Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]([C@H:27]2[CH2:32][CH2:31][C@H:30]([C:33](OCC)=[O:34])[CH2:29][CH2:28]2)[C:11]2[C:16]([N:17]=1)=[CH:15][N:14]=[C:13]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[N:12]=2.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)(C(F)(F)F)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH2:33][OH:34])[CH2:29][CH2:28]2)[C:11]2[C:16]([N:17]=1)=[CH:15][N:14]=[C:13]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[N:12]=2
Reactant: CCOC(=O)[C@H]1CC[C@H](n2c(Nc3ccccc3F)nc3cnc(Nc4ccc(OC)cc4)nc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc3nc(Nc4ccccc4F)n([C@H]4CC[C@H](CO)CC4)c3n2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Ethyl 4-{8-[(2-fluorophenyl)amino]-2-[(4-methoxyphenyl)amino]purin-9-yl}-trans-cyclohexanecarboxylate (0.28 g, 0.55 mmol) was dissolved in 9 mL of THF and cooled to 0° C. (under nitrogen atmosphere). 1.38 mL of 1.0M LiAlH4 in THF was added dropwise. The solution turned a dark orange as the LiAlH4 was added. The reaction mixture was stirred for about 5 h and quenched by the addition of 40 mL of water. The reaction was extracted three times with ethyl acetate. Organics were combined and dried with magnesium sulfate, filtered and the solvent was removed in vacuo. The crude reaction mixture was then purified using reverse-phase preparative HPLC (20-80% acetonitrile/water (0.1% TFA) over 30 min) to obtain 0.126 g of the desired product (50% yield) after neutralization of the TFA salt. ES-MS: 463 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][O:10][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].CN(C=O)C>O>[CH2:27]([O:18][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][O:10][C:6]=2[CH:5]=1)[CH:26]=[CH2:25]
Reactant: Oc1cc(Cl)c2c(-c3ccccc3F)noc2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(Cl)c2c(-c3ccccc3F)noc2c1
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A mixture of 4-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (7.7 g), potassium carbonate (7.1 g), allyl bromide (6.0 g) and DMF (100 ml) was stirred at 50°-60° C. for 3 hours. After cooling the mixture, water was added and the mixture was extracted with ether. The ether layer was washed with water and dried, and the solvent was distilled off to obtain 8.8 g of 6-allyloxy-4-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole. This compound (8.8 g) was refluxed in 100 ml of aniline for 3.5 hours. After cooling the mixture, concentrated hydrochloric acid and then water were added and the mixture was extracted with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was purified by column chromatography using 1% methanol/methylene chloride as an eluant, and 6.3 g of 7-allyl-4-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (m.p. 211°-212° C.) was obtained. This compound (6.4 g) was dissolved in 300 ml of methylene chloride and 10.2 g of m-chloroperbenzoic acid was slowly added to the solution while it was stirred and cooled, and the stirring was continued for 3 hours. After cooling, water and then 50 ml of a 2N sodium hydroxide aqueous solution were added to the mixture, which was extracted with methylene chloride. The mehtylene chloride layer was washed with water and dried, then the solvent was distilled off to yield 5 g of 4-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-methanol. m.p. 109.5°-111° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 319.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:16][CH2:17][CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:3]=1
Reactant: Cc1ccc(Cn2nc(C3=NC(c4ccccc4)CO3)cc2C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccccc4)co3)cc2C)cc1
Temperature: 25 °C
Yield: 15.2 %

Procedure:
A solution of 2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-4-phenyl-4,5-dihydro-1,3-oxazole (Example 69, 100 mg, 0.3 mmol) in dioxane (10 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (137 mg, 0.6 mmol), and the resultant mixture was heated at reflux for 16 h. After being cooled to rt, the mixture was diluted with water (10 mL), extracted with ethyl acetate (1×25 mL), washed with NaOH (0.5 N aq., 1×25 mL) and brine (1×25 mL), dried (Na2SO4), filtered, and concentrated to dryness. The crude material was purified by HPLC eluting with a gradient from 20% to 80% acetonitrile in water containing 0.1% TFA. The combined fractions were then diluted with ethyl acetate and washed with NaHCO3 (sat. aq., 1×25 mL) dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a white solid (15 mg, 15%): 1H NMR (300 MHz, CD3OD) δ 8.19 (s, 1H), 7.73 (d, 2H), 7.29-7.35 (m, 2H), 7.21-7.25 (m, 1H), 7.04 (d, 2H), 6.95 (d, 2H), 6.62 (s, 1H), 5.28 (s, 2H), 2.20 (s, 3H), 2.18 (s, 3H); ES-MS m/z 330.12, HPLC RT (Method B) 3.89 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3(O)[CH2:22][C@@H:21]([CH3:23])[O:20][C@@H:19]([CH3:24])[CH2:18]3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH:18]=3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CC(O)(c2ccc3c(c2)CN(Cc2ccccc2)C3)C[C@H](C)O1
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: C[C@@H]1C=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)C[C@H](C)O1

Procedure:
Prepared in analogy to Example A65(a) from (2S,6R)-4-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-2,6-dimethyl-tetrahydro-pyran-4-ol (Example A70(a)) and methanesulfonyl chloride, triethylamine, and DBU. Brown oil. MS (m/e): 320.3 ([M+H]+, 100%).
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:8]=[C:9]([CH:13]=[C:14](N)[C:15]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.N1(C2C=C(C=C([S:45](=[O:48])(=[O:47])[NH2:46])C=2OC2C=CC=CC=2)C(O)=O)CCCC1>>[N:2]1([CH:7]2[C:15]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([S:45](=[O:48])(=[O:47])[NH2:46])[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Nc1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: Cl
Product: NS(=O)(=O)C1(Oc2ccccc2)C=CC(C(=O)O)=CC1N1CCCC1

Procedure:
The hydrochloride of the 3-(1-pyrrolidinyl)-4-phenoxy-5-aminobenzoic acid is converted in the manner described in Example 35 over the 3-(1-pyrrolidinyl)-4-phenoy-5-chlorosulphonyl-benzoic acid into the desired 3-(1-pyrrolidinyl)-4-phenoxy-5-sulphamylbenzoic acid melting at 225°-226° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)[C@@H:10]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C(COC)OC.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[C:16]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([OH:33])[CH:39]=3)[CH:17]=[CH:18][CH:19]=2)[C@@H:10]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(Br)c2)[C@@H](OCc2ccc3ccccc3c2)C1
Reactant: OB(O)c1cccc(O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(-c3cccc(O)c3)c2)[C@@H](OCc2ccc3ccccc3c2)C1
Temperature: 25 °C

Procedure:
A stirred mixture of (3R*,4R*)-4-(3-bromo-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester (150 mg, 0.3 mmol), 3-hydroxyphenylboronic acid (48 mg, 0.35 mmol), dimethoxyethane (3 mL), H2O (1 mL), tetrakis-(triphenylphosphin)-palladium (21 mg, 0.02 mmol) and Na2CO3 (47 mg, 0.45 mmol) is heated at reflux under argon for 16 h. The mixture is cooled to RT, dimethoxyethane is removed in vacuo and the residue is diluted with aqueous 2N Na2CO3 solution containing a few mL of concentrated NH4OH. The aqueous layer is extracted three times with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the dark residue (SiO2, hexane/ethyl acetate) affords (3R*,4R*)-4-(3′-hydroxy-biphenyl-3-yl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester as a yellowish resin: MS 508.4 [M−H]−; retention time 8.01 min (HPLC, Nucleosil C18; 5-100% CH3CN in H2O within 8 min, then 100% CH3CN for 2 min).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:25][CH3:26])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:12]1=[O:24])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C@@H:2]([CH2:25][CH3:26])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:12]1=[O:24])[C:4]([OH:6])=[O:5]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.6 %

Procedure:
A solution containing the product from Example 7A (6.15 g, 17.0 mmol) in dichloromethane (150 mL) was treated with trifluoracetic acid (50 mL), stirred at 25° C. for 2 hours and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (6.0 g, 84% yield) as the trifluoroacetic acid salt.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[NH:5][C:4](=[O:15])[CH:3]=1>C(O)(=O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([F:14])[C:8]=1[F:13])[NH:5][C:4](=[O:15])[CH:3]=[CH:2]2
Reactant: O=c1cc(Cl)c2cc(F)c(F)c(F)c2[nH]1
Solvent: CC(=O)O
Product: O=c1ccc2cc(F)c(F)c(F)c2[nH]1
Temperature: 40 °C
Yield: 93.2 %

Procedure:
4-Chloro-6,7,8-trifluorocarbostyril (60.83 g), suspended in acetic acid (520 cc) and triethylamine (38.15 cc), is hydrogenated under a pressure of 1 atmosphere at a temperature in the region of 25° C. in the presence of palladium on charcoal (5.25 g; 10% Pd) until the absorption of hydrogen is complete. The reaction mixture is then heated to approximately 40° C. and filtered at the same temperature through diatomaceous silica for filtration. The filtrate is concentrated under reduced pressure (20 kPa) at a temperature in the region of 50° C. The dry extract is taken up with water (400 cc); the insoluble matter is drained and washed with water (4×170 cc), ethanol (2×110 cc) and isopropyl ether (2×100 cc). 6,7,8-Trifluorocarbostyril (48.35 g) is obtained in the form of a colorless solid, subliming at 288° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CC[O:18][CH2:17][CH2:16]1.C(=O)C.C(N1CCC(N2CCOCC2)=CC1)C1C=CC=CC=1>O.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH:17]([OH:18])[CH3:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C1COCCN1
Agent: C1=C(N2CCOCC2)CCN(Cc2ccccc2)C1
Agent: CC=O
Solvent: ClCCl
Solvent: O
Product: CC(O)C1CN(Cc2ccccc2)CCC1=O
Reaction time: 8 h
Yield: 37.9 %

Procedure:
A 100 ml tolune solution of 10.0 g (52.9 mmol) of 1-benzyl-4-piperidone and 4.61 g (52.9 mmol) of morpholine was subjected to azeotropic dehydration for 5 hours under heating and reflux by using a water separator. After completion of the reaction, the solvent was distilled off under reduced pressure, whereby 13.7 g of 1-benzyl-4-morpholino-1,2,5,6-tetrahydropyridine were quantitatively obtained. In an argon atmosphere, a 20 ml methylene chloride solution of 1.52 g (34.6 mmol) of acetaldehyde was cooled to −40° C., followed by the dropwise addition of 5.3 ml (43 mmol) of a boron trifluoride-ether complex and 7.44 g (28.8 mmol) of the 1-benzyl-4-morpholino-1,2,5,6-tetrahydropyridine obtained above. After completion of the dropwise addition, the temperature was gradually raised and the reaction mixture was allowed to stand overnight at room temperature. Water was added to terminate the reaction, followed by extraction with methylene chloride. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (eluting solvent: toluene/ethyl acetate=4/1), whereby 4.68 g (yield: 69.7%) of 1-benzyl-3-(1-hydroxyethyl)-4-piperidone were obtained as a yellowish brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[Cl:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[Cl:49][C:50]1[CH:51]=[C:52]([NH:53][C:22](=[O:23])[CH2:21][O:20][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:26][CH:25]=2)[CH:54]=[CH:55][CH:56]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(OCC(=O)O)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(OCC(=O)Nc4cccc(Cl)c4)cc3)c2cc1OC
Yield: 71.8 %

Procedure:
2-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenoxy}acetic acid (150 mg), WSC.HCl (122 mg), and HOBT.H2O (86 mg) were dissolved in chloroform (5 ml) to prepare a solution. m-Chloroaniline (65 mg) was then added to the solution, and the mixture was heated under reflux for 3 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with 1 N hydrochloric acid, water, and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (141 mg, yield 72%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[CH:14]1([O:19][C:20]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:21]=2[CH:22]=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:22]/[C:21]1[CH:24]=[CH:25][CH:26]=[C:27]([O:28][CH3:29])[C:20]=1[O:19][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc(C=O)c1OC1CCCC1
Reactant: Cc1nc2ccccn2c(=O)c1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3ccccn3c(=O)c2Br)c1OC1CCCC1

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (500 mg, 2.091 mmol) and 2-(cyclopentyloxy)-3-methoxybenzaldehyde (514 mg, 2.503 mmol) in the presence of sodium ethoxide (213 mg, 3.131 mmol) in absolute ethanol (15 ml) as described in Intermediate 1 to give 383 mg of the product as a light yellow solid; 1H NMR (CDCl3) δ 1.61-1.69 (m, 4H), 1.70-1.79 (m, 4H), 2.33 (s, 3H), 4.51 (br s, 1H), 7.01-7.07 (m, 2H), 7.12-7.24 (m, 1H), 7.57-7.60 (m, 4H), 8.43 (d, J=15.6 Hz, 1H), 8.94 (d, J=6.3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[S:16][C:15]([C:17]([O:19]C)=O)=[CH:14][CH:13]=2)=[O:11])=[N:6][CH:7]=1.O.[NH2:22][NH2:23].C(Cl)(Cl)Cl>CO>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[S:16][C:15]([C:17]([NH:22][NH2:23])=[O:19])=[CH:14][CH:13]=2)=[O:11])=[N:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NCc2cnc(C)cn2)s1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cnc(CNC(=O)c2ccc(C(=O)NN)s2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
Methyl 5-(5-methylpyrazin-2-ylmethylcarbamoyl)thiophene-2-carboxylate (304 mg, 1.04 mmol) in methanol (3 mL) was stirred with hydrazine monohydrate at 60° C. for 12 hours. After addition of chloroform, it was stirred at room temperature for 5 hours. The precipitated solid was recovered by filtration to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid (5-methylpyrazin-2-ylmethyl)amide (yield 72%).
Reaction SMILES: COCCOC[O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][C:22]#[N:23]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[C:21](=[CH:10]/[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[OH:7])/[C:22]#[N:23])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COCCOCOc1ccccc1C=O
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccccc2O)cc1OC
Yield: 52.3 %

Procedure:
The hydroxyl group of 2-hydroxybenzaldehyde (3.0 g) was protected by use of 2-methoxyethoxymethyl chloride (3.1 g) in accordance with (production process 1), to thereby produce 2-methoxyethoxymethoxybenzaldehyde (3.7 g, yield: 70%). The thus-produced 2-methoxyethoxymethoxybenzaldehyde (2.0 g) and 3,4-dimethoxybenzyl cyanide (1.7 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.4 g, yield: 52%).
Reaction SMILES: I[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[OH-].[Na+]>C(OCC)(=O)C.CC(O)=O.CC(O)=O.[Pd].CCCCCC.O.C(#N)C>[CH3:15][C:3]1[C:2]([C:21]2[CH:22]=[CH:23][C:18]([S:17][CH3:16])=[CH:19][CH:20]=2)=[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1I
Reactant: CSc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Product: CSc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)O)c2C)cc1

Procedure:
A mixture of 5.8 g (17 mmol) of 3-iodo-2-methyl-4-methylsulfonylbenzoic acid, 4.0 g (23.8 mmol) of 4-methylthiophenylboronic acid, 11.7 g (85 mmol) of potassium carbonate, 50 mL of acetonitrile, and 12 mL of water was prepared and purged with nitrogen gas with stirring. The catalyst system, 190 mg (0.85 mmol) of palladium II acetate and 775 g (2.25 mmol) of tri-o-tolylphosphine, was added and the mixture was heated to reflux with stirring for several hours. The mixture was then cooled, basified with dilute aqueous sodium hydroxide solution, extracted with ether, and then acidified with concentrated aqueous hydrochloric acid. The resulting mixture was extracted with ether and the extract was concentrated by evaporation under reduced pressure. The residue was diluted with ethyl acetate and again concentrated by evaporation under reduced pressure. The residue was chromatographed on a preparative C-18 high pressure liquid chromatography (HPLC) column eluting with a 60:40:0.05 mixture of acetonitrile, water, and acetic acid. The product fractions were combined and extracted with ether. The ethereal extracts were concentrated by evaporation under reduced pressure and the residue obtained was diluted with ethyl acetate and again concentrated by evaporation under reduced pressure. The residue obtained was mixed with hexane and the insoluble solids were recovered by filtration and dried to obtain 2.2 g (39 percent of theory) of the title compound as a tan powder melting at 178-179° C.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>O1CCCC1>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:8][CH:9]=1
Reactant: Brc1ccccn1
Reactant: Clc1ccc(Br)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccccn2)cn1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
In a 300 mL inner volume flask replaced by nitrogen, tetrahydrofuran solution containing isopropylmagnesium chloride (19.5% by weight, 30.3 g, 57.5 mmol) was charged, and cooled at 10° C., and then, tetrahydrofuran solution (20 g) containing 5-bromo-2-chloropyridine (9.6 g, 50.0 mmol) was added dropwise in the range of 10 to 20° C. for 1.0 hour. After adding dropwise, the reaction mixture was stirred in the range of 10 to 20° C. for 1.5 hours, and then reaction mixture was added dropwise to the solution of tetrahydrofuran (20 g) containing 2-bromopyridine (7.9 g, 50.0 mmol) and [1,1′-bis(diphenylphosphino)propane]nickel dichloride (0.14 g, 0.25 mmol) in the range of 10 to 20° C. for 2.0 hours. After adding dropwise, the reaction mixture was stirred in the range of 10 to 20° C. for 4.0 hours. However, 6-chloro-3,2′-bipyridine could not be obtained.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:23])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]C(=O)C)=[C:13]([O:21][CH3:22])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([NH:7][C:8](=[O:23])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C=CC(=O)NC2CCCCC2)ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(C=CC(=O)NC2CCCCC2)ccc1O
Yield: 101.3 %

Procedure:
Using 2.64 g of N-cyclohexyl-4-acetoxy-3-methoxycinnamamide (Example 57), 70 ml of methanol, and 5 g of potassium carbonate, a reaction similar to that conducted in Example 54 was carried out. As a result, 2.32 g of N-cyclohexyl-4-hydroxy-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>O1CCCC1>[O:17]=[C:13]([CH3:12])[CH2:14][C:15]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)=[O:16]
Reactant: C=C1CC(=O)O1
Reactant: CCOC(=O)C1CCNCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)CC(C)=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 18.70 g (0.12 mol) ethyl 4-piperidinecarboxylate in 50 ml tetrahydrofuran was added dropwise to a solution of 10.00 g of diketene (0.12 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography.