Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[CH:14][CH:15]=1)(=[O:37])[CH3:36]
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 18 h
Yield: 41 %

Procedure:
A solution of the compound of Example 48 [(2R)-24N-(4-chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methyl-pentanoic acid amide (250 mg, 0.60 mmol) and Et3N (120 mg, 1.2 mmol) in CH2Cl2 (20 mL) was treated with acetyl chloride (56 mg, 0.72 mmol). After stirring for 18 h, the reaction was concentrated, chromatographed using silica gel flash chromatography (1% methanol/CH2Cl2) to afford the titled compound (110 mg, 41%). MS (ESI), (M−H)˜422.9; 1H NMR (CDCl3) δ 7.67 (d, 2H, J=8.0), 7.28-7.46 (m, 6H), 7.12 (br s, 1H), 6.24 (br s, 1H), 5.19 (br s, 1H), 4.48 (dd, 2H, J=50, 15), 4.27 (t, 1H, J=7.0), 2.18 (s, 3H), 1.80-2.01 (m, 1H), 1.12-1.32 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0).
Reaction SMILES: B(Br)(Br)Br.CO[C:7](=[O:23])[C:8]1[CH:17]=[CH:16][CH:15]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]=1[N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.O>ClCCl>[CH3:14][O:13][C:11]([C:10]1[CH:15]=[CH:16][CH:17]=[C:8]2[C:9]=1[N:18]1[CH:19]=[CH:20][CH:21]=[C:22]1[C:7]2=[O:23])=[O:12]
Reactant: COC(=O)c1cccc(C(=O)OC)c1-n1cccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc2c1-n1cccc1C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
In a 50 ml round-bottomed flask, 3 ml of a 1M solution of boron tribromide in dichloromethane are added, at ambient temperature, to a mixture of 260 mg of 2-pyrrol-1-ylisophthalic acid dimethyl ester (which can be prepared according to Helvetica Chim. Acta 1983, 66(7), 2135) dissolved in 4 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 2 hours and then 5 ml of water are added. After separation by settling out, the aqueous phase is re-extracted with twice 15 ml of dichloromethane. The combined organic phases are washed with twice 20 ml of water, dried over magnesium sulphate, and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of dichloromethane and cyclohexane (50/50 v/v). 122 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid methyl ester are obtained in the form of a yellowish solid, the characteristics of which are identical to those of the product obtained by method 1.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([CH:18]=O)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][OH:21]>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([CH:18]=[N:20][OH:21])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cccc2c(C=O)cccc12
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cccc2c(C=NO)cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-formyl-1-naphtoic acid tert-butyl ester (Example 9.3) (1.5 g) in ethanol (7.6 ml) was added aqueous hydroxylamine (50% w/v) (0.48 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to give 5-(hydroxyimino-methyl)-1-naphtoic acid tert-butyl ester (1.4 g). 1H-NMR (CDCl3, 400 MHz): 8.90 (d, 1H), 8.81 (s, 1H), 8.62 (d, 1H), 8.10 (d, 1H), 7.80 (d, 1H), 7.50-7.65 (m, 2H), 1.70 (s, 9H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].[C:27]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1)#[N:28].CC[N:41](C(C)C)C(C)C>C(Cl)Cl.C1COCC1.CN(C=O)C>[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]2[O:19][N:41]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:33][CH:34]=3)[N:28]=2)=[CH:16][C:15]=1[C:23]([F:26])([F:24])[F:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccc(S(N)(=O)=O)cc3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol) was added to a suspension of Intermediate 15 (144 mg; 0.5 mmol) and DMF (catalytic amount) in DCM (2 mL) and the reaction mixture was stirred at RT for 1 hour. After concentration to dryness, the residue was taken up in THF (2 mL) and added to a solution of 4-(aminosulfonyl)-N′-hydroxybenzenecarboximidamide, prepared as described in WO 2006/013104 A1 from 4-cyanobenzene-1-sulfonamide (ABCR; CD10716), (108 mg; 05 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol) in THF (1 mL). The reaction mixture was then stirred at 150° C. for 30 minutes in the microwave. After cooling, the mixture was filtered through a SPE-NH2 column, which was further washed with THF. After concentration in vacuo, the residue was purified by recrystallisation from DCM/n-pentane, affording the title compound as a white solid. LC/MS (Method A): 467.3 (M+H)+. HPLC (Method A) Rt 5.59 min (purity 99.3%).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][CH2:5]1>CCO>[OH:3][C@@H:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@H:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][CH2:5]1
Reactant: CCOC(=O)[C@@H]1CCC(=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC[C@H](O)CN1C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
NaBH4 (36 g, 1.0 mol) was added in portions to a solution of (S)-1-tert-butyl 2-ethyl 5-oxopiperidine-1,2-dicarboxylate (250 g, 0.92 mol) in EtOH (1500 mL) at −40° C. The reaction mixture was then stirred at −40° C. for 0.5 hr then quenched with 10% HOAc solution. After diluting with water, the mixture was extracted with DCM three times. The combined organic layer was concentrated in vacuum and purified by silica gel column chromatography (1:1 petroleum ether/EtOAc) to afford (2S,5S)-1-tert-butyl 2-ethyl 5-hydroxypiperidine-1,2-dicarboxylate (205 g, 80%) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.CON(C)[C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36].Cl.O1CCOCC1>O>[Cl:25][C:5]1[CH:6]=[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:19]([CH3:20])[CH3:21])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[C:2]([C:29]([C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:37])=[N:3][CH:4]=1
Reactant: CON(C)C(=O)c1cccnc1C
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(OC(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-bromo-5-chloro-pyridin-3-yl)-4-isopropoxy-N-methoxymethyl-benzenesulfonamide (592 mg, 1.32 mmol) was placed in a dry 25 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (5 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (1.72 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 60 minutes, followed by the addition of N-methoxy-2,N-dimethyl-nicotinamide (379 mg, 2.11 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 M HCl in dioxane (6 mL, 24.0 mmol) and H2O (6.0 mL), and then stirred at 80° C. for two hours. The resultant solution was concentrated in vacuo and saturated sodium bicarbonate was added to adjust to neutral pH. The solution was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude sulfonamide was finally purified via automated flash chromatography to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 10.90 (s, 1H), 8.58 (d, 1H), 8.17 (m, 2H), 7.80 (d, 2H), 7.49 (d, 1H), 7.16 (m, 1H), 6.89 (d, 2H), 4.57 (sep, 1H), 2.34 (s, 3H), 1.33 (d, 6H); MS (ES) M+H expect 445.9, found 446.1.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[C:3]([OH:5])=[O:4].BrCC(C)CC.NC(C[C@@H](C)CC)C(O)=O>CO.O>[CH3:9][CH2:8][CH:7]([CH2:6][C@H:2]([NH2:1])[C:3]([OH:5])=[O:4])[CH3:10]
Reactant: CCC(C)CC(N)C(=O)O
Agent: CCC(C)CBr
Agent: CC[C@H](C)CC(N)C(=O)O
Solvent: CO
Solvent: O
Product: CCC(C)C[C@H](N)C(=O)O

Procedure:
Two, 2-amino-4-methylhexanoic acid (homoisoleucine, Hil) units were identified after analyzing the PS (phase sensitive) DQF COSY and TOCSY spectra of vitilevuamide. The stereochemistry of the amino acids was confirmed by chemical synthesis of all four diastereomers, and evaluation of the 1-fluoro-2,4-dinitrophenyl-5-L-alanineamide (FDAA; Sigma Chemical Co., St. Louis, Mo.) derived amino acids by HPLC on a cyano column. The mixtures of (2RS,4S) and all four isomers of Hil were synthesized starting from S-(+) and (±)-1-bromo-2-methyl butane (Sigma Chemical Co. or Aldrich Chemical Co., Milwaukee, Wis.) respectively using the method of H. Han & R. A. Pascal, 55 J. Org. Chem. 5173 (1990). The diastereomeric mixture of (2RS,4S)-2-amino-4-methyl hexanoic acid was treated with catalase and L-amino acid oxidase (Aldrich Chemical Co.) at pH 8 for 12-18 hours. Upon acidification and reverse phase chromatography (9:1, MeOH/H2O), the pure (2R,4S) isomer of Hil was isolated. Using these standards it was possible to verify the stereochemistry of the two Hil residues in vitilevuamide by FDAA derivatization and cyano HPLC chromatography (MeOH/1% Acetic acid, 25:75-90:10 at 1 mL/min) with UV detection at 340 nm.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].C([Li])CCC.CCCCCC.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>O1CCCC1.O>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 24 h
Yield: 94.2 %

Procedure:
Imidazole (1) (20.0 g, 0.29 mol), triethylamine (41.0 mL, 0.29 mol) and N,N-dimethylsulfamoyl chloride (31.6 mL, 0.29 mol) were added to 320 mL of benzene. The reaction was stirred for 48 h at room temperature (rt) and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude product (˜0.5 mmHg, 115°-118° C.) afforded 38.7 g (76%) of a clear and colorless oil. Upon cooling the product solidifies to give white crystals (2). 1-(Dimethylsulfamoyl) imidazole (2) (18.8 g, 0.11 mol) was added to 430 mL of tetrahydrofuran (THF). The solution was cooled to −78° C. A solution of n-butyl lithium (n-BuLi) in hexane (1.6M, 70.9 mL, 0.11 mol) was added dropwise to the reaction flask. Upon completion, the reaction was stirred for 1 h at −78° C. t-Butyldimethylsilylchloride (17.8 g, 0.12 mol) in 50 mL of THF was added via cannula to the reaction. After the addition was completed the reaction mixture was warmed slowly to rt and then stirred for 24 h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane as eluant) afforded a light yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals (3). 1-Dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (3) (5.0 g, 17.3 mmol) was added to 100 mL of THF. The solution was cooled to −20° C. A solution of secondary butyl lithium (s-BuLi) in hexane (1.3M, 14.6 mL, 19 mmol) was added dropwise to the reaction flask. Upon completion the reaction was stirred for 1 h at −20° C. 8 mL of dimethylformamide (DMF) was added to the reaction and then stirred at rt for 3.5 h. The reaction was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography (20% ethyl acetate/hexane) afforded a light yellow oil. Upon cooling the product solidifies to give yellow crystals of 1-dimethylsulfamoyl-2-t-butyldimethylsilyl -5-imidazolecarboxaldehyde (4).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([C:19]1([CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH2:21][O:20]1)([CH3:18])[CH3:17]>C(O)CC>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([CH3:18])([CH3:17])[C:19]([CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)([OH:20])[CH2:21][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C1(Cn2cncn2)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCCO
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C(O)(Cn1cncn1)Cn1cncn1
Yield: 18.8 %

Procedure:
3.7 g (52.6 mmol) of 1,2,4-triazole are added to a solution of 0.11 g (47 mmol) of sodium in 30 ml of n-propanol at room temperature, while stirring. The mixture is heated to the reflux temperature and a solution of 15.4 g (47 mmol) of 2-(2,4-dichlorophenyl-tert.-butyl)-2-(1,2,4-triazol-1-yl-methyl)-oxirane in 20 ml of n-propanol is added. The reaction mixture is heated under reflux for 15 hours and then cooled and poured onto water. It is extracted with methylene chloride and the organic phase is dried over sodium sulphate and concentrated. The residue is purified by column chromatography (silica gel; ethyl acetate:cyclohexane=3:1). 3.5 g (18.8% of theory) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-yl-methyl)-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 126° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(NCC)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:23]#[C:22][C:20]([OH:24])([CH3:21])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)O)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one were mixed with 1.10 g (12 mmol) of 2-methyl-3-butyn-2-ol and 20 ml of diethylamine. Then, 70 mg of bis-(triphenyl -phosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide were added thereto and the mixture was stirred at room temperature for 60 hours. The reaction mixture was evaporated and the residue was dissolved in methylene chloride. The solution was washed twice with water, dried over magnesium sulfate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 193-194°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:32]4[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 150 °C
Yield: 10 %

Procedure:
A mixture of [4-(4-bromo-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (44 mg, 0.10 mmol), 4-methoxy-phenylboronic acid (3 mg, 0.15 mmol), sodium carbonate (21 mg, 0.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) in N,N-dimethylformamide (0.5 mL) was heated in a microwave oven at 150° C. for 30 minutes under an argon atmosphere. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford [4-(4′-methoxy-biphenyl-4-sulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (4.7 mg, 10%) as a white solid. MS cald. for C24H27N3O5S 469, obsd. (ESI+) [(M+H)+] 470.
Reaction SMILES: [CH3:1][NH:2][C:3]([S:5][CH2:6][CH2:7][NH2:8])=[S:4].C(N([CH2:14][CH3:15])CC)C.C[C:17]1[C:23](=O)[C:22]2N3[C@@:29](OC)([C@H:30]([CH2:31]OC(N)=O)[C:21]=2[C:19](=O)[C:18]=1OC)[C@H:28]1N[C@H:27]1[CH2:26]3>CO>[C:31]1([C:30]([C:21]2[CH:19]=[CH:18][CH:17]=[CH:23][CH:22]=2)([C:29]2[CH:28]=[CH:27][CH:26]=[CH:15][CH:14]=2)[NH:8][CH2:7][CH2:6][S:5][C:3]([NH:2][CH3:1])=[S:4])[CH:22]=[CH:23][CH:17]=[CH:18][CH:19]=1
Reactant: CNC(=S)SCCN
Reactant: CCN(CC)CC
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Solvent: CO
Product: CNC(=S)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 44 %

Procedure:
N-triphenylmethyl-2-methylaminothiocarbonylthioethylamine (0.89 g) which was prepared by the method of Reference 5 was subjected to a similar reaction to that described in Reference 4 to prepare 2-methylaminothiocarbonylthioethylamine (crude formate: 223 mg). The product was dissolved in anhydrous methanol (7 L ml). Triethylamine (732 μl) and mitomycin A (316 mg: 0.8 molar equivalent) were added to the reaction solution which was then treated in a similar manner to that described in Example 1 to obtain Compound 25 (233 mg) in the form of grayish blue powders with a yield of 44%.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]2[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]=1.[CH3:31][CH2:32][O-:33].[Na+]>C(O)C>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:5]3[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=[CH:25][C:4]=3[N:3]=[C:2]2[O:33][CH2:32][CH3:31])=[CH:9][CH:10]=1)#[N:21]
Reactant: CCOC(=O)c1cccc2nc(Cl)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 36.2 %

Procedure:
To a solution of ethyl 2-chloro-1-[(2′-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (1.0 g) in ethanol (30 ml) was added NaOEt (0.17 g) and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated to dryness. The resultant residue was dissolved in ethyl acetate and the solution was washed with water, and then dried. After evaporation of the solvent, the residue was purified by column chromatography on silica gel to give the title compound as colorless crystals(0.37 g, 70%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:15]N)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]=O.[BH3-][C:27]#[N:28].[Na+]>CC#N.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:15][N:28]([CH3:27])[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccc(Cl)cc2)CC1
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)CC(c1ccc(Cl)cc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
To 4-[2-Amino-1-(4-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (203) (0.18 g, 0.529 mmol) in MeCN (3.0 mL) at 0° C. was added formaldehyde(0.64 g, 21.18 mmol) and NaCNBH3 (0.17 g, 2.65 mmol). The reaction was allowed to warm to room temperature over 1 h. The reaction mixture was concnetrated to dryness. The resulting residue was taken up in EtOAc (50 mL) and washed with sat. NaHCO3 (50 mL) and H2O (50 mL). The desired product was then extracted into 1N HCl (50 mL) and washed with EtOAc. This aqueous phase was made alkaline with 5N NaOH (25 mL) and the desired product was extracted into EtOAc (100 mL). The organic phase was concentrated to dryness yielding 0.10 g (53%) product.
Reaction SMILES: [CH2:1]([NH:4][NH2:5])[CH:2]=[CH2:3].C(N(CC)CC)C.Br[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)(Cl)Cl.C(OC(=O)C)C>[CH2:1]([N:4]([C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH2:5])[CH:2]=[CH2:3]
Reactant: C=CCNN
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCN(N)C(C)(C)C(=O)OCC
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a solution of 70%-allylhydrazine (7.73 ml, 75 mmol) and triethylamine (1048 ml, 75 mmol) in chloroform (25 ml) was added ethyl 2-bromo-2-methylpropanoate (9.75 g, 50 mmol) and the mixture was sittred for 1 hr and then refluxed overnight. The reaction mixture was diluted with ethylacetate (150 ml) and washed with water (100 ml) and brine (100 ml). Then the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was subjected to silica gel column chromatography (eluent: chloroform:methanol=95:5) to obtain the title compound (5.0 g, 54%).