Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].[CH:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]>>[F:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CCCCC=O
Product: CCCCC(=O)c1ccc(C(F)(F)F)cc1F

Procedure:
The titled compound was prepared from 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (200 mg, 0.823 mmol) and valeraldehyde (0.05 mL, 0.8 mmol) in a procedure similar to that of Example 9 (1) as a pale yellow oil (114 mg, yield 97%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:22]>>[ClH:22].[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:20][CH:21]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Product: O=C(O)c1ccc(OCCCN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-(3-piperidin-1-ylpropoxy)benzoate (D1) (82.57 g) in concentrated hydrochloric acid (750 ml) was heated under reflux for 2 h. The mixture was cooled to rt then chilled to 5° C. and filtered. The filter cake was washed with acetone and dried to yield the title compound (D2) as a white crystalline solid (75.30 g) that displayed MS and 1H NMR spectra that were identical to those of the product obtained by D2 (Method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9](Br)[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].O.[CH3:15][N:16]1CCCC1=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:15]#[N:16])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7]
Reactant: CN1CCCC1=O
Reactant: COc1cc(C=O)cc(Br)c1OC
Solvent: O
Product: COc1cc(C=O)cc(C#N)c1OC

Procedure:
A mixture containing 2.5 g of 3,4-dimethoxy-5-bromobenzaldehyde and 1.0 g of cuprous cyanide in N-methylpyrrolidone was refluxed for 2 h. Water was added and the solution was extracted with dichloromethane. The solvent was evaporated in vacuo. Yield 1.55 g (81%), m.p. 109°-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[CH3:22].C[Si]([N:35]=[C:36]=[O:37])(C)C>C1COCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH:16]([NH:19][C:36]([NH2:35])=[O:37])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[CH3:22]
Reactant: C[Si](C)(C)N=C=O
Reactant: C[C@@H](Nc1cc(N2CCC(N3CCC(N)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](Nc1cc(N2CCC(N3CCC(NC(N)=O)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
To a stirred solution of 1-(1-(4-chloro-3-((R)-1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidin-4-yl)pyrrolidin-3-amine (0.056 g, 0.12 mmol) in THF (1 mL) and acetic acid (1 drop) was added a solution of (trimethylsily)isocyanate (0.015 g, 0.13 mmol) in THF (0.5 mL). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with diluted with aqueous saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude was purified by flash chromatography (SiO2, 2-10% methanol in dichloromethane) to afford the desired product as a white solid (0.016 g, 0.031 mmol, 26%). 1H NMR (400 MHz, CDCl3) δ 7.36-7.32 (m, 2H), 7.16 (dd, J=2.2, 8.4 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.82 (br, 1H), 6.16 (dd, J=2.5, 8.8 Hz, 1H), 5.77 (br, 1H), 5.23 (br, 1H), 4.87 (q, J=6.6 Hz, 1H), 4.64 (d, J=5.2 Hz, 1H), 3.44-3.37 (m, 2H), 3.08-2.82 (m, 3H), 2.69-2.40 (m, 4H), 2.25-1.85 (m, 6H), 1.60-1.42 (m, 5H); MS: (ES) m/z calculated for C24H31Cl3N5O [M+H]+ 510.2. found 510.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[C:29]([CH:30]=[CH:31][C:16]2=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:11][CH:10]=1)=[O:7].ClC1C=CC=C(C(OO)=[O:43])C=1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[C:29]([CH:30]=[CH:31][C:16]2=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:13][CH:14]=1)=[O:7])=[O:43]
Reactant: CSc1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)c1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
5-[4-[3-(Methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20 mg, 0.043 mmol) obtained in Example 126 was dissolved in dimethylformamide (0.4 mL), the solution was added with m-chloroperbenzoic acid (ii mg, 0.03 mmol) at −20° C., and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was added with ethyl acetate at −20° C., the organic layer was washed with saturated aqueous sodium hydrogencarbonate, water, and saturated brine. The solvent of the organic layer was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to obtain the title compound (8 mg, yield 38%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)(=[O:4])=[O:3].[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([C:8]([C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:6]=2[NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[O:10])[CH2:30][CH2:31]1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3NS(C)(=O)=O)CC2)c(C)c1
Yield: 55.5 %

Procedure:
Methyl 2-amino-4-nitrobenzoate (600 mg) and triethylamine (2.9 mL) were dissolved in tetrahydrofuran (11 mL), methanesulfonyl chloride (0.51 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. Methanol (18 mL) and 1N aqueous sodium hydroxide solution (9.1 mL) were added to the obtained residue, and the mixture was stirred at 50° C.-60° C. After completion of the reaction, to the reaction mixture was added aqueous sodium hydroxide solution, and the mixture was partitioned with ethyl acetate. The aqueous layer was neutralized with diluted hydrochloric acid, and the precipitated solid was collected by filtration to give 2-methanesulfonylamino-4-nitrobenzoic acid (358 mg). Using the obtained 2-methanesulfonylamino-4-nitrobenzoic acid (358 mg) and 1-(2,4-dimethylphenyl)piperazine (262 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, N-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-nitrophenyl}methanesulfonamide (330 mg) was obtained. Then, to a solution of ethanol (5.4 mL) and water (1.8 mL) were added ammonium chloride (528 mg) and iron (379 mg), and the obtained N-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-nitrophenyl}methanesulfonamide (267 mg) was added while stirring at 60° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (268 mg).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1)[C:23](Cl)=[O:24]>C1COCC1>[CH3:30][O:29][C:27]1[CH:26]=[C:22]([C:23]([C:2]2[CH:12]=[CH:11][C:5]3[N:6]([CH3:10])[CH2:7][CH2:8][O:9][C:4]=3[CH:3]=2)=[O:24])[CH:21]=[C:20]([O:19][CH3:18])[CH:28]=1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: CN1CCOc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=O)c2ccc3c(c2)OCCN3C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.9 %

Procedure:
To a solution of 7-bromo-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (0.9 g, 3.9 mmol) in THF (10 mL) was added n-butyllithium (1.3 mL, 2.5 N, 3.3 mmol) at −78° C. After 10 min, the solution was added to a solution of 3,5-dimethoxy-benzoyl chloride (650 mg, 3.2 mmol) in THF (10 mL) at −78° C. After 1 h, the cold bath was removed and the mixture was allowed to warm to room temperature. To the mixture was added iso-propanol (2 mL), water (30 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers was washed with sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (Silica Gel) gave (3,5-dimethoxy-phenyl)-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-methanone as a yellow solid (320 mg, 30% yield): 1H NMR (CDCl3) δ 2.86 (s, 3H, CH3), 3.42 (t, J=5 Hz, 2H, CH2), 3.82 (s, 6H, 2CH3), 4.27 (t, J=4 Hz, 2H, CH2), 6.60-6.64 (m, 2H, Ar), 6.85 (d, J=2 Hz, 2H, Ar), 7.36 (d, J=8 Hz, 1H, Ar), 7.43 (dd, J=2, 9 Hz, 1H, Ar).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:15]([O:19][C:20](=[O:28])[NH:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH:24]=O)([CH3:18])([CH3:17])[CH3:16]>CCCCCC.CCOC(C)=O>[C:15]([O:19][C:20](=[O:28])[NH:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Reactant: Nc1ccccc1C1(O)CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(CCNc1ccccc1C1(O)CCCCC1)NC(=O)OC(C)(C)C

Procedure:
The product is prepared analogously to intermediate product 1b starting from 1-(2-aminophenyl)cyclohexanol and tert-butyl(1,1-dimethyl-3-oxopropyl)carbamate. After column chromatography (silica gel, hexane/EtOAc 7:1) the product is obtained as a colorless oil. Yield: 2.65 g (66%); Rf=0.50 (silica gel, hexane/EtOAc 4:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13]C=O)[CH2:10][C@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@H](OC=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution of (2S,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (5.12 g: 18.7 mmole) in methanol (51.0 ml), aqueous 1N-sodium hydroxide (18.7 ml) is added under ice cooling. The mixture is stirred at the same temperature for 20 minutes to give (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (4.09 g). Yield: 89%. Colorless crystals. NMR δ(CDCl3) ppm: 1.44(d, J=8.2 Hz, 9H), 2.0 to 2.2(m, 1H), 2.2 to 2.5(m, 1H), 3.2 to 3.8(m, 3H), 3.79(d, J=2.8 Hz, 3H), 4.2 to 4.5(m, 2H). IR ν (KBr) cm-1 : 3460, 1728, 1677.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[N:23]1([CH2:29][CH2:30][CH2:31][OH:32])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(OCC)(=O)C.C(N(CC)CC)C>[OH:32][CH2:31][CH2:30][CH2:29][N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[C:15]3[CH3:20])=[O:8])[CH2:25][CH2:24]1
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Reactant: OCCCN1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCCCCN2CCN(CCCO)CC2)c2nccc(C)c2c1
Yield: 95.3 %

Procedure:
A mixture of 4.3 g (0.012 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 3.5 g (0.024 mole) of 1-piperazinepropanol was heated at 120° for 2 hr and allowed to cool. The mixture was diluted with ethyl acetate and excess triethylamine, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to dryness to afford 4.9 g (96%) of the desired compound as a gum. The IR and NMR (CDCl3) were consistent with the assigned structure.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[O:7])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].C([O-])([O-])=O.[K+].[K+].[C:29]1([CH3:41])[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CN(C=O)C>[N+:20]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:2]=1[N:38]1[CH2:39][CH2:40][N:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH3:41])[CH2:36][CH2:37]1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])=[O:7])([O-:22])=[O:21]
Reactant: O=C(NCCCN1CCCC1=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-Fluoro-3-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide (2.0 g, 6.47 mmol) in DMF (10 mL), K2CO3 (1.7 g, 12.94 mmol) was added followed by 1-o-tolyl-piperazine (1.7 g, 9.7 mmol), and the reaction mixture was stirred at room temperature for 16 h. DMF (2.0 mL) was added and filtered. The solid was washed with MeOH (300 mL) and methanol layer was evaporated to give the acid 3-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide in the first crop (1.8 g, 62%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1)=O>>[CH3:38][C:35]1[N:34]=[CH:33][C:32]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)=[CH:37][CH:36]=1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: Cc1ccc(C(=O)CBr)cn1
Product: Cc1ccc(-c2csc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)cn1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 58 mg (0.269 mmol) of 2-bromo-1-(6-methylpyridin-3-yl)ethanone were reacted according to the General Method 3. Yield: 18 mg (15% of theory)
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]3[C:16]([C:17]=2[O:18]C)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](OCC)(=O)[CH3:24]>S(=O)(=O)(O)O.C(O)C.O>[CH2:23]([O:22][C:20]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=1)=[O:21])[CH3:24]
Reactant: COc1c(Cc2ccccc2)cc(C(=O)O)c2ccccc12
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(Cc2ccccc2)c(O)c2ccccc12
Yield: 62 %

Procedure:
A solution of the compound of Example 95 (2.55 g, 9.2 mmole) and concentrated sulfuric acid (3 drops) in ethanol (125 mL) was heated at reflux for 80 hours. The mixture was cooled and diluted with water, and the crude product was isolated by extraction with ethyl acetate. This was chromatographed (9:1 hexane/ethyl acetate) and recrystallized (hexane) to provide the title compound (1.74 g 62%) as white needles, mp 79°-80°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([CH2:15][OH:16])[N:3]=1>CCO>[Cl:1][C:2]1[N:3]=[C:4]([CH2:15][OH:16])[CH:5]=[C:6]2[CH:9]=[C:10]([Si:11]([CH3:12])([CH3:14])[CH3:13])[O:8][C:7]=12
Reactant: C[Si](C)(C)C#Cc1cc(CO)nc(Cl)c1O
Solvent: CCO
Product: C[Si](C)(C)c1cc2cc(CO)nc(Cl)c2o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 46 %

Procedure:
C3 (7.9 g, 31.2 mmol) and cuprous iodide (297 mg, 1.6 mmol) in 60 mL EtOH/60 mL TEA are added to a flask. The reaction is placed in an oil bath at 70° C. for 3.5 h, is cooled to rt, and concentrated in vacuo. The residue is partitioned between 100 mL 5% HCl and CH2Cl2 (4×50 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give 6.5 g of a crude amber solid. The crude material is chromatographed over 300 g silica gel (230-400 mesh) eluting with 30-40% EtOAc/hexane. Two sets of fractions with two different desired compounds are identified by TLC/UV. The two compounds eluted separately. The early-eluting pool of fractions is combined and concentrated to afford [7-chloro-2-(trimethylsilyl)furo[2,3-c]pyridin-5-yl]methanol (C5) as a white solid (46% yield). The later-eluting pool of fractions is combined and concentrated to provide (7-chlorofuro[2,3-c]pyridin-5-yl)methanol (C4) as a white solid (27% yield). MS (EI) for C8H6ClNO2, m/z: 183 (M)+ for C4. HRMS (FAB) calculated for C11H14ClNO2Si m/z: 255.0482, found 255.0481 for C5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH2:16][CH2:17][CH:18]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:30]([O:29][C:27]([NH:26][CH:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:17][NH:16][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(CN)Cc1ccccc1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: CC(C)(C)OC(=O)NC(CNC(=O)C1CCN(c2ccncc2)CC1)Cc1ccccc1
Yield: 39 %

Procedure:
Using an analogous procedure to that described in the second paragraph of the portion of Example 2 which is concerned with the preparation of starting materials, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-amino-2-(tert-butoxycarbonylamino)-3-phenylpropane to give N-[2-(tert-butoxycarbonylamino)-3-phenylpropyl]-1-(4-pyridyl)piperidine-4-carboxamide in 39% yield.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH:10]C(=O)C>S(=O)(=O)(O)O.CO.O>[NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH2:10]
Reactant: CC(=O)Nc1nc2c([nH]1)CCCC2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: Nc1nc2c([nH]1)CCCC2
Yield: 101.2 %

Procedure:
N-(4,5,6,7-Tetrahydro-1H-benzo[d]imidazol-2-yl)acetamide (0.40 g) was heated at reflux in a stirred solution of 1:1 methanol/water (5 mL) containing 5 drops of concentrated sulfuric acid for 12 hours. The mixture was cooled and evaporated to dryness on the lyophilizer to give 0.31 g of 4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-amine. 1H-NMR (400 MHz, DMSO-d6) 13.4 (bs, 1H), 6.59 (bs, 2H), 2.55 (m, 2H), 2.49 (m, 2H), 1.67 (m, 2H), 1.62 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH:26]=1)[C:7]([N:9]([CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)=[O:8]>C(OC(=O)C)C.[Ni].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH:26]=1)[C:7]([N:9]([CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])=[O:8]
Reactant: CN1CCC(N(C(=O)c2cc(Cl)ccc2F)c2ccccc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCC(N(C(=O)c2cc(Cl)ccc2F)c2ccccc2N)CC1

Procedure:
A solution of 32.4 g 5-chloro-2-fluoro-N-(1-methyl-4-piperidinyl)-N-(2-nitrophenyl)-benzamide in 700 ml acetic acid ethyl ester and 2 to 3 g Raney nickel is hydrogenated at room temperature and normal pressure. The precipitated product is dissolved in methanol under warming and the catalyst is filtered off. The filtrate is evaporated and the crystalline residue suspended in ether and filtered, to give the heading compound, m.p. 179°-182°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][N:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH:17]([CH2:30][CH3:31])[S:16][C:15]2=[O:32])=[CH:11][CH:10]=1>ClCCl.C(N(CC)CC)C>[F:1][C:2]([F:7])([F:6])[C:3]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH:17]([CH2:30][CH3:31])[S:16][C:15]2=[O:32])=[CH:33][CH:34]=1)=[O:4]
Reactant: CCC1SC(=O)N(Cc2ccc(N)cc2)N=C1c1ccc(OC)c(OC)c1
Reactant: O=C(Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1SC(=O)N(Cc2ccc(NC(=O)C(F)(F)F)cc2)N=C1c1ccc(OC)c(OC)c1

Procedure:
0.8 ml of trifluoroacetyl chloride is added with stirring and ice cooling to a solution of 1.4 g of 3-(4-amino-benzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one ("D") in 60 ml of dichloromethane and 1 ml of triethylamine, and the mixture is subsequently stirred for 3 hours. The solvent is removed and the residue is worked up in the conventional manner. Recrystallization from isopropanol/petroleum ether gives 1.9 g of 3-(4-trifluoroacetamidobenzyl)-5(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 124°.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[C:26]([O:35][C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=2[O:44][CH3:45])=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:41]=[C:40]([C:39]2[CH:42]=[CH:43][C:36]([O:35][C:26]3[C:25]([Cl:24])=[CH:30][C:29]([C:31]([F:34])([F:33])[F:32])=[CH:28][N:27]=3)=[C:37]([O:44][CH3:45])[CH:38]=2)[N:2]([CH3:1])[N:3]=1
Reactant: COc1cc(C#N)ccc1Oc1ncc(C(F)(F)F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2nc(-c3c(F)cccc3Cl)nn2C)ccc1Oc1ncc(C(F)(F)F)cc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (0.90 g), 4-(3-chloro-5-trifluoromethylpyridine-2-yloxy)-3methoxybenzonitrile (0.90 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.