Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]([CH3:14])[C:11](=[O:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:1]([O:9][CH:10]([CH3:14])[C:11](=[O:13])[CH:12]=[CH:17][N:18]([CH3:20])[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)OC(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Product: CC(OC(=O)c1ccccc1)C(=O)C=CN(C)C
Reaction time: 8 h

Procedure:
A mixture of 3-benzoyloxybutan-2-one (15.5 g) and dimethylformamide dimethylacetal (14.4 g) was heated on a steam bath for 2 hours 30 minutes. The solvent was removed from the mixture under reduced pressure. Petroleum ether (b.p. 60°-80° C.) was added to the residue, with shaking and the ether layer separated from an insoluble red oil. Further petroleum ether was added to the oil with shaking and excess ether was removed under reduced pressure to give a red-brown oil which partially crystallised on standing overnight. Petroleum ether was added and the solid was collected by filtration and washed with petroleum ether to give a yellow crystalline solid of 4-benzoyloxy-1-dimethylamino-1-penten-3-one. Yield 5.6 g. The solid was used directly without further purification in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[CH2:8][CH2:7]2)(=[O:21])=[O:22])=[CH:28][CH:27]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(C)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(C)cc3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic ethyl ester (10.0 g, 22 mmol) dissolved in THF:Methanol (50:50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 7.2 g (72%); off white solid, mp 244° C.; MS: 446.3 (M+H)+
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:58]=[CH:57][C:29]3=[N:30][N:31]([C:33]4[CH:38]=[C:37]([C:39]([CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:47]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)([CH3:49])[CH3:48])[C:34]=4[OH:56])[N:32]=[C:28]3[CH:27]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:10][C:3]1([CH3:11])[CH2:4][CH2:5][CH2:6][C:7]([CH3:9])([CH3:8])[N:2]1[O:1][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:58]=[CH:57][C:29]3=[N:30][N:31]([C:33]4[CH:38]=[C:37]([C:39]([CH2:42][C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:47]([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)([CH3:48])[CH3:49])[C:34]=4[OH:56])[N:32]=[C:28]3[CH:27]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(-c4ccc(N)cc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Reactant: CC1(C)CCCC(C)(C)N1O
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(-c4ccc(ON5C(C)(C)CCCC5(C)C)cc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Yield: 87.3 %

Procedure:
The title compound is prepared reacting 0.59 g (3.75 mmol) of 1-oxyl-2,2,6,6-tetra-methylpiperidine, 1.0 g (10 mmol) of tert-butyl nitrite, 2.3 mg (0.0037 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II), 120 mL of pyridine and 24.0 g (75 mmol) of 5-(4-aminophenyl)-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole, prepared in Example 17, in 10 mL of pyridine at 70° C. The crude product obtained is purified by vacuum flash chromatography (2% ethyl acetate/heptane) to give 2.20 g of the title compound as a colorless oil in 87.3% yield. M/S [M+1] 673
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([OH:10])[N:5]=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O-:13].[Na+]>CO>[OH:10][C:6]1[N:5]=[C:4]([CH3:11])[CH:3]=[C:2]([O:13][CH3:12])[C:7]=1[C:8]#[N:9]
Reactant: Cc1cc(Cl)c(C#N)c(O)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)nc(O)c1C#N
Temperature: 100 °C
Reaction time: 16 h
Yield: 21.3 %

Procedure:
To a pressure vessel were added 4-chloro-2-hydroxy-6-methylnicotinonitrile (337 mg, 2.0 mmol), sodium methanolate (540 mg, 10.0 mmol), methanol (15 mL), and magnetic stirrer. The pressure vessel was sealed, and it was stirred at 100° C. for 16 hours. After being cooled to room temperature, the vessel was opened, and the reaction solution was transferred to an eggplant-shaped bottle. The solvent was removed by rotary evaporation. To the residue was added water (10 mL) and ethyl acetate (50 mL). The layers were separated. The organic phase was concentrated in vacuo to provide crude product which was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford 2-hydroxy-4-methoxy-6-methylnicotinonitrile (70 mg, 21%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Product: CC(C)(C(=O)NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(Cl)cc1

Procedure:
Example 115 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.94–7.81 (br, 1H), 7.53–7.40 (br, 1H), 7.39–7.15 (m, 6H), 6.82 (d, 1H, J=7.2 Hz), 6.68–6.49 (br, 1H), 3.33–3.19 (m, 2H), 3.19–3.06 (m, 2H), 2.63–2.39 (m, 3H), 2.31–2.09 (m, 2H), 1.89–1.62 (m, 7H), 1.54 (s, 6H), 1.13–0.98 (m, 2H), 0.90–0.72 (m, 2H); ESMS m/e: 482.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[C@H:6]([CH3:26])[CH2:5]1)[CH:2]=[CH2:3].C([Li])CCC>O1CCCC1>[CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:6]([CH3:26])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2ccc(Br)cc2)c2cccc(O)c2)C[C@@H]1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCN1C[C@@H](C)N([C@H](c2ccccc2)c2cccc(O)c2)C[C@@H]1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A solution of (-)-3-((αR)-α-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-bromobenzyl)phenol (3.00 g, 7.2 mmol), from Example 70, in 80 mL of dry tetrahydrofuran was cooled to -78° C. n-Butyllithium (9.9 mL of a 1.6M solution in hexanes) was added at a rate to keep the temperature below -70° C. After stirring at -78° C. for 30 minutes, the reaction was quenched with 15 mL of saturated aqueous ammonium chloride, warmed to room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate, and the solvent removed under vacuum to give a white solid which was recrystallized from acetonitrile to give 2.11 g (88%) of (-)-3-((αR)-α-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol as white crystals, mp 195°-197° C., [α]D20 =-2.8° (tetrahydrofuran, c=1.6). HPLC on β-cyclodextrin with methanol:0.1M ammonium acetate/1:1 gave one peak at tR =8.4 min. NMR (DMSO-d6, 200 MHz): δ0.95 (d, J=6 Hz, 3H); 1.1 (d, J=6 Hz, 3H); 1.8 (dd, J1 =7 Hz, J2 =11Hz, 1H); 2.1 (dd, J1 =7 Hz, J2 =9 Hz, 1H); 2.4-2.8 (m, 4H); 2.9 (dd, J1 =7 Hz, J2 =14 Hz, 1H); 3.15 (dd, J1 =5 Hz, J2 =14 Hz, 1H); 4.95 (s, 1H); 5.1 (d, J=10 Hz, 1H); 5.2 (d, J=18 Hz, 1H); 5.8 (m,1H); 6.6 (d, J=8 Hz, 1H); 6.8 (d, J=8 Hz, 1H); 6.95 (s, 1H); 7.1 (t, J=8 Hz, 1H); 7.3 (m, 5H); 9.3 (s, 1H). Mass spectrum (Cl--CH4) m/z: 337 (M+1, 69%); 336 (M+, 15%); 183 (100%); 153 (92%). Calc. for C22 H28N2O: C, 78.53; H, 8.39; N, 8.33. Found: C, 78.37; H, 8.47; N, 8.38.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.CCCCCC.[CH3:21][N:22]([CH3:36])[C:23]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:26]1([OH:29])[CH2:27][CH2:28][C:23]([N:22]([CH3:21])[CH3:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][CH2:25]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)C1(c2ccccc2)CCC(O)(c2nc3ccccc3s2)CC1
Temperature: -80 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of benzothiazole (622 mg, 4.60 mmol) in dry THF (30 ml) was cooled to −85° C. under a stream of argon. n-butyllithium (5.52 mmol, 3.45 ml of a 1.6 molar hexane solution) was added dropwise in such a way that a reaction temperature of −78° C. was not exceeded. Once all the substance had been added, the reaction mixture was stirred for 2 hours at −80° C. A solution of 4-dimethylamino-4-phenylcyclohexanone (1.00 g, 4.61 mmol) in dry THF (8 ml) was added dropwise at −80° C. The mixture was stirred for 30 minutes at −80° C. and then 3 days at ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution (30 ml), the organic phase was separated and the aqueous phase extracted four times with dichloromethane (30 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent removed under vacuum. Purification was carried out b y flash chromatography with cyclohexane/ethylacetate (V:V=7:3) over silica gel. 746 mg 1-benzothiazol-2-yl-4-dimethylamino-4-phenylcyclohexanol with a melting point of 155–157° C. were obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1)=[CH2:2]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1ccc(N)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(N)nc1
Yield: 94.4 %

Procedure:
0.25 g 5-vinylpyridin-2-yl amine (compound in Production Example 326) and 0.1 g of 10% palladium-carbon were stirred in 5 mL ethyl acetate at room temperature for 2 hours under hydrogen atmosphere. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate), to give 0.24 g of the title compound as a pale yellow oil.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38](=[O:45])[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)c1ccccc1
Yield: 88 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and benzoyl chloride. Yield: 88% of theory, C34H32N6O4 (588.7) Rf value: 0.37 (silica gel; dichloromethane/ethanol=19:1) 1H-NMR spectrum (D6 -DMSO): 2.61 (t,2H), 3.54 (s,3H), 3.76 (s,3H), 4.10 (t,2H), 4.61 (d,2H), 6.83 (d,2H), 7.05 to 7.55 (m,12H),8.03 (d,2H), 8.25 (dd,2H), 8.98 (s,1H), 10.48 (s,1H)
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[CH2:13]1[C:17]2[CH2:18][NH:19][CH2:20][C:16]=2[CH2:15][N:14]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([N:19]2[CH2:18][C:17]3[CH2:13][N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][C:16]=3[CH2:20]2)=[N:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC2=C(CNC2)C1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CC3=C(CN(C(=O)OC(C)(C)C)C3)C2)nc1
Yield: 72 %

Procedure:
Ethyl 6-chloronicotinate (567 mg, 3.05 mmol), tert-butyl 3,4,5,6-tetrahydro-1H-pyrrolo-[3,4-c]pyrrole-2-carboxylate (565.9 mg, 2.7 mmol) and cesium carbonate (878 mg, 2.7 mmol) were stirred in 20 ml of DMF at 100° C. for 8 h and at 120° C. for 8 h. The residue was filtered off, washed with water and ethyl acetate, and dried. The first filtrate was concentrated and stirred with ethyl acetate, and the product was filtered off. Yield: 72%, M+H+: 360.20.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:30]>CO.O1CCCC1>[ClH:30].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2.7 h

Procedure:
To a solution of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer)(1.4 g) in methanol (30 ml) and tetrahydrofuran (20 ml) was added conc. hydrochloric acid (1.0 ml), and the mixture was stirred at ambient temperature for 2.7 hours. After evaporation of the reaction mixture, the residue was washed with tetrahydrofuran to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxyic acid hydrochloride (syn isomer)(1.2 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[N:7][C:8]([C:12]([F:15])([F:14])[F:13])=[N:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([OH:16])=[N:7][C:8]([C:12]([F:15])([F:14])[F:13])=[N:9]3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNCC1
Reactant: Oc1nc(C(F)(F)F)nc2cc(Cl)ccc12
Product: Oc1nc(C(F)(F)F)nc2cc(N3CCCCC3)ccc12

Procedure:
The title compound was prepared from 7-chloro-4-hydroxy-2-trifluoromethylquinazoline (2.0 g, 8.0 mmol), as described in Example 43 (but using piperidine in place of N,N-dimethylamine) to provide the desired compound in a 96% (2.5 g) yield; m.p. 268-271° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(Cl)cc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(4-chloro-phenyl)-4-hydroxy-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [S:1]([Cl:4])(Cl)=[O:2].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH3:11][C:5]1[C:10]([S:1]([Cl:4])=[O:2])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: Cc1ccccc1S(=O)Cl

Procedure:
24.6 g (0.1 mol) of freshly recrystallized p-tolyldisulfide was slurried in 18.8 ml (0.2 mol) of distilled acetic anhydride in an oven-dried 250 ml sidearm round bottom flask with magnetic stirring bar and a stopcock connector. The resulting reaction composition was cooled to -10° to -20° C. in a water-ethylene glycol-dry ice bath. All transfers and reactions in this example occurred under nitrogen blanket. About 7 ml of chlorine was condensed at -78° C. and transferred by cannula over 15 minutes to the reaction composition. The reaction composition became a clear bright orange solution and then the orange color began to fade. Additional chlorine was added in 1 ml portions until the solution turned to a greenish-yellow color. The solution was stirred at -10° C. for 1 hour and acetyl chloride was distilled off under reduced pressure employing a water aspirator while allowing the solution to return to room temperature. Bubbling of the solution ceased after about 45 minutes and the solution was connected to a vacuum pump for 1/2 hour at room temperature and then hearted to about 40° C. under vacuum for 20 minutes to yield 34.5 g of a green liquid, p-toluene sulfinyl chloride. Thereafter, 34.43 g of p-toulene sulfinyl chloride were diluted into a 50 ml solution in toluene and stored under a nitrogen blanket for further use.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:6][N:7]=[C:8]([C:12]1[C:13](=[O:27])[CH2:14][CH2:15][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:17]=1[OH:18])[CH2:9][CH2:10][CH3:11])[CH:4]=[CH2:5]>CC(C)=O>[CH2:3]([O:6][N:7]=[C:8]([C:12]1[C:13](=[O:27])[CH2:14][CH2:15][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:17]=1[O:18][C:8](=[O:1])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][CH2:10][CH3:11])[CH:4]=[CH2:5]
Reactant: [OH-]
Reactant: C=CCON=C(CCC)C1=C(O)C(c2ccc(OC)cc2)CCC1=O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCON=C(CCC)C1=C(OC(=O)c2ccccc2)C(c2ccc(OC)cc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Aqueous 1% sodium hydroxide (14 ml) was added to a stirred solution of 2-[1-(allyloxyimino)-n-butyl]-3-hydroxy-4-(4-methoxyphenyl)-cyclohex-2-en-1-one (1.2 g) in acetone (150 ml). The mixture was stirred at ambient temperature for 5 minutes and then benzoyl choloride (0.5 g) was added dropwise. After 30 minutes, the mixture was evaporated in vacuo and the residue purified on a silica gel column using 10% v/v diethyl ether- methylene chloride as eluant to give the title compound (1 g) as a colourless oil.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21])#[N:12]>C([O-])(O)=O.[Na+].C(OCC)C.O>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[S:20]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:21])=[O:22])#[N:12]
Reactant: Cc1cc(O)cc(O)c1
Reactant: Cc1ccc(C#N)c(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(C)ccc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-cyano-5-methylbenzene-sulfonyl chloride (2.0 g, 9.0 mmol), as prepared in the preceding step, were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 4% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.1 g, 69%). 1H-NMR (300 MHz, CDCl3) δ 7.91 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 6.59 (s, 1H), 6.58 (s, 1H), 6.51 (s, 1H), 5.61 (s, 1H), 2.51 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH2:14][CH2:13][N:12]=[C:11]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].[CH2:24]=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH2:14][CH2:13][N:12]=[C:11]1[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:24]
Reactant: Clc1ccc(CN2CCN=C2Cc2ccccc2)c(Cl)c1
Reactant: C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C1=NCCN1Cc1ccc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
1-(2,4-Dichlorophenyl)methyl-4,5-dihydro-2-phenylmethylimidazole (3.19 g, 0.01 mol) was added to a slurry of sodium hydride (80% dispersion in mineral oil, 0.3 g, 0.01 mol) in dry dimethylformamide (15 ml) and the mixture was stirred at room temperature for 30 minutes. Paraformaldehyde (3 g, 0.01 mol) was added to the reaction mixture and the resulting mixture was heated at 70° C. for 6 hours. The reaction mixture was cooled, water was added and the resulting mixture was extracted with ether. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel in ammonia/methanol/ethyl acetate (1:4:45) to yield 1-(2,4-dichlorophenylmethyl)-4,5-dihydro-2-(1-phenylethenyl)imidazole (2.6 g), (δ(CDCl3) 3.3 (2H, t, J=6 Hz), 3.95 (2H, t, J=6 Hz), 4.1 (2H, s), 5.65 (1H, s), 5.8 (1H, s), and 7.0-7.5 (8H, m) p.p.m. having the formula ##STR24##