Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:29][CH:30]([F:32])[F:31])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Li+].O>C(O)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1)=[C:8]2[O:29][CH:30]([F:31])[F:32]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3)c(OC(F)F)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
A solution of [8-chloro-4-difluoromethoxy-3-(4-methanesulfonylbenzyl)-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.13 g), methanol (20 mL), saturated, aqueous lithium hydroxide solution (1.0 mL) and water (2.0 mL) was stirred at room temperature for 45 minutes. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the methanol removed under reduced pressured. The resulting precipitate was collected by filtration and purified by preparative reverse-phase HPLC using a gradient over 45 minutes of acetonitrile in water (10% to 95% of organic modifier) to afford title compound as a pale yellow solid, 0.014 g.
Reaction SMILES: [ClH:1].[C:2]([O:5][C@H:6]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:11][C:10]2[CH:21]=[C:22]([O:25]CC3C=CC=CC=3)[CH:23]=[CH:24][C:9]=2[N:8]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:7]1=[O:38])(=[O:4])[CH3:3]>CO.[Pd]>[ClH:1].[C:2]([O:5][C@H:6]1[C@@H:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:11][C:10]2[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:9]=2[N:8]([CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[C:7]1=[O:38])(=[O:4])[CH3:3]
Reactant: COc1ccc([C@H]2Cc3cc(OCc4ccccc4)ccc3N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc([C@H]2Cc3cc(O)ccc3N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Reaction time: 5 h
Yield: 102.4 %

Procedure:
A solution of 0.5 g (0.87 mmol) of (cis)-3-(acetyloxy)-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-7-(phenylmethoxy)-2H-1-benzazepin-2-one, monohydrochloride, (see Example 12) in 30 ml of methanol was treated under argon with 150 mg of 10% palladium on charcoal and shaken on the Parr hydrogenator at 50 p.s.i. for 5 hours. The catalyst was filtered off under argon, washed with methanol and the combined filtrates evaporated. The residue (which began to solidify) was rubbed under ether and the evaporation repeated. The solid was dried in vacuo for several hours yielding 0.40 g of the title compound, melting point 229°-231° C., dec., preceded by gradual sintering.
Reaction SMILES: [Li][C:2]1([Si](C)(C)C)C2N=CC(C)=CC=2CCC1.C(=O)=O.[CH3:20][C:21]1[CH:22]=[N:23][C:24]2[C:25]([Si](C)(C)C)([C:31]([O-:33])=[O:32])[CH2:26][CH2:27][CH2:28][C:29]=2[CH:30]=1.[Li+]>>[CH3:2][O:33][C:31]([CH:25]1[C:24]2[N:23]=[CH:22][C:21]([CH3:20])=[CH:30][C:29]=2[CH2:28][CH2:27][CH2:26]1)=[O:32]
Reactant: Cc1cnc2c(c1)CCCC2(C(=O)[O-])[Si](C)(C)C
Reactant: [Li]C1([Si](C)(C)C)CCCc2cc(C)cnc21
Agent: O=C=O
Agent: [Li+]
Product: COC(=O)C1CCCc2cc(C)cnc21

Procedure:
8-Lithio-5,6,7,8-tetrahydro-3-methyl-8-trimethylsilylquinoline, prepared as in Example 3, is blown over onto ether at 0° C. through which a vigorous stream of CO2 gas is being passed. After the addition the resulting solid, lithium 5,6,7,8-tetrahydro-3-methyl-8-trimethylsilylquinoline-8-carboxylate, is removed by filtration. This is then dissolved in methanol (200 ml) and the solution treated with HCl gas to excess and heated at reflux for 4 hours. The solvent is removed in vacuo and the residue dissolved in water (50 ml), made alkaline with 2N NaOH and extracted with chloroform. The extracts are dried, evaporated and the residue distilled to give the title compound as a pale yellow oil bp 120°/0.25 mm.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.CN(C)C=O.O=[C:15]1[CH2:20][CH2:19][CH2:18][S:17][CH:16]1[C:21](OCC)=[O:22]>C(O)(=O)C>[CH3:8][S:7][C:4]1[N:3]=[C:2]2[NH:1][C:15]3[CH2:20][CH2:19][CH2:18][S:17][C:16]=3[C:21](=[O:22])[N:6]2[N:5]=1
Reactant: CSc1n[nH]c(N)n1
Reactant: CCOC(=O)C1SCCCC1=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CSc1nc2[nH]c3c(c(=O)n2n1)SCCC3
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To the solution of 6.5 g (0.05 mole) of 5-amino-3-methylthio-1H-1,2,4-triazole, 2.5 ml of acetic acid and 12.5 ml of dimethylformamide 9.4 g (0.05 mole) of ethyl 3-oxo-3,4,5,6-tetrahydro-2H-thiopyrane-2-carboxylate are added and the reaction mixture is boiled for 60 minutes. The precipitated product is filtered off from the hot solution, then washed with acetic acid and i-propanol and recrystallized from dimethylformamide. Thus 6.5 g (51.1%) of 2-methylthio-5,7,8,9-tetrahydrothiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained. M.p.: higher than 350° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:13][CH2:14][C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[N:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[NH2:22][Al]CCl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:13][CH2:14][C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])=[N:9][C:10]=2[C:11](=[NH:22])[NH2:12])[CH:7]=1
Reactant: N[Al]CCl
Reactant: N#Cc1nc(CCC(F)(F)C(F)(F)F)n2cc(Cl)ccc12
Solvent: Cc1ccccc1
Product: N=C(N)c1nc(CCC(F)(F)C(F)(F)F)n2cc(Cl)ccc12
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Trimethyl aluminum (2.0 M toluene, 10 mL, 20 mmol) was added to ammonium chloride (1.07 g, 20 mmol) suspended in toluene (30 mL) at 0° C. The solution was then stirred at room temperature for 2 hours to give a 0.5 M amino(chloro)methylaluminum solution in toluene. To the intermediate from Step I (2 g, 6.33 mmol) in toluene (1 mL) was added amino(chloro)methylaluminum (40 mL of 0.5 M solution in toluene, 20 mmol). The resulting mixture was left stirring at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and quenched with silica-gel and 1:1 methanol-chloroform (50 mL). The resulting slurry was stirred vigorously for 30 minutes. The reaction mixture was filtered through a silca gel pad (1″) and washed with methanol. The filtrate was concentrated. The residue was suspended in water and extracted with 30% IPA/CHCl3 (3×). The organic layer was concentrated in vacuo to yield a brown solid. m/z=340.8 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccnc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1Cl)c1ccccc1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
3.9 g (28 mmol) of benzoyl chloride are added to 30 ml of pyridine while the temperature is maintained at approximately -5° C. A solution containing 3 g (23.3 mmol) of 3-amino-2-chloropyridine in 20 ml of pyridine is added to this solution using a pressure equalizing funnel. The reaction medium is left stirring overnight and then poured into a water/ice mixture. The solid obtained is then filtered off, washed several times with water and thereafter recrystallized in absolute ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:16]=[C:17]=[S:18].[NH2:19][C:20]1[C:21]([NH:44][CH3:45])=[N:22][C:23]([O:39][CH2:40][CH:41]([F:43])[F:42])=[C:24]([CH:38]=1)[C:25]([NH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH2:29]1)=[O:26]>CC#N>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[NH:16][C:17]([NH:19][C:20]1[CH:38]=[C:24]([C:25](=[O:26])[NH:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([C:34]([F:37])([F:35])[F:36])[CH2:30][CH2:29]2)[C:23]([O:39][CH2:40][CH:41]([F:42])[F:43])=[N:22][C:21]=1[NH:44][CH3:45])=[S:18]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: CNc1nc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Solvent: CC#N
Product: CNc1nc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1NC(=S)Nc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(4-Chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (68 mg, 0.24 mmol) is added to 5-amino-2-(2,2-difluoro-ethoxy)-6-methylamino-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (95 mg, 0.24 mmol) in MeCN (3.5 mL) and stirred at rt overnight. The reaction mixture is concentrated and used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][N+:3]=1[O-].P(Cl)(Cl)Cl.O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: Cc1nccc([N+](=O)[O-])c1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
2,3-Dimethyl-4-nitropyridin-N-oxide (75.6 g, 0.45 mol) prepared in Step 1 was dissolved in 300 ml of methylene chloride. A solution of phosphorus trichloride (44 ml) in methylene chloride (60 ml) was slowly added to the solution for 30 minutes at −15° C.˜−20° C. The reaction mixture was stirred for 15 minutes at the same temperature and further stirred for 15 minutes at room temperature. The reaction mixture was cooled to −78° C. 50 ml of water was added to the reaction mixture, which was neutralized with a sodium hydroxide solution and then extracted with methylene chloride. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound as a pale yellow solid (65 g, 95%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH2:36]([NH2:38])[CH3:37].O>C1COCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:38][CH2:36][CH3:37])[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: CCN
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 100 mg (0.17 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) were stirred in 2 ml of THF for 30 min. Another 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) was then added, and the mixture was stirred at RT for 2 h. About 15 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 81 mg (89% of theory) of the desired target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[H-].[Na+].I[CH3:15]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH3:15]
Reactant: CI
Reactant: COc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c1ccn2C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-methoxy-1H-indole (CAS#4837-90-5, 4.0 g, 27.2 mmol) in THF (100 ml) at 0° C. was added sodium hydride (60% dispersion in oil, 1.63 g, 40.08 mmol). The reaction was stirred for 15 minutes at 0° C. and then put at room temperature for 1 h. The reaction was then re-cooled to 0° C. and iodomethane (2.209 ml, 35.3 mmol) was added. The reaction was then put at room temperature and permitted to stir for 45 minutes. The reaction was then quenched with saturated aqueous ammonium chloride and concentrated to approximately half of its original volume. Next, the reaction mixture was diluted with water and dichloromethane and the layers were separated. The aqueous layer was then extracted two additional times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane 0 to 30%) to afford 4-methoxy-1-methyl-1H-indole; MS: (ES+) m/z 162.0 (M+H)+.
Reaction SMILES: [OH-].[CH3:2][O:3][N:4]=[C:5]([C:11]1[N:12]=[N:13][S:14][CH:15]=1)[C:6]([O:8]CC)=[O:7]>CO>[CH3:2][O:3][N:4]=[C:5]([C:11]1[N:12]=[N:13][S:14][CH:15]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(=NOC)c1csnn1
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1csnn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
1 N Aqueous solution of sodim hydroxide (6.7 ml.) was added to a solution of ethyl 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (syn isomer) (1.2 g.) in methanol (10 ml.) and the mixture was stirred for 1.5 hours at ambient temperature. Methanol was distilled off from the reaction mixture and water was added to the residue. The mixture was washed with ether, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give prisms of 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (0.7 g.), m.p. 110° to 113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O:9]=[C:10]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[S:22][C:23]([C:32]#[N:33])=[C:24](NC3C=CC=CC=3)[C:13]=2[CH:12]=[CH:11]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]2[C:13]3[CH:12]=[CH:11][C:10](=[O:9])[N:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:14]=3[S:22][C:23]=2[C:32]#[N:33])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Product: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1cccc(Cl)c1

Procedure:
The title compound was prepared from 3-chloroaniline (115 mg, 0.9 mmol) following the method described for the compound of Example 18 to give the product as a pale yellow solid (125 mg). δH (CDCl3) 7.67-7.58 (3H, m), 7.44-7.41 (2H, m), 7.39 (1H, d, J 9.7 Hz), 7.31-7.26 (1H, m), 7.12-7.09 (1H, m), 7.04 (1H, t, J 2.0 Hz), 6.95-6.92 (1H, m), 6.57 (1H, d, J 9.7 Hz), 6.54 (1H, bs). LCMS (ES+) 378 (M+H)+ 35Cl, 380 (M+H)+ 37Cl.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.N1C=CC=CC=1>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@H:19]([CH3:22])[CH:20]=[O:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)N[C@H](C)CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)N[C@H](C)C=O

Procedure:
Analogously to Example 194A, 500 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[(2R)-1-hydroxypropan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (Example 177A, 1.33 mmol) were oxidized with 847 mg (2.0 mmol) of Dess-Martin periodinane with addition of 0.11 ml of pyridine (105 mg, 1.33 mmol) and worked up. This gave 440 mg (53% of theory; purity 60%) of the title compound which was reacted further without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[CH2:23]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=2)[CH2:11][CH2:12]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1Nc1ccccc1
Yield: 45.4 %

Procedure:
A solution of 5-bromo-2-nitro-N-phenylbenzenamine (4.0 g, 13.6 mmol) and piperazine (4.7 g, 54.6 mmol) in 40 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×30 ml) and dried over anhydrous sodium sulfate. 2-Nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (3.5 g, 86%) was obtained by flash column chromatograph (10% methanol in dichoromethane). A solution of 2-nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (0.5 g, 1.7 mmol), benzyl bromide (0.2 g, 1.7 mmol) and triethylamine (0.60 ml, 4.19 mmol) in 20 ml dichloromethane was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. N-(5-(4-benzylpiperazin-1-yl)-2-nitrophenyl)benzenamine (0.30 g, 43%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.54 (t, J=5.0 Hz, 4H), 3.32 (t, J=2.0 Hz, 4H), 3.56 (s, 2H), 6.34 (dd, J=9.7, 2.1 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 7.22-7.44 (m, 9H), 8.14 (d, J=9.7 Hz, 1H), 9.90 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 47.3, 53.0, 63.3, 96.2, 106.2, 124.9, 125.8, 127.8, 128.9, 129.3, 129.6, 130.1, 138.0, 139.5, 145.9, 156.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>ClCCl.CN(C)C=O>[Cl:27][C:25]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([NH:16][C:7](=[O:9])[CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:26]=1
Reactant: O=C(O)Cc1ccsc1
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1ccsc1
Reaction time: 1 h
Yield: 40.4 %

Procedure:
To a solution of thiophene-3-acetic acid (1.4 g, 10 mmol) in dichloromethane (40 ml) was added oxalyl chloride (1.74 ml, 20 mmol) and dimethylformamide (catalytic, 3 drops) and the reaction stirred for 1 h. The solvent was evaporated and the residue co-evaporated with toluene (3×20 ml). The resulting acid chloride was dissolved in 1,2-dichloroethane (40 ml), methyl 2-amino-4-chlorobenzoate (1.5 g, 8 mmol) added and the reaction refluxed for 2 h. The residue remaining on evaporation of the solvent was triturated with diethyl ether to afford methyl 4-chloro-2-(3-thienyl)acetamidobenzoate as a tan solid (1 g), m.p. 96°-97° C. To a solution of the foregoing amide (0.5 g, 1.6 mmol) in tetrahydrofuran (25 ml) was added a solution of potassium hexamethyldisilazide in toluene (0.5M, 4 mmol) and the reaction stirred for 2 h. Methanol (5 ml) was added and the solvent evaporated. The residue was partitioned between aqueous sodium hydroxide (1M, 20 ml) and diethyl ether (20 ml), and the aqueous layer acidified with hydrochloric acid (5M). The resultant precipitate was collected and recrystallised from dimethylformamide/water to afford the title compound as a white solid; m.p. 341°-344° C. (from DMF/H2O) (Found: C, 55.07; H, 2.86; Cl, 12.94; N, 5.16; S, 11.42; C13H8ClNO2S, 0.5 H2O requires C, 55.32; H, 3.03, Cl, 12.56; N, 4.96; S, 11.36%); δ(DMSO-d6) 7.22 (1H, dd, J=8.6 and 2 Hz, 6-H), 7.31 (1H, s, 8-H), 7.43 (1H, d, J=4.9 Hz, 5'-H), 7.49-7.51 (1H, m, 4'-H), 7.76 (1H, s, 2'-H), 7.98 (1H, d, J=8.6 Hz, 5-H), 11.55 (1H, s, NH); m/z 277 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH3:27]CN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][O:14][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1

Procedure:
The product (0.867 g) obtained in the above (2) is dissolved in dichloromethane (15 ml), and thereto are added methanol (1.5 ml), 4-dimethylaminopyridine (34 mg) and WSC.HCl (0.633 g) under ice-cooling. The mixture is stirred under ice-cooling for two hours, and then stirred at room temperature for 12 hours. The mixture is concentrated under reduced pressure to the volume of about 5 ml, and the residue is poured into water. The mixture is extracted three time with ethyl acetate, and the organic layer is washed 1N HCl (twice), a saturated aqueous sodium hydrogen carbonate solution (twice), and with a saturated brine (twice), and then dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (0.875 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[CH:11]=[N:12][C:13](Cl)=[N:14][CH:15]=1.CCO.Cl>O>[Br:9][C:10]1[CH:11]=[N:12][C:13]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:14][CH:15]=1
Reactant: Nc1cccc(F)c1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Fc1cccc(Nc2ncc(Br)cn2)c1
Temperature: 50 °C

Procedure:
In a microwave vial is added 3-fluorophenylamine (0.293 mL, 2.58 mmol), 5-bromo-2-chloropyrimidine (500 mg, 2.58 mmol), EtOH (10 mL) and concentrated HCl (0.2 mL). The reaction mixture is then heated at 50° C. for 15 min. Water (20 mL) is added and it is extracted with EtOAc. The organic layer is washed with NaHCO3, dried with Na2SO4 and concentrated. The residue is purified by column chromatography to give the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.83-6.88 (m, 1H) 7.24-7.26 (m, 1H) 7.28 (br. s., 1H) 7.34-7.40 (m, 1H) 7.74 (dt, J=11.37, 2.27 Hz, 1H) 8.56 (s, 2H); (M+H)+269.9.
Reaction SMILES: [C:1]1([C:10]([OH:12])=[O:11])([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Mo+4:17].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C>CO>[Mo:17].[C:1]1([C:10]([OH:12])=[O:11])([C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [Mo+4]
Agent: CC(=O)[O-]
Agent: O=C(O)C1(C(=O)O)CCCCC1
Solvent: CO
Product: [Mo]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.885 g (5.14 mmol) of cyclohexane dicarboxylic acid and 1,000 g (2.34 mmol) of molybdenum acetate were dissolved in 900 ml of methanol. After this was stirred for three days at the room temperature, this was kept still for a few days. Thereafter, its precipitation product was suction-filtered, rinsed sufficiently with methanol and then vacuum-dried for 60° C./4 hours, whereby 1.216 g of target substance was obtained. This substance had the specific surface area of 212 m2 /g. And, a measurement according to the HK method using argon revealed that the substance had the pore diameter of 5.2 Å.
Reaction SMILES: C(O)C.[OH-].[Na+].[CH3:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl>O.C1COCC1>[CH3:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(COC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Ethanol (20 mL) and a 2.0 mol/L aqueous solution (10 mL) of sodium hydroxide were added to a THF (20 mL) solution of ethyl 4′-(methoxymethyl)biphenyl-4-carboxylate (3.5 g) as obtained in Example 3-(2), and the mixture was stirred for 1 hour at 80° C. Water was added to the reaction mixture, and the mixture was neutralized with an aqueous solution of hydrochloric acid. Then, the precipitate was collected by filtration to obtain 4′-(methoxymethyl)biphenyl-4-carboxylic acid (gray solid) (3.0 g, 96%).