Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C:18]2=[O:23])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[Cl:38][C:39]1[CH:40]=[C:41]([N:46]=[C:47]=[O:48])[CH:42]=[CH:43][C:44]=1[Cl:45]>ClCCl>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:47]([NH:46][C:41]3[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([Cl:38])[CH:40]=3)=[O:48])[CH2:19][C:18]2=[O:23])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CNCCN1CC1CCCN(Cc2ccccc2)C1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CN(C(=O)Nc2ccc(Cl)c(Cl)c2)CCN1CC1CCCN(Cc2ccccc2)C1
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a mixture of 1-[(1-benzylpiperidin-3-yl)methyl]piperazin-2-one dihydrochloride (83 mg) in dichloromethane (10 mL) was added N,N-di-iso-propylethylamine (0.1 mL). After 1 minute dimethylformamide (1 mL) was added followed by 3,4-dichlorophenyl isocyanate (47 mg). The solution was stirred for 5 minutes and then partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in dichloromethane to give the title compound as a white solid (92 mg, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6](=[O:32])[CH2:7][C:8](=[O:31])/[CH:9]=[CH:10]/[C:11]1[C:12]([CH:28]2[CH2:30][CH2:29]2)=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:2].C(N(CC)CC)C.C(O)=O.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@H:6]([OH:32])[CH2:7][C@H:8]([OH:31])/[CH:9]=[CH:10]/[C:11]1[C:12]([CH:28]2[CH2:29][CH2:30]2)=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:2]
Reactant: CCOC(=O)CC(=O)CC(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of (E)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dioxo-hept-6-enoic acid ethyl ester (600 mg, 1.347 mmol) in N,N-dimethylformamide (5 ml) under argon is added (1R,2R)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine-RuII-pcymene complex [cf. above] (40 mg, 0.067 mmol) and formic acid-triethylamine 5:2 (v/v)-mixture (2 ml). After stirring at 50° C. for 30 min, triethylamine (4.7 ml, 33.79 mmol) is added to the orange, clear solution, and stirring is continued at 50° C. for 19 hours. Evaporation of the reaction mixture under reduced pressure, followed by silica gel chromatography (toluene/ethyl acetate 3:1) of the dried residue affords (E)-(3R,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoic acid ethyl ester. MS (EI): [M+]447, diastereomeric purity (syn/anti): 90.0/10.0%, enantiomeric purity (3R5S/3S5R): 80.0/20.0% (HPLC on ChiralPak AD-column).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]3[CH:13]=[CH:14][N:15]=[C:9]3[N:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[Br-:16].[K+].C([O-])(=O)C.[Na+].BrBr>CO>[Br:16][C:13]1[N:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[N:8][C:9]2=[N:15][CH:14]=1
Reactant: c1cn2ccc(Cn3cncn3)nc2n1
Reactant: [Br-]
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: Brc1cnc2nc(Cn3cncn3)ccn12
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To 7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidine (3.38 g, 16.9 mmol) in methanol (300 ml) saturated with potassium bromide was added sodium acetate (4.16 g, 50.7 mmol). This mixture was cooled (−10° C.) and bromine (2.70 g, 16.9 mmol) added dropwise over a five minute period. Stirring at this temperature was continued for 15 min before quenching the reaction with 5% (w/v) sodium sulphite solution (20 ml). Mixture was stirred for 15 min and methanol removed under reduced pressure. Residue was partitioned between dichloromethane (100 ml) and saturated sodium hydrogencarbonate solution (100 ml). Product was extracted into dichloromethane (4×100 ml) then the combined organic extracts were washed with brine (300 ml) and dried over anhydrous magnesium sulphate. Drying agent was removed by filtration and filtrate dried under reduced pressure to give 3-bromo-7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidine (4.60 g, 97%) as a pale yellow solid: δH (360 MHz, d6-DMSO) 5.69 (2H, s), 7.06 (1H, d, J 7), 7.88 (1H, s), 8.05 (1H, s), 8.74 (1H, s), 8.80 (1H, d, J 7); m/z (ES+) 279, 281 (M++H).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[NH:10]1)=[O:8])(=O)C.[OH-].[NH4+]>>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[NH:10]1)=[O:8]
Reactant: CC(=O)SCCC(=O)N1NC(=O)CC1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=C1CC(C(=O)O)N(C(=O)CCS)N1
Reaction time: 1 h
Yield: 44.7 %

Procedure:
DL-2-[3-(Acetylthio)-1-oxopropyl]-5-oxo-3-pyrazolidinecarboxylic acid (1.2 g) is treated in an argon atmosphere with 8 ml of a cold solution of 6.5 N ammonium hydroxide. After one hour at room temperature, the solution is extracted with ethyl acetate and treated with concentrated hydrochloric acid to pH 2. The water soluble product is extracted with five 20 ml portions of ethyl acetate. The combined extracts are dried over magnesium sulfate and evaporated to an oil which gradually solidifies. This material is dried in vacuo at 100° C. for 1 hour yielding 0.45 g of the title compound, melting point 140°-142° C.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](N)=[O:7])C.[C:10]1([NH:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N>C1(C)C(C)=CC=CC=1>[C:18]1([N:17]2[C:6](=[O:7])[NH:5][C:4](=[O:3])[N:16]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)NC(N)=O
Reactant: c1ccc(NNc2ccccc2)cc1
Agent: N
Solvent: Cc1ccccc1C
Product: O=c1[nH]c(=O)n(-c2ccccc2)n1-c1ccccc1

Procedure:
50 g (0.378 Mol) of ethylallophanate and 76.6 g (0.416 Mol) of 1,2-diphenylhydrazine were suspended in 100 ml of anhydrous xylene and refluxed for 6 hours with stirring, during which time ammonia was released. The solvent was distilled off, the residue was mixed with 150 ml of xylene once more and refluxed for 1 hour. The mixture was left to cool, the reaction product was suction filtered, and thoroughly washed with cold xylene. After drying in vacuo, 60.0 g (63% of theory) of colourless crystals were obtained, mp. 216°-217° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[C@H:5](C)[NH:6][C:7](=[O:20])[CH:8]([O:10][N:11]=[CH:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][CH:14]=1)[Cl:9])[CH3:2].ClC(ON=CC1C(Cl)=CC=CC=1)C(N[C@H](C(O)=O)C)=O>>[Cl:9][CH:8]([O:10][N:11]=[CH:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([N:6]1[CH2:5][CH2:4][O:3][CH2:1][CH2:2]1)=[O:20]
Reactant: CCOC(=O)[C@H](C)NC(=O)C(Cl)ON=Cc1ccccc1Cl
Agent: C[C@H](NC(=O)C(Cl)ON=Cc1ccccc1Cl)C(=O)O
Product: O=C(C(Cl)ON=Cc1ccccc1Cl)N1CCOCC1

Procedure:
N-(2,6-dichlorobenzylideneaminooxyacetyl)alanine ethylester of N-(2,6-dichlorobenzylideneaminooxyacetyl)alanine
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=CN=[CH:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].O1C2=[CH:19][N:20]=CC=C2C=C1.O1C2C=CN=CC=2C=C1>>[S:1]([C:5]1[O:13][C:12]2=[CH:11][N:20]=[CH:19][CH:8]=[C:7]2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: c1cc2ccoc2cn1
Reactant: NS(=O)(=O)c1cc2cnccc2o1
Agent: c1cc2occc2cn1
Product: NS(=O)(=O)c1cc2ccncc2o1
Yield: 40 %

Procedure:
The title compound was prepared according to the procedure described for the preparation of 2-sulfamoylfuro[3,2-c]pyridine except furo[2,3-c]pyridine was substituted for furo[3,2-c]pyridine. This compound was obtained in 40% yield after recrystallization from ethyl acetate, m.p. 199°-201° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]1[C:29]2[C:34]([CH2:35][O:36][C:23]=1[CH:22]=3)=[CH:33][C:32]([C:37]1[CH:38]=[CH:39][C:40]3[N:44]=[C:43]([C@@H:45]4[CH2:49][CH2:48][CH2:47][N:46]4[C:50](=[O:60])[C@@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[NH:42][C:41]=3[CH:61]=1)=[CH:31][CH:30]=2)=O)(C)(C)C.Cl.[CH3:63][O:64][C:65]([NH:67][C@H:68]([C:72]1[CH:77]=CC=C[CH:73]=1)[C:69](O)=[O:70])=[O:66].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C.C(O)C>[CH3:59][O:58][C:56]([NH:55][C@@H:51]([CH:52]([CH3:53])[CH3:54])[C:50]([N:46]1[CH2:47][CH2:48][CH2:49][C@H:45]1[C:43]1[NH:42][C:41]2[CH:61]=[C:37]([C:32]3[CH:33]=[C:34]4[CH2:35][O:36][C:23]5[CH:22]=[C:21]6[C:26]([CH:27]=[CH:28][C:18]7[N:17]=[C:16]([C@@H:9]8[CH2:10][C@H:11]([CH2:13][O:14][CH3:15])[CH2:12][N:8]8[C@@:68]([NH:67][C:65](=[O:66])[O:64][CH3:63])([CH:72]([CH3:77])[CH3:73])[CH:69]=[O:70])[NH:20][C:19]=76)=[CH:25][C:24]=5[C:29]4=[CH:30][CH:31]=3)[CH:38]=[CH:39][C:40]=2[N:44]=1)=[O:60])=[O:57]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3ccc4nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c4c3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3ccc4nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c4c3)ccc2-5)N([C@@](C=O)(NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
A solution of (2S,4S)-tert-butyl-2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (156 mg, 0.18 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60° C. for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to (68 mg, 0.09 mmol) of this material was added a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (21 mg, 0.12 mmol) and COMU (41 mg, 01 mmol) in DMF (1 mL). To the resulting solution was added diisopropylethylamine (50 μL, 0.28 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl {(2S)-2-[(2S,4S)-2-{9-[2-((2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (32 mg, 40%). MS (ESI) m/z 886 [M+H]f.
Reaction SMILES: O.[F:2][C:3]1[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:6]([O:7][C:8]2[C:9]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([N+:36]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:36][C:5]1[CH:4]=[C:3]([F:2])[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:6]=1[O:7][C:8]1[C:9]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 35 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a mixture of 17 g of an iron powder, 30 ml of acetic acid and 3 ml of water was added a solution of 17.28 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(ethoxycarbonyl)methoxypyridine [present compound 9-46] in 20 ml of acetic acid dropwise while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture was stirred for 1 hour at room temperature, for 3 hours at 40° C., then, the reaction solution was filtrated through Celite, and diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate solution, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. Then, the resulted residue was subjected to silica gel column chromatography to obtain 15.46 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(ethoxycarbonyl)methoxypyridine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:13][CH2:14][CH3:15].S([O-])(O)(=O)=O.[K+]>CCOCC.O>[C:20]([O:19][C:17]([NH:16][C@@H:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=[O:24])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CCCC[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mechanically stirred suspension of lithium aluminum hydride (5.00 g, 0.131 mol) in ether (250 mL) was cooled to −45“C under nitrogen. A solution of the product from Step A (28.3 g, 0.103 mol) in ether (125 mL) was added, maintaining the temperature below −35° C. when the addition was complete, the reaction was warmed to 5° C., then recooled to −45° C. A solution of potassium hydrogen sulfate (27.3 g, 0.200 mol) in water was slowly added, maintaining the temperature below −5° C. After quenching, the reaction was stirred at room temperature for 1 h. The mixture was filtered through Celite, the ether evaporated, and the remainder partitioned between ethyl acetate and 2% potassium hydrogen sulfate. After washing with saturated brine, drying over magnesium sulfate and solvent removal, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:8]=1)[NH2:5].Cl[C:19]1[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=1.O1CCOCC1.CS(O)(=O)=O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:6]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:8]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC1(C)OB(c2cc(N)cc(F)c2)OC1(C)C
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)OB(c2cc(F)cc(Nc3nccc(C(F)(F)F)n3)c2)OC1(C)C
Temperature: 100 °C
Yield: 76.4 %

Procedure:
To a flask containing 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.3 g, 14.00 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (2.94 g, 16.10 mmol) were added dioxane (44 mL) and methanesulfonic acid (1.55 g, 16.10 mmol) and the reaction was heated at 100° C. overnight. The reaction was cooled, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield. N-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (4.10 g, 10.70 mmol, 76% yield). MS ESI: [M+H]+ m/z 384. 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.85 (d, J=4.9, 1H), 7.92 (dt, J=2.3, 12.1, 1H), 7.77 (d, J=1.5, 1H), 7.32 (d, J=4.9, 1H), 6.98 (dd, J=2.2, 8.4, 1H), 1.28 (s, 12H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C:5]=1[C:20]1[N:24]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>CN(C=O)C>[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[N:6]([S:34]([CH3:33])(=[O:36])=[O:35])[C:5]=1[C:20]1[N:24]([C:25]2[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=2)[N:23]=[CH:22][CH:21]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)n(S(C)(=O)=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 48.2 %

Procedure:
Sodium hydride (12 mg of a 60% dispersion in mineral oil, 0.30 mmol) was added to a solution of 4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (94 mg, 0.23 mmol) in DMF (1.5 mL) under a nitrogen atmosphere. The mixture was stirred for 5 minutes and the resultant yellow solution was treated with methanesulfonyl chloride (32 mg, 21.4 μL, 0.28 mmol). The mixture was stirred for 2 h then treated with water and extracted with EtOAc. The organic phase was washed with water and brine then dried (sodium sulfate) and concentrated in vacuo. T he residue was purified by chromatography using silica gel eluting with 25%-60% ethyl acetate in cyclohexane. The product thus obtained was freeze-dried from acetonitrile-water to afford the title compound (54 mg) a white solid.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[NH:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[CH:3][CH:4]=1
Reactant: CN(C)C=CC(=O)c1ccco1
Reactant: N#CCC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(-c2ccco2)[nH]c1=O
Temperature: 130 °C
Reaction time: 21 h
Yield: 76.8 %

Procedure:
A suspension of 3-(dimethylamino)-1-(2-furyl)-2-propen-1-one (15.0 g, 90.9 mmol), 2-cyanoacetamide (8.5 g, 101 mmol) and potassium carbonate (38.0 g, 275 mmol) in dimethyl sulfoxide (80 ml) was stirred at 120 to 140° C. for 21 hours. After cooling as it was, the reaction mixture was diluted with water. After adjusting to pH 3 with conc. hydrochloric acid, the resulting solid was collected by filtration and washed with water, to give the title compound (13.0 g, 77%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]([CH3:35])([CH3:34])[CH2:25][NH:26]C(=O)OC(C)(C)C)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[NH2:26][CH2:25][C:24]([NH:23][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[NH:18][CH:19]=1)=[O:22])([CH3:35])[CH3:34]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CNC(=O)OC(C)(C)C)c3n2)c2ccc(Cl)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CN)c3n2)c2ccc(Cl)cc21
Yield: 55.3 %

Procedure:
tert-Butyl 2-(2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-2-methylpropylcarbamate (0.05 g, 0.1 mmol) in 30 mL of a saturated solution of HCl (g) in dioxane was stirred at room temperature for 2 hours. The solvent was removed and the residue was triturated with ethyl acetate, filtered and filter cake washed with saturated aqueous NaHCO3 and water successively to give N-(1-amino-2-methylpropan-2-yl)-2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (22 mg, 55%) as a yellow solid. MS: (M+H)+=398; 1H NMR (300 MHz, DMSO): δ 8.97 (s, 1H), 8.60 (d, 1H, J=8.7 Hz), 8.36 (s, 1H), 7.96 (s, 1H), 7.90 (s, 1H), 7.32 (d, 1H, J=8.7 Hz), 4.17 (s, 3H), 2.90 (s, 2H), 1.30 (s, 6H).
Reaction SMILES: OC1C=CC(/C=C/C[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.Br[CH:33]([CH3:42])[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>>[C:34]([CH:33]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)[CH3:42])(=[O:35])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Product: CC(C(=O)c1ccccc1)N1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-bromopropiophenone to produce the above.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:13][C:14]([F:37])([F:36])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=2[N+:33]([O-:35])=[O:34])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([N:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:36])[F:37])=[CH:21][CH:20]=1)[S:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=1[N+:33]([O-:35])=[O:34])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: O=[N+]([O-])c1ccc(SNc2ccc(OC(F)(F)F)cc2)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N(Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccc(OC(F)(F)F)cc1)c1ccccc1Cl
Temperature: -5 °C
Reaction time: 144 h

Procedure:
A solution of 3.6 g of 2-chlorobenzoyl isocyanate in 20 ml of dry toluene was added to a stirred solution of 3.75 g of N-[4-(trifluoromethoxy)phenyl]-2,4-dinitrobenzenesulphenamide in 30 ml of the same solvent at room temperature. After 6 days, the reaction mixture was cooled to -5° C. and filtered, washed with cold toluene and with cold light petroleum (b.p. 40°-60° C.) to give 2, as pale yellow crystals, m.p.: 184°-186° C. (with decomposition).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[C:24]([C:26]([NH2:28])=O)[S:25][C:17]3=4)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[C:24]([C:26]#[N:28])[S:25][C:17]3=4)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: NC(=O)c1sc2c(ccc(=O)n2-c2ccc(OCCN3CCOCC3)cc2)c1-c1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1sc2c(ccc(=O)n2-c2ccc(OCCN3CCOCC3)cc2)c1-c1ccccc1
Reaction time: 0.08 h
Yield: 59.1 %

Procedure:
To a solution of the compound of Example 104 (128 mg, 0.27 mmol) in dry DCM (1.5 mL) was added pyridine (44 μL, 0.54 mmol) followed by trifluoroacetic anhydride (46 μL, 0.32 mmol). TLC showed the reaction was complete after 5 minutes and the reaction was then diluted with DCM (20 mL) and washed with 2M NaOH(aq) (20 mL). The DCM layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was co-evaporated with toluene (2×15 mL) to give the title compound as a solid (73 mg). δH (CDCl3) 7.62 (1H, d, J 9.7 Hz), 7.51–7.45 (5H, m), 7.29–7.26 (2H, m), 7.08–7.04 (2H, m), 6.62 (1H, d, J 9.7 Hz), 4.14 (2H, t, J 5.6 Hz), 3.71–3.68 (4H, m), 2.81 (2H, t, J 5.6 Hz), 2.58–2.54 (4H, m). LCMS (ES+) RT 2.47 minutes, 458 (M+H)+.