Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.ClS(C1C2C(=C([N+]([O-])=O)C=CC=2)N(S(C2C=CC=CC=2)(=O)=O)C=1C(OCC)=O)(=O)=O.ClC1C=C2C(=CC=1)N(S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(N1CCOCC1)(=O)=O.[N:92]1([S:98]([C:101]2[C:109]3[C:104](=[C:105]([N+:110]([O-:112])=[O:111])[CH:106]=[CH:107][CH:108]=3)[NH:103][C:102]=2[C:113]([O:115]CC)=O)(=[O:100])=[O:99])[CH2:97][CH2:96][O:95][CH2:94][CH2:93]1>>[N:92]1([S:98]([C:101]2[C:109]3[C:104](=[C:105]([N+:110]([O-:112])=[O:111])[CH:106]=[CH:107][CH:108]=3)[NH:103][C:102]=2[C:113]([NH2:7])=[O:115])(=[O:100])=[O:99])[CH2:97][CH2:96][O:95][CH2:94][CH2:93]1
Reactant: CCOC(=O)c1[nH]c2c([N+](=O)[O-])cccc2c1S(=O)(=O)N1CCOCC1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: CCOC(=O)c1c(S(=O)(=O)Cl)c2cccc([N+](=O)[O-])c2n1S(=O)(=O)c1ccccc1
Agent: CCOC(=O)c1c(S(=O)(=O)N2CCOCC2)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Product: NC(=O)c1[nH]c2c([N+](=O)[O-])cccc2c1S(=O)(=O)N1CCOCC1

Procedure:
Following the procedures described in Steps B and C of Example 2 and E of Example 1, replacing in Step B of Example 2 ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(chlorosulfonyl)-7-nitro-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and replacing in Step E of Example 1 ethyl 5-chloro-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(morpholin-4-ylsulfonyl)-7-nitro-1H-indole-2-carboxylate, the title compound was obtained. HRMS (ES) exact mass calculated for C13H15N4O6S (M+H+): 355.0707. Found 355.0713.
Reaction SMILES: [N:1]12[CH2:7][C:5]([C:8]([O:10]C)=O)([CH2:6]1)[CH2:4][CH2:3][CH2:2]2.[NH3:12].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[N:1]12[CH2:7][C:5]([C:8]([NH2:12])=[O:10])([CH2:6]1)[CH2:4][CH2:3][CH2:2]2
Reactant: COC(=O)C12CCCN(C1)C2
Reactant: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: NC(=O)C12CCCN(C1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4, 1.35 g, 0.0087 mole) was treated with 20M aqueous ammonia solution (25 ml) and the mixture stirred at room temperature for 2 days. The solution was saturated with potassium carbonate and shaken with chloroform (40 ml) The mixture separated into three layers. The chloroform solution contained some product, however the majority was in the middle layer. These two were combined and concentrated in vacuo and the residue then treated with toluene (60 ml) and again concentrated in vacuo to azeotrope out the water. The title compound (D12) remained as a white solid (1.07 g, 88%) m.p. 188°-1920° C.
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]([C:12]3[C:13]([C:18](OC)=[O:19])=[N:14][CH:15]=[CH:16][CH:17]=3)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:25][NH2:26]>CCO>[N:1]1([C:6]2[CH:23]=[CH:22][C:9]([C:10]3[C:12]4[CH:17]=[CH:16][CH:15]=[N:14][C:13]=4[C:18](=[O:19])[NH:25][N:26]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ncccc1C(=O)c1ccc(-n2ccnc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccc(-n3ccnc3)cc2)c2cccnc12

Procedure:
A mixture of 3-[4-(1H-imidazol-1-yl)benzoyl]-2-carbomethoxypyridine (1.21 g, 3.94 mmol) in 50 mL of EtOH is treated with 0.22 g (4.33 mmol) of hydrazine monohydrate and heated to reflux for 1 day. The white solid which precipitates from the reaction mixture is filtered and recrystallized from DMF-H2O to give 5-[4-(1H-imidazol-1-yl)phenyl]-8-oxo-7,8-dihydropyrido[2,3-d]pyridazine. M.P. 359°-361° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[C:16](Cl)(=O)[C:17](Cl)=O.CN(C=O)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[N:1]1([C:6]2[CH:7]=[C:8]3[C:9](=[CH:10][CH:11]=2)[CH2:12][C:13](=[O:15])[CH2:17][CH2:16]3)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2cc(-n3cnnn3)ccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-(1H-tetrazol-1-yl)phenyl]acetic acid (0.50 g, 2.4 mmol) in DCM (10 mL) was added oxalyl chloride (0.37 g, 2.9 mmol) and a drop of DMF. The mixture was allowed to stir at RT for 2 hours. The solvent was removed under reduced pressure, and the residue was redissolved in DCM. The solution was cooled to 0° C. with an ice bath. To this solution was added aluminum chloride (0.98 g, 7.4 mmol) in small portions. Ethylene was then bubbled into the reaction via a long needle for 2 hours. LC showed formation of the desired product. The reaction was poured into ice and extracted with DCM. The extractions were combined, dried over sodium sulfate, adsorbed onto silica gel, and purified by MPLC (Hexane/EtOAc). The desired 6-(1H-tetrazol-1-yl)-3,4-dihydronaphthalen-2(1H)-one was collected as a off-white solid. LC-MS (IE, m/z): 215 [M+1]+.
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](=[O:29])[CH3:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:37](N(C)C)[N:38]([CH3:40])[CH3:39])(C)(C)C>ClCCl>[CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](=[O:29])/[CH:28]=[CH:37]/[N:38]([CH3:40])[CH3:39])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: ClCCl
Product: CN(C)/C=C/C(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[10-(4-cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-ethanone of Example 6 Step B (1.0 g), tert-butoxybis(dimethylamino) methane (5 mL) and dichloromethane (25 mL) was refluxed for six hours and then allowed to stir at room temperature overnight. All volatiles were then removed at reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with water, dried over anhydrous sodium sulfate and filtered through a short column of Magnesol®. The eluate was refluxed with the gradual addition of hexane to provide pale yellow crystals of the title compound (0.16 g), m.p. 237–240° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:28]=[CH:29][N:30]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[CH:23]=O)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:28]=[CH:29][N:30]=3)[N:17]=[C:18]([C:20]3[CH:27]=[CH:26][CH:25]=[C:22]([CH2:23][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C=O)c3)nn3ccnc23)n1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CN4CCCC4)c3)nn3ccnc23)n1
Reaction time: 1 h
Yield: 22.7 %

Procedure:
3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzaldehyde (70 mg, 0.175 mmol) and pyrrolidine (14 mg, 0.194 mmol) were dissolved in 1,2-dichloroethane (10 mL), stirred for 1 h, then sodium triacetoxyborohydride (111 mg, 0.525 mmol) was added followed by AcOH (0.2 mL). After 15 h, the solvent was removed and the residue purified by chromatography (silica gel, dichloromethane/methanol 90:1) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(pyrrolidin-1-ylmethyl)phenyl)imidazo[1,2-b]pyridazin-8-amine (18 mg, 23%) as an orange solid. 1H NMR (300 MHz, CD3OD): δ 8.70 (s, 1H), 8.05 (s, 1H), 7.91-7.85 (m, 2H), 7.59-7.48 (m, 3H), 7.38-7.35 (m, 1H), 6.21 (d, 1H, J=7.5 Hz), 6.01 (d, 1H, J=7.8 Hz), 4.25-4.17 (m, 3H), 3.55 (s, 1H), 3.37-3.44 (m, 1H), 3.17 (brs, 4 h), 2.08-1.97 (m, 7H), 1.72 (brs, 1H), 1.13 (d, 3H, J=4.5 Hz). LC-MS: [M+H]+, 454, tR=1.367 min, HPLC: 99.54% at 214 nm, 99.89% at 254 nm, tR=5.164 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].[OH-].[Na+].O1CCCC1>CO>[CH2:10]([C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2])[CH3:11]
Reactant: CCc1ccsc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccsc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
3-Acetyl-2-thiophenecarboxylic acid methyl ester (3.87 g) synthesized in this manner was dissolved in methanol (50 ml), and sodium borohydride (0.95 g) was added under ice-cooling. The mixture was stirred at room temperature for 1 hour, and 1N hydrochloric acid (50 ml) was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-(1-hydroxyethyl)-2-thiophenecarboxylic acid methyl ester (3.77 g). This product was dissolved in ethyl acetate (100 ml), and methanesulfonyl chloride (2.86 g), triethylamine (3.5 g) and dimethylaminopyridine (0.2 g) were added. The mixture was stirred at room temperature for 2 hours, and 1N hydrochloric acid (50 ml) was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone (100 ml), and sodium iodide (10 g) was added. The mixture was stirred at room temperature for 2 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The desired fractions were concentrated under reduced pressure to give 3-(1-iodoethyl)-2-thiophenecarboxylic acid methyl ester (3.0 g). 3-(1-iodoethyl)-2-thiophenecarboxylic acid methyl ester was dissolved in dimethylsulfoxide (10 ml), and sodium borohydride (0.4 g) was added at room temperature. The mixture was stirred for 1 hour, and 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-ethyl-2-thiophenecarboxylic acid methyl ester (1.0 g). A mixture of 3-ethyl-2-thiophenecarboxylic acid methyl ester (1.0 g), 1N aqueous sodium hydroxide (15 ml), tetrahydrofuran (30 ml) and methanol (10 ml) was stirred at room temperature for 1 hour. The mixture was washed with diethyl ether, and the aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-ethyl-2-thiophenecarboxylic acid (0.9 g) as crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:11]=1)=[O:9])=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:11]=1)=[O:9])([OH:4])=[O:2]
Reactant: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cccc(C(=O)OC)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cccc(C(=O)O)c2)n1
Yield: 77.7 %

Procedure:
Under the conditions of example 2, 20 mg of 2-(3-methoxycarbonylbezoyl)-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 1 ml of methanol is saponified with 2 ml of 1 n sodium hydroxide solution and worked up. 15 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6]([OH:8])=O.[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1O>O>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]2[O:8][C:6]([C:5]3[CH:9]=[CH:10][C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:18][C:19]=2[CH:24]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Solvent: O
Product: COc1cc(-c2nc3cc(Cl)ccc3o2)ccc1-c1ccccn1

Procedure:
3-Methoxy-4-pyridin-2-yl benzoic acid (500 mg, 2.2 mmol), 2-amino-4-chlorophenol (620 mg, 4.3 mmol) and trimethyl silylpolyphosphate (2 mL) was heated to 180° C. overnight under argon. To the cooled reaction mixture, water (100 mL) was added and extracted with EtOAc (4×20 mL). Set aside organic layer. Filtered aqueous layer through Celite pad and basified filtrate to pH 9 (solid NaHCO3). Extracted with EtOAc (2×30 mL), combined all organic layers and concentrated in vacuo. The resulting orange oil was purified by flash chromatography using a gradient elution of 15:85 ethyl acetate:hexane to 1:1 ethyl acetate:hexane to give the desired intermediate, 5-chloro-2-(3-methoxy-4-pyridin-2-ylphenyl)-1,3-benzoxazole as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.[N:35]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][N:38]3[CH2:39][CH2:40][N:35]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][CH2:37]3)=[CH:6][N:5]2[C:12]=1[C:13]1[S:14][C:15]([C:24]2[N:28]=[CH:27][N:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc2ccc(C=O)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 25 °C
Reaction time: 46 h
Yield: 61.9 %

Procedure:
To the suspension of 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine-6-carbaldehyde (0.0300 g, 0.0638 mmol), tert-Butyl 1-piperazinecarboxylate (20.8 mg, 0.112 mmol) and Acetic acid (11 mg, 0.18 mmol) in dry Methylene chloride (2.0 mL, 31 mmol) was added Sodium triacetoxyborohydride (27.0 mg, 0.128 mmol). The mixture was stirred at r.t. for 46 hours. The mixture was washed with water (2×2 mL) and brine, dried over Na2SO4, filtered and the filtrate was chromatographed in an 8 g AnaLogix column using MeOH/DCM (0/100 to 5/95) to give a solid product (0.0253 g, 61.9% yield). LCMS: (FA) ES+ 641. 1H NMR (400 MHz, d-chroloform) 9.91 (s, 1H), 8.28 (s, 1H), 7.94-7.97 (m, 2H), 7.58-7.60 (m, 1H), 7.34-7.46 (m, 4H), 5.47-5.51 (m, 1H), 4.05-4.13 (m, 1H), 3.70-3.76 (m, 1H), 3.58 (s, 2H), 3.42 (s, br, 4H), 2.81 (s, 3H), 2.45 (s, br, 4H), 2.00-2.17 (m, 3H), 1.65-1.72 (m, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([CH3:23])[C:19](=[O:22])[NH:20][CH:21]=2)[CH2:3][CH2:2]1.CS(O[CH2:29][C:30]1[N:31]=[CH:32][O:33][CH:34]=1)(=O)=O.CS(OCC1COC1)(=O)=O>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([CH3:23])[C:19](=[O:22])[N:20]([CH2:29][C:30]3[N:31]=[CH:32][O:33][CH:34]=3)[CH:21]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c[nH]c1=O
Reactant: CS(=O)(=O)OCc1cocn1
Agent: CS(=O)(=O)OCC1COC1
Product: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)cn(Cc2cocn2)c1=O

Procedure:
The title compound from Example 242, step 1 was reacted in a manner similar to Example 245 except that 1,3-oxazol-4-ylmethyl methanesulfonate was substituted for oxetan-3-ylmethyl methanesulfonate to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.82 (s, 5H), 7.52 (s, 1H), 7.01 (d, J=9.2 Hz, 1H), 5.11 (s, 2H), 3.94 (d, J=6.8 Hz, 1H), 3.06 (s, 3H), 2.21 (s, 3H), 1.27-1.24 (m, 1H), 0.68-0.65 (m, 2H), 0.37-0.36 (m, 2H). LCMS: 415.1 (M+1)+
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([NH:25][O:26]C3CCCCO3)=[O:24])=[CH:17][C:16]=2[Cl:33])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34]>CCO.CO>[ClH:33].[ClH:34].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([NH:25][OH:26])=[O:24])=[CH:17][C:16]=2[Cl:33])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1cnc(NC2CCN(Cc3ccccc3)CC2)c(Cl)c1)NOC1CCCCO1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: O=C(/C=C/c1cnc(NC2CCN(Cc3ccccc3)CC2)c(Cl)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-5-chloro-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (168 mg) in EtOH (2 ml) was treated with 10% HCl in MeOH (1.76 ml) and was stirred at 25° C. for 1 hour. The precipitate was collected, washed with EtOH, dried under reduced pressure to give (2E)-3-{6-[(1-benzyl-4-piperidyl)amino]-5-chloro-3-pyridyl}-N-hydroxyacrylamide dihydrochloride (137 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[S:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[N:28]=[N:27]1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:37][C:34]4[CH:33]=[CH:32][C:31]([C:29]5[N:28]=[N:27][S:26][CH:30]=5)=[CH:36][CH:35]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(-c2csnn2)cc1
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc(-c5csnn5)cc4)nn23)cn1
Yield: 24 %

Procedure:
Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.138 g, 0.369 mmol and 4-[1,2,3]Thiadiazol-4-yl-phenylamine (0.0817 g, 0.461 mmol) were reacted in an analogous manner to Example 908D at 50° overnight. The reaction mixture was filtered and the resulting solid was washed with acetone to give the title compound as a pale yellow solid (36 mg, 24%). HPLC rt=3.347, purity=99%. LCMS=401.9 (M+H). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.81 (s, 1H), 9.52 (s, 1H), 9.04 (s, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.54 (dd, J=8.7 Hz, 2.3 Hz, 1H), 8.08 (d, J=7.9 Hz, 2H), 7.91 (d, J=8.6 Hz, 2H), 7.21 (d, J=4.4 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H), 7.00 (d, J=4.3 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: ClC(OCC(C)C)=O.[Cl:9][C:10]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:11]=1[C:12]([OH:14])=O.C(N(CC)CC)C.[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:29]1([NH:35][C:12](=[O:14])[C:11]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:10]=2[Cl:9])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NC1CCCCC1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.75 h

Procedure:
Isobutyl chloroformate (1.43 ml) was added under ice cooling to a solution of 2-chloro-5-nitrobenzoic acid (2.01 g) and triethylamine (1.53 ml) in methylene chloride (40 ml). The mixture was stirred under ice cooling for 45 min. Thereafter, cyclohexylamine (1.25 ml) was added thereto. The reaction solution was stirred at room temperature for 1.5 hr. The precipitated crystals were dissolved in chloroform. The organic layer was washed with water, dilute hydrochloric acid, and water in that order, dried over magnesium sulfate, and then concentrated under the reduced pressure. Ethyl ether was added to the residue. The precipitated crystals were collected by filtration, and then dried to give 2.63 g of N-cyclohexyl-2-chloro-5-nitrobenzamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[C:28](C)(C)[O:29][SiH2]C(C)(C)C)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[CH2:28][OH:29])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(S(=O)(=O)N3CCCC3C(C)(C)O[SiH2]C(C)(C)C)cc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(S(=O)(=O)N3CCCC3CO)cc2)n1
Yield: 85.4 %

Procedure:
A solution of crude (6-{4-[2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine 1-sulfonyl]phenyl}-pyridin-2-yl)carbamic acid tert-butyl ester (22.2 g, 40.5 mmol) and TBAF (21.2 g, 81.0 mmol) in DCM (300 mL) was stirred at room temperature overnight. The mixture was washed with brine (100 mL×3), dried over Na2SO4 and evaporated under vacuum to give {6-[4-(2-hydroxymethyl-pyrrolidine-1-sulfonyl)-phenyl]pyridin-2-yl}carbamic acid tert-butyl ester (15.0 g, 86%), which was used directly in the next step.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.Br[C:13]1[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=1[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1>CN(C=O)C>[N:3]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1Br
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(n2cnc3ccccc32)=C1c1c[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 3.8 %

Procedure:
260 mg of a 60% dispersion of sodium hydride in mineral oil were added to a solution of 295 mg of benzimidazole in 10 ml of DMF and the mixture was stirred under nitrogen for 0.5 hour. 582 mg of 3-bromo-4-(3-indolyl)-1H-pyrrole-2,5-dione were added and the mixture was heated to 50° C. for 18 hours. A solution of 767 mg of benzimidazole and 260 mg of sodium hydride in 10 ml of DMF was added and the mixture was heated to 90° C. for 18 hours under nitrogen. The solvent was evaporated and the residue was partitioned between dichloromethane and 2M hydrochloric acid. The precipitate was purified on silica gel with ethyl acetate/petroleum ether. Recrystallization from ethyl acetate gave 25 mg of 3-(1-benzimidazolyl)-4-(3-indolyl)-1H-pyrrole-2,5-dione, m.p. 310°-320° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:4](=[O:22])[C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][N:13]=2)=[O:9])=[N:6][CH:7]=1.[Br:33]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:33][C:7]1[N:6]=[C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][N:13]=2)=[O:9])[C:4](=[O:22])[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[CH:24]=2)[C:2]=1[CH3:1]
Reactant: Cc1cnc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)nc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
5-Methyl-N-{[5-(methylsulfonyl)-pyridin-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.097 g, 0.21 mmol) was dissolved in DMF (2 ml) in a vial. To this mixture was added N-bromosuccinimide (0.055 g, 0.31 mmol), and the vial was sealed and the mixture was heated at 50° C. with stirring for 1 h. The crude mixture was added dropwise to water (40 ml) under magnetic stirring. The precipitate was isolated by filtration to give 0.105 g (92%) of 6-bromo-5-methyl-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide as a solid.