Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:30])[C@:7]1([OH:29])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[C@@H:13]([CH3:27])[CH2:12]3)[CH2:9][C@@H:8]1[CH3:28])(=[O:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([O:4][CH2:5][C:6](=[O:30])[C@:7]1([OH:29])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[C@@H:13]([CH3:27])[CH2:12]3)[CH2:9][C@@H:8]1[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Yield: 40.2 %

Procedure:
A solution of 30.0 g of 21-acetoxy-17α-hydroxy-6α,16β-dimethyl-4,9(11)-pregnadiene-3,20-dione in 800 ml of dioxane is reacted with 30.0 g of dichlorodicyanobenzoquinone analogously to Example 6(A), worked up and purified, yielding 12.0 g of 21-acetoxy-17α-hydroxy-6α,16β-dimethyl-1,4,9(11)-pregnatriene-3,20-dione, mp 215°-216° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]([C:11]([O:13]C)=[O:12])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.O[Li].O.Cl>C1COCC1.CO.O>[NH2:1][C:2]1[S:3][C:4]2[CH:10]([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: COC(=O)C1CCCc2nc(N)sc21
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2c(s1)C(C(=O)O)CCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxylate (52 mg, 0.24 mmol) and LiOH.H2O (12 mg, 0.29 mmol) in THF/MeOH/H2O (2.5 mL, 3:1:1) was stirred at RT for 2 h. The mixture was neutralized with aq. HCl and conc. in vacuo. The crude yellow solid was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:30](Cl)(=[O:32])[CH3:31].Cl>[N+](C)([O-])=O>[C:30]([C:8]1[C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:25])=[C:5]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]([CH3:23])[C:13]3=[O:24])[C:6]=2[O:10][C:9]=1[CH3:11])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: Cc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1c(C)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Reaction time: 5 h
Yield: 68.2 %

Procedure:
1.6 g (4.2 mmol) of 3-(4-chloro-6-fluoro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 50 ml of nitromethane, and 5.6 g (42 mmol) of aluminum chloride was added thereto at room temperature. Further, 3.3 g (42 mmol) of acetyl chloride was dropwise added thereto. After completion of the dropwise addition, stirring was carried out for 5 hours under heating and ref refluxing. After completion of the reaction, the reaction solution was poured into a mixture of dilute hydrochloric acid and ice and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.2 g (yield: 66.7%) of the desired product as pale yellow crystals. Melting point: 138-140° C.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]([CH3:15])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]=1[CH3:8])=O.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[C:23]([NH:25][C:26]1[CH:27]=[C:28]([CH:32]2[CH2:33][CH2:34][N:35]([CH2:1][C:3]3[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]([CH3:15])[N:6]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:7]=3[CH3:8])[CH2:36][CH2:37]2)[CH:29]=[CH:30][CH:31]=1)(=[O:24])[CH:22]([CH3:38])[CH3:21]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CCOC(=O)c1c(C=O)c(C)n(-c2ccccc2)c1C
Product: CCOC(=O)c1c(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c(C)n(-c2ccccc2)c1C

Procedure:
Prepared by Procedure F and Scheme R using ethyl 4-formyl-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 502.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:12]([N:19]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[CH2:6][CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2ccc(F)cc21
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)C(=NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
Combine 6-fluoroindan-1-one (14.57 g, 97.04 mmol) and benzylamine (10.60 mL, 97.04 mmol) in toluene (75 mL). Add p-toluenesulfonic acid monohydrate (0.923 g, 4.85 mmol). Attach a reflux condenser and heat the mixture under nitrogen to reflux over six hours, then stir at room temperature for 14 hours. Extract the mixture with ethyl acetate and water. Dry the resulting organics with magnesium sulfate, filter, and concentrate in vacuo to give the title compound as a red oil (23.22 g, 100%). MS (ES) m/z=240 [M+1].
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]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1C(=O)N([Cl:33])C(=O)C1>C(Cl)Cl>[Cl:33][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=4)[O:16][N:15]=3)[CH:18]=2)[NH:22][CH:21]=1
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]cc(Cl)c4c3)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
D5 (300 mg) and NCS (113 mg) were dissolved in DCM (4.2 ml) and stirred overnight at room temperature. The reaction mixture was then diluted with DCM and washed with H2O. The aqueous solution was extracted with two further portions of DCM and the combined organic solutions were evaporated to dryness. The crude product was triturated with methanol to give the title compound (42 mg) as a brown solid. The methanol was then evaporated and the resultant brown solid triturated with DCM to give a second batch of the title compound (205 mg) as a brown solid. δH (d6-DMSO, 400 MHz): 1.37 (6H, d), 4.89 (1H, septet), 7.45 (1H, d), 7.62 (1H, d), 7.70 (1H, s), 7.93 (1H, d), 8.15 (1H, d), 8.24 (1H, s), 8.25 (1H, s), 11.77 (1H, s). MS (ES): C19H1535Cl2N3O2 requires 387; found 388 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CC(C)=O.ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CN1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a mixture of 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (0.1 g 0.209 mmol) and cesium carbonate (80 mg; 0.245 mmol) in acetone (2 mL) was added a solution of chloroacetic acid, 1,1-dimethylethyl ester (0.04 mL; 0.279 mmol) in dichloromethane (0.1 mL) by syringe. The reaction mixture was stirred at 40° C. in a sand bath for 16 h, cooled to room temperature and concentrated. The reaction was diluted with DCM and water. The organics were concentrated and purified by ISCO (0-10% MeOH/DCM) to yield tert-butyl 2-(4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:14])[C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:15]1([CH3:33])[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=[C:23]([C:29]([F:32])([F:31])[F:30])[N:22]=2)[CH:16]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:14])[C:11]([NH:28][CH2:27][C:26]2[C:21]([C:17]3[CH:16]=[C:15]([CH3:33])[CH:20]=[CH:19][CH:18]=3)=[N:22][C:23]([C:29]([F:32])([F:30])[F:31])=[CH:24][CH:25]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C(=O)O)c1ccc(C#N)c(Cl)c1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(C#N)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.6 %

Procedure:
To a stirred solution of 2-(3-chloro-4-cyanophenyl)propanoic acid (95 mg, 0.454 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (121 mg, 0.454 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (131 mg, 0.681 mmol), 1-hydroxybenzotriazole (92 mg, 0.681 mmol) and triethylamine (0.16 mL, 1.135 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(3-chloro-4-cyanophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (182 mg) was obtained as 88% yield.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH:16]3[CH:20]4[CH2:21][CH2:22][CH:17]3[CH2:18][CH2:19]4)=[O:12])=[CH:9][N:10]=2)[CH2:2]1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([NH:27][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH:16]2[CH:20]3[CH2:21][CH2:22][CH:17]2[CH2:18][CH2:19]3)=[O:12])=[CH:9][N:10]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N
Reactant: O=C(NCCC1C2CCC1CC2)c1cnc(OCC2CO2)s1
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1ncc(C(=O)NCCC2C3CCC2CC3)s1
Temperature: -20 °C
Reaction time: 12 h

Procedure:
This example illustrates the second step of the process of the invention for preparing the compounds of formula C. In this example a mixture containing 12 g. (0.037 mole) of 1,2-epoxy-3-[5-(2-(bicyclo[2.2.1]hept-7-yl]ethylaminocarbonyl)thiazol-2-yloxy]propane, 12 g. (0.164 mole) of t-butylamine and 20 ml. of ethanol is allowed to stand at room temperature for 12 hours. The mixture is then evaporated under vacuum to remove the ethanol solvent and the resulting residue dissolved in 50 ml. of ethyl acetate and cooled to -20° C, and maintained at this temperature for 2 hours. The mixture is then filtered and the resulting filter cake washed with cold (about 0° C) ethyl ether and then recrystallized from ethyl acetate affording 1-t-butylamino-3-(5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazol-2-yloxy)propan-2-ol.
Reaction SMILES: [F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[O:10])[CH2:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[OH-].[Na+].OO>C1COCC1.CO>[F:1][C@H:2]1[C@@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[O:10])[CH2:3]1
Reactant: O=C1CCN(C(=O)OCc2ccc3ccccc3c2)CC1F
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(OCc1ccc2ccccc2c1)N1CC[C@H](O)[C@H](F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
To a suspension of naphthalen-2-ylmethyl 3-fluoro-4-oxopiperidine-1-carboxylate (41.75 g, 138.6 mmol) in anhydrous THF (800 mL) at 0° C. was added L-Selectride (346 mL, 1.0 M, 346 mmol) dropwise over 30 minutes, during which a yellow solution formed. The solution was allowed to warm to ambient temperature and stir for 16 hours. The mixture was cooled to 0° C., then treated with methanol (160 mL) and 2 N NaOH (350 mL) followed by the dropwise addition of 30% H2O2 (160 mL), during which an exotherm was observed. After stirring at 0° C. for an additional 1 hour and then at ambient temperature for 3 hours, the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on a large silica gel plug eluting with hexanes:EtOAc, 1:1 to afford 26.78 g (64%) of desired product as a solid.
Reaction SMILES: [Na].S(N[N:13]=[CH:14][C:15]1C=CC=C[C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)(C1C=CC(C)=CC=1)(=O)=O.C(N1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])=C.O1CCOCC1.CCOC(C)=O.CCCCCC>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2].O.CCOC(C)=O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C@H:16]2[CH2:15][C@H:14]2[N:13]2[C:34](=[O:35])[C:33]3[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:31]2=[O:40])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)NN=Cc2ccccc2-c2ccc(F)cc2)cc1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
4-Fluorophenyl benzaldehyde-tosylhydrazone sodium salt (1.57 g, 5 mmol), N-vinyl-phthalimide (2.59 g, 15 mmol), benzyltriethylammonium chloride (114 mg, 0.5 mmol), and rhodium acetate dimer (22 mg, 0.05 mmol) were stirred with dioxane (23 ml) to give a thick slurry. This was stirred overnight at room temperature. TIc (20% EtOAc/hexane) showed good conversion, so the mixture was shaken between EtOAc and water. The organic phase was dried with MgSO4 and evaporated to yield 3.8 g of a crude mixture. This was chromatographed on silica with EtOAc/hexane to yield 169 mg (12%) of 2-[cis-2-(4-fluoro-phenyl)cyclopropyl]-isoindole-1,3-dione
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C[O-].[Na+].[CH:8]([CH:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=2[S:13][CH2:12][CH2:11]1)=O>CO.O1CCCC1.C([BH3-])#N.[Na+]>[CH3:2][N:3]([CH2:8][CH:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=2[S:13][CH2:12][CH2:11]1)[CH3:4]
Reactant: O=CC1CCSc2c1c1ccccc1n2-c1ccccc1
Reactant: CNC
Agent: C[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CC1CCSc2c1c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Dimethylamine hydrochloride (1.74 g) is dissolved in absolute methanol (18 ml) and sodium methoxide (813 mg) is added thereto. To the solution are added a solution of the product of the above (1), (1.1 g) in tetrahydrofuran (10 ml) and sodium cyanoborohydride (1 g). The mixture is stirred at room temperature overnight and evaporated after addition of an aqueous solution (4 ml) of sodium hydroxide. The residue is extracted with ether after addition of water and a 10% aqueous solution of sodium hydroxide. The extract is condensed to give the title compound as an oil (1.10 g). The oil is treated with L-tartaric acid (443 mg) in ethanol to give the tartrate (750 mg) melting at 172°-177° C. (decomp.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:19])[CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:19][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CBr
Reactant: CCC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COC(CC)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (1 g., 50% w/w suspension in mineral oil) was added gradually to a stirred solution of 1-[4-(4-chlorophenyl)phenyl]propanol (4.9 g.) in dry dimethylformamide (20 ml.), keeping the temperature below 40° C. After 2 hours stirring ethyl bromoacetate (2.3 ml.) was then added, keeping the temperature below 30° C. After stirring for 16 hours at room temperature, the mixture was poured into water (150 ml.), and the subsequent mixture was extracted with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated to give ethyl 2-{1-[4-(4-chlorophenyl)-phenyl]propoxy}acetate as an oil (5 g.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH2:24][CH:23]2[OH:40])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH2:24][C:23]2=[O:40])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3cc(F)ccc3-n3cccc3)CC2O)CCCCC1)c1cc2ccccc2o1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NC1(C(=O)NC2CCN(c3cc(F)ccc3-n3cccc3)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To the solution 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(pyrrol-1-yl)-5-fluorophenyl]piperidin-3-ol (1.8 g) obtained in Step 1 in 10 ml of dimethylsulfoxide, was added 2 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (1.8 g) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate, washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 1.5 g of the titled compound.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:15]([O-:18])(=[S:17])[CH3:16].[K+].CN(C=O)C>O>[C:15]([S:17][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4])(=[O:18])[CH3:16]
Reactant: CC([O-])=S
Reactant: COC(=O)C(Br)Cc1ccc(C)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(C)cc1)SC(C)=O
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of methyl 2-bromo-3-(4-methylphenyl)propionate (25.7 g), potassium thioacetate (CH3COSK) (13.7 g) and DMF (120 ml) was stirred for an hour at room temperature. The mixture was poured into water and extracted with ether. The ethereal layer was washed with water, dried (MgSO4) and concentrated to give methyl 2-acetylthio-3-(4-methylphenyl)propionate (25.2 g, 100%) as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[O:29][CH3:30]>C1COCC1>[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[C:20]([O:29][CH3:30])[CH:21]=2)(=[O:26])=[O:27])[C:8]=1[CH3:16]
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(OC)c2)c2ncccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, ice-cooled (0° C.). solution of sodium hydride (0.026 g of a 60% dispersion in mineral oil, 0.686 mmol) in THF (3 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.1 g, 0.49 mmol) in dry THF (3 ml). The reaction mixture is stirred at 0° C. for 1 hour and then treated with 4-fluoro-3-methoxy-benzenesulfonyl chloride (0.154 g, 0.686 mmol) in dry THF (3 ml). Stirring continued at 0° C. for 30 minutes and then the reaction mixture is poured onto water (100 ml) and extracted with ethyl acetate (3×50 ml). The organic portions are separated and washed with water (2×50 ml), brine (50 ml), dried (MgSO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) yields the titled product. (MH+ 392).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:8]([F:14])([F:13])[CH:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=3)[CH2:6][CH2:5][C:4]=2[C:3]=1[OH:30].[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>CCOCC>[F:14][C:8]1([F:13])[C:9]2[C:4](=[C:3]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:2]([F:1])=[C:11]([F:12])[CH:10]=2)[CH2:5][CH2:6][CH:7]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1ccc(C2CCc3c(cc(F)c(F)c3O)C2(F)F)cc1
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(C2CCc3c(cc(F)c(F)c3OCCCCCCCC)C2(F)F)cc1

Procedure:
From 2,3,5,5-tetrafluoro-6-(4-octyloxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-ol and 1-octyl bromide by means of the Williamson ether synthesis.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17](N(OC)C)=[O:18])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[Mg]Br.O1CCCC1.[Cl-].[NH4+].O>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)=[O:18])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Br[Mg]c1cccs1
Reactant: CON(C)C(=O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCc1nnc(-c2ccc3c(c2)CCO3)o1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a solution of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]-N-methoxy-N-methylpropionamide (2.50 g, 8.24 mmol) in tetrahydrofuran (50 mL) was added 1 M (2-thienyl)magnesium bromide-tetrahydrofuran solution (9.9 mL, 9.9 mmol), and the resulting mixture was stirred at room temperature for 1 hr. A saturated aqueous ammonium chloride solution (50 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (1.10 g, yield 41%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[C:21]([C:23]([O:25]C)=[O:24])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)co3)cc2)nc1Cl
Yield: 48.5 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}phenyl)-1,3-oxazole-4-carboxylate obtained in Example (96c) (0.12 g, 0.32 mmol), 2 N lithium hydroxide (2 mL, 4 mmol), methanol (3 mL) and tetrahydrofuran (5 mL), to obtain 56 mg of the title compound as a light brown solid (48%).