
H
Br
H
O
CH2CF3


F162
H
F
H
Br
CF3
H
Cl
H
O
CH2CF3


F163
H
F
H
Br
CF3
H
CF3
H
O
CH2CF3


F164
H
F
H
Br
CF3
H
CH3
H
O
CH2CF3


F165
H
F
H
Br
CF3
H
Br
H
S
CH2CF3


F166
H
F
H
Br
CF3
H
Cl
H
S
CH2CF3


F167
H
F
H
Br
CF3
H
CF3
H
S
CH2CF3


F168
H
F
H
Br
CF3
H
CH3
H
S
CH2CF3


F169
H
CH3
Cl
H
CF3
H
Br
CH3
O
CH2CH3


F170
H
CH3
Cl
H
CF3
H
Cl
CH3
O
CH2CH3


F171
H
CH3
Cl
H
CF3
H
CF3
CH3
O
CH2CH3


F172
H
CH3
Cl
H
CF3
H
CH3
CH3
O
CH2CH3


F173
H
CH3
Cl
H
CF3
H
Br
CH3
S
CH2CH3


F174
H
CH3
Cl
H
CF3
H
Cl
CH3
S
CH2CH3


F175
H
CH3
Cl
H
CF3
H
CF3
CH3
S
CH2CH3


F176
H
CH3
Cl
H
CF3
H
CH3
CH3
S
CH2CH3


F177
H
CH3
Cl
H
CF3
H
Br
H
O
CH2CH3


F178
H
CH3
Cl
H
CF3
H
Cl
H
O
CH2CH3


F179
H
CH3
Cl
H
CF3
H
CF3
H
O
CH2CH3


F180
H
CH3
Cl
H
CF3
H
CH3
H
O
CH2CH3


F181
H
CH3
Cl
H
CF3
H
Br
H
S
CH2CH3


F182
H
CH3
Cl
H
CF3
H
Cl
H
S
CH2CH3


F183
H
CH3
Cl
H
CF3
H
CF3
H
S
CH2CH3


F184
H
CH3
Cl
H
CF3
H
CH3
H
S
CH2CH3


F185
H
CH3
Cl
H
CF3
CF3
Br
H
O
CH2CF3


F186
H
CH3
Cl
H
CF3
CF3
Cl
H
O
CH2CF3


F187
H
CH3
Cl
H
CF3
CF3
CF3
H
O
CH2CF3


F188
H
CH3
Cl
H
CF3
CF3
CH3
H
O
CH2CF3


F189
H
CH3
Cl
H
CF2CF3
H
Br
H
O
CH2CF3


F190
H
CH3
Cl
H
CF2CF3
H
Cl
H
O
CH2CF3


F191
H
CH3
Cl
H
CF2CF3
H
CF3
H
O
CH2CF3


F192
H
CH3
Cl
H
CF2CF3
H
CH3
H
O
CH2CF3


F193
H
CH3
Cl
H
CF3
H
Br
H
O
CH2CF3


F194
H
CH3
Cl
H
CF3
H
Cl
H
O
CH2CF3


F195
H
CH3
Cl
H
CF3
H
CF3
H
O
CH2CF3


F196
H
CH3
Cl
H
CF3
H
CH3
H
O
CH2CF3


F197
H
CH3
Cl
H
CF3
H
Br
H
S
CH2CF3


F198
H
CH3
Cl
H
CF3
H
Cl
H
S
CH2CF3


F199
H
CH3
Cl
H
CF3
H
CF3
H
S
CH2CF3


F200
H
CH3
Cl
H
CF3
H
CH3
H
S
CH2CF3


F201
H
Cl
CH3
H
CF3
H
Br
CH3
O
CH2CH3


F202
H
Cl
CH3
H
CF3
H
Cl
CH3
O
CH2CH3


F203
H
Cl
CH3
H
CF3
H
CF3
CH3
O
CH2CH3


F204
H
Cl
CH3
H
CF3
H
CH3
CH3
O
CH2CH3


F205
H
Cl
CH3
H
CF3
H
Br
CH3
S
CH2CH3


F206
H
Cl
CH3
H
CF3
H
Cl
CH3
S
CH2CH3


F207
H
Cl
CH3
H
CF3
H
CF3
CH3
S
CH2CH3


F208
H
Cl
CH3
H
CF3
H
CH3
CH3
S
CH2CH3


F209
H
Cl
CH3
H
CF3
H
Br
H
O
CH2CH3


F210
H
Cl
CH3
H
CF3
H
Cl
H
O
CH2CH3


F211
H
Cl
CH3
H
CF3
H
CF3
H
O
CH2CH3


F212
H
Cl
CH3
H
CF3
H
CH3
H
O
CH2CH3


F213
H
Cl
CH3
H
CF3
H
Br
H
S
CH2CH3


F214
H
Cl
CH3
H
CF3
H
Cl
H
S
CH2CH3


F215
H
Cl
CH3
H
CF3
H
CF3
H
S
CH2CH3


F216
H
Cl
CH3
H
CF3
H
CH3
H
S
CH2CH3


F217
H
Cl
CH3
H
CF3
CF3
Br
H
O
CH2CF3


F218
H
Cl
CH3
H
CF3
CF3
Cl
H
O
CH2CF3


F219
H
Cl
CH3
H
CF3
CF3
CF3
H
O
CH2CF3


F220
H
Cl
CH3
H
CF3
CF3
CH3
H
O
CH2CF3


F221
H
Cl
CH3
H
CF2CF3
H
Br
H
O
CH2CF3


F222
H
Cl
CH3
H
CF2CF3
H
Cl
H
O
CH2CF3


F223
H
Cl
CH3
H
CF2CF3
H
CF3
H
O
CH2CF3


F224
H
Cl
CH3
H
CF2CF3
H
CH3
H
O
CH2CF3


F225
H
Cl
CH3
H
CF3
H
Br
H
O
CH2CF3


F226
H
Cl
CH3
H
CF3
H
Cl
H
O
CH2CF3


F227
H
Cl
CH3
H
CF3
H
CF3
H
O
CH2CF3


F228
H
Cl
CH3
H
CF3
H
CH3
H
O
CH2CF3


F229
H
Cl
CH3
H
CF3
H
Br
H
S
CH2CF3


F230
H
Cl
CH3
H
CF3
H
Cl
H
S
CH2CF3


F231
H
Cl
CH3
H
CF3
H
CF3
H
S
CH2CF3


F232
H
Cl
CH3
H
CF3
H
CH3
H
S
CH2CF3


F233
H
CH3
F
CH3
CF3
H
Br
CH3
O
CH2CH3


F234
H
CH3
F
CH3
CF3
H
Cl
CH3
O
CH2CH3


F235
H
CH3
F
CH3
CF3
H
CF3
CH3
O
CH2CH3


F236
H
CH3
F
CH3
CF3
H
CH3
CH3
O
CH2CH3


F237
H
CH3
F
CH3
CF3
H
Br
CH3
S
CH2CH3


F238
H
CH3
F
CH3
CF3
H
Cl
CH3
S
CH2CH3


F239
H
CH3
F
CH3
CF3
H
CF3
CH3
S
CH2CH3


F240
H
CH3
F
CH3
CF3
H
CH3
CH3
S
CH2CH3


F241
H
CH3
F
CH3
CF3
H
Br
H
O
CH2CH3


F242
H
CH3
F
CH3
CF3
H
Cl
H
O
CH2CH3


F243
H
CH3
F
CH3
CF3
H
CF3
H
O
CH2CH3


F244
H
CH3
F
CH3
CF3
H
CH3
H
O
CH2CH3


F245
H
CH3
F
CH3
CF3
H
Br
H
S
CH2CH3


F246
H
CH3
F
CH3
CF3
H
Cl
H
S
CH2CH3


F247
H
CH3
F
CH3
CF3
H
CF3
H
S
CH2CH3


F248
H
CH3
F
CH3
CF3
H
CH3
H
S
CH2CH3


F249
H
CH3
F
CH3
CF3
CF3
Br
H
O
CH2CF3


F250
H
CH3
F
CH3
CF3
CF3
Cl
H
O
CH2CF3


F251
H
CH3
F
CH3
CF3
CF3
CF3
H
O
CH2CF3


F252
H
CH3
F
CH3
CF3
CF3
CH3
H
O
CH2CF3


F253
H
CH3
F
CH3
CF2CF3
H
Br
H
O
CH2CF3


F254
H
CH3
F
CH3
CF2CF3
H
Cl
H
O
CH2CF3


F255
H
CH3
F
CH3
CF2CF3
H
CF3
H
O
CH2CF3


F256
H
CH3
F
CH3
CF2CF3
H
CH3
H
O
CH2CF3


F257
H
CH3
F
CH3
CF3
H
Br
H
O
CH2CF3


F258
H
CH3
F
CH3
CF3
H
Cl
H
O
CH2CF3


F259
H
CH3
F
CH3
CF3
H
CF3
H
O
CH2CF3


F260
H
CH3
F
CH3
CF3
H
CH3
H
O
CH2CF3


F261
H
CH3
F
CH3
CF3
H
Br
H
S
CH2CF3


F262
H
CH3
F
CH3
CF3
H
Cl
H
S
CH2CF3


F263
H
CH3
F
CH3
CF3
H
CF3
H
S
CH2CF3


F264
H
CH3
F
CH3
CF3
H
CH3
H
S
CH2CF3


F265
H
Cl
H
Br
CF3
H
Br
CH3
O
CH2CH3


F266
H
Cl
H
Br
CF3
H
Cl
CH3
O
CH2CH3


F267
H
Cl
H
Br
CF3
H
CF3
CH3
O
CH2CH3


F268
H
Cl
H
Br
CF3
H
CH3
CH3
O
CH2CH3


F269
H
Cl
H
Br
CF3
H
Br
CH3
S
CH2CH3


F270
H
Cl
H
Br
CF3
H
Cl
CH3
S
CH2CH3


F271
H
Cl
H
Br
CF3
H
CF3
CH3
S
CH2CH3


F272
H
Cl
H
Br
CF3
H
CH3
CH3
S
CH2CH3


F273
H
Cl
H
Br
CF3
H
Br
H
O
CH2CH3


F274
H
Cl
H
Br
CF3
H
Cl
H
O
CH2CH3


F275
H
Cl
H
Br
CF3
H
CF3
H
O
CH2CH3


F276
H
Cl
H
Br
CF3
H
CH3
H
O
CH2CH3


F277
H
Cl
H
Br
CF3
H
Br
H
S
CH2CH3


F278
H
Cl
H
Br
CF3
H
Cl
H
S
CH2CH3


F279
H
Cl
H
Br
CF3
H
CF3
H
S
CH2CH3


F280
H
Cl
H
Br
CF3
H
CH3
H
S
CH2CH3


F281
H
Cl
H
Br
CF3
CF3
Br
H
O
CH2CF3


F282
H
Cl
H
Br
CF3
CF3
Cl
H
O
CH2CF3


F283
H
Cl
H
Br
CF3
CF3
CF3
H
O
CH2CF3


F284
H
Cl
H
Br
CF3
CF3
CH3
H
O
CH2CF3


F285
H
Cl
H
Br
CF2CF3
H
Br
H
O
CH2CF3


F286
H
Cl
H
Br
CF2CF3
H
Cl
H
O
CH2CF3


F287
H
Cl
H
Br
CF2CF3
H
CF3
H
O
CH2CF3


F288
H
Cl
H
Br
CF2CF3
H
CH3
H
O
CH2CF3


F289
H
Cl
H
Br
CF3
H
Br
H
O
CH2CF3


F290
H
Cl
H
Br
CF3
H
Cl
H
O
CH2CF3


F291
H
Cl
H
Br
CF3
H
CF3
H
O
CH2CF3


F292
H
Cl
H
Br
CF3
H
CH3
H
O
CH2CF3


F293
H
Cl
H
Br
CF3
H
Br
H
S
CH2CF3


F294
H
Cl
H
Br
CF3
H
Cl
H
S
CH2CF3


F295
H
Cl
H
Br
CF3
H
CF3
H
S
CH2CF3


F296
H
Cl
H
Br
CF3
H
CH3
H
S
CH2CF3


F297
H
H
Br
Br
CF3
H
Br
CH3
O
CH2CH3


F298
H
H
Br
Br
CF3
H
Cl
CH3
O
CH2CH3


F299
H
H
Br
Br
CF3
H
CF3
CH3
O
CH2CH3


F300
H
H
Br
Br
CF3
H
CH3
CH3
O
CH2CH3


F301
H
H
Br
Br
CF3
H
Br
CH3
S
CH2CH3


F302
H
H
Br
Br
CF3
H
Cl
CH3
S
CH2CH3


F303
H
H
Br
Br
CF3
H
CF3
CH3
S
CH2CH3


F304
H
H
Br
Br
CF3
H
CH3
CH3
S
CH2CH3


F305
H
H
Br
Br
CF3
H
Br
H
O
CH2CH3


F306
H
H
Br
Br
CF3
H
Cl
H
O
CH2CH3


F307
H
H
Br
Br
CF3
H
CF3
H
O
CH2CH3


F308
H
H
Br
Br
CF3
H
CH3
H
O
CH2CH3


F309
H
H
Br
Br
CF3
H
Br
H
S
CH2CH3


F310
H
H
Br
Br
CF3
H
Cl
H
S
CH2CH3


F311
H
H
Br
Br
CF3
H
CF3
H
S
CH2CH3


F312
H
H
Br
Br
CF3
H
CH3
H
S
CH2CH3


F313
H
H
Br
Br
CF3
CF3
Br
H
O
CH2CF3


F314
H
H
Br
Br
CF3
CF3
Cl
H
O
CH2CF3


F315
H
H
Br
Br
CF3
CF3
CF3
H
O
CH2CF3


F316
H
H
Br
Br
CF3
CF3
CH3
H
O
CH2CF3


F317
H
H
Br
Br
CF2CF3
H
Br
H
O
CH2CF3


F318
H
H
Br
Br
CF2CF3
H
Cl
H
O
CH2CF3


F319
H
H
Br
Br
CF2CF3
H
CF3
H
O
CH2CF3


F320
H
H
Br
Br
CF2CF3
H
CH3
H
O
CH2CF3


F321
H
H
Br
Br
CF3
H
Br
H
O
CH2CF3


F322
H
H
Br
Br
CF3
H
Cl
H
O
CH2CF3


F323
H
H
Br
Br
CF3
H
CF3
H
O
CH2CF3


F324
H
H
Br
Br
CF3
H
CH3
H
O
CH2CF3


F325
H
H
Br
Br
CF3
H
Br
H
S
CH2CF3


F326
H
H
Br
Br
CF3
H
Cl
H
S
CH2CF3


F327
H
H
Br
Br
CF3
H
CF3
H
S
CH2CF3


F328
H
H
Br
Br
CF3
H
CH3
H
S
CH2CF3


F329
H
H
Cl
NO2
CF3
H
Br
CH3
O
CH2CH3


F330
H
H
Cl
NO2
CF3
H
Cl
CH3
O
CH2CH3


F331
H
H
Cl
NO2
CF3
H
CF3
CH3
O
CH2CH3


F332
H
H
Cl
NO2
CF3
H
CH3
CH3
O
CH2CH3


F333
H
H
Cl
NO2
CF3
H
Br
CH3
S
CH2CH3


F334
H
H
Cl
NO2
CF3
H
Cl
CH3
S
CH2CH3


F335
H
H
Cl
NO2
CF3
H
CF3
CH3
S
CH2CH3


F336
H
H
Cl
NO2
CF3
H
CH3
CH3
S
CH2CH3


F337
H
H
Cl
NO2
CF3
H
Br
H
O
CH2CH3


F338
H
H
Cl
NO2
CF3
H
Cl
H
O
CH2CH3


F339
H
H
Cl
NO2
CF3
H
CF3
H
O
CH2CH3


F340
H
H
Cl
NO2
CF3
H
CH3
H
O
CH2CH3


F341
H
H
Cl
NO2
CF3
H
Br
H
S
CH2CH3


F342
H
H
Cl
NO2
CF3
H
Cl
H
S
CH2CH3


F343
H
H
Cl
NO2
CF3
H
CF3
H
S
CH2CH3


F344
H
H
Cl
NO2
CF3
H
CH3
H
S
CH2CH3


F345
H
H
Cl
NO2
CF3
CF3
Br
H
O
CH2CF3


F346
H
H
Cl
NO2
CF3
CF3
Cl
H
O
CH2CF3


F347
H
H
Cl
NO2
CF3
CF3
CF3
H
O
CH2CF3


F348
H
H
Cl
NO2
CF3
CF3
CH3
H
O
CH2CF3


F349
H
H
Cl
NO2
CF2CF3
H
Br
H
O
CH2CF3


F350
H
H
Cl
NO2
CF2CF3
H
Cl
H
O
CH2CF3


F351
H
H
Cl
NO2
CF2CF3
H
CF3
H
O
CH2CF3


F352
H
H
Cl
NO2
CF2CF3
H
CH3
H
O
CH2CF3


F353
H
H
Cl
NO2
CF3
H
Br
H
O
CH2CF3


F354
H
H
Cl
NO2
CF3
H
Cl
H
O
CH2CF3


F355
H
H
Cl
NO2
CF3
H
CF3
H
O
CH2CF3


F356
H
H
Cl
NO2
CF3
H
CH3
H
O
CH2CF3


F357
H
H
Cl
NO2
CF3
H
Br
H
S
CH2CF3


F358
H
H
Cl
NO2
CF3
H
Cl
H
S
CH2CF3


F359
H
H
Cl
NO2
CF3
H
CF3
H
S
CH2CF3


F360
H
H
Cl
NO2
CF3
H
CH3
H
S
CH2CF3


F361
H
H
F
CN
CF3
H
Br
CH3
O
CH2CH3


F362
H
H
F
CN
CF3
H
Cl
CH3
O
CH2CH3


F363
H
H
F
CN
CF3
H
CF3
CH3
O
CH2CH3


F364
H
H
F
CN
CF3
H
CH3
CH3
O
CH2CH3


F365
H
H
F
CN
CF3
H
Br
CH3
S
CH2CH3


F366
H
H
F
CN
CF3
H
Cl
CH3
S
CH2CH3


F367
H
H
F
CN
CF3
H
CF3
CH3
S
CH2CH3


F368
H
H
F
CN
CF3
H
CH3
CH3
S
CH2CH3


F369
H
H
F
CN
CF3
H
Br
H
O
CH2CH3


F370
H
H
F
CN
CF3
H
Cl
H
O
CH2CH3


F371
H
H
F
CN
CF3
H
CF3
H
O
CH2CH3


F372
H
H
F
CN
CF3
H
CH3
H
O
CH2CH3


F373
H
H
F
CN
CF3
H
Br
H
S
CH2CH3


F374
H
H
F
CN
CF3
H
Cl
H
S
CH2CH3


F375
H
H
F
CN
CF3
H
CF3
H
S
CH2CH3


F376
H
H
F
CN
CF3
H
CH3
H
S
CH2CH3


F377
H
H
F
CN
CF3
CF3
Br
H
O
CH2CF3


F378
H
H
F
CN
CF3
CF3
Cl
H
O
CH2CF3


F379
H
H
F
CN
CF3
CF3
CF3
H
O
CH2CF3


F380
H
H
F
CN
CF3
CF3
CH3
H
O
CH2CF3


F381
H
H
F
CN
CF2CF3
H
Br
H
O
CH2CF3


F382
H
H
F
CN
CF2CF3
H
Cl
H
O
CH2CF3


F383
H
H
F
CN
CF2CF3
H
CF3
H
O
CH2CF3


F384
H
H
F
CN
CF2CF3
H
CH3
H
O
CH2CF3


F385
H
H
F
CN
CF3
H
Br
H
O
CH2CF3


F386
H
H
F
CN
CF3
H
Cl
H
O
CH2CF3


F387
H
H
F
CN
CF3
H
CF3
H
O
CH2CF3


F388
H
H
F
CN
CF3
H
CH3
H
O
CH2CF3


F389
H
H
F
CN
CF3
H
Br
H
S
CH2CF3


F390
H
H
F
CN
CF3
H
Cl
H
S
CH2CF3


F391
H
H
F
CN
CF3
H
CF3
H
S
CH2CF3


F392
H
H
F
CN
CF3
H
CH3
H
S
CH2CF3


F393
H
Cl
OCF3
Cl
CF3
H
Br
CH3
O
CH2CH3


F394
H
Cl
OCF3
Cl
CF3
H
Cl
CH3
O
CH2CH3


F395
H
Cl
OCF3
Cl
CF3
H
CF3
CH3
O
CH2CH3


F396
H
Cl
OCF3
Cl
CF3
H
CH3
CH3
O
CH2CH3


F397
H
Cl
OCF3
Cl
CF3
H
Br
CH3
S
CH2CH3


F398
H
Cl
OCF3
Cl
CF3
H
Cl
CH3
S
CH2CH3


F399
H
Cl
OCF3
Cl
CF3
H
CF3
CH3
S
CH2CH3


F400
H
Cl
OCF3
Cl
CF3
H
CH3
CH3
S
CH2CH3


F401
H
Cl
OCF3
Cl
CF3
H
Br
H
O
CH2CH3


F402
H
Cl
OCF3
Cl
CF3
H
Cl
H
O
CH2CH3


F403
H
Cl
OCF3
Cl
CF3
H
CF3
H
O
CH2CH3


F404
H
Cl
OCF3
Cl
CF3
H
CH3
H
O
CH2CH3


F405
H
Cl
OCF3
Cl
CF3
H
Br
H
S
CH2CH3


F406
H
Cl
OCF3
Cl
CF3
H
Cl
H
S
CH2CH3


F407
H
Cl
OCF3
Cl
CF3
H
CF3
H
S
CH2CH3


F408
H
Cl
OCF3
Cl
CF3
H
CH3
H
S
CH2CH3


F409
H
Cl
OCF3
Cl
CF3
CF3
Br
H
O
CH2CF3


F410
H
Cl
OCF3
Cl
CF3
CF3
Cl
H
O
CH2CF3


F411
H
Cl
OCF3
Cl
CF3
CF3
CF3
H
O
CH2CF3


F412
H
Cl
OCF3
Cl
CF3
CF3
CH3
H
O
CH2CF3


F413
H
Cl
OCF3
Cl
CF2CF3
H
Br
H
O
CH2CF3


F414
H
Cl
OCF3
Cl
CF2CF3
H
Cl
H
O
CH2CF3


F415
H
Cl
OCF3
Cl
CF2CF3
H
CF3
H
O
CH2CF3


F416
H
Cl
OCF3
Cl
CF2CF3
H
CH3
H
O
CH2CF3


F417
H
Cl
OCF3
Cl
CF3
H
Br
H
O
CH2CF3


F418
H
Cl
OCF3
Cl
CF3
H
Cl
H
O
CH2CF3


F419
H
Cl
OCF3
Cl
CF3
H
CF3
H
O
CH2CF3


F420
H
Cl
OCF3
Cl
CF3
H
CH3
H
O
CH2CF3


F421
H
Cl
OCF3
Cl
CF3
H
Br
H
S
CH2CF3


F422
H
Cl
OCF3
Cl
CF3
H
Cl
H
S
CH2CF3


F423
H
Cl
OCF3
Cl
CF3
H
CF3
H
S
CH2CF3


F424
H
Cl
OCF3
Cl
CF3
H
CH3
H
S
CH2CF3


F425
H
Cl
CN
Cl
CF3
H
Br
CH3
O
CH2CH3


F426
H
Cl
CN
Cl
CF3
H
Cl
CH3
O
CH2CH3


F427
H
Cl
CN
Cl
CF3
H
CF3
CH3
O
CH2CH3


F428
H
Cl
CN
Cl
CF3
H
CH3
CH3
O
CH2CH3


F429
H
Cl
CN
Cl
CF3
H
Br
CH3
S
CH2CH3


F430
H
Cl
CN
Cl
CF3
H
Cl
CH3
S
CH2CH3


F431
H
Cl
CN
Cl
CF3
H
CF3
CH3
S
CH2CH3


F432
H
Cl
CN
Cl
CF3
H
CH3
CH3
S
CH2CH3


F433
H
Cl
CN
Cl
CF3
H
Br
H
O
CH2CH3


F434
H
Cl
CN
Cl
CF3
H
Cl
H
O
CH2CH3


F435
H
Cl
CN
Cl
CF3
H
CF3
H
O
CH2CH3


F436
H
Cl
CN
Cl
CF3
H
CH3
H
O
CH2CH3


F437
H
Cl
CN
Cl
CF3
H
Br
H
S
CH2CH3


F438
H
Cl
CN
Cl
CF3
H
Cl
H
S
CH2CH3


F439
H
Cl
CN
Cl
CF3
H
CF3
H
S
CH2CH3


F440
H
Cl
CN
Cl
CF3
H
CH3
H
S
CH2CH3


F441
H
Cl
CN
Cl
CF3
CF3
Br
H
O
CH2CF3


F442
H
Cl
CN
Cl
CF3
CF3
Cl
H
O
CH2CF3


F443
H
Cl
CN
Cl
CF3
CF3
CF3
H
O
CH2CF3


F444
H
Cl
CN
Cl
CF3
CF3
CH3
H
O
CH2CF3


F445
H
Cl
CN
Cl
CF2CF3
H
Br
H
O
CH2CF3


F446
H
Cl
CN
Cl
CF2CF3
H
Cl
H
O
CH2CF3


F447
H
Cl
CN
Cl
CF2CF3
H
CF3
H
O
CH2CF3


F448
H
Cl
CN
Cl
CF2CF3
H
CH3
H
O
CH2CF3


F449
H
Cl
CN
Cl
CF3
H
Br
H
O
CH2CF3


F450
H
Cl
CN
Cl
CF3
H
Cl
H
O
CH2CF3


F451
H
Cl
CN
Cl
CF3
H
CF3
H
O
CH2CF3


F452
H
Cl
CN
Cl
CF3
H
CH3
H
O
CH2CF3


F453
H
Cl
CN
Cl
CF3
H
Br
H
S
CH2CF3


F454
H
Cl
CN
Cl
CF3
H
Cl
H
S
CH2CF3


F455
H
Cl
CN
Cl
CF3
H
CF3
H
S
CH2CF3


F456
H
Cl
CN
Cl
CF3
H
CH3
H
S
CH2CF3


F457
H
CH3
H
Br
CF3
H
Br
CH3
O
CH2CH3


F458
H
CH3
H
Br
CF3
H
Cl
CH3
O
CH2CH3


F459
H
CH3
H
Br
CF3
H
CF3
CH3
O
CH2CH3


F460
H
CH3
H
Br
CF3
H
CH3
CH3
O
CH2CH3


F461
H
CH3
H
Br
CF3
H
Br
CH3
S
CH2CH3


F462
H
CH3
H
Br
CF3
H
Cl
CH3
S
CH2CH3


F463
H
CH3
H
Br
CF3
H
CF3
CH3
S
CH2CH3


F464
H
CH3
H
Br
CF3
H
CH3
CH3
S
CH2CH3


F465
H
CH3
H
Br
CF3
H
Br
H
O
CH2CH3


F466
H
CH3
H
Br
CF3
H
Cl
H
O
CH2CH3


F467
H
CH3
H
Br
CF3
H
CF3
H
O
CH2CH3


F468
H
CH3
H
Br
CF3
H
CH3
H
O
CH2CH3


F469
H
CH3
H
Br
CF3
H
Br
H
S
CH2CH3


F470
H
CH3
H
Br
CF3
H
Cl
H
S
CH2CH3


F471
H
CH3
H
Br
CF3
H
CF3
H
S
CH2CH3


F472
H
CH3
H
Br
CF3
H
CH3
H
S
CH2CH3


F473
H
CH3
H
Br
CF3
CF3
Br
H
O
CH2CF3


F474
H
CH3
H
Br
CF3
CF3
Cl
H
O
CH2CF3


F475
H
CH3
H
Br
CF3
CF3
CF3
H
O
CH2CF3


F476
H
CH3
H
Br
CF3
CF3
CH3
H
O
CH2CF3


F477
H
CH3
H
Br
CF2CF3
H
Br
H
O
CH2CF3


F478
H
CH3
H
Br
CF2CF3
H
Cl
H
O
CH2CF3


F479
H
CH3
H
Br
CF2CF3
H
CF3
H
O
CH2CF3


F480
H
CH3
H
Br
CF2CF3
H
CH3
H
O
CH2CF3


F481
H
CH3
H
Br
CF3
H
Br
H
O
CH2CF3


F482
H
CH3
H
Br
CF3
H
Cl
H
O
CH2CF3


F483
H
CH3
H
Br
CF3
H
CF3
H
O
CH2CF3


F484
H
CH3
H
Br
CF3
H
CH3
H
O
CH2CF3


F485
H
CH3
H
Br
CF3
H
Br
H
S
CH2CF3


F486
H
CH3
H
Br
CF3
H
Cl
H
S
CH2CF3


F487
H
CH3
H
Br
CF3
H
CF3
H
S
CH2CF3


F488
H
CH3
H
Br
CF3
H
CH3
H
S
CH2CF3


F489
H
H
F
CH3
CF3
H
Br
CH3
O
CH2CH3


F490
H
H
F
CH3
CF3
H
Cl
CH3
O
CH2CH3


F491
H
H
F
CH3
CF3
H
CF3
CH3
O
CH2CH3


F492
H
H
F
CH3
CF3
H
CH3
CH3
O
CH2CH3


F493
H
H
F
CH3
CF3
H
Br
CH3
S
CH2CH3


F494
H
H
F
CH3
CF3
H
Cl
CH3
S
CH2CH3


F495
H
H
F
CH3
CF3
H
CF3
CH3
S
CH2CH3


F496
H
H
F
CH3
CF3
H
CH3
CH3
S
CH2CH3


F497
H
H
F
CH3
CF3
H
Br
H
O
CH2CH3


F498
H
H
F
CH3
CF3
H
Cl
H
O
CH2CH3


F499
H
H
F
CH3
CF3
H
CF3
H
O
CH2CH3


F500
H
H
F
CH3
CF3
H
CH3
H
O
CH2CH3


F501
H
H
F
CH3
CF3
H
Br
H
S
CH2CH3


F502
H
H
F
CH3
CF3
H
Cl
H
S
CH2CH3


F503
H
H
F
CH3
CF3
H
CF3
H
S
CH2CH3


F504
H
H
F
CH3
CF3
H
CH3
H
S
CH2CH3


F505
H
H
F
CH3
CF3
CF3
Br
H
O
CH2CF3


F506
H
H
F
CH3
CF3
CF3
Cl
H
O
CH2CF3


F507
H
H
F
CH3
CF3
CF3
CF3
H
O
CH2CF3


F508
H
H
F
CH3
CF3
CF3
CH3
H
O
CH2CF3


F509
H
H
F
CH3
CF2CF3
H
Br
H
O
CH2CF3


F510
H
H
F
CH3
CF2CF3
H
Cl
H
O
CH2CF3


F511
H
H
F
CH3
CF2CF3
H
CF3
H
O
CH2CF3


F512
H
H
F
CH3
CF2CF3
H
CH3
H
O
CH2CF3


F513
H
H
F
CH3
CF3
H
Br
H
O
CH2CF3


F514
H
H
F
CH3
CF3
H
Cl
H
O
CH2CF3


F515
H
H
F
CH3
CF3
H
CF3
H
O
CH2CF3


F516
H
H
F
CH3
CF3
H
CH3
H
O
CH2CF3


F517
H
H
F
CH3
CF3
H
Br
H
S
CH2CF3


F518
H
H
F
CH3
CF3
H
Cl
H
S
CH2CF3


F519
H
H
F
CH3
CF3
H
CF3
H
S
CH2CF3


F520
H
H
F
CH3
CF3
H
CH3
H
S
CH2CF3


F521
H
H
F
Cl
CF3
H
Br
CH3
O
CH2CH3


F522
H
H
F
Cl
CF3
H
Cl
CH3
O
CH2CH3


F523
H
H
F
Cl
CF3
H
CF3
CH3
O
CH2CH3


F524
H
H
F
Cl
CF3
H
CH3
CH3
O
CH2CH3


F525
H
H
F
Cl
CF3
H
Br
CH3
S
CH2CH3


F526
H
H
F
Cl
CF3
H
Cl
CH3
S
CH2CH3


F527
H
H
F
Cl
CF3
H
CF3
CH3
S
CH2CH3


F528
H
H
F
Cl
CF3
H
CH3
CH3
S
CH2CH3


F529
H
H
F
Cl
CF3
H
Br
H
O
CH2CH3


F530
H
H
F
Cl
CF3
H
Cl
H
O
CH2CH3


F531
H
H
F
Cl
CF3
H
CF3
H
O
CH2CH3


F532
H
H
F
Cl
CF3
H
CH3
H
O
CH2CH3


F533
H
H
F
Cl
CF3
H
Br
H
S
CH2CH3


F534
H
H
F
Cl
CF3
H
Cl
H
S
CH2CH3


F535
H
H
F
Cl
CF3
H
CF3
H
S
CH2CH3


F536
H
H
F
Cl
CF3
H
CH3
H
S
CH2CH3


F537
H
H
F
Cl
CF3
CF3
Br
H
O
CH2CF3


F538
H
H
F
Cl
CF3
CF3
Cl
H
O
CH2CF3


F539
H
H
F
Cl
CF3
CF3
CF3
H
O
CH2CF3


F540
H
H
F
Cl
CF3
CF3
CH3
H
O
CH2CF3


F541
H
H
F
Cl
CF2CF3
H
Br
H
O
CH2CF3


F542
H
H
F
Cl
CF2CF3
H
Cl
H
O
CH2CF3


F543
H
H
F
Cl
CF2CF3
H
CF3
H
O
CH2CF3


F544
H
H
F
Cl
CF2CF3
H
CH3
H
O
CH2CF3


F545
H
H
F
Cl
CF3
H
Br
H
O
CH2CF3


F546
H
H
F
Cl
CF3
H
Cl
H
O
CH2CF3


F547
H
H
F
Cl
CF3
H
CF3
H
O
CH2CF3


F548
H
H
F
Cl
CF3
H
CH3
H
O
CH2CF3


F549
H
H
F
Cl
CF3
H
Br
H
S
CH2CF3


F550
H
H
F
Cl
CF3
H
Cl
H
S
CH2CF3


F551
H
H
F
Cl
CF3
H
CF3
H
S
CH2CF3


F552
H
H
F
Cl
CF3
H
CH3
H
S
CH2CF3


F553
H
F
F
F
CF3
H
Br
CH3
O
CH2CH3


F554
H
F
F
F
CF3
H
Cl
CH3
O
CH2CH3


F555
H
F
F
F
CF3
H
CF3
CH3
O
CH2CH3


F556
H
F
F
F
CF3
H
CH3
CH3
O
CH2CH3


F557
H
F
F
F
CF3
H
Br
CH3
S
CH2CH3


F558
H
F
F
F
CF3
H
Cl
CH3
S
CH2CH3


F559
H
F
F
F
CF3
H
CF3
CH3
S
CH2CH3


F560
H
F
F
F
CF3
H
CH3
CH3
S
CH2CH3


F561
H
F
F
F
CF3
H
Br
H
O
CH2CH3


F562
H
F
F
F
CF3
H
Cl
H
O
CH2CH3


F563
H
F
F
F
CF3
H
CF3
H
O
CH2CH3


F564
H
F
F
F
CF3
H
CH3
H
O
CH2CH3


F565
H
F
F
F
CF3
H
Br
H
S
CH2CH3


F566
H
F
F
F
CF3
H
Cl
H
S
CH2CH3


F567
H
F
F
F
CF3
H
CF3
H
S
CH2CH3


F568
H
F
F
F
CF3
H
CH3
H
S
CH2CH3


F569
H
F
F
F
CF3
CF3
Br
H
O
CH2CF3


F570
H
F
F
F
CF3
CF3
Cl
H
O
CH2CF3


F571
H
F
F
F
CF3
CF3
CF3
H
O
CH2CF3


F572
H
F
F
F
CF3
CF3
CH3
H
O
CH2CF3


F573
H
F
F
F
CF2CF3
H
Br
H
O
CH2CF3


F574
H
F
F
F
CF2CF3
H
Cl
H
O
CH2CF3


F575
H
F
F
F
CF2CF3
H
CF3
H
O
CH2CF3


F576
H
F
F
F
CF2CF3
H
CH3
H
O
CH2CF3


F577
H
F
F
F
CF3
H
Br
H
O
CH2CF3


F578
H
F
F
F
CF3
H
Cl
H
O
CH2CF3


F579
H
F
F
F
CF3
H
CF3
H
O
CH2CF3


F580
H
F
F
F
CF3
H
CH3
H
O
CH2CF3


F581
H
F
F
F
CF3
H
Br
H
S
CH2CF3


F582
H
F
F
F
CF3
H
Cl
H
S
CH2CF3


F583
H
F
F
F
CF3
H
CF3
H
S
CH2CF3


F584
H
F
F
F
CF3
H
CH3
H
S
CH2CF3


F585
H
CF3
H
CF3
CF3
H
Br
CH3
O
CH2CH3


F586
H
CF3
H
CF3
CF3
H
Cl
CH3
O
CH2CH3


F587
H
CF3
H
CF3
CF3
H
CF3
CH3
O
CH2CH3


F588
H
CF3
H
CF3
CF3
H
CH3
CH3
O
CH2CH3


F589
H
CF3
H
CF3
CF3
H
Br
CH3
S
CH2CH3


F590
H
CF3
H
CF3
CF3
H
Cl
CH3
S
CH2CH3


F591
H
CF3
H
CF3
CF3
H
CF3
CH3
S
CH2CH3


F592
H
CF3
H
CF3
CF3
H
CH3
CH3
S
CH2CH3


F593
H
CF3
H
CF3
CF3
H
Br
H
O
CH2CH3


F594
H
CF3
H
CF3
CF3
H
Cl
H
O
CH2CH3


F595
H
CF3
H
CF3
CF3
H
CF3
H
O
CH2CH3


F596
H
CF3
H
CF3
CF3
H
CH3
H
O
CH2CH3


F597
H
CF3
H
CF3
CF3
H
Br
H
S
CH2CH3


F598
H
CF3
H
CF3
CF3
H
Cl
H
S
CH2CH3


F599
H
CF3
H
CF3
CF3
H
CF3
H
S
CH2CH3


F600
H
CF3
H
CF3
CF3
H
CH3
H
S
CH2CH3


F601
H
CF3
H
CF3
CF3
CF3
Br
H
O
CH2CF3


F602
H
CF3
H
CF3
CF3
CF3
Cl
H
O
CH2CF3


F603
H
CF3
H
CF3
CF3
CF3
CF3
H
O
CH2CF3


F604
H
CF3
H
CF3
CF3
CF3
CH3
H
O
CH2CF3


F605
H
CF3
H
CF3
CF2CF3
H
Br
H
O
CH2CF3


F606
H
CF3
H
CF3
CF2CF3
H
Cl
H
O
CH2CF3


F607
H
CF3
H
CF3
CF2CF3
H
CF3
H
O
CH2CF3


F608
H
CF3
H
CF3
CF2CF3
H
CH3
H
O
CH2CF3


F609
H
CF3
H
CF3
CF3
H
Br
H
O
CH2CF3


F610
H
CF3
H
CF3
CF3
H
Cl
H
O
CH2CF3


F611
H
CF3
H
CF3
CF3
H
CF3
H
O
CH2CF3


F612
H
CF3
H
CF3
CF3
H
CH3
H
O
CH2CF3


F613
H
CF3
H
CF3
CF3
H
Br
H
S
CH2CF3


F614
H
CF3
H
CF3
CF3
H
Cl
H
S
CH2CF3


F615
H
CF3
H
CF3
CF3
H
CF3
H
S
CH2CF3


F616
H
CF3
H
CF3
CF3
H
CH3
H
S
CH2CF3


F617
H
F
H
CF3
CF3
H
Br
CH3
O
CH2CH3


F618
H
F
H
CF3
CF3
H
Cl
CH3
O
CH2CH3


F619
H
F
H
CF3
CF3
H
CF3
CH3
O
CH2CH3


F620
H
F
H
CF3
CF3
H
CH3
CH3
O
CH2CH3


F621
H
F
H
CF3
CF3
H
Br
CH3
S
CH2CH3


F622
H
F
H
CF3
CF3
H
Cl
CH3
S
CH2CH3


F623
H
F
H
CF3
CF3
H
CF3
CH3
S
CH2CH3


F624
H
F
H
CF3
CF3
H
CH3
CH3
S
CH2CH3


F625
H
F
H
CF3
CF3
H
Br
H
O
CH2CH3


F626
H
F
H
CF3
CF3
H
Cl
H
O
CH2CH3


F627
H
F
H
CF3
CF3
H
CF3
H
O
CH2CH3


F628
H
F
H
CF3
CF3
H
CH3
H
O
CH2CH3


F629
H
F
H
CF3
CF3
H
Br
H
S
CH2CH3


F630
H
F
H
CF3
CF3
H
Cl
H
S
CH2CH3


F631
H
F
H
CF3
CF3
H
CF3
H
S
CH2CH3


F632
H
F
H
CF3
CF3
H
CH3
H
S
CH2CH3


F633
H
F
H
CF3
CF3
CF3
Br
H
O
CH2CF3


F634
H
F
H
CF3
CF3
CF3
Cl
H
O
CH2CF3


F635
H
F
H
CF3
CF3
CF3
CF3
H
O
CH2CF3


F636
H
F
H
CF3
CF3
CF3
CH3
H
O
CH2CF3


F637
H
F
H
CF3
CF2CF3
H
Br
H
O
CH2CF3


F638
H
F
H
CF3
CF2CF3
H
Cl
H
O
CH2CF3


F639
H
F
H
CF3
CF2CF3
H
CF3
H
O
CH2CF3


F640
H
F
H
CF3
CF2CF3
H
CH3
H
O
CH2CF3


F641
H
F
H
CF3
CF3
H
Br
H
O
CH2CF3


F642
H
F
H
CF3
CF3
H
Cl
H
O
CH2CF3


F643
H
F
H
CF3
CF3
H
CF3
H
O
CH2CF3


F644
H
F
H
CF3
CF3
H
CH3
H
O
CH2CF3


F645
H
F
H
CF3
CF3
H
Br
H
S
CH2CF3


F646
H
F
H
CF3
CF3
H
Cl
H
S
CH2CF3


F647
H
F
H
CF3
CF3
H
CF3
H
S
CH2CF3


F648
H
F
H
CF3
CF3
H
CH3
H
S
CH2CF3


F649
H
Cl
H
CF3
CF3
H
Br
CH3
O
CH2CH3


F650
H
Cl
H
CF3
CF3
H
Cl
CH3
O
CH2CH3


F651
H
Cl
H
CF3
CF3
H
CF3
CH3
O
CH2CH3


F652
H
Cl
H
CF3
CF3
H
CH3
CH3
O
CH2CH3


F653
H
Cl
H
CF3
CF3
H
Br
CH3
S
CH2CH3


F654
H
Cl
H
CF3
CF3
H
Cl
CH3
S
CH2CH3


F655
H
Cl
H
CF3
CF3
H
CF3
CH3
S
CH2CH3


F656
H
Cl
H
CF3
CF3
H
CH3
CH3
S
CH2CH3


F657
H
Cl
H
CF3
CF3
H
Br
H
O
CH2CH3


F658
H
Cl
H
CF3
CF3
H
Cl
H
O
CH2CH3


F659
H
Cl
H
CF3
CF3
H
CF3
H
O
CH2CH3


F660
H
Cl
H
CF3
CF3
H
CH3
H
O
CH2CH3


F661
H
Cl
H
CF3
CF3
H
Br
H
S
CH2CH3


F662
H
Cl
H
CF3
CF3
H
Cl
H
S
CH2CH3


F663
H
Cl
H
CF3
CF3
H
CF3
H
S
CH2CH3


F664
H
Cl
H
CF3
CF3
H
CH3
H
S
CH2CH3


F665
H
Cl
H
CF3
CF3
CF3
Br
H
O
CH2CF3


F666
H
Cl
H
CF3
CF3
CF3
Cl
H
O
CH2CF3


F667
H
Cl
H
CF3
CF3
CF3
CF3
H
O
CH2CF3


F668
H
Cl
H
CF3
CF3
CF3
CH3
H
O
CH2CF3


F669
H
Cl
H
CF3
CF2CF3
H
Br
H
O
CH2CF3


F670
H
Cl
H
CF3
CF2CF3
H
Cl
H
O
CH2CF3


F671
H
Cl
H
CF3
CF2CF3
H
CF3
H
O
CH2CF3


F672
H
Cl
H
CF3
CF2CF3
H
CH3
H
O
CH2CF3


F673
H
Cl
H
CF3
CF3
H
Br
H
O
CH2CF3


F674
H
Cl
H
CF3
CF3
H
Cl
H
O
CH2CF3


F675
H
Cl
H
CF3
CF3
H
CF3
H
O
CH2CF3


F676
H
Cl
H
CF3
CF3
H
CH3
H
O
CH2CF3


F677
H
Cl
H
CF3
CF3
H
Br
H
S
CH2CF3


F678
H
Cl
H
CF3
CF3
H
Cl
H
S
CH2CF3


F679
H
Cl
H
CF3
CF3
H
CF3
H
S
CH2CF3


F680
H
Cl
H
CF3
CF3
H
CH3
H
S
CH2CF3


F681
H
H
F
CF3
CF3
H
Br
CH3
O
CH2CH3


F682
H
H
F
CF3
CF3
H
Cl
CH3
O
CH2CH3


F683
H
H
F
CF3
CF3
H
CF3
CH3
O
CH2CH3


F684
H
H
F
CF3
CF3
H
CH3
CH3
O
CH2CH3


F685
H
H
F
CF3
CF3
H
Br
CH3
S
CH2CH3


F686
H
H
F
CF3
CF3
H
Cl
CH3
S
CH2CH3


F687
H
H
F
CF3
CF3
H
CF3
CH3
S
CH2CH3


F688
H
H
F
CF3
CF3
H
CH3
CH3
S
CH2CH3


F689
H
H
F
CF3
CF3
H
Br
H
O
CH2CH3


F690
H
H
F
CF3
CF3
H
Cl
H
O
CH2CH3


F691
H
H
F
CF3
CF3
H
CF3
H
O
CH2CH3


F692
H
H
F
CF3
CF3
H
CH3
H
O
CH2CH3


F693
H
H
F
CF3
CF3
H
Br
H
S
CH2CH3


F694
H
H
F
CF3
CF3
H
Cl
H
S
CH2CH3


F695
H
H
F
CF3
CF3
H
CF3
H
S
CH2CH3


F696
H
H
F
CF3
CF3
H
CH3
H
S
CH2CH3


F697
H
H
F
CF3
CF3
CF3
Br
H
O
CH2CF3


F698
H
H
F
CF3
CF3
CF3
Cl
H
O
CH2CF3


F699
H
H
F
CF3
CF3
CF3
CF3
H
O
CH2CF3


F700
H
H
F
CF3
CF3
CF3
CH3
H
O
CH2CF3


F701
H
H
F
CF3
CF2CF3
H
Br
H
O
CH2CF3


F702
H
H
F
CF3
CF2CF3
H
Cl
H
O
CH2CF3


F703
H
H
F
CF3
CF2CF3
H
CF3
H
O
CH2CF3


F704
H
H
F
CF3
CF2CF3
H
CH3
H
O
CH2CF3


F705
H
H
F
CF3
CF3
H
Br
H
O
CH2CF3


F706
H
H
F
CF3
CF3
H
Cl
H
O
CH2CF3


F707
H
H
F
CF3
CF3
H
CF3
H
O
CH2CF3


F708
H
H
F
CF3
CF3
H
CH3
H
O
CH2CF3


F709
H
H
F
CF3
CF3
H
Br
H
S
CH2CF3


F710
H
H
F
CF3
CF3
H
Cl
H
S
CH2CF3


F711
H
H
F
CF3
CF3
H
CF3
H
S
CH2CF3


F712
H
H
F
CF3
CF3
H
CH3
H
S
CH2CF3


F713
H
Cl
Cl
Cl
CF3
H
Br
CH3
S
CH2CH3


F714
H
Cl
Cl
Cl
CF3
H
Cl
CH3
S
CH2CH3


F715
H
Cl
Cl
Cl
CF3
H
CF3
CH3
S
CH2CH3


F716
H
Cl
Cl
Cl
CF3
H
CH3
CH3
S
CH2CH3


F717
H
Cl
Cl
Cl
CF3
H
Br
H
O
CH2CH3


F718
H
Cl
Cl
Cl
CF3
H
Cl
H
O
CH2CH3


F719
H
Cl
Cl
Cl
CF3
H
CF3
H
O
CH2CH3


F720
H
Cl
Cl
Cl
CF3
H
CH3
H
O
CH2CH3


F721
H
Cl
Cl
Cl
CF3
H
Br
H
S
CH2CH3


F722
H
Cl
Cl
Cl
CF3
H
Cl
H
S
CH2CH3


F723
H
Cl
Cl
Cl
CF3
H
CF3
H
S
CH2CH3


F724
H
Cl
Cl
Cl
CF3
H
CH3
H
S
CH2CH3


F725
H
Cl
Cl
Cl
CF3
CF3
Br
H
O
CH2CF3


F726
H
Cl
Cl
Cl
CF3
CF3
Cl
H
O
CH2CF3


F727
H
Cl
Cl
Cl
CF3
CF3
CF3
H
O
CH2CF3


F728
H
Cl
Cl
Cl
CF3
CF3
CH3
H
O
CH2CF3


F729
H
Cl
Cl
Cl
CF2CF3
H
Br
H
O
CH2CF3


F730
H
Cl
Cl
Cl
CF2CF3
H
Cl
H
O
CH2CF3


F731
H
Cl
Cl
Cl
CF2CF3
H
CF3
H
O
CH2CF3


F732
H
Cl
Cl
Cl
CF2CF3
H
CH3
H
O
CH2CF3


F733
H
Cl
H
Cl
CF3
H
Br
CH3
O
CH2CH3


F734
H
Cl
H
Cl
CF3
H
Cl
CH3
O
CH2CH3


F735
H
Cl
H
Cl
CF3
H
CF3
CH3
O
CH2CH3


F736
H
Cl
H
Cl
CF3
H
CH3
CH3
O
CH2CH3


F737
H
Cl
H
Cl
CF3
H
Br
CH3
S
CH2CH3


F738
H
Cl
H
Cl
CF3
H
Cl
CH3
S
CH2CH3


F739
H
Cl
H
Cl
CF3
H
CF3
CH3
S
CH2CH3


F740
H
Cl
H
Cl
CF3
H
CH3
CH3
S
CH2CH3


F741
H
Cl
H
Cl
CF3
H
Br
H
O
CH2CH3


F742
H
Cl
H
Cl
CF3
H
Cl
H
O
CH2CH3


F743
H
Cl
H
Cl
CF3
H
CF3
H
O
CH2CH3


F744
H
Cl
H
Cl
CF3
H
CH3
H
O
CH2CH3


F745
H
Cl
H
Cl
CF3
H
Br
H
S
CH2CH3


F746
H
Cl
H
Cl
CF3
H
Cl
H
S
CH2CH3


F747
H
Cl
H
Cl
CF3
H
CF3
H
S
CH2CH3


F748
H
Cl
H
Cl
CF3
H
CH3
H
S
CH2CH3


F749
H
Cl
H
Cl
CF3
CF3
Br
H
O
CH2CF3


F750
H
Cl
H
Cl
CF3
CF3
Cl
H
O
CH2CF3


F751
H
Cl
H
Cl
CF3
CF3
CF3
H
O
CH2CF3


F752
H
Cl
H
Cl
CF3
CF3
CH3
H
O
CH2CF3


F753
H
Cl
H
Cl
CF2CF3
H
Br
H
O
CH2CF3


F754
H
Cl
H
Cl
CF2CF3
H
Cl
H
O
CH2CF3


F755
H
Cl
H
Cl
CF2CF3
H
CF3
H
O
CH2CF3


F756
H
Cl
H
Cl
CF2CF3
H
CH3
H
O
CH2CF3


F757
H
Cl
H
Cl
CF3
H
Br
H
O
CH2CF3


F758
H
Cl
H
Cl
CF3
H
Cl
H
O
CH2CF3


F759
H
Cl
H
Cl
CF3
H
CF3
H
O
CH2CF3


F760
H
Cl
H
Cl
CF3
H
CH3
H
O
CH2CF3


F761
H
Cl
H
Cl
CF3
H
Br
H
S
CH2CF3


F762
H
Cl
H
Cl
CF3
H
Cl
H
S
CH2CF3


F763
H
Cl
H
Cl
CF3
H
CF3
H
S
CH2CF3


F764
H
Cl
H
Cl
CF3
H
CH3
H
S
CH2CF3


F765
H
H
Cl
Cl
CF3
H
Br
CH3
O
CH2CH3


F766
H
H
Cl
Cl
CF3
H
Cl
CH3
O
CH2CH3


F767
H
H
Cl
Cl
CF3
H
CF3
CH3
O
CH2CH3


F768
H
H
Cl
Cl
CF3
H
CH3
CH3
O
CH2CH3


F769
H
H
Cl
Cl
CF3
H
Br
CH3
S
CH2CH3


F770
H
H
Cl
Cl
CF3
H
Cl
CH3
S
CH2CH3


F771
H
H
Cl
Cl
CF3
H
CF3
CH3
S
CH2CH3


F772
H
H
Cl
Cl
CF3
H
CH3
CH3
S
CH2CH3


F773
H
H
Cl
Cl
CF3
H
Br
H
O
CH2CH3


F774
H
H
Cl
Cl
CF3
H
Cl
H
O
CH2CH3


F775
H
H
Cl
Cl
CF3
H
CF3
H
O
CH2CH3


F776
H
H
Cl
Cl
CF3
H
CH3
H
O
CH2CH3


F777
H
H
Cl
Cl
CF3
H
Br
H
S
CH2CH3


F778
H
H
Cl
Cl
CF3
H
Cl
H
S
CH2CH3


F779
H
H
Cl
Cl
CF3
H
CF3
H
S
CH2CH3


F780
H
H
Cl
Cl
CF3
H
CH3
H
S
CH2CH3


F781
H
H
Cl
Cl
CF3
CF3
Br
H
O
CH2CF3


F782
H
H
Cl
Cl
CF3
CF3
Cl
H
O
CH2CF3


F783
H
H
Cl
Cl
CF3
CF3
CF3
H
O
CH2CF3


F784
H
H
Cl
Cl
CF3
CF3
CH3
H
O
CH2CF3


F785
H
H
Cl
Cl
CF2CF3
H
Br
H
O
CH2CF3


F786
H
H
Cl
Cl
CF2CF3
H
Cl
H
O
CH2CF3


F787
H
H
Cl
Cl
CF2CF3
H
CF3
H
O
CH2CF3


F788
H
H
Cl
Cl
CF2CF3
H
CH3
H
O
CH2CF3


F789
H
H
Cl
Cl
CF3
H
Br
H
O
CH2CF3


F790
H
H
Cl
Cl
CF3
H
Cl
H
O
CH2CF3


F791
H
H
Cl
Cl
CF3
H
CF3
H
O
CH2CF3


F792
H
H
Cl
Cl
CF3
H
CH3
H
O
CH2CF3


F793
H
H
Cl
Cl
CF3
H
Br
H
S
CH2CF3


F794
H
H
Cl
Cl
CF3
H
Cl
H
S
CH2CF3


F795
H
H
Cl
Cl
CF3
H
CF3
H
S
CH2CF3


F796
H
H
Cl
Cl
CF3
H
CH3
H
S
CH2CF3


F797
H
Cl
F
Cl
CF3
H
Br
CH3
O
CH2CH3


F798
H
Cl
F
Cl
CF3
H
Cl
CH3
O
CH2CH3


F799
H
Cl
F
Cl
CF3
H
CF3
CH3
O
CH2CH3


F800
H
Cl
F
Cl
CF3
H
CH3
CH3
O
CH2CH3


F801
H
Cl
F
Cl
CF3
H
Br
CH3
S
CH2CH3


F802
H
Cl
F
Cl
CF3
H
Cl
CH3
S
CH2CH3


F803
H
Cl
F
Cl
CF3
H
CF3
CH3
S
CH2CH3


F804
H
Cl
F
Cl
CF3
H
CH3
CH3
S
CH2CH3


F805
H
Cl
F
Cl
CF3
H
Br
H
O
CH2CH3


F806
H
Cl
F
Cl
CF3
H
Cl
H
O
CH2CH3


F807
H
Cl
F
Cl
CF3
H
CF3
H
O
CH2CH3


F808
H
Cl
F
Cl
CF3
H
CH3
H
O
CH2CH3


F809
H
Cl
F
Cl
CF3
H
Br
H
S
CH2CH3


F810
H
Cl
F
Cl
CF3
H
Cl
H
S
CH2CH3


F811
H
Cl
F
Cl
CF3
H
CF3
H
S
CH2CH3


F812
H
Cl
F
Cl
CF3
H
CH3
H
S
CH2CH3


F813
H
Cl
F
Cl
CF3
CF3
Cl
H
O
CH2CF3


F814
H
Cl
F
Cl
CF3
CF3
CF3
H
O
CH2CF3


F815
H
Cl
F
Cl
CF3
CF3
CH3
H
O
CH2CF3


F816
H
Cl
F
Cl
CF2CF3
H
Br
H
O
CH2CF3


F817
H
Cl
F
Cl
CF2CF3
H
Cl
H
O
CH2CF3


F818
H
Cl
F
Cl
CF2CF3
H
CF3
H
O
CH2CF3


F819
H
Cl
F
Cl
CF2CF3
H
CH3
H
O
CH2CF3


F820
H
Cl
F
Cl
CF3
H
Cl
H
O
CH2CF3


F821
H
Cl
F
Cl
CF3
H
CF3
H
O
CH2CF3


F822
H
Cl
F
Cl
CF3
H
CH3
H
O
CH2CF3


F823
H
Cl
F
Cl
CF3
H
Cl
H
S
CH2CF3


F824
H
Cl
F
Cl
CF3
H
CF3
H
S
CH2CF3


F825
H
Cl
F
Cl
CF3
H
CH3
H
S
CH2CF3


F826
H
Br
H
Br
CF3
H
Cl
CH3
O
CH2CH3


F827
H
Br
H
Br
CF3
H
CF3
CH3
O
CH2CH3


F828
H
Br
H
Br
CF3
H
CH3
CH3
O
CH2CH3


F829
H
Br
H
Br
CF3
H
Br
CH3
S
CH2CH3


F830
H
Br
H
Br
CF3
H
Cl
CH3
S
CH2CH3


F831
H
Br
H
Br
CF3
H
CF3
CH3
S
CH2CH3


F832
H
Br
H
Br
CF3
H
CH3
CH3
S
CH2CH3


F833
H
Br
H
Br
CF3
H
Br
H
O
CH2CH3


F834
H
Br
H
Br
CF3
H
Cl
H
O
CH2CH3


F835
H
Br
H
Br
CF3
H
CF3
H
O
CH2CH3


F836
H
Br
H
Br
CF3
H
CH3
H
O
CH2CH3


F837
H
Br
H
Br
CF3
H
Br
H
S
CH2CH3


F838
H
Br
H
Br
CF3
H
Cl
H
S
CH2CH3


F839
H
Br
H
Br
CF3
H
CF3
H
S
CH2CH3


F840
H
Br
H
Br
CF3
H
CH3
H
S
CH2CH3


F841
H
Br
H
Br
CF3
CF3
Br
H
O
CH2CF3


F842
H
Br
H
Br
CF3
CF3
Cl
H
O
CH2CF3


F843
H
Br
H
Br
CF3
CF3
CF3
H
O
CH2CF3


F844
H
Br
H
Br
CF3
CF3
CH3
H
O
CH2CF3


F845
H
Br
H
Br
CF2CF3
H
Br
H
O
CH2CF3


F846
H
Br
H
Br
CF2CF3
H
Cl
H
O
CH2CF3


F847
H
Br
H
Br
CF2CF3
H
CF3
H
O
CH2CF3


F848
H
Br
H
Br
CF2CF3
H
CH3
H
O
CH2CF3


F849
H
Br
H
Br
CF3
H
Cl
H
O
CH2CF3


F850
H
Br
H
Br
CF3
H
CF3
H
O
CH2CF3


F851
H
Br
H
Br
CF3
H
CH3
H
O
CH2CF3


F852
H
Br
H
Br
CF3
H
Cl
H
S
CH2CF3


F853
H
Br
H
Br
CF3
H
CF3
H
S
CH2CF3


F854
H
Br
H
Br
CF3
H
CH3
H
S
CH2CF3









Example A: Bioassays on Beet Armyworm (“BAW”) and Corn Earworm (“CEW”) and Cabbage Looper (“CL”)

BAW has few effective parasites, diseases, or predators to lower its population. BAW infests many weeds, trees, grasses, legumes, and field crops. In various places, it is of economic concern upon asparagus, cotton, corn, soybeans, tobacco, alfalfa, sugar beets, peppers, tomatoes, potatoes, onions, peas, sunflowers, and citrus, among other plants. CEW is known to attack corn and tomatoes, but it also attacks artichoke, asparagus, cabbage, cantaloupe, collards, cowpeas, cucumbers, eggplant, lettuce, lima beans, melon, okra, peas, peppers, potatoes, pumpkin, snap beans, spinach, squash, sweet potatoes, and watermelon, among other plants. CEW is also known to be resistant to certain insecticides. CL feeds on a wide variety of cultivated plants and weeds. It feeds readily on crucifers, and has been reported damaging broccoli, cabbage, cauliflower, Chinese cabbage, collards, kale, mustard, radish, rutabaga, turnip, and watercress. Other vegetable crops injured include beet, cantaloupe, celery, cucumber, lima bean, lettuce, parsnip, pea, pepper, potato, snap bean, spinach, squash, sweet potato, tomato, and watermelon. CL is also known to be resistant to certain insecticides. Consequently, because of the above factors control of these pests is important. Furthermore, molecules that control these pests are useful in controlling other pests.


Certain molecules disclosed in this document were tested against BAW and CEW and CL using procedures described in the following examples. In the reporting of the results, the “BAW & CEW & CL Rating Table” was used (See Table Section).


Bioassays on BAW (Spodoptera exigua)


Bioassays on BAW were conducted using a 128-well diet tray assay, one to five second instar BAW larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 μg/cm2 of the test compound (dissolved in 50 μL of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover, and held at 25° C., 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged. The results are indicated in the table entitled “Table 3: Assay Results” (See Table Section).


Bioassays on CEW (Helicoverpa zea)


Bioassays on CEW were conducted using a 128-well diet tray assay, one to five second instar CEW larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 μg/cm2 of the test compound (dissolved in 50 μL of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover, and held at 25° C., 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged. The results are indicated in the table entitled “Table 3: Assay Results” (See Table Section).


Bioassays on CL (Trichoplusia ni)

Bioassays on CL were conducted using a 128-well diet tray assay. One to five second instar CL larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 μg/cm2 of the test compound (dissolved in 50 L of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover, and held at 25° C., 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged. The results are indicated in the table entitled “Table 3A: Assay Results” (See Table Section).


Example B: Bioassays on Green Peach Aphid (“GPA”) (Myzus persicae)

GPA is the most significant aphid pest of peach trees, causing decreased growth, shriveling of the leaves, and the death of various tissues. It is also hazardous because it acts as a vector for the transport of plant viruses, such as potato virus Y and potato leafroll virus to members of the nightshade/potato family Solanaceae, and various mosaic viruses to many other food crops. GPA attacks such plants as broccoli, burdock, cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce, macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, and zucchini, among other plants. GPA also attacks many ornamental crops such as carnation, chrysanthemum, flowering white cabbage, poinsettia, and roses. GPA has developed resistance to many pesticides.


Certain molecules disclosed in this document were tested against GPA using procedures described in the following example. In the reporting of the results, the “GPA Rating Table” was used (See Table Section).


Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) true leaves, were used as test substrate. The seedlings were infested with 20-50 GPA (wingless adult and nymph stages) one day prior to chemical application. Four pots with individual seedlings were used for each treatment. Test compounds (2 mg) were dissolved in 2 mL of acetone/MeOH (1:1) solvent, forming stock solutions of 1000 ppm test compound. The stock solutions were diluted 5× with 0.025% Tween 20 in H2O to obtain the solution at 200 ppm test compound. A hand-held aspirator-type sprayer was used for spraying a solution to both sides of cabbage leaves until runoff. Reference plants (solvent check) were sprayed with the diluent only containing 20% by volume of acetone/MeOH (1:1) solvent. Treated plants were held in a holding room for three days at approximately 25° C. and ambient relative humidity (RH) prior to grading. Evaluation was conducted by counting the number of live aphids per plant under a microscope. Percent Control was measured by using Abbott's correction formula (W. S. Abbott, “A Method of Computing the Effectiveness of an Insecticide” J. Econ. Entomol. 18 (1925), pp. 265-267) as follows.





Corrected % Control=100*(X×Y)/X

    • where
    • X=No. of live aphids on solvent check plants and
    • Y=No. of live aphids on treated plants


The results are indicated in the table entitled “Table 3: Assay Results” (See Table Section).


Pesticidally Acceptable Acid Addition Salts, Salt Derivatives, Solvates, Ester Derivatives, Polymorphs, Isotopes and Radionuclides

Molecules of Formula One may be formulated into pesticidally acceptable acid addition salts. By way of a non-limiting example, an amine function can form salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxymethanesulfonic, and hydroxyethanesulfonic acids. Additionally, by way of a non-limiting example, an acid function can form salts including those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Examples of preferred cations include sodium, potassium, and magnesium.


Molecules of Formula One may be formulated into salt derivatives. By way of a non-limiting example, a salt derivative can be prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt. A free base may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide (NaOH), potassium carbonate, ammonia, and sodium bicarbonate. As an example, in many cases, a pesticide, such as 2,4-D, is made more water-soluble by converting it to its dimethylamine salt.


Molecules of Formula One may be formulated into stable complexes with a solvent, such that the complex remains intact after the non-complexed solvent is removed. These complexes are often referred to as “solvates.” However, it is particularly desirable to form stable hydrates with water as the solvent.


Molecules of Formula One may be made into ester derivatives. These ester derivatives can then be applied in the same manner as the invention disclosed in this document is applied.


Molecules of Formula One may be made as various crystal polymorphs. Polymorphism is important in the development of agrochemicals since different crystal polymorphs or structures of the same molecule can have vastly different physical properties and biological performances.


Molecules of Formula One may be made with different isotopes. Of particular importance are molecules having 2H (also known as deuterium) in place of 1H.


Molecules of Formula One may be made with different radionuclides. Of particular importance are molecules having 14C.


Stereoisomers

Molecules of Formula One may exist as one or more stereoisomers. Thus, certain molecules can be produced as racemic mixtures. It will be appreciated by those skilled in the art that one stereoisomer may be more active than the other stereoisomers. Individual stereoisomers may be obtained by known selective synthetic procedures, by conventional synthetic procedures using resolved starting materials, or by conventional resolution procedures. Certain molecules disclosed in this document can exist as two or more isomers. The various isomers include geometric isomers, diastereomers, and enantiomers. Thus, the molecules disclosed in this document include geometric isomers, racemic mixtures, individual stereoisomers, and optically active mixtures. It will be appreciated by those skilled in the art that one isomer may be more active than the others. The structures disclosed in the present disclosure are drawn in only one geometric form for clarity, but are intended to represent all geometric forms of the molecule.


Combinations

Molecules of Formula One may also be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more compounds having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or virucidal properties. Additionally, the molecules of Formula One may also be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with compounds that are antifeedants, bird repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant activators, plant growth regulators, or synergists.


Examples of such compounds in the above groups that may be used with the Molecules of Formula One are—(3-ethoxypropyl)mercury bromide, 1,2-dichloropropane, 1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol, 2-(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA, 2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6-TBA-potassium, 2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl, 2,4,5-T-2-ethylhexyl, 2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T-butotyl, 2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl, 2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T-sodium, 2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D, 2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl, 2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium, 2,4-DB-isoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl, 2,4-D-butyl, 2,4-D-diethylammonium, 2,4-D-dimethylammonium, 2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethyl, 2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D-isoctyl, 2,4-D-isopropyl, 2,4-D-isopropylammonium, 2,4-D-lithium, 2,4-D-meptyl, 2,4-D-methyl, 2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl, 2,4-D-sodium, 2,4-D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D-triethylammonium, 2,4-D-tris(2-hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP, 2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP, 4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA-sodium, 4-CPB, 4-CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate, 8-phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate, acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole, acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl, acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein, acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor, alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, allicin, allidochlor, allosamidin, alloxydim, alloxydim-sodium, allyl alcohol, allyxycarb, alorac, alpha-cypermethrin, alpha-endosulfan, ametoctradin, ametridione, ametryn, amibuzin, amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron, aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl, aminocyclopyrachlor-potassium, aminopyralid, aminopyralid-potassium, aminopyralid-tris(2-hydroxypropyl)ammonium, amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole, ammonium sulfamate, ammonium α-naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam, asulam-potassium, asulam-sodium, athidathion, atraton, atrazine, aureofungin, aviglycine, aviglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl, azinphos-methyl, aziprotryne, azithiram, azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin-ethyl, benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, benfluralin, benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap, bentaluron, bentazone, bentazone-sodium, benthiavalicarb, benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox, benzadox-ammonium, benzalkonium chloride, benzamacril, benzamacril-isobutyl, benzamorf, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid, benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzyl benzoate, benzyladenine, berberine, berberine chloride, beta-cyfluthrin, beta-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox, bifenthrin, bifujunzhi, bilanafos, bilanafos-sodium, binapacryl, bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl, brevicomin, brodifacoum, brofenvalerate, brofluthrinate, bromacil, bromacil-lithium, bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos, bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT, bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil, bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxynil octanoate, bromoxynil-potassium, brompyrazon, bromuconazole, bronopol, bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundy mixture, busulfan, butacarb, butachlor, butafenacil, butamifos, butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron, butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin, butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos, cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide, calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor, captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam, carbendazim, carbendazim benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartap hydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure, Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone, chlomethoxyfen, chloralose, chloramben, chloramben-ammonium, chloramben-diolamine, chloramben-methyl, chloramben-methylammonium, chloramben-sodium, chloramine phosphorus, chloramphenicol, chloraniformethan, chloranil, chloranocryl, chlorantraniliprole, chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside, chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenac-ammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole, chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide, chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren, chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequat chloride, chlornidine, chlornitrofen, chlorobenzilate, chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron, chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin, chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron, chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos, chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos, chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II, cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide, cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium, clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl, clopyralid-olamine, clopyralid-potassium, clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet, cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel, clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA, codlelure, colophonate, copper acetate, copper acetoarsenite, copper arsenate, copper carbonate, basic, copper hydroxide, copper naphthenate, copper oleate, copper oxychloride, copper silicate, copper sulfate, copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure, cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide, cyclethrin, cycloate, cycloheximide, cycloprate, cycloprothrin, cyclosulfamuron, cycloxaprid, cycloxydim, cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat chloride, cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromid, cyprosulfamide, cyromazine, cythioate, daimuron, dalapon, dalapon-calcium, dalapon-magnesium, dalapon-sodium, daminozide, dayoutong, dazomet, dazomet-sodium, DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, desmedipham, desmetryn, d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos, diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate, dicamba, dicamba-diglycolamine, dicamba-dimethylammonium, dicamba-diolamine, dicamba-isopropylammonium, dicamba-methyl, dicamba-olamine, dicamba-potassium, dicamba-sodium, dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl, dichlormate, dichlormid, dichlorophen, dichlorprop, dichlorprop-2-ethylhexyl, dichlorprop-butotyl, dichlorprop-dimethylammonium, dichlorprop-ethylammonium, dichlorprop-isoctyl, dichlorprop-methyl, dichlorprop-P, dichlorprop-P-2-ethylhexyl, dichlorprop-P-dimethylammonium, dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine, diclomezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl, dicrotophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl, diethatyl-ethyl, diethofencarb, dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin, diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium, diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin, dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate, dimethylvinphos, dimetilan, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole, diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb acetate, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium, dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, diphacinone, diphacinone-sodium, diphenamid, diphenyl sulfone, diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquat dibromide, disparlure, disul, disulfiram, disulfoton, disul-sodium, ditalimfos, dithianon, dithicrofos, dithioether, dithiopyr, diuron, d-limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium, dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicin hydrochloride, dodicin-sodium, dodine, dofenapyn, dominicalure, doramectin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothal, endothal-diammonium, endothal-dipotassium, endothal-disodium, endothion, endrin, enestroburin, EPN, epocholeone, epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdépalléthrine, esfenvalerate, esprocarb, etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol, ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen, ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl α-naphthaleneacetate, ethyl-DDD, ethylene, ethylene dibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercury bromide, ethylmercury chloride, ethylmercury phosphate, etinofen, etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole, fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos, fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobucarb, fenoprop, fenoprop-3-butoxypropyl, fenoprop-butometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl, fenoprop-methyl, fenoprop-potassium, fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazon, fenridazon-potassium, fenridazon-propyl, fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop-ethyl, fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride, fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA, fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil, flamprop, flamprop-isopropyl, flamprop-M, flamprop-methyl, flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, flocoumafen, flometoquin, flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl, fluazifop-P, fluazifop-P-butyl, fluazinam, fluazolate, fluazuron, flubendiamide, flubenzimine, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph, fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid, fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate, flupropanate-sodium, flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl, flupyrsulfuron-methyl-sodium, fluquinconazole, flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone, flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide, fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldehyde, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl, fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling, fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr, furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin, furfural, furilazole, furmecyclox, furophanate, furyloxyfen, gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, gibberellins, gliftor, glufosinate, glufosinate-ammonium, glufosinate-P, glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime, glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium, glyphosate-isopropylammonium, glyphosate-monoammonium, glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium, glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatine acetates, halacrinate, halfenprox, halofenozide, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl, haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide, hydroprene, hymexazol, hyquincarb, IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalil sulfate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic, imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin, imazaquin-ammonium, imazaquin-methyl, imazaquin-sodium, imazethapyr, imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, iminoctadine, iminoctadine triacetate, iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan, indaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane, iodosulfuron, iodosulfuron-methyl, iodosulfuron-methyl-sodium, iofensulfuron, iofensulfuron-sodium, ioxynil, ioxynil octanoate, ioxynil-lithium, ioxynil-sodium, ipazine, ipconazole, ipfencarbazone, iprobenfos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, isamidofos, isazofos, isobenzan, isocarbamid, isocarbophos, isocil, isodrin, isofenphos, isofenphos-methyl, isolan, isomethiozin, isonoruron, isopolinate, isoprocarb, isopropalin, isoprothiolane, isoproturon, isopyrazam, isopyrimol, isothioate, isotianil, isouron, isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos, japonilure, japothrins, jasmolin I, jasmolin II, jasmonic acid, jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kadethrin, karbutilate, karetazan, karetazan-potassium, kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox, ketospiradox-potassium, kinetin, kinoprene, kresoxim-methyl, kuicaoxi, lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure, looplure, lufenuron, lvdingjunzhi, lvxiancaolin, lythidathion, MAA, malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper, mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA, MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium, MCPA-diolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl, MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl, MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil, mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl, mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl, mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium, mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform, medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr, mefenpyr-diethyl, mefluidide, mefluidide-diolamine, mefluidide-potassium, megatomoic acid, menazon, mepanipyrim, meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride, mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron, mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop, metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron, metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron, methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole, methfuroxam, methidathion, methiobencarb, methiocarb, methiopyrisulfuron, methiotepa, methiozolin, methiuron, methocrotophos, methometon, methomyl, methoprene, methoprotryne, methoquin-butyl, methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methyl apholate, methyl bromide, methyl eugenol, methyl iodide, methyl isothiocyanate, methylacetophos, methylchloroform, methyldymron, methylene chloride, methylmercury benzoate, methylmercury dicyandiamide, methylmercury pentachlorophenoxide, methylneodecanamide, metiram, metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb, metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone, metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos, mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, mipafox, mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron, monochloroacetic acid, monocrotophos, monolinuron, monosulfuron, monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquat dichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid, moxidectin, MSMA, muscalure, myclobutanil, myclozolin, N-(ethylmercury)-p-toluenesulphonanilide, nabam, naftalofos, naled, naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyacetic acids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin, neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine, nifluridide, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin, nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal-isopropyl, norbormide, norflurazon, nornicotine, noruron, novaluron, noviflumuron, nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace, omethoate, orbencarb, orfralure, ortho-dichlorobenzene, orthosulfamuron, oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil, oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon, oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone, oxine-copper, oxolinic acid, oxpoconazole, oxpoconazole fumarate, oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen, oxymatrine, oxytetracycline, oxytetracycline hydrochloride, paclobutrazol, paichongding, para-dichlorobenzene, parafluron, paraquat, paraquat dichloride, paraquat dimetilsulfate, parathion, parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid, penconazole, pencycuron, pendimethalin, penflufen, penfluron, penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin, pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, phenazine oxide, phenisopham, phenkapton, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercury derivative of pyrocatechol, phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim, phosalone, phosdiphen, phosfolan, phosfolan-methyl, phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram, picloram-2-ethylhexyl, picloram-isoctyl, picloram-methyl, picloram-olamine, picloram-potassium, picloram-triethylammonium, picloram-tris(2-hydroxypropyl)ammonium, picolinafen, picoxystrobin, pindone, pindone-sodium, pinoxaden, piperalin, piperonyl butoxide, piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide, piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl, pirimiphos-methyl, plifenate, polycarbamate, polyoxins, polyoxorim, polyoxorim-zinc, polythialan, potassium arsenite, potassium azide, potassium cyanate, potassium gibberellate, potassium naphthenate, potassium polysulfide, potassium thiocyanate, potassium α-naphthaleneacetate, pp′-DDT, prallethrin, precocene I, precocene II, precocene III, pretilachlor, primidophos, primisulfuron, primisulfuron-methyl, probenazole, prochloraz, prochloraz-manganese, proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol, profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl, prohexadione, prohexadione-calcium, prohydrojasmon, promacyl, promecarb, prometon, prometryn, promurit, propachlor, propamidine, propamidine dihydrochloride, propamocarb, propamocarb hydrochloride, propanil, propaphos, propaquizafop, propargite, proparthrin, propazine, propetamphos, propham, propiconazole, propineb, propisochlor, propoxur, propoxycarbazone, propoxycarbazone-sodium, propyl isome, propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarb hydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute, proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl, pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb, pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl, pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon, pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobac-sodium, pyrolan, pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl, quinazamid, quinclorac, quinconazole, quinmerac, quinoclamine, quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, quizalofop-P-tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide, rebemide, resmethrin, rhodethanil, rhodojaponin-III, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong, salicylanilide, sanguinarine, santonin, schradan, scilliroside, sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz, semiamitraz chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolin, siduron, siglure, silafluofen, silatrane, silica gel, silthiofam, simazine, simeconazole, simeton, simetryn, sintofen, SMA, S-metolachlor, sodium arsenite, sodium azide, sodium chlorate, sodium fluoride, sodium fluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodium orthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide, sodium thiocyanate, sodium α-naphthaleneacetate, sophamide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin sesquisulfate, strychnine, sulcatol, sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl fluoride, sulglycapin, sulprofos, sultropen, swep, tau-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonium, TCA-calcium, TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, tebuconazole, tebufenozide, tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron, tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim, terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton, terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane, tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin, tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate, thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid, thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone, thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl, thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam, thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole-copper, thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon, thionazin, thiophanate, thiophanate-methyl, thioquinox, thiosemicarbazide, thiosultap, thiosultap-diammonium, thiosultap-disodium, thiosultap-monosodium, thiotepa, thiram, thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid, tirpate, tolclofos-methyl, tolfenpyrad, tolylfluanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol, triadimefon, triadimenol, triafamone, tri-allate, triamiphos, triapenthenol, triarathene, triarimol, triasulfuron, triazamate, triazbutil, triaziflam, triazophos, triazoxide, tribenuron, tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamide, trichlorfon, trichlormetaphos-3, trichloronat, triclopyr, triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium, tricyclazole, tridemorph, tridiphane, trietazine, trifenmorph, trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium, triflumizole, triflumuron, trifluralin, triflusulfuron, triflusulfuron-methyl, trifop, trifop-methyl, trifopsime, triforine, trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac, trinexapac-ethyl, triprene, tripropindan, triptolide, tritac, triticonazole, tritosulfuron, trunc-call, uniconazole, uniconazole-P, urbacide, uredepa, valerate, validamycin, valifenalate, valone, vamidothion, vangard, vaniliprole, vernolate, vinclozolin, warfarin, warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan, xiwojunan, XMC, xylachlor, xylenols, xylylcarb, yishijing, zarilamid, zeatin, zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide, zinc thiazole, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong, α-chlorohydrin, α-ecdysone, α-multistriatin, and α-naphthaleneacetic acid. For more information consult the “Compendium of Pesticide Common Names” located at http://www.alanwood.net/pesticides/index.html. Also consult “The Pesticide Manual” 14th Edition, edited by C D S Tomlin, copyright 2006 by British Crop Production Council, or its prior or more recent editions.


Biopesticides

Molecules of Formula One may also be used in combination (such as in a compositional mixture, or a simultaneous or sequential application) with one or more biopesticides. The term “biopesticide” is used for microbial biological pest control agents that are applied in a similar manner to chemical pesticides. Commonly these are bacterial, but there are also examples of fungal control agents, including Trichoderma spp. and Ampelomyces quisqualis (a control agent for grape powdery mildew). Bacillus subtilis are used to control plant pathogens. Weeds and rodents have also been controlled with microbial agents. One well-known insecticide example is Bacillus thuringiensis, a bacterial disease of Lepidoptera, Coleoptera, and Diptera. Because it has little effect on other organisms, it is considered more environmentally friendly than synthetic pesticides. Biological insecticides include products based on:

    • 1. entomopathogenic fungi (e.g. Metarhizium anisopliae);
    • 2. entomopathogenic nematodes (e.g. Steinernemafeltiae); and
    • 3. entomopathogenic viruses (e.g. Cydia pomonella granulovirus).


Other examples of entomopathogenic organisms include, but are not limited to, baculoviruses, bacteria and other prokaryotic organisms, fungi, protozoa and Microsproridia.


Biologically derived insecticides include, but not limited to, rotenone, veratridine, as well as microbial toxins; insect tolerant or resistant plant varieties; and organisms modified by recombinant DNA technology to either produce insecticides or to convey an insect resistant property to the genetically modified organism. In one embodiment, the molecules of Formula One may be used with one or more biopesticides in the area of seed treatments and soil amendments. The Manual of Biocontrol Agents gives a review of the available biological insecticide (and other biology-based control) products. Copping L. G. (ed.) (2004). The Manual of Biocontrol Agents (formerly the Biopesticide Manual) 3rd Edition. British Crop Production Council (BCPC), Farnham, Surrey UK.


Other Active Compounds

Molecules of Formula One may also be used in combination (such as in a compositional mixture, or a simultaneous or sequential application) with one or more of the following:

  • 1. 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one;
  • 2. 3-(4′-chloro-2,4-dimethyl[1,1′-biphenyl]-3-yl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one;
  • 3. 4-[[(6-chloro-3-pyridinyl)methyl]methylamino]-2(5H)-furanone;
  • 4. 4-[[(6-chloro-3-pyridinyl)methyl]cyclopropylamino]-2(5H)-furanone;
  • 5. 3-chloro-N2-[(1S)-1-methyl-2-(methylsulfonyl)ethyl]-N1-[2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxamide;
  • 6. 2-cyano-N-ethyl-4-fluoro-3-methoxy-benenesulfonamide;
  • 7. 2-cyano-N-ethyl-3-methoxy-benzenesulfonamide;
  • 8. 2-cyano-3-difluoromethoxy-N-ethyl-4-fluoro-benzenesulfonamide;
  • 9. 2-cyano-3-fluoromethoxy-N-ethyl-benzenesulfonamide;
  • 10. 2-cyano-6-fluoro-3-methoxy-N,N-dimethyl-benzenesulfonamide;
  • 11. 2-cyano-N-ethyl-6-fluoro-3-methoxy-N-methyl-benzenesulfonamide;
  • 12. 2-cyano-3-difluoromethoxy-N,N-dimethylbenzenesulfon-amide;
  • 13. 3-(difluoromethyl)-N-[2-(3,3-dimethylbutyl)phenyl]-1-methyl-1H-pyrazole-4-carboxamide;
  • 14. N-ethyl-2,2-dimethylpropionamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl) hydrazone;
  • 15. N-ethyl-2,2-dichloro-1-methylcyclopropane-carboxamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl) hydrazone nicotine;
  • 16. O-{(E-)-[2-(4-chloro-phenyl)-2-cyano-1-(2-trifluoromethylphenyl)-vinyl]} S-methyl thiocarbonate;
  • 17. (E)-N1-[(2-chloro-1,3-thiazol-5-ylmethyl)]-N2-cyano-N1-methylacetamidine;
  • 18. 1-(6-chloropyridin-3-ylmethyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydro-imidazo[1,2-a]pyridin-5-ol;
  • 19. 4-[4-chlorophenyl-(2-butylidine-hydrazono)methyl)]phenyl mesylate; and
  • 20. N-Ethyl-2,2-dichloro-1-methylcyclopropanecarboxamide-2-(2,6-dichloro-alpha, alpha, alpha-trifluoro-p-tolyl)hydrazone.


Synergistic Mixtures

Molecules of Formula One may be used with certain active compounds to form synergistic mixtures where the mode of action of such compounds compared to the mode of action of the molecules of Formula One are the same, similar, or different. Examples of modes of action include, but are not limited to: acetylcholinesterase inhibitor; sodium channel modulator; chitin biosynthesis inhibitor; GABA and glutamate-gated chloride channel antagonist; GABA and glutamate-gated chloride channel agonist; acetylcholine receptor agonist; acetylcholine receptor antagonist; MET I inhibitor; Mg-stimulated ATPase inhibitor; nicotinic acetylcholine receptor; Midgut membrane disrupter; oxidative phosphorylation disrupter, and ryanodine receptor (RyRs). Generally, weight ratios of the molecules of Formula One in a synergistic mixture with another compound are from about 10:1 to about 1:10, in another embodiment from about 5:1 to about 1:5, and in another embodiment from about 3:1, and in another embodiment about 1:1.


Formulations

A pesticide is rarely suitable for application in its pure form. It is usually necessary to add other substances so that the pesticide can be used at the required concentration and in an appropriate form, permitting ease of application, handling, transportation, storage, and maximum pesticide activity. Thus, pesticides are formulated into, for example, baits, concentrated emulsions, dusts, emulsifiable concentrates, fumigants, gels, granules, microencapsulations, seed treatments, suspension concentrates, suspoemulsions, tablets, water soluble liquids, water dispersible granules or dry flowables, wettable powders, and ultra-low volume solutions. For further information on formulation types see “Catalogue of Pesticide Formulation Types and International Coding System” Technical Monograph n° 2, 5th Edition by CropLife International (2002).


Pesticides are applied most often as aqueous suspensions or emulsions prepared from concentrated formulations of such pesticides. Such water-soluble, water-suspendable, or emulsifiable formulations are either solids, usually known as wettable powders, or water dispersible granules, or liquids usually known as emulsifiable concentrates, or aqueous suspensions. Wettable powders, which may be compacted to form water dispersible granules, comprise an intimate mixture of the pesticide, a carrier, and surfactants. The concentration of the pesticide is usually from about 10% to about 90% by weight. The carrier is usually selected from among the attapulgite clays, the montmorillonite clays, the diatomaceous earths, or the purified silicates. Effective surfactants, comprising from about 0.5% to about 10% of the wettable powder, are found among sulfonated lignins, condensed naphthalenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and non-ionic surfactants such as ethylene oxide adducts of alkyl phenols.


Emulsifiable concentrates of pesticides comprise a convenient concentration of a pesticide, such as from about 50 to about 500 grams per liter of liquid dissolved in a carrier that is either a water miscible solvent or a mixture of water-immiscible organic solvent and emulsifiers. Useful organic solvents include aromatics, especially xylenes and petroleum fractions, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as the terpenic solvents including rosin derivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiable concentrates are selected from conventional anionic and non-ionic surfactants.


Aqueous suspensions comprise suspensions of water-insoluble pesticides dispersed in an aqueous carrier at a concentration in the range from about 5% to about 50% by weight. Suspensions are prepared by finely grinding the pesticide and vigorously mixing it into a carrier comprised of water and surfactants. Ingredients, such as inorganic salts and synthetic or natural gums may also be added, to increase the density and viscosity of the aqueous carrier. It is often most effective to grind and mix the pesticide at the same time by preparing the aqueous mixture and homogenizing it in an implement such as a sand mill, ball mill, or piston-type homogenizer.


Pesticides may also be applied as granular compositions that are particularly useful for applications to the soil. Granular compositions usually contain from about 0.5% to about 10% by weight of the pesticide, dispersed in a carrier that comprises clay or a similar substance. Such compositions are usually prepared by dissolving the pesticide in a suitable solvent and applying it to a granular carrier which has been pre-formed to the appropriate particle size, in the range of from about 0.5 to about 3 mm. Such compositions may also be formulated by making a dough or paste of the carrier and compound and crushing and drying to obtain the desired granular particle size.


Dusts containing a pesticide are prepared by intimately mixing the pesticide in powdered form with a suitable dusty agricultural carrier, such as kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1% to about 10% of the pesticide. They can be applied as a seed dressing or as a foliage application with a dust blower machine.


It is equally practical to apply a pesticide in the form of a solution in an appropriate organic solvent, usually petroleum oil, such as the spray oils, which are widely used in agricultural chemistry.


Pesticides can also be applied in the form of an aerosol composition. In such compositions the pesticide is dissolved or dispersed in a carrier, which is a pressure-generating propellant mixture. The aerosol composition is packaged in a container from which the mixture is dispensed through an atomizing valve.


Pesticide baits are formed when the pesticide is mixed with food or an attractant or both. When the pests eat the bait they also consume the pesticide. Baits may take the form of granules, gels, flowable powders, liquids, or solids. They can be used in pest harborages.


Fumigants are pesticides that have a relatively high vapor pressure and hence can exist as a gas in sufficient concentrations to kill pests in soil or enclosed spaces. The toxicity of the fumigant is proportional to its concentration and the exposure time. They are characterized by a good capacity for diffusion and act by penetrating the pest's respiratory system or being absorbed through the pest's cuticle. Fumigants are applied to control stored product pests under gas proof sheets, in gas sealed rooms or buildings or in special chambers.


Pesticides can be microencapsulated by suspending the pesticide particles or droplets in plastic polymers of various types. By altering the chemistry of the polymer or by changing factors in the processing, microcapsules can be formed of various sizes, solubility, wall thicknesses, and degrees of penetrability. These factors govern the speed with which the active ingredient within is released, which in turn, affects the residual performance, speed of action, and odor of the product.


Oil solution concentrates are made by dissolving pesticide in a solvent that will hold the pesticide in solution. Oil solutions of a pesticide usually provide faster knockdown and kill of pests than other formulations due to the solvents themselves having pesticidal action and the dissolution of the waxy covering of the integument increasing the speed of uptake of the pesticide. Other advantages of oil solutions include better storage stability, better penetration of crevices, and better adhesion to greasy surfaces.


Another embodiment is an oil-in-water emulsion, wherein the emulsion comprises oily globules which are each provided with a lamellar liquid crystal coating and are dispersed in an aqueous phase, wherein each oily globule comprises at least one compound which is agriculturally active, and is individually coated with a monolamellar or oligolamellar layer comprising: (1) at least one non-ionic lipophilic surface-active agent, (2) at least one non-ionic hydrophilic surface-active agent and (3) at least one ionic surface-active agent, wherein the globules having a mean particle diameter of less than 800 nanometers. Further information on the embodiment is disclosed in U.S. patent publication 20070027034 published Feb. 1, 2007, having patent application Ser. No. 11/495,228. For ease of use, this embodiment will be referred to as “OIWE”.


For further information consult “Insect Pest Management” 2nd Edition by D. Dent, copyright CAB International (2000). Additionally, for more detailed information consult “Handbook of Pest Control—The Behavior, Life History, and Control of Household Pests” by Arnold Mallis, 9th Edition, copyright 2004 by GIE Media Inc.


Other Formulation Components

Generally, when the molecules disclosed in Formula One are used in a formulation, such formulation can also contain other components. These components include, but are not limited to, (this is a non-exhaustive and non-mutually exclusive list) wetters, spreaders, stickers, penetrants, buffers, sequestering agents, drift reduction agents, compatibility agents, anti-foam agents, cleaning agents, and emulsifiers. A few components are described forthwith.


A wetting agent is a substance that when added to a liquid increases the spreading or penetration power of the liquid by reducing the interfacial tension between the liquid and the surface on which it is spreading. Wetting agents are used for two main functions in agrochemical formulations: during processing and manufacture to increase the rate of wetting of powders in water to make concentrates for soluble liquids or suspension concentrates; and during mixing of a product with water in a spray tank to reduce the wetting time of wettable powders and to improve the penetration of water into water-dispersible granules. Examples of wetting agents used in wettable powder, suspension concentrate, and water-dispersible granule formulations are: sodium lauryl sulfate; sodium dioctyl sulfosuccinate; alkyl phenol ethoxylates; and aliphatic alcohol ethoxylates.


A dispersing agent is a substance which adsorbs onto the surface of particles and helps to preserve the state of dispersion of the particles and prevents them from reaggregating. Dispersing agents are added to agrochemical formulations to facilitate dispersion and suspension during manufacture, and to ensure the particles redisperse into water in a spray tank. They are widely used in wettable powders, suspension concentrates and water-dispersible granules. Surfactants that are used as dispersing agents have the ability to adsorb strongly onto a particle surface and provide a charged or steric barrier to reaggregation of particles. The most commonly used surfactants are anionic, non-ionic, or mixtures of the two types. For wettable powder formulations, the most common dispersing agents are sodium lignosulfonates. For suspension concentrates, very good adsorption and stabilization are obtained using polyelectrolytes, such as sodium naphthalene sulfonate formaldehyde condensates. Tristyrylphenol ethoxylate phosphate esters are also used. Non-ionics such as alkylarylethylene oxide condensates and EO-PO block copolymers are sometimes combined with anionics as dispersing agents for suspension concentrates. In recent years, new types of very high molecular weight polymeric surfactants have been developed as dispersing agents. These have very long hydrophobic ‘backbones’ and a large number of ethylene oxide chains forming the ‘teeth’ of a ‘comb’ surfactant. These high molecular weight polymers can give very good long-term stability to suspension concentrates because the hydrophobic backbones have many anchoring points onto the particle surfaces. Examples of dispersing agents used in agrochemical formulations are: sodium lignosulfonates; sodium naphthalene sulfonate formaldehyde condensates; tristyrylphenol ethoxylate phosphate esters; aliphatic alcohol ethoxylates; alkyl ethoxylates; EO-PO block copolymers; and graft copolymers.


An emulsifying agent is a substance which stabilizes a suspension of droplets of one liquid phase in another liquid phase. Without the emulsifying agent the two liquids would separate into two immiscible liquid phases. The most commonly used emulsifier blends contain alkylphenol or aliphatic alcohol with twelve or more ethylene oxide units and the oil-soluble calcium salt of dodecylbenzenesulfonic acid. A range of hydrophile-lipophile balance (“HLB”) values from 8 to 18 will normally provide good stable emulsions. Emulsion stability can sometimes be improved by the addition of a small amount of an EO-PO block copolymer surfactant.


A solubilizing agent is a surfactant which will form micelles in water at concentrations above the critical micelle concentration. The micelles are then able to dissolve or solubilize water-insoluble materials inside the hydrophobic part of the micelle. The types of surfactants usually used for solubilization are non-ionics, sorbitan monooleates, sorbitan monooleate ethoxylates, and methyl oleate esters.


Surfactants are sometimes used, either alone or with other additives such as mineral or vegetable oils as adjuvants to spray-tank mixes to improve the biological performance of the pesticide on the target. The types of surfactants used for bioenhancement depend generally on the nature and mode of action of the pesticide. However, they are often non-ionics such as: alkyl ethoxylates; linear aliphatic alcohol ethoxylates; aliphatic amine ethoxylates.


A carrier or diluent in an agricultural formulation is a material added to the pesticide to give a product of the required strength. Carriers are usually materials with high absorptive capacities, while diluents are usually materials with low absorptive capacities. Carriers and diluents are used in the formulation of dusts, wettable powders, granules and water-dispersible granules.


Organic solvents are used mainly in the formulation of emulsifiable concentrates, oil-in-water emulsions, suspoemulsions, and ultra-low volume formulations, and to a lesser extent, granular formulations. Sometimes mixtures of solvents are used. The first main groups of solvents are aliphatic paraffinic oils such as kerosene or refined paraffins. The second main group (and the most common) comprises the aromatic solvents such as xylene and higher molecular weight fractions of C9 and C10 aromatic solvents. Chlorinated hydrocarbons are useful as cosolvents to prevent crystallization of pesticides when the formulation is emulsified into water. Alcohols are sometimes used as cosolvents to increase solvent power. Other solvents may include vegetable oils, seed oils, and esters of vegetable and seed oils.


Thickeners or gelling agents are used mainly in the formulation of suspension concentrates, emulsions and suspoemulsions to modify the rheology or flow properties of the liquid and to prevent separation and settling of the dispersed particles or droplets. Thickening, gelling, and anti-settling agents generally fall into two categories, namely water-insoluble particulates and water-soluble polymers. It is possible to produce suspension concentrate formulations using clays and silicas. Examples of these types of materials, include, but are not limited to, montmorillonite, bentonite, magnesium aluminum silicate, and attapulgite. Water-soluble polysaccharides have been used as thickening-gelling agents for many years. The types of polysaccharides most commonly used are natural extracts of seeds and seaweeds or are synthetic derivatives of cellulose. Examples of these types of materials include, but are not limited to, guar gum; locust bean gum; carrageenam; alginates; methyl cellulose; sodium carboxymethyl cellulose (SCMC); hydroxyethyl cellulose (HEC). Other types of anti-settling agents are based on modified starches, polyacrylates, polyvinyl alcohol and polyethylene oxide. Another good anti-settling agent is xanthan gum.


Microorganisms can cause spoilage of formulated products. Therefore preservation agents are used to eliminate or reduce their effect. Examples of such agents include, but are not limited to: propionic acid and its sodium salt; sorbic acid and its sodium or potassium salts; benzoic acid and its sodium salt; p-hydroxybenzoic acid sodium salt; methyl p-hydroxybenzoate; and 1,2-benzisothiazolin-3-one (BIT).


The presence of surfactants often causes water-based formulations to foam during mixing operations in production and in application through a spray tank. In order to reduce the tendency to foam, anti-foam agents are often added either during the production stage or before filling into bottles. Generally, there are two types of anti-foam agents, namely silicones and non-silicones. Silicones are usually aqueous emulsions of dimethyl polysiloxane, while the non-silicone anti-foam agents are water-insoluble oils, such as octanol and nonanol, or silica. In both cases, the function of the anti-foam agent is to displace the surfactant from the air-water interface.


“Green” agents (e.g., adjuvants, surfactants, solvents) can reduce the overall environmental footprint of crop protection formulations. Green agents are biodegradable and generally derived from natural and/or sustainable sources, e.g. plant and animal sources. Specific examples are: vegetable oils, seed oils, and esters thereof, also alkoxylated alkyl polyglucosides.


For further information, see “Chemistry and Technology of Agrochemical Formulations” edited by D. A. Knowles, copyright 1998 by Kluwer Academic Publishers. Also see “Insecticides in Agriculture and Environment—Retrospects and Prospects” by A. S. Perry, I. Yamamoto, I. Ishaaya, and R. Perry, copyright 1998 by Springer-Verlag.


Pests

In general, the molecules of Formula One may be used to control pests e.g. beetles, earwigs, cockroaches, flies. aphids, scales, whiteflies, leafhoppers, ants, wasps, termites, moths, butterflies, lice, grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites, ticks, nematodes, and symphylans.


In another embodiment, the molecules of Formula One may be used to control pests in the Phyla Nematoda and/or Arthropoda.


In another embodiment, the molecules of Formula One may be used to control pests in the Subphyla Chelicerata, Myriapoda, and/or Hexapoda.


In another embodiment, the molecules of Formula One may be used to control pests in the Classes of Arachnida, Symphyla, and/or Insecta.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Anoplura. A non-exhaustive list of particular genera includes, but is not limited to, Haematopinus spp., Hoplopleura spp., Linognathus spp., Pediculus spp., and Polyplax spp. A non-exhaustive list of particular species includes, but is not limited to, Haematopinus asini, Haematopinus suis, Linognathus setosus, Linognathus ovillus, Pediculus humanus capitis, Pediculus humanus humanus, and Pthirus pubis.


In another embodiment, the molecules of Formula One may be used to control pests in the Order Coleoptera. A non-exhaustive list of particular genera includes, but is not limited to, Acanthoscelides spp., Agriotes spp., Anthonomus spp., Apion spp., Apogonia spp., Aulacophora spp., Bruchus spp., Cerosterna spp., Cerotoma spp., Ceutorhynchus spp., Chaetocnema spp., Colaspis spp., Ctenicera spp., Curculio spp., Cyclocephala spp., Diabrotica spp., Hypera spp., Ips spp., Lyctus spp., Megascelis spp., Meligethes spp., Otiorhynchus spp., Pantomorus spp., Phyllophaga spp., Phyllotreta spp., Rhizotrogus spp., Rhynchites spp., Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp., and Tribolium spp. A non-exhaustive list of particular species includes, but is not limited to, Acanthoscelides obtectus, Agrilus planipennis, Anoplophora glabripennis, Anthonomus grandis, Ataenius spretulus, Atomaria linearis, Bothynoderes punctiventris, Bruchus pisorum, Callosobruchus maculatus, Carpophilus hemipterus, Cassida vittata, Cerotoma trifurcata, Ceutorhynchus assimilis, Ceutorhynchus napi, Conoderus scalaris, Conoderus stigmosus, Conotrachelus nenuphar, Cotinis nitida, Crioceris asparagi, Cryptolestes ferrugineus, Cryptolestes pusillus, Cryptolestes turcicus, Cylindrocopturus adspersus, Deporaus marginatus, Dermestes lardarius, Dermestes maculatus, Epilachna varivestis, Faustinus cubae, Hylobius pales, Hypera postica, Hypothenemus hampei, Lasioderma serricorne, Leptinotarsa decemlineata, Liogenys fuscus, Liogenys suturalis, Lissorhoptrus oryzophilus, Maecolaspis joliveti, Melanotus communis, Meligethes aeneus, Melolontha melolontha, Oberea brevis, Oberea linearis, Oryctes rhinoceros, Oryzaephilus mercator, Oryzaephilus surinamensis, Oulema melanopus, Oulema oryzae, Phyllophaga cuyabana, Popillia japonica, Prostephanus truncatus, Rhyzopertha dominica, Sitona lineatus, Sitophilus granarius, Sitophilus oryzae, Sitophilus zeamais, Stegobium paniceum, Tribolium castaneum, Tribolium confusum, Trogoderma variabile, and Zabrus tenebrioides.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Dermaptera.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Blattaria. A non-exhaustive list of particular species includes, but is not limited to, Blattella germanica, Blatta orientalis, Parcoblatta pennsylvanica, Periplaneta americana, Periplaneta australasiae, Periplaneta brunnea, Periplaneta fuliginosa, Pycnoscelus surinamensis, and Supella longipalpa.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Diptera. A non-exhaustive list of particular genera includes, but is not limited to, Aedes spp., Agromyza spp., Anastrepha spp., Anopheles spp., Bactrocera spp., Ceratitis spp., Chrysops spp., Cochliomyia spp., Contarinia spp., Culex spp., Dasineura spp., Delia spp., Drosophila spp., Fannia spp., Hylemyia spp., Liriomyza spp., Musca spp., Phorbia spp., Tabanus spp., and Tipula spp. A non-exhaustive list of particular species includes, but is not limited to, Agromyza frontella, Anastrepha suspensa, Anastrepha ludens, Anastrepha obliqa, Bactrocera cucurbitae, Bactrocera dorsalis, Bactrocera invadens, Bactrocera zonata, Ceratitis capitata, Dasineura brassicae, Delia platura, Fannia canicularis, Fannia scalaris, Gasterophilus intestinalis, Gracillia perseae, Haematobia irritans, Hypoderma lineatum, Liriomyza brassicae, Melophagus ovinus, Musca autumnalis, Musca domestica, Oestrus ovis, Oscinella frit, Pegomya betae, Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletis mendax, Sitodiplosis mosellana, and Stomoxys calcitrans.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Hemiptera. A non-exhaustive list of particular genera includes, but is not limited to, Adelges spp., Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastes spp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp., Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp., Nephotettix spp., Nezara spp., Philaenus spp., Phytocoris spp., Piezodorus spp., Planococcus spp., Pseudococcus spp., Rhopalosiphum spp., Saissetia spp., Therioaphis spp., Toumeyella spp., Toxoptera spp., Trialeurodes spp., Triatoma spp. and Unaspis spp. A non-exhaustive list of particular species includes, but is not limited to, Acrosternum hilare, Acyrthosiphon pisum, Aleyrodes proletella, Aleurodicus dispersus, Aleurothrixus floccosus, Amrasca biguttula biguttula, Aonidiella aurantii, Aphis gossypii, Aphis glycines, Aphis pomi, Aulacorthum solani, Bemisia argentifolii, Bemisia tabaci, Blissus leucopterus, Brachycorynella asparagi, Brevennia rehi, Brevicoryne brassicae, Calocoris norvegicus, Ceroplastes rubens, Cimex hemipterus, Cimex lectularius, Dagbertus fasciatus, Dichelops furcatus, Diuraphis noxia, Diaphorina citri, Dysaphis plantaginea, Dysdercus suturellus, Edessa meditabunda, Eriosoma lanigerum, Eurygaster maura, Euschistus heros, Euschistus servus, Helopeltis antonii, Helopeltis theivora, Icerya purchasi, Idioscopus nitidulus, Laodelphax striatellus, Leptocorisa oratorius, Leptocorisa varicornis, Lygus hesperus, Maconellicoccus hirsutus, Macrosiphum euphorbiae, Macrosiphum granarium, Macrosiphum rosae, Macrosteles quadrilineatus, Mahanarva frimbiolata, Metopolophium dirhodum, Mictis longicornis, Myzus persicae, Nephotettix cinctipes, Neurocolpus longirostris, Nezara viridula, Nilaparvata lugens, Parlatoria pergandii, Parlatoria ziziphi, Peregrinus maidis, Phylloxera vitifoliae, Physokermes piceae, Phytocoris californicus, Phytocoris relativus, Piezodorus guildinii, Poecilocapsus lineatus, Psallus vaccinicola, Pseudacysta perseae, Pseudococcus brevipes, Quadraspidiotus perniciosus, Rhopalosiphum maidis, Rhopalosiphum padi, Saissetia oleae, Scaptocoris castanea, Schizaphis graminum, Sitobion avenae, Sogatella furcifera, Trialeurodes vaporariorum, Trialeurodes abutiloneus, Unaspis yanonensis, and Zulia entrerriana.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Hymenoptera. A non-exhaustive list of particular genera includes, but is not limited to, Acromyrmex spp., Atta spp., Camponotus spp., Diprion spp., Formica spp., Monomorium spp., Neodiprion spp., Pogonomyrmex spp., Polistes spp., Solenopsis spp., Vespula spp., and Xylocopa spp. A non-exhaustive list of particular species includes, but is not limited to, Athalia rosae, Atta texana, Iridomyrmex humilis, Monomorium minimum, Monomorium pharaonis, Solenopsis invicta, Solenopsis geminata, Solenopsis molesta, Solenopsis richtery, Solenopsis xyloni, and Tapinoma sessile.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Isoptera. A non-exhaustive list of particular genera includes, but is not limited to, Coptotermes spp., Cornitermes spp., Cryptotermes spp., Heterotermes spp., Kalotermes spp., Incisitermes spp., Macrotermes spp., Marginitermes spp., Microcerotermes spp., Procornitermes spp., Reticulitermes spp., Schedorhinotermes spp., and Zootermopsis spp. A non-exhaustive list of particular species includes, but is not limited to, Coptotermes curvignathus, Coptotermes frenchi, Coptotermes formosanus, Heterotermes aureus, Microtermes obesi, Reticulitermes banyulensis, Reticulitermes grassei, Reticulitermes flavipes, Reticulitermes hageni, Reticulitermes hesperus, Reticulitermes santonensis, Reticulitermes speratus, Reticulitermes tibialis, and Reticulitermes virginicus.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Lepidoptera. A non-exhaustive list of particular genera includes, but is not limited to, Adoxophyes spp., Agrotis spp., Argyrotaenia spp., Cacoecia spp., Caloptilia spp., Chilo spp., Chrysodeixis spp., Colias spp., Crambus spp., Diaphania spp., Diatraea spp., Earias spp., Ephestia spp., Epimecis spp., Feltia spp., Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela spp., Lithocolletis spp., Loxagrotis spp., Malacosoma spp., Peridroma spp., Phyllonorycter spp., Pseudaletia spp., Sesamia spp., Spodoptera spp., Synanthedon spp., and Yponomeuta spp. A non-exhaustive list of particular species includes, but is not limited to, Achaea janata, Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbia cuneana, Amyelois transitella, Anacamptodes defectaria, Anarsia lineatella, Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archips rosana, Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes, Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Carposina niponensis, Chlumetia transversa, Choristoneura rosaceana, Cnaphalocrocis medinalis, Conopomorpha cramerella, Cossus cossus, Cydia caryana, Cydia funebrana, Cydia molesta, Cydia nigricana, Cydia pomonella, Darna diducta, Diatraea saccharalis, Diatraea grandiosella, Earias insulana, Earias vittella, Ecdytolopha aurantianum, Elasmopalpus lignosellus, Ephestia cautella, Ephestia elutella, Ephestia kuehniella, Epinotia aporema, Epiphyas postvittana, Erionota thrax, Eupoecilia ambiguella, Euxoa auxiliaris, Grapholita molesta, Hedylepta indicata, Helicoverpa armigera, Helicoverpa zea, Heliothis virescens, Hellula undalis, Keiferia lycopersicella, Leucinodes orbonalis, Leucoptera coffeella, Leucoptera malifoliella, Lobesia botrana, Loxagrotis albicosta, Lymantria dispar, Lyonetia clerkella, Mahasena corbetti, Mamestra brassicae, Maruca testulalis, Metisa plana, Mythimna unipuncta, Neoleucinodes elegantalis, Nymphula depunctalis, Operophtera brumata, Ostrinia nubilalis, Oxydia vesulia, Pandemis cerasana, Pandemis heparana, Papilio demodocus, Pectinophora gossypiella, Peridroma saucia, Perileucoptera coffeella, Phthorimaea operculella, Phyllocnistis citrella, Pieris rapae, Plathypena scabra, Plodia interpunctella, Plutella xylostella, Polychrosis viteana, Prays endocarpa, Prays oleae, Pseudaletia unipuncta, Pseudoplusia includens, Rachiplusia nu, Scirpophaga incertulas, Sesamia inferens, Sesamia nonagrioides, Setora nitens, Sitotroga cerealella, Sparganothis pilleriana, Spodoptera exigua, Spodoptera frugiperda, Spodoptera eridania, Thecla basilides, Tineola bisselliella, Trichoplusia ni, Tuta absoluta, Zeuzera coffeae, and Zeuzera pyrina.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Mallophaga. A non-exhaustive list of particular genera includes, but is not limited to, Anaticola spp., Bovicola spp., Chelopistes spp., Goniodes spp., Menacanthus spp., and Trichodectes spp. A non-exhaustive list of particular species includes, but is not limited to, Bovicola bovis, Bovicola caprae, Bovicola ovis, Chelopistes meleagridis, Goniodes dissimilis, Goniodes gigas, Menacanthus stramineus, Menopon gallinae, and Trichodectes canis.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Orthoptera. A non-exhaustive list of particular genera includes, but is not limited to, Melanoplus spp., and Pterophylla spp. A non-exhaustive list of particular species includes, but is not limited to, Anabrus simplex, Gryllotalpa africana, Gryllotalpa australis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla, Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria, and Scudderia furcata.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Siphonaptera. A non-exhaustive list of particular species includes, but is not limited to, Ceratophyllus gallinae, Ceratophyllus niger, Ctenocephalides canis, Ctenocephalides felis, and Pulex irritans.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Thysanoptera. A non-exhaustive list of particular genera includes, but is not limited to, Caliothrips spp., Frankliniella spp., Scirtothrips spp., and Thrips spp. A non-exhaustive list of particular sp. includes, but is not limited to, Frankliniella fusca, Frankliniella occidentalis, Frankliniella schultzei, Frankliniella williamsi, Heliothrips haemorrhoidalis, Rhipiphorothrips cruentatus, Scirtothrips citri, Scirtothrips dorsalis, and Taeniothrips rhopalantennalis, Thrips hawaiiensis, Thrips nigropilosus, Thrips orientalis, Thrips tabaci.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Thysanura. A non-exhaustive list of particular genera includes, but is not limited to, Lepisma spp. and Thermobia spp.


In another embodiment, the molecules of Formula One may be used to control pests of the Order Acarina. A non-exhaustive list of particular genera includes, but is not limited to, Acarus spp., Aculops spp., Boophilus spp., Demodex spp., Dermacentor spp., Epitrimerus spp., Eriophyes spp., Ixodes spp., Oligonychus spp., Panonychus spp., Rhizoglyphus spp., and Tetranychus spp. A non-exhaustive list of particular species includes, but is not limited to, Acarapis woodi, Acarus siro, Aceria mangiferae, Aculops lycopersici, Aculus pelekassi, Aculus schlechtendali, Amblyomma americanum, Brevipalpus obovatus, Brevipalpus phoenicis, Dermacentor variabilis, Dermatophagoides pteronyssinus, Eotetranychus carpini, Notoedres cati, Oligonychus coffeae, Oligonychus ilicis, Panonychus citri, Panonychus ulmi, Phyllocoptruta oleivora, Polyphagotarsonemus latus, Rhipicephalus sanguineus, Sarcoptes scabiei, Tegolophus perseaflorae, Tetranychus urticae, and Varroa destructor.


In another embodiment, the molecules of Formula One may be used to control pest of the Order Symphyla. A non-exhaustive list of particular sp. includes, but is not limited to, Scutigerella immaculata.


In another embodiment, the molecules of Formula One may be used to control pests of the Phylum Nematoda. A non-exhaustive list of particular genera includes, but is not limited to, Aphelenchoides spp., Belonolaimus spp., Criconemella spp., Ditylenchus spp., Heterodera spp., Hirschmanniella spp., Hoplolaimus spp., Meloidogyne spp., Pratylenchus spp., and Radopholus spp. A non-exhaustive list of particular sp. includes, but is not limited to, Dirofilaria immitis, Heterodera zeae, Meloidogyne incognita, Meloidogyne javanica, Onchocerca volvulus, Radopholus similis, and Rotylenchulus reniformis.


For additional information consult “Handbook of Pest Control—The Behavior, Life History, and Control of Household Pests” by Arnold Mallis, 9th Edition, copyright 2004 by GIE Media Inc.


Applications

Molecules of Formula One are generally used in amounts from about 0.01 grams per hectare to about 5000 grams per hectare to provide control. Amounts from about 0.1 grams per hectare to about 500 grams per hectare are generally preferred, and amounts from about 1 gram per hectare to about 50 grams per hectare are generally more preferred.


The area to which a molecule of Formula One is applied can be any area inhabited (or maybe inhabited, or traversed by) a pest, for example: where crops, trees, fruits, cereals, fodder species, vines, turf and ornamental plants, are growing; where domesticated animals are residing; the interior or exterior surfaces of buildings (such as places where grains are stored), the materials of construction used in building (such as impregnated wood), and the soil around buildings. Particular crop areas to use a molecule of Formula One include areas where apples, corn, sunflowers, cotton, soybeans, canola, wheat, rice, sorghum, barley, oats, potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes, peppers, crucifers, pears, tobacco, almonds, sugar beets, beans and other valuable crops are growing or the seeds thereof are going to be planted. It is also advantageous to use ammonium sulfate with a molecule of Formula One when growing various plants.


Controlling pests generally means that pest populations, pest activity, or both, are reduced in an area. This can come about when: pest populations are repulsed from an area; when pests are incapacitated in or around an area; or pests are exterminated, in whole, or in part, in or around an area. Of course, a combination of these results can occur. Generally, pest populations, activity, or both are desirably reduced more than fifty percent, preferably more than 90 percent. Generally, the area is not in or on a human; consequently, the locus is generally a non-human area.


The molecules of Formula One may be used in mixtures, applied simultaneously or sequentially, alone or with other compounds to enhance plant vigor (e.g. to grow a better root system, to better withstand stressful growing conditions). Such other compounds are, for example, compounds that modulate plant ethylene receptors, most notably 1-methylcyclopropene (also known as 1-MCP). Furthermore, such molecules may be used during times when pest activity is low, such as before the plants that are growing begin to produce valuable agricultural commodities. Such times include the early planting season when pest pressure is usually low.


The molecules of Formula One can be applied to the foliar and fruiting portions of plants to control pests. The molecules will either come in direct contact with the pest, or the pest will consume the pesticide when eating leaf, fruit mass, or extracting sap, that contains the pesticide. The molecules of Formula One can also be applied to the soil, and when applied in this manner, root and stem feeding pests can be controlled. The roots can absorb a molecule taking it up into the foliar portions of the plant to control above ground chewing and sap feeding pests.


Generally, with baits, the baits are placed in the ground where, for example, termites can come into contact with, and/or be attracted to, the bait. Baits can also be applied to a surface of a building, (horizontal, vertical, or slant surface) where, for example, ants, termites, cockroaches, and flies, can come into contact with, and/or be attracted to, the bait. Baits can comprise a molecule of Formula One.


The molecules of Formula One can be encapsulated inside, or placed on the surface of a capsule. The size of the capsules can range from nanometer size (about 100-900 nanometers in diameter) to micrometer size (about 10-900 microns in diameter).


Because of the unique ability of the eggs of some pests to resist certain pesticides, repeated applications of the molecules of Formula One may be desirable to control newly emerged larvae.


Systemic movement of pesticides in plants may be utilized to control pests on one portion of the plant by applying (for example by spraying an area) the molecules of Formula One to a different portion of the plant. For example, control of foliar-feeding insects can be achieved by drip irrigation or furrow application, by treating the soil with for example pre- or post-planting soil drench, or by treating the seeds of a plant before planting.


Seed treatment can be applied to all types of seeds, including those from which plants genetically modified to express specialized traits will germinate. Representative examples include those expressing proteins toxic to invertebrate pests, such as Bacillus thuringiensis or other insecticidal toxins, those expressing herbicide resistance, such as “Roundup Ready” seed, or those with “stacked” foreign genes expressing insecticidal toxins, herbicide resistance, nutrition-enhancement, drought resistance, or any other beneficial traits. Furthermore, such seed treatments with the molecules of Formula One may further enhance the ability of a plant to better withstand stressful growing conditions. This results in a healthier, more vigorous plant, which can lead to higher yields at harvest time. Generally, about 1 gram of the molecules of Formula One to about 500 grams per 100,000 seeds is expected to provide good benefits, amounts from about 10 grams to about 100 grams per 100,000 seeds is expected to provide better benefits, and amounts from about 25 grams to about 75 grams per 100,000 seeds is expected to provide even better benefits.


It should be readily apparent that the molecules of Formula One may be used on, in, or around plants genetically modified to express specialized traits, such as Bacillus thuringiensis or other insecticidal toxins, or those expressing herbicide resistance, or those with “stacked” foreign genes expressing insecticidal toxins, herbicide resistance, nutrition-enhancement, or any other beneficial traits.


The molecules of Formula One may be used for controlling endoparasites and ectoparasites in the veterinary medicine sector or in the field of non-human animal keeping. The molecules of Formula One are applied, such as by oral administration in the form of, for example, tablets, capsules, drinks, granules, by dermal application in the form of, for example, dipping, spraying, pouring on, spotting on, and dusting, and by parenteral administration in the form of, for example, an injection.


The molecules of Formula One may also be employed advantageously in livestock keeping, for example, cattle, sheep, pigs, chickens, and geese. They may also be employed advantageously in pets such as, horses, dogs, and cats. Particular pests to control would be fleas and ticks that are bothersome to such animals. Suitable formulations are administered orally to the animals with the drinking water or feed. The dosages and formulations that are suitable depend on the species.


The molecules of Formula One may also be used for controlling parasitic worms, especially of the intestine, in the animals listed above.


The molecules of Formula One may also be employed in therapeutic methods for human health care. Such methods include, but are limited to, oral administration in the form of, for example, tablets, capsules, drinks, granules, and by dermal application.


Pests around the world have been migrating to new environments (for such pest) and thereafter becoming a new invasive species in such new environment. The molecules of Formula One may also be used on such new invasive species to control them in such new environment.


The molecules of Formula One may also be used in an area where plants, such as crops, are growing (e.g. pre-planting, planting, pre-harvesting) and where there are low levels (even no actual presence) of pests that can commercially damage such plants. The use of such molecules in such area is to benefit the plants being grown in the area. Such benefits, may include, but are not limited to, improving the health of a plant, improving the yield of a plant (e.g. increased biomass and/or increased content of valuable ingredients), improving the vigor of a plant (e.g. improved plant growth and/or greener leaves), improving the quality of a plant (e.g. improved content or composition of certain ingredients), and improving the tolerance to abiotic and/or biotic stress of the plant.


Before a pesticide can be used or sold commercially, such pesticide undergoes lengthy evaluation processes by various governmental authorities (local, regional, state, national, and international). Voluminous data requirements are specified by regulatory authorities and must be addressed through data generation and submission by the product registrant or by a third party on the product registrant's behalf, often using a computer with a connection to the World Wide Web. These governmental authorities then review such data and if a determination of safety is concluded, provide the potential user or seller with product registration approval. Thereafter, in that locality where the product registration is granted and supported, such user or seller may use or sell such pesticide.


A molecule according to Formula One can be tested to determine its efficacy against pests. Furthermore, mode of action studies can be conducted to determine if said molecule has a different mode of action than other pesticides. Thereafter, such acquired data can be disseminated, such as by the internet, to third parties.


The headings in this document are for convenience only and must not be used to interpret any portion hereof.


Table Section
















% Control (or Mortality)
Rating
















BAW & CEW & CL Rating Table










50-100
A



More than 0-Less than 50
B



Not Tested
C



No activity noticed in this bioassay
D







GPA Rating Table










80-100
A



More than 0-Less than 80
B



Not Tested
C



No activity noticed in this bioassay
D

















TABLE 1







Structures for Compounds








Compound



Number
Structure





AI34


embedded image







AI36


embedded image







AI37


embedded image







AI38


embedded image







AI39


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AI40


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AI41


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AI44


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AI45


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AC1


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AC2


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AC3


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AC4


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AC5


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AC6


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AC7


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AC8


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AC9


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AC10


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AC11


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AC12


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AC13


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AC14


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AC15


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AC16


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AC17


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AC18


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AC19


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AC20


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AC21


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AC22


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AC23


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AC24


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AC25


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AC26


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AC27


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AC28


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AC29


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AC30


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AC31


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AC32


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AC33


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AC34


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AC35


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AC36


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AC37


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AC38


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AC39


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AC40


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AC41


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AC42


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AC43


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AC44


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AC45


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AC46


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AC47


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AC48


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AC49


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AC50


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AC51


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AC52


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AC53


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AC54


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AC57


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AC58


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AC59


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AC60


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AC61


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AC62


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AC63


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AC64


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AC65


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AC66


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AC67


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AC68


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AC69


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AC70


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AC75


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AC100


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AC101


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AC102


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AC103


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AC104


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AC105


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AC106


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AC107


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AC108


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AC109


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AC110


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AC111


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AC112


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AC113


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AC114


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AC115


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AC116


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AC117


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AC118


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BC1


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BC2


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BC4


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BC11


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BC14


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CI4


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CI8


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CI34


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CI37


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CI39


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CI40


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CI49


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CI55


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TABLE 1A







Structures for F Compounds













Prepared


Compound


according


Number
Structure
Appearance
to Example:








F1


embedded image


Light brown foam
128





F7


embedded image


Glassy oil
128
















TABLE 1B







Structures for FA Compounds













Prepared


Compound


according


Number
Structure
Appearance
to Example:








FA1


embedded image


Brown gum
129





FA2


embedded image


Pale brown solid
129





FA3


embedded image


Brown gum
129





FA4


embedded image


Brown gum
129





FA5


embedded image


Pale yellow solid
129





FA6


embedded image


Pale yellow gum
129





FA7


embedded image


Pale yellow gum
129





FA8


embedded image


Brown solid
129





FA9


embedded image


Brown solid
129





FA10


embedded image


Yellow-green viscous oil
135
















TABLE 2







Analytical Data for Compounds in Table 1.











Compound






Number
mp (° C.)
ESIMS

1H NMR (δ)a
IR (cm−1)





AC1
156-161
386.09
7.83 (m, 2H), 7.68-7.63





([M − H]−)
(m, 5H), 6.93 (dd, J =





15.6, 8.0 Hz, 1H), 6.81





(d J = 15.6 Hz, 1H,),





4.15 (m, 1H), 2.80 (s, 3H)


AC2
110-112
374
7.80 (d, J = 8.4 Hz, 2H),




([M + H]+)
7.48 (d, J = 8.0 Hz, 2H),





7.38 (m, 1H), 7.30 (s,





2H), 6.65 (d, J = 16.0





Hz, 1H), 6.46 (dd, J =





16.0, 8.0 Hz, 1H), 4.15





(m, 1H)


AC3
162-166
402.24
7.42 (m, 4H), 7.37 (t, J =




([M + H]+)
1.8 Hz, 1H), 7.28 (s,





2H), 6.63 (d, J = 16.0





Hz, 1H), 6.41 (dd, J =





16.0, 8.4 Hz, 1H), 4.15





(m, 1H), 3.20 (s, 3H),





3.00 (s, 3H)


AC4
122-126
454
7.79 (d, J = 1.2 Hz, 2H),




([M − H]−)
7.48 (d, J = 8.4 Hz, 2H),





7.38 (t, J = 1.8 Hz, 1H),





7.30 (s, 2H), 6.64 (d, J =





15.6 Hz, 1H), 6.40 (dd,





J = 15.6, 8.0 Hz, 1H),





6.30 (m, 1H), 4.15 (m, 3H)


AC5

444.12
7.67 (s, 3H), 7.64 (d, J =




([M + H]+)
8.0 Hz, 2H), 7.42 (d, J =





8.0 Hz, 2H), 6.91 (dd, J =





15.6, 8.0 Hz, 1H), 6.80





(d, J = 15.6 Hz, 1H),





4.80 (m, 1H), 3.60





(br s, 8H)


AC6

468.40
7.40 (m, 2H), 7.26 (m,
1657, 1113,




([M − H]−)
3H), 6.56 (d, J = 16.0
804





Hz, 1H), 6.48 (dd, J =





16.0, 8.0 Hz, 1H), 5.82





(br s, 1H), 4.08 (m, 3H),





2.52 (s, 3H)


AC7

511.02
8.39 (s, 1H), 7.74 (m,
3276, 1645,




([M − H]−)
1H), 7.39 (m, 3H), 7.24
1111, 801





(m, 4H), 6.58 (d, J =





16.0 Hz, 1H), 6.38 (dd,





J = 16.0, 8.0 Hz, 1H),





6.16 (br s, 1H), 4.63 (m,





2H), 4.12 (m, 1H), 2.41





(s, 3H)


AC8

454.11
7.39 (s, 1H), 7.22 (m,
1748, 1112,




([M − H]−)
2H), 7.19 (m, 3H), 6.53
801





(d, J = 16.0 Hz, 1H),





6.39-6.34 (dd, J = 16.0,





8.0 Hz, 1H), 4.22 (m,





1H), 3.95 (t, J = 7.0 Hz,





2H), 2.62 (t, J = 8.0 Hz,





2H), 2.30 (s, 3H), 2.18





(m, 2H)


AC9

494.02
7.45 (t, J = 7.6 Hz, 1H),
3276, 1645,




([M − H]−)
7.36 (m, 2H), 7.21 (m,
1112, 801





3H), 7.15 (m, 4H), 6.56





(d, J = 16.0 Hz, 1H),





6.38 (dd, J = 16.0, 8.4





Hz, 1H), 6.08 (br s, 1H),





4.68 (d, J = 5.6 Hz, 2H),





4.11 (m, 1H), 2.44 (s, 3H)


A10
140-143
458.00
7.38 (t, J = 1.6 Hz, 1H),




([M − H]−)
7.34 (d, J = 7.6 Hz, 1H),





7.27 (m, 2H), 7.24 (m,





2H), 6.57 (d, J = 16.0





Hz, 1H), 6.40 (dd, J =





16.0, 8.0 Hz, 1H), 6.16





(m 1H), 5.44 (m, 1H),





4.12 (m, 1H), 3.51 (m,





2H), 3.40 (m, 2H), 2.44





(s, 3H)


AC11

476.17
7.39-7.29 (m, 9H), 7.24
3287, 1644,




([M − H]−)
(m, 2H), 6.56 (d, J =
1112, 801





16.0 Hz, 1H), 6.38 (dd,





J = 16.0, 8.0 Hz, 1H),





5.99 (br s, 1H), 4.63 (d,





J = 6.0 Hz, 1H), 4.11





(m, 1H), 2.47 (s, 3H)


AC12

479.30
8.63 (d, J = 4.4 Hz, 1H),
3293, 1653,




([M + H]+)
7.71 (m, 1H), 7.47 (d, J =
1112, 800





8.4 Hz, 1H), 7.37 (m,





2H), 7.32 (m, 2H), 7.23





(m, 2H), 7.13 (m, 1H),





6.58 (d, J = 16.0 Hz,





1H), 6.40 (dd, J = 16.0,





8.0 Hz, 1H), 4.75 (d, J =





4.8 Hz, 2H), 4.12 (m,





1H), 2.49 (s, 3H)


AC13
75-78
490.04
7.38 (m, 2H), 7.27 (m,




([M − H]−)
3H), 7.23 (br s, 1H),





6.58 (d, J = 16.0 Hz,





1H), 6.45 (m 1H), 6.42





(dd, J = 16.0, 8.4 Hz,





1H), 4.91 (m 1H), 4.64





(m, 2H), 4.14 (m, 1H),





4.04 (m, 2H), 2.46 (s, 3H)


AC14

480.99
8.63 (s, 2H), 7.76 (d, J =
3293, 1645,




([M + 2H]+)
8.0 Hz, 1H), 7.36 (m,
1113, 800





3H), 7.22 (m, 1H), 7.13





(m, 2H), 6.57 (d, J =





16.0 Hz, 1H), 6.39 (dd,





J = 16.0, 8.0 Hz, 1H),





6.13 (br s, 1H), 4.66 (d,





J = 5.6 Hz, 2H), 4.11





(m, 1H), 2.46 (s, 3H)


AC15
59-61
516.86
7.45 (s, 1H), 7.37 (m,
3246, 1635,




([M − H]−)
1H), 7.34 (m, 1H), 7.26
1112, 801





(m, 3H), 7.22 (m, 1H),





6.57 (d, J = 16.0 Hz,





1H), 6.40 (dd, J = 16.0,





8.0 Hz, 1H), 6.18 (m,





1H), 4.71 (d, J = 6.4 Hz,





2H), 4.11 (m, 1H), 2.46





(s, 3H)


AC16

506.93
8.47 (m, 1H), 8.19 (s,
1657, 1113,




([M + H]+)
1H), 7.76 (m, 1H), 7.47
801





(m, 2H), 7.37 (m, 1H),





7.28 (m, 2H), 7.24 (m,





1H), 7.21 (m, 1H), 6.59





(d, J = 16.0 Hz, 1H),





6.39 (dd, J = 16.0, 8.4





Hz, 1H), 4.12 (m, 1H),





2.48 (s, 3H), 1.88 (s, 6H)


AC17
70-73
494.98
7.49 (m, 2H), 7.38 (m,




([M − H]−)
1H), 7.29 (m, 4H), 7.08





(m, 3H), 6.91 (m, 1H),





6.61 (d, J = 16.0 Hz,





1H), 6.48 (m, 1H), 6.43





(dd, J = 16.0, 8.0 Hz,





1H), 4.13 (m, 1H), 2.49





(s, 3H)


AC18
155-158
480.44
8.73 (d, J = 4.8 Hz, 2H),




([M + H]+)
7.53 (d, J = 8.4 Hz, 1H),





7.37 (m, 1H), 7.27 (m,





4H), 7.23 (m, 1H), 7.11





(m, 1H), 6.60 (d, J =





16.0 Hz, 1H), 6.41 (dd,





J = 16.0, 8.0 Hz, 1H),





4.90 (d, J = 4.8 Hz, 2H),





4.13 (m, 1H), 2.52 (s, 3H)


AC19
55-57
471.66
7.37 (m, 1H), 7.33 (d, J =




([M + H]+)
7.6 Hz, 1H), 7.27 (m,





2H), 7.22 (m, 2H), 6.57





(d, J = 16.0 Hz, 1H),





6.39 (dd, J = 16.0, 8.0





Hz, 1H), 6.10 (brs, 1H),





4.13 (m, 2H), 3.94 (m,





1H), 3.79 (m, 2H), 3.35





(m, 1H), 2.45 (s, 3H),





2.14 (m, 1H), 1.71 (m,





2H), 1.65 (m, 1H).


AC20

467.68
7.37 (m, 2H), 7.27 (m,
3437, 1664,




([M + H]+)
2H), 7.23 (m, 2H), 6.57
1265, 1114,





(d, J = 16.0 Hz, 1H),
746





6.38 (m, 3H), 6.01 (m,





1H), 4.63 (d, J = 5.6 Hz,





2H), 4.13 (m, 1H), 2.45





(s, 3H)


AC21
61-64
528.78
8.44 (s, 1H), 8.18 (s,




([M + H]+)
1H), 7.83 (br s, 1H),





7.38 (m, 2H), 7.27 (m,





2H), 7.25 (m, 2H), 7.21





(m, 1H), 6.57 (d, J =





16.0 Hz, 1H), 6.40 (dd,





J = 16.0, 8.0 Hz, 1H),





5.01 (s, 2H), 4.11 (m,





1H), 2.43 (s, 3H)


AC22

545.08
8.39 (s, 1H), 7.73 (m,
3270, 1642,




([M − H]−)
1H), 7.40 (s, 1H), 7.35
1111, 809





(m, 2H), 7.22 (m, 3H),





6.57 (d, J = 16.0 Hz,





1H), 6.38 (dd, J = 16.0,





7.6 Hz, 1H), 6.14 (br s,





1H), 4.62 (d, J = 6.0 Hz,





2H), 4.13 (m, 1H), 2.45





(s, 3H)


AC23

492.35
7.42 (s, 2H), 7.36 (m,
3273, 1641,




([M − H]−)
1H), 7.24 (m, 2H), 6.59
1250, 1113,





(d, J = 16.0 Hz, 1H),
807





6.40 (dd, J = 16.0, 8.0





Hz, 1H), 6.20 (br s, 1H),





5.46 (m, 1H), 4.15 (m,





1H), 3.52 (m, 2H), 3.41





(m, 2H), 2.45 (s, 3H)


AC24
129-132
526.98
7.40 (m, 2H), 7.27 (m,
3298, 1664,




([M + H]+)
2H), 7.25 (m, 2H), 6.92
1113, 803





(br s, 2H), 6.60 (m, 1H),





6.48(dd, J = 16.0, 8.0





Hz, 1H), 4.19 (d, J =





5.2, 2H), 4.08 (m, 1H),





3.99 (m, 2H), 2.46 (s, 3H)


AC25

542.24
7.41 (m, 3H), 7.27 (m,
3257, 1652,




([M − H]−)
2H), 6.58 (d, J = 15.6
1316, 1109,





Hz, 1H), 6.42 (m, 2H),
807





4.92 (m, 1H), 4.65 (m,





2H), 4.14 (m, 1H), 4.09





(m, 2H), 2.46 (s, 3H)


AC26

550.69
7.45 (s, 1H), 7.40 (s,
3255, 1638,




([M − H]−)
2H), 7.34 (d, J = 8.0 Hz,
1113, 809





1H), 7.22 (m, 2H), 6.54





(d, J = 16.0 Hz, 1H),





6.38 (dd, J = 16.0, 8.0





Hz, 1H), 4.71 (d, J = 6.0





Hz, 2H), 4.11 (m, 1H),





2.46 (s, 3H)


AC27

541.00
8.46 (d, J = 4.0 Hz, 1H),
1653, 1113,




([M − H]−)
8.20 (s, 1H), 7.76 (m,
809





1H), 7.47 (m, 2H), 7.41





(s, 2H), 7.23 (m, 2H),





7.21 (m, 1H), 6.59 (d, J =





16.0 Hz, 1H), 6.37





(dd, J = 16.0, 8.4 Hz,





1H), 4.11 (m, 1H), 2.48





(s, 3H), 1.88 (s, 6H)


AC28
65-67
564.84
8.40 (s, 1H), 7.74 (m,
3267, 1650,




([M − H]−)
2H), 7.42 (m, 3H), 7.36
1112, 809





(m, 2H), 6.72 (br s, 1H),





6.52 (d, J = 16.0 Hz,





1H), 6.43 (dd, J = 16.0,





8.0 Hz, 1H), 4.66 (d, J =





6.4 Hz, 2H), 4.12 (m, 1H)


AC29
75-78
511.78
7.71 (d, J = 8.4 Hz, 1H),




([M − H]−)
7.42 (m, 3H), 7.35 (m,





1H), 6.75 (br s, 1H),





6.56 (d, J = 16.0 Hz,





1H), 6.43 (dd, J = 16.0,





8.0 Hz, 1H), 5.49 (m,





1H), 4.14 (m, 1H), 3.50





(m, 4H)


AC30
110-113
543.72
7.42 (d, J = 8.4 Hz, 1H),




([M − H]−)
7.44 (s, 1H), 7.40 (s,





1H), 7.38 (m, 1H), 7.06





(br s, 1H), 6.58 (d, J =





15.6 Hz, 1H), 6.45 (dd,





J = 15.6, 8.0 Hz, 1H),





4.93 (m, 1H), 4.65 (m,





2H), 4.13 (m, 3H)


AC31
68-70
610.73
8.42 (s, 1H), 7.76 (m,




([M + H]+)
1H), 7.61 (m, 2H), 7.39





(m, 4H), 6.54-6.39 (m,





3H), 4.66 (d, J = 6.0 Hz,





2H), 4.12 (m, 1H)


AC32
78-80
555.89
7.61 (m, 2H), 7.40 (m,




([M − H]−)
3H), 6.54 (m, 2H), 6.40





(dd, J = 16.0, 8.0 Hz,





1H), 5.46 (m, 1H), 4.14





(m, 1H), 3.50 (m, 4H)


AC33
182-184
587.68
7.62 (s, 1H), 7.58 (d, J =




([M − H]−)
8.0 Hz, 1H), 7.40 (m,





3H), 6.84 (br s, 1H),





6.55 (d, J = 15.6 Hz,





1H), 6.45 (dd, J = 15.6,





7.6 Hz, 1H), 4.93 (m





1H), 4.65 (m, 2H), 4.13





(m, 4H)


AC34
151-153
545.83
7.67 (s, 1H), 7.61 (d, J =




([M − H]−)
6.0 Hz, 1H), 7.53 (m,





1H), 7.41 (s, 2H), 6.64





(d, J = 16.0 Hz, 1H),





6.40 (dd, J = 16.0, 8.0





Hz, 1H), 6.18 (br s, 1H),





5.44 (m, 1H), 4.14 (m,





1H), 3.50 (m, 2H), 3.40





(m, 2H)


AC35
100-102
577.71
7.70 (s, 1H), 7.63 (m,
3257, 1655,




([M − H]−)
1H), 7.53 (d, J = 7.6 Hz,
1113, 808





1H), 7.41 (s, 2H), 6.53





(d, J = 16.0 Hz, 1H),





6.49 (m, 2H), 4.93 (m,





1H), 4.64 (m, 2H), 4.13





(m, 1H), 4.03 (m, 2H)


AC36
81-83
600.83
8.40 (s, 1H), 7.73 (m,




([M + H]+)
2H), 7.61 (d, J = 8.4 Hz,





1H), 7.52 (d, J = 8.0 Hz,





1H), 7.40 (s, 2H), 7.35





(d, J = 8.0 Hz, 1H), 6.63





(d, J = 16.0 Hz, 1H),





6.46 (dd, J = 16.0, 7.6





Hz, 1H), 6.14 (m, 1H),





4.63 (d, J = 6.0 Hz, 2H),





4.14 (m, 1H)


AC37

512.68
8.39 (s, 1H), 7.73 (m,
3268, 1644,




([M + H]+)
1H), 7.48 (m, 2H), 7.34
1109, 820





(d, J = 7.6 Hz, 1H), 7.24





(m, 3H), 6.55 (d, J =





16.0 Hz, 1H), 6.41 (dd,





J = 16.0, 7.6 Hz, 1H),





6.12 (m, 1H), 4.62 (d, J =





6.0 Hz, 2H), 4.13 (m,





1H), 2.45 (s, 3H)


AC38
79-80
528.85
8.46 (m, 1H), 7.73 (m,




([M − H]−)
1H), 7.35 (m, 4H), 7.22





(m, 2H), 6.56 (d, J =





16.0 Hz, 1H), 6.38 (dd,





J = 16.0, 8.0 Hz, 1H),





4.62 (d, J = 6.0 Hz, 2H),





4.10 (m, 1H), 2.45 (s, 3H)


AC39
141-144
477.83
9.19 (s, 1H), 8.79 (s,




([M − H]−)
2H), 7.37 (m, 2H), 7.23





(m, 2H), 7.21 (m, 1H),





6.57 (d, J = 16.0 Hz,





1H), 6.40 (dd, J = 16.0,





7.6 Hz 1H), 6.21 (m,





1H), 4.65 (s, 2H), 4.11





(m, 1H), 2.46 (s, 3H)


AC40
69-72
484.67
8.33 (t, J = 5.6 Hz, 1H),




([M + H]+)
8.61 (m, 1H), 7.68 (m,





3H), 7.48 (m, 2H), 6.86





(dd, J = 15.6, 8.2 Hz





1H), 6.74 (d, J = 15.6





Hz, 1H), 4.44 (m, 1H),





3.76 (d, J = 6.0 Hz, 2H),





2.54 (m, 1H), 2.67 (s,





3H), 0.59 (m, 2H), 0.54





(m, 2H)


AC41
196-199
515.00
8.66 (d, J = 7.6 Hz, 1H),




([M − H]−)
8.39 (t, J = 5.6 Hz, 1H),





7.65 (s, 3H), 7.45 (m,





3H), 6.86 (dd, J = 15.6,





8.8 Hz, 1H), 6.74 (d, J =





15.6 Hz, 1H), 5.01 (m,





1H), 4.99 (m, 1H), 3.78





(d, J = 6.0 Hz, 2H), 3.40





(m, 2H), 3.22 (m, 2H),





2.37 (m, 3H)


AC42
79-82
534.72
7.99 (d, J = 8.0 Hz,




([M + H]+)
1H), 7.89 (d, J = 8.0 Hz,





1H), 7.51 (m, 2H), 7.44





(m, 2H), 7.27 (m, 4H),





6.71 (t, J = 5.2 Hz, 1H),





6.59 (d, J = 16.0 Hz, 1H),





6.41 (dd, J = 16.0,





8.0 Hz, 1H), 5.05 (d, J =





1.6 Hz, 2H), 4.12 (m,





1H), 2.52 (m, 3H)


AC43

481.75
8.69 (s, 1H), 8.52 (s,
1663, 1608,




([M + H]+)
2H), 7.45 (d, J = 7.6 Hz,
1168, 1114,





1H), 7.37 (d, J = 2.0 Hz,
801





1H), 7.26 (m, 2H), 7.21





(m, 1H), 6.83 (s, 1H),





6.58 (d, J = 16.0 Hz,





1H), 6.40 (dd, J = 16.0,





8.4 Hz, 1H), 4.81 (d, J =





5.6 Hz, 2H), 4.12 (t, J =





8.4 Hz 1H), 2.45 (s, 3H)


AC44

528.01
8.44 (d, J = 2.4 Hz, 1H),
1640, 1166,




([M + H]+)
7.69 (d, J = 2.4 Hz, 1H),
1112, 800





7.37 (m, 1H), 7.33 (s,





1H), 7.31 (s, 1H), 7.26





(m, 1H), 7.24 (m, 3H),





6.57 (d, J = 16.0 Hz,





1H), 6.39 (dd, J = 16.0,





8.0 Hz, 1H), 5.96 (d, J =





7.2 Hz, 1H), 5.32 (t, J =





7.2 Hz, 1H), 4.11 (t, J =





8.4 Hz, 1H), 2.41 (s,





3H), 1.61 (d, J = 7.2 Hz,





3H)


AC45

512.88
7.66 (s, 1H), 7.37 (d, J =
1657, 1167,




([M + H]+)
6.8 Hz, 2H), 7.26 (m,
1106, 800





3H), 7.18 (m, 1H), 7.11





(m, 2H), 6.99 (m, 1H),





6.57 (d, J = 15.6 Hz,





1H), 6.39 (dd, J = 15.6,





8.0 Hz, 1H), 4.11 (t, J =





8.4 Hz, 1H), 3.36 (s, 3H),





2.43 (s, 3H)


AC46
61-64
575.93
8.42 (d, J = 2.0 Hz, 1H),




([M + H]+)
7.76 (d, J = 2.4 Hz, 1H),





7.61 (m, 2H), 7.39 (m,





3H), 7.26 (s, 2H), 6.54





(d, J = 16.0 Hz, 1H),





6.42 (dd, J = 16.0, 7.6





Hz, 1H), 4.65 (d, J = 6.0





Hz, 2H), 4.14 (m, 1H)


AC47

525.89
10.02 (s, 1H), 9.87 (s,
3280, 1640




([M − H]−)
1H), 8.47 (t, J = 6.0 Hz,





1H), 7.66 (s, 3H), 7.44





(s, 1H), 7.40 (d, J = 3.6





Hz, 2H), 6.86 (dd, J =





15.6, 9.2 Hz, 1H), 6.74





(d, J = 15.6 Hz, 1H),





4.82 (t, J = 9.6 Hz, 2H),





3.88 (d, J = 6.0 Hz, 2H),





2.36 (s, 3H), 1.63 (m,





1H), 0.76 (m, 4H)


AC48

509.96
7.37 (m, 7H), 7.34 (m,
3275, 1642




([M − H]−)
3H), , 6.57 (d, J = 16.0





Hz, 1H), 6.39 (dd, J =





16.0, 8.0 Hz, 1H), 6.01





(m, 1H), 4.60 (d, J = 6.0





Hz, 2H), 4.13 (m, 1H),





2.46 (s, 3H)


AC49

518.85
8.39 (d, J = 2.0 Hz, 1H),
1658, 1112,




([M + H]+)
8.11 (m, 1H), 7.71 (d,
1025, 2219





J = 2.4 Hz, 1H), 7.41 (m,





3H), 7.17 (m, 3H), 6.59





(d, J = 16.0 Hz, 1H),





6.47 (dd, J = 16.0, 8.0





Hz, 1H), 4.66 (d, J = 5.6





Hz, 2H), 4.14 (m, 1H)


AC50

481.88
8.72 (m, 1H), 7.67 (s,
1654, 1112,




([M + H]+)
3H), 7.46 (s, 1H), 7.40
800, 3069





(m, 2H), 7.08 (s, 1H),





6.82 (m, 2H), 6.55 (d,





J = 7.6 Hz, 1H), 4.82 (m,





1H), 4.48 (s, 2H), 3.65





(s, 3H), 2.38 (s, 3H)


AC51

540.83
7.45 (d, J = 7.6 Hz, 1H),
1652, 1571,




([M + H]+)
7.38 (m, 1H), 7.27 (m,
802, 1114,





2H), 7.22 (m, 2H), 6.85
2926





(m, 1H), 6.58 (d, J =





16.0 Hz, 1H), 6.40 (dd,





J = 16.0, 8.0 Hz, 1H),





4.33 (m, 2H), 4.14 (m,





3H), 3.18 (s, 3H), 2.48





(s, 3H)


AC52

488.29
7.33 (m, 2H), 7.25 (m,
1635, 11134,




([M − H]−)
3H), 6.56 (d, J = 15.6
813, 2927





Hz, 1H), 6.37 (dd, J =





15.6, 8.0 Hz, 1H), 5.61





(d, J = 8.0 Hz, 1H), 4.21





(m, 1H), 4.01 (m, 1H),





4.08 (m, 2H), 3.56 (t, J =





10.0 Hz, 2H), 2.48 (m,





2H), 2.08 (m, 2H), 1.5





(m, 3H)


AC53

532.92
8.49 (d, J = 2.0 Hz, 1H),
1651, 3027,




([M + H]+)
7.69 (d, J = 2.4 Hz, 1H),
815, 1113





7.43 (d, J = 8.0 Hz, 1H),





7.34 (m, 3H), 7.26 (m,





2H), 6.95 (m, 1H), 6.58





(d, J = 16.0 Hz, 1H),





6.38 (dd, J = 16.0, 8.0





Hz, 1H), 4.72 (d, J = 5.2





Hz, 2H), 4.09 (m, 1H),





2.47 (s, 3H)


AC54

529.06
8.37 (d, J = 5.2 Hz, 1H),
1654, 3434,




([M − H]−)
7.41 (d, J = 8.0 Hz, 1H),
814, 1112





7.36 (m, 3H), 7.31 (m,





1H), 7.26 (m, 2H), 6.58





(d, J = 16.0 Hz, 1H),





6.40 (dd, J = 16.0, 7.6





Hz, 1H), 5.20 (t, J = 5.6





Hz, 1H), 4.63 (d, J = 6.0





Hz, 2H), 4.13 (m, 1H),





2.18 (s, 3H)


AC57

464.96
8.69 (t, J = 6.0 Hz, 1H),
3417, 1658,




([M + H]+)
8.58 (t, J = 6.0 Hz, 1H),
1165, 817





7.92 (s, 1H), 7.87 (d, J =





6.4 Hz, 2H), 7.62 (d, J =





8.4 Hz, 1H), 7.45 (d, J =





8.4 Hz, 1H), 7.0 (m,





1H), 6.76 (d, J = 15.6





Hz, 1H), 6.76 (dd, J =





15.6, 8.0 Hz, 1H), 4.01





(m, J = 8.0 Hz, 1H),





3.71 (m, 2H), 3.49 (m,





2H)


AC58
124.4-126.9
599.76
7.62 (m, 2H), 7.40 (s,




([M + H]+)
2H), 7.37 (d, J = 1.6 Hz,





1H), 6.61 (t, J = 4.8 Hz,





1H), 6.55 (d, J = 16.0





Hz, 1H), 6.41 (dd, J =





16.0, 7.6 Hz, 1H), 4.16





(d, J = 6.0 Hz, 2H), 4.01





(m, 1H), 1.56 (s, 9H)


AC59
80-83
497.40
8.42 (d, J = 2.1 Hz, 1H),




([M − H]−)
8.29 (d, J = 7.5 Hz, 1H),





7.51 (m, 2H), 7.39 (m,





1H), 7.36 (m, 4H), 7.28





(m, 1H), 6.61 (d, J =





15.9 Hz, 1H), 6.45 (dd,





J = 15.9, 7.8 Hz 1H),





4.14 (t, J = 8.4 Hz, 1H),





2.51 (s, 3H)


AC60

515.09
8.52 (s, 1H), 8.39 (d, J =
1668, 1589,




([M + H]−)
1.8 Hz, 2H), 7.70 (d, J =
1167, 1113,





2.1 Hz, 1H), 7.62 (s,
802





1H), 7.43 (s, 1H), 7.35





(m, 3H), 6.62 (d, J =





16.2 Hz, 1H), 6.52 (dd,





J = 16.2, 7.5 Hz, 1H),





4.62 (d, J = 6.3 Hz, 2H),





4.19 (m, 1H), 2.76 (s, 3H)


AC61

461.90
8.07 (t, J = 8.0 Hz, 1H),
1658, 1114,




([M − H]−)
7.39 (t, J = 2.0 Hz, 1H),
801





7.28 (d, J = 1.2 Hz, 3H),





7.17 (d, J = 1.6 Hz, 1H),





7.11 (m, 1H), 6.59 (d, J =





15.6 Hz, 1H), 6.47





(dd, J = 15.6, 7.6 Hz,





1H), 5.49 (m, 1H), 4.14





(t, J = 8.4 Hz, 1H), 3.48





(m, 4H)


AC62
105-108
528.88
8.62 (t, J = 6.4 Hz, 1H),




([M − H]−)
8.46 (m, 1H), 7.73 (m,





5H), 7.48 (d, J = 7.6 Hz,





1H), 7.03 (dd, J = 15.6,





9.2 Hz, 1H), 6.81 (d, J =





15.6 Hz, 1H), 4.86 (m,





1H), 3.97 (m, 4H)


AC63
77-80
594.67
8.43 (s, 1H), 7.76 (d, J =
3257, 1653




([M + H]+)
2.4 Hz, 1H), 7.60 (m,





2H), 7.38 (d, J = 7.6 Hz,





1H), 7.33 (d, J = 6.4 Hz,





3H), 6.54 (d, J = 16.0





Hz, 1H), 6.46 (m, 1H),





6.41 (dd, J = 16.0 8.0





Hz, 1H), 4.65 (d, J = 6.0





Hz, 2H), 4.15 (m, 1H)


AC64
83-85
580.72
7.72 (d, J = 8.0 Hz, 1H),




([M − H]−)
7.44 (s, 1H), 7.40 (s, 2H),





7.36 (d, J = 6.8 Hz, 1H),





7.05 (t, J = 5.2 Hz, 1H),





6.70 (t, J = 5.2 Hz, 1H),





6.57 (d, J = 15.6





Hz, 1H), 6.44 (dd, J =





15.6, 8.0 Hz, 1H), 4.23





(d, J = 5.6 Hz, 2H), 4.15





(m, 1H), 4.01 (m, 2H)


AC65

534.72
8.39 (d, J = 2.0 Hz, 1H),
1658, 1113,




([M − H]−)
8.12 (t, J = 8.4 Hz, 1H),
817, 2925





7.71 (d, J = 2.4 Hz, 1H),





7.34 (m, 3H), 7.26 (m,





1H), 7.11 (m, 2H), 6.59





(d, J = 16.0 Hz, 1H),





6.46 (dd, J = 16.0, 8.0





Hz, 1H), 4.66 (d, J = 5.2





Hz, 2H), 4.13 (m, 1H)


AC66
73-75
624.61
7.88 (s, 1H), 7.63 (d, J =




([M − H]−)
1.6 Hz, 1H), 7.57 (d, J =





8.0 Hz, 1H), 7.40 (m,





2H), 6.80 (t, J = 5.6 Hz,





1H), 6.70 (t, J = 5.6 Hz,





1H), 6.56 (d, J = 16.0





Hz, 1H), 6.44 (dd, J =





16.0, 8.0 Hz, 1H), 4.22





(m, 2H), 4.12 (m, 1H),





4.01 (m, 2H)


AC67

479.82
8.07 (t, J = 8.0 Hz, 1H),
3272, 1644




([M − H]−)
7.34 (d, J = 6.0 Hz, 2H),





7.28 (s, 1H), 7.17(s, 2H),





6.59 (d, J = 15.6





Hz, 1H), 6.46 (dd, J =





15.6, 8.0 Hz, 1H), 5.49





(m, 1H), , 4.12 (m, 1H),





3.49 (m, 4H).


AC68
90-93
546.80
8.6 (t, J = 6.4 Hz, 1H),
3315, 1684




([M − H]−)
8.45 (m, 1H), 7.86 (d, J =





6.4 Hz, 2H), 7.75 (t, J =





8.0 Hz, 1H), 7.63 (d, J =





12.0 Hz, 1H), 7.48 (d, J =





8.0 Hz, 1H), 7.03





(dd, J = 15.6, 9.6 Hz,





1H), 6.80 (d, J = 15.6





Hz, 1H), 4.88 (m, 1H),





3.96 (m, 4H)


AC69

542.82
7.41 (d, J = 8.0 Hz, 1H),
3294, 1685




([M − H]−)
7.34 (d, J = 5.6 Hz, 2H),





7.26 (m, 1H), 7.23 (m,





1H), 6.81 (s, 1H), 6.57





(d, J = 15.6 Hz, 1H),





6.55 (s, 1H), 6.39 (dd,





J = 15.6, 8.0 Hz, 1H),





4.18 (m, 2H), 4.13 (m,





1H), 3.97 (m, 2H), 2.46





(s, 3H)


AC70
176-178
545.23
8.38 (d, J = 2.4 Hz, 1H),




([M − H]−)
8.22 (d, J = 6.8 Hz, 2H),





7.71 (d, J = 2.4 Hz, 1H),





7.35 (d, J = 6.0 Hz, 2H),





7.30 (d, J = 7.6 Hz, 1H),





7.15 (d, J = 1.6 Hz, 1H),





6.93 (d, J = 1.2 Hz, 1H),





6.60 (d, J = 15.6 Hz, 1H),





6.43 (dd, J = 15.6,





7.6 Hz, 1H), 4.66 (d, J =





6.0 Hz, 2H), 4.13 (m,





1H), 3.98 (s, 3H)


AC71

492.20
8.24 (d, J = 7.6 Hz, 1H),
1639, 3079,




([M − H]−)
8.15 (d, J = 8.4 Hz, 1H),
858





7.35 (d, J = 6.0 Hz, 2H),





7.13 (d, J = 1.2 Hz, 1H),





6.92 (s, 1H), 6.61 (d, J =





16.0 Hz, 1H), 6.43 (dd,





J = 16.0, 7.6 Hz, 1H),





5.48 (m, 1H), 4.13 (m,





1H), 4.03 (s, 3H), 3.48





(m, 4H)


AC72

543.05
8.42 (d, J = 2.4 Hz, 1H),
1642, 3246,




([M − H]−)
7.75 (d, J = 2.4 Hz, 1H),
814, 1113





7.34 (m, 4H), 7.20 (m,





2H), 6.60 (d, J = 16.0





Hz, 1H), 6.36 (dd, J =





16.0, 8.0 Hz, 1H), 6.12





(t, J = 5.6 Hz, 1H), 4.62





(d, J = 6.0 Hz, 2H), 4.20





(m, 1H), 2.82 (m, 2H),





1.45 (t, J = 5.6 Hz, 3H)


AC75

644.78
8.72 (s, 1H), 7.97 (d, J =
3431, 1652,




([M + H]+)
7.2 Hz, 1H), 7.70 (d, J =
1171, 809





8.4 Hz, 1H), 7.61 (m,





2H), 7.40 (m, 2H), 6.55





(m, 2H), 6.42 (dd, J =





16.0, 8.0 Hz, 1H), 4.76





(d, J = 6.0 Hz, 2H), 4.12





(m, 1H)


AC76

531.34
8.87 (t, J = 6.0 Hz, 1H),
3120, 1708,




([M + H]+)
8.34 (d, J = 2.1 Hz, 1H),
1171





7.85 (d, J = 6.3 Hz, 3H),





7.48 (m, 4H), 6.57 (d, J =





15.6 Hz, 1H), 6.45





(dd, J = 15.6, 9.0 Hz, 1H),





4.84 (m, 1H), 4.49





(d, J = 5.7 Hz, 2H), 2.82





(m, 2H), 2.36 (t, J = 5.6





Hz, 3H)


AC77

531.1
8.87 (t, J = 6.0 Hz, 1H),
3444, 1648,




([M + H]+)
8.34 (d, J = 2.1 Hz, 1H),
1114, 814





7.85 (d, J = 6.3 Hz, 3H),





7.48 (m, 4H), 6.57 (d, J =





15.6 Hz, 1H), 6.45





(dd, J = 15.6, 8.0 Hz, 1H),





4.84 (m, 1H), 4.49





(d, J = 5.7 Hz, 2H), 2.36





(s, 3H)


AC78

561.06
8.59 (t, J = 6.4 Hz, 1H),
3432, 1631,




([M + H]+)
8.47 (t, J = 5.6 Hz, 1H),
1161, 840





7.89 (s, 2H), 7.45 (m,





3H), 6.87 (m, 1H), 6.75





(d, J = 15.6 Hz, 1H),





4.85 (t, J = 8.0 Hz 1H),





3.98 (m, 4H), 2.58 (s, 3H)


AC79

610.97
8.69 (t, J = 6.0 Hz, 1H),
3303, 1658,




([M + H]+)
8.58 (t, J = 6.0 Hz, 1H),
1166, 817





7.92 (s, 1H), 7.87 (d, J =





6.4 Hz, 2H), 7.62 (d, J =





8.4 Hz, 1H), 7.45 (d, J =





8.4 Hz, 1H), 7.0 (m,





1H), 6.76 (d, J = 15.6





Hz, 1H) 4.83 (t, J = 8.0





Hz, 1H), 3.98 (m, 4H)


AC80

561.06
7.37 (m, 3H), 7.26 (m,
3412, 1624,




([M + H]+)
1H), 7.24 (m, 1H), 6.59
1157, 825





(d, J = 15.6 Hz, 1H),





6.39 (dd, J = 15.6, 8.0





Hz, 1H), 4.24 (m, 4H),





3.90 (m, 1H), 2.83 (m,





2H), 1.26 (m, 3H)


AC81
 9-92
546.93
8.73 (d, J = 5.6 Hz, 1H),




([M − H]−)
8.45 (t, J = 6.0 Hz, 1H),





7.76 (s, 3H), 7.45 (m,





3H), 6.86 (dd, J = 16.0,





9.2 Hz, 1H), 4.83 (m,





1H), 4.56 (m, 2H), 4.51





(m, 1H), 4.10 (m, 2H),





3.85 (d, J = 6.0 Hz, 2H),





2.50 (m, 3H)


AC82

477.69
7.38 (d, J = 1.8 Hz, 2H),
1646, 1353,




([M + H]+)
7.33 (s, 1H), 7.27 (s, 3H),
1196, 1112,





6.58 (d, J = 16.0
800





Hz, 1H), 6.42 (d, J = 8.1





Hz, 1H), 6.36 (dd, J =





16.0, 7.8 Hz, 1H), 4.71





(m, 1H), 4.23 (m, 3H),





3.26 (m, 2H), 2.45 (s, 3H)


AC83

493.83
8.07 (t, J = 8.4 Hz, 1H),
1527, 1113,




([M − H]−)
7.39 (t, J = 1.6 Hz, 1H),
801, 1167,





7.31 (d, J = 1.2 Hz, 1H),
1321





7.26 (m, 2H), 7.23 (m,





1H), 7.19 (d, J = 1.6 Hz,





1H), 6.60 (d, J = 16.8





Hz, 1H), 6.49 (dd, J =





16.8, 7.6 Hz, 1H), 4.90





(m, 1H), 4.64 (m, 2H),





4.14 (m, 2H), 4.10 (m,





1H)


AC84

511.75
8.07 (t, J = 8.0 Hz, 1H),
1645, 1113,




([M − H]−)
7.34 (m, 3H), 7.19 (d, J =
804, 3030,





13.2 Hz, 1H), 6.60 (d, J =
1245





16.4 Hz, 1H), 6.48





(dd, J = 16.4, 8.0 Hz, 1H),





4.88 (m, 1H), 4.62





(m, 2H), 4.12 (m, 3H)


AC85

523.83
8.60 (d, J = 6.8 Hz, 1H),
1652, 3039,




([M − H]−)
8.15 (d, J = 8.4 Hz, 1H),
802, 1114





7.35 (d, J = 6.0 Hz, 1H),





7.15 (d, J = 7.2 Hz, 1H),





6.94 (s, 1H), 6.60 (d, J =





15.6 Hz, 1H), 6.44 (dd,





J = 7.6, 7.6 Hz, 1H),





4.93 (m, 1H), 4.62 (m,





2H), 4.13 (m, 6H)


AC86

524.36
7.35 (d, J = 6.3 Hz, 3H),
3333, 1651,




([M + H]+)
7.26 (m, 2H), 7.20 (m,
815





1H), 6.60 (d, J = 15.9





Hz, 1H), 6.47 (dd, J =





15.9, 6.6 Hz, 1H), 4.86





(m, 1H), 4.65 (m, 2H),





4.13 (m, 3H), 2.84 (q,





2.8 Hz, 2H), 1.26 (m, 3H)


AC87

495.82
8.07 (t, J = 8.0 Hz, 1H),
1623, 1114,




([M − H]−)
7.52 (m, 3H), 7.19 (d,
816





J = 13.2 Hz, 1H), 6.59 (d,





J = 16.4 Hz, 1H), 6.47





(dd, J = 16.4, 8.0 Hz,





1H), 4.69 (m, 1H), 4.23





(m, 3H), 3.29 (m, 2H)


AC89

509.89
7.43 (m, 2H), 7.27 (m,
1666, 1166,




([M + H]+)
2H), 7.23 (m, 2H), 6.58
1112, 800





(d, J = 16.0 Hz, 1H),





6.41 (dd, J = 16.0, 7.6





Hz, 1H), 4.79 (d, J = 5.6





Hz, 2H), 4.14 (m, 1H),





2.48 (s, 3H), 2.18 (m,





1H), 1.16 (m, 4H)


AC90

656.9
8.34 (m, 1H), 8.27 (m,




([M − H]−)
1H), 7.60 (d, J = 1.6 Hz,





1H), 7.49 (d, J = 8.0 Hz,





2H), 7.40 (s, 2H), 7.36





(dd, J = 8.2, 1.7 Hz,





1H), 6.53 (d, J = 16.0





Hz, 1H), 6.38 (dd, J =





15.9, 7.9 Hz, 1H), 4.89





(d, J = 8.4 Hz, 2H), 4.48





(d, J = 9.0 Hz, 2H), 4.11





(m, 1H)


AC91

640.9
8.18 (t, J = 5.0 Hz, 1H),




([M − H]−)
7.58 (d, J = 1.6 Hz, 1H),





7.47 (d, J = 8.0 Hz, 1H),





7.40 (s, 2H), 7.34 (dd,





J = 8.1, 1.6 Hz, 1H), 6.52





(m, 2H), 6.37 (dd, J =





15.9, 7.9 Hz, 1H), 4.54





(d, J = 4.9 Hz, 2H), 4.12





(m, 1H), 3.99 (qd, J =





8.9, 6.5 Hz, 2H)


AC92

640.9
9.16 (d, J = 6.1 Hz, 1H),




([M − H]−)
7.65 (d, J = 1.6 Hz, 1H),





7.57 (d, J = 8.0 Hz, 1H),





7.41 (m, 3H), 7.21 (t, J =





5.6 Hz, 1H), 6.55 (d, J =





15.9 Hz, 1H), 6.41





(dd, J = 15.9, 7.8 Hz,





1H), 4.59 (d, J = 5.6 Hz,





2H), 4.45 (qd, J = 9.0,





6.0 Hz, 2H), 4.12 (q,





J = 7.2 Hz, 1H)


AC93

485.5
7.52-7.41 (d, J = 8.2 Hz,

13C NMR (δ)3




([M + H]+)
1H), 7.39-7.34 (m, 1H),
169.91, 169.84,





7.24-7.17 (d, J = 1.8 Hz,
138.23, 137.41,





2H), 7.02-6.92 (m, 2H),
136.84, 134.79,





6.90-6.83 (d, J = 11.4
134.69, 131.07,





Hz, 1H), 6.71 (br s, 1H),
128.69, 127.49,





6.17 (br s, 1H), 6.12-
127.43, 126.72,





6.01 (dd, J = 11.4, 10.3
126.61 (q, J =





Hz, 1H), 4.44-4.38 (d,
212.10 Hz),





J = 4.2 Hz, 1H), 4.35-4.27
125.61,





(m, 1H), 4.10-3.99 (d, J =
123.76, 47.89





5.1 Hz, 2H), 2.78-2.67
(q, J = 28.28





(m, 1H), 2.44 (s, 3H),
Hz), 43.46,





0.88-0.78 (m, 2H), 0.60-
22.65, 19.97,





0.45 (m, 2H)
8.21


AC94

511.6
8.36-8.24 (d, J = 2.4
3262, 1607,




([M]−)
Hz, 1H), 7.75-7.64 (m,
1247, 1164,





1H), 7.38-7.24 (m, 3H),
1111





7.24-7.09 (d, J = 1.8 Hz,





2H), 6.99-6.90





(m, 2H), 6.89-6.74 (d,





J = 11.4 Hz, 1H), 6.63-





6.43 (m, 1H), 6.14-





5.98 (m, 1H), 4.69-





4.51 (d, J = 6.1 Hz, 2H),





4.37-4.20 (m, 1H),





2.46-2.31 (s, 3H)


AC95
48-61
626.9
7.58 (d, J = 7.9 Hz, 1H),




([M + H]+)
7.44-7.29 (m, 3H),





7.14 (dd, J = 7.9, 1.6





Hz, 1H), 6.86 (d, J =





11.4 Hz, 1H), 6.76 (t, J =





5.9 Hz, 1H), 6.59 (br





s, 1H), 6.21-6.04 (m,





1H), 4.23 (d, J = 5.5 Hz,





1H), 3.98 (qd, J = 9.0,





6.5 Hz, 2H)


AC96

619.6
8.83 (s, 1H), 8.06 (br,
1616, 1114




([M + H]+)
1H), 7.90 (s, 2H), 7.63





(d, J = 8.1 Hz, 2H), 7.53





(m, 1H), 6.94 (m, 1H),





6.77 (d, J = 15.3 Hz,





1H), 6.63 (d, J = 9.3 Hz,





1H), 4.84 (m, 1H), 4.30





(d, J = 5.6 Hz, 2H), 2.99





(s, 6H)


AC97

606.6
8.20 (d, J = 2.1 Hz, 1H),
1644, 1113




([M + H]+)
7.73 (d, J = 2.7 Hz, 1H),





7.60 (m, 2H), 7.39 (s,





2H), 7.29 (m, 1H), 6.79





(d, J = 8.4 Hz, 1H), 6.55





(d, J = 15.9 Hz, 1H),





6.40 (m, 2H), 4.60 (d,





J = 2.7 Hz, 2H), 4.13 (m,





1H), 3.95 (s, 3H)


AC98

577.87
9.04 (t, J = 6.0 Hz, 1H),
1663, 1168




([M + H]+)
8.60 (t, J = 6.6 Hz, 1H),





8.25 (s, 1H), 7.97 (d,





J = 8.1 Hz, 1H), 7.87 (d,





J = 6.3 Hz, 2H), 7.69 (d,





J = 7.5 Hz, 1H), 7.15 (dd,





J = 15.9, 9.3 Hz, 1H),





6.89 (d, J = 15.9 Hz,





1H), 4.86 (m, 1H), 3.98





(m, 4H).


AC99

574.81
8.69 (t, J = 6.0 Hz, 1H),
1650, 1164




([M + H]+)
8.58 (t, J = 6.6 Hz, 1H),





7.91 (s, 1H), 7.85 (m, 1H),





7.61 (m, 2H), 7.52





(m, 2H), 6.98 (dd, J =





15.3, 9.0 Hz, 1H), 6.76





(d, J = 15.3 Hz, 1H),





4.81 (m, 1H), 4.01 (m, 4H)


AC100

673.80
8.29 (s, 1H), 8.22 (d, J =
3403, 1659




([M + H]+)
8.1 Hz, 1H), 7.93 (d, J =





7.8 Hz, 1H), 7.72 (m,





1H), 7.65 (m, 2H), 7.40





(s, 2H), 7.18 (br, 1H),





6.59 (d, J = 16.0 Hz,





1H), 6.43 (dd, J = 16.0,





7.6 Hz, 1H), 5.02 (d, J =





1.2 Hz, 2H), 4.12 (m, 1H)


AC101

636.83
7.56 (d, J = 9.0 Hz, 1H),
1637, 1113




([M + H]+)
7.39 (d, J = 6.0 Hz, 2H),





7.26 (m, 2H), 6.54 (d,





J = 15.9 Hz, 1H), 6.37





(dd, J = 8.0, 15.9 Hz,





1H), 4.01 (m, 1H), 3.84





(m, 2H), 3.33 (m, 2H),





3.04 (m, 2H), 2.84 (m,





3H), 2.62 (m, 1H)


AC102

592.84
7.60 (m, 2H), 7.32 (m, 1H),
1668, 1167




([M + H]+)
7.03 (d, J = 7.2 Hz, 2H),





6.74 (br, 1H), 6.62





(br, 1H), 6.56 (d, J =





16.2 Hz, 1H), 6.41 (dd,





J = 16.2, 7.8 Hz, 1H),





4.22 (d, J = 5.4 Hz, 2H),





4.14 (m, 1H), 4.01 (m, 2H)


AC103
 99.2-105.0
612.7
8.40 (d, J = 8.0 Hz, 1H),
1634, 1113,




([M + H]+)
7.92 (d, J = 5.2 Hz, 1H),
809





7.59 (d, J = 8.0 Hz, 1H),





7.35 (d, J = 8.0 Hz, 1H),





6.99 (dd, J = 16.0, 7.6





Hz, 1H), 6.76 (d, J =





16.0 Hz, 1H), 4.84 (m,





1H), 4.23 (d, J = 13.2





Hz, 1H), 3.97 (m, 1H),





3.79 (d, J = 13.6 Hz,





1H), 3.16 (t, J = 11.2





Hz, 1H), 2.77 (t, J =





11.2 Hz, 1H), 1.99 (s,





3H), 1.88 (m, 2H), 1.45





(m, 2H)


AC104

680.97
7.60 (m, 2H), 7.40 (m
3437, 1644,




([M + H]+)
3H), 6.55 (d, J = 15.6
1113, 807,





Hz, 1H), 6.41 (dd, J =
511





15.6, 7.8 Hz, 1H), 4.24





(m, 1H), 3.34 (m, 2H),





2.90 (m, 1H), 2.24 (m,





2H), 1.52(m, 2H), 1.34





(m, 4H)


AC105

609.9
7.59 (s, 1H), 7.55 (m,
3303, 1649,




([M + H]+)
1H), 7.50 (m, 1H), 7.40
1115, 2242,





(m, 2H), 6.54(d, J =
809, 506





16.0 Hz, 1H), 6.50 (J =





16.0, 8.0 Hz, 1H), 4.14





(m, 2H), 3.08 (m, 4H),





2.67 (m, 2H), 2.12 (m,





2H), 1.70 (m, 2H).


AC106

584.95
7.59 (s, 1H), 7.51 (d, J =
3417, 1648,




([M + H]+)
8.4 Hz, 1H), 7.40 (s, 2H),
1112, 805,





7.36 (d, J = 6.8 Hz, 1H),
555





6.54 (d, J = 16.0





Hz, 1H), 6.40 (dd, J =





16.0, 8.0 Hz, 1H), 6.03





(d, J = 8.0 Hz, 1H), 4.11





(m, 2H), 3.10 (m, 2H),





2.50 (m, 2H ), 2.50 (s,





3H) (m, 2H), 1.94 (m, 2H)


AC107

609.9
8.41 (d, J = 7.8 Hz, 1H),
3303, 1645,




([M + H]+)
7.90 (s, 2H), 7.62 (m,
1115, 2243,





2H), 7.51(m, 1H), 6.92
810, 507





(dd, J = 15.9, 9.0 Hz,





1H), 6.77 (d, J = 15.9





Hz, 1H), 4.81 (m, 1H),





3.73 (s, 2H), 3.31 (m,





1H), 3.28 (m, 1H), 2.82





(t, J = 11.4 Hz, 2H),





2.82 (m, 2H), 2.30 (m,





2H), 1.88 (m, 2H), 1.57





(m, 2H)


AC108

626.9
7.60 (m, 2H) 7.39 (s,
3420, 1649,




([M + H]+)
2H), 7.28 (m, 1H), 6.56
1113, 809,





(d, J = 15.6 Hz, 1H),
554





6.40 (dd, J = 15.6, 7.8





Hz, 1H), 5.91 (m, 1H),





4.65 (m, 2H), 4.10 (m,





1H), 4.07 (m, 2H), 3.59





(m, 1H), 2.74 (m, 2H),





2.13 (m, 4H), 2.07 (m, 1H)


AC109

614.6
7.56 (m, 2H), 7.39 (s,
1647, 1113




([M + H]+)
2H), 7.29 (s, 1H), 6.50





(d, J = 15.9 Hz, 1H),





6.41 (dd, J = 15.9, 8.0





Hz 1H), 4.09 (m, 1H),





3.88 (m, 2H), 3.49 (m,





2H), 2.92 (m, 2H), 2.81





(m, 1H), 2.74 (m, 2H),





2.25 (m, 4H)


AC110

572.6
11.20 (s, 1H), 8.66 (br,
3412, 1690,




([M + H]+)
1H), 7.92 (m, 3H), 7.62
1114, 846,





(d, J = 8.0 Hz, 1H), 7.45
559





(d, J = 8.0 Hz, 1H), 6.77





(dd, J = 15.6, 9.2 Hz,





1H), 6.77 (d, J = 15.6





Hz, 1H), 4.85 (m, 1H),





3.74 (d, J = 5.2 Hz, 2H),





3.61 (s, 3H)


AC111

582.79
8.63 (t, J = 6.0 Hz, 1H),
3419, 1659,




([M + H]+)
8.04 (t, J = 6.0 Hz, 1H),
843, 557





7.92 (m, 3H), 7.62 (d,





J = 1.2 Hz, 1H), 7.47 (d,





J = 7.6 Hz, 1H), 7.00 (dd,





J = 15.6, 8.8 Hz, 1H),





6.77 (d, J = 15.6 Hz, 1H),





5.19 (d, J = 1.6 Hz, 1H),





5.01 (d, J = 1.2 Hz, 1H),





4.85 (m, 1H), 3.86





(d, J = 5.6 Hz, 2H), 3.75





(t, J = 5.6 Hz, 2H)


AC112

582.79
8.84 (br, 1H), 8.58 (m,
3399, 1662,




([M + H]+)
1H), 8.30 (m, 1H), 7.91
1114, 807,





(s, 2H), 7.61 (d, J = 8.1
582





Hz, 1H), 7.42 (d, J = 7.8





Hz, 1H), 7.00 (dd, J =





15.6, 9.3 Hz, 1H), 6.77





(d, J = 15.6 Hz, 1H),





4.85 (m, 1H), 4.11 (d, J =





5.6 Hz, 1H), 3.73 (d, J =





5.6 Hz, 1H), 3.04 (s, 6H)


AC113

626.88
8.48 (t, J = 5.2 Hz, 1H),
3431, 1651,




([M + H]+)
8.3 (s, 1H), 7.90 (s, 2H),
1113, 808,





7.79 (dd, J = 2.0, 2.0 Hz
554





2H), 7.58 (d, J = 8.4 Hz,





1H) 7.46 (d, J = 7.6 Hz,





1H) 7.26 (d, J = 7.6 Hz,





1H), 6.98 (m, 1H), 6.75





(d, J = 15.6 Hz, 1H),





4.85 (m, 1H), 3.49 (d, J =





6.4 Hz, 2H) 2.87 (t, J =





6.4 Hz, 2H)


AC114
113.7-117.5
570.7
8.77 (s, 1H), 8.58 (d, J =




([M + H]+)
7.2 Hz, 2H), 7.93 (d, J =





7.2 Hz, 2H), 7.60 (dd,





J = 1.2, 0.8 Hz, 1H), 7.37





(d, J = 7.6 Hz, 1H), 6.99





(m, 1H), 6.77 (d, J = 16





Hz, 1H), 4.85 (m, 1H),





4.10 (m, 1H) 3.29 (m,





2H), 3.05 (m, 2H), 2.0





(m, 2H), 1.76 (m, 2H)


AC115

529.00
8.43 (s, 1H), 7.79 (d, J =
1589, 3459,




([M + H]+)
8.0 Hz, 1H), 7.51 (m, 1H),
801, 1110





7.36 (d, J = 8.4 Hz, 3H),





7.21 (m, 3H), 6.55





(d, J = 15.6 Hz, 1H),





6.36 (dd, J = 15.6, 8.0





Hz, 1H), 5.04 (d, J = 5.6





Hz, 2H), 4.10 (m, 1H),





2.35 (s, 3H)


AC116

614.87
7.99 (d, J = 8.4 Hz, 1H),
3424, 1657,




([M + H]+)
7.46 (d, J = 1.6 Hz, 1H),
1165





7.34 (d, J = 6.4 Hz, 2H),





7.28 (m, 2H), 6.62 (m,





2H), 6.47 (dd, J = 16.0,





7.2 Hz, 1H), 4.23 (m,





2H), 4.12 (m, 1H), 4.00





(m, 2H)


AC117

525.42
8.39 (br, 1H), 7.85 (br,
3401, 1636,




([M − H]−)
1H), 7.62 (m, 3H), 7.53
1113, 750





(d, J = 8.0 Hz, 1H), 7.46





(s, 1H), 7.40 (d, J = 8.0





Hz, 1H), 7.17 (m, 1H),





6.78 (dd, J = 16.0, 8.8





Hz, 1H), 6.70 (m, 1H),





4.77 (m, 1H), 4.66 (s,





1H), 4.32 (s, 1H), 2.97





(s, 3H), 2.16 (s, 3H)


AC118

471.79
7.36 (d, J = 8.0 Hz, 2H),
3437, 1655,




([M + H]+)
7.27 (m, 2H), 7.22 (m,
1262, 1105,





2H), 6.57 (d, J = 16.0
802





Hz, 1H), 6.38 (dd, J =





16.0, 8.0 Hz, 1H), 6.10





(br, 1H), 4.15 (m, 2H),





3.89 (m, 1H), 3.80 (m,





2H), 3.35 (m, 1H), 2.46





(s, 3H), 2.06 (s, 1H),





1.96 (m, 2H), 1.65 (m, 1H)


BC1

492.17
7.39 (s, 2H), 7.25-7.18
3211, 1569,




([M + H]+)
(m, 3H), 6.58 (d, J =
1113, 806





16.0 Hz, 1H), 6.30 (dd,





J = 16.0, 8.4 Hz, 1H),





5.91-5.70 (br, 2H),





4.05 (m, 1H), 3.05-





2.80 (m, 6H), 2.70 (m,





1H), 1.81 (m, 1H)


BC2

506.4
8.80 (s, 1H), 8.20 (s,
2923, 1542,




([M + H]+)
1H), 7.82 (m, 3H), 7.4
1033, 805





(s, 2H), 6.62 (d, J = 16.0





Hz, 1H), 6.52 (dd, J =





16.0, 8.0 Hz, 1H),





4.18(m, 1H), 3.38 (m,





2H), 2.98 (m, 2H), 2.71





(m, 1H), 2.04 (m,





2H), 1.54 (s, 3H).


BC3

518.04
7.40 (s, 2H), 7.33-7.22
3120, 1592,




([M − H]−)
(m, 3H), 6.61 (d, J =
1146, 895





16.0 Hz, 1H), 6.34-





6.28 (dd, J = 16.0, 8.0





Hz, 1H), 5.96-5.80 (m,





3H), 5.22 (m, 4H), 4.01





(m, 2H), 2.84-2.99 (m,





2H), 2.71 (m, 1H), 1.86





(m, 1H)


BC4

529.02
7.39 (s, 2H), 7.25-7.20
3283, 1652,




([M + H]+)
(m, 3H), 6.34 (d, J =
1241, 811





16.0 Hz, 1H), 6.30 (dd,





J = 16.0, 8.0 Hz, 1H),





5.81 (br, 1H), 5.48 (m,





1H), 4.10 (m, 1H), 3.10





(m, 2H), 2.86-3.07 (m,





2H), 2.86 (m, 1H), 1.81





(m, 1H);


BC5

544.25
7.40 (s, 2H), 7.21 (s,
3489, 3291,




([M − H]−)
1H), 7.12 (m, 1H), 6.56
1655, 1112,





(d, J = 16.0 Hz, 1H),
808





6.32 (dd, J = 16.0, 8.4





Hz, 1H), 5.85 (br s, 1H),





5.23 (br s, 1H), 4.12 (m,





1H), 3.18 (m, 3H), 2.80





(m, 3H), 2.08 (m, 2H),





1.83 (m, 5H), 1.25 (m,





2H), 1.01 (m, 3H), 0.78





(m, 2H)


BC6

485.96
7.40 (s, 2H), 7.31-7.18
3429, 1114,




([M − H]−)
(m, 3H), 6.58 (d, J =
804





16.0 Hz, 1H), 6.24-





6.28 (dd, J = 16.0, 8.0





Hz, 1H), 5.40 (br, 1H),





4.01 (m, 2H), 2.78-





3.01 (m, 2H), 2.51 (s,





1H), 1.86 (m, 1H), 1.20





(m, 2H), 1.01 (m, 2H),





0.78 (m, 2H)


BC7

500.01
7.40 (s, 2H), 7.31 (s, 1H),
3296, 1115,




([M − H]−)
7.18 (m, 1H), 7.18
806





(s, 1H), 6.58 (d, J = 16.0





Hz, 1H), 6.32 (dd, J =





16.0, 8.0 Hz, 1H), 5.78





(br s, 1H), 5.21 (br s,





1H), 4.01 (m, 1H), 2.78





(m, 2H), 2.01 (m, 1H),





1.86 (m, 4H), 1.25 (m,





2H), 1.01 (m, 3H), 0.78





(m, 2H)


BC8

511.88
7.38-7.20 (m, 5H), 6.62
1657, 1113,




([M − H]−)
(d, J = 16.0 Hz, 1H),
855





6.34 (dd, J = 16.0, 8.0





Hz, 1H), 5.83 (br, 1H),





5.52 (m, 1H), 4.12 (m,





1H), 3.12 (m, 2H), 3.06-





2.82 (m, 2H), 2.75 (m,





1H), 1.85 (m, 1H)


BC9
179-181
556.83
8.30 (s, 1H), 7.68 (d, J =




([M − H]−)
6.4 Hz, 1H), 7.38-7.20





(m, 5H), 6.60 (d, J =





16.0 Hz, 1H), 6.34 (dd,





J = 16.0, 8.0 Hz, 1H),





5.63 (br, 1H), 5.52 (m,





1H), 4.12 (m, 1H), 3.56





(s, 2H), 3.06-2.82 (m,





2H), 2.70 (m, 1H), 1.82





(m, 1H)


BC10

497.98
7.38-7.20 (m, 5H), 6.62
3027, 1654,




([M − H]−)
(d, J = 16.0 Hz, 1H),
815





6.34 (dd, J = 16.0, 8.0





Hz, 1H), 5.83 (br, 1H),





5.52 (m, 1H), 4.12 (m,





1H), 3.02 (m, 3H), 2.82





(m, 1H), 2.50 (m, 3H),





1.82 (m, 1H), 1.42 (m, 1H)


BC11

530.09
7.80 (m, 1H), 7.48 (m,
1715, 1113,




([M − H]−)
2H), 7.32 6.65 (d, J =
816





16.0 Hz, 1H), 6.54 (dd,





J = 16.0, 8.0 Hz, 1H),





5.38 (m, 1H), 4.18 (m,





1H), 3.62 (m, 1H), 3.32





(m, 1H), 2.86 (m, 1H),





1.81 (m, 1H)


BC12

514.86
7.32, (d, J = 6.0 Hz, 2H)
3428, 1112,




([M + H]+)
7.28 (m, 1H), 7.20 (d, J =
857





8.0, 1H), 7.14 (d, J =





8.8, 1H), 6.70 (d, J =





8.0 Hz, 1H), 6.60 (m,





2H), 4.15 (m, 1H), 3.85





(m, 1H), 3.65 (m, 1H),





3.46 (m, 2H), 3.19 (m,





2H);


BC13
121-126
553.06
8.33 (br, 1H), 7.59 (s,




([M − H]−)
1H), 7.45 (m, 3H), 6.72





(d, J = 3.6, 1H), 6.39





(m, 1H), 4.71 (t, J = 7.2





Hz, 2H), 4.15 (m, 2H)


BC14
172-175
554.0
8.83 (t, J = 6.6 Hz, 1H),




([M − H]−)
8.42 (t, J = 14.7 Hz,





1H), 8.22 (d, J = 8.1 Hz,





1H), 8.13 (t, J = 6.3 Hz,





1H), 7.98-7.86 (m, 2H),





7.16-7.07 (m, 1H),





7.01-6.93 (m, 1H),





4.96-4.81 (m, 3H),





4.00-3.88 (m, 2H)


CC1
107-109
402.00
7.37 (m, 3H), 7.28 (m,




([M + H]+)
4H), 6.60 (d, J = 16.0





Hz, 1H), 6.36 (dd, J =





16.0, 8.0 Hz, 1H), 5.75





(br s, 1H), 4.46 (d, J = 6





Hz, 2H), 4.01 (m, 1H),





2.11 (s, 3H)


CC2
118-120
428.11
7.37 (m, 3H), 7.28 (m,




([M + H]+)
4H), 6.60 (d, J = 16.0





Hz, 1H), 6.35 (dd, J =





16.0, 8.0 Hz, 1H), 5.83





(br s, 1H), 4.46 (d, J =





6.0 Hz, 2H), 4.11 (m,





1H), 1.40 (m, 1H), 1.02





(m, 2H), 0.77 (m, 2H)


CC3
119-122
468.20
7.38 (m, 3H), 7.27 (m,




([M − H]−)
3H), 6.60 (d, J = 16.0





Hz, 1H), 6.36 (dd, J =





16.0, 8.4 Hz, 1H), 5.00





(br s, 1H), 4.48 (d, J =





5.6 Hz, 2H), 4.11 (m,





1H), 3.15 (q, J = 10.4





Hz, 2H)


CC4

414.16
7.37 (m, 3H), 7.28 (m,




([M − H]−)
3H), 6.60 (d, J = 16.0





Hz, 1H), 6.35 (dd, J =





16.0, 8.0 Hz, 1H), 5.69





(br s, 1H), 4.46 (d, J =





6.0 Hz, 2H), 4.21 (m,





1H), 2.29 (q, J = 5.8 Hz,





2H), 1.30 (t, J = 7.2 Hz,





3H)


CC5

460.28
7.40 (m, 3H), 7.28 (m,




([M − H]−)
2H), 6.60 (d, J = 15.6





Hz, 1H), 6.33 (dd, J =





15.6, 8.0 Hz, 1H), 5.84





(br s, 1H), 4.46 (d, J =





5.6 Hz, 2H), 4.10 (m,





1H), 1.36 (m, 1H), 1.02





(m, 2H), 0.77 (m, 2H)


CC6
106-108
504.08
7.40 (m, 3H), 7.26 (m,




([M − H]−)
1H), 6.60 (d, J = 16.0





Hz, 1H), 6.34 (dd, J =





16.0, 8.0 Hz, 1H), 5.96





(br s, 1H), 4.49 (d, J =





5.6 Hz, 2H), 4.10 (m,





1H), 3.15 (q, J = 10.8





Hz, 2H)


CC7
127-128
436.03
7.42 (m, 4H), 7.24 (m,




([M + H]+)
2H), 6.53 (d, J = 16.0





Hz, 1H), 6.36 (dd, J =





16.0, 8.0 Hz, 1H), 5.86





(br s, 1H), 4.51 (d, J =





6.0 Hz, 2H), 4.05 (m,





1H), 2.02 (s, 3H)


CC8
129-131
462.15
8.58 (t, J = 5.6 Hz, 1H),




([M + H]+)
7.72 (m, 1H), 7.66 (m,





3H), 7.49 (d, J = 8.0 Hz,





1H), 7.30 (d, J = 8.0 Hz,





1H), 6.90 (dd, J = 16.0,





8.0 Hz, 1H), 6.73 (d, J =





16 Hz, 1H), 4.81 (m, 1H),





4.33 (d, J = 6.0 Hz, 1H),





1.64 (m, 1H), 0.68





(m, 4H)


CC9
132-134
504.25
7.41 (m, 3H), 7.26 (m,




([M + H]+)
3H), 6.54 (d, J = 16.0





Hz, 1H), 6.37 (dd, J =





16.0, 8.0 Hz, 1H), 6.13





(br s, 1H), 4.56 (d, J =





6.0 Hz, 2H), 4.11 (m,





1H), 3.13 (m, 2H)


CC10

538.03
7.38 (m, 4H), 6.56 (d,
1651, 1112,




([M + 2H]+)
J = 16.0 Hz, 1H), 6.38
807





(dd, J = 16.0, 8.0 Hz,





1H), 6.18 (m, 1H), 4.58





(m, 2H), 4.08 (m, 1H),





3.08 (m, 2H)


CC11
111-112
494.12
7.42 (m, 3H), 7.24 (m,




([M − H]−)
1H), 6.54 (d, J = 15.6





Hz, 1H), 6.34 (dd, J =





16.0, 8.0 Hz, 1H), 6.03





(m, 1H), 4.53 (d, J = 6.0





Hz, 1H), 4.10 (m, 1H),





1.39 (m, 1H), 1.00 (m,





2H), 0.77 (m, 2H)


CC12
76-78
510.07
7.39 (s, 4H), 7.34 (d, J =




([M − H]−)
8.0 Hz, 1H), 7.26 (m,





1H), 6.57 (d, J = 16.0





Hz, 1H), 6.35 (dd, J =





16.0, 8.0 Hz, 1H), 6.10





(br s, 1H), 4.49 (d, J =





6.0 Hz, 2H), 4.10 (m,





1H), 1.20 (s, 9H)


CC13
73-76
563.37
8.51 (d, J = 5.2 Hz, 1H),




([M − H]−)
7.63 (s, 1H), 7.51 (m,





1H), 7.45 (m, 2H), 7.39





(s, 2H), 7.28 (m, 1H),





6.58 (m, 2H), 6.37 (dd,





J = 16.0, 8.0 Hz, 1H),





4.71 (d, J = 6.0 Hz, 1H),





4.11 (m, 1H)


CC14

581.45
8.51 (m, 1H), 8.30 (d,
3430, 1656,




([M+1H]+)
J = 2.4 Hz, 1H), 7.73 (m,
1109, 806





1H), 7.61 (s, 2H), 7.51





(s, 1H), 7.32 (m, 3H),





6.66 (d, J = 16.0 Hz,





1H), 6.56 (dd, J = 16.0,





8.4 Hz, 1H), 4.50 (m,





1H), 4.45 (d, J = 5.6 Hz,





1H), 3.56 (s, 2H)


CC15

480.24
7.40 (m, 3H), 7.33 (m,
3293, 1651,




([M + H]+)
1H), 7.22 (m, 2H), 6.54
1543, 1114,





(d, J = 15.6 Hz, 1H),
812





6.34 (dd, J = 16.0, 8.0





Hz, 1H), 6.03 (br s, 1H),





4.53 (d, J = 6.0 Hz, 2H),





4.13 (m, 1H), 1.41 (m,





1H), 1.00 (m, 2H), 0.77





(m, 2H)


CC16

520.33
7.42 (s, 1H), 7.37 (m,
3307, 1665,




([M − H]−)
3H), 7.22 (m, 1H), 6.54
1114, 813





(d, J = 16.0 Hz, 1H),





6.36 (dd, J = 16.0, 8.0





Hz, 1H), 6.19 (br s, 1H),





4.51 (d, J = 6.0 Hz, 2H),





4.21 (m, 1H), 3.33 (m, 2H)


CC17
117-119
459.83
7.51 (m, 2H), 7.39 (m,
3293, 1633,




([M − H]−)
2H), 7.24 (m, 2H), 6.52
1110, 820





(d, J = 15.6 Hz, 1H),





6.38 (dd, J = 15.6, 7.6





Hz, 1H), 6.02 (br s, 1H),





4.53 (d, J = 6.0 Hz, 2H),





4.14 (m, 1H), 1.38 (m,





1H)), 1.00 (m, 2H),





0.77 (m, 2H)


CC18
119-123
501.88
7.48 (m, 2H), 7.41 (s,
3435, 1644,




([M − H]−)
1H), 7.36 (d, J = 8.0 Hz,
1111, 817





1H), 7.23 (m, 2H), 6.52





(d, J = 16.0 Hz, 1H),





6.39 (dd, J = 16.0, 8.0





Hz, 1H), 6.13 (br s, 1H),





4.56 (d, J = 6.0 Hz, 2H),





4.15 (m, 1H), 3.13 (m, 2H)


CC19

530
7.41 (m, 2H), 7.24 (m,
3435, 1644,




([M + H]+)
1H), 6.53 (d, J = 16.0
1111, 817





Hz, 1H), 6.35 (dd, J =





16.0, 8.0 Hz, 1H), 4.53





(m, 2H), 4.10 (m, 1H),





3.42 (m, 2H), 2.97 (s,





3H), 2.78 (m, 2H)


CC20

512
7.42 (m, 3H), 7.24 (m,
3293, 1633,




([M + H]+)
1H), 6.54 (d, J = 15.6
1110, 820





Hz, 1H), 6.34 (dd, J =





15.6, 8.0 Hz, 1H), 6.03





(m 1H), 4.53 (d, J = 6.0





Hz, 1H), 4.10 (m, 1H),





1.19 (m, 1H), 1.00 (m,





2H), 0.77 (m, 2H)


CC21
55-58
493.99
(DMSO-d6) 8.62 (m,




([M − H]−)
1H), 7.95 (s, 1H), 7.85





(m, 1H), 7.66 (m, 3H),





7.47 (d, J = 8.0 Hz, 1H),





6.98 (dd, J = 16.0, 8.0





Hz, 1H), 6.84 (d, J =





16.0 Hz, 1H), 4.83 (m,





1H), 4.44 (s, 2H), 1.68





(m, 1H), 0.71 (m, 4H)


CC22
67-69
530.01
8.62 (m, 1H), 7.90 (s,




([M + H]+)
3H), 7.82 (m, 1H), 7.45





(m, 1H), 6.98 (m, 1H),





6.84 (d, J = 16.0 Hz,





1H), 4.82 (m, 1H), 4.4





(s, 2H), 1.66 (m, 1H),





0.72 (m, 4H)


CC23
69-71
564.99
9.02 (br s, 1H), 8.54 (br




([M − H]−)
s, 1H), 8.26 (br s, 1H),





7.48-7.54 (m, 3H),





7.22-7.42 (m, 3H),





6.59-6.62 (m, 2H),





6.38-6.42 (m, 1H),





4.82 (m, 2H), 4.19 (s, 1H)


CC24
125-127
570.26
7.64 (s, 1H), 7.54 (s,




([M − H]−)
2H), 7.46 (s, 2H), 6.62





(d, J = 16.0 Hz, 1H),





6.41 (dd, J = 16.0, 8.4





Hz, 1H), 6.03 (m, 1H),





4.65 (d, J = 6.4 Hz, 2H),





4.14 (m, 1H,), 3.13 (q,





J = 10.6 Hz, 2H)


CC25

579.86
7.60 (s, 1H), 7.40 (s,
3297, 1663,




([M − H]−)
2H), 7.37 (d, J = 8.0 Hz,
1114, 809





1H), 7.31 (d, J = 8.0 Hz,





1H), 6.53 (d, 1H, J =





16.0 Hz), 6.35 (dd, J =





16.0, 8.0 Hz, 1H), 6.17





(br s, 1H), 4.56 (d, J =





6.4 Hz, 2H), 4.12 (m,





1H), 3.15 (q, J = 10.6





Hz, 2H)


CC26
129-131
539.89
7.59 (s, 1H), 7.39 (m,




([M + H]+)
2H), 7.30 (s, 1H), 6.53





(d, J = 16.0 Hz, 1H),





6.35 (dd, J = 16.0, 8.0





Hz, 1H), 6.06 (br s, 1H),





4.42 (d, J = 4.4 Hz, 2H),





4.12 (m, 1H), 1.35 (br s,





1H), 0.95 (br s, 2H),





0.75 (m, 2H)


CC27

519.95
7.39 (s, 2H), 7.33 (t, J =
3306, 1786




([M − H]−)
7.6 Hz, 1H), 7.14 (m,





2H), 6.56 (d, J = 16.0





Hz, 1H), 6.35 (dd, J =





16.0, 7.6 Hz, 1H), 6.06





(br s, 1H), 4.52 (d, J =





16.0 Hz, 2H), 4.08 (m,





1H), 3.90 (s, 2H), 3.13





(m, 2H)


CC28

477.93
7.39 (s, 2H), 7.35 (m,
3625, 1747




([M − H]−)
1H), 7.14 (m, 2H), 6.55





(d, J = 15.6 Hz, 1H),





6.33 (dd, J = 15.6, 8.0





Hz, 1H), 5.93 (br s, 1H),





4.49 (d, J = 16.0 Hz,





2H), 4.10 (m, 1H), 1.36





(m, 1H), 1.00 (m,





2H), 0.77 (m, 2H)


CC29

620.86
8.58 (d, J = 4.6 Hz, 1H),
1645, 1115,




([M − H]−)
7.74 (m, 1H), 7.62 (m, 2H),
808





7.52 (m, 1H), 7.4





(s, 2H), 7.3 (m, 1H), 7.2





(m, 2H), 6.60 (d, J =





16.0 Hz, 1H), 6.38 (dd,





J = 16.0, 8.0 Hz, 1H),





5.02 (s, 1H), 4.8 (s, 1H),





4.8 (d, J = 10 Hz, 2H),





4.10 (m, 1H), 1.8 (m,





1H), 1.2 (m, 2H), 0.6





(m, 2H)


CC30
101-104
559.75
7.41 (m, 4H), 7.24 (m,




([M − H]−)
1H), 6.53 (d, J = 16.0





Hz, 1H), 6.35 (dd, J =





16.0, 8.0 Hz, 1H), 6.12





(br s, 1H), 4.53 (m, 2H),





4.10 (m, 1H), 3.42 (m,





2H), 2.91 (s, 3H), 2.78





(m, 2H)


CC31
177-178
463
7.58 (m, 2H), 7.41 (m,




([M − H]−)
3H), 7.24 (m, 1H), 6.53





(d, J = 16.0 Hz, 1H),





6.35 (dd, J = 16.0, 8.0





Hz, 1H), 4.70 (br s,





1H), 4.43 (s, 2H), 4.08 (m,





1H), 3.21 (m, 2H), 1.25





(m, 3H);


CC32
141-142
532.99
7.66 (m, 2H), 7.54 (m,




([M + H]+)
1H), 7.41 (s, 2H), 6.62





(d, J = 16.0 Hz, 1H),





6.40 (dd, J = 16.0, 8.0





Hz, 1H), 4.59 (s, 3H),





4.19 (m, 1H), 3.25 (m,





2H), 1.15 (m, 2H)


CC33

540.88
7.57 (s, 1H), 7.40 (m, 2H),
3338, 1631,




([M − H]−)
7.30 (s, 1H), 7.20
1578, 1114,





(br s, 1H), 6.53 (d, J =
809





16.0 Hz, 1H), 6.33 (dd,





J = 16.0, 8.0 Hz, 1H),





6.06 (br s, 1H), 4.75 (br





s, 1H), 4.42 (s, 2H), 4.20





(br s, 1H), 4.15 (m, 2H),





3.20 (m, 2H), 1.15 (m, 3H)


CC34
118-120
541.40
7.42 (m, 3H), 7.28 (m,




([M + H]+)
2H), 6.54 (d, J = 16.0





Hz, 1H), 6.36 (dd, J =





16.0, 8.0 Hz, 1H), 4.96





(m, 1H), 4.51 (d, J = 5.6





Hz, 2H), 4.12 (m, 1H),





3.69 (t, J = 4.8 Hz, 4H),





3.35 (t, J = 4.8 Hz, 1H)


CC35
78-79
547.82
9.95 (br s, 1H), 8.17 (d,




([M + H]+)
J = 4.8 Hz, 1H), 7.61 (d,





J = 6.4 Hz), 7.43 (m,





3H), 7.24 (m, 2H), 6.90





(t, J = 5.6 Hz, 1H), 6.66





(d, J = 8.4 Hz, 1H), 6.54





(d, J = 16.0 Hz, 1H),





6.33 (dd, J = 16.0, 8.0





Hz, 1H), 4.65 (d, J = 6.0





Hz, 1H), 4.09 (m, 1H)


CC36

497
7.39 (m, 4H), 7.28 (m,
3350, 1705,




([M − H]−)
1H), 6.54 (d, J = 16.0
1114, 808





Hz, 1H), 6.34 (dd, J =





16.0, 8.0 Hz, 1H), 4.97





(br s, 1H), 4.38 (d, J =





6.0 Hz, 2H), 4.10 (m,





1H), 2.9 (s, 3H), 2.7 (s,





3H)


CC37
88-91
515.01
7.49 (d, J = 8 Hz, 1H),




([M + H]+)
7.41 (d, J = 7.2 Hz, 2H),





7.26 (m, 2H), 6.50 (d,





J = 16 Hz, 1H), 6.35 (dd,





J = 16.0, 8.0 Hz, 1H),





6.0 (brs, 1H), 5.73 (br s,





1H), 4.80 (br s, 2H),





4.09 (m, 1H), 1.23 (m, 3H)


CC38
63-66
526.97
7.48 (d, J = 8 Hz, 1H),




([M + H]+)
7.39 (m, 3H), 7.27 (m,





1H), 6.54 (d, J = 16 Hz,





1H), 6.33 (dd, J = 6.0,





8.0 Hz, 1H), 6.17 (br s,





1H), 5.92 (br s, 1H),





5.83 (m, 2H), 5.29 (t, J =





15.4 Hz, 2H), 4.80 (br





s, 2H), 4.12 (m, 1H),





4.02 (br s, 2H)


CC39

526.09
7.39 (m, 4H), 7.28 (m,
3350, 1705,




([M − H]−)
1H), 6.54 (d, J = 16.0
1114, 808





Hz, 1H), 6.34 (dd, J =





16.0, 8.0 Hz, 1H), 4.97





(br s, 1H), 4.38 (d, J =





6.0 Hz, 2H), 4.10 (m,





1H), 1.53 (s, 9H)


CC40
159-160
580.25
7.46 (m, 5H), 7.29 (m,




([M − H]−)
1H), 7.20 (m, 3H), 6.55





(d, J = 16.0 Hz, 1H),





6.37 (dd, J = 16.0, 8.0





Hz, 1H), 5.62 (br s, 1H),





4.55 (d, J = 6.4 Hz, 2H),





4.11 (m, 1H)


CC41

512.22
7.48 (m, 1H), 7.43 (m,
1740, 1701,




([M − H]−)
3H), 7.38 (m, 1H), 7.23
1114, 808





(s, 1H), 6.55 (d, J = 16.0





Hz, 1H), 6.36 (d, J =





16.0 Hz, 1H), 4.60 (d,





2H), 4.18 (m, 1H), 3.85





(s, 3H)


CC42
161-163
578.96
(DMSO-d6) 9.45 (br s,




([M − H]−)
2H), 7.90 (s, 2H), 7.75





(s, 1H), 7.46 (br s, 1H),





7.28 (br s, 1H), 6.93 (m,





1H), 6.75 (br s, 1H),





4.80 (m, 1H), 4.40 (br s,





2H), 3.90 (br s, 2H)


CC43
140-142
505.39
8.11 (d, J = 4.0 Hz, 1H),




([M + H]+)
7.40 (m, 5H), 7.22 (m,





1H), 6.61 (m, 2H), 6.35





(m, 2H), 4.94 (br s, 1H)





4.61 (d, J = 6.4 Hz,





2H), 4.11 (m, 1H)


CC44

536.88
8.41 (s, 1H), 7.77 (s,
3320, 1674,




([M − H]−)
1H), 7.47 (br s, 1H),
1114, 808





7.40 (s, 2H), 6.58 (d, J =





16.0 Hz, 1H), 6.45 (dd,





J = 16.0, 8.0 Hz, 1H),





4.68 (d, J = 4.0 Hz, 2H),





4.14 (m, 1H), 3.24 (q,





J = 10.8 Hz, 2H)


CC45

494.88
8.41 (s, 1H), 7.76 (s,
3309, 1659,




([M − H]−)
1H), 7.40 (s, 2H), 7.15
1115, 808





(br s, 1H), 6.58 (d, J =





16.0 Hz, 1H), 6.44 (dd,





J = 16.0, 8.0 Hz, 1H),





4.67 (d, J = 4.4 Hz, 2H),





4.16 (m, 1H), 1.57 (m,





1H), 1.04 (m, 2H), 0.87





(m, 2H)


CC46
151-153
554.04
8.06 (m, 1H), 7.61 (m,




([M − H]−)
4H), 7.48 (s, 2H), 7.44





(d, J = 8.0 Hz, 1H), 7.38





(m, 1H), 6.42 (m, 1H),





5.92 (br s, 1H), 4.92 (m,





2H), 4.24 (m, 1H), 3.12





(m, 2H)


CC47

478.09
8.06 (m, 2H), 7.61 (m,
3309, 1659,




([M + H]+)
4H), 7.48 (s, 2H), 7.44
1115, 808





(d, J = 8.0 Hz, 1H), 7.38





(m, 2H), 6.42 (m, 1H),





4.92 (s, 2H), 1.36 (m,





1H), 1.00 (m, 2H), 0.77





(m, 2H)


CC48

511.05
8.06 (m, 2H), 7.61 (m,
3309, 1659,




([M + H]+)
3H), 7.48 (s, 2H), 7.44
1115, 808





(d, J = 8.0 Hz, 1H), 7.38





(m, 2H), 6.42 (m, 1H),





4.92 (s, 2H), 1.36 (m,





1H), 1.00 (m, 2H), 0.77





(m, 2H)


CC49
84-87
515.33
8.06 (m, 1H), 7.98 (m,




([M + H]+).
1H), 7.61 (m, 3H), 7.48





(s, 2H), 7.44 (d, J = 8.0





Hz, 1H), 7.38 (m, 2H),





6.42 (m, 1H), 4.92 (s,





2H), 4.6 (br s, 1H), 4.24





(m, 1H), 3.21 (m, 2H),





1.2 (t, J = 4.6 Hz, 3H)


CC50
138-140
461.32
9.81 (s, 1H), 7.90 (s,




([M − 1H]−))
1H), 7.84 (s, 2H), 7.34





(d, J = 8.4 Hz, 2H), 6.65





(d, J = 15.6 Hz, 1H),





6.61 (m, 1H), 6.57 (s,





1H), 6.48 (dd, J = 15.6,





8.8 Hz, 1H), 4.74 (m,





1H), 1.64 (m, 1H), 0.75





(m, 4H);


CC51
149-150
505.31
7.56 (br s, 1H), 7.4 (s,




([M − H]−)
3H), 7.3 (m, 3H), 7.05





(br s, 1H), 6.8 (d, J = 6





Hz, 2H), 6.57 (m, 2H),





6.20 (m, 2H), 4.05 (m,





1H), 3.2 (q, J = 10.4 Hz,





2H)


CC52

464.87
7.40 (s, 2H), 7.18 (s,
3309, 1659,




([M − H]−)
1H), 7.08 (s, 1H), 6.85
1115, 808





(m, 1H), 6.45 (m, 1H),





6.20 (m, 1H), 5.55





(s, 1H), 4.08 (m, 1H),





1.30-1.10 (m, 4H),





1.90 (m, 1H)


CC53

506
7.40 (s, 2H), 7.18 (s,
3309, 1659,




([M + H]+)
1H), 7.08 (s, 1H), 6.85
1115, 808





(m, 1H), 6.45 (m, 1H),





6.20 (m, 1H), 5.55





(s, 1H), 4.08 (m,





1H), 3.21 (m, 2H)


CC54

504
7.28 (s, 2H), 7.25 (m,




([M + H]+)
2H), 7.10 (d, J = 8.0 Hz,





2H), 6.89 (d, J = 11.4





Hz, 1H), 6.07 (br s, 1H),





6.01 (m, 1H), 4.51 (d,





J = 5.8 Hz, 2H), 4.34 (m,





1H), 3.12 (q, J = 7.5 Hz,





2H)


DC1
93-97
398.05
8.56 (s, 1H), 8.11 (s,




([M + H]+)
1H), 7.68 (d, J = 8.4 Hz,





2H), 7.54 (d, J = 8.4 Hz,





2H), 7.38 (t, J = 1.8 Hz,





1H), 7.29 (s, 2H), 6.62





(d, J = 15.6 Hz, 1H),





6.42 (dd, J = 15.6, 8.2





Hz, 1H), 4.15 (m, 1H)


DC2

363.0746
8.59 (s, 1H), 8.13 (s,
3121, 1524,




(363.075)
1H), 7.69 (d, J = 8.5 Hz,
1251, 1165,





2H), 7.55 (d, J = 8.5 Hz,
1119





2H), 7.41-7.29 (m, 4H),





6.64 (d, J = 15.7





Hz, 1H), 6.47 (dd, J =





15.9, 8.0 Hz, 1H), 4.17





(m, 1H)


DC3

329.1144
8.56 (s, 1H), 8.11 (s,
1521, 1246,




(329.114)
1H), 7.65 (d, J = 8.4 Hz,
1219, 1162,





2H), 7.52 (d, J = 8.3 Hz,
1152, 1107





2H), 7.40 (m, 5H), 6.61





(d, J = 15.8 Hz, 1H),





6.51 (dd, J = 15.9, 7.7





Hz, 1H), 4.18 (m, 1H)


DC4

364.11
8.56 (s, 1H), 8.10 (s, 1H),
3147, 1528,




([M + H]+)
7.66 (d, J = 2.0 Hz, 2H),
1494, 1246,





7.52 (d, J = 8.8 Hz, 2H),
1165, 1108





7.38 (d, J = 2.4 Hz, 2H),





7.34 (d, J = 8.4 Hz, 2H),





6.61 (d, J = 16.0





Hz, 1H), 6.40 (dd, J =





16.0, 7.6 Hz, 1H), 4.15





(m, 1H)


DC5

344.25
8.54 (s, 1H), 8.10 (s, 1H),
3122, 3047,




([M + H]+)
7.62 (d, J = 8.3 Hz, 2H),
1523, 1252,





7.50 (d, J = 8.4 Hz, 2H),
1160, 1107





7.25 (d, J = 8.3 Hz, 2H),





7.20 (d, J = 8.0 Hz, 2H),





6.60 (d, J = 16.0





Hz, 1H), 6.51 (dd, J =





16.0, 8.0 Hz, 1H), 4.15





(m, 1H), 2.37 (s, 3H)


DC6

360.28
8.55 (s, 1H), 8.10 (s, 1H),
3124, 2936,




([M + H]+)
7.65 (d, J = 8.8 Hz, 2H),
1522, 1249,





7.52 (d, J = 8.8 Hz, 2H),
1160





7.32 (d, J = 8.8 Hz, 2H),





6.95 (d, J = 8.8 Hz, 2H),





6.60 (d, J = 16.0





Hz, 1H), 6.56 (dd, J =





16.0, 7.4 Hz, 1H), 4.15





(m, 1H), 3.82 (s, 3H)


DC7

348
8.55 (s, 1H), 8.10 (s, 1H),
3141, 1512,




([M + H]+)
7.62 (d, J = 8.8 Hz, 2H),
1246, 1118





7.5 (d, J = 8.4 Hz, 2H),





7.38 (m, 2H), 7.12





(m, 2H), 6.61 (d, J =





16.0 Hz, 1H), 6.40 (dd,





J = 16.0, 7.6 Hz, 1H),





4.15 (m, 1H)


DC8

366.13
8.57 (s, 1H), 8.11 (s, 1H),
3116, 1628,




([M + H]+)
7.65 (d, J = 7.2 Hz, 2H),
1524, 1252,





7.52 (d, J = 8.0 Hz, 2H),
1168, 1118





6.95 (m, 2H), 6.82





(m, 1H), 6.65 (d, J =





16.0 Hz, 1H), 6.50 (dd,





J = 16.0, 8.0 Hz, 1H),





4.15 (m, 1H)


DC9

348.11
8.71 (s, 1H), 8.20 (s, 1H),
3115, 1525,




([M + H]+)
7.70 (d, J = 8.0 Hz, 2H),
1248, 1174





7.57 (d, J = 8.0 Hz, 2H),





7.40 (m, 1H), 7.19





(m, 3H), 6.60 (d, J =





16.0 Hz, 1H), 6.40 (dd,





J = 16.0, 8.4 Hz, 1H),





4.15 (m, 1H)


DC10

348.11
8.75 (s, 1H), 8.20 (s, 1H),
3114, 1526,




([M + H]+)
7.72 (d, J = 8.4 Hz, 2H),
1259, 1238,





7.6 (d, J = 8.4 Hz, 2H),
1193, 1114





7.20-7.40 (m, 4H),





6.60 (d, J = 16.0





Hz, 1H), 6.40 (dd, J =





16.0, 8.0 Hz, 1H,), 4.60





(m, 1H)


DC11
75.5-78.5
358.14
8.55 (s, 1H), 8.10 (s,




([M + H]+)
1H), 7.65 (d, J = 8.8 Hz,





2H), 7.52 (d, J = 8.4 Hz,





2H), 7.01 (s, 3H), 6.60





(d, J = 16.0 Hz, 1H),





6.51 (dd, J = 16.0, 7.8





Hz, 1H), 4.15 (m, 1H),





2.34 (s, 6H)


DC12

398.05
8.58 (s, 1H), 8.10 (s,
3055, 2930,




([M + H]+)
1H), 7.68 (d, J = 8.4 Hz,
1523, 1250,





2H), 7.53 (m, 4H), 7.2
1165





(s, 1H) 6.62 (d, J = 15.6





Hz, 1H), 6.44 (dd, J =





15.6, 8.0 Hz, 1H), 4.15





(m, 1H)


DC13

396.16
8.58 (s, 1H), 8.10 (s,
3108, 1523,




([M + H]+)
1H), 7.62 (d, J = 8.4 Hz,
1249, 1166,





2H), 7.55 (m, 4H), 7.25
1127





(m, 1H), 6.64 (d, J =





16.0 Hz, 1H), 6.40 (dd,





J = 16.0, 8.0 Hz, 1H),





4.90 (m, 1H)


DC14

398.05
8.58 (s, 1H), 8.10 (s, 1H),
3117, 2925,




([M + H]+)
7.62 (d, J = 8.4 Hz, 2H),
1526, 1246,





7.55 (m, 4H), 7.25
1172, 1117





(m, 1H), 6.67 (d, J =





16.0 Hz, 1H), 6.40 (dd,





J = 16.0, 8.0 Hz, 1H),





5.00 (m, 1H)


DC15

397.95
8.58 (s, 1H), 8.10 (s, 1H),
3120, 1524,




([M + H]+)
7.66 (d, J = 8.0 Hz, 2H),
1267, 1176,





7.52 (m, 3H), 7.40
1112





(d, J = 8.0 Hz, 1H), 7.30





(dd, J = 8.4, 2.9 Hz,





1H), 6.64 (d, J = 16.0





Hz, 1H), 6.40 (dd, J =





16.0, 8.0 Hz, 1H), 4.90





(m, 1H)


DC16

466
8.61 (s, 1H), 8.13 (s,




([M + H]+)
1H), 7.92 (s, 1H), 7.86





(s, 2H), 7.70 (d, J = 7.0





Hz, 2H), 7.54 (d, J = 7.0





Hz, 2H), 6.67 (d, J =





16.0 Hz, 1H), 6.46 (dd,





J = 16.0, 8.0 Hz, 1H),





4.35 (m, 1H)


DC17

430.06
8.58 (s, 1H), 8.1 (s, 1H),
3122, 3076,




([M + H]+)
7.68 (d, J = 8.4 Hz, 2H),
2929, 1523,





7.54 (d, J = 8.4 Hz, 2H),
1250, 1168,





7.51 (s, 1H), 7.42 (s, 1H),
1114





6.68 (d, J = 16.0





Hz, 1H), 6.35 (dd, J =





16.0, 8.0, Hz, 1H), 4.98





(m, 1H)


DC18
92-95
429.91
8.57 (s, 1H), 8.11 (s, 1H),




([M + H]+)
7.69 (d, J = 8.8 Hz, 2H),





7.54 (d, J = 8.4 Hz, 2H),





7.42 (s, 2H), 6.65





(d, J = 16.0 Hz, 1H),





6.40 (dd, J = 16.0, 8.0





Hz, 1H), 4.10 (m, 1H)


DC19
97-99
430.321
8.58 (s, 1H), 8.12 (s, 1H),




([M + H]+)
7.68 (d, J = 8.0 Hz, 2H),





7.64 (s, 1H), 7.59





(s, 1H), 7.55 (m, 3H),





6.60 (d, J = 16.0 Hz,





1H), 6.40 (dd, J = 16.0,





8.0 Hz, 1H), 4.22 (m, 1H)


DC20

427.0463
8.58 (s, 1H), 8.15 (s, 1H),
2937, 1524,




(427.0466)
7.70 (d, J = 8.4 Hz, 2H),
1482, 1278,





7.58 (d, J = 8.4 Hz, 2H),
1249, 1166,





7.36 (s, 2H), 6.62
1112





(d, J = 16.0 Hz, 1H),





6.43 (dd, J = 16.0, 8.0





Hz, 1H), 4.12 (m, 1H),





3.88 (s, 3H)


DC21

412.04
8.42 (s, 1H), 7.60 (d, J =
3108, 1572,




([M + H]+)
8.0 Hz, 2H), 7.50 (d, J =
1531, 1242,





8.0 Hz, 2H), 7.40 (s,
1172, 1104





1H), 7.22 (s, 2H), 6.60





(d, J = 16.0 Hz, 1H),





6.42 (dd, J = 16.0, 8.0





Hz, 1H), 4.15 (m, 1H),





2.5 (s, 3H)


DC22
147-149
441.01
8.62 (s, 1H), 7.78 (d, J =




([M − H]−)
8.0 Hz, 2H), 7.60 (d, J =





8.0 Hz, 2H), 7.40 (s,





1H), 7.30 (s, 2H), 6.67





(d, J = 16.0 Hz, 1H),





6.48 (dd, J = 16.0, 8.0





Hz, 1H), 4.15 (m, 1H)


DC23

412.05
7.95 (s, 1H), 7.35 (d, J =
1112, 799




([M + H]+)
8.0 Hz, 2H), 7.46 (d, J =





8.0 Hz, 2H), 7.39 (s,





1H), 7.29 (s, 2H), 6.67





(d, J = 16.0 Hz, 1H),





6.45 (dd, J = 16.0, 8.0





Hz, 1H), 4.12 (m, 1H),





2.51 (s, 3H)


DC24
133-134
440.03
8.10 (s, 1H), 7.52 (d, J =




([M + H]+)
8.0 Hz, 2H), 7.42-7.38





(m, 3H), 7.28 (s, 2H),





6.67 (d, J = 16.0 Hz,





1H), 6.45 (dd, J = 16.0,





8.0 Hz, 1H), 4.16 (m,





1H), 2.79 (s, 3H)


DC25

442.02
7.97 (s, 1H), 7.59 (d, J =
1167, 1114,




([M − H]−)
8.0 Hz, 2H), 7.53 (d, J =
800





8.0 Hz, 2H), 7.38 (m,





1H), 7.29 (s, 2H), 6.65





(d, J = 16.0 Hz, 1H),





6.42 (dd, J = 16.0, 8.0





Hz, 1H), 4.17 (m, 1H),





2.74 (s, 3H)


DC26

464.03
8.12 (s, 1H), 7.49 (d, J =
1689, 1253,




([M − H]−)
8.0 Hz, 2H), 7.40-7.37
1166, 1114,





(m 3H), 7.28 (s, 2H),
979, 964





6.66 (d, J = 16.0 Hz, 1H),





6.44 (dd, J = 16.0, 8.0 Hz,





1H), 4.14 (m, 1H), 3.22 (m,





1H), 1.09-1.16 (m, 4H)


DC27

473.94
8.19 (s, 1H), 7.64 (d, J =
1571, 1331,




([M − H]−)
7.2 Hz, 2H), 7.55 (d, 7.2
1170, 1113,





Hz, 2H), 7.39 (s, 1H),
764





7.30 (s, 2H), 6.62 (d, J =





16.0 Hz, 1H), 6.42 (dd,





J = 8.0, 16.0 Hz, 1H),





4.18 (m, 1H), 3.58 (s, 3H)


DC28

421.22
8.79 (s, 1H), 8.18 (s,
3126, 2233,




([M + H]+)
1H), 7.80 (m, 3H), 7.52
1516, 1250,





(m, 2H), 7.24 (m, 1H),
1165, 1109





6.63 (d, J = 16.0 Hz,





1H), 6.54 (d, J = 16.0,





7.6 Hz, 1H), 4.19 (m, 1H)


DC29

421.22
8.80 (s, 1H), 8.2 (s, 1H),
3005, 1716,




([M + H]+)
7.75-7.82 (m, 3H),
1363, 1223





7.41 (t, J = 2 Hz, 1H),





7.26 (m, 2H), 6.65 (d,





J = 16.0 Hz, 1H), 6.52





(dd, J = 16.0, 7.6 Hz,





1H), 4.16 (m, 1H)


DC30

489.17
8.81 (s, 1H), 8.20 (s,
2964, 2234,




([M + H]+)
1H), 7.94 (s, 1H), 7.85
1289, 1166,





(m, 3H), 7.79 (m, 2H),
1136





6.70 (d, J = 16.0 Hz,





1H), 6.58 (dd, J = 16.0,





8.0 Hz, 1H), 4.35 (m, 1H)


DC31
117-118
455.27
8.80 (s, 1H), 8.20 (s,




([M + H]+)
1H), 7.82 (m, 3H), 7.4





(s, 2H), 6.62 (d, J = 16.0





Hz, 1H), 6.52 (dd, J =





16.0, 8.0 Hz, 1H), 4.18





(m, 1H)


DC32

388.0705
8.82 (s, 1H), 8.22 (s,
3126, 2234,




(388.0703)
1H), 7.82-7.78 (m, 3H),
1520, 1280,





7.38-7.30 (m, 3H), 6.62
1164, 1112





(d, J = 16.1 Hz, 1H),





6.56 (dd, J = 16.1, 6.8





Hz, 1H), 4.18 (m, 1H)


DC33

455.22
8.80 (s, 1H), 8.20 (s,
3122, 3086,




([M − H]−)
1H), 7.82-7.80 (m, 3H),
2234, 1517,





7.70-7.50 (m, 3H), 6.65
1327, 1168,





(d, J = 16.9 Hz, 1H),
1113





6.54 (dd, J = 16.9, 6.8





Hz, 1H), 4.25 (m, 1H)


DC34

452.0412
8.85 (s, 1H), 8.23 (br s,
3122, 2934,




(452.0419)
1H), 7.83-7.78 (m, 3H),
2231, 1516,





7.33 (s, 2H), 6.69 (d, J =
1480, 1248,





14.9 Hz, 1H), 6.50 (dd,
1211, 1165,





J = 14.9, 7.2 Hz, 1H),
1111





4.15 (m, 1H), 3.90 (s, 3H)


DC35

439.01
8.60 (s, 1H), 8.20 (s,
2233, 1518,




([M − H]−)
1H), 7.82 (m, 3H), 7.28
1250, 1169,





(m, 2H), 6.65 (d, J =
1035, 817





16.0 Hz, 1H), 6.48 (dd,





J = 16.0, 8.0 Hz, 1H),





4.20 (m, 1H)


DC36

437.25
8.70 (s, 1H), 7.80 (m,
2927, 2233,




([M + H]+)
3H), 7.40 (s, 1H), 7.28
1572, 1531,





(s, 2H), 6.63 (d, J = 16.0
1248, 1166,





Hz, 1H), 6.50 (dd, J =
1112





16.0, 8.0 Hz, 1H), 4.18





(m, 1H), 2.50 (s, 1H)


DC37
109-111
466.10
8.86 (s, 1H), 7.89 (m,




([M − H]−)
3H), 7.40 (s, 1H), 7.30





(s, 2H), 6.68 (d, J = 16.0





Hz, 1H), 6.57 (dd, J =





16.0, 8.0 Hz, 1H), 4.18





(m, 1H)


DC38
96-98
436.11
8.58 (s, 1H), 7.75 (m,




([M − H]−)
3H), 7.40 (s, 1H), 7.28





(s, 2H), 6.61 (d, J = 16.0





Hz, 1H), 6.42 (dd, J =





16.0, 8.2 Hz, 1H), 4.40





(br s, 2H), 4.15 (m, 1H)


DC39
224-226
480.30
8.65 (s, 1H), 8.18 (br s,
3352, 2237,




([M + H]+)
1H), 7.80-7.70 (m, 3H),
1707, 1163,





7.40 (s, 1H), 7.27 (s,
841





2H), 7.36 (m, 1H), 7.28





(m, 2H), 6.60 (d, J =





16.8 Hz, 1H), 6.47 (m,





1H), 4.16 (m, 1H), 2.40





(br s, 3H)


DC40
70-73
436.11
8.86 (s, 1H), 7.88 (m,




([M − 2H]−)
3H), 7.44 (s, 2H), 6.67





(d, J = 16.0 Hz, 1H),





6.56 (dd, J = 16.0 7.6





Hz, 1H), 4.19 (m, 1H)


DC41
72-75
469.95
(DMSO-d6) 8.72 (s,




([M − H]−)
1H), 8.26 (s, 1H), 8.01





(d, J = 8.4 Hz, 1H), 7.91





(s, 2H), 7.77 (d, J = 8.4





Hz, 1H), 6.42 (dd, J =





15.6, 9.2 Hz, 1H), 6.83





(d, J = 15.6 Hz, 1H),





5.87 (s, 2H), 4.89 (m, 1H)


DC42
104-107
609.98
8.78 (s, 2H), 7.83 (s,
2234, 1714,




([M + H]+)
1H), 7.80 (m, 2H), 7.42
1114, 807





(s, 2H), 6.65 (d, J = 16.4





Hz, 1H), 6.51 (dd, J =





16.4, 7.8 Hz, 1H), 4.17





(m, 1H), 4 2.16 (m, 2H),





1.25 (m, 4H), 1.00 (m, 4H),


DC43
109-112
540.04
(DMSO-d6) 10.94 (br s,
3233, 2233,




([M + H]+)
1H), 8.36 (s, 1H), 8.08
1699, 1114,





(m, J = 8.4 Hz, 1H),
807





7.91 (s, 2H), 7.84 (d, J =





8.4 Hz, 1H), 7.13 (dd, J =





15.6, 9.2 Hz, 1H),





6.87 (d, J = 15.6 Hz,





1H), 4.92 (m, 1H), 1.99





(br s, 1H), 0.82 (s, 4H)


DC44

435.26
8.33 (s, 1H), 8.23 (s,
2236, 1510,




[M − H]−
1H), 7.66 (s, 1H), 7.60
1114, 801





(s, 1H), 7.41 (m, 1H),





7.28 (m, 2H), 6.62 (d, J =





16.0 Hz, 1H), 6.51





(dd, J = 16.0, 7.8 Hz,





1H), 4.16 (m, 1H), 2.20





(s, 3H)


DC45
75-78
468.87
8.36 (s, 1H), 8.23 (s,




[M − H]−
1H), 7.66 (s, 1H), 7.60





(s, 1H), 7.41 (s, 2H),





6.62 (d, J = 16.4 Hz,





1H), 6.51 (dd, J = 16.4,





7.6 Hz, 1H), 4.16 (m,





1H), 2.20 (s, 3H)


DC46

411.4
8.83 (s, 1H), 8.21 (s, 1H),

13C NMR (δ)3




([M]+)
7.83 (d, J = 8.5 Hz, 1H),
155.63, 153.27,





7.61 (d, J = 1.9 Hz, 1H),
153.12, 143.01,





7.52 (dd, J = 8.4,
137.89, 136.25,





1.9 Hz, 1H), 7.28 (d, J =
134.03, 133.88,





3.8 Hz, 2H), 6.93 (d, J =
132.23, 131.23,





11.5 Hz, 1H), 6.26-6.20 (m,
131.18, 129.20,





1H), 4.22 (m, 1H)
126.17, 125.04,






124.99


DC47
139-141
474.16
8.51 (s, 1H), 8.14 (s,




([M − H]−)
1H), 7.75 (s, 1H), 7.5





(m, 2H), 7.4 (s, 1H),





7.30 (m, 2H), 6.60 (d,





J = 16.0 Hz, 1H), 6.50





(dd, J = 16.0, 8.0 Hz,





1H), 4.15 (m, 1H)


DC48
124-126
414.05
8.69 (s, 1H), 8.14 (s,




[M − H]−
1H), 7.96 (d, J = 4.8 Hz,





1H), 7.39-7.27 (m, 5H),





6.95 (d, J = 16.0 Hz,





1H), 6.51 (dd, J = 16.0,





7.6 Hz, 1H), 4.13 (m, 1H)


DC49
81-83
463.96
8.57 (s, 1H), 8.14 (s,




[M − H]−
1H), 7.60 (m, 2H), 7.44





(m, 3H), 6.95 (d, J =





16.0 Hz, 1H), 6.51 (dd,





J = 16.0, 7.6 Hz, 1H),





4.13 (m, 1H)


DC50
140-143
430.07
8.56 (s, 1H), 8.13 (s,
1110, 803




[M − H]−)
1H), 7.59 (d, J = 1.2 Hz,





2H), 7.44 (m, 2H), 7.28





(m, 2H), 6.61 (d, J =





16.0 Hz, 1H), 6.47 (dd,





J = 16.0, 8.0 Hz, 1H),





4.15 (m, 1H)


DC51
118-121
464.22
8.32 (s, 1H), 8.15 (s,




([M − H]−)
1H), 7.82 (s, 1H), 7.73





(d, J = 8.4 Hz, 1H), 7.53





(d, J = 8.4 Hz, 1H), 7.41





(s, 1H), 7.29 (s, 2H),





6.70 (d, J = 15.6 Hz,





1H), 6.50 (dd, J = 15.6,





8.0 Hz, 1H), 4.20 (m, 1H)


DC52


9.99 (s, 1H), 8.42 (s,
3123, 3079,





1H), 8.12 (s, 1H), 8.01
2925, 1692,





(s, 1H), 7.68 (m, 1H),
1571, 1512,





7.44 (m, 1H), 7.33 (m,
1253, 1164,





1H), 7.22 (s, 2H), 6.62
1111





(d, J = 16.7 Hz, 1H),





6.45 (dd, J = 16.7, 9.3





Hz, 1H), 4.10 (m, 1H)


DC53


8.30 (m, 1H), 8.00 (br s,
3250, 3043,





1H), 7.75 (m, 1H), 7.68
1683, 1116





(m, 1H), 7.55 (m, 1H),





7.36 (m, 1H), 7.28 (m,





2H), 6.70 (m, 1H), 6.58





(br s, 1H), 6.33 (m, 1H),





5.88 (m, 2H), 4.10 (m, 1H)


DC54
56-58
441.07
8.40 (s, 1H), 8.13 (s,




([M − H]−)
1H), 8.02 (s, 1H), 7.76





(d, J = 8.4 Hz, 1H), 7.59





(d, J = 8.0 Hz, 1H), 7.4





(s, 1H), 7.29 (m, 2H),





6.69 (d, J = 15.6 Hz,





1H), 6.57 (dd, J = 15.6,





7.8 Hz, 1H), 4.15 (m, 1H)


DC55

412.97
8.37 (s, 1H), 8.18 (s,




([M + H]+)
1H), 7.39 (s, 1H), 7.30





(m, 2H), 7.19 (d, J = 8.0





Hz, 1H), 6.90 (m, 2H),





6.55 (d, J = 15.6 Hz,





1H), 6.38 (dd, J = 15.6,





8.2 Hz, 1H), 4.20 (m,





1H), 2.50 (br s, 2H)


DC56
175-177
453
9.59 (br s, 1H), 8.55 (s,




([M − H]−)
1H), 8.47 (s, 2H), 8.23





(s, 1H), 7.30 (m, 4H),





6.62 (d, J = 16.0 Hz,





1H), 6.40 (dd, J = 16.0,





8.0 Hz, 1H), 4.15 (m,





1H), 2.20 (s, 3H)


DC57

426.0627
8.33 (s, 1H), 8.16 (s,
3342, 3112,




(426.0626)
1H), 7.38 (s, 1H), 7.29
2931, 1606,





(s, 2H), 7.15 (d, J = 7.6
1583, 1574,





Hz, 1H), 6.80 (d, J = 7.6
1528, 1153





Hz, 1H), 6.74 (m, 1H),





6.60 (d, J = 15.6 Hz, 1H),





6.35 (dd, J = 15.6,





8.4 Hz, 1H), 5.40 (br s,





1H), 4.15 (m, 1H), 2.90





(s, 3H)


DC58
94-97
440.0424
(DMSO-d6) 8.76 (s,
3403, 3304,




(440.0419)
1H), 8.16 (s, 1H), 7.90
3178, 1674,





(br s, 1H), 7.83 (s, 1H),
1571, 1169,





7.70 (d, J = 7.9 Hz, 1H),
1108





7.71-7.67 (m, 3H), 7.58





(d, J = 7.9 Hz, 1H), 7.52





(br s, 1H), 7.00 (dd, J =





15.8, 8.7 Hz, 1H), 6.85





(d, J = 15.8 Hz, 1H),





4.85 (m, 1H)


DC59
87-90

(DMSO-d6) 9.00 (s,





1H), 8.63 (s, 1H), 8.17





(s, 1H), 7.70-7.59 (m,





5H), 7.00 (dd, J = 16.2,





9.7 Hz, 1H), 6.85 (d, J =





16.2 Hz, 1H), 5.90 (br s





2H), 4.83 (m, 1H)


DC60

469.0577
8.32 (s, 1H), 8.10 (s,
2987, 1725,




(469.0572)
1H), 7.97 (s, 1H), 7.65
1518, 1275,





(d, J = 8.1 Hz, 1H), 7.47
1166, 1113





(d, J = 8.1 Hz, 1H), 7.40





(m, 1H), 7.28 (s, 2H),





6.62 (d, J = 16.5 Hz,





1H), 6.49 (dd, J = 16.5,





7.7 Hz, 1H), 4.23-4.04





(m, 3H), 1.15 (t, J = 8.0





Hz, 3H)


DC61
130-132
442.15
(DMSO-d6) 9.90 (s,




([M + H]+)
1H), 8.17 (s, 1H), 8.15





(m, 1H), 7.90 (m, 1H),





7.71 (m, 2H), 7.67 (m,





1H), 7.62 (d, J = 7.3 Hz,





1H), 7.03 (dd, J = 16.5,





8.3 Hz, 1H), 6.62 (d, J =





16.5 Hz, 1H), 4.87 (m, 1H)


DC62

412.10
8.27 (s, 1H), 8.23 (s,
1513, 1252,




([M + H]+)
1H), 7.40 (m, 3H), 7.30
1166, 1112,





(m, 3H), 6.64 (d, J =
801





16.0 Hz, 1H), 6.45 (dd,





J = 16.0, 8.0 Hz, 1H),





4.19 (m, 1H), 2.21 (s, 3H)


DC63

446.01
8.26 (s, 1H), 8.12 (s,
2928, 2525,




([M + H]+)
1H), 7.42 (s, 2H), 7.18-
1249, 1169,





7.28 (m, 3H), 6.62 (d,
1114, 809





J = 15.6 Hz, 1H), 6.39





(dd, J = 15.6, 9.4 Hz,





1H), 4.10 (m, 1H), 2.25





(s, 3H)


DC64

475.03
8.84 (d, J = 5.8 Hz, 2H),
1683, 1167,




([M + H]+)
8.33 (s, 1H), 8.20 (s,
650, 479





1H), 7.75 (m, 1H), 7.60





(d, J = 28.6 Hz, 1H),





7.58-7.48 (m, 3H), 7.42





(m, 1H), 7.28 (s, 2H),





6.71 (d, J = 16.9 Hz,





1H), 6.39 (dd, J = 16.9,





8.2 Hz, 1H), 4.15 (m, 1H)


DC65

412.05
8.55 (s, 1H), 8.12 (s,
722, 111




([M + H]+)
1H), 7.55 (m, 3H), 7.39





(m, 1H), 7.30 (d, J = 1.6





Hz, 1H), 6.85 (d, J =





16.0 Hz, 1H), 6.41 (dd,





J = 16.0, 8.0 Hz, 1H),





4.17 (m, 1H), 2.40 (s, 3H)


DC66
60-61
468.26
8.59 (s, 1H), 8.14 (s,




([M + H]+)
1H), 7.94 (s, 1H), 7.70





(d, J = 8.0 Hz, 1H), 7.61





(d, J = 8.0 Hz, 1H), 7.43





(s, 2H), 7.23 (d, J = 16.0





Hz, 1H), 6.41 (dd, J =





16.0, 8.0 Hz, 1H), 4.20





(m, 1H)


DC67
133-134
432.30
8.59 (s, 1H), 8.12 (s,
800, 114




([M + H]+)
1H), 7.78 (br s, 1H),





7.71 (m, 1H), 7.62 (m,





1H), 7.39 (s, 1H), 7.32





(s, 2H), 7.03 (d, J = 16.0





Hz, 1H), 6.43 (dd, J =





16.0, 8.0 Hz, 1H), 0.21





(m, 1H)


DC68

412.03
8.71 (s, 1H), 8.18 (s,




([M + H]+)
1H), 7.71 (d, J = 8.0 Hz,





2H), 7.55 (d, J = 8.0 Hz,





2H), 7.37 (s, 1H), 7.28





(m, 2H), 6.08 (d, J =





16.0 Hz, 1H), 4.26 (m,





1H), 2.05 (s, 3H)


DC69
162-168
414.03
8.56 (s, 1H), 8.11 (s, 1H),




([M + H]+)
7.70 (d, J = 8.5 Hz, 2H),





7.56 (d, J = 8.5 Hz, 2H),





7.54 (m, 2H), 7.40





(m, 1H), 6.91 (d, J =





16.5 Hz, 1H), 6.66 (d,





J = 16.5 Hz, 1H)


DC70
 99-103
428.05
8.58 (s, 1H), 8.13 (s,




([M + H]+)
1H), 7.73 (d, J = 8.7 Hz,





2H), 7.60 (d, J = 8.7 Hz,





2H), 7.46 (m, 2H), 7.42





(m, 1H), 6.85 (d, J =





16.2 Hz, 1H), 6.40 (d,





J = 16.2 Hz, 1H),





3.42 (s, 3H)






a1H NMR spectral data were acquired using a 400 MHz instrument in CDCl3 except where noted. HRMS data are noted observed value (theoretical value).













TABLE 2A







Analytical Data for Compounds in Table 1A.











Com-






pound
mp


IR (cm−1);


Number
(° C.)
ESIMS

1H NMR (δ)a

19F NMR














F1

588.10
(400 MHz, CDCl3) δ

19F NMR




([M + H]+)
7.64 (d, J = 1.6 Hz,
(376 MHz,





1H), 7.61 (s, 1H), 7.58
CDCl3) δ





(d, J = 8.0 Hz, 1H), 7.43
−68.56





(dd, J = 8.1, 1.6 Hz,






1H), 7.41 (s, 2H), 6.55






(d, J = 15.9 Hz, 1H),






6.42 (dd, J = 16.0, 7.7






Hz, 1H), 5.33 (s, 1H),






4.12 (m, 1H), 3.29 (m,






5H), 1.15 (t, J = 7.2 Hz,






3H).



F7

627.9
8.12 (s, 1H), 7.65 (s,

19F NMR




([M + H]+)
1H), 7.60 (d, J = 8.0 Hz,
(376 MHz,





1H), 7.50 (s, 1H), 7.40
CDCl3) δ





(s, 3H), 6.54 (d, J = 15.8
−68.56,





Hz, 1H), 6.42 (dd, J =
−73.02





16.0, 7.7 Hz, 1H), 5.95






(t, 1H), 4.10 (q, J = 8.9






Hz, 1H), 3.91 (m, 2H).






a1H NMR spectral data were acquired using a 400 MHz instrument in CDCl3 except where noted. HRMS data are noted observed value (theoretical value).













TABLE 2B







Analytical Data for Compounds in Table 1B.











Com-






pound
mp


IR (cm−1);


Number
(° C.)
ESIMS

1H NMR (δ)a

19F NMR














FA1

637.9
(300 MHz, DMSO-d6) δ
  3444,




([M − H]−)
10.45 (s, 1H), 7.98 (s,
  1649,





1H), 7.91 (s, 2H), 7.74
  1261,





(d, J = 7.5 Hz, 1H),
   749





7.66 (d, J = 7.5 Hz,






1H), 7.19 (t, J = 6.3 Hz,






1H), 7.04 (dd, J = 15.9,






9.3 Hz, 1H), 6.79 (d, J =






15.6 Hz, 1H), 4.88-






4.81 (m, 1H), 3.86-






3.78 (m, 2H), 3.08 (s,






3H)



FA2

628.0
(300 MHz, DMSO-d6) δ
  3395,




([M − H]−)
10.53 (s, 1H), 8.06 (s,
  1698,





1H), 7.96 (s, 2H), 7.92
  1163,





(s, 2H), 7.23 (bs, 1H),
   809





7.14 (dd, J = 15.3, 9.0






Hz, 1H), 6.91 (d, J =






15.9 Hz, 1H), 4.89-






4.82 (m, 1H), 3.86-






3.81(m, 2H), 3.02 (s,






3H)



FA3

575.7
(300 MHz, DMSO-d6) δ

19F NMR




([M −
9.87 (s, 1H), 8.00 (s,
(300 MHz,




CH2CF3]+)
1H), 7.92-7.87 (m,
DMSO-





3H), 7.49 (d, J = 7.8
d6) δ





Hz, 1H), 7.10 (dd, J =
 −57.86,





15.3, 8.7 Hz, 1H), 6.89
 −67.95,





(d, J = 15.6 Hz, 1H),
 −71.72





6.80 (t, J = 6.3 Hz, 1H),






4.89-4.82 (m, 1H),






3.90-3.78 (m, 2H),






3.11-3.07 (m, 1H),






1.01 (d, J = 6.3 Hz, 6H).



FA4

684.4
(300 MHz, DMSO-d6) δ
  3395,




([M + H]+)
10.52 (s, 1H), 8.06 (s,
  1698,





1H), 7.96 (s, 2H),
  1163,





7.90(s, 1H), 7.85 (s,
   809





2H), 7.24 (t, J = 6.0 Hz,






1H), 7.14 (dd, J = 15.6,






9.0 Hz, 1H), 6.90 (d, J =






15.9 Hz, 1H), 4.88-






4.80 (m, 1H), 3.86-






3.78 (m, 2H), 3.02 (s,






3H)



FA5

715.6
(400 MHz, DMSO-d6) δ





([M − H]−)
10.53 (s, 1H), 8.05 (s,






3H), 7.96 (s, 2H), 7.24






(t, J = 6.4 Hz, 1H), 7.13






(dd, J = 15.6, 9.2 Hz,






1H), 6.89 (d, J = 15.6






Hz, 1H), 4.88-4.83 (m,






1H), 3.86-3.82 (m,






2H), 3.02 (s, 3H)



FA6

674.0
(300 MHz, DMSO-d6) δ
  3390,




([M + H]+)
10.53 (s, 1H), 8.06 (s,
  2925,





1H), 7.96 (s, 2H), 7.88
  1673,





(s, 1H), 7.69 (s, 1H),
  1165,





7.23 (t, J = 6.0 Hz, 1H),
   750





7.13 (dd, J = 15.6, 8.7






Hz, 1H), 6.91 (d, J =






15.6 Hz, 1H), 4.89-






4.83 (m, 1H), 3.86-






3.81 (m, 2H), 3.02 (s,






3H)



FA7

611.8
(400 MHz, DMSO-d6) δ





([M − H]−)
10.53 (s, 1H), 8.06 (s,






1H), 7.96 (s, 2H), 7.88






(d, J = 6.4 Hz, 2H), 7.24






(t, J = 6.4 Hz, 1H), 7.12






(dd, j = 15.6, 8.8 Hz,






1H), 6.89 (d, J = 16.0






Hz, 1H), 4.87-4.82 (m,






1H), 3.86-3.77 (m,






2H), 3.02 (s, 3H)



FA8
115-
614.4
(300 MHz, DMSO-d6) δ




119
([M + H]+)
10.50 (bs, 1H), 8.07-






8.05 (m, 1H), 7.95-






7.92 (m, 4H), 7.14 (dd,






J = 16.2, 9.0 Hz, 1H),






6.91 (d, J = 15.9 Hz,






1H), 6.15-5.78 (m,






1H), 4.90-4.84 (m,






1H), 3.49-3.39 (m,






2H), 3.01 (s, 3H)



FA9
112-
645.6
(300 MHz, DMSO-d6) δ




115
([M + H]+)
10.44 (bs, 1H), 8.06-






8.05 (m, 1H), 7.93-7.92






(m, 4H), 7.08 (dd, J =






15.6, 9.0 Hz, 1H), 6.91






(d, J = 15.3 Hz, 1H),






6.79 (bs, 1H), 4.88-






4.85 (m, 1H), 3.37-






3.24 (m, 2H), 2.99 (s,






3H), 2.43-2.38 (m, 2H)



FA10

644.7
8.00 (t, J = 6.5 Hz, 1H),

19F NMR




([M + H]+)
7.73-7.62 (m, 2H),
(376 MHz,





7.44-7.34 (m, 3H),
CDCl3) δ





6.65 (d, J = 15.9 Hz,
 −59.79,





1H), 6.47 (dd, J = 15.9,
 −68.59,





7.8 Hz, 1H), 4.19-4.11
 −72.70.





(m, 1H), 4.11-3.98 (m,






4H), 3.89 (m, 2H)






a1H NMR spectral data were acquired using a 400 MHz instrument in CDCl3 except where noted. HRMS data are noted observed value (theoretical value).













TABLE 3







Assays Results












Compound
BAW
CEW
GPA



Number
Rating
Rating
Rating







AC1
D
D
B



AC2
C
C
C



AC3
D
D
B



AC4
D
A
B



AC5
D
D
B



AC6
D
A
B



AC7
A
A
B



AC8
D
B
B



AC9
A
A
B



AC10
A
A
B



AC11
A
A
D



AC12
A
A
D



AC13
A
A
B



AC14
A
B
D



AC15
A
A
B



AC16
A
A
C



AC17
A
A
B



AC18
A
A
B



AC19
D
D
B



AC20
A
A
C



AC21
D
D
C



AC22
A
A
D



AC23
A
A
B



AC24
A
A
D



AC25
A
A
D



AC26
A
A
B



AC27
A
A
B



AC28
A
A
B



AC29
A
A
B



AC30
A
A
B



AC31
A
A
B



AC32
A
A
B



AC33
A
A
B



AC34
A
A
B



AC35
A
A
C



AC36
A
A
B



AC37
A
A
B



AC38
A
A
C



AC39
A
A
C



AC40
A
A
D



AC41
A
D
D



AC42
A
D
D



AC43
A
A
B



AC44
A
A
B



AC45
A
A
D



AC46
A
A
D



AC47
D
D
B



AC48
A
A
B



AC49
A
A
B



AC50
A
D
B



AC51
A
A
B



AC52
A
A
B



AC53
A
A
B



AC54
A
A
B



AC57
A
A
B



AC58
A
A
B



AC59
A
A
B



AC60
A
A
B



AC61
A
A
B



AC62
A
A
D



AC63
A
A
B



AC64
A
A
B



AC65
A
A
B



AC66
A
A
B



AC67
A
A
B



AC68
A
A
D



AC69
A
A
A



AC70
D
D
B



AC71
A
A
B



AC72
A
A
B



AC75
A
A
B



AC76
A
A
D



AC77
A
A
B



AC78
A
A
A



AC79
A
A
A



AC80
A
A
B



AC81
A
D
D



AC82
A
A
B



AC83
A
A
B



AC84
A
A
D



AC85
A
A
B



AC86
A
A
D



AC87
A
A
B



AC89
A
A
B



AC90
A
A
C



AC91
A
A
C



AC92
A
A
C



AC93
A
D
C



AC94
D
B
B



AC95
A
A
C



AC96
D
D
C



AC97
D
D
C



AC98
A
A
C



AC99
A
A
C



AC100
C
C
C



AC101
D
D
C



AC102
D
A
C



AC103
A
A
D



AC104
A
A
B



AC105
A
A
D



AC106
A
A
B



AC107
B
A
D



AC108
B
D
D



AC109
D
D
C



AC110
A
A
C



AC111
A
A
C



AC112
A
A
C



AC113
B
A
D



AC114
A
B
D



AC115
A
A
D



AC116
C
C
C



AC117
A
D
B



AC118
A
D
D



BC1
A
A
D



BC2
A
A
D



BC3
A
A
D



BC4
A
A
B



BC5
A
A
B



BC6
A
A
D



BC7
A
A
D



BC8
A
A
B



BC9
A
A
D



BC10
A
A
B



BC11
C
C
C



BC12
C
C
C



BC13
A
A
D



BC14
A
D
D



CC1
D
D
D



CC2
A
A
B



CC3
A
A
D



CC4
A
B
B



CC5
A
A
B



CC6
A
A
B



CC7
A
A
B



CC8
A
A
D



CC9
A
A
B



CC10
A
A
B



CC11
A
A
B



CC12
D
D
B



CC13
A
A
B



CC14
A
D
D



CC15
A
A
B



CC16
A
A
B



CC17
A
A
B



CC18
A
A
B



CC19
A
A
B



CC20
A
A
D



CC21
A
A
D



CC22
A
A
B



CC23
A
A
B



CC24
A
A
D



CC25
A
A
B



CC26
A
D
B



CC27
A
A
D



CC28
A
A
D



CC29
A
A
B



CC30
A
A
D



CC31
B
D
C



CC32
A
A
B



CC33
A
A
B



CC34
A
A
B



CC35
D
D
D



CC36
A
A
D



CC37
A
A
D



CC38
A
A
D



CC39
D
D
B



CC40
D
A
D



CC41
D
D
B



CC42
D
D
D



CC43
A
B
B



CC44
A
A
B



CC45
A
A
D



CC46
D
A
C



CC47
D
D
C



CC48
D
D
C



CC49
D
D
D



CC50
A
A
D



CC51
A
A
D



CC52
A
D
D



CC53
D
D
B



CC54
A
A
C



DC1
A
A
D



DC2
D
D
C



DC3
B
D
C



DC4
A
D
C



DC5
D
D
C



DC6
D
D
C



DC7
A
D
C



DC8
A
D
C



DC9
D
D
C



DC10
D
D
C



DC11
A
D
C



DC12
A
A
B



DC13
A
A
C



DC14
D
D
C



DC15
D
D
C



DC16
A
A
C



DC17
A
A
C



DC18
A
A
C



DC19
A
A
C



DC20
A
D
C



DC21
D
D
C



DC22
D
D
C



DC23
D
A
C



DC24
D
D
C



DC25
D
D
C



DC26
D
D
C



DC27
D
D
C



DC28
A
A
B



DC29
A
A
C



DC30
A
A
C



DC31
A
A
B



DC32
D
D
C



DC33
A
A
C



DC34
A
A
B



DC35
A
A
B



DC36
D
D
C



DC37
A
A
C



DC38
A
A
C



DC39
A
A
C



DC40
A
A
C



DC41
A
A
C



DC42
A
A
C



DC43
A
A
C



DC44
A
A
C



DC45
A
A
C



DC46
A
A
C



DC47
A
A
C



DC48
A
A
C



DC49
A
A
C



DC50
A
A
C



DC51
A
A
C



DC52
D
D
C



DC53
D
A
C



DC54
D
D
C



DC55
D
D
C



DC56
D
D
C



DC57
A
A
C



DC58
D
D
C



DC59
D
D
C



DC60
A
A
C



DC61
D
D
C



DC62
A
A
C



DC63
A
A
C



DC64
D
D
C



DC65
D
A
C



DC66
A
A
C



DC67
A
A
C



DC68
A
A
C



DC69
D
D
C

















TABLE 3A







Assays Results












Compound
BAW
CL
GPA



Number
Rating
Rating
Rating







F1
A
A
C



F7
A
A
C

















TABLE 3B







Assays Results












Compound
BAW
CL
GPA



Number
Rating
Rating
Rating







FA1
A
A
C



FA2
A
A
C



FA3
C
C
C



FA4
A
A
C



FA5
A
A
C



FA6
A
A
C



FA7
A
A
C



FA8
A
A
C



FA9
A
A
C



FA10
D
D
C









Claims
  • 1. A composition comprising a molecule according to Formula One:
  • 2. A composition according to claim 1 further comprising: (a) one or more compounds having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or virucidal properties; or(b) one or more compounds that are antifeedants, bird repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant activators, plant growth regulators, or synergists; or(c) both (a) and (b).
  • 3. A composition according to claim 1 wherein further comprising one or more compounds selected from: (3-ethoxypropyl)mercury bromide, 1,2-dichloropropane, 1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol, 2-(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA, 2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6-TBA-potassium, 2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl, 2,4,5-T-2-ethylhexyl, 2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T-butotyl, 2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl, 2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T-sodium, 2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D, 2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl, 2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium, 2,4-DB-isoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl, 2,4-D-butyl, 2,4-D-diethylammonium, 2,4-D-dimethylammonium, 2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethyl, 2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D-isoctyl, 2,4-D-isopropyl, 2,4-D-isopropylammonium, 2,4-D-lithium, 2,4-D-meptyl, 2,4-D-methyl, 2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl, 2,4-D-sodium, 2,4-D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D-triethylammonium, 2,4-D-tris(2-hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP, 2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP, 4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA-sodium, 4-CPB, 4-CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate, 8-phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate, acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole, acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl, acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein, acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor, alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, allicin, allidochlor, allosamidin, alloxydim, alloxydim-sodium, allyl alcohol, allyxycarb, alorac, alpha-cypermethrin, alpha-endosulfan, ametoctradin, ametridione, ametryn, amibuzin, amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron, aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl, aminocyclopyrachlor-potassium, aminopyralid, aminopyralid-potassium, aminopyralid-tris(2-hydroxypropyl)ammonium, amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole, ammonium sulfamate, ammonium α-naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam, asulam-potassium, asulam-sodium, athidathion, atraton, atrazine, aureofungin, aviglycine, aviglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl, azinphos-methyl, aziprotryne, azithiram, azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin-ethyl, benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, benfluralin, benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap, bentaluron, bentazone, bentazone-sodium, benthiavalicarb, benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox, benzadox-ammonium, benzalkonium chloride, benzamacril, benzamacril-isobutyl, benzamorf, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid, benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzyl benzoate, benzyladenine, berberine, berberine chloride, beta-cyfluthrin, beta-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox, bifenthrin, bifujunzhi, bilanafos, bilanafos-sodium, binapacryl, bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl, brevicomin, brodifacoum, brofenvalerate, brofluthrinate, bromacil, bromacil-lithium, bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos, bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT, bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil, bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxynil octanoate, bromoxynil-potassium, brompyrazon, bromuconazole, bronopol, bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundy mixture, busulfan, butacarb, butachlor, butafenacil, butamifos, butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron, butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin, butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos, cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide, calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor, captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam, carbendazim, carbendazim benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartap hydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure, Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone, chlomethoxyfen, chloralose, chloramben, chloramben-ammonium, chloramben-diolamine, chloramben-methyl, chloramben-methylammonium, chloramben-sodium, chloramine phosphorus, chloramphenicol, chloraniformethan, chloranil, chloranocryl, chlorantraniliprole, chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside, chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenac-ammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole, chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide, chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren, chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequat chloride, chlornidine, chlornitrofen, chlorobenzilate, chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron, chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin, chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron, chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos, chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos, chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II, cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide, cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium, clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl, clopyralid-olamine, clopyralid-potassium, clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet, cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel, clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA, codlelure, colophonate, copper acetate, copper acetoarsenite, copper arsenate, copper carbonate, basic, copper hydroxide, copper naphthenate, copper oleate, copper oxychloride, copper silicate, copper sulfate, copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure, cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide, cyclethrin, cycloate, cycloheximide, cycloprate, cycloprothrin, cyclosulfamuron, cycloxaprid, cycloxydim, cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat chloride, cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromid, cyprosulfamide, cyromazine, cythioate, daimuron, dalapon, dalapon-calcium, dalapon-magnesium, dalapon-sodium, daminozide, dayoutong, dazomet, dazomet-sodium, DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, desmedipham, desmetryn, d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos, diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate, dicamba, dicamba-diglycolamine, dicamba-dimethylammonium, dicamba-diolamine, dicamba-isopropylammonium, dicamba-methyl, dicamba-olamine, dicamba-potassium, dicamba-sodium, dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl, dichlormate, dichlormid, dichlorophen, dichlorprop, dichlorprop-2-ethylhexyl, dichlorprop-butotyl, dichlorprop-dimethylammonium, dichlorprop-ethylammonium, dichlorprop-isoctyl, dichlorprop-methyl, dichlorprop-P, dichlorprop-P-2-ethylhexyl, dichlorprop-P-dimethylammonium, dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine, diclomezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl, dicrotophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl, diethatyl-ethyl, diethofencarb, dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin, diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium, diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin, dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate, dimethylvinphos, dimetilan, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole, diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb acetate, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium, dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, diphacinone, diphacinone-sodium, diphenamid, diphenyl sulfone, diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquat dibromide, disparlure, disul, disulfiram, disulfoton, disul-sodium, ditalimfos, dithianon, dithicrofos, dithioether, dithiopyr, diuron, d-limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium, dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicin hydrochloride, dodicin-sodium, dodine, dofenapyn, dominicalure, doramectin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothal, endothal-diammonium, endothal-dipotassium, endothal-disodium, endothion, endrin, enestroburin, EPN, epocholeone, epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdépalléthrine, esfenvalerate, esprocarb, etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol, ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen, ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl α-naphthaleneacetate, ethyl-DDD, ethylene, ethylene dibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercury bromide, ethylmercury chloride, ethylmercury phosphate, etinofen, etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole, fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos, fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobucarb, fenoprop, fenoprop-3-butoxypropyl, fenoprop-butometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl, fenoprop-methyl, fenoprop-potassium, fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazon, fenridazon-potassium, fenridazon-propyl, fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop-ethyl, fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride, fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA, fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil, flamprop, flamprop-isopropyl, flamprop-M, flamprop-methyl, flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, flocoumafen, flometoquin, flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl, fluazifop-P, fluazifop-P-butyl, fluazinam, fluazolate, fluazuron, flubendiamide, flubenzimine, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph, fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid, fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate, flupropanate-sodium, flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl, flupyrsulfuron-methyl-sodium, fluquinconazole, flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone, flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide, fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldehyde, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl, fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling, fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr, furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin, furfural, furilazole, furmecyclox, furophanate, furyloxyfen, gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, gibberellins, gliftor, glufosinate, glufosinate-ammonium, glufosinate-P, glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime, glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium, glyphosate-isopropylammonium, glyphosate-monoammonium, glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium, glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatine acetates, halacrinate, halfenprox, halofenozide, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl, haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide, hydroprene, hymexazol, hyquincarb, IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalil sulfate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic, imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin, imazaquin-ammonium, imazaquin-methyl, imazaquin-sodium, imazethapyr, imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, iminoctadine, iminoctadine triacetate, iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan, indaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane, iodosulfuron, iodosulfuron-methyl, iodosulfuron-methyl-sodium, iofensulfuron, iofensulfuron-sodium, ioxynil, ioxynil octanoate, ioxynil-lithium, ioxynil-sodium, ipazine, ipconazole, ipfencarbazone, iprobenfos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, isamidofos, isazofos, isobenzan, isocarbamid, isocarbophos, isocil, isodrin, isofenphos, isofenphos-methyl, isolan, isomethiozin, isonoruron, isopolinate, isoprocarb, isopropalin, isoprothiolane, isoproturon, isopyrazam, isopyrimol, isothioate, isotianil, isouron, isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos, japonilure, japothrins, jasmolin I, jasmolin II, jasmonic acid, jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kadethrin, karbutilate, karetazan, karetazan-potassium, kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox, ketospiradox-potassium, kinetin, kinoprene, kresoxim-methyl, kuicaoxi, lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure, looplure, lufenuron, lvdingjunzhi, lvxiancaolin, lythidathion, MAA, malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper, mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA, MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium, MCPA-diolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl, MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl, MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil, mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl, mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl, mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium, mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform, medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr, mefenpyr-diethyl, mefluidide, mefluidide-diolamine, mefluidide-potassium, megatomoic acid, menazon, mepanipyrim, meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride, mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron, mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop, metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron, metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron, methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole, methfuroxam, methidathion, methiobencarb, methiocarb, methiopyrisulfuron, methiotepa, methiozolin, methiuron, methocrotophos, methometon, methomyl, methoprene, methoprotryne, methoquin-butyl, methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methyl apholate, methyl bromide, methyl eugenol, methyl iodide, methyl isothiocyanate, methylacetophos, methylchloroform, methyldymron, methylene chloride, methylmercury benzoate, methylmercury dicyandiamide, methylmercury pentachlorophenoxide, methylneodecanamide, metiram, metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb, metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone, metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos, mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, mipafox, mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron, monochloroacetic acid, monocrotophos, monolinuron, monosulfuron, monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquat dichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid, moxidectin, MSMA, muscalure, myclobutanil, myclozolin, N-(ethylmercury)-p-toluenesulphonanilide, nabam, naftalofos, naled, naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyacetic acids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin, neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine, nifluridide, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin, nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal-isopropyl, norbormide, norflurazon, nornicotine, noruron, novaluron, noviflumuron, nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace, omethoate, orbencarb, orfralure, ortho-dichlorobenzene, orthosulfamuron, oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil, oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon, oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone, oxine-copper, oxolinic acid, oxpoconazole, oxpoconazole fumarate, oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen, oxymatrine, oxytetracycline, oxytetracycline hydrochloride, paclobutrazol, paichongding, para-dichlorobenzene, parafluron, paraquat, paraquat dichloride, paraquat dimetilsulfate, parathion, parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid, penconazole, pencycuron, pendimethalin, penflufen, penfluron, penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin, pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, phenazine oxide, phenisopham, phenkapton, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercury derivative of pyrocatechol, phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim, phosalone, phosdiphen, phosfolan, phosfolan-methyl, phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram, picloram-2-ethylhexyl, picloram-isoctyl, picloram-methyl, picloram-olamine, picloram-potassium, picloram-triethylammonium, picloram-tris(2-hydroxypropyl)ammonium, picolinafen, picoxystrobin, pindone, pindone-sodium, pinoxaden, piperalin, piperonyl butoxide, piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide, piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl, pirimiphos-methyl, plifenate, polycarbamate, polyoxins, polyoxorim, polyoxorim-zinc, polythialan, potassium arsenite, potassium azide, potassium cyanate, potassium gibberellate, potassium naphthenate, potassium polysulfide, potassium thiocyanate, potassium α-naphthaleneacetate, pp′-DDT, prallethrin, precocene I, precocene II, precocene III, pretilachlor, primidophos, primisulfuron, primisulfuron-methyl, probenazole, prochloraz, prochloraz-manganese, proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol, profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl, prohexadione, prohexadione-calcium, prohydrojasmon, promacyl, promecarb, prometon, prometryn, promurit, propachlor, propamidine, propamidine dihydrochloride, propamocarb, propamocarb hydrochloride, propanil, propaphos, propaquizafop, propargite, proparthrin, propazine, propetamphos, propham, propiconazole, propineb, propisochlor, propoxur, propoxycarbazone, propoxycarbazone-sodium, propyl isome, propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarb hydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute, proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl, pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb, pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl, pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon, pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobac-sodium, pyrolan, pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl, quinazamid, quinclorac, quinconazole, quinmerac, quinoclamine, quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, quizalofop-P-tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide, rebemide, resmethrin, rhodethanil, rhodojaponin-III, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong, salicylanilide, sanguinarine, santonin, schradan, scilliroside, sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz, semiamitraz chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolin, siduron, siglure, silafluofen, silatrane, silica gel, silthiofam, simazine, simeconazole, simeton, simetryn, sintofen, SMA, S-metolachlor, sodium arsenite, sodium azide, sodium chlorate, sodium fluoride, sodium fluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodium orthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide, sodium thiocyanate, sodium α-naphthaleneacetate, sophamide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin sesquisulfate, strychnine, sulcatol, sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl fluoride, sulglycapin, sulprofos, sultropen, swep, tau-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonium, TCA-calcium, TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, tebuconazole, tebufenozide, tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron, tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim, terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton, terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane, tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin, tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate, thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid, thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone, thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl, thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam, thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole-copper, thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon, thionazin, thiophanate, thiophanate-methyl, thioquinox, thiosemicarbazide, thiosultap, thiosultap-diammonium, thiosultap-disodium, thiosultap-monosodium, thiotepa, thiram, thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid, tirpate, tolclofos-methyl, tolfenpyrad, tolylfluanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol, triadimefon, triadimenol, triafamone, tri-allate, triamiphos, triapenthenol, triarathene, triarimol, triasulfuron, triazamate, triazbutil, triaziflam, triazophos, triazoxide, tribenuron, tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamide, trichlorfon, trichlormetaphos-3, trichloronat, triclopyr, triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium, tricyclazole, tridemorph, tridiphane, trietazine, trifenmorph, trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium, triflumizole, triflumuron, trifluralin, triflusulfuron, triflusulfuron-methyl, trifop, trifop-methyl, trifopsime, triforine, trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac, trinexapac-ethyl, triprene, tripropindan, triptolide, tritac, triticonazole, tritosulfuron, trunc-call, uniconazole, uniconazole-P, urbacide, uredepa, valerate, validamycin, valifenalate, valone, vamidothion, vangard, vaniliprole, vernolate, vinclozolin, warfarin, warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan, xiwojunan, XMC, xylachlor, xylenols, xylylcarb, yishijing, zarilamid, zeatin, zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide, zinc thiazole, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong, α-chlorohydrin, α-ecdysone, α-multistriatin, and α-naphthaleneacetic acid.
  • 4. A composition according to claim 1 further comprising an agriculturally acceptable carrier.
  • 5. A composition according to claim 1 wherein said molecule is in the form of a pesticidally acceptable acid addition salt.
  • 6. A composition according to claim 1 wherein said molecule is in the form of a salt derivative.
  • 7. A composition according to claim 1 wherein said molecule is in the form a hydrate.
  • 8. A composition according to claim 1 wherein said molecule is in the form an ester derivative.
  • 9. A composition according to claim 1 wherein said molecule is in the form a crystal polymorph.
  • 10. A composition according to claim 1 wherein said molecule has a 2H in place of 1H.
  • 11. A composition according to claim 1 wherein said molecule has a 14C in place of a 12C.
  • 12. A composition according to claim 1 further comprising a biopesticide.
  • 13. A composition according to claim 1 further comprising one or more of the following compounds: (a) 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one;(b) 3-(4′-chloro-2,4-dimethyl[1,1′-biphenyl]-3-yl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-one;(c) 4-[[(6-chloro-3-pyridinyl)methyl]methylamino]-2(5H)-furanone;(d) 4-[[(6-chloro-3-pyridinyl)methyl]cyclopropylamino]-2(5H)-furanone;(e) 3-chloro-N2-[(1S)-1-methyl-2-(methylsulfonyl)ethyl]-N1-[2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxamide;(f) 2-cyano-N-ethyl-4-fluoro-3-methoxy-benenesulfonamide;(g) 2-cyano-N-ethyl-3-methoxy-benzenesulfonamide;(h) 2-cyano-3-difluoromethoxy-N-ethyl-4-fluoro-benzenesulfonamide;(i) 2-cyano-3-fluoromethoxy-N-ethyl-benzenesulfonamide;(j) 2-cyano-6-fluoro-3-methoxy-N,N-dimethyl-benzenesulfonamide;(k) 2-cyano-N-ethyl-6-fluoro-3-methoxy-N-methyl-benzenesulfonamide;(l) 2-cyano-3-difluoromethoxy-N,N-dimethylbenzenesulfon-amide;(m) 3-(difluoromethyl)-N-[2-(3,3-dimethylbutyl)phenyl]-1-methyl-1H-pyrazole-4-carboxamide;(n) N-ethyl-2,2-dimethylpropionamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl) hydrazone;(o) N-ethyl-2,2-dichloro-1-methylcyclopropane-carboxamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl) hydrazone nicotine;(p) O-{(E-)-[2-(4-chloro-phenyl)-2-cyano-1-(2-trifluoromethylphenyl)-vinyl]} S-methyl thiocarbonate;(q) (E)-N1-[(2-chloro-1,3-thiazol-5-ylmethyl)]-N2-cyano-N1-methylacetamidine;(r) 1-(6-chloropyridin-3-ylmethyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydro-imidazo[1,2-a]pyridin-5-ol;(s) 4-[4-chlorophenyl-(2-butylidine-hydrazono)methyl)]phenyl mesylate; and(t) N-Ethyl-2,2-dichloro-1-methylcyclopropanecarboxamide-2-(2,6-dichloro-alpha,alpha,alpha-trifluoro-p-tolyl)hydrazone.
  • 14. A composition according to claim 1 further comprising a compound having one or more of the following modes of action: acetylcholinesterase inhibitor; sodium channel modulator; chitin biosynthesis inhibitor; GABA and glutamate-gated chloride channel antagonist; GABA and glutamate-gated chloride channel agonist; acetylcholine receptor agonist; acetylcholine receptor antagonist; MET I inhibitor; Mg-stimulated ATPase inhibitor; nicotinic acetylcholine receptor; Midgut membrane disrupter; oxidative phosphorylation disrupter, and ryanodine receptor (RyRs).
  • 15. A composition according to claim 1 further comprising a seed.
  • 16. A composition according to claim 1 further comprising a seed that has been genetically modified to express one or more specialized traits.
  • 17. A composition according to claim 1 wherein said composition is encapsulated inside, or placed on the surface of, a capsule.
  • 18. A composition according to claim 1 wherein said composition is encapsulated inside, or placed on the surface of, a capsule, wherein said capsule has a diameter of about 100-900 nanometers or about 10-900 microns.
  • 19. A process comprising applying a composition according to claim 1, to an area to control a pest, in an amount sufficient to control such pest.
  • 20. A process according to claim 19 wherein said pest is selected from beetles, earwigs, cockroaches, flies, aphids, scales, whiteflies, leafhoppers, ants, wasps, termites, moths, butterflies, lice, grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites, ticks, nematodes, and symphylans.
  • 21. A process according to claim 19 wherein said pest is from the Phyla Nematoda or Arthropoda.
  • 22. A process according to claim 19 wherein said pest is from the Subphyla Chelicerata, Myriapoda, or Hexapoda.
  • 23. A process according to claim 19 wherein said pest is from the Class of Arachnida, Symphyla, or Insecta.
  • 24. A process according to claim 19 wherein said pest is from the Order Anoplura, Order Coleoptera, Order Dermaptera, Order Blattaria, Order Diptera, Order Hemiptera, Order Hymenoptera, Order Isoptera, Order Lepidoptera, Order Mallophaga, Order Orthoptera, Order Siphonaptera, Order Thysanoptera, Order Thysanura, Order Acarina, or Order Symphyla.
  • 25. A process according to claim 19 wherein said pest is BAW, CEW, or GPA.
  • 26. A process according to claim 19 wherein said amount is from about 0.01 grams per hectare to about 5000 grams per hectare.
  • 27. A process according to claim 19 wherein said amount is from about 0.1 grams per hectare to about 500 grams per hectare.
  • 28. A process according to claim 19 wherein said amount is from about 1 gram per hectare to about 50 grams per hectare.
  • 29. A process according to claim 19 wherein said area is an area where apples, corn, cotton, soybeans, canola, wheat, rice, sorghum, barley, oats, potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes, peppers, crucifers, pears, tobacco, almonds, sugar beets, or beans, are growing, or the seeds thereof are going to be planted.
  • 30. A process according to claim 19 further comprising applying said composition to a genetically modified plant that has been genetically modified to express one or more specialized traits.
  • 31. A process according to claim 1 where said composition further comprise ammonium sulfate.
  • 32. A process comprising: orally administering; or topically applying; a composition according to claim 1, to a non-human animal, to control endoparasites, ectoparasites, or both.
  • 33. A process comprising applying a composition according to claim 1 to a plant to enhance the plant's health, yield, vigor, quality, or tolerance, at a time when pest activity is low.
CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of, and claims the benefit of, U.S. patent application Ser. No. 14/930,790, now allowed, which was filed on Nov. 3, 2015, which is a continuation of, and claims the benefit of, U.S. patent application Ser. No. 14/132,871, now U.S. Pat. No. 9,210,927, which was filed on Dec. 18, 2013, which claims the benefit of, and priority from, U.S. Provisional Patent Application Ser. No. 61/739,045 filed Dec. 19, 2012. The entire disclosures of each of these applications is expressly incorporated herein by reference.

Provisional Applications (1)
Number Date Country
61739045 Dec 2012 US
Continuations (2)
Number Date Country
Parent 14930790 Nov 2015 US
Child 15439241 US
Parent 14132871 Dec 2013 US
Child 14930790 US