Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]#[N:19])=[C:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:20][C:21]1[CH:29]=[C:28]([C:30]([F:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])[CH:27]=[C:26]([CH3:40])[C:22]=1[C:23](Cl)=[O:24]>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[C:18]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:24])[C:22]2[C:21]([CH3:20])=[CH:29][C:28]([C:30]([F:39])([C:31]([F:32])([F:33])[F:34])[C:35]([F:36])([F:37])[F:38])=[CH:27][C:26]=2[CH3:40])=[CH:7][C:6]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)#[N:19]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)Cl
Reactant: N#Cc1ccc(N)cc1NC(=O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)Nc1ccc(C#N)c(NC(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.2 %

Procedure:
To a solution of N-(5-amino-2-cyano-phenyl)-4-fluoro-benzamide (0.20 g, 0.78 mmol) (Example I9) in anhydrous tetrahydrofuran (2.5 ml) under an atmosphere of nitrogen was added at room temperature a solution of 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzoyl chloride (0.332 g, 1.04 mmol) (Example I4) in anhydrous tetrahydrofuran (2.5 ml). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate (saturated). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to give N-[4-cyano-3-(4-fluoro-benzoylamino)-phenyl]-2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzamide (131 mg, 66% yield). 1H-NMR (CDCl3, 400 MHz): 8.98 (s, 1H), 8.51 (d, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.21 (dd, 1H), 7.84 (m, 2H), 7.68 (d, 1H), 7.34 (s, 1H), 6.78 (t, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH:4]([CH:5](OC(=O)C)[C:6](Cl)([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)=[O:18]>CN(C=O)C.[Zn]>[CH3:1][C:2]1([CH3:34])[CH:4]([CH:5]=[C:6]([Cl:11])[C:7]([F:9])([F:10])[F:8])[CH:3]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:18]
Reactant: CC(=O)OC(C1C(C(=O)OCc2cccc(Oc3ccccc3)c2)C1(C)C)C(Cl)(Cl)C(F)(F)F
Agent: [Zn]
Solvent: CN(C)C=O
Product: CC1(C)C(C=C(Cl)C(F)(F)F)C1C(=O)OCc1cccc(Oc2ccccc2)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
To a solution of 260 mg (0.501 mmol) of (3-phenoxyphenyl)methyl 2,2-dimethyl-3-(1-acetoxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 13, in 1 ml of DMF, 35 mg (0.521 mmol) of zinc powder was added, and the mixture was stirred at 60° C. for 6 hours. The subsequent operation was conducted in the same manner as in Reference Example 9, whereby 157 mg of (3-phenoxyphenyl)methyl 2,2-dimethyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)cyclopropanecarboxylate was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].N1CCCC1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1/[CH:12]=[CH:15]/[N:16]([CH3:18])[CH3:17]
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (5.0 g, 21.37 mmol) in N,N-dimethylformamide (50 mL) was added N,N-dimethylformamide dimethyl acetal (8.58 mL, 64.1 mmol) and pyrrolidine(1.767 mL, 21.37 mmol). The reaction mixture was heated at 110° C. for 4 hours. After cooling to room temperature, the N,N-dimethylformamide was removed by evaporation. The residue was taken up in diethyl ether and water. After separation of the organic layer, the aqueous layer was re-extracted with diethyl ether. The combined organic layers were dried over magnesium sulphate, filtered and concentrated to give a red/brown oil which was used directly in the following reaction without purification.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][CH:7]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([Si:5]([CH3:17])([CH3:16])[O:6][CH:7]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(O)CCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCCC(=O)CCC1
Temperature: 25 °C

Procedure:
Tetrapropylammonium perruthenate (0.82 g, 2.43 mmol) was added to a stirred and cooled (0° C.) solution of Example 5A (12.11 g, 46.90 mmol), 4-methylmorpholine N-oxide (8.24 g, 70.35 mmol), and 4 Å molecular sieves (23 g) in dry dichloromethane (120 mL). After the addition, the mixture was warmed to room temperature and stirred for another three hours. The black mixture was filtered through a pad of Celite and the solvent was evaporated. The residue was purified over silica gel using 5-50% ethyl acetate in hexanes to give the title compound as an oil.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[CH3:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH:18]=[N+:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CC1C=C(C=CC=1)C=O.N1CCCCC1>>[N:19]1([CH:18]([C:17]2[CH:16]=[C:15]([CH3:14])[CH:27]=[CH:26][CH:25]=2)[C:5]2[N:1]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH2:12])[CH:2]=[CH:3][CH:4]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccccc1-n1cccc1
Reactant: Cc1cccc(C=[N+]2CCCCC2)c1
Agent: Cc1cccc(C=O)c1
Agent: [Cl-]
Solvent: C1CCNCC1
Product: Cc1cccc(C(c2cccn2-c2ccccc2N)N2CCCCC2)c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-phenylamine and 1-(3-methyl-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 3 from 3-methylbenzaldehyde and piperidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH2:9][CH3:10]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH3:10]
Reactant: CCC(O)c1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=Cc1ccccc1Br

Procedure:
With the exception of three compounds, the styrene compounds herein utilized for preparing the α-chloro oximes are known and their preparations are published in the prior art. The compounds not previously known are synthesized following well-known published procedures. Thus, 2-bromobenzaldehyde is allowed to react with a Grignard reagent, ethyl magnesium bromide in anhydrous ether, to yield 1-(2-bromophenyl)propanol. This propanol derivative is then dehydrated by refluxing it in toluene in the presence of p-toluenesulfonic acid catalyst to yield the desired 1-bromo-2-(1-propenyl)benzene. Another previously unknown substituted styrene, namely, 1,2-dichloro-4-(1-propenyl)benzene is prepared by the same general procedure from 3,4-dichlorobenzaldehyde and ethyl magnesium bromide, followed by dehydration of the intermediate substituted propanol.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]=1[CH:4]=[N:5]O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]=1[C:4]#[N:5])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(O)c(C=NO)c1
Product: COC(=O)c1ccc(OC(C)=O)c(C#N)c1

Procedure:
70.3 g (0.36 mol) of the compound from Example XXXVII are stirred under reflux in 0.5 l of acetic anhydride for 1.5 hours. The mixture is concentrated to dryness, the residue is dissolved in methylene chloride and the title compound is crystallised out by addition of petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([O:23][CH3:24])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][C:8]=1[O:21][CH3:22])O.S(Cl)(C)(=O)=O>CN(C1C=CN=CC=1)C.ClCCl.CCOCC.CO>[CH3:1][O:2][C:3](=[O:25])[CH:4]([O:23][CH3:24])[CH2:5][C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:15])[CH3:16])=[CH:9][C:8]=1[O:21][CH3:22]
Reactant: COC(=O)C(OC)C(O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1OC)OC
Temperature: 0 °C

Procedure:
A mixture of 3-[4-(tert-Butyl-dimethyl-silanyloxy)-2-methoxy-phenyl]-3-hydroxy-2-methoxy-propionic acid methyl ester (1 eq), Mesylchloride (1 eq) triethylamine (4 eq) and a catalytic amount of DMAP (0.1 eq) in dichloromethane was stirred at room temperature over night. The reaction mixture was diluted with ether and washed with HCl 1N. Dried and concentrated in vacuo to give a residue which was chromatographed in silica gel to yield a compound which was dissolved in methanol was treated with Mg (20 eq) and stirred until gas evolution was observed. Cooled to 0° C. and stirred for 4 hours. The solvent was removed and the residue reconstituted in ether washed with HCl 1N and brine and concentrated to give the title product.
Reaction SMILES: [C:1]([C:3](=[C:11]1[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][NH:12]1)C(OC(C)(C)C)=O)#[N:2].O1CCOCC1>Cl>[F:20][C:17]([F:18])([F:19])[C:15]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:3][C:1]#[N:2])[N:16]=1
Reactant: CC(C)(C)OC(=O)C(C#N)=C1N=C(C(F)(F)F)C=CN1
Agent: Cl
Solvent: C1COCCO1
Product: N#CCc1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.8 %

Procedure:
tert-Butyl 2-cyanoacetate (97.45 g, 690 mmol) was dissolved in anhydrous THF (1 L), and cooled on an ice-bath for 90 min with stirring under nitrogen. A 1M solution of lithium hexamethyldisilazane in THF (690 mL, 690 mmol) was added dropwise. The mixture was stirred for an additional 1 hr, then 2-chloro-4-trifluoromethylpyrimidin (105 g, 590 mmol) was added dropwise. The mixture was then heated to 50° C. for 3 hr with stirring under nitrogen, allowed to cool, and the solvent removed under reduced pressure. Hydrochloric acid (1N) was added to the residue to achieve a pH of 1-2. The precipitated solids were collected by filtration and dried under vacuum to give tert-butyl 2-cyano-2-[4-trifluoromethylpyrimidin-2(1H)-ylidene]acetate (135 g, 82% yield) as a bright yellow solid, >98% pure by LC/MS. tert-Butyl 2-cyano-2-[4-trifluoromethylpyrimidin-2(1H)-ylidene]acetate (48 g; 166 mmol) was suspended in 4M hydrogen chloride in dioxane (415 mL, 1.66 mol) and the mixture stirred at room temperature for 6 hr, then concentrated under reduced pressure to give 2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (31 g, 100% yield) as an orange oil, >98% pure by LC/MS. To a stirred solution of 2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (31.0 g; 166 mmol) in absolute ethanol (800 mL) was added potassium O-ethylxanthate (26.6 g; 166 mmol) followed by potassium carbonate (45.8 g; 332 mmol). The mixture was heated to 100° C. for 3 hr, cooled to room temperature, iodomethane (47.1 g; 332 mmol) added dropwise, and 1N hydrochloric acid (2 L) added. The resulting mixture was extracted with DCM (1.5 L), and the DCM layer was washed twice with brine (1 L each). The solvent was removed under reduced pressure to give 3,3-bis(methylthio)-2-(4-trifluoromethylpyrimidin-2-yl)acrylonitrile (36 g, 75% yield) as a light brown solid, >95% pure by LC/MS.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][N:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Product: COc1ccc(C(=O)n2cc(C3=CCN(C)CC3)c3cccnc32)cc1

Procedure:
(16.4 mg, 41%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (24.8 mg, 0.12 mmol) and 4-methoxybenzoyl chloride (35 μL, 0.24 mmol); HRMS-FAB+ for C21H21N3O25 calculated MH+: 348.17120. Found: 348.16994.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1C=CC(S(O[CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)(=O)=O)=CC=1.O>CN(C)C=O>[CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(O)cc12
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(OC3CCOCC3)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 103 %

Procedure:
Cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methanone (5.2 g) synthesized in the above-mentioned (3) was dissolved in dimethylformamide (100 mL), and potassium phosphate (7.4 g) and tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (9.0 g) synthesized by the method of EP-A-1367058 were added to the mixture at room temperature, and the mixture was stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature, water (150 mL) was added and the mixture was extracted with diethyl ether (100 mL×2). The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10, volume ratio) to give the title object compound (7.1 g, 99%) as a pale-yellow solid.
Reaction SMILES: [C@@H:1]1([N:9]2[CH2:16][NH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:17](O)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CO>[C:17]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH2:16][NH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: NC1=NC(=O)N([C@H]2C[C@H](O)[C@@H](CO)O2)CN1
Reactant: CCCCCCCCCCCCCCCC(=O)O
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](N2CNC(N)=NC2=O)C[C@@H]1O
Yield: 107.6 %

Procedure:
To a solution of (9) (0.26 g, 1.13 mmol) in MeOH (50 mL) was added a solution of palmitic acid (0.29 g, 1.13 mmol) in hot MeOH (10 mL) and evaporated. The residue was triturated with ether and filtered giving 0.57 g (quantitative yield) of a colorless product with m.p. 123-124°. MS ES+ 231 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.C1N=C[N:30](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH2:30])=[O:23])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(N)=O)cn2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (70 mg, 0.192 mmol) in DMF (2 mL) was added CDI (38 mg, 0.231 mmol) and the resulting mixture stirred at 60° C. for 1 h. After cooling to room temperature ammonium hydroxide (300 μL, 1.92 mmol) was added and reaction mixture was stirred for 16 h and then evaporated. Purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (61 mg, 87%) as an off white solid. MS: m/e=364.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][CH:25]([CH:27]([OH:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][C:23]2=[O:35])=[CH:18][C:17]=1[F:36].[H-].[Na+].[CH3:39]I>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][CH:25]([CH:27]([O:34][CH3:39])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][C:23]2=[O:35])=[CH:18][C:17]=1[F:36]
Reactant: CI
Reactant: COc1cc2nccc(Oc3ccc(N4CC(C(O)c5ccccc5)CC4=O)cc3F)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(N4CC(C(OC)c5ccccc5)CC4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-4-(hydroxy(phenyl)methyl)pyrrolidin-2-one (Example 48, 0.1 g, 0.2 mmol) in THF/DMF (1 mL:1 mL) was added NaH (0.1 g, 2.5 mmol) solid. The reaction was stirred at RT for 1 h. MeI (0.1 mL, 1.6 mmol) was added via a syringe and the reaction was stirred for 1 h. The reaction was quenched with 10 mL of satd. NH4Cl solution and 10 mL of water. The solution was diluted with 50 mL of EtOAc. The organic phase was separated and was washed with 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The crude oil was purified by chromatography (10% EtOAc/hexanes to EtOAc) to give colorless film. MS (ESI pos. ion) m/z: 503.5 (M+H). Calc'd Exact Mass for C29H27FN2O5: 502.53.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[CH3:9][C:10]([CH:12]=[O:13])=O>C(O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[N:2]=[C:10]([CH3:9])[CH:12]=[O:13]
Reactant: CC(=O)C=O
Reactant: NNc1ccccn1
Solvent: CCO
Product: CC(C=O)=NN(c1ccccn1)c1ccccn1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
To 2-hydrazinopyridine (4.36 g, 40 mmol) was added slowly methyl glyoxal (40% aqueous, 3.99 g, 22 mmol) in ethyl alcohol (88 mL). The solution was refluxed for 17 hours and cooled to room temperature, The yellow product which separated was filtered, washed with ethyl alcohol and dried to give methyl glyoxal bis-(2-pyridyl) hydrazone 3.00 g (29%), mp. 196°-198° C. as the free base. The entire product was added to water and hydrogen chloride gas was bubbled through the solution until the solution was clear. The water was evaporated to give the hydrochloride salt, mp. 270°-270° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([C:10]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)=[O:11])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])=[CH:17][CH:18]=1
Reactant: O=C(CNC(=O)c1ccc(F)cc1)c1ccoc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)c1ccoc1
Yield: 69.8 %

Procedure:
8.5 g of N-(4-fluorobenzoyl)-(3-furylcarbonyl)methylamine, 1.6 g of 61% sodium hydride and 6.3 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 8.0 g of ethyl 3-(4-fluorobenzoylamino)-3-(3-furylcarbonyl)propionate are thereby obtained. Yield: 69.6%
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH2:38]([O:45][N:46]=[CH:47][CH:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:16]([N:49]1[CH2:50][CH2:51][C:47](=[N:46][O:45][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:48]1[CH3:52])=[O:18])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: C(=NOCc1ccccc1)C1CCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1C(=NOCc2ccccc2)CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The solution of boc-L-α-cyclohexylglycine (1.27 g, 4.92 mmole), 1-hydroxylbenzotriazole (0.99 g, 7.38 mmole), diisopropylethylamine (2.54 g, 19.68 mmole), and O-benzotriazole-N,N,N,N-tetramethyl-urounium hexafluorophosphate (2.80 g, 7.38 mmole) in dichloromethane (30 ml) is stirred for 15 minutes at room temperature. A solution of pyrrolidine-2-carbaldehyde-O-benzyl-oxime (˜1.00 g, 0.49 mmole) in dichloromethane is added. The reaction solution is stirred for three hours at room temperature and then quenched with saturated NaHCO3 aqueous., extracted with dichloromethane. The organic layer is combined, dried, and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; from 20% to 70% of ethyl acetate in hexane) to provide 1.81 g (83% over 2 steps) of the title compound. M+H+=444.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18].O>CC(C)=O>[CH2:18]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])[CH:17]=[CH2:16]
Reactant: Oc1ccc(F)cc1Br
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc(F)cc1Br
Yield: 100 %

Procedure:
To a mixture of 2-bromo-4-fluorophenol (9.75 g, 0.051 mol) and potassium carbonate (7.76 g, 0.056 mol) in acetone (125 mL) was added allyl bromide (4.64 mL, 0.054 mol) and the reaction mixture heated to reflux for 3.5 hours. The cooled reaction mixture was then poured into water and the resulting oily suspension extracted with dichloromethane (2×500 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 11.79 g (100%) of 1-(allyloxy)-2-bromo-4-fluorobenzene as a yellow oil. MS (ESI) m/z 229.9 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2([CH3:12])[O:16][CH2:15][CH2:14][O:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: OCCO
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc([N+](=O)[O-])c(Cl)c2)OCCO1
Yield: 106.5 %

Procedure:
A solution of 3'-chloro-4'-nitroacetophenone (3 g), ethylene glycol (9.3 g), and p-toluenesulfonic acid monohydrate (0.5 g) in toluene (30 ml) was refluxed for 6 hours. Water formed in the reaction was removed by means of Dean Stark apparatus. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated to give an oil of 2-(3-chloro-4-nitrophenyl)-2-methyl-1,3-dioxolane (3.9 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([Cl:18])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)c(C(F)(F)F)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cl)c(C(F)(F)F)n1
Reaction time: 1.5 h

Procedure:
A solution of 0.45 g of 6-methyl-2-trifluoromethylpyridin-3-ylcarboxyi ic acid in 20 ml of dichloromethane is charged initially, 3 drops of dimethylformamid c are added and the mixture is subsequently treated with 1.6 ml of oxalyl chloride. After the intensive evolution of gas has ceased, the mixture is kept at a bath temperature of 40° C. for another 1.5 hours and then evaporated. The crude product (0.56 g) that remains as residue can be directly reacted further. 1H NMR (CDCl3, ppm): 8.20 (1H,d); 7.51 (1H,d); 2.65 (3H, s).