Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3]N(N=O)/C(/N)=N/[N+]([O-])=O.[S:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:16])(=[O:15])[NH2:14]>O.CCOCC>[CH3:3][O:22][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([S:13](=[O:15])(=[O:16])[NH2:14])=[CH:25][CH:24]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CN(N=O)/C(N)=N/[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of KOH (108 mg, 2.0 mmol) in water (1 mL) was added Et2O and cooled to 0° C. MNNG (292 mg, 1.99 mmol) was added and the resulting yellow solution was added to a suspension of 4-Sulfamoyl-benzoic acid in Et2O at room temperature and stirred overnight. The reaction was quenched with acetic acid and the resulting mixture was diluted with water. The mixture was then extracted with ethyl acetate and the combined organic extracts was washed with bine and dried over Na2SO4. Removal of solvent gave the crude product which was used in the next reaction without further purification. 1H NMR (400 MHz, MeOD) δ8.17 (d, 2H), 8.00 (d, 2H), 3.92 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:16]3[N:12]([C:13]([CH3:17])=[N:14][N:15]=3)[C:11]3[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=3[C:9]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:9]2[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[N:12]3[C:16]([N:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:30][CH:29]=4)[N:8]=2)=[N:15][N:14]=[C:13]3[CH3:17])=[CH:27][CH:26]=1.[CH3:38][S:39]([N:1]([S:39]([CH3:38])(=[O:41])=[O:40])[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:16]3[N:12]([CH:13]=[N:14][N:15]=3)[C:11]3[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=3[C:9]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:8]2)=[CH:4][CH:3]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nnc2n1-c1ccccc1C(c1ccc(Cl)cc1)=NN2Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc(CN2N=C(c3ccc(Cl)cc3)c3ccccc3-n3cnnc32)cc1)S(C)(=O)=O
Product: Cc1nnc2n1-c1ccccc1C(c1ccc(Cl)cc1)=NN2Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
4-(4-Aminobenzyl)-6-(4-chlorophenyl)-1-methyl-4H-2,3,4,5,10b-pentaazabenz[e]azulene (24.8 mg) obtained in Example 188 was dissolved in dichloromethane (2 ml) and triethylamine (30 μl) was added. The mixture was ice-cooled and methanesulfonyl chloride (7 μl) was added. The mixture was stirred under ice-cooling for 10 minutes and at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and a 5% aqueous citric acid solution and ethyl acetate were added. The organic layer, was separated, and successively washed with a saturated aqueous sodium hydrogencarbonate solution and water. The organic layer was dried, filtered and concentrated under reduced pressure. The residue obtained was separated and purified by preparative thin-layer chromatography. Both compounds were individually crystallized from ethyl acetate-diethyl ether to give 8 mg of 6-(4-chlorophenyl)-4-(4-methylsulfonylaminobenzyl)-1-methyl-4H-2,3,4,5,10b-pentaazabenz[e]azulene (m.p. 273°-275° C.) and 16 mg of 4-[4-bis(methylsulfonyl)aminobenzyl]-6-(4-chlorophenyl)-4H-2,3,4,5,10b-pentaazabenz[e]azulene (m.p. 220°-221° C.).
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C1O[C:21]2([CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[O:20]C1>C(OCC)C.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][C:24]1([OH:27])[CH2:25][CH2:26][C:21](=[O:20])[CH2:22][CH2:23]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=C(CBr)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CCOCC
Product: O=C1CCC(O)(CC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
To a suspension of zinc dust (2.06 g, 31.5 mmol) in diethyl ether (50 mL) under argon was added trimethylsilyl chloride (3.0 mL, 23.6 mmol) and the reaction stirred for 15 min at RT. The reaction was then heated at reflux for 25 min. Benzyl bromoacetate (3.9 mL, 24.6 mmol) and 1,4-cyclohexanedione monoethylene acetal (3.05 g, 19.6 mmol) were added and the reaction was kept at reflux for 1.3 hr. The reaction was then cooled to RT, quenched with 1N HCl (125 mL) and stirred overnight. The aqueous layer was extracted with Et2O (3×). The combined organic layers were washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0-60% EtOAc:Hexane) to provide 2.79 g (54%) of pure product. ESI-MS m/z 285 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:5]([C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[C:9]([O:11]CC1C=CC=CC=1)=O)=[O:6].[CH3:27][O:28][C:29]([NH:31][C:32](=NC(OC)=O)SC)=[O:30]>C(O)(=O)C>[CH3:27][O:28][C:29](=[O:30])[NH:31][C:32]1[NH:26][C:25]2[CH:24]=[CH:23][C:4]([C:5](=[O:6])[C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[C:9]([CH2:5][C:4]3[CH:23]=[CH:24][CH:25]=[CH:2][CH:3]=3)=[O:11])=[CH:3][C:2]=2[N:1]=1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)OCc2ccccc2)cc1N
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(C(=O)c3ccccc3C(=O)Cc3ccccc3)ccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of benzyl 2-(3,4-diaminobenzoyl)benzoate (25 g, 72 mmole) and 1,3-bis(methoxy carbonyl)-2-methyl-2-thiopseudourea (19.3 g, 94 mmole) in acetic acid (100 ml) was heated to 75° C. for 45 minutes. The solution was cooled to room temperature and concentrated in-vacuo. The resultant oil was diluted in ethyl acetate (300 mL) and washed with 1N sodium hydroxide (200 mL), water (2×200 mL), dried over sodium sulfate, filtered and concentrated in-vacuo. The resultant solid was re-crystallized using ethyl ether and ethyl acetate (2:1). The solid was isolated by vacuum filtration and washed ethyl ether to afford [5-(2-benzylcarbanoyl-benzoyl)-1H-benzoimidazol-2-yl]-carbamic acid methyl ester, 21.4 g, 49.8 mmol, (69%) as a yellow solid. 1H NMR (400 MHz, d6-DMSO): 8.04 (br s, 1H), 7.77-7.68 (m, 3H), 7.52-7.41 (m, 3H), 7.28-7.10 (m, 5H), 5.05 (s, 2H), 3.76 (s, 3H); MS (EI) for C—24H20N4O4: 430 (MH+)
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(OC([N:31]1[CH2:35][C@H:34]([C:36]#[N:37])[CH2:33][C@H:32]1[C:38](=[O:40])[NH2:39])=O)(C)(C)C.CO>C(Cl)Cl>[C:36]([C@H:34]1[CH2:35][N:31]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:32]([C:38]([NH2:39])=[O:40])[CH2:33]1)#[N:37]
Reactant: CC(C)(C)OC(=O)N1C[C@H](C#N)C[C@H]1C(N)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3C[C@H](C#N)C[C@H]3C(N)=O)cc1OCC2
Yield: 72 %

Procedure:
Following the procedure for Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and (2S,4R)-2-carbamoyl-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester were reacted. The crude product was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 430 as an off-white solid (41 mg, 72%). LCMS: RT=2.85 min, [M+H]+=435. 1H NMR 400 MHz (DMSO-d6) δ: 9.08 (1H, s), 7.88 (1H, d, J=0.63 Hz), 7.85 (1H, s), 7.56 (1H, br, s), 7.11 (1H, br, s), 6.04 (1H, s), 5.94-5.93 (1H, m), 4.51 (4H, d, J=15.42 Hz), 4.44 (1H, d, J=5.97 Hz), 3.92 (1H, dd, J=10.05, 7.55 Hz), 3.72 (1H, t, J=8.49 Hz), 3.61-3.53 (1H, m), 2.55-2.54 (1H, m), 2.35 (1H, ddd, J=12.61, 6.87, 3.63 Hz), 1.47 (6H, dd, J=6.59, 3.21 Hz)
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>O.C(OCC)(=O)C.C(#N)C>[CH2:8]([N:15]([CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7])[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1OCCC1Br
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C(=O)N(Cc2ccccc2)C2CCOC2=O)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of 10 g of 3-bromo-2-oxooxolane, 6.6 g of benzylamine, 21 g of potassium carbonate and 200 mL of acetonitrile was stirred at 70° C. for 1 hour 30 minutes. Thereafter, 7.9 mL of 4-methylbenzoyl chloride was added dropwise to the reaction mixture at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, 400 mL of ethyl acetate and 200 mL of water were added to the reaction mixture. The organic layer was fractionated. The obtained organic layer was successively washed with 100 mL of water and 100 mL of a saturated sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then dissolved in 100 mL of ethyl acetate under heating. After that, 100 mL of hexane was added dropwise to the reaction mixture at 50° C. A solid was collected by filtration, so as to obtain 11.2 g of N-benzyl-4-methyl-N-(2-oxooxolan-3-yl)benzamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.[O:40](C(OC(C)(C)C)=O)[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=O.Cl>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][N:14]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:25])([F:24])[F:26])[N:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (85 mg, 0.16 mmol) in THF (10 mL) was added BOC2O (4 g, 18.6 mmol) in THF (10 mL), and the reaction mixture was stirred at RT for 16 h. Then the reaction was diluted with CH2Cl2, cooled to 0° C., and the pH adjusted to 2 with 2 N HCl. The reaction mixture was then extracted CH2Cl2 and concentrated in vacuo to provide (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid that was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[C:15]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=[CH:13][C:12]=2[O:22][CH2:23][CH2:24][CH3:25])[NH:5][C:6](=[O:10])[C:7]=1[N:8]=O.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[C:15]([S:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH:14]=[CH:13][C:12]=2[O:22][CH2:23][CH2:24][CH3:25])[NH:5][C:6](=[O:10])[C:7]=1[NH2:8]
Reactant: CCCOc1ccc(SC(C)(C)C)cc1-c1nc(N)c(N=O)c(=O)[nH]1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCOc1ccc(SC(C)(C)C)cc1-c1nc(N)c(N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
4-Amino-5-nitroso-2-(2-propoxy-5-t-butylthiophenyl)-pyrimid-6-one (6.5 g.) (see Reference Example 7) was dissolved in boiling ethanol (150 ml.), and the solution was added all at once to a solution of sodium dithionite (26 g.) in water (150 ml.) at 80° C. The mixture immediately turned yellow. After 2 minutes, the mixture was cooled to room temperature and diluted with water (700 ml.), and then it was left to stand in an ice bath for 1 hour. The solid formed [4,5-diamino-2-(2-propoxy-5-t-butylthiophenyl)-pyrimid-6-one] was filtered off and washed with water. This material was used immediately for the next stage of the synthesis, because darkening occurred on standing.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:24]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(S)CCCCCCC.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:42])[C@@H:13]([NH2:24])[CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCNC(=O)OC(C)(C)C)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: CCCCCCCCS
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCNC(=O)OC(C)(C)C)CC1

Procedure:
A solution of 1.71 g 4-[(S)-4-tert-butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 30 ml THF was stirred in the presence of 8.9 ml 1-octanethiol and 101 μl DBU. After 12 h the mixture was concentrated, the residue dissolved in dichloromethane and extracted with 0.1 M HCl. The aqueous phase was brought to pH 9 by adding aqueous NaHCO3 before being extracted with dichloromethane. The product was obtained after evaporation of the solvent and was used in the subsequent reaction. Yield: 2.27 g colorless foam.
Reaction SMILES: [ClH:1].Cl.C([CH:5]1[CH2:33][CH2:32][CH2:31][C:6]1([C:34]([OH:36])=[O:35])[N:7]([S:13]([C:16]1[CH:25]=[C:24]2[C:19]([C:20]([Br:30])=[CH:21][N:22]=[C:23]2[NH:26][C:27]([NH2:29])=[NH:28])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])C.[OH-].[Na+].Cl>CCO>[ClH:1].[ClH:1].[Br:30][C:20]1[C:19]2[C:24](=[CH:25][C:16]([S:13]([N:7]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[C:6]3([C:34]([OH:36])=[O:35])[CH2:31][CH2:32][CH2:33][CH2:5]3)(=[O:14])=[O:15])=[CH:17][CH:18]=2)[C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[N:22][CH:21]=1
Reactant: CCC1CCCC1(C(=O)O)N(CCN(C)C)S(=O)(=O)c1ccc2c(Br)cnc(NC(=N)N)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc2c(Br)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 31.8 %

Procedure:
Ethyl N-[(4-Bromo-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[2-(dimethylamino)ethyl]cycloleucine dihydrochloride (95 mg, 0.17 mmol) in EtOH (3 ml) was treated with NaOH (4N, 8 ml) and the solution stirred at 60° C. for 5 h and allowed to stand for 60 h at room temperature. The reaction mixture was acidified using 2N HCl, concentrated in vacuo and the residue azeotroped with i-PrOH to give an off-white solid. This was extracted into MeOH, the solution evaporated in vacuo and the residue purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880 NH3 (80:20:5) as eluant. The product was suspended in EtOAc, treated with ethereal HCl, the mixture evaporated in vacuo and the product triturated with EtOAc to afford N-({4-bromo-1-guanidino-7-isoquinolinyl}sulphonyl)-N-[2-(dimethylamino)ethyl]cycloleucine dihydrochloride (15 mg, 0.027 mmol) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]([CH3:32])([CH2:25][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O1CCCC1>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]([CH3:32])([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:28][CH2:27]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: CN(c1cccc2cc(C3=NCC(C)(CN4CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(C)(CN4CCN(S(C)(=O)=O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a mixture of N-methyl-N-{2-[5-methyl-5-(piperazine-1-ylmethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.28 g), triethylamine (0.17 ml) and tetrahydrofuran (6 ml) was added methanesulfonyl chloride (0.06 ml) at 0° C., and the reaction mixture was stirred overnight at room temperature, and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.26 g, yield 81%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). melting point 209-210° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[C:13]([Cl:15])[CH:14]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:15][C:13]1[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(Cl)cc2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2c(cc(Cl)cc2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 359.2 %

Procedure:
To a stirred mixture solution of 7-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (800 mg, 0.5 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 7-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (720 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25ClN2O3 (M+H)+: 401.91, observed: 401.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.[N:25]([C@H:28]([C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=1)[C@@H:29]([OH:31])[CH3:30])=[N+]=[N-].[C:41]([O:45][C:46](=O)[O:47]C(C)(C)C)([CH3:44])([CH3:43])[CH3:42]>O>[C:41]([O:45][C:46](=[O:47])[NH:25][C@H:28]([C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=1)[C@@H:29]([OH:31])[CH3:30])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: C[C@H](O)[C@H](N=[N+]=[N-])c1cc(F)c(F)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
In nitrogen atmosphere, triphenylphosphine (5.85 g) was added to a THF solution (75 mL) of (1R,2S)-1-azido-1-(3,4,5-trifluorophenyl)propan-2-ol (5.16 g). This reaction solution was stirred at room temperature for 10 min, then water (5 mL) was added the reaction solution. This mixture was stirred at 60° C. for 3.5 hr. The reaction solution was cooled to room temperature, and then di-tert-butylcarbonate (5.35 g) was added to the reaction solution. The resulting reaction solution was stirred at room temperature for 45 min and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene:ethyl acetate=9:1) to give 5.88 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24](C(OC(C)(C)C)=O)[N:23]=[C:22]4[C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[N:16]=[N:15]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][N:23]=[C:22]4[C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[N:16]=[N:15]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(-c3ccc4c(c3)c(-c3ccncc3)nn4C(=O)OC(C)(C)C)nn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(-c2n[nH]c3ccc(-c4cn([C@@H]5CCCNC5)nn4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the crude (R)-tert-butyl 5-(1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-1H-1,2,3-triazol-4-yl)-3-(pyridin-4-yl)-1H-indazole-1-carboxylate in CH2Cl2 (40 mL), added TFA (2.5 mL) and stirred at room temperature overnight under a stream of nitrogen. Evaporated the solvents and column purified (5-10% MeOH in CH2Cl2) to give (R)-5-(1-(piperidin-3-yl)-1H-1,2,3-triazol-4-yl)-3-(pyridin-4-yl)-1H-indazole (0.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.COC1C=CC(C[CH:19]([CH2:47][C:48]2C=CC(Br)=CC=2)[CH2:20][CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([CH2:39][C:40]2[CH:45]=[CH:44][C:43](Br)=[CH:42][CH:41]=2)CC2C=CC(OC)=CC=2)=CC=1.[C:57]([O:61][Na])(C)(C)C>C1(C)C(C)=CC=CC=1.[Pd].P>[CH3:57][O:61][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([NH:1][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=3)=[CH:44][CH:45]=2)=[CH:48][CH:47]=1
Reactant: COc1ccc(CC(CCCCSCCCCC(Cc2ccc(Br)cc2)Cc2ccc(OC)cc2)Cc2ccc(Br)cc2)cc1
Reactant: Nc1cccc2ccccc12
Reactant: CC(C)(C)O[Na]
Agent: [Pd]
Agent: P
Solvent: Cc1ccccc1C
Product: COc1ccc(CSCCCCCCc2ccc(Nc3cccc4ccccc34)cc2)cc1

Procedure:
In an orthoxylene solvent, 1-aminonaphthalene was reacted with 4-methoxybenzyl-5-(4-bromobenzyl)pentyl sulfide in the presence of Pd/phosphine and t-butoxy sodium to obtain 4-(6-(4-methoxybenzylthio)hexyl)phenyl-1-naphthylamine. Then, 4,4′-dibromobiphenyl was added into the resultant compound to obtain N,N′-bis(4-(6-(4-methoxybenzylthio)hexyl)phenyl)-N,N′-bis(α-naphtyl)-1,1′-biphenyl-4,4′-diamine through the same reaction. N,N′-bis(4-(6-mercaptohexyl)phenyl)-N,N′-bis(α-naphtyl)-1,1′-biphenyl-4,4′-diamine, the intended product having a mercapto group, was removed from the compound in the presence of anisole in a trifluoroacetic acid. Its structure was confirmed by the elementary analysis or NMR analysis.
Reaction SMILES: [Na].CCCCCC.Cl[C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[CH2:18]([OH:21])[CH2:19][CH3:20]>>[CH2:18]([O:21][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[CH2:19][CH3:20]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCCO
Agent: [Na]
Solvent: CCCCCC
Product: CCCOc1ncccc1C(=O)O
Reaction time: 0.5 h

Procedure:
Sodium metal (9.2 g, 0.4 mol), washed free of oil (with hexane), was added in small pieces, over 2 h, to anhydrous n-propanol (350 mL) whilst maintaining a temperature between 50° C. and 100° C. To the resultant clear, yellow solution was added a slurry of 2-chloronicotinic acid (31.5 g, 0.2 mol) in anhydrous propanol (100 mL), and the suspension heated to reflux for 6 h. The bulk of the solvent was distilled off, and replaced, after cooling, with diethyl ether (200 mL) to afford a thick white solid which was removed by filtration and washed with diethyl ether (500 mL). The solid was taken up in water (300 mL), washed with dichloromethane (200 mL), and the aqueous phase acidified with concentrated hydrochloric acid to pH 4.5 and extracted with dichloromethane (3×200 mL). The combined extracts were washed with brine, dried over MgSO4, and concentrated to an oil (40 g). The oil was taken up in pentane (150 mL) and stood in ice for 30 mins to deliver a white crystalline solid which was collected by filtration, washed with fresh pentane (3×200 mL) and dried under vacuum to afford 2-propoxynicotinic acid (26.5 g, 146 mmol).