Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([NH:29]C(OCC2C3CC4C(=CC=CC=4)C=3C=CC=2)=O)=[C:6]([CH:28]=1)[C:7]([C:9]1[CH:27]=[CH:26][C:12](OCC2C=CC(OCC(O)=O)=CC=2)=[CH:11][CH:10]=1)=[O:8].O.OC1C2N=NNC=2C=CC=1.C(N=C=NC(C)C)(C)C.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CN(C=O)C>[NH2:29][C:5]1[CH:4]=[CH:3][CH:2]=[CH:28][C:6]=1[C:7]([C:9]1[CH:27]=[CH:26][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(O)COc1ccc(COc2ccc(C(=O)c3cc(Cl)ccc3NC(=O)OCc3cccc4c3Cc3ccccc3-4)cc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1C(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a 30 mL peptide reaction flask was added 4-(4-(5-chloro-2-fluorenylmethoxycarbonylamino-benzoyl)-phenoxymethyl)phenoxyacetic acid (1.52 g, 2.4 mmol, 2.0 equivalents), aminomethyl resin (1.99 g, 1.19 mmol of 1% crosslinked divinylbenzene-styrene, 100 mesh size, substitution level 0.60 milliequivalents/g), and hydroxybenzotriazole monohydrate (0.808 g, 5.28 mmol, 4.4 equivalents). Anhydrous DMF (12 mL) was added to the flask and the mixture was vortexed for 0.5 hour to fully solvate the resin. Diisopropylcarbodiimide (808 mg, 5.28 mmol, 4.4 equivalents) was added by syringe. The reaction flask was stoppered and then vortexed for 24 hours at which point the ninhydrin test on approximately 10 mg of the solid support demonstrated that coupling was complete. The solvent and reagents were filtered away from the solid support and the support was rinsed five times with 20 mL DMF and five times with 20 mL CH2Cl2 (for each rinse the mixture was vortexed for at least 30 seconds before filtering off the solvent) and then dried in vacuo for 12 hours.
Reaction SMILES: [F:1][C@H:2]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=CC=CC=3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1.CO.[H][H]>O1CCCC1>[F:1][C@H:2]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:8][CH:7]=1
Reactant: CCCC[C@@H](F)CCOc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC[C@@H](F)CCOc1cnc(-c2ccc(O)cc2)nc1
Reaction time: 6 h
Yield: 102 %

Procedure:
A mixture of 1.41 g of 5-[3-(R)-fluoroheptyloxy]-2-(4-benzyloxyphenyl)pyrimidine, 0.22 g of 10palladium-on-carbon, 14 ml of methanol, and 14 ml of tetrahydrofuran (THF) was kept at 30° C., and hydrogen gas was blown thereinto over 6 hours with stirring. The catalyst was removed by filtration, and the solvent was removed by distillation to obtain 1.11 g of 5-[3-(R)-fluoroheptyloxy]-2-(4-hydroxyphenyl)pyrimidine.
Reaction SMILES: [OH2:1].C.[Se](=O)=O.[C:6]([C:9]1[CH:10]=[C:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[CH3:7].[O:25]1CCO[CH2:27][CH2:26]1>>[CH2:26]([O:25][CH:7]([OH:1])[C:6]([C:9]1[CH:10]=[C:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)=[O:8])[CH3:27]
Reactant: CC(=O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Reactant: O
Reactant: C1COCCO1
Agent: O=[Se]=O
Product: CCOC(O)C(=O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
1 ml of water, 1 g activated charcoal and 2.66 g (24 mmol) selenium dioxide are added to a solution of 1.65 g (6 mmol) N-(3-acetyl-phenyl)-benzenesulphonamide in 10 ml dioxane. The reaction mixture is stirred for 4 days at 80° C. and then concentrated by evaporation in the rotary evaporator. The residue is dissolved in 30 ml of ethanol and refluxed for 4 hours. Then the reaction mixture is concentrated by evaporation in the rotary evaporator. The residue is dissolved in 100 ml of ethyl acetate, washed several times with 30 ml saturated, aqueous sodium hydrogen carbonate solution, dried on sodium sulphate and again concentrated by evaporation in the rotary evaporator. The crude product thus obtained as a yellow solid is reacted further without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[C:24]#[N:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[BH4-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][NH2:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C#N)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2′-cyano-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.545 g, 1.5 mmol) and cobalt(Π) chloride hexahydrate (0.71 g, 3.0 mmol) in MeOH (60 mL) and THF (24 mL) was added sodium borohydride (0.58 g, 15.3 mmol), and the reaction was stirred at room temperature for 2 hours. 2N Aqueous HCl (67 mL) was added, and the mixture was concentrated. 2N Aqueous NH4OH was added until the solution was basic, and the mixture was extracted twice with CH2Cl2. The combined organic layers were washed three times with H2O, dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: C[C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5]C=1CO.[H-].[Na+].[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26](CBr)[CH:25]=1.[CH2:33]1[CH2:37][O:36][CH2:35][CH2:34]1>CCOCC>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:25]=[CH:26][C:27]([CH:35]([C:34]2[S:5][CH:4]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=3)[N:3]([CH3:2])[CH:33]=2)[O:36][CH3:37])=[CH:28][CH:29]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)c1ccc(C(OC)C2=CN(C)C(c3ccc(C(F)(F)F)cc3)S2)cc1
Reaction time: 0.08 h

Procedure:
Cool (0° C.) a solution of 2-([4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl)-methanol (450 mg, 1.64 mmol) in THF and add NaH (70 mg, 50% dispersion in mineral oil, 1.75 mmol). Stir the resulting mixture for 5 min. Remove the cold bath and continue stirring for 1 hr. To this mixture add 3-(bromomethyl)-benzoic acid methyl ester (450 mg, 1.95 mmol). Stir the resulting mixture for 3 hr then quench the reaction with sat. NH4Cl solution. Dilute the mixture with ether, wash with brine, dry over MgSO4 and concentrate under vacuum. Purify the residue by flash chromatography (eluting with 30% ethyl acetate in heptane) to give the title compound (181 mg) as an oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)[C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:40]2[CH:45]=[CH:44][C:43]([S:7]([CH3:1])(=[O:9])=[O:8])=[CH:42][CH:41]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 94.6 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (prepared as in Example 67, 0.5 g, 0.93 mmol), 4-(trifluoromethyl)phenylboronic acid (0.56 g, 2.8 mmol) and dichlorobis(triphenylphosphine)palladium (II) (63 mg, 0.09 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 1.4 mL). The resulting mixture was subjected to microwave irradiation for 4 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.23 g, 47%) as a white solid.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1.[CH3:16][C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1>C(O)(CC)(C)C>[OH:1][C@@H:2]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1)[CH2:3][N:22]1[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C@@H:17]1[CH3:16]
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCC(C)(C)O
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)ccc2s1
Temperature: 100 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
To a solution of 5-(((R)-oxiran-2-yl)methoxy)-2-methylbenzo[d]thiazole (3.24 g, 14.6 mmol) in tert-amyl alcohol (50 ml) was added (S)-tert-butyl 3-methylpiperazine-1-carboxylate (2.67 g, 13.3 mmol). The resulting mixture was stirred at 100° C. for 16 hours. It was then cooled, concentrated, and purified by chromatography (1:20 MeOH:CH2Cl2) to yield tert-butyl 4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](3S)-3-methylpiperazinecarboxylate (4.8 g, 11.4 mmol).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([C:18]([CH:20]2[CH2:22][CH2:21]2)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:23]([NH2:26])[CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH:20]1([CH:18]([NH:26][CH2:23][CH2:24][CH3:25])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][CH2:21]1
Reactant: O=C(c1ccccc1)C1CC1
Reactant: CCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCNC(c1ccccc1)C1CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
4 Å molecular sieves and 100 mg of para-toluenesulphonic acid are added to 10 g of cyclopropyl phenyl ketone in 60 ml of anhydrous toluene, followed by 6 g of propylamine. Imine formation is monitored by gas chromatographic assay. After heating for 6 hours at 55° C., the reaction mixture is cooled, the molecular sieves are filtered off and the solution is evaporated to dryness under vacuum. The residue is taken up in 100 ml of anhydrous ethanol. The solution is cooled to 0° C. and 2.65 g of sodium borohydride are added portionwise. After stirring overnight at room temperature, the mixture is evaporated to dryness under vacuum and the residue is taken up in water, hydrolysed with 1N hydrochloric acid in order to bring the pH to 2, and washed with ethyl acetate. The pH is brought to 9 by addition of 2N sodium hydroxide and the mixture is then extracted several times with methylene chloride.
Reaction SMILES: C(OC(=O)C)(=O)C.[O:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:12]=2[O:11][CH2:10][CH2:9]1.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[N+:21]([C:16]1[CH:15]=[CH:14][C:13]2[O:8][CH2:9][CH2:10][O:11][C:12]=2[C:17]=1[C:18]([OH:20])=[O:19])([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc2c1OCCO2
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1c([N+](=O)[O-])ccc2c1OCCO2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1,600 ml of acetic acid, 1,600 ml of acetic anhydride, and 1000 g of 1,4-benzodioxane-5-carboxylic acid were introduced in a 6-liter balloon flask provided with an agitator and a thermometer. The mixture was heated to 40° C. and a solution of 400 ml of nitric acid in 400 ml of acetic acid was added. After the introduction, the mixture was stirred at 40°-45° C. for two hours and then cooled to 5° C. The precipitate was dried off, washed with 600 ml of acetic acid and then with water and dried at 40° C. 700 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid were collected, the structure of which was confirmed by nuclear magnetic resonance (M.P.: 246° C.). The mother liquors were diluted with 25 liters of water and the obtained precipitate was dried off, washed with water and dried. 6-nitro-1,4-benzodioxane-5-carboxylic acid was obtained (M.P.: 188° C.).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Br[C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1
Reactant: Cc1ccc(Br)nn1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1H-pyrazol-1-yl)phenyl)methanone and 3-bromo-6-methylpyridazine. MS (ESI) 405 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Reactant: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3ccccc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-methoxy-2-methylaniline (40 mg, 0.290 mmol) similar to Example 77 and isolated as a tan oil (33 mg, 48%). 1H NMR (CDCl3): 8.46–8.42 (m, 2H), 7.50–7.46 (m, 3H), 7.22 (d, J=8.4 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.92 (s, 1H), 6.80 (dd, J=2.6, 8.6 Hz, 1H), 6.61 (s, 1H), 3.81 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([Si:15]([CH3:22])([CH3:21])[O:16][CH2:17][CH2:18][CH2:19]O)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[CH2:30]([O:32][C:33]([CH:35]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:34])[CH3:31]>ClCCl>[Si:15]([O:16][CH2:17][CH2:18][CH:19]=[CH:35][C:33]([O:32][CH2:30][CH3:31])=[O:34])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C=CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl sulphoxide (1.9 ml, 26.8 mmol) was added to a cooled (−78° C.) solution of oxalyl chloride (2.16 ml, 24.7 mmol) in dichloromethane (100 ml), and after 10 minutes, a solution of 3-(tert-butyl-dimethyl-silanyloxy)-propan-1-ol (3 g, 15.8 mmol) in dichloromethane (25 ml) was added dropwise. Once addition was complete, the solution was stirred for a further 15 minutes. Triethylamine (8 ml, 57.5 mmol) was added, followed by dropwise addition of a solution of (ethoxycarbonylmethylene)triphenylphosphorane (10 g, 29.9 mmol) in dichloromethane (50 ml), and the reaction mixture allowed to warm to room temperature. The mixture was washed with water (4×), dried (MgSO4) and concentrated under reduced pressure. The residue was pre-adsorbed onto silica gel and purified by column chromatography using diethyl ether:pentane (2.5:97.5) as eluant to afford the title compound, 1.3 g; 1H NMR (CDCl3, 400 MHz) δ: 0.02 (s, 6H), 0.87 (s, 9H), 1.26 (t, 3H), 2.40 (m, 2H), 3.74 (t, 2H), 4.18 (q, 2H), 5.84 (d, 1H), 6.95 (m, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19](Cl)(=O)[CH:20]=C.[CH2:24]([NH2:27])[CH:25]=[CH2:26]>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([NH:27][CH2:24][CH:25]=[CH2:26])=[O:18])(=[O:7])[CH:19]=[CH2:20]
Reactant: C=CCN
Reactant: C=CC(=O)Cl
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCNC(=O)[C@@H]1CC(=NOC)CN1C(=O)C=C

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, acryloyl chloride, and allylamine the title compound was obtained in 81% purity by LC/MS. MS(ESI+): m/z=252.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:24][CH2:23]4)[C:12]([C:35]([F:38])([F:37])[F:36])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].O.[Li+].[OH-]>C1COCC1.CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([OH:32])=[O:31])[CH2:24][CH2:23]4)[C:12]([C:35]([F:38])([F:36])[F:37])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(-c2ccc(C(F)(F)F)c(NCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 107 %

Procedure:
To a solution of ethyl [(1S)-5-(3-{[6-(4-ethylphenyl)-3-(trifluoromethyl)-2-pyridinyl]amino}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 317, 0.07 9, 0.09 mmol) in THF (2 mL), methanol (1 mL), and water (1 mL) was added LiOH (0.03 9, 1.37 mmol). The mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The residue was taken up in water and acidified to pH ˜5 using H3PO4 (a 5% aqueous solution). The aqueous solution was then extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the product (0.048 g, 71%). 1H NMR (400 MHz, CD2Cl2) δ 7.99 (d, 2H), 7.71 (d, 1H), 7.29 (d, 2H), 7.09 (dd, 2H), 6.81 (d, 1H), 6.73 (dd, 1H), 5.41 (b, 1H), 4.11 (t, 2H), 3.84 (q, 2H), 3.53 (qt, 1H), 2.95-2.70 (m, 5H), 2.52-2.38 (m, 2H), 2.20 (qt, 2H), 1.82-1.75 (m, 1H), 1.29 (m, 3H); LC-MS: RT=4.10 min, (M+H)+ 499.3.
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([O:22]CC)=[O:21])[NH:8]2)=[CH:4][CH:3]=1.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([OH:22])=[O:21])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(C)c(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2cc(C(=O)O)[nH]c2c1NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88 %

Procedure:
To a mixed solution of ethyl 6-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.48 g) in tetrahydrofuran (10 mL)-methanol (10 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.35 g), and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (390 mg, yield 88%) as pale-yellow prism crystals. melting point>280° C. (decomposition).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:18]1[CH:26]2[CH:21]([CH2:22][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:25]2)[CH2:20][NH:19]1.COCCO.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[NH2:8][C:6]1[N:7]=[C:2]([N:19]2[CH2:18][CH:26]3[CH:21]([CH2:22][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:25]3)[CH2:20]2)[C:3]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]=2[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC2C1
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2CN(c3nc(N)nc4c3CCCc3ccccc3-4)CC2C1
Temperature: 115 °C

Procedure:
The product from Example 68A (40 mg, 0.16 mmol) was mixed with tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (55 mg, 0.24 mmol) and to this was added 2-methoxyethanol (0.65 mL), and N,N-diisopropylethylamine (0.20 mL, 1.2 mmol); the reaction was heated at 115° C. for 16 hours, cooled, diluted with CH2Cl2 (25 mL) and washed with 1 M NaOH (10 mL). The aqueous layer was extracted with CH2Cl2 (15 mL). The combined organics were dried (MgSO4), filtered, concentrated and chromatographed and eluted with a gradient of 1:0 to 0:1 CH2Cl2:EtOAc to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17]C)[CH:16]=1)[C:5]([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[O:6].B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([OH:17])[CH:16]=1)[C:5]([N:7]([CH:8]([CH3:9])[CH3:10])[CH:11]([CH3:12])[CH3:13])=[O:6]
Reactant: COc1cc(Cl)cc(C(=O)N(C(C)C)C(C)C)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(C)N(C(=O)c1cc(O)cc(Cl)c1)C(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 79.8 %

Procedure:
To a stirred solution of 3-chloro-N,N-diisopropyl-5-methoxy-benzamide (2.96 g) in anhydrous dichloromethane (30 ml) at −78° C. was added boron tribromide solution in dichloromethane (40 ml). The reaction mixture was allowed to warm to ambient temperature and stirred for 19 h. The reaction mixture was cooled to −78° C. and methanol (20 ml) added. The reaction mixture was allowed to warm back to ambient temperature, stirred for 24 h, and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with water and dried with brine and over sodium sulphate. The crude product was purified by flash column chromatography, eluting with cyclohexane:ethyl acetate (1:1), to give the title compound as a white solid (2.24 g).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1)[CH3:26]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[C@H:27]([CH2:25][CH3:26])[CH2:31][O:30][C:29]4=[O:32])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: CC[C@@H]1COC(=O)N1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cn1
Yield: 61.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 31 and using (6-bromopyridin-3-yl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (2 g) described in Preparation Example 23 and (R)-4-ethyloxazolidin-2-one (300 mg) described in Preparation Example 26, the title compound (710 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].Cl[CH:20]([CH:24]([CH3:26])[CH3:25])[C:21](O)=[O:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:18]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:21](=[O:22])[CH:20]([CH:24]([CH3:26])[CH3:25])[S:13]1
Reactant: CC(C)CN
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)C(Cl)C(=O)O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(C(C)C)C(=O)N1CC(C)C

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with isobutylamine followed by 2-chloro-3-methylbutanoic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5-isopropyl-1,3-thiazolidin-4-one.