Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[N+]([C:19]1[CH:20]=C2C(=[CH:27][CH:28]=1)C(=O)C=CC2=O)([O-])=O>O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[C:7]1[CH2:20][CH2:19][CH2:28][CH2:27][C:8]=1[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=C1C=CC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Yield: 87 %

Procedure:
49.6 g of a crude 5-nitronaphthoquinone cake (which had a water content of 50 wt% and a dry weight of 24.8 g, and comprised of 82 wt% of 5-nitronaphthoquinone and 10 wt% of 6-nitronaphthoquinone when determined under dried condition by a gas chromatography), 12.1 g of 1,3-butadiene and 49.6 g of benzene were introduced into an autoclave, which was then hermetically sealed for reaction at 80°C for 2.5 hours. The resultant reaction solution was cooled to 25°-30°C to crystalize 5-nitrotetrahydroanthraquinone, subjected to filtration, washed with 40 g of methanol, and dried to obtain 22.4 g of 5-nitrotetrahydroanthraquinone. The yield was 87.0% of the theoretical (based on the 5-nitronaphthoquinone contained in the crude starting material).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12]C)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+]>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2[nH]ncc2c1
Yield: 103.6 %

Procedure:
To a stirred solution of methyl 1H-indazole-5-carboxylate (6.5 g, 1.0 eq) in 200 mL MeOH was added a solution of NaOH (4.4 g, 3.0 eq) in 150 mL H2O. The mixture was refluxed for 1 h. The organic solvent was removed in vacuo, the remaining aqueous solution was washed with EtOAc, acidified with 3 N HCl to pH=5-6, and the precipitate was collected by filtration, and washed with water, to give the desired product as a yellow solid (6.2 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[CH:17][N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:35]([NH2:37])[CH3:36].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([NH:37][CH2:35][CH3:36])[N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCN
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 100 mg (0.17 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) were stirred in 2 ml of THF for 30 min. Another 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) was then added, and the mixture was stirred at RT for 2 h. About 15 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 81 mg (89% of theory) of the desired target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.N1C=CC=CC=1[Li].[O:20]=[C:21]1[CH2:27][CH:26]2[CH2:28][CH:22]1[CH2:23][N:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25]2>C(OCC)C.C1COCC1>[OH:20][C:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:27][CH:26]2[CH2:28][CH:22]1[CH2:23][N:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25]2
Reactant: CCOC(=O)N1CC2CC(=O)C(C2)C1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Agent: [Li]c1ccccn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CC2CC(C1)C(O)(c1cccnc1)C2
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of 3-bromopyridine (1.04 g, 6.58 mmol) in dry diethyl ether (20 ml) at −78° C. was added 2.5 M n-butyllithium (2.63 ml, 6.6 mmol). The reaction was stirred for 30 min under nitrogen. The pyridinyllithium solution was then slowly transferred by cannula into a solution of ethyl 6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (1.00 g, 5.07 mmol) in THF (10 ml) at −78° C. The reaction was stirred 4 h at −78° C. and then quenched with saturated aqueous ammonium chloride (10 ml). The reaction was then extracted with chloroform (3×25 ml), the combined extracts dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Excess pyridine was removed by repeated azeotropic rotary evaporation with toluene to yield the desired product (1.20 g, 86%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]2[C:13]3[N:17]([CH2:18][CH2:19][O:20][C:11]=2[CH:10]=1)[C:16]1[CH:21]=[C:22]([C:25]([O:27]C)=[O:26])[CH:23]=[CH:24][C:15]=1[C:14]=3[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.O>CO.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]2[C:13]3[N:17]([CH2:18][CH2:19][O:20][C:11]=2[CH:10]=1)[C:16]1[CH:21]=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=[CH:24][C:15]=1[C:14]=3[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OCc2ccccc2)ccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OCc2ccccc2)ccc1-3
Reaction time: 13 h
Yield: 48.1 %

Procedure:
To a solution of methyl 3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (173 mg, 0.36 mmol) in methanol (3.5 ml) and tetrahydrofuran (3.5 ml) was added 4N aqueous sodium hydroxide solution (1.7 ml), and the mixture was stirred for 13 hr. To the reaction mixture were added 2N hydrochloric acid (3.7 ml) and water, and the precipitated solid was collected by filtration and dried in vacuo. The obtained solid was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give 3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (81 mg, yield 48%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:10]([CH2:14][OH:15])[NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(C)=O.C(Cl)(=O)C([Cl:30])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:30][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[S:16][C:9]1[C:8]2[C:12](=[CH:13][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[NH:11][C:10]=1[CH:14]=[O:15]
Reactant: CS(=O)(=O)c1ccc2c(Sc3ccccc3)c(CO)[nH]c2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc2c(Sc3ccccc3Cl)c(C=O)[nH]c2c1

Procedure:
A solution of alcohol [3-(2-chloro-phenylsulfanyl)-6-methanesulfonyl-1H-indol-2-yl]-methanol (75 mg) (prepared as described in Example 5) in CH2Cl2 (5 ml) was added to a solution of DMSO (0.2 ml) and oxalyl chloride (0.1 ml) that had been prepared at −78°. After 15 min triethylamine (0.45 ml) was added and the reaction was allowed to warm to 200 over 30 min. It was partitioned between EtOAc and water and the organic phase evaporated to give 3-(2-chloro-phenylsulfanyl)-6-methanesulfonyl-1H-indole-2-carboxaldehyde, 801, MS: 343 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:9]2[C:4](=[C:5]([NH2:23])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:23][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([CH3:1])[N:11]=[C:10]3[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Cc1nc(Nc2cccc(C(F)(F)F)c2)c2cccc(N)c2n1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(Nc2cccc(C(F)(F)F)c2)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 9.2 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 2-methyl-N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-27, 100 mg, 0.314 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 181 mg, 0.629 mmol), oxalyl chloride (119 mg, 0.94 mmol), DMF (1 drop) and DIPEA (122 mg, 0.94 mmol) in CH2Cl2 (4 mL) to afford 17 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 10.04 (s, 1H), 8.77 (d, 1H), 8.43 (s, 1H), 8.31 (m 2H), 8.16 (m, 1H), 7.64 (m, 2H), 7.48-7.36 (m, 3H), 4.31 (d, 2H), 2.58 (s, 3H), 1.14 (s, 9H); MS (m/z): 588.31 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.[NH:19]1[CH2:22][CH2:21][CH2:20]1>>[N:19]1([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[O:13])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: C1CNC1
Agent: [Li+]
Solvent: O=S(Cl)Cl
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Yield: 83 %

Procedure:
This material was prepared from lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (100 mg, 0.47 mmole) by treatment with thionyl chloride followed by coupling with azetidine, in a manner as previously described for example 9d to afford 98 mg (83%) of a dark yellow solid. 1H NMR (DMSO-d6) δ 8.72 (1H, d, J=5.1 Hz), 7.96 (1H, s), 7.70 (1H, d, J=5.1 Hz), 4.62 (2H, t, J=7.4 Hz), 4.12 (2H, t, J=7.7 Hz), 2.34 (2H, tt, J=7.4, 7.7 Hz).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[CH2:4][CH2:5][C:6]([CH:8]1[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:9]1)=O.C([O:28][C:29](=[O:32])[NH:30][NH2:31])CCC.O.[C:34]1([CH3:44])[CH:39]=CC(S(O)(=O)=O)=C[CH:35]=1>C(Cl)Cl>[C:34]([O:32][C:29]([NH:30]/[N:31]=[C:6](/[CH:8]1[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:9]1)\[CH2:5][CH2:4][CH:3]([O:22][CH3:23])[O:2][CH3:1])=[O:28])([CH3:44])([CH3:39])[CH3:35]
Reactant: CCCCOC(=O)NN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(CCC(=O)C1CN(C(=O)OCc2ccccc2)C1)OC
Solvent: ClCCl
Solvent: O
Product: COC(CC/C(=N\NC(=O)OC(C)(C)C)C1CN(C(=O)OCc2ccccc2)C1)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of benzyl 3-(4,4-dimethoxybutanoyl)azetidine-1-carboxylate (1.91 g, 5.94 mmol) in CH2Cl2 (30 mL) was treated with Pert-butylcarbazate (824 mg, 6.24 mmol) followed by para-toluensulfonic acid monohydrate (170 mg, 0.89 mmol). The reaction was stirred at rt for 16 h. The mixture was washed with H2O (25 mL), saturated aqueous NaHCO3 (25 mL), and brine. The organic phase was dried (Na2SO4), filtered and concentrated to afford 2.47 (95%) of the desired product. ES-MS m/z 458.47 [M+Na]+, HPLC RT (min) 3.32.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][NH2:21])[CH2:14]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.[BH4-].[Na+].C(=O)(O)[O-].[Na+].C(Cl)(Cl)[Cl:43]>CO.C(Cl)Cl>[ClH:43].[ClH:43].[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][NH:21][CH2:33][C:31]2[CH:30]=[CH:29][C:26]3[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=3[N:32]=2)[CH2:14]1
Reactant: ClC(Cl)Cl
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2nccc(N3CCC(NCCN)C3)c2n1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2nccc(N3CCC(NCCNCc4ccc5c(n4)NC(=O)CO5)C3)c2n1
Product: Cl
Reaction time: 8 h
Yield: 40 %

Procedure:
N1-[1-(6-Methoxy-[1,5]naphthyridin-4-yl)-pyrrolidin-3-yl]-ethane-1,2-diamine (250 mg, 0.77 mmol) (from Example 2c) was dissolved in MeOH:DCM (8 mL, 1:1) and treated with 3-oxo-3,4-dihydro-2H -pyrido[3,2-b ][1,4]oxazine-6-carbaldehyde (138 mg, 0.77 mmol). After stirring overnight, the reaction mixture was treated with sodium borohydride (29 mg, 0.77 mmol) and stirred 1 h. The reaction mixture was diluted with chloroform and poured into saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted several times with chloroform. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated to dryness and purified by colume chromatography (silica, 0-10% MeOH in CDCl3 (1% NH4OH)) to afford the title compound as a white solid (140 mg, 40%): LC/MS m/z 450 (M+H)+; 1H NMR (CDCl3, 400 MHz) δ 8.34 (d, J=5 Hz, 1H), 8.07 (d, J=9 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 7.01 (d, J=9 Hz, 1H), 6.88 (d, J=8 Hz, 1H), 6.40 (d, J=5 Hz, 1H), 4.62 (s, 2H), 4.15 (m, 1H), 4.05 (m, 1H), 3.99 (s, 3H), 3.95 (m, 1H), 3.77 (s, 3H), 3.47 (m, 1H), 2.82 (m, 2H), 2.80 (s, 2H), 2.20 (m, 1H), 1.92 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH2:17].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:9]([C:8]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:13])=[O:11]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C(Nc1ccc(F)cc1F)c1cc([N+](=O)[O-])ccc1O
Yield: 32.4 %

Procedure:
A solution of 5-nitrosalicylic acid (1.4 g, 7.7 mmol) and 2,4-difluoroaniline (0.8 mL, 7.7 mmol) in chlorobenzene (40 mL) was treated with PCl3 (0.338 mL, 3.8 mmol). The solution was heated at reflux under an argon atmosphere. After 2 h. the solution was filtered hot and the filtrate was left standing at RT. After 18 h the solution was filtered and the solid was recrystallized from MeOH to give the title compound (0.733 g, 35% yield): 1H NMR (400 MHz, DMSO-d6) δ 2.5-2.6 (s, 3H), 7.1-8.9 (m, 6H), 10.6-10.7 (s, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:11][N:10]=1)=[O:7])([O-])=O>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)=[CH:11][N:10]=1)=[O:7]
Reactant: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)benzamide (140 mg, 0.30 mmol, 1.00 equiv) in methanol/tetrahydrofuran (5 mL/2 mL). The mixture was treated with Pd/C and stirred under a hydrogen atmosphere for 1 h at room temperature. The solids were filtered out. The resulting solution was diluted with 50 mL of ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 100 mg (76%) of 2-amino-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)benzamide as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21]CSC)[CH:6]=[CH:7][C:8]1[S:9][C:10]2[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[N:17]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.O>[OH:21][C:20]1[CH:19]=[CH:18][C:5]([CH:6]=[CH:7][C:8]2[S:9][C:10]3[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[N:17]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C=Cc2nc3c(s2)NCCCC3)ccc1OCSC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc(C=Cc2nc3c(s2)NCCCC3)ccc1O
Yield: 20.3 %

Procedure:
2-(3-Methoxy-4-methylthiomethoxystyryl)-5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]azepine (1.88 g) obtained in Example 87, was dissolved in a mixture of dimethylformamide, acetonitrile and water, following by addition of mercuric chloride (2.11 g). The mixture was refluxed for 15 hrs. After completing the reaction, an aqueous sodium hydrogen carbonate was added to the mixture. The mixture was extracted with a mixture of chloroform and methanol, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to a column chromatography on silica gel eluting a mixture of chloroform and methanol (98:2, v/v) to give the title compound (yield 318 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[NH2:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:23])([CH3:24])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
A mixture of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (8.7 g, 26.8 mmol) in methanol (80 mL) and tetrahydrofuran (100 mL), 30% sodium hydroxide in water (50 mL) was stirred at 60° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (7 g, 88%) as a brown solid which was used for next step without further purification: LC/MS m/e calcd for C18H20N2O2 (M+H)+: 297.37, observed: 297.2.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13]2)=[O:9].[Cl:20][C:21]1[N+:26]([O-])=[CH:25][C:24]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=1.P(Cl)(Cl)Cl>CN(C)C=O>[ClH:20].[OH:19][C:14]1[NH:15][C:16]2[C:12]([C:13]=1[C:21]1[CH:22]=[CH:23][C:24]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][N:26]=1)=[CH:11][C:10]([C:8]([NH:7][CH2:6][CH2:5][O:4][CH3:3])=[O:9])=[CH:18][CH:17]=2
Reactant: COCCNC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: COCCNC(=O)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Product: Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.4 %

Procedure:
To a suspension of sodium hydride (97%, 0.030 g, 1.25 mmol) in N,N-dimethylformamide (1.5 mL) was added N-(2-methoxyethyl)-2-oxoindoline-5-carboxamide (0.176 g, 0.75 mmol). The formed mixture was stirred for 5 min at room temperature followed by the addition of 4-[(6-chloro-1-oxidopyridin-3-yl)methyl]morpholine (0.114 g, 0.5 mmol). The resulting reaction mixture was set under an N2 atmosphere and stirred for 1 h at 120° C. and then concentrated in vacuo. The remaining N,N-dimethylformamide was removed by co-evaporation with toluene (1×). The residue was purified on a silica gel column using chloroform/methanol/triethylamine, (90:10:1), as the eluent. The material was dissolved in chloroform (4 mL), and phosphorus trichloride (0.275 g, 2.0 mmol) was added. The reaction mixture was stirred for 1 h at 60° C. and then concentrated in vacuo. The residue was purified on a silica gel column using chloroform/methanol/triethylamine, (90:10:1), as the eluent followed by further purification by washing with diethyl ether (3 mL) to give 0.050 g (24% yield) of the title compound as the base. The base (0.050 g, 0.12 mmol) was dissolved in chloroform/methanol, (1:1), and treated with HCl in diethyl ether (1 M) at 0° C. The resulting yellow crystals were collected by filtration and washed with diethyl ether to obtain 0.029 g (50% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 11.48 (br s, 1H), 10.74 (br s, 1H), 8.54 (br s, 1H), 8.27 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 8.03 (s, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.29 (br s, 1H), 4.00 (d, J=11.2 Hz, 2H), 3.87 (d, J=11.2 Hz, 1H), 3.83 (d, J=12.4 Hz, 1H), 3.50 (br s, 4H), 3.38 (d, J=12.4 Hz, 2H), 3.32 (s, 3H), 3.13 (m, 2H); MS (EI) m/z 411 (M++1).
Reaction SMILES: [Mg].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[CH3:11][C:12](C)=O.C(=O)=O.[Cl:18][C:19]1[C:27]([F:28])=[C:26]([Cl:29])[CH:25]=[C:24]([F:30])[C:20]=1[C:21](Cl)=[O:22].S(=O)(=O)(O)O>C(O)C.C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Cl:18][C:19]1[C:27]([F:28])=[C:26]([Cl:29])[CH:25]=[C:24]([F:30])[C:20]=1[C:21]([CH:3]([C:4]([O:6][CH2:11][CH3:12])=[O:5])[C:2]([O:8][CH2:9][CH3:10])=[O:7])=[O:22]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1c(F)cc(Cl)c(F)c1Cl
Reactant: CC(C)=O
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
2.1 g of magnesium filings are suspended in 5 ml of anhydrous ethanol. 0.5 ml of carbon tetrachloride is added and, when the reaction has started, a mixture of 14 g of ethyl malonate, 10 ml of absolute ethanol and 41 ml of toluene is added dropwise. The mixture is then heated at 70° C. for a further 1.5 hours and cooled to -5° C. to -10° C. with acetone/dry ice, and a solution of 21.5 g of 2,4-dichloro-3,6-difluorobenzoyl chloride in 30 ml of toluene is slowly added dropwise at this temperature. The mixture is stirred at 0° C. for 1 hour and allowed to come to room temperature overnight, and a mixture of 35 ml of ice-water and 5 ml of concentrated sulphuric acid is allowed to run in, while cooling with ice. The phases are separated and subsequent extraction is carried out twice with toluene. The combined toluene solutions are washed once with saturated sodium chloride solution and dried with Na2SO4 and the solvent is stripped off in vacuo. 34.7 g of diethyl (2,4-dichloro-3,6-difluorobenzoyl)-malonate are obtained as a crude product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:27](=[O:28])[NH:26][N:25]=[CH:24][C:12]3=[C:13]([C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)[NH:14][C:15]([CH:16]=1)=[C:11]23)(C)(C)C.[ClH:30]>>[Cl-:30].[CH3:23][C:20]1[N:19]=[CH:18][C:17]([C:13]2[NH:14][C:15]3[CH:16]=[C:8]([NH3+:7])[CH:9]=[C:10]4[C:27](=[O:28])[NH:26][N:25]=[CH:24][C:12]=2[C:11]=34)=[CH:22][CH:21]=1
Reactant: Cl
Reactant: Cc1ccc(-c2[nH]c3cc(NC(=O)OC(C)(C)C)cc4c3c2C=NNC4=O)cn1
Product: Cc1ccc(-c2[nH]c3cc([NH3+])cc4c3c2C=NNC4=O)cn1
Product: [Cl-]

Procedure:
Compound 267 (b) was obtained by reacting tert-butyl[2-(6-methylpyridin-3-yl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]carbamate with 4M HCl in dioxanes. Product 267(b) was isolated in quantitative yield as an orange powder after filtration and ether rinse and was carried on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=2)[CH2:17][CH2:16]1.N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:31](=[O:33])[CH3:32])[CH:22]=2)[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCc4ccc(N)cc43)c2cc1OC
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc2ncnc(N3CCc4ccc(NC(C)=O)cc43)c2cc1OC
Yield: 68.8 %

Procedure:
To 1-(6,7-dimethoxy-quinazolin-4-yl)-2,3-dihydro-1H-indol-6-ylamine (99 mg, 0.307 mmol; from Example 30) and pyridine (32 μL, 0.620 mmol) in CHCl3 (5 mL) was added acetyl chloride (33 μL, 0.455 mmol). The mixture was refluxed 2 hours, diluted with CHCl3 (15 mL), and the organic solution was washed with saturated aqueous NaHCO3, dried over Na2SO4(s), filtered and concentrated in vacuo. Flash chromatography on silica (5% MeOH/CHCl3) afforded 77 mg of product. (M.P. 223°-229° C. (dec); GC-MS: 364 (M+); anal. RP18-HPLC RT: 3.42 min.).