Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)C1CCN(Cc2c[nH]c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN5CCC(C(=O)O)CC5)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of ethyl 1-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-4-piperidinecarboxylate (D74) (280 mg) in tetrahydrofuran (10 mL) and methanol (10 mL) stirred at 20° C. was added a solution of sodium hydroxide (54 mg) in water (10 mL) in one charge. The reaction mixture was stirred at 20° C. for 8 hours. The reaction mixture was concentrated and then H2SO4 (0.1 M) solution was added dropwise until no further white precipitate was formed. The solid was filtered and dried to afford 1-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-4-piperidinecarboxylic acid (E48) (98 mg). δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 1.61-3.02 (9H, m), 3.95 (2H, s), 4.87-4.93 (1H, m), 7.26 (1H, t), 7.45-7.47 (2H, m), 7.96 (1H, s), 7.96 (1H, s), 8.21 (1H, dd), 8.37 (1H, d), 11.07 (1H, s). MS (ES): C26H27ClN4O4 requires 494; found 495.2 (M+H+).
Reaction SMILES: [Na].[F:2][CH:3]([F:14])[C:4]1[C:8]([C:9](F)=[O:10])=[C:7]([F:12])[N:6]([CH3:13])[N:5]=1.Cl.S1(=O)(=[O:21])CCCC1>>[F:12][C:7]1[N:6]([CH3:13])[N:5]=[C:4]([CH:3]([F:14])[F:2])[C:8]=1[C:9]([OH:21])=[O:10]
Reactant: O=S1(=O)CCCC1
Reactant: Cn1nc(C(F)F)c(C(=O)F)c1F
Agent: Cl
Agent: [Na]
Product: Cn1nc(C(F)F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 400 ml of a 1N sodium hydroxyde aqueous solution, was added dropwise 67.5 g of a solution (10% molar) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl fluoride in tetrahydrothiophene 1,1-dioxide. The temperature was kept below 20° C. during the addition. After 2 hours of stirring at room temperature, the reaction mixture was carefully acidified to pH 2 with concentrated aqueous hydrochloric acid. The resulting white precipitate was filtered, washed with water, and dried to yield 6 g of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid as a white solid.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.C(N=C=NCCCN(C)C)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]2[S:42][CH:43]=[C:44]([C:46](O)=[O:47])[N:45]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCl.O>[CH:1]1([O:7][C:46]([C:44]2[N:45]=[C:41]([CH:38]3[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:40][CH2:39]3)[S:42][CH:43]=2)=[O:47])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: OC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)OC3CCCCC3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, cyclohexanol (1.21 g), dimethylaminopyridine (113 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (1.87 g) are added to a solution of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (VIII-1, 2.90 g) in dichloromethane (30 ml). The mixture is stirred at room temperature overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives tert-butyl 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.63 g, 72%)
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:14])=[C:10]([CH2:11][CH2:12][CH3:13])[C:5]=2[O:4][N:3]=1.[CH2:15]([O:17][C:18](=[O:34])[CH2:19][C@H:20]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32]Br)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:34])[CH2:19][C@H:20]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][O:14][C:9]3[CH:8]=[CH:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[C:10]=3[CH2:11][CH2:12][CH3:13])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH3:16]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: CCCc1c(O)ccc2c(C)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2)CC[C@H]3CC(=O)OCC)ccc2c(C)noc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To a mixture of 3-methyl-7-propyl-1,2-benzisoxazol-6-l (269 mg, 1.01 mmol) (Example 67) and ethyl[(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (331 mg, 1.01 mmol) (Example 45) in DMF (8 mL, containing 1 vol % water) was added Cs2CO3 (661 mg, 2.03 mmol). The mixture was stirred for 16 h at rt, and then the reaction mixture was concentrated under reduced pressure. The residue was suspended in EtOAc and filtered through a small plug of silica to give 204 mg (39%) of the title compound as a white solid that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:40][S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:40][S:41]([C:44]([F:47])([F:45])[F:46])(=[O:43])=[O:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=3)=[O:24])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NS(=O)(=O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)cc1)NS(=O)(=O)C(F)(F)F
Yield: 65.9 %

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (1.02 g, 3.01mmol) and ethyl (S)-3-(4-aminophenyl)-2-(trifluoromethylsulfonylamino)propionate (1.03 g, 3.03 mmol) were condensed. The reaction mixture was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1-1/2) to give 1.31 g of ethyl (S)-3-[4-[[5-(benzyloxycarbonylamidino)-2-benzofuranyl]carbonylamino]phenyl]-2-(trifluoromethylsulfonylamino)propionate as a colorless solid (65%). Ethanol (200 ml), 10% palladium-carbon (450 mg) and 1N hydrochloric acid (2 ml) were added to this solid (1.30 g, 1.97 mmol) and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure to quantitatively give 1.11 g of hydrochloride of compound (54) as a colorless solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:22]([OH:23])[C:21]3[S:24][CH2:25][CH:26]([O:29][CH3:30])[CH2:27][S:28][C:20]=3[C:19]2=[O:31])=[N:16][CH:17]=1>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:19]([O:31][C:2]([O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:3])[C:20]3[S:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][S:24][C:21]=3[C:22]2=[O:23])=[N:16][CH:17]=1
Reactant: COC1CSC2=C(SC1)C(O)N(c1ccc(Cl)cn1)C2=O
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: COC1CSC2=C(SC1)C(OC(=O)Oc1ccccc1)N(c1ccc(Cl)cn1)C2=O
Yield: 60.9 %

Procedure:
By reacting phenyl chloroformate (16.7 g) with 7-(5-chloropyrid-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]-pyrrole (prepared as described in Example 1; 12.3 g) in anhydrous pyridine (100 cc) at between -10° C. and +20° C., 7-(5-chloropyrid-2-yl)-3-methoxy-8-oxo-6-phenoxycarbonyloxy-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (m.p. 167° C.; 10.1 g) is obtained.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[CH3:24][CH:25]([OH:33])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[CH3:24][CH:25]([O:33][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1)[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CC(O)c1ccc(F)cc1
Product: CC(Oc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1)c1ccc(F)cc1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with α-methyl-4-fluorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(α-methyl-4-fluorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=473 (M++1); Rt=4.80 min; 1H-NMR 400 MHz (CDCl3): δ 1.76 (d, J=9 Hz, 3H), 6.22-6.30 (dd, J=6 Hz, J=9 Hz, 1H), 6.90-7.05 (m, 4H), 7.15-7.18 (d, J=9 Hz, 2H), 7.21-7.23 (m, 3H), 7.38 (d, 1H), 7.45-7.52 (m, 2H), 8.58 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[S:19])[NH2:18])[CH2:13][C@@H:12]1[C:20](=[O:32])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH3:31])=[CH:25][CH:24]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][C:38](=[O:44])[CH:39](Br)[C:40](=O)[CH3:41])([CH3:36])([CH3:35])[CH3:34]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:19][C:39]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:44])=[C:40]([CH3:41])[N:18]=2)[CH2:13][C@@H:12]1[C:20](=[O:32])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH3:31])=[CH:25][CH:24]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1ccc(CNC(=O)[C@H]2CN(C(N)=S)CCN2C(=O)OCc2ccccc2)cc1
Reactant: CC(=O)C(Br)C(=O)OC(C)(C)C
Solvent: CC#N
Product: CCCc1ccc(CNC(=O)[C@H]2CN(c3nc(C)c(C(=O)OC(C)(C)C)s3)CCN2C(=O)OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
A mixture of the compound (1.51 g) obtained in Step 4 and 2-bromo-3-oxobutyric acid tert-butyl ester (1.58 g) in acetonitrile (15 ml) was stirred at 80° C. for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:2-2:3) to give the title compound (1.29 g).
Reaction SMILES: [OH-].[Li+].O.C([O:6][P:7]([CH2:15][C@@H:16]([OH:19])[CH2:17][NH2:18])([CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)=[O:8])C.P(=O)(O)(O)O>C(O)C>[NH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][P:7]([CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)(=[O:6])[OH:8]
Reactant: CCOP(=O)(C[C@@H](O)CN)C1CC=CCC1
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC[C@H](O)CP(=O)(O)C1CC=CCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.2 g of lithium hydroxide and 4 ml of water are added to a solution of 1.1 g of 3-amino-2(S)-hydroxy-propyl-(cyclohex-3-enyl)-phosphinic acid ethyl ester in 4 ml of ethanol. The mixture is heated to 60° and stirred for 20 hours. The mixture is then allowed to cool to room temperature, adjusted to pH 7 with aqueous phosphoric acid, concentrated to dryness by evaporation, taken up in methanol/water and filtered. After removal of the solvent there remains behind a foam which, after crystallisation from ethanol/methanol, yields 3-amino-2(S)-hydroxy-propyl-(cyclohex-3-enyl)-phosphinic acid in the form of white crystals having a melting point of 221°-225°.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:35]1([C:41](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
A mixture of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (3.0 g), triphenylmethyl chloride (1.96 g) and triethylamine (1.0 ml) in CH2Cl2 (20 ml) was stirred at room temperature for 16 hours. The reaction solution was washed with H2O, dried over Na2SO4 and concentrated to dryness to give a solid residue. The residue was purified by column chromatography on silica gel to give a colorless powder (4.25 g, 91%), m.p. 120-123° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]=[C:27]=[O:28]>C1COCC1>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[NH:26][C:27](=[O:28])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 18 h
Yield: 59 %

Procedure:
To a mixture of tert-butyl 4-amino-3-methoxyphenylacetate (2.15 g, 9.04 mmol), 2,6-dichlorophenyl isocyanate (1.70 g, 9.04 mmol) in THF (40 ml) was added Et3 N (0.25 ml, 9.04 mmol) at room temperature. After 18 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetate (2.27 g, 59%) as a colorless powder. mp 177–181° C. (dec.); 1H-NMR (CDCl3) δ 1.43 (s, 9H), 3.74 (s, 2H), 3.83 (s, 3H), 6.34 (s, 1H), 6.81 (s, 1H), 6.84 (d, J=8.3 Hz, 1H), 7.06 (br, 1H), 7.27 (t, J=8.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 8.04 (d, J=8.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[CH:31]1([C:34]2[CH:35]=[CH:36][C:37]([F:41])=[C:38]([CH:40]=2)[NH2:39])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:39][C:38]3[CH:40]=[C:34]([CH:31]4[CH2:32][CH2:33]4)[CH:35]=[CH:36][C:37]=3[F:41])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Reactant: Nc1cc(C2CC2)ccc1F
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3cc(C4CC4)ccc3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 22.3 %

Procedure:
The title compound was prepared by following the procedure as described for Example-108 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.150 g, 0.400 mmol), thionyl chloride (2.0 mL), 5-cyclopropyl-2-fluoroaniline (Intermediate-47, 0.090 g, 0.600 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.045 g of the desired product. 1HNMR (DMSO-d6): δ 0.62-0.63 (m, 2H), 0.93-0.96 (m, 2H), 1.54 (s, 6H), 1.93 (m, 1H), 3.13 (s, 2H), 6.80 (s, 1H), 7.14-7.50 (m, 5H), 8.24 (d, J=7.8 Hz, 1H), 10.07 (s, 1H), 11.20 (s, 2H); MS [M+H]+: 505.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:24])=[O:23])=[CH:17]2.[S:37]1[CH:41]=[CH:40][N:39]=[C:38]1[NH2:42].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22]([NH:42][C:38]1[S:37][CH:41]=[CH:40][N:39]=1)(=[O:24])=[O:23])=[CH:17]2
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Reactant: Nc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Temperature: -78 °C
Yield: 66 %

Procedure:
To a vial charged with perfluorophenyl 5-(2-chloro-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonate (0.200 g, 0.362 mmol) and THF (1 mL), was added thiazol-2-amine (0.040 g, 0.398 mmol) as a solution in THF (2 mL). The solution was cooled to −78° C., and a THF solution of lithium bis(trimethylsilyl)amide (0.724 ml, 0.724 mmol, 1M) was added dropwise by syringe. The solution was maintained at −78° C. for 5 min and then allowed to warm to rt. The solution was concentrated and the crude residue was absorbed onto a 5 g plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 5% to 90% EtOAc in hexane, to provide 5-(2-chloro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (0.112 g, 0.239 mmol) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 6.83 (d, J=4.59 Hz, 1H) 7.24 (d, J=4.59 Hz, 1H) 7.47 (d, J=8.98 Hz, 1H) 7.60 (d, J=7.16 Hz, 1H) 7.66-7.83 (m, 3H) 7.88 (d, J=8.23 Hz, 1H) 8.09 (s, 1H) 8.29 (d, J=8.33 Hz, 1H) 8.56 (d, J=1.71 Hz, 1H) 12.80 (br. s., 1H); m/z (ESI, +ve ion) 468.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[Cl:23][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:3][C:2]=1[F:1]
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)c(F)c2)cs1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(CCc2ccc(CCl)c(F)c2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of N-(4-{2-[3-fluoro-4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (196.6% mg, 0.668 mmol) in chloroform (10 ml) was added thionyl chloride (0.144 ml, 2.00 mmol), and the mixture was stirred at room temperature for 1 hr. Thionyl chloride (0.077 ml, 1.00 mmol) was added, and the mixture was stirred at room temperature for 1 hr and concentrated. Ethyl acetate (10 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. The operation was performed 3 times to remove thionyl chloride azeotropically. A mixture of ethyl acetate (1 ml) and diisopropyl ether (10 ml) was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to give N-(4-{2-[4-(chloromethyl)-3-fluorophenyl]ethyl}-1,3-thiazol-2-yl)acetamide (205.3 mg, 0.656 mmol, yield 98.3%) as a slightly yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ccc(C(F)(F)F)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Yield: 54.2 %

Procedure:
6-Trifluoromethyl-quinazolin-4-ol (0.95 g, 4.44 mmol, 1 eq.), phosphorous oxychloride (2.48 mL, 26.6 mmol, 6 eq.) and triethylamine (3.71 mL, 26.6 mmol, 6 eq.) were refluxed for 2.5 hours. Stripped 3× from methylene chloride then dissolved in methylene chloride and rinsed 3× with saturated NaHCO3, 1× with brine. Dried and stripped in vacuo to give and amber oil. Purified over silica gel in 9:1 Hexanes/EtOAc. Obtained 560 mg of off-white solids as product. The product was used immediately in Ex 111 part C.
Reaction SMILES: [H-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2([CH:17](C)[OH:18])[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[CH3:20]I.[K]>CCCCCC.O1CCCC1.CN(C)C=O.C(Cl)(Cl)Cl.O.CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2([CH2:17][O:18][CH3:20])[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(O)C1(c2cccc(Cl)c2)CCN(C)CC1
Reactant: CI
Agent: [H-]
Agent: [K+]
Agent: [K]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: COCC1(c2cccc(Cl)c2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Potassium hydride oil suspension (3.80 g of 35%; 33 mmoles) was washed with hexane, 15 mL of tetrahydro-furan was added, and the suspension was treated with 4.25 g (16 mmoles) of 4-(3′-chlorophenyl)-α, 1-dimethyl-4-piperidinemethanol (Example 1) dissolved in 15 mL of tetrahydrofuran. The mixture was stirred at room temperature for 1 hour; methyl iodide (9.1 g, 64 mmoles) was added which caused the temperature to rise to 50° C. Methanol (5 mL) was added after stirring for 2.75 hours, keeping the temperature below 25° C. Water and chloroform were added, and the mixture was filtered to remove 4.70 g of the methiodide of the title compound. This solid was combined with the products obtained on removal of the solvent from the chloroform layer, and heated with 7.0 g of potassium methylmercaptide in 30 mL of dimethyl formamide in an 80° C. oil bath for 2.5 hours. The solvent was removed, water was added to the residue and the mixture was extracted with methylene chloride. Removal of the solvent from the dried extracts and short-path distillation of the residue (130° C. bath temperature, 1 micron) gave 3.94 g (88% yield) of the title compound as an oil. 1H NMR (CDCl3): δ 7.2-7.4 (m,4H); 3.3 (s,3H); 3.2 (quartet, J=7 Hz,1H); 2.7 (m,2H); 2.2 (s,3H); 1.8-2.4 (m,6H); and 0.9 (d,J=7 Hz,3H). High resolution mass spectrum: m/e calcd. for C15H22ClNO: 267.1390; measured: 267.1393.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.Cl.[O:13]([C:20]1[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH3:1][N:2]([CH3:10])[CH:3]1[CH2:4][C:5]2[C:24]3[C:23](=[CH:22][CH:21]=[C:20]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:25]=3)[NH:26][C:6]=2[CH2:7][CH2:8]1
Reactant: NNc1ccc(Oc2ccccc2)cc1
Reactant: CN(C)C1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CN(C)C1CCc2[nH]c3ccc(Oc4ccccc4)cc3c2C1

Procedure:
To a solution of 14.1 g. of 4-dimethylaminocyclohexanone in 100 ml. of a 6-N solution of hydrogen chloride in absolute ethyl alcohol was added 23.5 g. of 4-phenoxyphenylhydrazine hydrochloride and the mixture was heated at reflux for 6 hours. The mixture was filtered, the filtrate was made alkaline with 10% potassium hydroxide and extracted with chloroform, and the chloroform extract was washed with water and evaporated to dryness under reduced pressure to give 3-(dimethylamino)-6-phenoxy-1,2,3,4-tetrahydrocarbazole.