Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[CH2:11]=[O:12].Cl.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11][OH:12]
Reactant: COc1cc(Cl)cc(Cl)c1
Reactant: C=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(Cl)c(CO)c(Cl)c1
Temperature: 100 °C
Yield: 39.9 %

Procedure:
To a mixture of 1,3-dichloro-5-methoxybenzene (10.0 g), paraformaldehyde (2.21 g), and concentrated hydrochloric acid (100 mL) was added concentrated sulfuric acid (1.00 mL) at room temperature. After heating and refluxing at 100° C. for 8 hours, and leaving to be cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue were added dioxane (56.0 mL) and a 1 M aqueous sodium hydroxide solution (113 mL), followed by heating and refluxing at 100° C. for 3 hours. The reaction solution was left to be cooled, and then water was added thereto, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain (2,6-dichloro-4-methoxyphenyl)methanol (4.67 g).
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].CC#N.[Cl:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(OCC)C>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[C:11]([O:19][CH2:2][O:3][CH3:4])[CH:10]=1
Reactant: Oc1cc(Cl)cc(C(F)(F)F)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: COCOc1cc(Cl)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Neat chloro(methoxy)methane (1.8 mL, 23.8 mmol) was added to a MeCN solution (20 mL) of 3-chloro-5-(trifluoromethyl)phenol (3.6 g, 18.3 mmol) and Cs2CO3 and the resulting mixture was stirred at room temperature. After 5 h the resulting mixture was diluted with diethyl ether, filtered and concentrated. The resulting material was filtered through a short pad of silica gel, followed by concentration to yield 1-chloro-3-(methoxymethoxy)-5-(trifluoromethyl)benzene.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[CH:3]=1.[BH4-].[Na+].O.Cl>O1CCCC1.CO>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[CH:3]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(C=O)cc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(CO)cc2)c1
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
To a solution of the title compound provided by Example 12 (25 mg, 0.068 mmol) in tetrahydofuran (5 ml) and methanol (10 ml) was added sodium borohydride (20 mg, 0.53 mmol). After stirring for 1.5 hours, the mixture was treated with water (10 ml) and hydrochloric acid (1 M, 0.6 ml). The mixture was concentrated to a volume of 8 ml and the solid was collected by filtration. The solid was treated with aqueous sodium carbonate solution (10%, 10 ml) and extracted with ethyl acetate (3×30 ml). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with methanol-dichloromethane (5:95) to give the title compound (10 mg, 39% yield). 1H NMR (acetone-d6) δ1.36 (t, 3H, J=6.9 Hz, CH3), 3.95 (bs, 1H, OH), 4.09 (q, 2H, J=7.0 Hz, CH2), 4.56 (s, 2H, CH2), 5.28 (bs, 2H, NH2), 6.16 (d, 1H, J=1.1 Hz, Ar), 6.34 (d, 1H, J=1.1 Hz, Ar), 7.09 (d, 1H, J=8.5 Hz, Ar), 7.24 (d, 2H, J=8.8 Hz, Ar), 7.30-7.34 (m, 2H, Ar), 7.60-7.63 (m, 2H, Ar), 7.80 (s, 1H, NH).
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:16]([F:19])([F:18])[F:17])=[C:12]([CH2:14]O)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:21].C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:21][CH2:14][C:12]1[CH:13]=[C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=[CH:10][C:11]=1[C:16]([F:19])([F:18])[F:17]
Reactant: BrP(Br)Br
Reactant: OCc1cc(Oc2ccccc2)ccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1ccc(Oc2ccccc2)cc1CBr
Temperature: -5 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
[5-(phenyloxy)-2-(trifluoromethyl)phenyl]methanol (0.493 g, 1.84 mmol) in dichloromethane (12 ml) under nitrogen was stirred and cooled to −5° C. A solution of phosphorus tribromide (173 μl, 1.84 mmol) in DCM (3.5 ml) was added dropwise over about 2 min. The solution was then allowed to warm to room temperature and left to stand overnight. The solution was cooled to 4° C. and stirred well as saturated aqueous sodium bicarbonate (11 ml) was added in portions over 2 min. The biphasic mixture was stirred for a further 20 min. The mixture was diluted with water and DCM. The phases were separated using a hydrophobic frit and the aqueous phase washed with DCM. The combined organic extracts were stored in a freezer over the weekend and the DCM solution decanted off from crystals of ice. The organic phase was further dried (MgSO4), filtered and the solvent removed in vacuo to leave crude 2-(bromomethyl)-4-(phenyloxy)-1-(trifluoromethyl)benzene as a colourless oil (0.425 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([C:29](O)=[O:30])[CH3:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:32]1([CH:38]([NH2:40])[CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([C:29](=[O:30])[NH:40][CH:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:39])[CH3:28])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(C)C(=O)O)cc3)cc2)CC1
Reactant: CC(N)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(C)C(=O)NC(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(1-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-phenyl-ethylamine.
Reaction SMILES: F[C:2](F)(F)[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[CH:21][C:20](O)=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:2][S:3]([O:6][C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][C:19]=1[CH:24]([CH3:26])[CH3:25])(=[O:5])=[O:4]
Reactant: CC(C)c1cc(Br)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)c1cc(Br)ccc1OS(C)(=O)=O
Temperature: 0 °C

Procedure:
Trifluoromethanesulfonic anhydride (0.47 mL) was added to an ice-cooled mixture of 4-bromo-2-isopropylphenol (0.5 g) and pyridine (0.28 mL) in methylene chloride (5 mL) with stirring. The mixture was stirred for 10 min, and poured into a mixture of ethyl acetate and 1 mol/L hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: diethyl ether/n-hexane=1/10) to afford 4-bromo-2-isopropylphenyl methanesulfonate (0.71 g).
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].B(F)(F)F.CCOCC.[CH3:15][CH:16]([CH3:22])[CH2:17][C:18](=[CH2:21])[CH:19]=[CH2:20].[OH-].[Na+]>C(Cl)Cl>[CH2:17]([C:18]1[CH2:21][CH:3]([CH3:4])[CH:2]([CH:1]=[O:5])[CH2:20][CH:19]=1)[CH:16]([CH3:22])[CH3:15]
Reactant: C=CC(=C)CC(C)C
Reactant: C/C=C/C=O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)CC1=CCC(C=O)C(C)C1
Temperature: -30 °C
Yield: 94 %

Procedure:
Crotonaldehyde cis/trans (16 g, 230 mmol) was dissolved in methylene chloride and cooled to −30° C. With stirring, and under nitrogen, BF3.OEt2 (3.6 ml, 29 mmol) was added gradually. A solution of 5-methyl-3-methylenehex-1-ene 2 (21 g, 191 mmol) in methylene chloride (50 ml) was then added at −30° C. over 1 h and the pot allowed to warm to −20° C. The solution was stirred at this temperature for a further 1.5 h before being poured onto 2M NaOH (100 ml). After brief agitation the phases were separated and the lower organic phase washed with water (100 ml) and brine (2×100 ml). The combined aqueous phases were extracted with MTBE (150 ml), phase separated and the upper organic part washed to neutral with brine. The organic phases were combined, dried (Na2SO4) and concentrated in vacuo to afford 3b as a pale yellow oil (33 g, 94% yield; 98% pure). The product was used in the next steps without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)=O.C([NH2:25])C1C=CC=CC=1.C(N(CC)CC)C>C(OCC)C.CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:17])([F:16])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)[NH2:25]
Reactant: NCc1ccccc1
Reactant: O=C(c1ccc(F)c(C(F)(F)F)c1)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NC(c1ccc(F)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.7 %

Procedure:
2,2,2-Trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (21.0 g, 81 mmol) was initially charged in diethyl ether (200 ml), and benzylamine (9.1 g, 85 mmol) and triethylamine (16.4 g, 162 mmol) were added at 0° C. Subsequently, a solution of titanium tetrachloride (7.8 g, 41 mmol) in hexane (100 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. The resulting suspension was filtered, and the solids were washed with diethyl ether and discarded. The solvent of the filtrate was removed under reduced pressure and the residue was taken up in triethylamine (100 ml). The solution was left to stand at room temperature for 16 h. The triethylamine was removed under reduced pressure, and the residue was taken up in dichloromethane and acidified with 10% hydrochloric acid. The mixture was stirred at room temperature for 16 h and then the phases were separated. The organic phase was washed with water and the combined aqueous phases were adjusted to pH 12 with 33% sodium hydroxide solution while cooling with ice. The aqueous phase was extracted three times with dichloromethane and the combined organic phases were dried over magnesium sulphate. The solvent was removed under reduced pressure. 6.5 g (31% of theory) of 2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanamine were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][N:8](C(=O)C)[C:7]=2[CH:15]=1.O.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][NH:8][C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)N(C(C)=O)CCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)NCCO2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The compound obtained in Step C (1.5 g; 7.26 mmol) is dissolved in 7 ml of methanol, and then water (14 eq.; 101.6 mmol; 1.9 ml) and potassium hydroxide (6 eq.; 43.5 mmol; 2.44 g) are added. The solution is stirred vigorously at 60° C. for 2 hours. After extraction three times with dichloromethane, the organic phase is dried over MgSO4 and then removed under reduced pressure. The residue obained is purified by flash chromatography on silica gel (eluant: PE/AcOEt (1/1)). The title product is obtained in the form of a red solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]([CH:5]=[N:6][O:7][CH2:8][CH:9]([CH3:11])[CH3:10])[C@H:3]1[C:12]([OH:14])=[O:13].[O:16]([C:23]1[N:28]=[C:27]([CH2:29]O)[CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCCCCC>[CH3:15][C:2]1([CH3:1])[CH:4]([CH:5]=[N:6][O:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]1[C:12]([O:14][CH2:29][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:28]=1)=[O:13]
Reactant: CC(C)CON=C[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: OCc1cccc(Oc2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)CON=CC1C(C(=O)OCc2cccc(Oc3ccccc3)n2)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a stirred solution of 0.75 g of (1R,cis)-2,2-dimethyl-3-((isobutoxyimino)methyl)cyclopropanecarboxylic acid, 0.71 g of 6-phenoxy-2-pyridinemethanol and a catalytic amount of 4-dimethylaminopyridine in 40 ml of methylene chloride under argon was added as one portion 1.19 g of N,N-dicyclohexylcarbodiimide. The reaction mixture was stirred at ambient temperature overnight, then diluted with an equal volume of hexane, filtered and stripped. The resulting oil was dissolved in hexane, filtered, washed with dilute potassium carbonate solution, dried and stripped. The crude product was chromatographed using 20% diethyl ether in hexane as eluent to yield 1.0 g of the desired product.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([O:23][CH2:24][CH3:25])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[OH-].[Na+]>ClCCl.C(O)C>[CH2:24]([O:23][C:16](=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[NH:4][C:5]1=[O:26])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:25]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
17.6 g (50 mmol) of 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone are suspended in 200 ml of dichloromethane and 150 ml of ethanol. 75 ml of 1N sodium hydroxide solution are added at 0° C. and the mixture is then stirred for another 30 minutes at ambient temperature. The reaction solution is evaporated down by half and 200 ml of water are then added. The product precipitated is suction filtered, washed with water, isopropanol and ether and dried.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][OH:11].C1COCC1.C(=O)(O)[O-].[Na+].[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[OH:11][CH2:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1Cc2ccccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1c2ccccc2CC1CO
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution containing 2,3-dihydro-1H-indol-2-ylmethanol (Preparation 5, 4.31 g) and THF (60 mL) is added to a flask containing sodium bicarbonate (24.27 g) and water (15 mL). Benzylchloroformate (4.5 mL) is slowly added. Once addition is complete, the mixture is stirred overnight. The crude mixture is filtered and washed with a large amount of CH2Cl2. The filtrate is poured into water and the separated organic phase is washed with 5% HCl and brine. The organic layer is dried (Na2SO4), filtering, and concentrated to give a yellow oil. The crude product is chromatographed eluting with EtOAc/heptane (1/1) to give 8.11 g (99%) of the title compound as a pale colored oil. Physical characteristics: MS (ESI+) m/z 284 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>CN(C)C=O.C(OCC)(=O)C>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CCl)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.452 mmol) produced in Example A7(vi) in N,N-dimethylformamide (2.0 mL) was added chloroacetic acid chloride (79 μL, 0.995 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogencarbonate solution (100 mL), water (100 mL) and saturated brine (100 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure to give N-[5-({2-[(chloroacetyl)amino]-1,3-benzothiazol-6-yl}oxy)-2-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[CH:15]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:39][CH3:40]>C(#N)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:39][CH3:40])[CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=3)[CH:15]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(NCc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCC(N(CC)Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(ethoxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methylamino]piperidine (400 mg) in acetonitrile (5 mL) was added potassium carbonate (13 mg) and iodoethane (145 mg). The mixture was placed in sealed vessel and stirred at 80° C. for 2 hours. After removing the solvent in vacuo, ethyl acetate was added, washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to a column of silica gel using chloroform-methanol (30:1) as an eluent. Fractions containing the product were collected and evaporated to give the title compound as yellow syrup.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:23]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([NH:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl.O>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29]([C:24]4[C:23]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:30])=[N:37][CH:36]=3)=[O:39])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cn1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a chilled (0° C.) solution of 0.293 g of 6,11-dihydro-5H-dibenz[b,e]azepine and 625 μL triethylamine in 3.5 ml of dichloromethane is added a solution of 0.657 g of 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride in 1.5 ml of dichloromethane. The mixture is stirred under argon at room temperature for 16 hours and diluted with 40 ml of dichloromethane and 20 ml of water. The organic layer is separated and washed with 20 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness under vacuum. The residual solid is chromatographed on silica gel with ethyl acetate-hexane(1:1) as solvent to give the product as a glass. Crystallization from ethyl acetate gives 0.395 g of white crystals, m.p. 134°-142° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[OH:24])=[N:21][C:20]([O:25][CH3:26])=[CH:19][CH:18]=2.[CH2:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH2:27]([O:24][C:23]1[C:14]([Br:13])=[CH:15][N:16]=[C:17]2[C:22]=1[N:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18]2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc2ncc(Br)c(O)c2n1
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc(Br)c(OCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.9 %

Procedure:
Diethyl azodicarboxylate (1.37 g, 7.84 mmol, 2.0 eq) is added at room temperature to a stirred solution of 3-bromo-6-methoxy-[1,5]naphthyridin-4-ol (1.0 g, 3.92 mmol, 1.0 eq), benzyl alcohol (640 mg, 5.88 mmol, 1.5 eq) and triphenylphosphine (2.05 g, 7.84 mmol, 2.0 eq) in tetrahydrofuran (25 mL). After 15 hours stirring at room temperature, tetrahydrofuran is evaporated and the resulting crude product is purified by column chromatography (silica gel, eluent: petroleum ether: ethyl acetate, 10:1, v/v) to afford 8-benzyloxy-7-bromo-2-methoxy-[1,5]naphthyridine as a white solid (1.0 g, 74% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C(C)=[O:13])C(C)C.OO>>[C:1]1([C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:13])[OH:7].[C:1]1([CH:6]=[CH:5][C:4]([OH:13])=[CH:3][CH:2]=1)[OH:7]
Reactant: Oc1ccccc1
Reactant: CC(=O)CC(C)C
Agent: OO
Product: Oc1ccc(O)cc1
Product: Oc1ccccc1O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
In a 300 ml four-necked flask equipped with a stirrer, a condenser, and a thermometer were charged 65.8 g (0.7 mol) of phenol, 3.5 g (0.035 mol) of methyl isobutyl ketone, and 50 mg of each of the compounds shown in Table 1 below as a catalyst. The mixture was heated to 100° C., and 1.98 g (0.035 mol) of 60 wt % aqueous hydrogen peroxide was added thereto, followed by stirring for 30 minutes. The resulting reaction mixture was analyzed by gas chromatography to obtain yields of catechol and hydroquinone. The results obtained are shown in Table 1.