Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H][H]>[Rh]>[C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:15]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: [H][H]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C#CCO)ncc1Cl
Agent: [Rh]
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCO)ncc1Cl
Yield: 62.8 %

Procedure:
A stirred suspension of N-(1-adamantylmethyl)-5-chloro-2-(3-hydroxy-1-propynyl)isonicotinamide (Example 1 (iii)) (0.48 g) and 5% rhodium on carbon (0.020 g) was stirred under a positive pressure (3 barr) of hydrogen until no further uptake was observed. The mixture was filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate to afford the sub-titled compound (0.305 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:4]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:16]([OH:19])(=[O:18])=[O:17])=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:4]=1
Reactant: COc1cccc(N2CCOCC2)c1
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(S(=O)(=O)O)c(N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 20.3 %

Procedure:
To a cooled (0° C.), stirred portion of 1-methoxy-3-morpholin-4-yl-benzene (1.08 g; 5.6 mmol) was added neat to chlorosulfonic acid (1.8 mL; 28 mmol) via pipette over 2 minutes under calcium sulfate-dried atmosphere. The resulting thick, red solution was allowed to warm to room temperature and stirred for 5 hours. The resulting solution was poured onto ice, then extracted with CH2Cl2 (3×50 mL). Combined organic layers then were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the acid as a light green solid (0.31 g; 20%).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:16]([CH3:17])=[C:15](Br)[CH:14]=[C:13]([N+:19]([O-])=O)[C:12]=1[NH2:22])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>[Ni]>[CH2:1]([N:8]([CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([NH2:19])[C:12]=1[NH2:22])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cc([N+](=O)[O-])c(N)c1CN(C)Cc1ccccc1
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(N)c(N)c1CN(C)Cc1ccccc1
Yield: 99.4 %

Procedure:
2-[(Benzyl-methyl-amino)-methyl]-4-bromo-3-methyl-6-nitro-phenylamine (6 g, 16.5 mmol) was hydrogenated (Ra Ni, 3 g) in the presence of KOH (0.498N). Reaction mixture filtered and extracted in CHCl3 (200 mL) and washed with water and dried (MgSO4). Solvent evaporated to give a dark oil 4.19 g=99%. H-NMR: 1.96 (s, 3H), 2.08 (s, 3H), 3.36-3.39 (m, 4H), 4.23 (s, 2H), 4.73 (s, 2H), 6.18 (d, 1H, J=7.3 Hz), 6.33 (d, 1H, J=7.3 Hz), 7.21-7.26 (m, 5H).
Reaction SMILES: [OH:1][C@@:2]([CH3:31])([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[C:27]3[S:28][CH:29]=[CH:30][C:26]=3[O:25][N:24]=2)[CH:18]=1)[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH2:32]([NH:39][CH2:3][C@@:2]([CH3:31])([OH:1])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[C:27]3[S:28][CH:29]=[CH:30][C:26]=3[O:25][N:24]=2)[CH:18]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@](C)(O)COc2cccc(-c3noc4ccsc34)c2)cc1
Solvent: C1CCOC1
Product: C[C@@](O)(CNCc1ccccc1)COc1cccc(-c2noc3ccsc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stir a solution of toluene-4-sulfonic acid (S)-2-hydroxy-2-methyl-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl ester (intermediate prepared as described in example 6, 2.45 g, 0.00533 g) and tetrahydrofuran (40 mL), and treat dropwise at 0° C. with a solution of benzylamine (0.57 g, 0.00533 mol, Aldrich Chemical Company) and tetrahydrofuran (10 mL). Stir overnight at room temperature, concentrate in vacuo and partition the residue between ethyl acetate (100 mL) and water (100 mL). Separate the organic phase, dry (MgSO4), filter and concentrate in vacuo. Purify the residue by flash chromatography (silica gel, elute with 9:1 dichloromethane:methanol) to give the free base of the title compound. The maleate salt may be prepared as described for example 66.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Ni]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(OCc2ccc(F)cc2)cc1

Procedure:
1-Nitro-4-(4-fluorobenzyloxy)-benzene (2.37 g) was dissolved in 200 ml of methanol and catalytic amount of Raney Ni was added. The mixture was stirred at room temperature under atmospheric pressure in a hydrogen atmosphere for 3 hours. After filtering off Raney Ni over Celite and washing with methanol, the obtained filtrate was concentrated under reduced pressure to give a solid product 4-(4-fluoro-benzyloxy)-aniline, which is pure enough for next step.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([CH:5]1[C:12]2[N:8]([CH:9]=[CH:10][CH:11]=2)[CH2:7][CH2:6]1)=[O:4].[C:19](N1CCCCC1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].N1CCCCC1>O.C1(C)C=CC=CC=1>[C:19]([C:9]1[N:8]2[C:12](=[CH:11][CH:10]=1)[CH:5]([C:3]([N:2]([CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4])[CH2:6][CH2:7]2)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C(=O)C1CCn2cccc21)c1ccccc1
Reactant: O=C(c1ccccc1)N1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C(=O)C1CCn2c(C(=O)c3ccccc3)ccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
N-Methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide (115.35 g, 480 mmol) and toluene (100 mL) were added to a mixture of benzoylpiperidine (95.4 g, 1.05 equivalents) and phosphorus oxychloride (88 mL, 147 g, 0.96 equivalents), which had been stirred at 25° C. for 1 hour. An additional 100 mL toluene was added. The suspension was heated to a temperature of 40° C. to 45° C. for 4 hours. The resulting syrup was transferred into a rapidly stirring solution of sodium hydroxide (180 g, 4.5 mol), piperidine (1.0 mL), and water (650 mL). The temperature was maintained at 25° C. to 35° C. and the mixture was stirred for 1 hour. A mixture of toluene (100 mL), water (50 mL), and sodium hydroxide (12 g, 300 mmol) was added to the reaction flask, and the entire reaction mixture was stirred at 25° C. for 1 hour. The suspension was then heated to 75° C. and the layers were separated. The organic layer was cooled to 60° C. and hexane (100 mL) was slowly added, and the solution slowly stirred and cooled to −15° C. The precipitate was filtered, washed with toluene/hexane (150 mL, 2:1 v/v) and then with hexane (150 mL), and dried under vacuum at 25° C. to yield 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide (138.01 g, 83.5% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C@@H:8]1[CH2:11][C@H:10]([C:12]([O:14][C@H](C2C=CC=CC=2)C)=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@@H:8]1[CH2:9][C@H:10]([C:12]([OH:14])=[O:13])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](OC(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-1-phenylethyl cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylate (1.8 g, 5.65 mmol) and 10% palladium-carbon (0.602 g, 5.65 mmol, 50% wet) in MeOH (20 mL) was stirred at room temperature for 2 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (1.200 g, 5.60 mmol, 99%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ1.43 (9H, s), 1.92-2.10 (2H, m), 2.29-2.48 (4H, m), 2.48-2.78 (1H, m), 2.93-3.16 (1H, m) (The peak derived from COOH was not observed).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:37])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:36])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[CH2:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:3][S:4]([NH:7][C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[C:28]([NH:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:36])[CH2:10][C:9]2([CH3:37])[CH3:8])=[O:20])(=[O:6])=[O:5]
Reactant: CC1(C)CC(c2cccc(C(=O)Nc3ccccc3)c2)Nc2ccc(C(=O)O)cc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C(=O)Nc3ccccc3)c2)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.3 %

Procedure:
To a suspension of 60% sodium hydride (198 mg, 4.95 mmol) in N,N-dimethylformamide (2 mL) was added methanesulfonamide (475 mg, 5 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A20. A solution of 4,4-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (400 mg, 1 mmol) and 1,1′-carbonyldiimidazole (324 mg, 2 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B20. Solution B20 was added to Solution A20 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-(6-methanesulfonylaminocarbonyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-N-phenyl-benzamide (35 mg, 7%) as a white solid: MS (ESI) M+1=478.2.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:23][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:14]=3[S:15][C:7]=2[C:6]=1[O:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:4].[Li+].[OH-]>C1COCC1.O>[C:26]([CH2:25][O:24][C:6]1[C:7]2[S:15][C:14]3[C:13]([NH:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]=2[S:23][C:5]=1[C:3]([OH:4])=[O:2])([OH:28])=[O:27]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NC3CCCCC3)cccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1c(C(=O)O)sc2c1sc1c(NC3CCCCC3)cccc12
Temperature: 25 °C

Procedure:
Step C Hydrolysis: To a solution of 7-Cyclohexylamino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (30 mg, 0.07 mmol) in THF/H2O (1.5 mL/0.5 mL) was added 2.0M LiOH (0.15 mL, 0.35 mmol). The reaction was allowed to stir at ambient temperature over a 16-hour period, after which it was judged complete by LCMS. The THF was removed in vacuo and the resultant aqueous solution was acidified to pH ˜1-2 using 10% HCl to precipitate the desired compound which was filtered, rinsed with water, and oven-dried (55° C.). No purification was necessary. (Yield=20 mg, 71%)
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH2:15])[CH3:14])=[CH:9][CH:8]=1.Cl([O-])(=O)(=O)=O.[Li+].CCOCC>C(Cl)(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15][CH2:4][C:2]([CH3:3])([OH:5])[CH3:1])[CH3:14])=[CH:9][CH:8]=1
Reactant: CC1(C)CO1
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C[C@H](NCC(C)(C)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Isobutylene oxide (1.0 g) and (S)-1-(4-fluorophenyl)ethylamine (2.25 mL) were added to a solution of lithium perchlorate (14.8 g) in an ether (27.8 mL) at room temperature, and the reaction solution was stirred at room temperature for 1.5 hours. Isobutylene oxide (0.5 mL) was added to the reaction solution, which was then stirred overnight. Ice water and chloroform were added to the reaction solution, and the organic layer was separated. Thereafter, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (chloroform:2-propanol=100:1 to 1:1) to obtain 2.13 g of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:32])[C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[C:23]([OH:30])[C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[O:21][C:20](=[O:31])[CH:19]=1>>[CH:4]1([CH2:3][CH2:2][O:30][C:23]2[C:24]([O:28][CH3:29])=[CH:25][CH:26]=[C:27]3[C:22]=2[O:21][C:20](=[O:31])[CH:19]=[C:18]3[NH:17][C:16]2[C:15]([Cl:32])=[CH:14][N:13]=[CH:12][C:11]=2[Cl:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: BrCCC1CCCCC1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCC1CCCCC1

Procedure:
The title compound was prepared from (2-bromoethyl)cyclohexane and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.82 (s, 2H), 7.95 (d, 1H), 7.21 (d, 1H), 4.64 (s, 1H), 4.02 (t, 2H), 3.92 (s, 3H), 1.80-1.50 (m, 8H), 1.70 (m, 3H), 0.90 (m, 2H); MS (ESI): 463.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)[O:5][CH:6]=1.[CH3:29][O:30][C:31](=[O:50])[C:32]([CH3:49])([C:34]1[CH:39]=[CH:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=1)[CH3:33]>COCCOC.CCOCC.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:29][O:30][C:31](=[O:50])[C:32]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([C:2]2[CH:3]=[C:4]([C:7]3[N:12]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=4[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:26])([F:28])[F:27])[CH:8]=3)[O:5][CH:6]=2)[CH:39]=1)([CH3:49])[CH3:33]
Reactant: COC(=O)C(C)(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: N#Cc1c(C(F)(F)F)cc(-c2cc(Br)co2)n(Cc2ccc(F)cc2F)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: CCOCC
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)C(C)(C)c1cccc(-c2coc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
Alternatively, to 6-(4-bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (185 mg, 0.40 mmol) was added 2-methyl-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]propionic acid methyl ester (1.7 mL of a 0.47 M solution in 1,2-dimethoxyethane, 0.8 mmol). The mixture was diluted with 1,2-dimethoxyethane (2.3 mL) and nitrogen was bubbled through the solution as an aqueous solution of K2CO3 (0.4 mL of a 35% w/v solution in H2O, 1.0 mmol) was added. The addition of the K2CO3 solution caused the reaction mixture to turn dark. The mixture was then treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene)palladium (II) dichloromethane adduct (33 mg, 40 μmol). After several minutes the nitrogen sparge was discontinued, and the vial was immersed in an oil bath held at 80° C. After stirring for 16 hours the dark reaction was allowed to cool to ambient temperature, and diluted with ether (30 mL), and H2O (10 mL). The aqueous layer was extracted with ether (1×10 ml), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to afford a dark oil. The crude material was purified by flash chromatography eluting with a gradient from 0% to 20% ethyl acetate/hexane to afford bright yellow product containing fractions from the column. Some of these fractions deposited yellow crystals upon standing. The crystals were collected and found to be pure 2-(3-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-phenyl)-2-methyl-propionic acid methyl ester (74 mg, 33% yield). 1H-NMR (400 MHz, CDCl3): δ 7.89 (1H, br s), 7.41-7.28 (4H, m), 7.11-7.05 (2H, m), 6.91-6.82 (3H, m), 5.60 (2H, s), 3.67 (3H, s), 1.61 (6H, s).
Reaction SMILES: C(O[CH:4]=[C:5]1[S:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])C.[Na].[CH2:13]([SH:15])[CH3:14].O>C(O)C>[CH2:13]([S:15][CH:4]=[C:5]1[S:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH3:14]
Reactant: CCS
Reactant: CCOC=C1SC(=O)NC1=O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCSC=C1SC(=O)NC1=O
Reaction time: 3 h

Procedure:
To a suspension of 5.20 g of 5-(ethoxymethylene)thiazolidine-2,4-dione (1:1.71 mixture with thiazolidine-2,4-dione, about 13.9 mmol) in 50 ml of ethanol, 5.0 g (59 mmol) of ethanethiol sodium salt was added at room temperature, followed by stirring under heating conditions for 3 hours. After cooling, the reaction mixture was poured into water and adjusted to a pH level of about 2. The resulting precipitate was collected by filtration, washed with water and then with n-hexane/diethyl ether and dried to yield 1.38 g (52.0%, light yellow powder) of the desired product.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(N(CC)CC)C>[CH:38]1([N:37]([CH3:36])[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:24]=[CH:23][C:22]4[CH2:21][C@@H:20]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[C:19]5[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=5[C:17]=4[N:16]=3)=[CH:10][CH:9]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CNC1CCCCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(F)cc2)C3)cc1
Solvent: CCN(CC)CC
Product: CN(CCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(F)cc2)C3)cc1)C1CCCCC1

Procedure:
This was synthesized by using (S)-4-(6-(4-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-methylcyclohexanamine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=160-162° C. 1H NMR (DMSO-d6) 400 MHz δ 10.37 (brs, 1H), 9.68 (s, 1H), 8.32-8.36 (m, 2H), 7.80 (d, J=7.8 Hz, 2H), 7.50-7.52 (m, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.10-7.17 (m, 4H), 4.43 (t, J=6.6 Hz, 1H), 3.27-3.30 (m, 5H), 3.01-3.13 (m, 2H), 2.73 (d, J=4.6 Hz, 3H), 2.03-2.09 (m, 2H), 1.99 (s, 1H), 1.81 (d, J=12.1 Hz, 2H), 1.61 (d, J=12.5 Hz, 1H), 1.40-1.44 (m, 3H), 1.27-1.32 (m, 3H), 1.09-1.17 (m, 2H). LCMS m/e 507 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[C:24](=O)[CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH2:22][CH2:21][CH2:20]1>>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:23]1[C:22]2[N:17]=[C:15]([NH:14][C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]4)=[C:2]([F:1])[CH:3]=3)[S:16][C:21]=2[CH2:20][CH2:19][CH2:24]1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2F)cn1
Reactant: O=C1C(Br)CCCC1c1ccccc1Cl
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3Cl)cc2F)cn1

Procedure:
The title compound was prepared from [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (45 mg, 0.18 mmol) and 6-bromo-2-(2-chloro-phenyl)-cyclohexanone (145 mg, ca. 0.5 mmol) using in analogous manner the procedure described in example 1b). Obtained as a light-brown solid (68 mg, 76%). MS ISP (m/e): 439.1 [(M+H)+]. mp 204-206° C.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][CH2:7][C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)(O)[C:4]=2[CH:3]=1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][CH2:7][C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10](=[C:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:4]=2[CH:3]=1
Reactant: CN1CCC(C2(O)c3ccccc3COc3ccc(Br)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(=C2c3ccccc3COc3ccc(Br)cc32)CC1
Yield: 72.8 %

Procedure:
A TFA (150 mL) solution of 2-bromo-11-(1-methylpiperidin-4-yl)-6,11-dihydrodibenz[b,e]oxepin-11-ol (21.7 g, 56.0 mmol) was stirred overnight at room temperature. The solvent was distilled off under a reduced pressure, a 10% aqueous potassium carbonate solution was then added to the residue to neutralize, and the product was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was then distilled off under a reduced pressure, and the reside was purified by column chromatography (chloroform-methanol=9:1), to give 15.1 g (73%) of the captioned compound in the form of crystals.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH2:11][CH2:12]Cl)=[O:10])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH:11]([C:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)=[O:10])=[CH2:12]
Reactant: COc1ccc(C(=O)CCCl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(O)cc1
Yield: 73.2 %

Procedure:
2-Chloroethyl 4-methoxyphenyl ketone (b) (69.4 g) was dissolved in methylene chloride (200 mL), to which was added aluminium chloride (130.8 g) little by little. The resulting mixture was heated with a mantle heater for 2 hours under reflux. After the reaction, the reaction liquid was cooled and poured into ice, and the organic phase was extracted out with ethyl acetate (200 mL) and transferred into a separating funnel. The organic phase was washed with water, and then processed with aqueous 2 M NaOH solution to extract out the intended product into the solution. The aqueous alkali solution was acidified with 6 M hydrochloric acid, and then again extracted with ethyl acetate. The solvent was evaporated away under reduced pressure, and the residue was recrystallized from toluene to obtain 37.9 g of colorless crystals, 4-hydroxyphenyl vinyl ketone (c).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]1[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[OH:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: OCCCBr
Reactant: Oc1cccc2sccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCCOc1cccc2sccc12

Procedure:
3-Bromo-1-propanol (1.67 g) was added to a stirred solution of 4-hydroxybenzo[b]thiophene (1.50 g) and potassium carbonate (3.04 g) in 2-butanone (40 ml) under an atmosphere of nitrogen and the mixture was heated under reflux for 3 hours. The mixture was filtered and the filtrate evaporated to dryness. The solid residue was recrystallised from ethanol to give 4-(3-hydroxypropyloxy)benzo[b]thiophene of m.p. 82° C. A solution of N-chloroacetylpyrrolidine (1.47 g) in tetrahydrofuran (THF, 10 ml) was added in one portion to a stirred solution of 4-(3-hydroxypropyloxy)benzo[b]thiophene (1.75 g) and sodium hydride (60% suspension, 0.40 g) in tetrahydrofuran under an atmosphere of nitrogen and stirring was continued for 1 hour at room temperature. The solution was filtered and the filtrate evaporated to afford an oil, which was purified by flash chromatography (silica, ethylacetate:petroleum, 1:1 v/v) to yield the pyrrolidine amide of 3-(4-benzothiophenoxy)propyloxy acetic acid.