Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:15][CH:14]([NH2:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[CH:11][C:12]=2[Cl:17])[NH:7]1)=[O:5].C(N(CC)CC)C.[C:26]([O:30][C:31]([NH:33][CH2:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39])=[O:32])([CH3:29])([CH3:28])[CH3:27].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:2][O:3][C:4]([C@H:6]1[CH2:15][C@H:14]([NH:16][C:38]([C:37]2[CH:41]=[CH:42][CH:43]=[C:35]([CH2:34][NH:33][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH:36]=2)=[O:39])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[CH:11][C:12]=2[Cl:17])[NH:7]1)=[O:5]
Reactant: COC(=O)C1CC(N)c2c(Cl)cc(Cl)cc2N1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2cccc(CNC(=O)OC(C)(C)C)c2)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 2-methoxycarbonyl-5,7-dichloro-4-amino-1,2,3,4-tetrahydroquinoline hydrochloride (Example 9) (300 mg, 0.963 mmol) in anhydrous dichloromethane (15 ml) under an atmosphere of nitrogen was added dry triethylamine (403 μl, 2.89 mol) and the resulting mixture was stirred at room temperature for 5 min. To this was added 3-(tertbutyloxycarbonylamino)methyl benzoic acid (step a) (290 mg, 1.16 mmol), 1-hydroxybenzotriazole (156 mg, 1.16 mol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (222 mg, 1.16 mmol) and stirring was continued for approximately 18 h. The mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate (100 ml) and 0.5M citric acid (150 ml). The organic layer was retained and washed successively with 0.5M citric acid (150 ml), saturated sodium bicarbonate solution (2×150 ml) and brine (100 ml) before drying (Na2SO4). The solvent was removed and the residue was recrystallised from ethyl acetate/hexane to give the title compound as colourless crystals (351 mg), m.p. 222°-223° C. δ (DMSO, 250 MHz) 1.39 (9H, s, C(CH3)3), 1.78 (1H, ddd, J=12.8, 12.6 and 3.9 Hz, CHACHBHCCHD), 2.26 (1H, dm, J=12.8 Hz, CHACHBHCCHD), 3.71 (3H, s, COOCH3), 4.05 (1H, dd, J=13.0 and 3.0 Hz, CHACHBHCCHD), 4.14 (2H, d, J=5.8 Hz, ArCH2NH), 5.26 (1H, m, CHACHBHCCHD), 6.69 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.90 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.93 (1H, s, ArNHCH), 7.37 (3H, m, Ar-H and CH2NHCO), 7.71-7.76 (2H, m, Ar-H), 8.68 (1H, d, J=7.1 Hz); m/e 507 (M+), 198 (100%, M-H, CO2CH2CH3,NHCOC6H4CH2NHCOOC(CH3)3).
Reaction SMILES: O[C:2]1[N:3]([C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:4](=[O:11])[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[N:10]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[N:3]([C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:4](=[O:11])[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2nc[nH]c2nc(O)n1-c1ccc(Cl)nc1
Product: O=c1c2nc[nH]c2nc(Cl)n1-c1ccc(Cl)nc1
Temperature: 135 °C

Procedure:
2-Hydroxy-1-(6-chloropyridin-3-yl)-1,9-dihydro-6H-purin-6-one from the above reaction is suspended in a large excess of phosphorous oxychloride (150 mL) and heated to 135° C. for 24 h. The reaction mixture is cooled, evaporated in vacuo, and additional toluene is added and evaporated (2×) under reduced pressure. The resulting sticky brown oil is dissolved in DCM (200 mL), and then neutralized with saturated NaHCO3 (aqueous). The aqueous layer is extracted with DCM (2×200 mL) and dried (MgSO4). The dried extract is filtered and concentrated under vacuum to afford crude product as a light brown solid. The crude product is purified by flash column chromatography using 1-2.5% MeOH/CH2Cl2 to afford the title compound as white solid. 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.78 (s, 1H), 7.58 (d, J=6 Hz, 1H), 7.53 (d, J=6 Hz, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])/[CH:13]=[CH:14]/[C:15](OC)=[O:16])=[C:7]([C:20](=[O:27])[NH:21][CH:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:13]2[CH2:14][C:15](=[O:16])[NH:3][NH:2]2)=[O:19])=[C:7]([C:20](=[O:27])[NH:21][CH:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[CH:6]=1
Reactant: NN
Reactant: COC(=O)/C=C/C(=O)Nc1ccc(Cl)cc1C(=O)NC(C)C1CC1
Solvent: CCO
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(=O)NN1)C1CC1
Yield: 28.6 %

Procedure:
A mixed liquid of 90 mg of hydrazine monohydrate and 3 ml of ethanol, was added to a mixed liquid of 0.56 g of methyl 4-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylamino)-4-oxocrotonate and 3 ml of ethanol, followed by rinsing with 2 ml of ethanol and then by heating and refluxing for 6 hours. The reaction liquid was left to cool, and then, the precipitated crystals were collected by suction filtration, and the crystals were washed with ethanol and air-dried to obtain 0.16 g of the desired product (melting point: 248° C.).
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([C:15]([O:17][CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:38](O)[CH2:39][OH:40]>C1(C)C=CC=CC=1>[ClH:1].[C:2]1([C:8]2([C:15]([O:17][CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:22])[CH3:23])=[O:16])[CH2:9][CH2:10][C:11]3([O:40][CH2:39][CH2:38][O:14]3)[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: CC(C)N(CCOC(=O)C1(c2ccccc2)CCC(=O)CC1)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)N(CCOC(=O)C1(c2ccccc2)CCC2(CC1)OCCO2)C(C)C

Procedure:
2-(Diisopropylamino)ethyl 1-phenyl-4-oxocyclohexanecarboxylate hydrochloride (3 mmol), prepared in Example 119, was refluxed for 4 h with p-toluenesulfonic acid (1.5 mmol) and ethyleneglycol (4 mmol) in toluene (50 mL) using a Dean-Stark trap. The reaction mixture was partitioned between Et2O and 2 M NaHCO3. The organic layer was dried (Na2SO4) and evaporated. The residue was dissolved in Et2O and HCl (g)/Et2O was added. The amine salt was recrystallized from acetone/Et2O to yield 0.53 g (43%); mp 121-128° C.; 1H NMR (CD3OD) δ 1.25 (d, 12H), 1.72 (m, 4H), 2.13 (m, 2H), 2.47 (m, 2H), 3.35 (t, 2H), 3.59 (m, 2H), 3.93 (m, 4H), 4.42 (t, 2H), 7.26-7.47 (m, 5H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH3:32])[C:15]=2[C@H:16]2[O:22][CH2:21][C@@H:20]([F:23])[C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:33].[F:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1B(O)O>>[NH2:24][C@H:19]1[C@H:20]([F:23])[CH2:21][O:22][C@H:16]([C:15]2[N:14]([CH3:32])[N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:33])=[C:2]([C:36]3[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=3[F:34])[N:7]=2)[CH2:17][CH2:18]1
Reactant: COc1ccc(B(O)O)c(F)c1
Reactant: Cn1ncc(NC(=O)c2ccc(F)c(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: COc1ccc(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)ccc2F)c(F)c1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(6-bromo-5-fluoropicolinamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 103), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-4-methoxyphenyl)boronic acid gave 226. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.18 (dd, J=8.6, 3.8 Hz, 1H), 8.03 (dd, J=9.6, 8.6 Hz, 1H), 7.88 (s, 1H), 7.69 (t, J=8.8 Hz, 1H), 7.04-6.95 (m, 2H), 4.83 (dd, J=10.5, 3.7 Hz, 1H), 4.32 (ddt, J=48.7, 6.0, 2.6 Hz, 1H), 4.16-3.89 (m, 2H), 3.86 (s, 3H), 3.77 (s, 3H), 3.20-3.06 (m, 1H), 2.13-2.01 (m, 1H), 1.88-1.74 (m, 1H), 1.73-1.56 (m, 4H). LCMS (ES+) m/z 476 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[C:5]([CH3:18])=[C:6]2[C:11]=1[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][CH:7]2[O:14][CH2:15][CH2:16][CH3:17].[OH-].[K+].O>[Zn].C(O)C>[CH2:15]([O:14][CH:7]1[C:6]2[C:11](=[CH:2][CH:3]=[C:4]([C:19]([OH:21])=[O:20])[C:5]=2[CH3:18])[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8]1)[CH2:16][CH3:17]
Reactant: CCCOC1CCS(=O)(=O)c2c(Cl)cc(C(=O)O)c(C)c21
Agent: [K+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CCCOC1CCS(=O)(=O)c2ccc(C(=O)O)c(C)c21
Yield: 81.7 %

Procedure:
A 50-ml egg-plant type flask was charged with 1.36 g (0.0041 mol) of 8-chloro-4-n-propoxy-5-methylthiochroman-6-carboxylic acid-1,1-dioxide, 1.35 g (0.02 mol) of potassium hydroxide, 0.81 g (0.012 mol) of a zinc powder, 10 ml of water and 6 ml of ethanol, and the mixture was refluxed under heat for 10 hours. After allowed to cool, insolubles were removed by filtration, and the ethanol was distilled off under reduced pressure. Then, while the remainder was cooled with ice, 50 ml of 5% hydrochloric acid was added to adjust the pH to 1. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 2% hydrochloric acid, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1.0 g of 4-n-propoxy-5-methylthiochroman-6-carboxylic acid-1,1-dioxide (Compound 32) shown in Table 2.
Reaction SMILES: [CH3:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:17].Cl[C:19]1[N:20]=[C:21]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:22]2[S:27][CH:26]=[CH:25][C:23]=2[N:24]=1>>[CH3:1][C:2]1[C:7]([C:19]2[N:20]=[C:21]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:22]3[S:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:17]
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1c(N)cccc1-c1nc(N2CCOCC2)c2sccc2n1

Procedure:
Reaction of 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine under Suzuki conditions yielded 2-methyl-3-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine. To a solution of 2-methyl-3-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine (80 mg) in chloroform (8 mL) and acetic acid (4 mL) was added isoamyl nitrite (36 μL). The reaction mixture was stirred for 1 day at room temperature. The mixture was then quenched with sodium bicarbonate solution and extracted in to chloroform and reduced in vacuo. The residue was purified using flash chromatography to yield 270. MS: ESI MH+ 338
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:4]=1[NH:19][C:20](=O)[CH3:21])#[N:2].P(=O)(O)(O)[OH:24]>>[CH3:21][C:20]1[NH:2][C:1](=[O:24])[C:3]2[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[C:4]=2[N:19]=1
Reactant: O=P(O)(O)O
Reactant: CC(=O)Nc1c(C#N)c(C)c(C)n1-c1c(C)cc(C)cc1C
Product: Cc1cc(C)c(-n2c(C)c(C)c3c(=O)[nH]c(C)nc32)c(C)c1
Temperature: 130 °C

Procedure:
A mixture of the compound of step B(157.600 g, 0.53 mol) and 100 ml of 85% phosphoric acid was heated for 0.5 hours in an oil bath at a temperature of 130° C. All the starting material was consumed and the desired product formed. The mixture was cooled, poured into 1200 ml of ice-water, and stirred. Precipitate formed and was filtered. The solid was washed with water, dried overnight to give 113.220 g of the title compound as brick-pink solid. 1H NMR (CDCl3) δ 1.85(s, 6H), 1.87(s, 3H), 2.34(s, 3H), 2.41(s, 3H), 2.44(s, 3H), 7.00(s, 2H) ppm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][C:9]([NH2:11])=[O:10].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])([O-:14])=[O:13]>CC(C)=O>[C:9]([CH2:8][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])(=[O:10])[NH2:11]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)COc1ccccc1[N+](=O)[O-]

Procedure:
8.0 g of potassium carbonate and 11.4 g of iodoacetamide are added to a solution of 4.0 g of 2-nitrophenol in 50 ml acetone. The reaction mixture is heated under reflux for 7 h and then concentrated. The residue is dissolved in chloroform and extracted with 0.05N of sodium hydroxide solution. Recyrstallization of the crude product from tetrahydrofuran gives 2-(carbamoylmethoxy)nitrobenzene of mp 190°-1° C.; Rf (O)=0.55.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].ClCCl>C(N(CC)CC)C>[CH:23]([S:24]([NH:1][CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:26])=[O:25])=[CH2:22]
Reactant: Cc1c(-c2ccccc2)oc2c(CN)cccc2c1=O
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NCc1cccc2c(=O)c(C)c(-c3ccccc3)oc12

Procedure:
This compound can be prepared by reacting Intermediate XXIV with 2-chloroethylsulfonylchloride in an halogenated solvent (e.g., dichloromethane) in presence of triethylamine at 0°-40° C., according to A. A. Goldberg, Jr., J. Chem. Soc., 464 (1945).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:28]([N:33]=[C:34]=[S:35])(=[O:32])[O:29][CH2:30][CH3:31].O>CS(C)=O>[F:25][C:23]([F:26])([F:24])[C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:34]([NH:33][C:28](=[O:32])[O:29][CH2:30][CH3:31])=[S:35])=[N:7][CH:6]=1)=[O:27]
Reactant: Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Reactant: CCOC(=O)N=C=S
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (600 mg, 1.61 mmol) in DMSO (30 mL) was added ethyl isothiocyanatocarbonate (230 μL, 1.95 mmol), and the mixture was stirred at room temperature for 12 hr. Water (150 mL) was slowly added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl ({[5-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (485 mg, 59%) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[CH:15]1([C:21](O)=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:21]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: O=C(O)C1CCCCC1
Product: CC1(C)C(=O)Nc2cc3[nH]c(C4CCCCC4)nc3cc21

Procedure:
Analogously to Example 1, from 960 mg. (5.0 mmole) 5,6-diamino-3,3-dimethylindolin-2-one and 640 mg. (5.0 mmole) cyclohexanecarboxylic acid, after 1.5 hours at 240° C., there is obtained 1.37 g. of crude product. 300 mg. thereof are purified over a silica gel column (elution agent: dichloromethane/methanol 9:1 v/v). After removal of the solvent in a vacuum, there is obtained a greenish oil which is crystallised with diethyl ether. There are obtained 192 mg. (53% of theory) of the title compound in the form of pale brown crystals; m.p. 315°-318° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:29][N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>>[CH3:27][C:26]1[C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:13]([C:5]3[CH:4]=[CH:3][C:2]([N:32]4[CH2:33][CH2:34][N:30]([CH3:29])[C:31]4=[O:35])=[CH:7][C:6]=3[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:14])[CH2:16][CH2:17]2)=[N:22][CH:23]=[C:24]([CH3:28])[CH:25]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3NS(C)(=O)=O)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3NS(C)(=O)=O)CC2)c(C)c1
Yield: 26.7 %

Procedure:
Using N-{5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (187 mg) described in Preparation Example 226 and 1-methylimidazolidin-2-one (40 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (52 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22]S(C)(=O)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of ethyl 3-(4-benzyloxyphenyl)-2-methanesulfonyloxypropionate (8.82 g) obtained from Reference example 24(b) and 4-chlorophenol (3.00 g) in N,N-dimethylformamide (110 ml) was added potassium carbonate (6.44 g), and the mixture was stirred at 70° C. for 16 hours. The reaction solution was partitioned between ethyl acetate and water, and then the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant; hexane/ethyl acetate=9/1) to afford the target compound (5.99 g) as colorless crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.[Cl-].[Na+]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:16][CH2:15][C:14]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=3)=[N:11][O:12][C:13]=2[CH3:17])=[N:20][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1onc(-c2cccc(F)c2)c1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.68 g, 18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded the title compound (4.1 g, 68%) which was obtained as a white solid. MS: m/e=343.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1.[N:29]1[C:38]2[C:37](=O)[CH2:36][CH2:35][CH2:34][C:33]=2[CH:32]=[CH:31][CH:30]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)[CH:37]1[C:38]2[N:29]=[CH:30][CH:31]=[CH:32][C:33]=2[CH2:34][CH2:35][CH2:36]1
Reactant: O=C1CCCc2cccnc21
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CN(Cc2ncc[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.5 %

Procedure:
The compound (203.5 mg) obtained in Example 9-2 was dissolved in anhydrous methanol (8.1 ml) and added with 6,7-dihydro-5H-quinolin-8-one (117.7 mg) which was synthesized by a known method and sodium cyanoborohydride (99.9 mg). After the solution was adjusted to pH 5 with acetic acid, the whole was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (69.5 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH3:3].[S:10](Cl)[Cl:11].N1C=CC=CC=1>C(Cl)Cl>[Cl:11][S:10][N:4]([CH:2]([CH3:3])[CH3:1])[C:5](=[O:9])[O:6][CH2:7][CH3:8]
Reactant: ClSCl
Reactant: CCOC(=O)NC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N(SCl)C(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 63.2 %

Procedure:
To a solution of ethyl (1-methylethyl)carbamate (13.1 g, 0.1 mol) in 100 ml methylene chloride cooled to 0° C. was added sulfur dichloride (11.3 g, 0.11 mol) in one portion. While maintaining the temperature of the mixture at 0° C., pyridine (8.7 g, 0.11 mol) was added dropwise over eleven minutes. After complete addition of the pyridine the temperature was allowed to rise to room temperature and stirring was continued for additional 1.5 hours. The mixture was let stand overnight. Methylene chloride was evaporated under vacuum and 100 ml hexane was added. Filteration of the pyridine hydrochloride and evaporation of hexane resulted in an orange oil which was distilled in a Kugelrohr apparatus to give 12.5 g of the title compound Bp: 64°-80° (bath temperature) at 1.4 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:19]([N+:21]([O-:23])=[O:22])[CH3:20])[CH:15]=2)[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C=O.[CH3:26][O:27][Na]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([N+:21]([O-:23])=[O:22])([CH3:20])[CH2:26][OH:27])[CH:15]=2)[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc2cc(C(C)[N+](=O)[O-])ccc2n1
Reactant: CO[Na]
Agent: C=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc2cc(C(C)(CO)[N+](=O)[O-])ccc2n1
Temperature: 80 °C
Reaction time: 15 h
Yield: 111.5 %

Procedure:
2-(heptyloxy)-6-(1-nitroethyl)quinoline (1.823 g, 5.77 mol) and paraformaldehyde (346 mg, 11.54 mmol, 2.0 eq.) were dissolved in THF (10 mL). CH3ONa (115 mg, 2.13 mmol, 0.37 eq.) in methanol (2 mL) was added to the solution. The mixture was stirred at 80° C. under nitrogen atmosphere for 15 h. The mixture was extracted with ethyl acetate and the organic layer was concentrated and purified by silica gel column chromatography using petroleum/ethyl acetate (5/1) as eluent to give product as a slight red oil (823 mg, 43%). ESI-MS: 347.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.56 (q, 1H), 6.93 (d, 1H), 4.62 (d, 1H), 4.47 (t, 2H), 3.90 (d, 1H), 2.15 (s, 3H), 1.84-1.80 (m, 2H), 1.49-1.24 (m, 8H), 0.89 (t, 3H).