Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.NN.C(Cl)Cl>C(O)C>[F:1][C:2]1([CH2:8][NH2:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1CC1(F)CCOCC1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: NCC1(F)CCOCC1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 409B (1.4 g) and hydrazine (1.548 mL) in ethanol (40 mL) was heated at 70° C. overnight, cooled to room temperature, slurried with CH2Cl2 (200 mL) and the solid removed by filtration. The filtrate was concentrated and chromatographed on silica gel with 100:5:1 ethyl acetate/methanol/NH4OH as eluent to give the product.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25].C(O[K])(C)(C)C>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:23][C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: O[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: O=C(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of trans-4-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]cyclohexanol (311 mg), 4-(chloroacetyl)morpholine (532 mg) and tert-butoxy potassium (365 mg) in THF (5 mL) was stirred at room temperature overnight and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (427 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[C:10]([C:16](=[O:18])[CH3:17])[C:11]([O:13]CC)=O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:16]([C:10]1[C:11](=[O:13])[C:4]2[C:3](=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[NH:8][CH:9]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)C(=CNc1ccccc1Br)C(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)c1c[nH]c2c(Br)cccc2c1=O
Temperature: 250 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To Dowtherm (20 ml) at apx 200° C. was added solid ethyl 2-(((2-bromophenyl)amino) methylene)-3-oxobutanoate (3 g, 9.61 mmol). The reaction was heated to 250° C. and stirred for 1 h. LCMS showed consumption of starting material and formation of desired product along with an unknown biproduct of lower mass. The reaction was allowed to cool to room temperature and was them poured into 150 mL of hexanes. The mixture was stirred for 15 min, then the precipitate was collected by filtration and dried to afford 3-acetyl-8-bromoquinolin-4(1H)-one (1.77 g, 6.65 mmol, 69.2% yield) as a light brown solid. LCMS: (M+H)+: 265.9.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([C:10]2[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=2)=[C:4]([F:22])[CH:3]=1.Br.O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:10]2[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 140 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A mixture of 2.04 g of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-144) and 35 ml of 48% hydrobromic acid was dissolved in 12 ml of acetic acid, and the solution was stirred at 140° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate solution, water, and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 1.55 g (yield, 79%) of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-61; m.p., 188.1° C.).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH2:8][CH3:9])[NH:4][C:3]=1[C:10]([OH:12])=O.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]([C:26]([NH2:28])=[O:27])=[CH:24][N:25]=2)[CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH2:8][CH3:9])[NH:4][C:3]=1[C:10]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]([C:26]([NH2:28])=[O:27])=[CH:24][N:25]=2)[CH2:17][CH2:16]1)=[O:12]
Reactant: CCc1[nH]c(C(=O)O)c(Cl)c1Cl
Reactant: NC(=O)c1cnc(N2CCC(N)CC2)s1
Agent: Cl
Product: CCc1[nH]c(C(=O)NC2CCN(c3ncc(C(N)=O)s3)CC2)c(Cl)c1Cl

Procedure:
Title compound was synthesized by an analogous method to Example 29 by coupling 3,4-dichloro-5-ethyl-1H-pyrrole-2-carboxylic acid (Intermediate 73) with 2-(4-aminopiperidin-1-yl)-1,3-thiazole-5-carboxamide hydrochloride (Intermediate 81).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>C(O)C.O>[OH:3][NH:2][C:17](=[NH:18])[C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc([N+](=O)[O-])cc1
Temperature: 85 °C
Yield: 97.4 %

Procedure:
Hydroxylamine hydrochloride (1.9 g, 27.2 mmol) then sodium carbonate (2.2 g, 20.4 mmol) were added to a stirred solution of 4-nitro-benzonitrile (1 g, 6.8 mmol) in ethanol (20 mL) and water (8 mL). The resulting mixture was refluxed at 85° C. under an atmosphere of nitrogen for 2 hours. The volatiles were then evaporated and the residue was extracted with ethyl acetate. The organics were washed with brine solution, dried over Na2SO4 and evaporated to afford 1.2 g (98%) of N-hydroxy-4-nitro-benzamidine. 1H NMR: (DMSO-d6): δ 10.2 (s, 1H), 8.24 (d, 2H), 7.97 (d, 2H), 6.03 (s, 2H).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9](=[O:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH:6]=1>C1COCC1>[Br:4][C:5]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9]([CH3:1])([OH:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH:6]=1
Reactant: O=c1c2ccccc2cc(Br)c2ccncc12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)c2ccccc2C=C(Br)c2ccncc21
Reaction time: 22 h

Procedure:
Methyl magnesium bromide (27.6 ml., 2.9 M in ether) is added dropwise to a solution of 5-bromobenzo[5,6]cyclohepta[1,2-c]pyridin-11-one (20.02 g., 0.07 mol) in dry THF (300 ml.) with cooling. When addition is complete, the cooling bath is removed and the mixture is stirred for 20-24 hours. The solvent is removed in vacuo, the residue is taken up in water (300 ml.) and acidified by the addition of acetic acid. The solid that forms is collected, washed with water then recrystallized from 2-propanol to give 16.25 g., m.p. 226.5°-229.5° C.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2NC(=S)N2CCN(C)CC2)CC1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a stirred solution of 90 g of 2-tert-butyl-6-isothiocyanato-5-(4-methylpiperidin-1-yl)benzothiazole in 900 ml of methylene chloride is added dropwise 26 g of N-methylpiperazine. The solution is stirred for 1 hour, washed with water, dried over anhydrous sodium sulphate and evaporated to give 110 g of 2-tert-butyl-6-[(4-methylpiperazin-1-yl)thiocarbonylamino]-5-(4-methylpiperidin-1-yl)benzothiazole, melting at 192°-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:32]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)([O:15][CH3:32])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCC[C@@](OC)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C

Procedure:
To a mixture of (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-piperidine-1-carboxylate (0.1874 g, 0.45 mmol, 1.0 equiv) and 60% NaH in oil (0.345 g, 8.6 mmol, 19 equiv) in THF (15 mL) was added iodomethane (1.195 g, 8.4 mmol, 18.5 equiv). The resulting mixture was heated at 70° C. for 16 h and then quenched with water, extracted with EtOAc and dried over Na2SO4. After the solvent was removed, the crude (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1,5-dimethoxypentyl)piperidine-1-carboxylate (0.3175 g) was used in the next step without further purification. LC-MS (3 min) tR=2.44 min m/z 450, 448 (M+Na+), 426 (M+H+), 340, 338, 294.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][C:8]1O[C:10](=O)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)([O-:3])=[O:2].C(=O)(O)O.[NH2:26][NH:27][C:28]([NH2:30])=[NH:29]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][C:8]1[N:26]2[N:27]=[C:28]([NH2:30])[N:29]=[C:10]2[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)([O-:3])=[O:2]
Reactant: N=C(N)NN
Reactant: O=c1oc(Cc2cccc([N+](=O)[O-])c2)nc2ccccc12
Agent: O=C(O)O
Solvent: c1ccncc1
Product: Nc1nc2c3ccccc3nc(Cc3cccc([N+](=O)[O-])c3)n2n1
Temperature: 180 °C
Yield: 30 %

Procedure:
To a solution of commercially available (3-nitro-phenyl)-acetyl chloride (2.20 g, 11.05 mmol) in anhydrous DCM (9 mL) was added 2-aminobenzoic acid (0.76 g, 5.50 mmol). Pyridine (3 mL) was then added to the mixture and the reaction mixture was heated under microwave condition at 120° C. for 30 minutes, then diluted with dichloromethane and washed with NaHCO3 satured solution, then with water followed by brine. The organic phase was dried over Na2SO4, filtered and evaporated to give the 2-(3-nitro-benzyl)-benzo[d][1,3]oxazin-4-one intermediate as red oil. To a solution of 2-(3-nitro-benzyl)-benzo[d][1,3]oxazin-4-one in dry pyridine (10 mL) was added aminoguanidine hydrogencarbonate (0.90 g, 6.60 mmol) and the mixture was heated under microwave condition at 180° C. for 20 minutes. The solvent was then evaporated and the crude was purified by flash column chromatography on silica gel eluting with DCM/CH3OH 95/5 to afford the title compound as orange solid (0.35 g, 30% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][S:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>>[CH3:18][S:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:22][CH:21]=1
Reactant: CSc1ccc(C(=O)O)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CSc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 57.2 %

Procedure:
Beginning with 20.0 mg (0.087 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 44.0 mg (0.131 mMol) 4-(methylthio)benzoic acid, 18.9 mg (57.1%) of the title compound were recovered.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:13]=[C:14]([C@H:19]2[NH:24][C:23](=O)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20]2)[CH:15]=[C:16]([F:18])[CH:17]=1>C1(C)C=CC=CC=1.C1COCC1>[F:18][C:16]1[CH:15]=[C:14]([C@@H:19]2[CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][NH:24]2)[CH:13]=[C:12]([F:11])[CH:17]=1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
7.0 mL (7.0 mmol) of a 1 molar di-isobutyl-aluminium hydride solution in toluene were added to 0.48 g (2.0 mmol) (S)-6-(3,5-difluorophenyl)-3,3-dimethylpiperidin-2-one in 10 mL THF while cooling with ice and stirred for 20 h at RT. Then the reaction mixture was refluxed for 8 h. A 1M diisobutylaluminium hydride solution in toluene was added twice more and the mixture was refluxed for 8 h and 24 h in each case. After hydrolysis of the reaction mixture the precipitate formed was suction filtered and washed with THF. The filtrate was evaporated down and the residue was purified by flash chromatography (aluminium oxide).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)([O-:3])=[O:2].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[C:34]([NH2:36])[C:33]([NH2:37])=[CH:32][C:31]=2[F:38])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CO>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:30]2[C:31]([F:38])=[CH:32][C:33]3[N:37]=[C:15]([C:5]4[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH:9]5[CH2:14][CH2:13][CH2:12][CH2:11][O:10]5)[N:6]=4)[NH:36][C:34]=3[CH:35]=2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)c(N)cc2F)CC1
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4[N+](=O)[O-])nc3cc2F)CC1
Temperature: 22 °C
Reaction time: 16 h
Yield: 26.6 %

Procedure:
0.9 g of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde is added to a solution of 1.2 g of 4-(4,5-diamino-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester in 30 mL of methanol. The reaction medium is stirred at 22° C. for 16 hours. After evaporation, the reaction crude is purified by flash chromatography, elution being carried out with a mixture of dichloromethane/acetone. 530 mg of 4-{6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester are isolated in the form of a red foam. 1H NMR (400 MHz, DMSO-d6, δ in ppm): from 1.35 to 2.25 (m, 6H); 1.43 (s, 9H); 3.03 (m, 4H); 3.52 (m, 4H); 3.72 (m, 1H); 4.00 (m, 1H); 5.65 (dd, J=2.0 and 10.0 Hz, 1H); 7.31 (d, J=8.0 Hz, 1H); 7.54 (d, J=12.0 Hz, 1H); 9.17 (s, 1H). ES mass spectrum: m/z=516 MH+ (base peak).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH3:23].O>CS(C)=O>[NH2:23][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: N
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N
Temperature: 90 °C
Yield: 79.3 %

Procedure:
A mixture of 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (0.30 g, 1.01 mmol) and ammonia (4.05 mL, 8.10 mmol) in DMSO (5 mL) was heated at 90° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, treated with water, and extracted with DCM (3×). The extracts were dried over Na2SO4, concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give 2-(3-amino-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (445a, 235 mg, 79%). m/z (ESI, +ve) 294 (M+H)+. A mixture of 2-(3-amino-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (445a, 50 mg, 0.17 mmol) and Ac2O (0.016 mL, 0.17 mmol) in pyridine (2 mL) was heated at 50° C. for 16 h. It was concentrated under reduced pressure. The residue was purified by reverse phase HPLC. The pure fractions were combined and concentrated to dryness. The solid was dissolved in MeOH and neutralized by pass through Stratosphere SPE (PL-HCO3 MP-Resin) to give N-(3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)acetamide as a tan solid (445) (10 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.21 (1H, br. s.), 10.22 (1H, s), 8.07-8.20 (1H, m), 7.71 (1H, dd, J=8.2, 1.2 Hz), 7.63 (1H, t, J=7.8 Hz), 7.09 (1H, d, J=2.3 Hz), 6.99 (1H, br. s.), 3.41-3.51 (2H, t, J=6.8 Hz), 2.94 (2H, t, J=6.8 Hz), 2.75 (3H, s), 2.36 (3H, s). m/z (ESI, +ve) 336 (M+H)+.
Reaction SMILES: [C:1]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]>C(O)C.O1CCOCC1.[C].[Pd]>[C:1]([NH:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)NNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)NNc1ccc(N)cc1
Yield: 96.4 %

Procedure:
Then, 25.3 g of the resulting 1-ethoxalyl-2-(p-nitrophenyl)hydrazine was dissolved in a mixed solvent of 300 ml ethanol and 200 ml dioxane. To the solution was added 20 g of 10% palladium-carbon to carry out catalytic reduction in the conventional manner to obtain 21.5 g of 1-ethoxalyl-2-(p-aminophenyl)hydrazine. m.p. 97°-99° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:5]([N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3([CH3:35])[CH2:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)[CH3:8])=[O:6].C1(P([CH:53]2[CH2:58][CH2:57]CCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O>[Cl:39][C:38]1[CH:37]=[CH:36][C:4]([C:5]([N:7]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH2:12][N:11]([C:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C:32]4([CH3:35])[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:10]2)[CH3:8])=[O:6])=[CH:3][C:2]=1[CH:57]1[CH2:58][CH2:53]1
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C(=O)c1ccc(Cl)c(C2CC2)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 821.9 %

Procedure:
To a solution of 3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzamide (78 mg, 0.12 mmol) in toluene (1 mL) and water (0.048 mL) was added under an atmosphere of nitrogen potassium phosphate, tribasic mono hydrate (88 mg, 0.42 mmol), tricyclohexylphosphine (4 mg, 0.014 mmol) palladium(II) acetate (2 mg, 0.009 mmol). The reaction mixture was stirred for 18 h at 80° C. under an atmosphere of nitrogen. It was concentrated and purification by chromatography (SiO2, ethyl acetate:methanol=100:0 to 85:15) afforded the title compound (71 mg, 97%) as a light brown foam. MS m/e: 616.2 [M]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37]>>[NH2:1][C:2]1[C:7]2=[C:8]([C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cccc(C(=O)NCc4ccccc4)c3)c12
Reactant: CN(C)CC(=O)O
Product: CN(C)CC(=O)N1CCC(c2cc(-c3cccc(C(=O)NCc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 18 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 342 and using 3-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-benzylbenzamide and N,N-dimethylglycine as starting material, 10 mg (18%) of the desired product was isolated. 1H NMR (400 MHz, CO3OD) δ 7.98 (s, 1H), 7.85 (d, 1H), 7.82 (s, 1H), 7.62 (d, 1H), 7.55 (t, 1H), 7.36-7.28 (m, 4H), 7.25-7.20 (m, 1H), 6.57 (s, 1H), 4.62-4.57 (m, 3H), 4.18-4.14 (m, 1H), 3.51-3.42 (m, 1H), 3.31-3.16 (m, 5H), 2.82-2.78 (m, 1H), 2.29 (s, 6H), 2.19-2.11 (m, 2H), 1.78-1.59 (m, 2H); 512.3, LC-MS m/z [M+H]+ 512.3, RT 1.96 min.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:16][CH3:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:39][CH3:40])[C:22]([Cl:41])=[CH:21][N:20]=1>>[Cl:41][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:39][CH3:40])=[N:24][C:19]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:16][CH3:17])=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)c2OC
Yield: 31.4 %

Procedure:
Following a procedure analogous to 101b, 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (46 mg) and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine (60 mg) were reacted to give 7-{5-Chloro-4-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-2-ylamino}-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (29 mgs, 26%) as an off-white solid. 1H-NMR (CDCl3, 400 MHz): δ 8.27 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.6 Hz, 1H), 8.06 (s, 1H), 7.55 (s, 1H), 7.40 (s, 1H), 6.94 (d, J=8.9 Hz, 1H), 6.59-6.55 (m, 2H), 3.93 (s, 3H), 3.85-3.81 (broad m, 2H) 3.80 (s, 3H), 3.26-3.23 (m, 4H), 2.65-2.63 (M, 4H), 2.39 (s, 3H), 2.32 (broad s, 2H), 1.74 (broad s, 4H), 1.22 (t, J=6.1 Hz, 3H); LC/MS Found (M+H)+=565.98; MP: 186-187° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:14]([NH2:19])[C:15]([NH2:18])=[N:16][N:17]=1)=[CH:7][CH:6]=2.[CH:20]([CH:22]=O)=O.C(O)(=O)C>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:14]3[N:19]=[CH:20][CH:22]=[N:18][C:15]3=[N:16][N:17]=1)=[CH:7][CH:6]=2
Reactant: O=CC=O
Reactant: Nc1nnc(Cc2ccc3ncc(Br)cc3c2)n1N
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc2ccc(Cc3nnc4nccnn34)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(3-bromo-quinolin-6-ylmethyl)-[1,2,4]triazole-3,4-diamine (977 mg, 3 mmol), glyoxal (40% solution in water, 5 mL), acetic acid (10 mL) and water (2 mL) was stirred at ambient temperature for 18 hours. After such time the mixture was filtered and the filtrate was concentrated onto silica gel and via flash column chromatography (SiO2 12 g, dichloromethane/CH3OH, 0-10%) to return the title compound a white solid (298 mg, 29%). Analytical data presented in Table 1.