Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(N)(N)(=O)=O.[C:6]([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH2:22]O)[CH2:11]1)(=[O:8])[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]([O:47][C:48]([NH:50][S:51]([NH2:54])(=[O:53])=[O:52])=[O:49])([CH3:46])([CH3:45])[CH3:44].C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[C:6]([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C@@H:12]([CH2:22][N:50]([C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[S:51](=[O:52])(=[O:53])[NH2:54])[CH2:11]1)(=[O:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NS(N)(=O)=O
Reactant: CC(=O)S[C@H]1C[C@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: NS(N)(=O)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)S[C@H]1C[C@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)N(C(=O)OC(C)(C)C)C1

Procedure:
Preparation of a sulfamide compound To a solution of (2R,4S)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (i.e., a substrate) in tetrahydrofuran (THF), triphenylphosphine (PPh3), N-t-butoxycarbonylsulfamide (BSMD), and azodicarboxylic acid diethyl ester (DEAD) are successively added under ice cooling. The conditions for this reaction are shown in Table 2, Step A-6. The reaction mixture is diluted with toluene, concentrated, diluted with toluene, and the formed crystals are filtered off. The filtrate is concentrated. The residue is purified by silica gel column chromatography to give (2R,4S)-4-acetylthio-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino)methylpyrrolidine. NMR δ(CDCl3) ppm: 1.41(s, 9H), 1.55(s, 9H), 1.19 to 2.0(m, 2H), 2.35(s, 3H), 3.32(dd, J=11.4 Hz, J=8.2 Hz, 1H), 3.6 to 3.9(m, 3H), 3.9 to 4.1(m, 1H), 4.5(m, 1H), 6.15(s, 2H). IR ν (KBr) cm-1 : 3420, 3320, 1706, 1686, 1666.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[CH:11]([CH3:17])[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(C)C(=O)Nc1cc(F)ccc1Cl
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)Nc1cc(F)ccc1Cl

Procedure:
The acid was prepared according to Procedure B using ethyl 3-(2-chloro-5-fluorophenylamino)-2-methyl-3-oxopropanoate (5.0 g, 18.27 mmol) in THF (18.3 mL) to give 3-(2-chloro-5-fluorophenylamino)-2-methyl-3-oxopropanoic acid. Mass Spectrum (ESI) m/e=245.9 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[C:16]2[C:11](=[C:12]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[CH3:34][CH:32]([CH3:33])[C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:11]=3[CH:10]=[CH:9][N:8]4[C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:19][CH2:20]2)[CH:25]=1)=[O:35]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Ic1cccnc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3cccnc3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 3-iodopyridine and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 453.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+].O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:17][CH2:18][CH2:19][C:20]2=[O:21])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)CCCCl
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCCN1c1ccc(Br)cc1
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 86.2 %

Procedure:
To a solution of 4-bromoaniline (10 g, 58 mmol) in dry THF (150 ml), under argon was added triethylamine (6 g, 59 mmol) and 4-chlorobutyrylchloride (8.2 g 58 mmol) at 5° C. The mixture was stirred at 5° C. for 40 mins and potassium tert-butoxide (16 g, 142 mmol) added in one portion. After 10 mins the mixture was warmed to 25° C. and stirred for 4 hours, then left to stand overnight. Water (10 ml) was added and the mixture stirred for 30 mins. The mixture was diluted with ethyl acetate (200 ml) and 3% Na2CO3 (aq) (120 ml). The aqueous layer was reextracted with ethyl acetate (100 ml) and the combined extracts dried over Na2SO4. The solvent was evaporated in vacuo to give a brown solid (12 g). Chromatography on silica gel (~200 g) using 30-60% ethyl acetate/hexane gradient elution gave the title compound as a yellow crystalline solid (10.24 g, 74%).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18](C#N)#[N:19].N1C=CC=CC=1.Cl>O.CN1CCCC1=O>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([C:18]#[N:19])=[CH:3][CH:4]=2)=[CH:12][N:11]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N#CC#N
Reactant: CCCCCc1ccc(-c2ccc(Cl)s2)cn1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Solvent: O
Product: CCCCCc1ccc(-c2ccc(C#N)s2)cn1
Temperature: 70 °C

Procedure:
A mixture of 26.6 g of 5-chloro-2-(2-pentyl-5-pyridyl)-thiophene, 10 g of Cu2 (CN)2, 120 ml of pyridine and 60 ml of N-methylpyrrolidone is heated at 150° for 2 hours. It is cooled, a solution of 120 g of FeCl3.6 H2O in 600 ml of 20% strength hydrochloric acid is added and the mixture is warmed at 70° C. for 1.5 hours, with stirring, and worked up in the customary manner to give 2-(2-pentyl-5-pyridyl)-thiophene-5-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1>Cl.CCOC(C)=O>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2F)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(OC2CCNCC2)c(F)c1

Procedure:
A solution of tert-butyl 4-(2,4-difluorophenoxyl)piperidine-1-carboxylate (20 g, 63.8 mmol) in 4:1 HCl/EtOAc (250 mL) was stirred at 25° C. for 1 h. The mixture was concentrated to give the title compound, as its HCl salt, as a white solid (15.4 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (m, 2H), 2.08 (m, 2H), 3.05 (m, 2H), 3.20 (m, 2H), 4.57 (m, 1H), 7.04 (m, 1H), 7.31 (m, 2H), 8.95 (br d, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:35]#[N:36])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[CH3:1][C:2]([CH3:19])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:35]#[N:36])[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:9])([CH3:10])[CH3:11])=[O:4]
Reactant: CC(C)(Cc1ccncc1)C(=O)OCC[Si](C)(C)C
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccnc(C#N)c1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-(4-pyridyl)propionate (0.77 g, 2.8 mmol) was dissolved in ethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 0.68 g, 3.0 mmol) was added thereto. The reaction mixture was stirred at room temperature for 5 hrs and subjected to a silica gel (35 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (4:1, v/v) were collected and concentrated. The residue was dissolved in acetonitrile (6 ml), and trimethylsilyl cyanide (0.49 g, 4.9 mmol) and N,N-dimethylcarbamoyl chloride(0.45 g, 4.2 mmol) were added thereto. The reaction mixture was stirred at room temperature for 14 hrs and combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution, 1 N hydrochloric acid and saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected and concentrated to give the titled compound (0.69 g, 91%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(C(C)C)C(C)C.C(O)CO.O.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:12][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([Br:1])[S:3][C:4]=2[CH:10]=1)(=[O:30])=[O:29]
Reactant: OCc1ccc2nc(Br)sc2c1
Reactant: CS(=O)(=O)Cl
Solvent: OCCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc2nc(Br)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of (2-bromobenzo[d]thiazol-6-yl)methanol (205 mg, 0.83 mmol) from Step 2 of this Example and DIEA (118 mg, 0.92 mmol) in CH2Cl2 (20 mL) cooled in an ethylene glycol-water (4:1, v/v) dry ice bath was added methanesulfonyl chloride (105 mg, 0.92 mmol) slowly. The reaction solution was warmed to rt and stirred at rt for 1 h. The resulting mixture was quenched with 20 mL of water. The separated aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give (2-bromobenzo[d]thiazol-6-yl)methyl methanesulfonate as a light yellow solid (267 mg, 100%). LCMS (ESI) m/z 322, 324 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.C(O)(C)C.O.C(=O)([O-])[O-].[K+].[K+]>[Fe].C(O)(=O)C>[NH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[N:3][CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1cc(N)cnc1Br
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 77.2 %

Procedure:
To a suspension of 2-bromo-3-methyl-5-nitropyridine (10.01 g), isopropanol (130 ml), water (26 ml) and iron (12.9 g) was added acetic acid (5.27 ml), and stirred at 80° C. for 3.5 hours. To the reaction solution was added potassium carbonate (13.37 g), filtered through Celite, then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The precipitated solid was collected by filtration to give 5-amino-2-bromo-3-methylpyridine (6.66 g) as a gray solid. MS (ESI) m/z: 187, 189 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][S:6]([C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:8])=[O:7].S(O)(O)(=O)=O.CS[C:32](=[NH:34])[NH2:33].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:1]([CH2:2][CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][S:6]([C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:8])=[O:7])[C:32]([NH2:34])=[NH:33]
Reactant: NCC(CNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: N=C(N)NCC(CNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Yield: 85.9 %

Procedure:
In 30 ml of a 60% methanol/water solution (volume ratio) was dissolved 2 g of N-(3-amino-2-phenylpropyl)-5-isoquinolinesulfonamide obtained Referential example 2, 2.05 g of S-methylisothiourea sulfate and 1.67 g of potassium carbonate, and the mixed solution was heated at reflux for two hours. After the reflux, the methanol was distilled therefrom under reduced pressure and the white crystalline residue the obtained was separated by filtration under reduced pressure. The residue was recrystallized from methanol to give 1.93 g of N-(3-guanidino-2-phenylpropyl)-5-isoquinolinesulfonamide, i.e., Compound (31) in a yield of 86%.
Reaction SMILES: [NH2:1][C:2](=[N:38][OH:39])[CH2:3][O:4][NH:5][C:6]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37])=[O:7].C1N=CN([C:45](N2C=NC=C2)=[O:46])C=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[CH:9]1[CH:8]([C:6]([NH:5][O:4][CH2:3][C:2]2[NH:1][C:45](=[O:46])[O:39][N:38]=2)=[O:7])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[NH:25][S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(N)=NO)C1c1ccc(Cl)cc1Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2noc(=O)[nH]2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
To a mixed liquid of 400 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 40 ml of acetonitrile were added 108 mg of CDI and 0.4 ml of DBU under ice-cooling, followed by stirring at room temperature overnight. After concentrating the reaction solution, a saturated aqueous ammonium chloride solution and ethyl acetate were added thereto, followed by extraction. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 40 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:28]3[CH:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[O:30][N:29]=3)=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: NCc1cc(C(F)(F)F)on1
Agent: Cl
Product: O=C(NCc1cc(C(F)(F)F)on1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 5-trifluoromethyl-isoxazol-3-methanamine hydrochloride (example BG) as starting materials; LC-MS (UV peak area/ESI) 100%, 480.0532 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([C:10]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)SCCCS2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[OH2:25]>C(OCC)(=O)C>[OH:9][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:25]
Reactant: OC(Cc1ccccc1)C1(c2ccccc2)SCCCS1
Reactant: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(c1ccccc1)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
To a solution of 2-phenyl-1-(2-phenyl-[1,3]-dithian-2-yl)-ethanol (66) (2.50 g, 7.9 mmol) in 100 mL of a 9:1 mixture of acetonitrile and water was added mercuric perchlorate hydrate (4.1 g, 10.3 mmol). The resulting mixture was stirred at room temperature for 5 minutes and thin layer chromatography indicated that the reaction was completed. The mixture was diluted with ethyl acetate, filtered through a pad of Celite and the filtrate was washed with saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica gel, (20% ethyl acetate in hexanes) to afford 1.32 g (74%) of the title compound (67). 1H NMR (CDCl3, 400 MHz): δ 2.90 dd, J=14.4, 7.0 Hz, 1H), 3.20 (dd, J=14.4, 4.0 Hz, 1H), 3.70 (d, J=6.8 Hz, 1H), 5.35 (m, 1H), 7.28-7.11 (m, 5H), 7.53 (m, 2H), 7.65 (m, 1H), 7.93 (d, J=7.2 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH2:3][NH:2][C:39](=[O:41])[CH3:40])[CH:9]=[CH:8][CH:7]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (700 mg, 1.40 mmol) was added triethylamine (0.583 mL, 4.20 mmol) and DCM (3 mL) to give a suspension. Acetic anhydride (0.146 mL, 1.54 mmol) was added dropwise at room temperature and the resulting mixture was stirred at ambient temperature for 2 h. LCMS showed completion of the reaction. The reaction mixture was diluted with DCM (20 mL) and a saturated solution of NaHCO3 in water (20 mL). The organic solution was separated and the aqueous layer was further extracted with DCM (20 mL). Organic solutions were combined, washed with brine (20 mL), dried through an hydrophobic frit and concentrated under reduced pressure. The residue was loaded in 1:1 MeOH-DMSO and purified on reverse phase (C18) silica (330 g) using a gradient of 5% to 80% MeCN (+0.1% of NEt3) in water (pH=10 with ammonium bicarbonate) over 14 column lengths. The appropriate fractions were combined and evaporated in vacuo to give the title compound (570 mg, 81%) as a white solid. LCMS (System A) RT=1.01 min, ES+ve m/z 505/507 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH2:10][CH2:11][C:12](=[O:14])[CH3:13].S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:22][CH2:23][CH2:24][CH2:25]O>CO>[CH3:13][C:12]1([CH2:11][CH2:10][C:3]2[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=2[CH3:1])[NH:22][CH2:23][CH2:24][CH2:25][O:14]1
Reactant: NCCCO
Reactant: CC(=O)CCC1=C(C)CCCC1(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC1=C(CCC2(C)NCCCO2)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 0° C. stirred solution of 4-(2,6,6-trimethyl-cyclohex-1-enyl)-butan-2-one (25.2 g, 0.13 mol) and sodium sulfate (20 g) in 80 mL of methanol is added 3-amino-1-propanol (10 g, 0.13 mol). The reaction is allowed to warm to room temperature. After stirring for 24 h the mixture is cooled to 0° C. and the solids are removed via vacuum filtration through Celite. Evaporation of the solvent gives a clear yellow oil.
Reaction SMILES: CN(/[CH:4]=[CH:5]/[C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)=O)C.[N+]([O-])(O)=O.[CH2:18]([O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([NH:29][C:30]([NH2:32])=[NH:31])[CH:23]=1)[CH3:19].[N+]([O-])(O)=O.C(OC(=O)C1C=CC(NC(N)=N)=CC=1)C>>[CH2:18]([O:20][C:21](=[O:33])[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([NH:29][C:30]2[N:32]=[C:6]([C:8]3[CH:13]=[N:12][CH:11]=[CH:10][N:9]=3)[CH:5]=[CH:4][N:31]=2)[CH:23]=1)[CH3:19]
Reactant: CCOC(=O)c1ccc(C)c(NC(=N)N)c1
Reactant: CN(C)/C=C/C(=O)c1cnccn1
Agent: CCOC(=O)c1ccc(NC(=N)N)cc1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1ccc(C)c(Nc2nccc(-c3cnccn3)n2)c1

Procedure:
3-dimethylamino-1-pyrazin-2-yl-propenone prepared in Preparation 2 and 3-guanidino-4-methylbenzoic acid ethyl ester nitrate were used instead 3-dimethylamino-1-pyridin-3-yl-propenone and 4-guanidino-benzoic acid ethyl ester nitrate according to the similar procedure to Preparation 8 to give the titled compound as yellow solid.
Reaction SMILES: COC(=S)C1C=C(C)C=C(O)C=1.BrCCCCCCCCCCCCCCCCCC.C(=O)([O-])[O-].[K+].[K+].C[O:39][C:40](=[O:68])[C:41]1[CH:46]=[C:45]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH:44]=[C:43]([S:66][CH3:67])[CH:42]=1.[OH-].[Na+]>CO>[CH3:67][S:66][C:43]1[CH:42]=[C:41]([CH:46]=[C:45]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH:44]=1)[C:40]([OH:68])=[O:39]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(SC)cc(C(=O)OC)c1
Agent: CCCCCCCCCCCCCCCCCCBr
Agent: COC(=S)c1cc(C)cc(O)c1
Agent: O=C([O-])[O-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(SC)cc(C(=O)O)c1
Yield: 95 %

Procedure:
A mixture of 2.54 g (12.8 mmol) of 3-hydroxy-5-methylthiobenzoic acid methyl ester, 4.7 g (14.1 mmol) of 1-bromooctadecane and 2.7 g (19.2 mmol) of potassium carbonate in 60 ml of anhydrous DMP was stirred and heated at 80° under an argon atmosphere for 21 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated at reduced pressure. Water was added to the residue and the product was filtered and recrystallized from methylene chloride-methanol to give 5.5 g (95% yield), mp 64°-66°, of 3-(methylthio)-5-(octadecyloxy)benzoic acid methyl ester. The nmr and mass spectra were consistent with the structure. A solution of 2.7 g (6 mmol) of 3-(methylthio)-5-(octadecyloxy)benzoic acid methyl ester and 5.0 ml (30 mmol) of 6 N NaOH in 125 ml of methanol was stirred at reflux under argon for 5 hours. The solvent was removed at reduced pressure, the residue was acidified with 6 N HCl and the product was extracted with chloroform. The dried extract was concentrated to a solid which was triturated with hexane and filtered to give 2.6 g, mp 90°-92°, of 3-(methylthio)-5-(oxtadecyloxy)benzoic acid. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([O:24]CC3C=CC=CC=3)=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H][H]>[Pd].CO>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Yield: 96.2 %

Procedure:
20 mg of 10% w/w palladium on charcoal was added to a solution of 100 mg of benzyl 9-benzoyl-1,2,3,4-tetrahydrocarbazole-3-carboxylate, as obtained in Example 51, in 5 ml each of methanol and of tetrahydrofuran. The reaction mixture was stirred for 3 hours under a stream of hydrogen gas at room temperature, filtered to remove the catalyst, and concentrated by evaporation under reduced pressure. The resulting residue was recrystallized from ethyl acetate and hexane, to yield 75 mg of the title compound, melting at 189°-190° C.