Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:11]=2[CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1>C1COCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:25]=3)[C:11]=2[CH2:12][S:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:39])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CSc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CS(=O)c2ccccc2)cc1
Temperature: 0 °C
Yield: 25.3 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[(phenylthio)methyl]-1H-1,2,3-triazole-4-carboxamide (145 mg, 0.344 mmol) obtained in Example 130 was dissolved in THF (3.0 ml), m-chloroperbenzoic acid (purity 65%, 110 mg, 0.412 mmol, 1.2 eq.) was added with stirring at 0° C., and the mixture was stirred for additional 1.5 hr. The reaction mixture was diluted with ethyl acetate (20 ml), washed with 5% aqueous sodium sulfite solution, 2% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography (elution solvent, ethyl acetate-hexane=1:1-5:1) on silica gel (manufactured by E. Merck, Art.7734, 10 g). The fraction obtained by elution with ethyl acetate-hexane (5:1) was concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (38 mg, 0.087 mmol, 25.3%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][NH:6][CH:7]=1)=[O:2].[Cl:13][C:14]1[C:15](F)=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:13][C:14]1[C:15]([N:6]2[CH:7]=[C:3]([CH:1]=[O:2])[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1ncccc1Cl
Reactant: CCOC(=O)c1n[nH]cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ncccc2Cl)cc1C=O
Temperature: 100 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
To a solution of ethyl 4-formyl-pyrazole-3-carboxylate (1.70 g, 10.1 mmol) and 3-chloro-2-fluoropyridine (1.99 g, 15.1 mmol) in dimethylformamide (20 mL) is added potassium carbonate (2.80 g, 20.2 mmol) and the mixture is stirred at 100° C. for 16 hours. After completion, the reaction mixture is partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer is extracted with ethyl acetate (3×25 mL) and the combined organic extracts are dried over sodium sulfate, concentrated in vacuo and purified by column chromatography over silica gel eluting with hexane/ethyl acetate (50:50) to yield 1.5 g (54%) of the title compound. MS (m/z): 280 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[OH-].[K+].Cl>C1COCC1.CO>[F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C(=O)OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)O)ccc1-c1cc(OC)ncc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.5 %

Procedure:
To a stirred solution of 83.21A (0.860 g, 2.7 mmol) in THF (7.00 mL) and MeOH (7.00 mL) at 0° C. was added potassium hydroxide (1.5 mL, 3.0 mmol) slowly to maintain the temperature below 6° C. The reaction mixture was allowed to warm to room temperature and stirred for 17 hours. After which, the reaction was acidified with 1N HCl and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure to yield 83.21B as a colorless solid (0.82 g, 100% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([OH:14])[C:10]=1[C:15]#[N:16].C(N(CC)CC)C.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>ClCCl>[F:29][C:28]([F:31])([F:30])[S:25]([O:14][C:11]1[C:10]([C:15]#[N:16])=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[S:13][N:12]=1)(=[O:26])=[O:24]
Reactant: Cc1ccc(-c2snc(O)c2C#N)c(F)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2snc(OS(=O)(=O)C(F)(F)F)c2C#N)c(F)c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed 5-(2-fluoro-4-methylphenyl)-3-hydroxy-1,2-thiazole-4-carbonitrile (700 mg, 2.99 mmol, 1.00 equiv), dichloromethane (20 mL), triethylamine (302 mg, 2.98 mmol, 1.00 equiv). This was followed by the addition of Tf2O (1.69 g, 5.99 mmol, 2.00 equiv) at 0-5° C. The resulting solution was stirred overnight at 20° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 800 mg (73%) of 4-cyano-5-(2-fluoro-4-methylphenyl)-1,2-thiazol-3-yl trifluoromethanesulfonate as colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([N:9]2[C:13](C)=[C:12]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)[N:11]=[N:10]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:30]>ClCCl>[Cl:2][C:3]1[C:8]([N:9]2[CH:13]=[C:12]([C:15]3[CH2:16][CH2:17][N:18]([C:29]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:30])[CH2:19][CH:20]=3)[N:11]=[N:10]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(C2=CCNCC2)nnn1-c1cccnc1Cl
Reactant: COCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)N1CC=C(c2cn(-c3cccnc3Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-3-[5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,3]triazol-1-yl]-pyridine hydrochloride (3.0 mg) prepared in Example 42-1 was dissolved in 1.0 ml of dichloromethane and 0.02 ml of triethylamine and 0.02 ml of 2-methoxyethyl chloroformate were added thereto followed by stirring at room temperature for 10 minutes. The solvent was evaporated in vacuo and the residue was separated and purified by a thin-layer chromatography (ethyl acetate) to give 1.36 mg of the title compound as a white solid.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][C:21]=1[C:22]([O:24]C)=[O:23].[F:32][C:33]([F:50])([F:49])[CH2:34]P(=O)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Cl:19][C:20]1[CH:29]=[C:28](/[CH:30]=[CH:34]/[C:33]([F:50])([F:49])[F:32])[CH:27]=[CH:26][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(/C=C/C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
4 Å molecular sieves (powder, 16 g) was added to a 1 M solution of TBAF in THF (20 mL, 20 mmol), and the mixture was stirred at room-temperature overnight under an argon atmosphere. To the mixture were added a solution of methyl 2-chloro-4-formylbenzoate (210 mg, 0.0010 mol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (600 mg, 0.0021 mol) in THF (15 mL). After the mixture was stirred for 2 h, the molecular sieves were removed by filtration. The filtrate was concentrated and water (120 mL) was added. The mixture was extracted with AcOEt. The organic extract was washed with brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel with AcOEt [1% HOAc]-hexane to give the product as a white solid. LC-MS: t=3.12 min, m/z=248.9 & 250.9 (M−1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11].[OH-].[K+].Cl>CO.O>[OH:1][C@@H:2]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCCCC(O)CC[C@H]1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC(O)CC[C@H]1CC[C@@H](O)[C@@H]1CCCCCCC(=O)O

Procedure:
A solution of ethyl 9β,15-dihydroxyprostanoate in 32 ml. of methanol-water (1:1), containing 890 mg. of potassium hydroxide is kept at ambient temperature for 18 hours. The solution is acidified with dilute hydrochloric acid and extracted several times with ether. The ether phase is washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.63 g. of an oil; nmr 3H singlet δ 5.53 (hydroxyl and carboxyl protons), 1H singlet 4.23 (9β-carbinolic proton, 30%), 1H singlet 3.90 (9α-carbinolic proton, 70%), 1H singlet 3.65 (15-carbinolic proton), and 3H distorted triplet 0.90 (terminal methyl).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:29]=[CH:28][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([N+:25]([O-])=O)[CH:19]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>[Pd].C(OCC)(=O)C.CO>[CH3:1][N:2]([CH3:30])[C:3]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:29]=[CH:28][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CN(C)C(=O)N1CCN(c2ccc3[nH]c(-c4ccc(N)c([N+](=O)[O-])c4)nc3c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)N1CCN(c2ccc3[nH]c(-c4ccc(N)c(N)c4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[2-(4-amino-3-nitro-phenyl)-1H-benzoimidazol-5-yl]-piperazine-1-carboxylic acid dimethylamide (1.0 g, 2.4 mmol) in 4:1 ethyl acetate/methanol (100 ml) under nitrogen, was added 5% palladium on carbon (240 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 4-[2-(3,4-diamino-phenyl)-1H-benzoimidazol-5-yl]-piperazine-1-carboxylic acid dimethylamide as an orange solid that was used in the next step without any purification.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([C:11]1[CH2:12][O:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:16][CH:15]=2)(=[O:10])[CH3:9].S(=O)(=O)(O)O.C(OCC)C>COCOC.O1CCCC1.[Zn]>[OH:10][C:8]([C:11]1[CH2:12][O:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:16][CH:15]=2)([CH3:9])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)C1=Cc2cc(-c3ccccc3)ccc2OC1
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CCOCC
Solvent: COCOC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(O)C1=Cc2cc(-c3ccccc3)ccc2OC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.35 g (0.0665 At-g) of activated zinc are covered with 12 ml of dimethoxymethane, and then 1 ml (9 mmol) of pure ethyl bromoacetate is added under an argon atmosphere. After induction of the reaction by heating, a solution of 6.38 ml (57.5 mmol) of ethyl bromoacetate in 20 ml of dimethoxymethane is added in such a manner as to maintain reflux. After the zinc has been completely consumed and the reaction mixture has returned to room temperature, a solution of 11.1 g (43.5 mmol) of 3-acetyl-6-phenyl-2H-chromene in 60 ml of anhydrous tetrahydrofuran is added dropwise over a period of from 10 to 15 minutes. After one hour's stirring at room temperature, the mixture, cooled to +4° C., is treated with 25 ml of a 10% sulphuric acid solution. After addition of 70 ml of diethyl ether, the aqueous phase is separated off, and the ethereal phase is washed with 3×20 ml of water and then dried over magnesium sulphate. The solvents are evaporated off under reduced pressure, yielding a solid which is used in the following step without additional purification.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.Br[C:21]1[N:26]=[C:25](/[CH:27]=[C:28]2/[C:29](=[O:34])[NH:30][C:31](=[O:33])[S:32]/2)[CH:24]=[CH:23][CH:22]=1>CS(C)=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:21]1[N:26]=[C:25](/[CH:27]=[C:28]2/[C:29](=[O:34])[NH:30][C:31](=[O:33])[S:32]/2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1NC(=O)/C(=C/c2cccc(Br)n2)S1
Reactant: CNCCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(CCc1ccccc1)c1cccc(/C=C2\SC(=O)NC2=O)n1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
An 8 mL round-bottomed vial was charged with N-methyl-2-phenylethanamine (43 mg, 0.318 mmol, 1 equiv.) and DMSO (1 mL, 0.3 M), DiPEA (105 μL, 0.636 mmol, 2 equiv.), (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (91 mg, 0.318 mmol, 1 equiv.), and the vial was purged with argon. The mixture was shaken for 48 h at 110° C. The reaction mixture was then partitioned between CH2Cl2 (10 mL) and sat. NaCl (20 mL). The aqueous layer was back extracted with CH2Cl2 (2×15 mL) and the combined organic layer was dried over xxx and concentrated under reduced pressure to provide an orange residue. The orange residue was triturated with ether (3×15 mL) to provide (Z)-5-((6-(methyl(phenethyl)amino)pyridin-2-yl)methylene)thiazolidine-2,4-dione as an orange film (2.6 mg, 175 mg theoretical, 5%). LC-MS m/z: 340 (M+1).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1>O1CCCC1>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1

Procedure:
To a mixture of sodium hydride (189 mg, 4.73 mmol) in anhydrous tetrahydrofuran (2 mL) at 0° C., a solution of 2-chloro-5-nitropyridine (500 mg, 3.16 mmol) and 1-methylpiperidin-4-ol (455 mg, 3.96 mmol) in anhydrous tetrahydrofuran (4 mL) was added dropwise. The reaction was heated reflux for 16 h. The THF was evaporated and water (100 mL) and EtOAc (200 mL) were added. The aqueous layer was extracted with EtOAc (200 mL). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated to give a brown oil. Purification by silica gel column chromatography using 3% methanol/methylene chloride yielded 2-(1-methylpiperidin-4-yloxy)-5-nitropyridine as a yellow solid, (367 mg, 49%). LC/MS (m/z): 238.0 (MH+), Rt 1.59 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1([CH3:11])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(#N)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:5][C:6]1([CH3:11])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1(C)CCCC1)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](CC1(C)CCCC1)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 25 %

Procedure:
2-Benzyloxycarbonylamino-3-(1-methylcyclopentyl)-propionic acid methyl ester (7.6 g, 23.8 mmol) was dissolved in a mixture of acetonitrile (82 mL) and 0.2 M aqueous NaHCO3 (158 mL) and Alcalase 2.4 L (1.1 mL) was added and the reaction mixture wa stirred vigorously for 8 h. The reaction mixture was then evaporated at 30° C. to remove acetonitrile, and the aqueous residue was washed with ether. The ethereal layer was concentrated to yield 1.9 g of (R)-2-benzyloxycarbonylamino-3-(1-methylcyclopentyl)-propionic acid methyl ester. The aqueous phase was filtered with Celite, the pH was adjusted to 3 with 6 N HCl, and the solution was extracted with ethylacetate. The ethyl acetate layer was dried and evaporated to yield 1.4 g of (S)-2-benzyloxycarbonylamino-3-(1-methyl-cyclopentyl)-propionic acid. MS: 304.2 (M−1), 306.0 (M+1), 327.9 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22](OC)=[O:23])(=[O:17])=[O:16])=[CH:11][CH:10]=1.C[Mg]I.[CH2:32]1COC[CH2:33]1>O.C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:28]=[CH:27][CH:26]=[C:21]([C:22]3([OH:23])[CH2:33][CH2:32]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: C[Mg]I
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cccc(C2(O)CC2)c1)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-(2′,4′-dichlorobiphenyl-4-ylsulfonamido)benzoate (500 mg, 1.03 mmol) and titanium isopropoxide (61 μL, 0.206 mmol) in anhydrous THF (10 mL) was cooled under nitrogen to −10° C. A solution of 3 Methylmagnesium iodide in THF (2.4 mL, 7.2 mmol) was added by syringe and the solution was stirred at 0° C. for 1 hour, then at room temperature overnight. The mixture was diluted with water (5 mL) and ethyl acetate (20 mL) and filtered through Celite. The layers were separated. The organic phase was washed with water (10 mL) and brine (10 mL) and dried over MgSO4. Evaporation of the solvents gave an orange gum which was purified by column chromatography on silica, eluting with acetone/hexane (1:4) and the title compound obtained as a light yellow foam (100 mg). 1H NMR (300 MHz, CDCl3): δ 0.95-1.05 (2H, m), 1.20-1.24 (2H, m), 6.90-7.10 (3H, m), 7.20-7.46 (3H, m), 7.47-7.48 (3H, m) and 7.83 (2H, d). MS, m/z: Calcd, 433.031. Found, 433.22 (M).
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:17]([C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([Cl:34])[CH:26]=2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C>ClCCl>[N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][N:11]([C:29]([C:28]3[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:17]4[C:16]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[CH:26][C:27]=3[Cl:34])=[O:30])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1cccnc1O2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Oc3ncccc32)c(Cl)c1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 66, reaction of 0.198 g of 5,6-dihydropyrido[2,3-b][1,4]benzoxazepine with 0.444 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride in dichloromethane in the presence of N,N-diisopropylethylamine gives the product as a solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([OH:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CCCCCCCCO
Product: CCCCCCCCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 1-octanol there is obtained octyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resinous product, 1H-NMR(CDCl3): 0.88 (t, CH3), 1.0-2.0 (12H), 4.15 (t, OCH2), 4.23 (s, 4H), 4.87 (broad s, NH), 7.3-7.7 (8H);
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][CH2:26][CH:27]=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH2:27][CH2:26][O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Reactant: O=CCOCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)[C@H]1CC[C@@H](NCCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cis-4-amino-cyclohexanecarboxylic acid benzyl ester (8 g, 34 mmol) and benzyloxyacetaldehyde (4.8 mL, 34 mmol) in 1,2-dichloroethane (2 L), was stirred at room temperature overnight. Then NaBH(OAc)3 (11 g, 51 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. Most of the solvent was then removed by vacuum. EtOAc (1 L) was added, and the resulting solution as washed with brine. The organic layer was dried over MgSO4, filtered, and evaporated to yield a residue. The residue was purified by column chromatography with flash silica gel (1:1 heptane/EtOAc) to yield cis-4-(2-benzyloxy-ethylamino)-cyclohexanecarboxylic acid benzyl ester as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[N+:8]([C:7]1[C:2]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Oc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1280 mg) in dimethylformamide (18 mL) were added phenol (800 mg) and cesium carbonate (5530 mg). The reaction mixture was stirred at 60° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and a saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified on silica gel column chromatography (hexane:ethyl acetate=1:19) to give the titled compound (370 mg) having the following physical data.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][C:26]1([CH3:46])[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[C:32]2[CH:31]=[C:30]([CH:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:39]=O)[CH:29]=[CH:28][C:27]1=2>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:39][CH:38]([C:30]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:46])([CH3:25])[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[C:32]=2[CH:31]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCC(C=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCC(C=C(Br)Br)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
1.62 g of carbon tetrabromide were dissolved in 25 ml of methylene chloride and treated, at −20° C., with a solution of 2.56 g of triphenylphosphine in 25 ml of methylene chloride. The mixture was stirred at 0° C. for 15 minutes. To the orange solution were added 733 mg of (RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanal in 4 ml of methylene chloride, at 0° C. The reaction mixture was stirred at room temperature for 4 hours. The mixture was quenched with the addition of 50 ml of water followed by 6 ml of a saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was further extracted with 2 portions of 25 ml of methylene chloride. The combined organic extracts were dried over MgSO4 and concentrated in vacuo, giving a yellow solid. The residue was triturated in pentane and the solid was removed by filtration. The filtrate was concentrated in vacuo, yielding a yellow oil which was purified by flash chromatography (SiO2, hexane), giving 1.03 g of (RS)-1,1-dibromo-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-oct-1-ene, as a colorless oil.