Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[CH2:11]1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O.[OH2:26]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([OH:9])=[C:6]([C:7]=1[F:8])[CH:11]=[O:26]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: Cc1cc(F)c(F)cc1O
Reactant: O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)c(F)c(C=O)c1O
Temperature: 98.5 °C
Reaction time: 2 h

Procedure:
30 g of 4,5-difluoro-2-methylphenol are dissolved in 180 ml of trifluoroacetic acid and admixed with 57.2 g of hexamethylenetetramine in portions. On completion of addition, the reaction solution is heated to 97-100° C. for 4 hours. After cooling, first 60 ml of 50% sulphuric acid and then 300 ml of water are added dropwise, then the solution is stirred further at room temperature for 2 hours. The reaction solution is extracted three times with methyl tert-butyl ether. The combined extracts are washed once with water and dried, and the solvent is distilled off under reduced pressure. The residue is extracted repeatedly with n-hexane, the extracts are combined and the solvent is distilled off under reduced pressure. 12.5 g (33% of theory) of a bright yellow solid are obtained having a melting point of 53-56° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=4[N:18](C(C)=C)[C:17]3=[O:29])[CH2:9][CH2:8]2)[C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[NH:3]1.[ClH:34].O>C(O)C>[OH2:1].[ClH:34].[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=4[NH:18][C:17]3=[O:29])[CH2:9][CH2:8]2)[C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[NH:3]1
Reactant: C=C(C)n1c(=O)n(CCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccc(C)cc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 6 parts of 1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 12 parts of a hydrochloric acid solution, 30 parts of water and 40 parts of ethanol is stirred first for a while at 50° C and further for 1 hour at room temperature. The reaction mixture is evaporated and the residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol. The product is filtered off and dried, yielding 3.7 parts (40%) of 1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-2H-benzimidazol-2-one hydrochloride hydrate; mp. 251.4° C.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)#[N:4].[CH3:11][CH:12](I)[CH3:13].O>CN(C)C=O.C(Cl)(Cl)Cl>[C:3]([CH2:5][C:6]1[N:7]=[CH:8][N:9]([CH:12]([CH3:13])[CH3:11])[CH:10]=1)#[N:4]
Reactant: N#CCc1c[nH]cn1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)n1cnc(CC#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
450 mg of sodium hydride (60%) was added to 5 ml of dimethylformamide, and a solution of 1.0 g of 4-cyanomethylimidazole in 10 ml of dimethylformamide was added dropwise to the resulting suspension. After 1 hour of stirring at room temperature, 0.94 ml of 2-propyl iodide was added to the resulting solution and stirred at room temperature for 2 hours. To the reaction solution was added water and chloroform, and the resulting organic layer was collected and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue was subjected to silica gel column chromatography eluted with chloroform-methanol (30:1) to obtain 500 mg of 4-cyanomethyl-1-(2-propyl)imidazole.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.Cl[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1>>[Cl-:11].[NH2:1][C:2]1[N:6]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:5]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:4]=2[N+:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1
Reactant: Cc1cccc(OCCl)c1
Reactant: Nc1nc2c(Cl)cccc2[nH]1
Product: Cc1cccc(OCn2c(N)[n+](COc3cccc(C)c3)c3cccc(Cl)c32)c1
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-7-chlorobenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 3-methylphenyl chloromethyl ether, the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25]=O)=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl.[NH2:28][OH:29].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:25]=[N:28][OH:29])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(C=NO)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of dimethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.6 g), hydroxylamine hydrochloride (764 mg) and sodium acetate (1.06 g) in acetic acid (20 ml) was stirred at room temperature for 45 minutes to form dimethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. To the reaction mixture was added acetic anhydride (3.37 g) and the mixture was stirred at room temperature for 15 minutes and then heated at 100° C. for 3 hours with stirring. After removal of the acetic acid, the residue was adjusted to pH 7.5 with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed twice with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resultant oil (3.80 g) was chromatographed on a column of silica-gel (110 g) and eluted with a mixture of benzene and ethyl acetate (9:1, v/v) to give crystals (2.05 g), which were recrystallized from a mixture of ethyl acetate (12 ml) and n-hexane (6 ml) to give yellow granules of dimethyl 2-methyl-4-(2-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate (1.19 g), mp 170.5° to 171.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]([CH:28]5[CH2:30][CH2:29]5)[OH:27])=[C:20]([O:31][CH3:32])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(N=C=NC(C)C)(C)C.C(OC([NH:49][C@H:50]([C:54](O)=[O:55])[CH:51]([CH3:53])[CH3:52])=O)(C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH2:49][C@@H:50]([CH:51]([CH3:53])[CH3:52])[C:54]([O:27][C@H:26]([CH:28]1[CH2:29][CH2:30]1)[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15]3[S:16][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:9][C:10]=3[N:11]=[CH:12]2)=[CH:19][C:20]=1[O:31][CH3:32])=[O:55]
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC[C@H](O)C1CC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC[C@H](OC(=O)[C@@H](N)C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of (R)-6-(4-chlorophenyl)-3-(4-(2-cyclopropyl-2-hydroxyethoxy)-3-methoxyphenyl)-thieno[3,2-d]pyrimidin-4(3H)-one described in Example 1 (1.3 g, 2.33 mmol), diisopropylcarbodiimide (0.88 g, 6.99 mmol), 4-dimethylaminopyridine (142 mg, 1.16 mmol) and N-(t-butoxycarbonyl)-L-valine (1.52 g, 6.99 mmol) in CH2Cl2 (10 mL) was stirred at rt for 19 h. By LCMS analysis no starting alcohol remained. The suspension was diluted with CH2Cl2 and washed with aq NaHCO3. After extracting the aqueous layer with CH2Cl2, the combined organic layers were washed sequentially with water and brine, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAC/hexane 0 to 40% gradient) to afford the title compound (1.12 g) as a white solid. 1H NMR (CDCl3) δ 0.41-0.46 (m, 1H), 0.49-0.53 (m, 1H), 0.58-0.63 (m, 1H), 0.64-0.68 (m, 1H), 0.925 (d, J=7 Hz), 3H), 0.99 (d, J=7 Hz), 1.16-1.19 (m, 1H), 1.44 (s, 9H), 2.19-2.23 (m, 1H), 3.86 (s, 3H), 4.23-4.32 (m, 3H), 4.67-4.71 (m, 1H), 5.06 (d, J=2 Hz, 1H), 6.92-6.95 (m, 2H), 7.04 (d, J=2 Hz, 1H), 7.26 (s, 2H), 7.45 (d, J=2 Hz), 7.54 (s, 1H), 7.66 (d, J=2 Hz, 2H), 8.16 (s, 1H). LCMS (ES): m/z 669 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:7]=1[Cl:8].[NH2:16][NH2:17]>>[Cl:8][C:7]1[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:5][N:4]=[N:3][C:2]=1[NH:16][NH2:17].[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:7]=1[NH:16][NH2:17]
Reactant: NN
Reactant: Cc1ccc(-c2cnnc(Cl)c2Cl)cc1
Product: Cc1ccc(-c2cnnc(Cl)c2NN)cc1
Product: Cc1ccc(-c2cnnc(NN)c2Cl)cc1
Temperature: 60 °C
Yield: 162.3 %

Procedure:
To a stirring suspension of 3,4-dichloro-5-p-tolylpyridazine (4.5 g, 18.9 mmol) in 2-BuOH (200 mL) at room temperature was added anhydrous hydrazine (9.1 g, 284 mmol). The reaction mixture was heated at 60° C. under argon. HPLC/MS analysis indicated complete reaction after 15 h. The reaction mixture was cooled to 0° C., and the product was collected by filtration and further washed with ice-cold 2-propanol (20 mL×2). After drying under vacuum at room temperature for 16 h, the title compound, 1-(4-chloro-5-p-tolylpyridazin-3-yl)hydrazine, was obtained in a 2.6:1 ratio with undesired 1-(3-chloro-5-p-tolylpyridazin-4-yl)hydrazine (3.6 g gross). 1-(4-chloro-5-p-tolylpyridazin-3-yl)hydrazine MS [M+H]+ 235; HPLC retention time=1.84 min. 1-(3-chloro-5-p-tolylpyridazin-4-yl)hydrazine MS [M+H]+ 235; HPLC retention time=1.35 min.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[N:3]1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:2]([O:1][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1-c1ccn(O)n1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1ccc(-c2ccccc2[N+](=O)[O-])n1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(2-nitrophenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (94%, oil).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[C:18]([C:24]([O:26]C)=[O:25])[CH2:19][C:20]([O:22]C)=[O:21].C[N+]1([O-])CC[O:32]CC1.O.OS([O-])=O.[Na+]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O.CC(C)=O>[C:24]([C@:18]1([OH:32])[C@H:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[O:21][C:20](=[O:22])[CH2:19]1)([OH:26])=[O:25]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC(=O)CC(=CCCCCCCCCc1ccc(Cl)cc1Cl)C(=O)OC
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC(C)=O
Product: O=C1C[C@](O)(C(=O)O)[C@H](CCCCCCCCc2ccc(Cl)cc2Cl)O1
Temperature: 25 °C
Reaction time: 64 h
Yield: 91.4 %

Procedure:
A mixture of (E) methyl 12-(2,4-dichlorophenyl)-3-methoxycarbonyl-3-dodecenoate (1.50 g, 3.61 mmol), osmium tetroxide (0.229 ml of a 2% solution in t-butanol, 0.018 mmol), N-methylmorpholine-N-oxide (634 mg, 5.42 mmol), water (2 ml), and acetone (2 ml) was stirred at room temperature for 64 h. Aqueous NaHSO3 (1.1M, 6 ml) was added, and the mixture filtered, after 20 min, through a plug of silica gel. The silica gel plug was washed with ether, then the filtrate washed with aqueous HCl, water, and saturated aqueous NaCl. After drying (MgSO4), the solvent was removed under vacuum, and the residue purified by chromatography on silica gel (50-100% ether/petroleum ether 40°-60° C.) to give the title compound (1.33 g), contaminated with the 5-ring lactone.
Reaction SMILES: CI.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[OH:13].[C:14]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[O:13][CH3:14]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(F)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1c(F)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
MeI (27.1 g, 191 mmol) was added dropwise to the suspension of 2-fluoro-6-nitrophenol (25.0 g, 159 mmol) and K2CO3 (44.0 g, 318 mmol) in 200 mL of DMF. The mixture was stirred overnight at 25° C. then warmed to 60° C. and stirred for 3 hours. The mixture was diluted with 1 L of EtOAc and washed with water (3×100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated to afford the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([O:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7](=[O:17])[CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.C1C=C(Cl)C=C(C(OO)=[O:46])C=1.[OH2:49]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([O:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:7](=[O:17])[CH2:8][S:9]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)(=[O:46])=[O:49]
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CSc1ccc(F)cc1)N(CCCCBr)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(CS(=O)(=O)c1ccc(F)cc1)N(CCCCBr)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
N-(4-Bromo-butyl)-2-(4-fluoro-phenylsulfanyl)-N-trityloxy-acetamide from step D (105.2 mg, 0.182 mmol) and mCPBA (max. 77%, 0.21 g) in CH2Cl2 was stirred at room temperature for 30 min. The reaction was diluted with CH2Cl2 and water. The organic layer was sequentially washed with saturated Na2CO3 solution, 10% aqueous Na2SO3 and saturated Na2CO3 solution again. The organic phase was then dried and concentrated under the reduced pressure and purified by a column chromatography (0˜30% EtOAc in hexane). MS: 632.0, (M+Na)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[CH3:17]I.[H-].[Na+].O>CN(C)C=O>[CH3:17][O:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1
Reactant: CI
Reactant: COC(=O)c1ccc(CO)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc(C(=O)OC)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a solution of methyl 4-(hydroxymethyl)-1-naphthalenecarboxylate (1.0 g, 4.62 mmol) in N,N-dimethylformamide (10 ml) was added methyl iodide (1 ml), and sodium hydride (222 mg, 5.55 mmol, 60% in oil) was further added at 0° C., and the mixture was stirred at room temperature for 10 min. To the reaction solution was added water (30 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1-10:1) to give methyl 4-((methyloxy)methyl)-1-naphthalenecarboxylate (898 mg, 84%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:27]#[N:28].[NH4+].[Cl-]>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[N:36]1[CH2:35][CH2:34][CH:33]([O:32][C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:23])[CH2:38][CH2:37]1
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: N#Cc1ccc(OC2CCNCC2)c(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 2,3-dichloropyrido[3,4-b]pyrazine (1.00 g, 5.00 mmol) in DCM (10.0 mL) at 0° C. was added DIPEA (2.62 mL, 15.00 mmol) and 3-fluoro-4-(piperidin-4-yloxy)benzonitrile hydrochloride (1.283 g, 5.00 mmol). The reaction mixture was stirred for 30 min, warming gradually to room temperature. The reaction mixture was treated with saturated aqueous NH4Cl. The organic layer containing yellow solid was collected and concentrated under reduced pressure. The solid was filtered, washing with water, and was lyophilized overnight to give the title compound as a yellow solid (1.325 g, 69%). ESI-MS m/z [M+H]+ 384.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: Cc1cc(F)ccc1-c1nc(OCCNC(=O)OC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)ccc1-c1nc(OCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 130 (1 g, 1.9 mmol) was dissolved in CH2Cl2 (8 mL) and stirred under Ar in an ice bath. A chilled solution of 25% TFA in CH2Cl2 (40 mL) was added, and the mixture was stirred for 45 min at 0° C. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and a saturated NaHCO3 solution. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-10% MeOH/CH2Cl2 gave the title compound as a white-amorphous solid. mp 96-99°, LC MS m/z=427 (MH+). Retention time=1.52 min.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:14]([CH2:32][CH2:33][CH2:34][Cl:35])[C:15]2[C:20]([C:21]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[Cl:35][CH2:34][CH2:33][CH2:32][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)[C:21]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:13]1[C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccn3C(=O)OC(C)(C)C)n(CCCCl)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc[nH]3)n(CCCCl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of methyl 2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-1-(3-chloropropyl)-3-cyclohexyl-1H-indole-6-carboxylate (167 mg, 0.344 mmol) in chloroform (1.5 ml) was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was evaporated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 1-(3-chloropropyl)-3-cyclohexyl-2-(1H-pyrrol-2-yl)-1H-indole-6-carboxylate (135 mg, yield 98%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[O:16][CH3:15])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COc1ccccc1C=CC(=O)O
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccccc3OC)nc2n(CC)c1=O
Yield: 23.1 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.48 g (13.9 mmol) of 2-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 990 mg (yield 24%) of Compound 108 as yellow grains.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:13].NN>CO.O.O.O.O.O.O.[Fe](Cl)Cl>[NH2:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:13])[C:2]=1[OH:1])[C:6]#[N:7]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1O
Agent: Cl[Fe]Cl
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cc(C#N)cc(N)c1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
Iron chloride hexahydrate (9.6 mg), 4-hydroxy-3-methyl-5-nitrobenzonitrile (126 mg), and 77 mg of activated carbon were suspended in 5 ml of methanol and heated under N2 at 70° C. for 10 min. Hydrazine (0.11 ml) was then added slowly and the mixture was stirred for 2 h at 70° C. The mixture was then cooled to room temperature and filtered through a plug of Celite, eluting with methanol. The eluent was concentrated in vacuo and the residue was purified on a 2×1500 micron preparative TLC plate, eluting with ethyl acetate (Rf=0.24), to provide 101 mg (96%) of the title compound. Mass spectrum (ESI) 150.1 (M+1). 1H NMR (500 MHz, CDCl3): □ 6.93 (s, 1H), 6.91 (s, 1H), 5.21 (bs, 1H), 3.76 (bs, 2H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[C:13](O)(=O)[CH3:14].[C:17](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:18].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH:13]1([CH2:14][NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])[CH2:18][CH2:17]1
Reactant: CC(=O)O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
A 5 L vessel was charged 4-methoxy-2-nitroaniline (160 g, 952 mmol) in dichloromethane (2.44 L). The mixture was cooled to 10° C. and cyclopropanecarboxyaldehyde (100 g, 143 mmol) was added in four 25 gram portions. The vessel was charged with acetic acid (300 ml, 523 mmol) via an addition funnel over 20 minutes. After 45 minutes, the vessel was charged with sodium triacetoxyborohydride (444 g, 209 mmol) portionwise. The mixture was warmed to ambient temperature over 4 hours and stirred for an additional 14 hours. The mixture was treated with saturated aqueous sodium bicarbonate (100 mL) and poured into sodium bicarbonate (4 L) and dichloromethane. The organic extract was concentrated in vacuo, providing the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=O)=[CH:31][CH:30]=1)[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:10]1([CH2:9][N:8]2[C:7]3[CH:6]=[CH:5][C:4]([NH:13][C:14](=[O:16])[CH3:15])=[CH:3][C:2]=3[N:1]=[C:36]2[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=2)[CH2:11][CH2:12]1
Reactant: CCOc1ccc(CC(=O)O)cc1
Reactant: CC(=O)Nc1ccc(NCC2CC2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Cc2nc3cc(NC(C)=O)ccc3n2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
Following procedure 13B, N-{3-amino-4-[(cyclopropylmethyl)amino]phenyl}acetamide (5.50 g, 25.11 mmol), DIPEA (6.50 ml, 37.5 mmol), 4-ethoxyphenylacetic acid (5.40 g, 30.0 mmol) and HATU (11.40 g, 30.0 mmol) in DMF (100 ml) were stirred at room temperature overnight. Isolated the desired product (4.5 g, 86%).