Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1>Cl>[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])[CH2:12][CH2:11]1
Reactant: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Agent: Cl
Product: NC1CCN(CCCC(=O)c2ccccc2)CC1
Reaction time: 8 h

Procedure:
4-Benzamido-1-(4-phenyl-4-oxobutyl)piperidine (0.5 g.) was suspended in 6 N HCl (10 ml.) and boiled for 8 hr. The solution was cooled, filtered (to remove benzoic acid) and the filtrate basified with potassium carbonate. The oil which separated was extracted into chloroform which on evaporation gave the title compound as the free base (0.30 g.). This was dissolved in ethanol, ethanol/HCl added until acid and the title compound filtered off (0.376 g.) as the dihydrochloride m.p. 269.7°.
Reaction SMILES: Br[CH:2]1[C:7]([CH3:8])=[C:6]([C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[N:5]2[C:15](=[O:19])[C@H:16]([O:17][CH3:18])[C@H:4]2[S:3]1(=[O:21])=[O:20].C([O:35][C:36]1[C:37](=[O:54])[N:38]=[C:39]([S:43][CH2:44][C:45]2[CH:53]=[CH:52][C:48]([C:49]([OH:51])=[O:50])=[CH:47][CH:46]=2)[N:40]([CH3:42])[N:41]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(#N)C.C(Cl)Cl>[C:11]([C:9]([C:6]1[N:5]2[C:15](=[O:19])[C@H:16]([O:17][CH3:18])[C@H:4]2[S:3](=[O:21])(=[O:20])[CH:2]([O:51][C:49](=[O:50])[C:48]2[CH:52]=[CH:53][C:45]([CH2:44][S:43][C:39]3[N:40]([CH3:42])[N:41]=[C:36]([OH:35])[C:37](=[O:54])[N:38]=3)=[CH:46][CH:47]=2)[C:7]=1[CH3:8])=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(C)C(Br)S(=O)(=O)[C@H]12
Reactant: Cn1nc(OC(c2ccccc2)c2ccccc2)c(=O)nc1SCc1ccc(C(=O)O)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(C)C(OC(=O)c3ccc(CSc4nc(=O)c(O)nn4C)cc3)S(=O)(=O)[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-4-tert-butylcarbonyl-7α-methoxy-3-methyl-3-cephem 1,1-dioxide (110 mg) in acetonitrile (100 ml) was treated with 4-[(6-benzhydryloxy-2,5-dihydro-2-methyl-5-oxo-1,2,4- triazin-3-yl)thiomethyl]benzoic acid siver salt (230 mg). The reaction mixture was stirred at room temperature for 30 minutes, then diluted with EtOAC, filtered and rotoevaporated. Upon purification of the residue by flash chromatography 4-tert-butylcarbonyl-2-{4-[(6-benzhydryloxy-2,5-dihydro-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl]benzoyloxy}-7α-methoxy-3-methyl-3-cephem 1,1-dioxide was obtained as a white solid (mg 75). This product was dissolved in methylene chloride (0.5 ml) and sequentially treated with anisole (0.03 ml) and trifluoroacetic acid (0.5 ml).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][OH:5].Cl[C:7]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1>C1COCC1>[CH2:4]([O:5][C:7]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1)[CH3:3]
Reactant: CCO
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ncnc2c([N+](=O)[O-])cccc12
Reaction time: 0.25 h

Procedure:
A solution of 8-nitroquinazolin-4(3H)-one (Intermediate-7, step-1, 300 mg, 1.57 mmol) in POCl3 (3 mL) was heated at reflux for 2 h. Then the reaction mixture was concentrated and dried to afford 4-chloro-8-nitroquinazoline which was used for the next step without further purification. Then NaH (263 mg, 11.54 mmol, 95%) was added to EtOH (2 mL) at 0° C. and stirred at that temperature for 15 minutes before it was added to a solution of 4-chloro-8-nitroquinazoline in THF (2 mL) at 0° C. Then the reaction mixture was stirred at rt for 4 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 200 mg of the title product. MS (m/z): 220.23 (M+H)+.
Reaction SMILES: C([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][CH:14]([CH3:16])[CH3:15])=[N:8][CH:7]=1)(C)C>Cl>[CH:14]([NH:13][C:9]1[C:10]([CH3:12])=[CH:11][C:6]([C:5]([OH:17])=[O:4])=[CH:7][N:8]=1)([CH3:16])[CH3:15]
Reactant: Cc1cc(C(=O)OC(C)C)cnc1NC(C)C
Agent: Cl
Product: Cc1cc(C(=O)O)cnc1NC(C)C
Yield: 118.1 %

Procedure:
A solution of 6-isopropylamino-5-methyl-nicotinic acid isopropyl ester (137 mg, 0.58 mmol) in 25% aq. HCl (5 mL) is stirred at 65° C. for 24 h before it is concentrated and dried to give the title compound (133 mg) as a yellow solid; LC-MS: tR=0.57 min, [M+1]+=195.54.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH2:6][C:5]=1[C:14](=[O:16])[CH3:15]>CCOCC>[Br:1][CH2:15][C:14]([C:5]1[CH:4]([CH3:3])[C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)=[O:16]
Reactant: BrBr
Reactant: CC(=O)C1=C(C)c2cc(C)ccc2C1
Solvent: CCOCC
Product: Cc1ccc2c(c1)C(C)C(C(=O)CBr)=C2
Yield: 59.5 %

Procedure:
Bromine (2.80 g) is added to 1-(3,5-dimethyl-inden-2-yl)ethanone (3.00 g) in dry ether (30 ml), while keeping the temperature at +10° C. The mixture is extracted with water, several times with the diluted NaHCO3 solution, again with water, dried and evaporated under reduced pressure to afford the product (2.54 g, 59%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21][C:22]([C:24]2[CH:33]=[C:32]([Cl:34])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-]>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:21][C:22]([C:24]2[CH:33]=[C:32]([Cl:34])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC)NC(=O)c2cc(Cl)c3ccccc3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(Cl)c3ccccc3n2)CC1
Reaction time: 2 h
Yield: 111.9 %

Procedure:
A solution of 4-ethoxycarbonyl-1-(1-amino-3-(methoxycarbonyl)propyl)carbonylpiperazine (0.97 g, 3.23 mmol), 2-carboxy-4-chloroquinoline (0.67 g, 3.23 mmol), EDCI (0.68 g, 3.55 mmol) and HOBT (0.48 g, 3.55 mmol) was combined in 30 mL of THF. The reaction mixture was stirred overnight at ambient temperature. The reaction was diluted with ethyl acetate and washed with water. The organic layer was concentrated to give a dark oil (0.87 g) that was purified by flash chromotography through silica gel with 2:1 ethyl acetate-hexanes to provide 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline (0.46 g). A solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline (0.15 g, 0.313 mmol) was dissolved in 5 mL THF and LiOH (0.25 M, 1.9 mL, 0.47 mmol) was added. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated to an oil, acidified with 10% HCl, extracted into ethyl acetate, and concentrated to provide pure 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-chloroquinoline, (167 mg); NMR 1.20 (t, 3), 1.90 (m, 1), 2.05 (m, 1), 2.35 (m, 2), 3.35-3.60 (m, 8), 3.65 (m, 2), 4.05 (q, 2), 5.07 (m, 1), 7.95 (m, 1), 8.02 (m, 1), 8.23 (s, 1), 8.30 (m, 1), 8.98 (m, 1) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6])C.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]2[C:9]3[NH:10][C:11]4[C:16]([C:8]=3[CH2:7][CH:5]([C:4]([O:3][CH3:1])=[O:17])[NH:6]2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(O)cc2)N1

Procedure:
The same method but starting from racemic tryptophan ethyl ester and 4-hydroxybenzaldehyde gave the title compound as pale yellow crystals 1H NMR (DMSO) δ (ppm): 10.3 (s, 1H, NH-indole) 9.4 (s, 1H, OH); 7.8-7.5 (m, 8H, H aromatic); 5.1 (brs, 1H, H-1); 3.9 (m, 1H, H-3); 3.75 (s, 3H, CO2CH3) 3.1 (m, 1H, H-4); 2.8 (m, 1H, H-4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([CH3:24])=[CH:4][N:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:26][OH:27])[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([CH3:24])=[CH:4][N:3]=1
Reactant: Cc1cnc(F)cc1C(=O)CC(c1ccccc1)c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cnc(F)cc1C(CC(c1ccccc1)c1ccccc1)=NO

Procedure:
In analogy to example 1, step 2, from 1-(2-fluoro-5-methyl-pyridin-4-yl)-3,3-diphenyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (1.5:1) as a white oil, MS (ESI+): m/z=335.1 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[C:1]([O:5][C:6](=[O:30])[CH:7]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN([C@H]1CC[C@H](OCC(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(O[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A solution of 1.19 g (2.6 mmol) trans-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-acetic acid tert-butyl ester in 20 ml of anhydrous THF was cooled to −78° and treated dropwise with a 1M solution of lithium bis-(trimethylsilyl)-amide in THF (6.2 ml, 2.5 eq). The mixture was allowed to reach RT within ca. 1 h and cooled again to −78°. A solution of 0.18 ml (2.9 mmol, 1.1 eq) of iodomethane in 2.5 ml of THF was added and the mixture allowed reach RT within ca. 1 h. After addition of ice, the mixture was extracted with EtOAc, dried over Na2SO4, and the solvent evaporated. Column chromatography on silica gel gave 600 mg (49%) of trans-2-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid tert-butyl ester as a colorless solid, MS: 483 (M+NH4+).
Reaction SMILES: CS(Cl)(=O)=O.O[CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].C(N(CC)CC)C.[NH:35]1[CH:39]=[CH:38][N:37]=[CH:36]1>ClCCl>[N:35]1([CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: c1c[nH]cn1
Reactant: CCCCCCCCCCCCC(O)CCCCC(=O)OC
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCC(CCCCC(=O)OC)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
Methanesulfonyl chloride (0.39 ml, 4.99 mmol) was added dropwise to a stirred solution of methyl 6-hydroxyoctadecanoate (1.55 g, 4.94 mmol) and triethylamine (0.89 ml, 6.42 mmol) in dry dichloromethane (30 ml) at 0° C. The reaction mixture was warmed to room temperature after the addition, and stirred for 2 h. The reaction mixture was quenched with water, diluted with 50 ml of dichloromethane, and the organic layer was washed with water and brine solution, dried on anhydrous MgSO4, concentrated and evaporated under vacuum. This crude compound was combined with imidazole (0.67 g, 9.88 mmol) and heated at 80° C. for 16 h. Crude compound was purified on silica gel (2% methanol in dichloromethane) to obtain a light brown liquid (605 mg, 33.7%).
Reaction SMILES: C1(C(=CC=CC=1)O)O.[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][C:11](O)([CH2:12]3)[CH2:10]1)[CH2:16]2>>[CH:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Agent: Oc1ccccc1O
Product: C1C2CC3CC1CC(C2)C3

Procedure:
Reaction of catechol with 1,3-adamantane-diol according to the method described by Lu et al (Lu et al. J Med Chem 2005, 48 (14), 4576-4585) gave the adduct 10 in reasonable yield.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[C:22]2[O:21][CH2:20][CH2:19][NH:18][C:17]=2[CH:16]=[C:15]([CH3:23])[CH:14]=1.N1C=CC=CC=1.Cl>ClCCl>[CH2:5]([O:4][C:2]([N:18]1[C:17]2[CH:16]=[C:15]([CH3:23])[CH:14]=[C:13]([Br:12])[C:22]=2[O:21][CH2:20][CH2:19]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(Br)c2c(c1)NCCO2
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(Br)c2c(c1)N(C(=O)OCc1ccccc1)CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A solution of benzyl chloroformate (1.32 g, 0.008 mol) in dichloromethane (20 mL) was added dropwise under nitrogen to an ice-cold solution of 8-bromo-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (1.78 g, 0.007 mol) and pyridine (1.06 g, 0.013 mol) in dichlormethane (40 mL). After 1 hour at ambient temperature, a 10% aqueous HCl solution was added. The layers were separated and the organic phase was washed with water (50 mL×2), dried (Na2SO4) and concentrated to give 8-bromo-6-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzyl ester as a colorless oil (2.34 g, 96%) which was used in the step 2 without purification. Synthesis of 8-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([F:25])([F:24])[CH2:12][N:13]1C(=O)C2=CC=CC=C2C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.Cl>C(O)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([F:24])([F:25])[CH2:12][NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(F)(F)CCOCc1ccccc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC(F)(F)CCOCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
The compound N-(4-benzyloxy-2,2-difluorobutyl)phthalimide (8.97 g, 26 mM) and a 1M solution of hydrazine hydrate in ethanol (26 mL) are stirred under reflux. After a few minutes, a heavy precipitate is observed. Stirring and heating (bath temperature: 90°-100° C.) are continued overnight. Ethanol (220 mL) and concentrated HCl (18 mL) are added, and the mixture is refluxed for an additional 11/2 hour. After cooling (ice) the phthaloyl hydrazide is filtered, and the filtrate is evaporated. The residue is dissolved in water, filtered, and the solution is again evaporated. Residual water is removed by stripping with ethanol (twice) and CCl4 (twice). The residue is dissolved in a minimum amount of ethanol. Crystallization occurs upon the addition of water, which after chilling to 5° C. yields white crystals of 4-benzyloxy-2,2-difluorobutylamine as the hydrochloride salt: 5.16 g (79%).
Reaction SMILES: [CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:9][NH:8][C:7](=[O:10])[CH2:6][CH2:5][CH2:4]1)[CH3:2].[H-].[Na+].[CH3:21]I>C1C=CC=CC=1>[CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:9][N:8]([CH3:21])[C:7](=[O:10])[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2cccc(OC)c2)CCCC(=O)NC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC1(c2cccc(OC)c2)CCCC(=O)N(C)C1
Temperature: 40 °C

Procedure:
6-Ethyl-6-(m-methoxyphenyl)hexahydro-2H-azepin-2-one (19.6 g) in dry benzene (200 ml.) was added dropwise to a stirred refluxing suspension of sodium hydride (60% suspension in oil; 4.0 g.) in dry benzene (200 ml.) under nitrogen. After the addition had been completed the reaction mixture was heated under reflux for 4 hours and then cooled to 40° C. Methyl iodide (20 ml.) was then added and the mixture stirred and heated at 40°-55° C. overnight. After cooling, the reaction mixture was washed with water, dried over magnesium sulphate and evaporated to an orange oil which was crystallised. The product was recrystallised from light petroleum (b.p. 80°-100° C.) to give 6-ethyl-6-(m-methoxyphenyl)-1-methylhexahydro-2H-azepin-2-one (19.1 g) as colourless crystals, m.p. 69°-71° C. (Found: C, 73.2; H, 8.9; N, 5.4%. C16H23NO2 requires: C, 73.5; H, 8.9; N, 5.4 %)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:43][CH2:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[CH3:39])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: Cc1ccccc1CN
Product: Cc1ccccc1CNC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and o-methylbenzylamine.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[SH:18].[NH2:19][C:20]1[N:28]=[C:27](Cl)[N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>[Cl-].[Na+].O>[NH2:19][C:20]1[N:28]=[C:27]([S:18][C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Sc1ccc2ccccc2c1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Sc2ccc3ccccc3c2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
To DMF suspension (20 ml) containing sodium hydride (800 mg, 20 mmol, 60% in mineral oil) were added 2-naphthalenethiol (3.8 g, 24 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred under heating at 100° C. for 10.5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtrated and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (244 mg, yield 83%).
Reaction SMILES: [CH2:1]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)CC)C>C(O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][N:13]3[CH2:14][CH2:15][N:10]([CH2:1][C:2]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:3])[CH2:11][CH2:12]3)[CH2:21][CH2:22]2)=[CH:28][CH:29]=1
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(CN1CCN(CCCN2CCN(Cc3ccc(Cl)cc3)CC2)CC1)c1ccccc1
Yield: 77.5 %

Procedure:
A mixture of 4.1 g of 1-phenacylpiperazine, 5.7 g of 1-chloro-3-[4-(4-chlorobenzyl)-1-piperazinyl]propane, 2.6 g of triethylamine and 35 ml of reagent ethanol was refluxed for 5 hours. The solvent was removed by rotary evaporation, 150 ml of water were added, and the mixture was extracted with ether (3×150 ml). The ether solution was evaporated to an oil, which was chromatographed on a silica column, the eluant being CH2Cl2 /CH3OH/ammonium hydroxide (45:5:1), to yield crude 1-[4-(4-chlorobenzyl)-1-piperazinyl]-3-(4-phenacyl-1-piperazinyl)propane (7.0 g, 50% of theory). This oil was dissolved in 200 ml of ether and precipitated with excess anhydrous hydrogen chloride. The precipitate was then dissolved in water and reprecipitated by addition of acetone to give 1-[4-(4-chlorobenzyl)-1-piperazinyl]-3-(4-phenacyl-1-piperazinyl)propane tetrahydrochloride monohydrate as a white crystalline product (m.p. 211°-218° C.).
Reaction SMILES: [CH3:1][CH:2]([SH:6])[CH:3]([SH:5])[CH3:4].Cl[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O>>[CH3:1][CH:2]1[S:6][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=2[S:5][CH:3]1[CH3:4]
Reactant: O=C1CCCCC1Cl
Reactant: CC(S)C(C)S
Product: CC1SC2=C(CCCC2)SC1C
Yield: 49 %

Procedure:
The procedure of Example 1(a) is followed using 2,3-butanedithiol and 2-chlorocyclohexanone to give 5,6,7,8-tetrahydro-2,3-dimethyl-1,4-benzodithian as a greenish oil, b.p. 90°-100°/0.07 mm. Yield 49%. NMR 1.34 (6d), 1.45-2.25 (8m), 2.7-3.1 (2m). IR 2900, 1610, 1435, 1365, 1320, 1115, 795, 690.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([C:14]#[C:13][C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][C:6]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)=[N:7][C:8]=23)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (77 mg, 0.25 mmol) (Example B.2) according to general procedure II. Obtained as a yellow solid (93 mg, 67%). MS (ISP) 556.3 [(M+H)+]; mp 190–191° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.[P:32]([O-:36])([O-:35])([O-:34])=[O:33]>>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[P:32]([O-:36])([O-:35])([O-:34])=[O:33]
Reactant: COC(=O)C(N)Cc1c[nH]c2ccccc12
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=P([O-])([O-])[O-]
Product: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12

Procedure:
A DL-Tryptophane methyl ester (10 mM) in 0.02 M phosphate buffer, pH 7.5, was pressed through a column of chymotrypsinsephadex particles. The permeate contained a mixture of L-tryptophane (5 mM) obtained by stereo-specific enzymatic hydrolysis, and D-tryptophane methyl ester (5 mM) and 20 mM phosphate buffer, pH 7.0. This mixture was separated in an electrodialysis cell as described in Example 1. Electric current of 5 mA/cm2 was applied through the electrodialysis cell in which the feed solution was circulated with a linear flow velocity of about 5 cm/sec. At the end of the experiment, the acid in the feed compartment was tested for chemical and optical purity. It was found to be 98.5% pure L-tryptophane.