Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH2:18][CH2:17][CH:16]([O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:15][C:14]=1[CH2:13][CH:12]=3)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO.ClCCl>[Si:24]([O:23][CH:16]1[CH2:17][CH2:18][C:19]2[C@@H:20]3[C:11]([C@H:8]4[C@@:6]([CH2:22][CH2:21]3)([CH3:7])[C@@H:5]([OH:4])[CH2:10][CH2:9]4)=[CH:12][CH2:13][C:14]=2[CH2:15]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)O[C@H]1CC[C@H]2C3=CCC4=C(CCC(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)C4)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](OC1CCC2=C(CC=C3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 65.3 %

Procedure:
To the acetates 11 (2.2 g, 4.0 mmol) in a mixture of methanol (60 mL) and dichloromethane (10 mL) was added potassium carbonate (0.1 eq, 55 mg, 0.4 mmol). After stirring for 4 h an additional portion of potassium carbonate (1.0 eq, 0.55 g, 4.0 mmol) was added. The mixture was stirred 16 h and more potassium carbonate (1.0 eq, 0.55 g, 4.0 mmol) was added. After 24 h water (100 mL) was added, the layers were separated and the aqueous layer was extracted with dichloromethane (3×100 mL). The organic layers were combined, washed with saturated aqueous NaCl solution (100 mL), dried over magnesium sulfate and concentrated under reduced pressure to give an oil that was purified by flash column chromatography on silica gel eluting with 20% EtOAc/hexane to give the alcohols 12 (1.34 g), Rf0.5 (30% EtOAc/hexane), as a white foam which was used directly.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:54])([CH3:53])[CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH:21]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:22]2)=[N:17]1>O.C(OCC)(=O)C>[OH:13][C:14]([CH3:53])([CH3:54])[CH2:15][N:16]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH:21]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]5[NH:3][C:4](=[O:7])[O:5][N:46]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:22]2)=[N:17]1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCc3nn(CC(C)(C)O)cc3C2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCc3nn(CC(C)(C)O)cc3C2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.15 g), sodium hydrogen carbonate (0.25 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 30 min, 4′-({4-[2-(2-hydroxy-2-methylpropyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.085 g) was added, and the mixture was stirred at 90° C. for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.030 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.027 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.032 g, 34%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[S:22][C:21]([C:23]([O:25]CC)=[O:24])=[CH:20][CH:19]=2)=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[K+].Cl>CO>[CH3:1][C:2]1[C:3]([C:16]([C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc(C(=O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(=O)c1ccc(C(=O)O)s1)C(C)(C)CCC2(C)C
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
To a suspension of the ester 37 (50 mg, 0.13 mmol) in 75% aqueous methanol (3 mL) was added one pellet of potassium hydroxide (0.1 g). The reaction mixture was stirred at 70° C. for 1.5 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 1N aqueous hydrochloric acid, and then extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgsO4, filtered, and concentrated to afford a white solid (46 mg). Recrystallization from methanol afforded the desired acid 38 as a white crystalline solid (42 mg, 91%): m.p. 214°-215° C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[C:3]=1[F:23]>CO.[Pd].C>[F:10][C:5]1[C:6]([F:9])=[C:7]([F:8])[CH:2]=[C:3]([F:23])[C:4]=1[S:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:12])=[O:13]
Reactant: COc1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(Br)c2F)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2c(F)cc(F)c(F)c2F)cc1
Reaction time: 4 h
Yield: 40.8 %

Procedure:
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzene (250 mg, 0.6 mmol) (Example 5) was dissolved in methanol (25 ml) and placed in a closed vessel. A catalytic amount of 10% Pd/charcoal (25 mg) was added and the mixture was hydrogenated at 60 psi H2 for 4 h. The mixture was filtered through celite, the solvent was evaporated and the residue was purified by chromatography (silica; EtOAc/Hexane, 1:4) to yield 82 mg of the title compound. 1H-NMR (CDCl3): δ 7.10 (2H, dd, J=9.0 and 2.0 Hz), 6.94 (1H, br s), 6.85 (1H, m), 6.79 (2H, dd, J=9.0 and 2.0 Hz), 3.75 (3H, s). MS(EI): 335 (20, M+), 122 (100). Anal. Calcd. for C13H9F4NO3S: C, 46.57; H, 2.71; N, 4.18; S, 9.56. Found: C, 46.46; H, 2.67; N, 4.17; S, 9.52.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][C:10]([F:17])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH2:4][CH2:3]1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:2]1([CH3:1])[C:6]([C:7]2[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:10]([F:17])=[CH:9][C:8]=2[C:29]2[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=2[F:27])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1cc(C2=CCCC2(C)C)c(OS(=O)(=O)C(F)(F)F)cc1F
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C2=CCCC2(C)C)c(-c2cc(OC)ccc2F)cc1F
Temperature: 90 °C
Reaction time: 17 h

Procedure:
To a stirred solution of 83.2F (1.05 g, 2.65 mmol) in DMF (5 mL) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (0.90 g, 5.32 mmol) (commercially available from Aldrich) and potassium carbonate (1.10 g, 7.96 mmol) followed by tetrakis(triphenylphosphine)palladium (0.31 g, 0.27 mmol). The mixture was heated to 90° C. After 17 hours, the mixture was cooled to room temperature and then diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo and the residue was then purified on silica gel (0%-10% EtOAc/hexane) to give 83.2G as a clear oil that was used without further purification (0.92 g, 93%). 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (1H, d, J=7.4 Hz), 7.13 (1H, d, J=11.3 Hz), 6.99 (1H, t, J=9.0 Hz), 6.84 (1H, dt, J=8.7, 3.7 Hz), 6.78 (1H, dd, J=5.9, 3.1 Hz), 5.55 (1H, s), 3.96 (3H, s), 3.79 (3H, s), 2.27 (2H, td, J=7.1, 2.5 Hz), 1.67 (2H, t, J=7.0 Hz), 0.84 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:25]=[CH2:26])=[C:4]([CH:8]=[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.Cl.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.O.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([CH:25]=[CH2:26])=[C:4]([CH:8]=[C:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:18][CH:19]=2)[C:10]=1[O:11][CH3:12])[C:5]([NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35])=[O:7]
Reactant: C=Cc1c(C(=O)O)cc(Cc2ccc(-n3cccn3)cc2)c(OC)c1Cl
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=Cc1c(C(=O)N[C@@H]2CCCC[C@H]2O)cc(Cc2ccc(-n3cccn3)cc2)c(OC)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.5 %

Procedure:
To a solution of 3-chloro-2-ethenyl-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid (0.06 g), trans-2-aminocyclohexanol hydrochloride (0.04 g), 1-hydroxybenzotriazole (0.03 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.05 g) in dichloromethane (10.0 mL) was added triethylamine (0.03 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.08 g).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](O)=[O:8])=[CH:3][CH:2]=1.O=S(Cl)[Cl:18]>CN(C=O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([Cl:18])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2ccccc2)cc1
Yield: 100 %

Procedure:
(1,1′-biphenyl)-4-carboxylic acid (20 g, 100.9 mmol) was refluxed for one night in 100 ml of SOCl2 in the presence of a few drops of DMF. Thionyl chloride was removed at ordinary pressure and the residue was triturated in Et2O and filtered. Yield 100% of (1,1′-biphenyl)-4-carbonyl chloride (21.9 g), white crystalline solid. m.p. 116-119° C. 1H-NMR(CHCl3) 7.41-7.73 (7H, m), 8.18 (2H, d, J=8.3 Hz). 13C-NMR(CHCl3) 128.0, 128.1, 129.5, 129.7, 132.4, 132.6, 139.6, 148.7, 168.6
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][N:4]=1.C(=O)(O)[O-].[Na+].Br[CH2:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[CH2:28][C:29]([OH:34])([C:30]([F:33])([F:32])[F:31])[N:21]=2)=[CH:5][N:4]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 87.5 °C
Yield: 42.5 %

Procedure:
To a mixture of the amidine of step 1 (1.9 g, 6.23 mmol) and sodium bicarbonate (1.05 g, 12.46 mmol) in isopropanol (150 ml), 3-bromo-1,1,1-trifluoroacetone (0.97 ml, 9.34 mmol) was added. After heating at 85-90° C. for 48 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude mixture (4.25 g) was purified by chromatography (silica gel, methylene chloride/methanol/ammonium hydroxide, 95/5/0.5) to give the 4,5-dihydro-imidazole (1.1 g, 42%) as a white solid: Anal. Calc'd. for C17H16N3SO4F3.0.5 EtOAc: C, 49.67, H, 4.39, N, 9.15. Found: C, 49.80, H, 4.06, N, 9.33.
Reaction SMILES: [C:1]1(B(O)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Br[C:11]1[CH:16]=[C:15]([C:17]2[CH2:18][CH2:19][N:20]([O:23][CH3:24])[CH2:21][CH:22]=2)[CH:14]=[CH:13][C:12]=1[NH2:25]>>[C:1]1([C:13]2[CH:14]=[C:15]([CH:17]3[CH2:22][CH2:21][N:20]([O:23][CH3:24])[CH2:19][CH2:18]3)[CH:16]=[CH:11][C:12]=2[NH2:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: OB(O)C1=CCCCC1
Reactant: CON1CC=C(c2ccc(N)c(Br)c2)CC1
Product: CON1CCC(c2ccc(N)c(C3=CCCCC3)c2)CC1
Yield: 76.8 %

Procedure:
The title compound was then prepared according to Suzuki coupling procedure of Example 12, step (d) using cyclohex-1-enyl boronic acid (27.9 mg, 1.00 mmol) and 2-bromo-4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine (as prepared above, 44 mg, 0.15 mmol) and chromatographed on silica (20-50% EtOAc/hexanes) afforded 2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenylamine (33 mg, 74%). Mass spectrum, (ESI, m/z): Calcd. for C18H26N2O, 287.2 (M+H), found 286.8.
Reaction SMILES: CB1OB(C)OB(C)O1.ClCCl.[C:13](=O)([O-])[O-].[K+].[K+].COC1C=C(OC)C=CC=1C[N:24]([C:52]1[S:56][N:55]=[CH:54][N:53]=1)[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=2[C:45]2[CH:50]=[CH:49][N:48]=[N:47][CH:46]=2)=[C:30](I)[CH:29]=1)(=[O:27])=[O:26].CC1CCCO1>>[CH3:13][C:30]1[CH:29]=[C:28]([S:25]([NH:24][C:52]2[S:56][N:55]=[CH:54][N:53]=2)(=[O:27])=[O:26])[CH:33]=[CH:32][C:31]=1[O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:37][C:36]=1[C:45]1[CH:50]=[CH:49][N:48]=[N:47][CH:46]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(I)c2)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: ClCCl
Solvent: CC1CCCO1
Product: Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(C(F)(F)F)cc1-c1ccnnc1
Temperature: 80 °C

Procedure:
A Reactivial™ containing trimethylboroxine (798 mg, 6.36 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium(II)dichloride, complex with dichloromethane (26 mg, 0.03 mmol), potassium carbonate (88 mg, 0.64 mmol), N-(2,4-dimethoxybenzyl)-3-iodo-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 38, 240 mg, 0.32 mmol) and 2-methyltetrahydrofuran (5 mL) was sparged with nitrogen and heated to 80° C. for 24 hours. The reaction mixture was cooled and purified directly by silica gel column chromatography (0% to 20% methanol in ethyl acetate gradient elution) followed by reverse phase HPLC to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][CH2:14][C:15](=O)[CH3:16])[CH:6]=1)[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]([NH:27]N)[CH:24]=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][C:14]2[C:24]3[C:23](=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[NH:27][C:15]=2[CH3:16])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OC)c(SCC(C)=O)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1ccc(OC)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 2, using the following starting materials: 4-methoxy-3-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C([O-])([O-])=O.[K+].[K+].I[C:13]1[CH:22]=[CH:21][C:16](C(NC)=O)=[C:15]([F:23])[CH:14]=1.Cl.[CH3:25][N:26]([CH:28]=[O:29])C>CCOC(C)=O.O>[CH3:25][NH:26][C:28]([C:13]1[CH:22]=[CH:21][C:16]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[C:15]([F:23])[CH:14]=1)=[O:29]
Reactant: NCC(=O)O
Reactant: CN(C)C=O
Reactant: CNC(=O)c1ccc(I)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(NCC(=O)O)c(F)c1
Temperature: 140 °C
Reaction time: 0.3 h

Procedure:
Glycine (80 mg, 1.07 mmol) and K2CO3 (207 mg, 1.5 mmol) were added to solution of 4-iodo-N-methyl-2-fluorobenzamide (279 mg, 1 mmol) in DMF (3 ml). The reaction mixture was stirred at 140° C. for 18 min. in microwave oven, cooled, diluted with AcOEt (10 ml) and water (10 ml), neutralized with HCl to pH 2-3, organic layer was separated, water layer was extracted with AcOEt (5×20 ml). The combined extracts were washed with brine, dried over Na2SO4 and evaporated in vacuo. The product was isolated by column chromatography on SiO2. It gave N-(4-methylcarbamoyl-2-fluorophenyl)glycine 4.2(1) (R1=CH3, R4=R5=H,). A solution of N-(4-methylcarbamoyl-2-fluorophenyl)glycine 4.2(1) (113 mg, 0.5 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonirile 3.2 (174 mg, 1.0 mmol) in DMF (2 ml) was stirred at 90° C. for 12 h. The reaction mixture was evaporated in vacuo, and N-methyl-4-{4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]-imidazolidin-1-yl}-2-fluorobenzamide 1.2(1), was isolated by HPLC method, LCMS (M+H)+437.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[CH:1]1([NH:7][C:10]([C:12]2[C:16]([NH:17][C:18]([C:20]3[C:25]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)=[CH:24][CH:23]=[C:22]([CH:33]4[CH2:35][CH2:34]4)[N:21]=3)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NC2CCCCC2)n1
Yield: 45 %

Procedure:
According to the general method described in step 5 of example 27, reaction of cyclohexylamine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (45%) as sticky yellow solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:31]2[CH2:33][CH2:32]2)[CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:5]1=[O:34])[CH:2]=[CH2:3].[H-].[Na+].I[CH2:39][CH3:40]>CN(C=O)C.CCOC(C)=O>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH:31]2[CH2:33][CH2:32]2)[CH2:25][N:26]([CH2:39][CH3:40])[S:27]([CH3:30])(=[O:29])=[O:28])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(C)(=O)=O)C2CC2)C1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CN(CC)S(C)(=O)=O)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)methanesulfonamide (Example 289, Step A, 86 mg, 0.161 mmol) in DMF (1.5 ml) was added sodium hydride (16.06 mg, 0.401 mmol) at rt and the reaction was stirred at rt for 30 minutes. To this reaction was added iodoethane (0.058 mL, 0.723 mmol) and the reaction was stirred at rt for 2 hours. The reaction was diluted with EtOAc, washed with water and sat. NaCl, dried with Na2SO4 and then concentrated. The crude was used on next reaction.
Reaction SMILES: Cl.[CH:2]1([CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[CH2:11][NH:12][C:13]2[C:14](=[O:24])[N:15]([CH2:20][C:21]([OH:23])=O)[C:16]([CH3:19])=[CH:17][N:18]=2)[CH2:4][CH2:3]1.[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][NH2:36])[CH:33]=2)[NH:28][CH:27]=1>>[NH3:6].[CH:2]1([CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[CH2:11][NH:12][C:13]2[C:14](=[O:24])[N:15]([CH2:20][C:21]([NH:36][CH2:35][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[C:26]4[CH3:25])=[O:23])[C:16]([CH3:19])=[CH:17][N:18]=2)[CH2:3][CH2:4]1
Reactant: Cc1cnc(NC[C@H]2CCCN2CC2CC2)c(=O)n1CC(=O)O
Reactant: Cc1c[nH]c2ccc(CN)cc12
Agent: Cl
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NC[C@H]4CCCN4CC4CC4)c3=O)cc12
Product: N

Procedure:
The title compound was prepared by a similar method to preparation 45 from 2-[3-({[(2R)-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid hydrochloride [see preparation 48] and (3-methyl-1H-indol-5-yl)methylamine (72 mg, 0.45 mmol) [see preparation 36]. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (96:3.5:0.5) as the eluant to afford the title compound as a yellow solid, 245 mg, (55%).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6]C=1)(=O)[CH3:2].[S:9]1[CH:13]=[CH:12][C:11]([C:14]([CH2:16][C:17]#[N:18])=[O:15])=[CH:10]1.[C:19]1(=O)CCCCC1.N1CCOCC1.[S]>>[NH2:18][C:17]1[S:6][C:7]2[CH2:8][CH2:4][CH2:1][CH2:2][C:19]=2[C:16]=1[C:14]([C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)=[O:15]
Reactant: O=C1CCCCC1
Reactant: N#CCC(=O)c1ccsc1
Reactant: CC(=O)c1ccsc1
Agent: [S]
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1ccsc1)CCCC2
Yield: 67 %

Procedure:
The procedure of Example 1 was followed except that 3-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophene-3-carbonyl)acetonitrile (Steps A and B). Cyclohexanone (Aldrich), 2-(thiophene-3-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 67%; IR (KBr) cm−1: 3323, 3107, 2929, 1576, 1433, 1266, 1151, 1080, 825,726; 1H NMR (CDCl3):δ 1.55 (m, 2H), 1.77 (m, 2H), 2.01 (t, 2H, J=6 Hz), 2.54 (t, 2H, J=6.2 Hz), 6.46 (bs, 2H), 7.28 (m, 2H), 7.58 (t, 1H, J=2.2 Hz); yellow solid, mp: 133–135° C. (petroleum ether).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:12][CH2:13][OH:14])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].CS(C)=O.C1(C)C=CC=CC=1>O>[C:15]([NH:19][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[C:3]([CH2:12][CH2:13][OH:14])[C:2]=1[F:1])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1CCO
Solvent: O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)Nc1ccc([N+](=O)[O-])c(CCO)c1F
Yield: 92.3 %

Procedure:
30.5 g (150 mmol) of 3,4-difluoro-2-(2-hydroxyethyl)nitrobenzene and 90 ml (900 mmol) of t-butylamine were added to 150 ml of dimethylsulfoxide and 25 ml of toluene, and the solution was heated at reflux for 8.5 hours. After air-cooling, the solution was poured into 1500 ml of water, and the deposited crystals were filtered. They were dissolved in 500 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was crystallized with n-hexane, and the crystals were filtered off to obtain 35.5 g of the subject compound (123) in a 93% yield.