Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:6]([CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[NH:17][S:16]2(=[O:26])=[O:25])[CH2:11][CH2:10]1)=[O:7].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH2:8][N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[NH:17][S:16]3(=[O:25])=[O:26])[CH2:13][CH2:14]2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(C(=O)CN2CCC(N3Cc4ccccc4NS3(=O)=O)CC2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(O)CN2CCC(N3Cc4ccccc4NS3(=O)=O)CC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.6 %

Procedure:
In 150 ml of methanol, 2.2 g of 1-(3,4-dimethoxybenzoylmethyl)-4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin-3-yl)-piperidine is suspended. While this suspension is stirred at room temperature, 1.0 g of sodium borohydride is added thereto by portions over a period of four hours. The mixture is stirred overnight at room temperature and 400 mg of sodium borohydride is added thereto. Then, the mixture is stirred overnight. The reaction solution is concentrated under reduced pressure. The residue is mixed with 100 ml of water and adjusted to pH 9.3 with concentrated hydrochloric acid. The resultant mixture is extracted with chloroform. The organic layer is washed with water, dried and freed from the solvent by distillation to obtain a syrup as a residue. This residue is crystallized by adding methanol thereto. The crystals are separated by filtration to obtain 1.93 g of crude crystals. The crude crystals are recrystallized from ethanol to obtain 1.45 g of 1-[2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]-4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin- 3-yl)-piperidine (Compound No. 10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:16](=[O:25])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(NC(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
p-Anisidine (25 g, 0.203 mol) was suspended in acetone (400 ml), to which pyridine (19.7 ml, 0.244 mol) was added. While cooling on ice, cinnamoyl chloride (37.2 g, 0.223 mol) was further added, followed by stirring at ambient temperature for 20 minutes. As a result, a uniform solution was obtained. The solvent was condensed under reduced pressure. To the residue, ethyl acetate and water were added. The sediment was collected by filtration, washed with ethyl acetate and water, and dried with air. 50.4 g of the title compound was obtained as pale greenish brown powder (98.0%, mp.: 147°-150° C.).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][CH:13]=[N:14]4)[N:7]=[CH:6][C:5]=2[C:19]([OH:21])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:8]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][CH:13]=[N:14]4)[N:7]=[CH:6][C:5]=2[C:19]([Cl:24])=[O:21])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
combining 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid and thionyl chloride in toluene to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid chloride; and
Reaction SMILES: C([N:8]1[CH2:39][CH2:38][C:11]2[N:12]=[C:13]([C:18]3[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>O.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:17][O:16][C:15]1[C:10]2[CH2:9][NH:8][CH2:39][CH2:38][C:11]=2[N:12]=[C:13]([C:18]2[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[N:21][N:22]3[S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[N:14]=1
Reactant: COc1nc(-c2c(C)ccc3c2cnn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(Cc1ccccc1)CC2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1nc(-c2c(C)ccc3c2cnn3S(=O)(=O)c2ccc(C)cc2)nc2c1CNCC2

Procedure:
A mixture of 6-benzyl-4-methoxy-2-(5-methyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.85 g, 3.43 mmol) and Pd(OH)2 on carbon (wet) (10%, 0.722 g, 1.03 mmol) in water (7.5 mL) and acetic acid (0.59 mL) was stirred under 1 atm of hydrogen at room temperature for 2.5 h. The reaction mixture was filtered through Celite® and the solids were washed with EtOAc. The combined filtrates were washed with saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH (10% NH4OH)/DCM) to provide 4-methoxy-2-(5-methyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 450.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[CH3:23][NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[CH:30][C:31]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Product: CNS(=O)(=O)c1ccc(-c2ccc3oc(C4CCN(C(=O)OC(C)C)CC4)nc3c2)cc1
Yield: 14.2 %

Procedure:
Following the General Procedure-3, the titled compound (35 mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and 4-(N-methylsulfamoyl)phenylboronic acid (120 mg, 0.54 mmol) as a white solid. M.P.: 179-181° C. MS (m/z): 458.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25]([C:36]3[S:37][CH:38]=[CH:39][N:40]=3)=[CH:24][C:23]=2[CH2:41][CH3:42])[C:12]=1[CH2:43][CH2:44][CH3:45].B(F)(F)F.CCOCC>C(S)C.O>[CH2:41]([C:23]1[CH:24]=[C:25]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:43][CH2:44][CH3:45])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:46])=[O:2])[CH3:42]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3nccs3)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCS
Solvent: O
Product: CCCc1c(OCCCOc2cc(O)c(-c3nccs3)cc2CC)cccc1Oc1ccccc1C(=O)O
Yield: 45.4 %

Procedure:
A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-2-yl-phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (282 mg, 0.442 mmol) in ethanethiol (3 mL) was treated with boron trifluoride etherate (0.56 mL, 4.4 mmol) at room temperature for 3 h. The reaction mixture was diluted with water, concentrated in vacuo, and extracted with diethyl ether. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, ethyl acetate/hexane) provided 107 mg (44%) of the title compound. 1H NMR (CDCl3) δ 7.88 (dd, J=8, 2 Hz, 1H), 7.80 (d, J=4 Hz, 1H), 7.35 (dt, J=8, 2 Hz, 1H), 7.28 (d, J=4 Hz, 1H), 7.24 (s, 1H), 7.09 (dt, J=9, 2 Hz, 1H), 7.05 (t, J=9 Hz, 1H), 6.79 (d, J=9 Hz, 1H), 6.66 (d, J=9 Hz, 1H), 6.61 (s, 1H), 6.42 (d, J=9 Hz, 1H), 4.24 (t, J=6 Hz, 2H), 4.18 (t, J=6 Hz, 2H), 3.81 (s, 3H), 2.63 (t, J=7 Hz, 2H), 2.58 (q, J=7 Hz, 2H), 2.34 (quintet, J=6 Hz, 2H), 1.52 (hextet, J=8 Hz, 2H), 1.17 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H); MS ES+ m/e 548 (p+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:16][C:17](=[O:19])[NH2:18])([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6](OCC)=[O:7])[CH3:2].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:5]1([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH2:16][C:17](=[O:19])[NH:18][C:6]1=[O:7])=[O:20])[CH3:2]
Reactant: CCOC(=O)C(CC(N)=O)(C(=O)OCC)n1cccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(n2cccc2)CC(=O)NC1=O
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a stirred solution of 2-carbamoylmethyl-2-(pyrrol-1-yl)malonic acid diethyl ester (29.0 g) in anhydrous dimethylformamide (30 ml) was added portionwise sodium hydride (63% dispersion in mineral oil, 4.3 g) under ice cooling. The resulting mixture was stirred under ice cooling for 1 hour, poured into 5% hydrochloric acid/ice-water, and extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (2:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure to give the title compound (23.0 g, 94.7%) as a colorless oil.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]([O:20]C)=[O:19])[C:15]([C:22]#[C:23][Si](C)(C)C)=[CH:14][CH:13]=2)=[C:8]([CH3:28])[C:7]=1[CH:29]1[C:42]2[C:41](=[O:43])[CH2:40][C:39]([CH3:45])([CH3:44])[CH2:38][C:37]=2[O:36][C:35]2[CH2:34][C:33]([CH3:47])([CH3:46])[CH2:32][C:31](=[O:48])[C:30]1=2.Cl>C1COCC1.O>[C:22]([C:15]1[C:16]([C:18]([OH:20])=[O:19])=[N:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[C:7]([CH:29]3[C:30]4[C:31](=[O:48])[CH2:32][C:33]([CH3:46])([CH3:47])[CH2:34][C:35]=4[O:36][C:37]4[CH2:38][C:39]([CH3:44])([CH3:45])[CH2:40][C:41](=[O:43])[C:42]3=4)[C:8]=2[CH3:28])=[CH:13][CH:14]=1)#[CH:23]
Reactant: COC(=O)c1nc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)ccc1C#C[Si](C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)nc1C(=O)O
Reaction time: 17 h
Yield: 89.6 %

Procedure:
Lithium hydroxide monohydrate (303 mg, 7.21 mmol) was added to a solution of the methyl 6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]-3-[(trimethylsilyl)ethynyl]pyridine-2-carboxylate produced in Example 12-2 (564 mg, 0.90 mmol) in THF (11 ml) and water (5.5 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 17 hours. Thereafter, a 1 N aqueous solution of hydrochloric acid (7.21 ml) was added to the reaction solution, and water was then added thereto. The solution thus mixed was then extracted with dichloromethane. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the solid thus obtained was then washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (435 mg, yield: 89%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1)(=O)=O.O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:36][CH:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:39][CH2:38]4)[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 1.20 g; 3.52 mmol) and Cs2CO3 (2.26 g; 6.94 mmol) in DMF (20 mL) was added tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate (1.32 g; 4.50 mmol) under nitrogen. The reaction mixture was stirred at 90° C. for 2 hours, cooled to r.t., added to water (200 mL) with vigorous stirring. The resulting solid was collected by vacuum filtration to afford 1.60 g (84%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:13])=[N:8][NH:9][C:10]=1[NH:11][CH3:12])=[O:5])[CH3:2].[OH-].[Na+].I[CH3:17]>CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:13])=[N:8][N:9]([CH3:17])[C:10]=1[NH:11][CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)n[nH]c1NC
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)c1c(C)nn(C)c1NC
Temperature: 25 °C
Yield: 31 %

Procedure:
To a solution of 100 mg of 3-methyl-5-methylamino-1H-pyrazole-4-carboxylic acid ethyl ester (0.55 mmol) in methanol (5 ml) were added 52 mg of sodium hydroxide (1.3 mmol) and 77 mg of iodomethane (0.54 mmol) and the mixture was stirred at RT over night. The reaction mixture was then concentrated in vacuo at low temperature and 33 mg (31%) of 1,3-dimethyl-5-methylamino-1H-pyrazole-4-carboxylic acid ethyl ester were isolated from the remaining solid by HPLC (reversed phase, MeCN/water 20:80 to 50:50). MS (ISP) 198.2 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH3:7].[C:10]1([CH3:16])[CH:15]=CC=C[CH:11]=1>>[C:1]([O:9][C:10]([CH3:16])([CH3:15])[CH3:11])(=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Cc1ccccc1
Reactant: CCCC/C=C/C(=O)O
Product: CCCC/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
74.79 ml (312 mmol) of 1,2-(di-tert-butyl)trimethylamine were added to a stirred mixture of 5 g (39 mmol) of (E)-2-heptenoic acid in 100 ml of toluene at 80° C. The mixture was stirred under reflux for 30 minutes and then cooled to room temperature. The mixture was washed in sequence with water and saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulphate and filtered. The solvent was removed by evaporation. There were obtained 7.5 g of tert-butyl (E)-2-heptenoate as a yellow oil; MS: m/e 185.0 [M+H].
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][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]1([CH3:32])[C:24]([N:29]=[C:30]=[O:31])=[CH:25][CH:26]=[CH:27][CH:28]=1.CO>C(Cl)(Cl)Cl>[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][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:32])=[O:31])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccccc1N=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccccc4C)cc3)c2cc1OC
Yield: 41 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml), and o-toluyl isocyanate (0.25 μl) was then added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 30 mg (yield 41%) of the title compound.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+]=[N-]>CO.[Pd]>[C:14]([O:13][C:11]([NH:10][C@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[NH2:1])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Yield: 93.4 %

Procedure:
(1R,2S)-1-Azido-2-(tert-butoxycarbonylamino)-cyclohexane (174 mg) was dissolved in methanol (10 ml), and to the solution 10% palladium on carbon (120 mg) was added to conduct catalytic reduction under atmospheric pressure. The catalyst was separated by filtration, and the filtrate was concentrated to obtain a crude title compound (145 mg) as a colorless amorphous substance. This compound was used in the next reaction without purifying it.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].Cl[CH2:11][CH:12]=O>C(O)CCC>[Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]2[N:6]([CH:11]=[CH:12][N:8]=2)[N:7]=1
Reactant: Cc1cc(N)nnc1Cl
Reactant: O=CCCl
Solvent: CCCCO
Product: Cc1cc2nccn2nc1Cl
Yield: 33.4 %

Procedure:
6-chloro-5-methylpyridazin-3-amine 7 (0.6 g, 4.18 mmol) was dissolved in n-butanol (10 ml) and chloroacetaldehyde (0.328 g, 4.18 mmol) was added. The reaction was refluxed for 6 hrs and n-butanol was removed under reduced pressure. The crude product was purified by column chromatography (DCM/hexane, 70:30) to afford compound 8 (0.234 g, yield=33.4%).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4]I.[CH2:6]([O:13][C:14]1[C:15](=[O:20])[NH:16][CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[CH2:6]([O:13][C:14]1[C:15](=[O:20])[N:16]([CH2:4][CH2:3][CH2:2][I:1])[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=c1[nH]cccc1OCc1ccccc1
Reactant: ICCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(OCc2ccccc2)cccn1CCCI
Temperature: 70 °C
Reaction time: 24 h
Yield: 10 %

Procedure:
To a solution of 1,3-diiodopropane (7.1 mL, 63 mmol) in tetrahydrofuran (50 mL) was added 3-(benzyloxy)pyridin-2(1H)-one (1.28 g, 6.3 mmol) and Na2CO3 (0.67 g, 6.3 mmol). The mixture was then stirred at 70° C. for 1 day. Reaction progress was monitored by ES-MS. After ESMS showed essentially complete consumption of the starting material 3-(benzyloxy)pyridin-2(1H)-one, the reaction was stopped. Then the reaction mixture was filtered, concentrated, and subjected to flash column chromatography (eluent: hexane:ethylacetate 1:1). Compound 7 was obtained (240 mg, 10% yield). Analysis: ES-MS (positive ion in MeOH/H2O): m/z=370.2, ([M+H]+, calculated: 370.03).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11]([CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>C(O)C>[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11]([CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12]2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)C=C(CCN1CCCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)C=C(CCN1CCCC1)CC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-[2-(3,4-Dihydro-7-methoxycarbonyl-2-naphthalenyl)ethyl]pyrrolidine (1.0 g) was dissolved in ethanol (5 ml), and thereto was added 1N aqueous sodium hydroxide solution (5.2 ml), and the mixture was stirred at 25° C. for 6 hours. The mixture was concentrated under reduced pressure to remove the solvent, and the residue was acidified with 10% hydrochloric acid. The precipitated crystals were collected by filtration, and subjected to desalting with using CHP-20P [manufactured by Mitsubishi Kasei Corporation, high porous polystyrene resin; 75-150 μm] (eluent; water, then acetonitrile). The eluents were concentrated under reduced pressure, and the residue was recrystallized from ethanol-ethyl methyl ketone to give the desired compound, m.p. 202°-203° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:16](Cl)(=[O:18])[CH3:17]>C1COCC1.CN(C)C1C=CN=CC=1.[Cl-].[Na+].O>[CH2:10]([O:9][C:7]([C:6]1[C:5]2[CH2:12][CH2:13][CH2:14][CH2:15][C:4]=2[S:3][C:2]=1[NH:1][C:16](=[O:18])[CH3:17])=[O:8])[CH3:11]
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 2-amino-4, 5, 6, 7-tetrahydrobenzothiophene-3-carboxylate (16 g, 71.1 mmol) in THF (100 mL) was added 4-(dimethylamino)pyridine (434 mg, 3.55 mmol) and acetyl chloride (6.1 mL, 85.3 mmol). After stirring for 2 h at room temperature, the solution was diluted with brine solution (500 mL) and extracted with ethyl acetate (500 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated to provide the title compound (18.3 g, 96%) as a light yellow solid: MS (ES) m/z 268 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@H:14](OS(C)(=O)=O)[CH2:13][C@H:12]2[CH2:21][NH:22][S:23](=[O:26])(=[O:25])[NH2:24])=[O:10])=[CH:5][CH:4]=1.[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:31][C:29](=[O:32])[CH3:30])[CH2:13][C@H:12]2[CH2:21][NH:22][S:23](=[O:25])(=[O:26])[NH2:24])=[O:10])=[CH:27][CH:28]=1
Reactant: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2CNS(N)(=O)=O)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)N2C[C@@H](SC(C)=O)C[C@H]2CNS(N)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
To a solution of crude (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxy-2-sulfamoylaminomethylpyrrolidine (2.26 g) obtained in Step 5 in dimethylformamide (12 ml), potassium thioacetate (1.7 g) is added. The mixture is stirred at 60° C. for 5 hours. The reaction mixture is diluted with ethyl acetate, successively washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene:ethyl acetate=1:2) to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-acetylthio-2-sulfamoylaminomethylpyrrolidine (971 mg). NMR δ(CDCl3) ppm: 1.8(br s, 1H), 2.33(s, 3H), 2.4 to 2.7(m, 1H), 3.1 to 3.5(m), 3.81(s, 3H), 3.9 to 4.2(m, 2H), 5.05(s, 2H), 6.89(d, J=8.8 Hz, 2H), 7.30(d, J=8.8 Hz, 2H). IR ν (CHCl3) cm-1 : 3414, 3276, 1688.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH3:25])=[S:23])=[CH:17][C:16]=1[O:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH3:25][NH:24][C:22](=[S:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:39])=[O:5])(=[O:13])=[O:14])=[C:16]([O:26][CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][CH:33]=[N:34]3)[CH:17]=1
Reactant: CNC(=S)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=S)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)O)c(OCCc2cccc3ncccc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of 0.084 g (0.147 mmol) 3-[4-(3-methyl-thioureido)-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester and 20 mL (3:1 CH2Cl2:TFA) was stirred 2 h at room temperature. TLC analysis indicated starting material consumed. The solvent was removed under reduced pressure. To the residue was added 25 mL CH2Cl2 and the solvent removed under reduced pressure. The residue was triturated with 15 mL ether and the solid was filtered, washed with ether and dried at 40° C. 36 h to give 0.087 g (94%) of 3-[4-(3-methyl-thioureido)-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid trifluoroacetate salt as a beige solid. MS (APCI) m/z 517 (M+1).