Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][C:30]2[C:31](=[O:38])[N:32]=[C:33](SC)[NH:34][CH:35]=2)=[CH:25][N:24]=1>C(O)C>[CH3:21][O:22][C:23]1[N:24]=[CH:25][C:26]([CH2:29][C:30]2[C:31](=[O:38])[N:32]=[C:33]([NH:18][CH2:17][CH2:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=4)=[CH:11][CH:12]=3)[NH:34][CH:35]=2)=[CH:27][N:28]=1
Reactant: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)nc2=O)cn1
Temperature: 125 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
2-[4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]ethylamine (0.246 mmol, 1.3 eq) and 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.189 mmol, 1 eq) were dissolved in dry ethanol (300 μL) and stirred at 125° C. for 16 hours. Solvent was evaporated and crude product was purified by Waters Mass Direct Autopurification system giving 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-{2-[4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl]-ethylamino}-1H-pyrimidin-4-one (0.090 mmol; yield: 36%, HPLC-MS/UV: [M+H]+=499.34; rt: 10.40 min; purity: 94%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.93 (t, J=7.05, 2H), 3.51 (s, 2H), 3.58-3.74 (m, 2H), 3.95 (s, 1H), 5.31 (br.s., 1H), 6.98-7.13 (m, 3H), 7.22-7.32 (m, 2H), 7.61-7.67 (m, 1H), 7.89 (dd, J=8.50, J=2.64, 1H), 8.38 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:27])[C:10]([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[O:15][CH2:14]2)([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[Br:28]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:27])[C:10]([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:16]([CH2:26][Br:28])[O:15][CH2:14]2)([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cccc(Cl)c2)CO1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C(=O)Nc1cccc(Cl)c1)N1COC(CBr)=C(c2ccccc2)C1=O
Temperature: 65 °C
Yield: 8.5 %

Procedure:
A mixture of N-(3-chlorophenyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (1.0 g), N-bromosuccinimide (0.45 g), azobis-isobutyronitrile (10 mg) in carbon tetrachloride was heated at 65° C. for 2 hours. A second addition of N-bromosuccinimide (0.1 g) was made and the solution heated at 65° C. for a further 2 hours. The solution was then allowed to cool and the solvent removed under reduced pressure to give a brown residue, which was purified by dry column chromatography on silica, eluting with ethyl acetate/dichloromethane to give N-(3-chlorophenyl)-2-(6-bromomethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 8, 0.1 g) as a white solid, m.p. 89.8-90.8° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][O-:14].[Na+].O>CO>[Cl:1][C:2]1[C:7]([O:14][CH3:13])=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N)c([N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
To a mixture of 4,5-dichloro-2-nitro-phenylamine (1.29 g, 6.23 mmol) and dry MeOH (2 mL), a 25 wt % solution of sodium methoxide in MeOH (10 mL) was added and the mixture stirred for 6 h at 100° C. in a sealed tube. The mixture was cooled to 23° C., poured into water (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (25 mL), dried, filtered, and concentrated under reduced pressure to afford the titled compound (0.700 g, 56%). The crude material was used without further purification in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:2].[CH3:23][Si](C)(C)N[Si](C)(C)C.[K].CI>C1COCC1>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:6]1[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:23])[CH3:2]
Reactant: CCOC(=O)Cc1cc2ccccc2n1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1cc2ccccc2n1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
tert-Butyl 2-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (3.0 g, 9.9 mmol) was added to anhydrous THF (29 mL) and cooled to −78° C. A 0.5M solution of potassium hexamethyldisilazane (20 mL, 9.9 mmol) was added slowly such that the internal temperature stayed below −60° C. Stirring was continued for 1 h at −78° C. Methyl iodide (727 μL, 11.7 mmol) was added to the mixture. The mixture was stirred for 30 minutes at room temperature. The mixture was quenched with sat. aq. ammonium chloride and partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethylacetate/hexane=1/9) to give tert-butyl 2-(1-ethoxy-1-oxopropan-2-yl)-1H-indole-1-carboxylate (2.8 g, 88%).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:26]I>CN(C)C=O.O>[CH3:26][N:19]1[C:20]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:17][C:18]1=[O:23]
Reactant: CI
Reactant: O=C1CCc2cc(OCCCCSc3ccccc3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CCc2cc(OCCCCSc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16.2 gm of 6-(4-phenylmercapto-butoxy)-3,4-dihydro-carbostyril were dissolved in 100 ml of dimethylformamide, and 4.8 gm of a 50% sodium hydride suspension in paraffin oil were added to this solution. After addition of 12.5 ml of methyl iodide, the mixture was stirred for 3 hours at room temperature, diluted with water and extracted with chloroform. The evaporation residue of the chloroform extract was recrystallized with methanol in the presence of activated charcoal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:22][CH:23]1[CH2:25][O:24]1>>[F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][CH:23]3[CH2:25][O:24]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(F)c(F)c2)CCN1
Reactant: BrCC1CO1
Product: O=C(/C=C/c1ccc(F)c(F)c1)N1CCC(=O)N(CC2CO2)CC1

Procedure:
In analogy to the procedure described for example 166A, 1-[(E)-3-(3,4-difluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 55) and 2-bromomethyl-oxirane gave the title compound as yellow oil. MS: 337.2 (MH+).
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][C:17]3=O)=[CH:12][CH:11]=2)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[CH3:27][NH:28][CH3:29]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:27][N:28]([CH3:29])[C:17]1[C:18]2[C:13](=[CH:12][CH:11]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:5]3[C:4](=[O:21])[C:3]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]4[C:1]3=[O:26])[CH:19]=2)[CH2:14][CH2:15][CH:16]=1
Reactant: O=C1CCCc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc21
Reactant: CNC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(C)C1=CCCc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc21
Temperature: 1 °C
Reaction time: 2 h

Procedure:
A solution of titanium tetrachloride (5.4 g) in toluene (20 ml) is added over a period of 15 minutes to a stirred solution of 7-(3-phthalimido) propoxy-1-tetralone (19.9 g) suspended in a solution of anhydrous dimethyl amine (22 g) in dry toluene (200 ml) while maintaining a reaction temperature of about 1° C. under a N2 atmosphere. When the addition is complete, the reaction mixture is allowed to warm to RT and stirred at RT for 41/2 hours. The reaction mixture is filtered, the salts washed with dry toluene and the clear filtrate evaporated, affording a light yellow oil, which is stored under N2 and used in the next step without any further treatment.
Reaction SMILES: Cl[C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[OH:18][CH2:19][CH:20]1[CH2:22][CH2:21]1.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:2]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)=[N:3][CH:4]=[C:5]([CH:9]=2)[C:6]([OH:8])=[O:7])=[CH:12][CH:13]=1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: OCC1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-5-(4-chloro-phenyl)-nicotinic acid (22.3 g, 0.083 mol) was dissolved in dimethylsulfoxide (130 mL). To this solution was added (hydroxymethyl)cyclopropane (10.1 g, 0.125 mol) and potassium hydroxide powder (18.7 g, 0.333 mol). This mixture was reacted (in ten portions) for 20 min in a microwave at 100° C. The reaction mixture was poured into ice-water (500 mL) and citric acid (10%, 3000 mL) was added with stirring. Stirring was continued for 30 min during which time the product precipitated. The product was filtered off washed with water and dissolved in ethylacetate (1500 mL). The solution was concentrated in vacuo and the title compound crystallized from the concentrated solution as a white solid (21.5 g); MS (ISP) 302.2 (M−H)
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:14]C)=[C:12]([F:13])[C:7]=2[N:6]([CH3:16])[C:5]1=[O:17].CC(C)=O.C(=O)=O.B(Br)(Br)Br>ClCCl>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[C:12]([F:13])[C:7]=2[N:6]([CH3:16])[C:5]1=[O:17]
Reactant: COc1ccc2c(c1F)n(C)c(=O)n2CC(C)(C)C
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(O)c(F)c21
Reaction time: 15 h

Procedure:
A solution of 1-(2,2-dimethylpropyl)-4-fluoro-5-methoxy-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (7-5, 193 mg, 0.73 mmol) in anhydrous Dichloromethane (10 ml) was cooled to −78 deg C. (Acetone/dry ice) and treated with Boron tribromide (1M in DCM, 1.45 ml, 1.45 mmol, 2 eq). The resulting mixture was allowed to slowly wann to 23 deg C. over 15 h. The reaction was only ˜75% complete by LC/MS, so it was treated with more BBr3 (360 ml, 0.36 mmol, 0.5 eq). The reaction was stirred at 23 deg C. for 1 h, then was carefully quenched by pouring directly into a solution of saturated aqueous NaHCO3 cooled to 0 deg C. The aqueous mixture was extracted with Methylene Chloride (2×200 ml), and the combined organic layers were dried over Na2SO4 and concentrated, thereby providing the title compound, 1-(2,2-dimethylpropyl)-4-fluoro-5-hydroxy-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (7-6), as a green-tan solid. 1H NMR (500 MHz, CDCl3) δ 6.65-6.73 (m, 2H), 3.61 (m, 5H), 1.02 (s, 9H). LRMS m/z: Calc'd for C13H17FN2O2 (M+H) 253.3, found 253.0.
Reaction SMILES: [OH-].[Na+].C(OC([N:10]([C:33]1[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=1)[S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([C:29]([O:31]C)=[O:30])[CH3:28])=[CH:22][CH:21]=2)=[N:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])=O)C(C)C>CO.C(COC)OC>[C:29]([CH:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]2[C:14]([S:11]([NH:10][C:33]3[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=3)(=[O:13])=[O:12])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1)[CH3:28])([OH:31])=[O:30]
Reactant: COC(=O)C(C)Oc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(OC(C)C(=O)O)cc1
Reaction time: 72 h
Yield: 40.8 %

Procedure:
2M Sodium hydroxide solution (1 ml) was added to a solution of N-(isobutoxycarbonyl)-2-(4-[1-(methoxycarbonyl)ethoxy]phenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.302 g) in methanol (5 ml) and dimethoxyethane (5 ml) and the solution was stirred for 3 days. Volatile material was removed by evaporation and the residue was dissolved in water (15 ml). The solution was washed with ethyl acetate (2×15 ml) and acidified to pH3 with 6M hydrochloric acid. The mixture was extracted with ethyl acetate (2×10 ml) and the extracts were re-extracted with saturated sodium bicarbonate solution (2×10 ml). The aqueous solution was acidified with 2M hydrochloric acid and extracted with ethyl acetate (2×10 ml). The extracts were washed with water (10 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was recrystallised from ethyl acetate to give 2-[4-(1-carboxyethoxy)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.098 g), m.p. 149-151° C.; microanalysis found: C, 53.6; H, 4.9; N, 11.7%; C18H18N4O6S.0.2C4H8O2 requires: C, 54.1; H, 4.7; N, 12.1%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[C:8]([CH3:15])[CH:7]=1.[N+:16]([NH:19][C:20](=[NH:23])SC)([O-:18])=[O:17]>C(O)C>[CH3:13][N:12]([CH2:11][C:9]1[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:20]([NH:19][N+:16]([O-:18])=[O:17])=[NH:23])=[CH:7][C:8]=1[CH3:15])[CH3:14]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: Cc1cc(CSCCN)oc1CN(C)C
Solvent: CCO
Product: Cc1cc(CSCCNC(=N)N[N+](=O)[O-])oc1CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-[[2-(amino)ethyl]thio]methyl-N,N,3-trimethyl-2-furanmethanamine (1.14 g) and N-nitro-S-methyl-isothiourea (0.65 g) in ethanol (10 ml) was warmed for 5 minutes and stirred for 30 minutes at ambient temperature. The solvent was removed in vacuo and the residue purified by column chromatography (silica/methanol: 0.88 ammonia 100:1). The resulting oil was triturated with petroleum ether (40°-60°) and the solid residue crystallised from toluene yielding the title compound (0.5 g) as a white powder m.p. 84°-85°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC(=O)C)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[OH:26])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A mixture of potassium 7β-[2-(2-amino-4-thiazolyl)-2-(Z-trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (25 gm) and activated carbon (2.5 gm) was added to an aqueous acetone solution (1:1, 70 ml) containing p-toluenesulphonic acid (17.7 gm) at 50° C. The reaction mixture was heated to 70° C. in 20 minutes and maintained at this temperature for 35 minutes. After completion of the reaction, chilled ethylacetate (200 ml) having temperature −15° C. was added to the reaction mixture to reduce the temperature to 30–35° C. The carbon was filtered and the carbon bed was washed with water (50 ml). The filtrate was diluted with water (200 ml), warmed to 35° C. and pH of the solution was adjusted to 6.0–6.5 using aqueous ammonia solution (20%). The aqueous layer was separated and treated with carbon (2.0 gm) at 35° C. for 35 min. The carbon was filtered and the carbon bed was washed with water (50 ml). Acetone (25 ml) was added to the filtrate and 10% (w/v) solution of sulphuric acid was added dropwise to bring down the pH from 4.5 to 2.8 at 33–35° C., stirred for 30 minutes and adjusted the pH again to 2.6. The resulting slurry was stirred for 15–20 minutes at 33–35° C., cooled to 20–25° C., and stirred for 30 minutes. The product thus obtained was filtered, washed with water (50 ml) and dried at 35° C. under vacuum for 3–4 hours to get the title compound (9.0 gm, HPLC purity>99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH:13]2[C:25]([NH2:27])=[O:26])=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:25]([NH2:27])=[O:26])=[CH:4][CH:3]=1
Reactant: NC(=O)C1CN(Cc2ccccc2)CCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)C1CNCCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 66.4 %

Procedure:
A mixture of 14.8 parts of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(phenylmethyl)-2-piperazinecarboxamide and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 7.9 parts (66.4%) of 1-[4,4-bis(4-fluorophenyl)butyl]-2-piperazinecarboxamide; m.p. 113.6° C. (intermediate 53).
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([C:11](=O)[CH3:12])[N:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(OC(=O)[N:20]([CH2:31][CH2:32][NH2:33])[CH2:21][C:22]1[CH:30]=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1)(C)(C)C>>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([CH2:21][NH:20][CH2:31][CH2:32][NH:33][CH:11]([C:9]3[N:10]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[S:7][CH:8]=3)[CH3:12])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N(CCN)Cc1ccc2c(c1)OCO2
Reactant: CC(=O)c1csc(-n2ccnc2)n1
Product: CC(NCCNCc1ccc2c(c1)OCO2)c1csc(-n2ccnc2)n1

Procedure:
N-Benzo[1,3]dioxol-5-ylmethyl-N′-[1-(2-imidazol-1-yl-thiazol-4-yl)-ethyl]-ethane-1,2-diamine was prepared following the procedures described in the preparation of Example 64 using 1-(2-imidazol-1-yl-thiazol-4-yl)-ethanone and (2-amino-ethyl)-benzo[1,3]dioxol-5-ylmethyl-carbamic acid tert-butyl ester. [M+H]+ 372.01; 1H NMR (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 7.82 (d, 1H), 7.31 (s, 1H), 7.18 (d, 1H), 6.92 (d, 1H), 6.84 (d, 1H), 6.77 (dd, 1H), 6.00 (s, 2H), 4.14 (br s, 2H), 3.82 (q, 1H), 3.60 (s, 2H), 3.21 (s, 2H), 2.57 (s, 2H), 1.34 (d, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[C:11](=[O:12])[CH:10]2[CH2:13][CH:7]([CH2:8][CH2:9]2)[C:6]1=[O:14])=O.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[S:21])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[S:21][CH:2]=[C:3]([CH:5]3[C:11](=[O:12])[CH:10]4[CH2:13][CH:7]([CH2:8][CH2:9]4)[C:6]3=[O:14])[N:22]=2)=[CH:18][CH:17]=1
Reactant: O=C(CCl)C1C(=O)C2CCC(C2)C1=O
Reactant: NC(=S)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C1C2CCC(C2)C(=O)C1c1csc(-c2ccc(Cl)cc2)n1
Yield: 53.3 %

Procedure:
3-(2-chloro-acetyl)bicyclo[3.2.1]octane-2,4-dione (3.16 g, 14.7 mmol) and 4-chloro-thiobenzamide (2.53 g, 14.7 mmol) are mixed together in toluene (50 ml) and heated under reflux overnight. Therefore, the reaction mixture was evaporated to a black gum and the gum was absorbed onto silica and purified by flash chromatography eluting with a gradient of hexane/ethyl acetate to give 3-[2-(4-chloro-phenyl)thiazol-4-yl]bicyclo[3.2.1]octane-2,4-dione (2.6 g).
Reaction SMILES: [S:1]([C:5]1[S:14][C:8]2=[N+:9]([O-:13])[CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C(#N)C>[CH3:17][N:18]([CH3:20])[CH:19]=[N:2][S:1]([C:5]1[S:14][C:8]2=[N+:9]([O-:13])[CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)(=[O:3])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1cc2ccc[n+]([O-])c2s1
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc2ccc[n+]([O-])c2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-sulfamoylthieno[2,3-b]pyridine-7-oxide (0.50 g, 2.2 mmol) and dimethylformamide dimethyl acetal (0.3 g, 2.2 mmol) in acetonitrile (3 ml) was stirred for 24 hours at 25° C. The solvent was evaporated and the residue was treated with water. After filtration and drying, there was obtained 0.57 g, (91%) m.p. 232°-234° C.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][O:14][CH2:15][C:16]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[C:20]([B:31]2[O:35][C:34](C)(C)C(C)(C)[O:32]2)[C:17]=1C=O>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][CH:34]1[O:35][B:31]([OH:32])[C:20]2[CH:21]=[C:22]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[CH:23]=[C:16]([CH2:15][O:14][CH3:13])[C:17]1=2)[CH3:12]
Reactant: COCc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(COC)c21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A suspension of zinc (8.04 g, 123 mmol) in THF (80 mL) was added TMSCl (2.31 ml, 18.2 mmol) at 40° C. The temperature was increased to 55° C. over 30 min. Then, the temperature was lowered to 37° C. and ethyl 2-bromoacetate (12.6 mL, 114 mmol) was added slowly. The resulting solution was stirred for 30 min and cooled from 45° C. to room temperature and stood by for 1 h. The top clear layer (25 mL) was added to a solution of 2-methoxymethyl-4-(tetrahydro-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (3.56 g, 9.46 mmol) in THF (50 ml) at −78° C. After the addition, the reaction was warmed to 0° C. using an ice bath and stirred at 0° C. 30 min. The reaction mixture was quenched with aqueous NH4Cl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=2:1) to afford the title compound (2.30 g, 67%). 1H NMR (300 MHz, CDCl3) δ 7.33 (s, 1H), 7.11 (s, 1H), 5.73-5.70 (m, 1H), 5.46-5.44 (m, 1H), 4.54-4.39 (m, 2H), 4.21-4.16 (q, 2H), 3.94-3.90 (m, 1H), 3.66-3.60 (m, 1H), 3.38 (s, 3H), 3.18-3.11 (m, 1H), 2.43-2.34 (m, 1H), 1.88-1.85 (m, 2H), 1.70-1.61 (m, 4H), 1.26 (t, 3H).
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:18]#[N:19])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:20])(OC)=O.S(=O)(=O)(O)O>C(O)(=O)C>[C:18]([C:9]1([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:10][CH2:5][C:6](=[O:20])[CH2:7][CH2:8]1)#[N:19]
Reactant: COC(=O)C1CC(C#N)(c2ccc(F)cc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N#CC1(c2ccc(F)cc2)CCC(=O)CC1
Reaction time: 24 h
Yield: 67 %

Procedure:
A reaction mixture consisting of 33.9 gm. (0.123 mole) of 2-carbomethoxy-4-cyano-4-(p-fluorophenyl)cyclohexanone (prepared in Part B, above), 900 ml. glacial acetic acid, and 450 ml. 10% aqueous sulfuric acid is heated with stirring on a steam bath for 24 hours. After allowing the reaction mixture to cool, it is diluted with 2000 ml. water and extracted thoroughly with benzene. The benzene extracts are combined and washed successively with water, with aqueous sodium bicarbonate, and finally with brine. The benzene is then removed by evaporation under reduced pressure, and the solid residue thus obtained is recrystallized from diethyl ether to afford 16.23 gm. (67% yield) of 4-cyano-4-(p-fluorophenyl)cyclohexanone having a melting point at 84° to 88° C.