Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH:21][S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[C:40]1(=[O:50])[O:45][C:43](=[O:44])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12>C1COCC1>[Cl:30][C:27]1[S:26][C:25]([S:22]([NH:21][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:40]([C:41]4[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=4[C:43]([OH:45])=[O:44])=[O:50])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:24])=[O:23])=[CH:29][CH:28]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)c2ccccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a solution of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 4) (0.046 g, 0.1 mmol) in THF (0.5 ml) was added N,N-diisopropylethylamine (0.035 ml, 0.2 mmol), followed by phthalic anhydride (0.014 g, 0.1 mmol). The solution was stirred for 18 hours at room temperature, concentrated in a blow-down unit and the residue was dissolved in DMSO (0.5 ml) and purified by mass directed auto-preparative HPLC (Method E) to give the title compound (35 mg, 51%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([O:12]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](OCC)=O.[H-].[Na+].S(O)(O)(=O)=O.[N:27]1([C:33](=[NH:35])[NH2:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([OH:12])=[N:35][C:33]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[N:34][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COCc1ccccc1
Reactant: N=C(N)N1CCOCC1
Reactant: CCOC=O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Oc1nc(N2CCOCC2)ncc1OCc1ccccc1

Procedure:
The 4-alkoxy-2-morpholino-5-pyrimidinols (D represents alkoxy) can be prepared by reacting a 1:1 mixture of ethyl benzyloxyacetate and ethyl formate with sodium hydride in toluene and the product is then reacted with 4-morpholinecarboximidamide sulfate to give 5-benzyloxy-2-morpholino-4-pyrimidinol. The latter compound is converted to 5-benzyloxy-4-chloro-2-morpholinopyrimidine by reaction with phosphorus oxychloride. The ring chlorine is then replaced by an alkoxy group with an alkali alkoxide to give 4-alkoxy-5-benzyloxy-2-morpholinopyrimidine. The benzyloxy group is then converted to the OH group by hydrogenation in the presence of a solvent and a hydrogenation catalyst.
Reaction SMILES: [OH2:1].[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[S:11][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1.N1C2C=CC=CC=2N=C1SCC1C(N)=NC=CC=1.ClC1C=CC=C(C(OO)=[O:46])C=1>ClCCl>[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[S:11]([CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)(=[O:46])=[O:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Reactant: Nc1ncccc1CSc1nc2ccccc2[nH]1
Solvent: ClCCl
Product: Nc1ncccc1CS(=O)(=O)c1nc2ccccc2[nH]1
Yield: 5.8 %

Procedure:
A suspension of 4.0 g (15 mmole) of 3-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine hemihydrate (see Example 79) in 50 ml of dichloromethane was cooled in an ice bath. A solution of 3.0 g (15 mmole) of ca. 85% m-chloroperbenzoic acid in the minimum amount of dichloromethane needed to form a solution was then added dropwise with stirring. After addition was complete, another 3.0 g of ca. 85% m-chloroperbenzoic acid was added. The reaction was quenched with 10 drops of dimethylsulfide. The mixture was washed with saturated aqueous sodium bicarbonate. The organic phase was concentrated in vacuo and chromatographed on silica gel (using ethanol-dichloromethane-triethylamine as eluent). Initial fractions yielded 249 mg of the title sulfone. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis. Analysis. Calc'd. for C12H12N4SO2: C, 54.15; H, 4.19; N, 19.43. Found: C, 53.79; H, 4.09; N, 19.29.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[CH3:5][C:6]([O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)([C@@H:8]1[CH2:10][O:9]1)[CH3:7]>CO>[CH3:5][C:6]([O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)([CH:8]1[O:9][C:2]([NH2:3])=[N:1][CH2:10]1)[CH3:7]
Reactant: CC(C)(Oc1ccc2c(c1)CCC2)[C@@H]1CO1
Reactant: N#CN
Agent: [Na]
Solvent: CO
Product: CC(C)(Oc1ccc2c(c1)CCC2)C1CN=C(N)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a vigorously stirred solution of sodium hydrogen cyanamide (0.21 g, 3.21 mmol) in methanol (10 mL) was added slowly (S)-2-(1,1-dimethyl-indan-5-yloxymethyl)-oxirane (0.57 g, 3.21 mmol). The reaction mixture was stirred at room temperature overnight after which the reaction mixture was concentrated. Anhydrous diethyl ether (50 mL) was added. The resulting white precipitate was filtered through Celite and the filtrate concentrated. The residue was purified by flash chromatography (silica, 7N NH3 in methanol/methylene chloride) to give 0.41 g (49%) of 5-(1,1-dimethyl-indan-5-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH2:14][OH:15])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:14][O:15][S:24]([CH3:27])(=[O:26])=[O:25])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of ((S)-1-hydroxymethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (250 mg, 0.756 mmol) and triethylamine (0.116 mL, 0.832 mmol) in CH2Cl2 (4 mL) cooled at −10° C. was added under nitrogen atmosphere mesylchloride (0.065 mL, 0.832 mmol) and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was quenched with ice and water then extracted twice with EtOAc. The combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated. The crude material (colorless oil) was used without purification in the next step. TLC, Rf (c-hexane/EtOAc 1:1): 0.46.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29]Br)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1cccc(-c2[nH]c(=O)c3ccccc3c2O)c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cccc(-c2[nH]c(=O)c3ccccc3c2OCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
To a solution of 3.79 g (14.19 mmol) of 4-hydroxy-3-(3-methoxy-phenyl)-2H-isoquinolin-1-one in N,N-dimethylacetamide (90 mL), 3.18 g (14.19 mmol) of (2-bromo-ethyl)-carbamic acid tert-butyl ester and 5.09 g (15.6 mmol) of cesium carbonate were added and the resulting mixture was stirred at room temperature for 2 hours under argon. Water was added to the reaction mixture and this was extracted twice with ethyl acetate. The combined organic layers were washed at least three times with water and then evaporated to dryness. The crude was purified by flash chromatography (eluant: ethyl acetate/hexane 1/1) to afford 3.2 g of the title compound (55%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[F:36][C:32]1[C:24]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]3[CH2:11][C@@H:10]([C:37]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13]3)=[O:20])=[N:22][C:23]=2[CH:35]=[CH:34][CH:33]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCCC3)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (1.65 g), pyrrolidine (500 μl), HOBt (270 mg) and triethylamine (1.27 ml) were dissolved in DMF (50 ml), WSC.HCl (1.15 g) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95)-ethyl acetate-ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object product (170 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16](F)[CH:15]=2)=[CH:8][CH:7]=1)[CH3:4].[OH2:23].C[S:25]([CH3:27])=O>>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]3[CH:18]=[C:27]([C:6]([O:5][CH2:3][CH3:4])=[O:23])[S:25][C:16]=3[CH:15]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: O
Reactant: CS(C)=O
Reactant: CCOc1ccc(CCc2ccc(C=O)c(F)c2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2ccc(CCc3ccc(OCC)cc3)cc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of ethyl mercaptoacetateester (0.450 mL, 4.07 mmol) in DMSO (10 mL) was added sodium hydride (60%, 196 mg, 4.89 mmol) and the mixture was stirred at room temperature for 10 min. To this reaction mixture was added 4-[2-(4-ethoxyphenyl)ethyl]-2-fluorobenzaldehyde (886 mg, 3.26 mmol) obtained in Reference Example 171, and the mixture was stirred at room temperature for 20 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=19:1 to 1:1) to give the title compound (723 mg, yield 63%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])=[CH:25][CH:24]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCBr
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 85.7 %

Procedure:
A solution of 4-{2-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol (1.50 g, 3.91 mmol), 1-bromoundecane (1.31 ml, 5.87 mmol) and potassium carbonate (811 mg, 5.87 mmol) in DMF (15 ml) was stirred at 80° C. for 4 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.80 g (yield: 85.7%)
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12]1[CH2:14][CH2:13]1.[CH2:15](N(CC)CC)[CH3:16]>[Cu]I>[CH:12]1([C:15]#[C:16][C:2]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH2:14][CH2:13]1
Reactant: CCN(CC)CC
Reactant: C1CC1
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Agent: [Cu]I
Product: Nc1ccc([N+](=O)[O-])cc1C#CC1CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
To a deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol), ethynyl-pane cyclopropane (1 g, 15 mmol) and CuI (10 mg, 0.05 mmol) in triethylamine (20 mL) was added Pd(Ph3)3Cl2 (210 mg, 0.3 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 hours. The solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 2-(cyclopropylethynyl)-4-nitroaniline (470 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J=2.7 Hz, 1H), 7.97 (dd, J=2.7, 9.0 Hz, 1H), 6.63 (d, J=9.0 Hz, 1H), 4.81 (brs, 2H), 1.55-1.46 (m, 1H), 0.98-0.90 (m, 2H), 0.89-0.84 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([S:13]([CH3:16])(=[O:15])=[O:14])[C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1.[OH-].[Li+].O1CCCC1.Cl>O>[CH3:1][N:2]([S:13]([CH3:16])(=[O:15])=[O:14])[C:3]1[O:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1coc(N(C)S(C)(=O)=O)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1nc(C(=O)O)co1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a 50 ml round bottom flask was added (61 mg, 0.2457 mmoles) ethyl 2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate, (51.5 mg, 1.2274 mmoles, 5.0 eq.) lithium hydroxide, (2.5 ml) tetrahydrofuran and (1.5 ml) water. The reaction was agitated at ambient temperature for ˜2 hours. The reaction was complete by electrospray mass spec. The reaction was worked up by adding (5 ml) 1N HCl and then extracting with ethyl acetate. The organic layer was washed with water and brine and then dried with magnesium sulfate. The solution was then evaporated to dryness, leaving (44.6 mg) of 2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxylic acid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[N:16]=[N:15][C:14]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:13][CH:12]=1.I[CH2:29][C:30]([NH2:32])=[O:31]>CN(C=O)C.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14](=[N:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:15]([CH2:29][C:30]([NH2:32])=[O:31])[N:16]=1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)nn2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Cl)nn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
N,N-Diisopropylethylamine (10.4 mL, 81 mmol) was added to a suspension of N-(6-chloropyridazin-3-yl)-4-methylbenzenesulfonamide (21 g, 74 mmol) in dry DMF (100 mL) under argon. To the resulting solution was added 2-iodoacetamide (15 g, 81 mmol, Aldrich, St. Louis, Mo.) and the mixture was stirred for 24 h at rt. The reaction mixture was diluted with water and precipitated solid was filtered off to afford the title compound (17 g, 68%). 1H NMR (DMSO-d6, 300 MHz): δ 2.4 (s, 3H), 4.8 (s, 2H), 7.3 (d, 2H), 7.6-7.8 (m, 4H), 7.95 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]1([N:25]2[C:29]([C:30]3[O:31][CH:32]=[CH:33][CH:34]=3)=[CH:28][C:27]([CH:35]=O)=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:29]1[N:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:26]=[C:27]([CH2:35][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)[CH:28]=1
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Product: O=[N+]([O-])c1ccc(N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)cc1
Yield: 93.3 %

Procedure:
Compound 54 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.Cl.[NH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:21][O:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:30][CH:31]3[S:35][C:34](=[O:36])[NH:33][C:32]3=[O:37])=[CH:38][CH:39]=2)[CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(OC)c(-c2ccc(C(C)=O)cc2)c1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: COc1ccc(OC)c(-c2ccc(C(C)=NOCCOc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Yield: 92.7 %

Procedure:
Following a procedure similar to that described in Example 40(f), 256 mg of 4'-(2,5-dimethoxyphenyl)acetophenone were reacted with 382 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 482 mg of the title compound as an amorphous solid, melting at 47°-52° C. (softening point).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:16]([OH:18])=O)=[N:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1)=[O:4].[C:19](N1C=CN=C1)([N:21]1C=CN=[CH:22]1)=O.CNC>CN(C=O)C>[CH3:19][N:21]([CH3:22])[C:16]([C:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:9][N:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]=1)=[O:18]
Reactant: COC(=O)c1nn(-c2ccccc2)nc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: CN(C)C=O
Product: COC(=O)c1nn(-c2ccccc2)nc1C(=O)N(C)C
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
A solution of 5-methoxycarbonyl-2-phenyl-2H-1,2,3-triazole-4-carboxylic acid (0.203 g, 0.82 mmol) in dry DMF (3 mL) at 23° C. was treated with carbonyldiimidazole (0.146 g, 0.90 mmol). The resulting mixture was stirred for 1.5 h at 23° C., cooled to 0° C. and treated with dimethylamine (2.0 M in THF, 2.05 mL, 4.10 mmol). The resulting mixture was allowed to warm to 23° C. over 16 h and concentrated in vacuo. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with an additional portion of EtOAc. The combined organic extracts were washed with HCl (1 M), brine, NaHCO3 (sat. aq. sol.) and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by filtering it through a silica gel plug (EtOAc-hexanes 50:50) to afford 0.201 g (89%) of methyl 5-(N,N-dimethylcarbamoyl)-2-phenyl-2H-1,2,3-triazole-4-carboxylate.
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])O.[Na+]>O.CC(C)=O>[CH3:16][O:15][C:13]([O:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:14]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(C#N)=NOC(=O)OC
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A solution of sodium salt of ethyl 2-hydroxyimino-2-cyanoacetate (41.0 g) in water (200 ml) is stirred under ice-cooling, and a solution of methyl chloroformate (23.6 g) in acetone (20 ml) is dropwise added thereto. The resulting mixture is adjusted to pH 6 to 7 with the addition of an aqueous solution of sodium hydrogencarbonate and stirred for 1 hour. The precipitates are collected by filtration, washed with water and dried to give ethyl 2-methoxycarbonyloxyimino-2-cyanoacetate (41.1 g) as crystals melting at 68° to 70°C which is identified with the compound obtained in Example 9 by IR absorption spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1F.[CH2:20]([NH2:23])[CH2:21][NH2:22].O>CN(C)C(=O)C>[NH2:22][CH2:21][CH2:20][NH:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[N:9]([CH:12]1[CH2:14][CH2:13]1)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: NCCN
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: NCCNc1cc2c(=O)c(C(=O)O)cn(C3CC3)c2cc1Cl
Temperature: 115 °C
Reaction time: 8.5 h
Yield: 10 %

Procedure:
7-Chloro-1-cyclopropyl-1,4-dihydro-6-fluoro4-oxo-quinoline-3-carboxylic acid (56.3 g) and ethylenediamine (36 g) were dissolved in N,N-dimethylacetamide (650 mL) at 100° C. and stirred for 8.5 h at 115° C. Water (700 mL) was added to the reaction mixture cooled at room temperature. The reaction mixture was stirred at room temperature for 2 h, cooled at 0-5° C. and stirred for 1 h. The precipitate obtained was filtered, washed with cold water, cold EtOH, and dried at 110° C. under reduced pressure for 1 h. The crude product was treated with HCl (6% aqueous solution) heating for 1 h in the presence of charcoal. After filtration, the solution was cooled to 35-40° C. and a first precipitation happened. The precipitate was filtered, washed with water and dried at 110° C. for 1 h. The title compound (6.4 g) was obtained as the hydrochloride salt. The hydrochloride salt was then converted to the free base using standard conditions.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](O)=[O:9])=[CH:6][CH:7]=1.C1(C)C(C([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=O)=CC=CC=1>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][OH:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(COC(=O)c2ccccc2C)cc1
Product: Cc1ccc(C=O)cc1
Product: Cc1ccc(CO)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To 2100 g of the reaction filtrate obtained in the same condition as of the Example 1, 364.0 g of aqueous sodium hydroxide solution (sodium hydroxide was 1.5 times in mole with respect to a total amount of the p-toluic acid and p-methylbenzyl toluate) was added, stirred at 90° C. for 4 hours, and after standing still 15 minutes, the solution was separated into 1937.5 g of organic layer and 372.0 g of water layer. To said organic layer, 0.27 g of aqueous 40% NaOH solution (sodium hydroxide was 0.11% with respect to total amount of the p-tolualdehyde and p-methylbenzyl alcohol contained in the solution) was added, and distilled to obtain 82.2 g of p-tolualdehyde, and 84.8 g of p-methylbenzyl alcohol. As the result of the analysis by gas chromatography, purities of the p-tolualdehyde and p-methylbenzyl alcohol were found as 99.3% and 99.5%, respectively.