Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:32]1C=C(S(Cl)(=O)=O)C=C[C:37]=1Cl>>[CH2:32]([O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][CH:30]=[C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])[CH:14]=2)=[CH:20][CH:21]=1)[CH3:37]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c2)cc1

Procedure:
4-[3-(3,4-Dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=462.9 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 4-[3-(3,4-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: C(OC([N:11]1[CH2:14][CH:13]([C:15]2([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16]2)[CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[C:22]([O:21][C:19]([NH:18][C:15]1([CH:13]2[CH2:12][NH:11][CH2:14]2)[CH2:16][CH2:17]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1(C2CN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C2CNC2)CC1
Reaction time: 8 h

Procedure:
To 1.84 g (5.31 mmol) of 1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)azetidine dissolved in 100 ml of ethanol was added 1.5 g of 10% palladium-carbon, followed by overnight catalytic hydrogenation at room temperature under normal pressure. After removal of the catalyst by filtration, the solvent was evaporated to yield quantitative amount of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[C:14]=2[CH:28]=1)(O)=[O:8].[NH3:29]>CN(C)C=O.C(Cl)Cl>[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[C:14]=2[CH:28]=1)(=[O:8])[NH2:29]
Reactant: N
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C(N)=O)cc2n1Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (0.437 g) was added to a solution of 0.490 g of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and 1 drop of N,N-dimethylformamide in 8 ml of methylene chloride while being cooled with ice, and the mixture was stirred at room temperature for 1.5 hours. Four milliliters of 28% aqueous ammonia were added thereto, and the solution was stirred at room temperature for 12 hours. The reaction solution was extracted with the addition of water and methylene chloride. The organic layer was concentrated, and the crystals precipitated were then collected, and were dried to give 0.240 g of 6-carbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (223).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH2:23])[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH2:23])=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: C=C(c1ccccc1)c1nc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cnc1N
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: C=C(c1ccccc1)c1nc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cnc1NC(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(1-phenylvinyl)pyrazin-2-amine (7c) (543 mg, 1.35 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C., and the mixture was heated with stirring at 50° C. for 16 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11c (292 mg, 448 μmol, 33.3%) as a yellow foamy solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.13 (s, 6H), 0.18 (s, 6H), 0.91 (s, 9H), 0.92 (s, 9H), 3.22 (s, 2H), 5.51 (s, 1H), 5.65 (s, 1H), 6.67-6.74 (AA′BB′, 2H), 6.90-6.97 (AA′BB′, 2H), 6.97-7.03 (AA′BB′, 2H), 7.19-7.26 (m, 2H), 7.26-7.31 (m, 3H), 7.91-7.98 (AA′BB′, 2H), 8.95 (s, 1H), 10.19 (s, 1H); 13C NMR (75.5 MHz, acetone-d6) δ −4.3 (4C), 18.6, 18.7, 26.0 (6C), 42.5, 118.8, 120.5 (2C), 121.1 (2C), 127.9 (2C), 128.4, 128.6, 128.78 (2C), 128.84 (2C), 130.1, 131,3 (2C), 138.4, 140.0, 144.2, 146.9, 148.7, 148.9, 155.1, 157.9, 169.7; IR (KBr, cm−1) 546, 696, 781, 806, 839, 914, 1007, 1082, 1169, 1261, 1362, 1420, 1435, 1472, 1508, 1605, 1670, 2857, 2886, 2930, 2955, 3030, 3055, 3231; HRMS (ESI+) m/z 652.3390 ([M+H]+, C38H50N3O3Si2+ requires 652.3385).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[F:13].[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[CH2:16]([O:15][P:14]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[F:13])([O:18][CH2:19][CH3:20])=[O:21])[CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Product: CCOP(=O)(Cc1ccc(C(=O)OC)cc1F)OCC
Temperature: 145 °C

Procedure:
A mixture of methyl 4-bromomethyl-3-fluorobenzenecarboxylate (240 mg) and triethyl phosphite (0.32 mL) was heated at 145° C. for 2 hours. The reaction solution was purified through silica gel column chromatography (ethyl acetate/methanol=9/1) to obtain the entitled compound (300 mg).
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:6][C:3]=1[C:4]#[N:5].N(OCCC(C)C)=O>C1COCC1.CC(OC)(C)C>[F:17][C:16]([F:18])([F:19])[CH2:15][O:14][C:7]1[CH:6]=[C:3]([CH:2]=[CH:9][C:8]=1[C:10]([F:13])([F:11])[F:12])[C:4]#[N:5]
Reactant: N#Cc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: N#Cc1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Yield: 79.1 %

Procedure:
To a solution of 2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile from step 4 (14.47 g, 50.9 mmol) in dry THF (153 mL) was added isoamyl nitrite (15.0 mL, 112.0 mmol), and the mixture was refluxed for 20 h. The solvent was removed in vacuum to give an orange oil, which was dissolved in TBME, washed with 1 N HCl, sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown solid (15.05 g), which was purified by Kugelrohr distillation (up to 155° C. bath temperature at 1.2 mbar) to give the title compound as alight yellow solid (10.83 g, 79%). MS (EI) 269 [M].
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C(O)C>CS(C)=O>[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Cc1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1ccc2c(C3CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.145 g, 0.767 mmol) and 6-methyl-3-(piperidin-4-yl)-1H-indole (0.150 g, 0.697 mmol) using ethanol as reaction solvent. Yield 0.140 g (49%) as a tan foam. FDMS m/e=403 (M+ of free base). α[D]589 =+3.8 (c=0.98, dimethylsulfoxide).
Reaction SMILES: C(O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H:14]2[O:24][Si:25]([C:28](C)(C)C)([CH3:27])[CH3:26])C1)(=O)C.N1C=CC=CC=1.[C:39]([O-:42])(O)=O.[Na+]>C(Cl)Cl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[CH3:26][Si:25]([CH3:28])([CH3:27])[O:24][CH2:14][CH2:39][O:42][Si:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C([O-])O
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[Si](C)(C)OCCO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a manner similar to that described in Tsunoda T., et al., Tet. Lett., 1980, 21(14), 1357-1358, Hwa et al., J. Org. Chem., 1987, 52(2), 188-191. A solution of 3β-acetoxy-17β-t-butyldimethylsilyloxy-androst-5-en-7-one (40.000 g, 86.821 mmol) from Example 16B or otherwise obtained and 1,2-bis(trimethylsiloxy)ethane (23.00 mL, 93.81 mmole) in CH2Cl2 (300 mL) is prepared at −78° C. Trimethylsilyl trifluoromethanesulfonate (0.20 mL, 1.035 mmol) is added under an inert atmosphere, the reaction is stirred for three hours, pyridine (2.00 mL, 24.73 mmol) is added and the stirred mixture is allowed to warm to room temperature. The organic solution is poured into saturated aqueous NaHCO3 (300 mL) and the resultant biphasic solution is extracted with EtOAc (3×300 mL). The combined organic extracts are washed with brine (200 mL), dried over MgSO4, filtered and evaporated to dryness. The residue is purified by flash chromatography (1:4 EtOAc/hexane) to give 7,7-ethylenedioxy-17β-t-butyldimethylsilylyoxy-androst-5-en-3-ol 3-acetate.
Reaction SMILES: C(O[CH:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(OC(=O)C)(=O)C.[BrH:44]>ClCCl>[C:8]([O:7][C@@H:6]1[C@@H:11]([NH:24][C:25](=[O:36])[C:26]2[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=2)[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]1[Br:44])(=[O:10])[CH3:9]
Reactant: Br
Reactant: COc1cc(OC)cc(C(=O)N[C@H]2[C@@H](OC(C)=O)[C@@H](COC(C)=O)OC(OC(C)=O)[C@@H]2OC(C)=O)c1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)N[C@@H]2[C@@H](OC(C)=O)[C@@H](Br)O[C@H](COC(C)=O)[C@@H]2OC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,2,4,6-Tetra-O-acetyl-3-deoxy-3-(3,5-dimethoxybenzamido)-D-galactopyranose 4 (50 mg, 0.098 mmol) was dissolved in dichloromethane (1 ml) which had been dried over 4 Å molecular sieves. Acetic anhydride (18 μl, 0.20 mmol) and HBr (0.2 ml, 33% in AcOH) were added, and the mixture was stirred under N2 at room temperature. After 2 h 30 min, the reaction mixture was diluted with dichloromethane (30 ml) and poured into ice-water (30 ml). The organic phase was washed with NaHCO3 (30 ml of a saturated aqueous solution), dried (MgSO4), filtered and concentrated in vacuo to give 2,4,6-tri-O-acetyl-3-deoxy-3-(3,5-dimethoxybenzamido)-α-D-galactopyranosyl bromide 9, which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1.C(OC)(OC)OC.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[BH4-].[Na+]>CO>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][N:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1)[CH2:11][C:9]1[NH:8][CH:7]=[CH:6][N:10]=1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CN)cc2n1CCC
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2n1CCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound (130 mg) obtained in Example 125-6 was dissolved in methanol (3.0 ml) and added with trimethyl orthoformate (0.130 ml) and 2-imidazole carboxaldehyde (37.3 mg), followed by stirring for 1 hour. Then, the solution was cooled to 0° C. The solution was added with sodium borohydride (21.5 mg) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. The solution was washed with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (16.4 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]2[N:10]([C:14]3[CH:19]=[C:18]([S:20]([C:23]([CH3:31])([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:24])(=[O:22])=[O:21])[C:17]([O:32][CH3:33])=[CH:16][C:15]=3[Cl:34])[C:11](=[O:13])[NH:12][C:7]2=[C:6]([CH3:35])[CH:5]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:44]([O:46][C:47]([O:49][CH:50](Cl)[CH3:51])=[O:48])[CH3:45]>CN(C)C=O.C(OCC)(=O)C>[Cl:34][C:15]1[CH:16]=[C:17]([O:32][CH3:33])[C:18]([S:20]([C:23]([CH3:24])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:31])(=[O:22])=[O:21])=[CH:19][C:14]=1[N:10]1[C:8]2=[N:9][C:4]([C:1]([O:3][CH:44]([O:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH3:45])=[O:2])=[CH:5][C:6]([CH3:35])=[C:7]2[NH:12][C:11]1=[O:13]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(C)cc(C(=O)O)nc32)cc1S(=O)(=O)C(C)(C)c1ccccc1
Reactant: CCOC(=O)OC(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1cc(C)c2[nH]c(=O)n(-c3cc(S(=O)(=O)C(C)(C)c4ccccc4)c(OC)cc3Cl)c2n1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 5-carboxy-3-[2-chloro-4-methoxy-5-(1-methyl-1-phenyl-ethylsulfonyl)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (49 mg), potassium carbonate (17 mg) and potassium iodide (8 mg) in N,N-dimethylformamide (1 mL) was added 1-ethoxycarbonyloxyethyl chloride (0.015 mL), and the mixture was stirred at 60° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/2) to give the title compound (29 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)(=[O:17])=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Ni]>[C:1]([O:5][C:6](=[O:27])[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])(=[O:17])=[O:16])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1ccc(CNS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CNS(=O)(=O)c2ccccc2N)cc1
Reaction time: 28 h

Procedure:
4-[(2-Nitro-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester (14.4 g, 40 mmol) was dissolved in 100 mL of tetrahydrofuran containing 10 g of Raney Nickel. The reaction was pressurized with 100 psi of hydrogen gas and stirred for 28 hours at 25° C. to 60° C. The reaction was filtered, and the filtrate was rotary evaporated to give a thick oil. Chromatography (20% ethyl acetate/hexanes, SiO2) of the oil gave 12.2 (92%) of 4-[(2-Amino-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester as a clear oil. 1H-NMR (CDCl3); δ 7.85 (d, 2H), 7.70 (dd, 1H), 7.27 (m, 3H), 6.78 (m, 2H), 5.18 (bt, 1H), 4.82 (bs, 2H), 4.08 (d, 2H), and 1.57 (s, 9H). MS: M+=363.1 Da Step (3): Synthesis of 4-[(2-Amino-5-bromo-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:26])[N:12]([CH2:14][CH2:15][NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C=O)C.O>[C:1]1([CH:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:26])[N:12]([CH2:14][CH2:15][NH:16][C:17]([C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[O:24][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:25])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O)c1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(C(=O)NCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Reaction time: 14 h

Procedure:
To a suspension of N-{2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}-3-hydroxybenzamide (60.0 mg) and K2CO3 (58.6 mg) in DMF (1.8 mL) was added dropwise ethyl bromoacetate (18.8 μL) at ambient temperature and the mixture was stirred at the same temperature for 14 hours. The resulting mixture was diluted with water (5.0 mL) and the aqueous solution was extracted with EtOAc (10.0 mL). The organic layer was washed successively with 1M HCl aqueous solution, saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=98:2) to give ethyl {3-[({2-[5-(diphenylmethyl)-2-oxo-1(2H) -pyridinyl]ethyl}amino)carbonyl]phenoxy}acetate (70 mg) as a colorless syrup.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]#[N:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CC(O)=[O:28].C([O-])([O-])=O.[Na+].[Na+].CCCCCC>Br.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:24]([NH2:25])=[O:28])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CC(=O)O
Reactant: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2)ccc1=O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 2 h

Procedure:
A suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbonitrile (143 mg) in 25% hydrogen bromide solution of AcOH (1.5 ml) was stirred at 25-30° C. for 2 hours. The reaction mixture was poured into a mixture of Na2CO3 (2 g) and ice-water (30 g), extracted with CHCl3, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarboxamide as a solid (136 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[ClH:19]>C(OCC)(=O)C>[ClH:19].[CH2:8]([O:6][C:5](=[O:7])[C@H:2]([CH2:3][SH:4])[NH2:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCO
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOC(=O)[C@@H](N)CS

Procedure:
L-Cysteine 157.4 g was added to 250 ml of decyl alcohol saturated with dry HCl. The mixture was heated to 150° for 6 h. The solution was cooled and was mixed with equal volume of ethyl acetate. The solution was cooled in a dry ice bath to give crystals. The crystals were filtered and were recrystallized from ethyl acetate, mp 96°-99° C., yield 100 g, IR (KBr) 1745 cm-1 ; NMR (CDCl3) δ.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:21]=[CH:20][C:11]([CH:12]=[C:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1.[OH:22][C@@H:23]([CH2:36][NH2:37])[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[OH:22][C@H:23]([CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:36][NH:37][CH:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:21]=[CH:20][C:11]([CH:12]=[C:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:2][CH2:7]1
Reactant: O=C1NC(=O)C(=Cc2ccc(N3CCCCC3=O)cc2)S1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 36) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 73 as a pale yellowish solid; mp>240° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.45–1.60 (m, 2 H), 2.00–2.15 (m, 2 H), 2.86 (brt, J=9.0 Hz, 2 H), 2.90–3.60 (m, 3 H), 3.91 (brd, J=9.4 Hz, 1 H), 3.93–4.10 (m, 3 H), 5.40 (brs, 1 H), 6.59 (d, J=6.0 Hz, 1 H), 6.63 (d, J=6.0 Hz, 1 H), 6.86 (t, J=6.0 Hz, 1 H), 7.02 (d, J=6.6 Hz, 2 H), 7.36 (s, 1 H), 7.40 (d, J=6.6 Hz, 2 H), 11.60 (s, 1 H), 11.70 (brs, 1 H); MS (ES) m/z: 509.9 (MH+); HRMS Calcd. for C25H28N5O5S (MH+): 510.1811. Found: 510.1861.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])(OCC)=O)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=O>O1CCCC1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[CH:11][C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Reactant: CCOP(=O)(CC(=O)N1CCOCC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc([N+](=O)[O-])cc2)cc1OC
Temperature: 25 °C
Yield: 624.4 %

Procedure:
10.3 g of sodium hydride with 20% paraffin oil (0.343 mol) were suspended in 350 ml of tetrahydrofuran while stirring, and 75 g of diethylphosphonoacetic acid morpholide (0.0283 mol) were added dropwise to the suspension over a period of 20 minutes while cooling with ice (internal temperature 25° C.). The mixture was allowed to react for an hour during which a clear solution was formed. 70 g (0.244 mol) of 3,4-dimethoxy-4'-nitrobenzophenone were added to this solution all at once, and the mixture was refluxed for 2 hour while stirring. The solution was then evaporated in vacuo in a rotary evaporator at 60° C., and the residue was dissolved in methylene chloride/water. The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo at 60° C. The residue was triturated with 300 ml of hot methanol. 70.4 g of the title compound were obtained in the form of a faintly beige powder (73% of theory), m.p. 149°-163° C.