Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])=[CH:5][CH:4]=1.[C:16]([C:24]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[Br:33][C:31]1[CH:32]=[C:24]2[C:25](=[CH:29][CH:30]=1)[C:26](=[O:27])[N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:15][CH:14]=1)[C:9]([C:10](=[O:13])[CH2:11][CH3:12])=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CCC(O)CNCc1ccc(SC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 35.4 %

Procedure:
To a solution of 1-(4-methylsulfanylbenzylamino)butan-2-ol (8.5 g) and 2-benzoyl-4-bromobenzoic acid (14.7 g) and 1-hydroxy-1H-benzotriazole (7.4 g) in DMF (100 ml) was added triethylamine (8.4 ml) and then WSC (11.5 g) was added at room temperature. The mixture was stirred at room temperature for 4 days. The solvent was evaporated under reduced pressure, and the residue was partitioned between dichloromethane and water, washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1-+13/7). The resulting colorless amorphous form was dissolved in dimethyl sulfoxide (100 ml) and triethylamine (25.3 ml) was added. Under ice-cooling, pyridine sulfur trioxide complex (14.5 g) was added, and the mixture was stirred at room temperature for 8 hrs. Water (300 ml) was added, and the mixture was extracted with ethyl acetate and washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine. Sodium sulfate was added to dry the mixture. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1→2/3). The obtained colorless amorphous form was dissolved in 0.1N potassium hydroxide-ethanol solution (75 ml) and heated under reflux for 12 hrs. 1N Hydrochloric acid (7.5 ml) was added and the mixture was stirred under ice-cooling for 1 hr. The crystals were collected by filtration and washed with 70% ethanol-water to give the title compound (6.58 g, 34%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:40]=[CH:39][C:30]([CH2:31][N:32]2[CH2:36][CH:35]([CH3:37])[NH:34][C:33]2=[O:38])=[CH:29][CH:28]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH:35]([CH3:37])[CH2:36][N:32]([CH2:31][C:30]5[CH:39]=[CH:40][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:33]4=[O:38])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: COc1ccc(CN2CC(C)NC2=O)cc1
Product: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(F)c3)C2=O)cc1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (132 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 1, 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one was obtained. Using the obtained 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one and by the reaction and treatment in the same manner as in Example 421, the title compound (89 mg) was obtained.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7][CH:6]=1)(=O)C>Cl>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Agent: Cl
Product: Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 86.7 %

Procedure:
A suspension of 4-(4-acetylamino-phenyl)-4-oxo-butyric acid (9.84 g, 0.0418 mol) in 1.0 M hydrocloric acid (125 mL) was heated on a steam bath for 1.5 hours, gravity filtered hot, and the filtrate allowed to cool. To the stirred solution was added 50% wt/wt sodium hydroxide (9.7 g) dropwise until pH equaled 3 to 4. The resulting precipitate was filtered, and the filtercake was washed with very dilute hydrochloric acid. The procedure was repeated on the solids with fresh 1.0 M hydrochloric acid (100 mL) to give 7.00 g of 4-(4-amino-phenyl)-4-oxo-butyric acid as a tan solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH:16]=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([F:21])([F:20])[F:19])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([F:19])([F:20])[F:21])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)C(=CCCc1cccc(Oc2ccccc2)c1)c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: FC(F)(F)C(CCCc1cccc(Oc2ccccc2)c1)c1ccccc1

Procedure:
4-(3-Phenoxyphenyl)-1-phenyl-1-trifluoromethyl-1-butene (3.18 g; 8.6 mmol) was hydrogenated in ethanol (40 ml) with hydrogen with the addition of Raney nickel (0.4 g) at room temperature and under atmospheric pressures. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the solvent removed under reduced pressure. After chromatography on silica gel with hexane/toluene, there remained 2.49 g of product (=78% of theory).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([N:22]4C(=O)C5C(=CC=CC=5)C4=O)[CH3:21])[O:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClCCl.O.NN>C(O)C>[CH:1]([O:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([NH2:22])[CH3:21])[O:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3noc(C(C)N4C(=O)c5ccccc5C4=O)n3)s2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2ncc(-c3noc(C(C)N)n3)s2)cc1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A solution of Example 40C (372 mg, 0.78 mmol) in 9:1 dichloromethane:ethanol (25 mL) was charged with hydrazine hydrate (379 uL, 7.8 mmol) and refluxed for 4 hours. The solvent was removed under vacuum and the reaction mixture was stirred in dichloromethane for 3 hours. The solid was removed by filtration and the residue was concentrated under vacuum to yield 265 mg of the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.91 (s, 1H) 7.15-7.25 (m, 2H) 6.88-7.00 (m, 2H) 4.46-4.61 (m, 1H) 4.28-4.41 (m, J=6.86 Hz, 1H) 1.58 (d, J=6.99 Hz, 3H) 1.36 (d, J=5.88 Hz, 6H). MS (DCI): m/z 347 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:14])[CH:8]=1)(=O)=O.[F:25][C:26]([F:36])([F:35])[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:19]([O:18][C:16](=[O:17])[NH:15][C@H:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([N:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[C:26]([F:36])([F:25])[F:35])[CH2:30][CH2:31]2)[CH:8]=1)[CH3:14])([CH3:20])([CH3:21])[CH3:22]
Reactant: O=C(N1CCNCC1)C(F)(F)F
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(N2CCN(C(=O)C(F)(F)F)CC2)c1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
The mixture of 306 mg of 3-{(1S)-1-[(t-butoxycarbonyl)amino]ethyl}phenyl trifluoromethanesulfonate (synthesized according to a method disclosed in J. Med. Chem. 2004, 47, 2887-2896), 181 mg of 2,2,2-trifluoro-1-piperazin-1-yl-ethanone, 47.6 mg of tris(dibenzylideneacetone)(chloroform)dipalladium (0), 49.4 mg of 2-(di-t-butylphosphino)biphenyl, 246 mg of tripotassium phosphate, and 4 mL of toluene, was stirred overnight at 100° C. After cooling the reaction mixture back to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, and was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the insolubles were filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, to obtain 277 mg of t-butyl((1S)-1-{3-[4-(trifluoroacetyl)piperazin-1-yl]phenyl}ethyl)carbamate [128-1] as a brown oily product.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23].[CH3:24][NH2:25]>C1C=CC=CC=1>[CH3:24][NH:25][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23]
Reactant: CN
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Solvent: c1ccccc1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNC)C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.2 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester and 2 g. of methylamine in 30 ml. of benzene is allowed to stir at room temperature overnight. The reaction mixture is concentrated to a foam which is subsequently crystallized twice from ethyl acetate-hexane, 1.95 g., m.p. 154°-156°C. A small sample is again recrystallized from the same solvent system for analysis, m.p. 155°-156°C.
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([NH:10][CH:11]([C:14]1[CH:24]=[CH:23][C:17]([C:18](OCC)=[O:19])=[CH:16][CH:15]=1)[CH2:12][F:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:13][CH2:12][CH:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:5])([CH3:4])[CH3:6])[C:14]1[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1ccc(C(CF)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CF)c1ccc(CO)cc1
Temperature: 65 °C
Yield: 66.8 %

Procedure:
Lithium boranuide (208.9 mg, 9.588 mmol) was added to a stirred solution ethyl 4-[1-(tert-butoxycarbonylamino)-2-fluoro-ethyl]benzoate (1.99 g, 6.392 mmol) in tetrahydrofuran (40 mL) and the reaction warmed to 65° C. for 15 hours. The reaction mixture was cooled to ambient temperature then poured onto crushed ice whilst stirring, 1 M hydrogen chloride solution was added drop wise until no effervescence was observed. The mixture was stirred for 1 hour then saturated aqueous sodium bicarbonate solution was added until the mixture was at pH 8. The aqueous layer was extracted with ethyl acetate (×3) and the combined organic extracts dried over MgSO4, filtered and concentrated in vacuo. Purification by column chromatography (ISCO Companion, 120 g column) loaded in dichloromethane, eluted with 0 to 100% ethyl acetate/petroleum ether. Product fractions were combined and concentrated in vacuo to give tert-butyl N-[2-fluoro-1-[4-(hydroxymethyl)phenyl]ethyl]carbamate as a white solid (1.15 g, 67%). 1H NMR (400.0 MHz, DMSO-d6) δ 1.37 (s, 9H), 4.44-4.49 (m, 4H), 4.80-4.89 (m, 1H), 5.16 (t, 1H), 7.27-7.38 (m, 4H) and 7.65 (d, 1H) ppm; LC/MS m/z 214.0 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:27])[N:7]([C:14]1([F:26])[CH2:19][CH:18]([O:20]C(=O)C)[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:27])[N:7]([C:14]1([F:26])[CH2:19][CH:18]([OH:20])[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-:3])=[O:2]
Reactant: CC(=O)OC1CC(F)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1NC(=O)C(F)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)CC1O

Procedure:
A solution of 3-(4-nitro-1,3-dioxoisoindolin-2-yl)-3-fluoro-2,6-dioxo-5-acetoxypiperidine (1 g, 2.9 mmol) and p-toluenesulfonic acid (0.28 g, 1.5 mmol) in methanol (10 mL) is heated at reflux for 5 h. The solvent is removed in vacuo to give 4-nitro-2-(3-fluoro-5-hydroxy-2,6-dioxopiperid-3-yl)isoindoline-1,3-dione which is further purified by column chromatography.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([O:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.Cl.[NH2:14][C@@H:15]1[CH2:19][C@H:18]([CH2:20][OH:21])[C@@H:17]([OH:22])[C@H:16]1[OH:23].C(N(CC)CC)C>CCO>[OH:21][CH2:20][C@H:18]1[CH2:19][C@@H:15]([NH:14][C:2]2[C:7]([I:8])=[C:6]([O:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=2)[C@H:16]([OH:23])[C@@H:17]1[OH:22]
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Reactant: COc1nc(SC)nc(Cl)c1I
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1nc(SC)nc(N[C@@H]2C[C@H](CO)[C@@H](O)[C@H]2O)c1I
Temperature: 130 °C

Procedure:
Compound 3 (5.00 g, 15.7 mmol) and (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (Compound 4) (5.80 g, 31.6 mmol) were dissolved in EtOH (50 mL). Triethylamine (6.60 mL, 47.4 mmol) was added, the reaction was sealed, and heated to 130° C. for 18 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via column chromatography on silica gel (EtOAc/hexanes) to give the title compound as a colorless oil. LCMS 1.23 min, 428 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[N:11]=[N:10][CH:9]=[C:8]2Cl)=[O:4].[NH3:26]>CO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[N:11]=[N:10][CH:9]=[C:8]2[NH2:26])=[O:4]
Reactant: N
Reactant: COC(=O)c1cc2c(Cl)cnnc2c(F)c1Nc1ccc(Br)cc1F
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(N)cnnc2c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
A solution of 7-(4-bromo-2-fluorophenylamino)-4-chloro-8-fluoro-cinnoline-6-carboxylic acid methyl ester (1.00 equiv.) in saturated NH3 in MeOH is refluxed for 16 hours. Additional saturated NH3 in MeOH is added as the reaction progresses if necessary. The reaction mixture is cooled to room temperature and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:27])=[C:11]([CH3:26])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:13]=2[C:24]=1[CH3:25])C1C=CC=CC=1>CCCCCC>[CH3:25][C:24]1[C:13]2[CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:15][O:16][C:12]=2[C:11]([CH3:26])=[C:10]([CH3:27])[C:9]=1[NH2:8]
Reactant: Cc1ccc(C2COc3c(C)c(C)c(NCc4ccccc4)c(C)c32)cc1
Solvent: CCCCCC
Product: Cc1ccc(C2COc3c(C)c(C)c(N)c(C)c32)cc1
Yield: 91 %

Procedure:
Using N-benzyl-4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 277, the title compound was synthesized in the same manner as in Reference Example 30. Yield 91%. Melting point: 121-122° C. (hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[N:21](OC(C)(C)C)=[O:22].Cl>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:21][OH:22])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)ON=O
Agent: Cl
Solvent: CCO
Product: O=C(C(=NO)c1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a mixture of 2-(2-fluoropyridin-4-yl)-1-(3-trifluoromethylphenyl)ethanone (10.80 g, 0.038 mol) in ethanol (200 mL), at −10° C., under argon, was added tert-butyl nitrite (5.0 mL, 0.042 mol) and hydrogen chloride (12.2 mL, 2.5M in ethanol, 0.031 mol) dropwise while maintaining the temperature below −5° C. Upon completion of addition, the reaction was allowed to warm to RT for 2 hrs. The reaction mixture was then concentrated in vacuo, diluted with water (100 mL), basified with saturated sodium bicarbonate (200 ml), and extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with water (300 mL), dried with brine (300 mL) and anhydrous sodium sulfate, filtered and concentrated to yield 11.4 g of the title compound, as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH3:13].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[O:2][CH3:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(OC)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OC)c(CBr)c1
Reaction time: 2 h

Procedure:
To a solution of methyl 4-methoxy-3-methylbenzoate (10.0 g, 55.6 mmol) dissolved in CCl4 (500 mL) was added N-bromosuccinimide (10.8 g, 61.1 mmol) and benzoyl perioxide (1.30 g, 5.56 mol). The mixture was irradiated with a sunlamp (250 W) to create a gentle reflux. After 2 hours of exposure the reaction was complete by TLC. The reaction mixture was cooled, filtered through celite, and concentrated to yield a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3](=[O:21])[C:4]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)=[CH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[BH4-].[Na+]>CO>[CH3:1][C:2]([CH3:23])([CH3:22])[CH:3]([OH:21])[C:4]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)=[CH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CC(C)(C)C(=O)C(=Cc1ccc2ccccc2c1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(O)C(=Cc1ccc2ccccc2c1)n1cncn1
Yield: 49.4 %

Procedure:
85 g (0.27 mole) of 4,4-dimethyl-1-(naphth-2-yl)-2-(1,2,4-triazol-1-yl)-1-penten-3-one (Example 1) were taken up in 200 ml of methanol, and 6 g of sodium borohydride were added in portions, while stirring and cooling. When the reaction had ended, the reaction mixture was adjusted to pH 6 and concentrated. The residue was taken up in methylene chloride, washed with saturated sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated. The oily residue was made to crystallized by adding ether. 41 g (49% of theory) of 4,4-dimethyl-1-(naphth-2-yl)-2-(1,2,4-triazol-1-yl)-1-penten-3-ol of melting point 122°-124° C. were obtained.
Reaction SMILES: O[C:2]1([CH3:11])[CH:6]([CH2:7][CH:8]=[CH2:9])[C:5](=[O:10])[CH:4]=[CH:3]1.[Na+].[Cl-].[OH2:14]>[Cl-].[Cl-].[Zn+2]>[CH2:7]([C:6]1[C:5](=[O:10])[CH2:4][CH:3]([OH:14])[C:2]=1[CH3:11])[CH:8]=[CH2:9]
Reactant: O
Reactant: C=CCC1C(=O)C=CC1(C)O
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Product: C=CCC1=C(C)C(O)CC1=O

Procedure:
Into a reaction vessel, a solution of 4-hydroxy-4-methyl-5-allyl-2-cyclopentenone (3 g) and ZnCl2 (5 g) in water (120 ml) was charged, and the temperature was elevated up to 100° C. The contents were refluxed for 15 hours while stirring. After cooling, NaCl (40 g) was added to the reaction mixture, and the resulting mixture was extracted with toluene (120 ml) 4 times. The extracts were combined together and concentrated at 50° C. under reduced pressure to give an oily substance (2.5 g). The oily substance was chromatographed on silica gel (30 g), followed by development with a solvent mixture of ethyl acetate and hexane (1:2 by volume) to give 2-allyl-3-methyl-4-hydroxy-2cyclopentenone (2.4 g). Yield, 80%.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:8][C:6]1[CH:7]=[C:2]([N:14]2[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=[C:13]2[CH3:12])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2c(C)nc3ccccc32)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (10.3 g), 2-methylbenzimidazole (8.7 g) and sodium carbonate (7.5 g) was heated with stirring in dimethylformamide (40 cm3) at 130° for 16 hours under nitrogen. The cooled mixture was evaporated in vacuo, water (50 cm3) added and the mixture extracted with methanol:chloroform, 1:10 by volume. The combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate. Combination and evaporation of appropriate fractions afforded a solid which was recrystallised from hexane/acetone to give the title compound, m.p. 144°-6°, (10.65 g).
Reaction SMILES: ClCCl.C(=O)=O.[CH:7](=[N:15]O)[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:7]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[OH:10])#[N:15]
Reactant: ON=Cc1ccccc1O
Agent: O=C(Cl)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1O
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
Into a dry 250 ml multi-necked flask equipped with gas tight stirrer, thermometer, pressure equalising dropping funnel and a dichloromethane/Drikold cooled reflux condenser (connected to an aqueous caustic scrubber) were charged salicylaldoxime prepared as described in Example 4 (15.82 g) and toluene (100 ml) to afford a solution which was heated to 93°-95° C. and stirred at this temperature for 0.5 hour. A solution of phosgene in toluene (89.1 g of 20% ww soln.) was then added dropwise, via a dropping funnel, over 0.75 hour whilst maintaining the temperature at 93°-95° C. to afford a pale yellow suspension. The temperature was maintained for 2 hours, after which G.C. analysis indicated reaction was complete. The apparatus was carefully set for atmospheric distillation (ensuring that the equipment was still connected to the caustic scrubber) and the toluene was distilled off up to an internal temperature of 120° C. to give 2-cyanophenol in 92.5% yield based on the phenol used in Example 4.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:11])[NH:6][S:7]([CH3:10])(=[O:9])=[O:8])(=[O:4])=[O:3].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]([O:21][CH3:22])=[O:20]>CC(C)=O>[CH3:1][S:2]([N:5]([CH3:11])[N:6]([S:7]([CH3:10])(=[O:8])=[O:9])[C:19]([O:21][CH3:22])=[O:20])(=[O:3])=[O:4]
Reactant: COC(=O)Cl
Reactant: CN(NS(C)(=O)=O)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)N(N(C)S(C)(=O)=O)S(C)(=O)=O

Procedure:
1,2-Bis(methylsulfonyl)-2-(methoxycarbonyl)-1-methylhydrazine (compound 6) was synthesized as follows: A mixture of 1,2-bis(methylsulfonyl)-1-methylhydrazine (Shyam et al., J. Med. Chem. 30 2157-2161 (1987)) (1.00 g, 0.005 mol), anhydrous sodium carbonate (1.9 g, 0.018 mol), methyl chloroformate (1.23 g, 0.013 mol) and acetone (30 ml) was heated under reflux for 18 hr. The reaction mixture was filtered and the filtrate evaporated to dryness in vacuo. The residue, a thick oil, was stirred with methanol (5 ml) and cooled in ice. The solid that separated was filtered and recrystallized from ethanol-petroleum ether (0.63 g, 48.9%). The melting point (Mp) of this compound was found to be approximately 88-89° C. Analysis of the compound by 1H NMR (CDCl3) showed the following results: δ 0 4.0(3H, s, OCH3), 3.5, 3.4, 3.1 (9H, 3s, 2 CH3SO2 and NCH3).