Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:14]=O>C(O)=O>[CH3:14][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:5]=2)[CH2:1]1
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: C=O
Solvent: O=CO
Product: COC(=O)c1ccc2c(c1)CN(C)C2
Temperature: 70 °C
Reaction time: 16 h

Procedure:
1.2 g (6.6 mmol) methyl 2,3-dihydro-1H-isoindole-5-carboxylate are dissolved in 5 ml formic acid, combined with 2 ml formalin solution (37% solution in water), heated to 70° C. for 3.5 hours and stirred for 16 hours at RT. The reaction mixture is evaporated down i. vac. and combined with 0.1 N sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:9]1[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]1=[O:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CN(C=O)C>[CH2:3]([N:9]1[CH2:14][CH2:13][N:12]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[C:11](=[O:15])[C:10]1=[O:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCN1CCNC(=O)C1=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1CCN(Cc2ccc([N+](=O)[O-])cc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
With 1.1 g of sodium hydride (50% purity) was mixed 50 ml of DMF, and 4.6 g of 1-n-hexyl-2,3-dioxopiperazine was added thereto with stirring at room temperature over a period of 10 minutes. Subsequently, the resulting mixture was subjected to reaction at 50° to 60° C. for 30 minutes, and 5.5 g of p-nitrobenzyl bromide was added to the reaction mixture over a period of 10 minutes, after which the mixture thus obtained was further subjected to reaction at 50° to 60° C. for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was extracted with 70 ml of ethyl acetate, and the ethyl acetate layer was washed with water and then a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The crystals thus obtained were recrystallized from isopropyl alcohol to obtain 4.0 g (51.9% yield) of 1-n-hexyl-4-(4-nitrobenzyl)-2,3-dioxopiperazine having a melting point of 115° to 117° C.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.Cl.[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:53])C(O)=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:55][CH2:56][O:57][CH2:58][CH2:59]1)=[O:53])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A mixture of 500 mg (0.90 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide [prepared as described in Example 9(a)] in 10 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature and under an atmosphere of nitrogen for 30 minutes, and then the reaction mixture was concentrated by evaporation under reduced pressure. Diethyl ether was added to the residue, and then the solvent was removed by distillation under reduced pressure. The same operation was repeated in total three times. The resulting residue was dried by evaporation under reduced pressure for 8 hours, and then the residue was suspended in 10 ml of anhydrous tetrahydrofuran. 275 mg (0.92 mmoles) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were added to the suspension, and then 0.15 ml (0.99 mmoles) of diethyl cyanophosphate and 0.42 ml (3.01 mmoles) of triethylamine were added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 8 hours, after which the solvent was removed by distillation under reduced pressure and the residue was purified by silica gel thin layer chromatography (using an 8:1 by volume mixture of methylene chloride and methanol as the developing solvent) and then recrystallization of the product from ethyl acetate, to give 500 mg (yield 78%) of the title compound as white crystals, melting at 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1.[CH2:24]([O:26][C:27](=[O:34])[CH:28](Br)[CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:27]([O:26][CH2:24][CH3:25])=[O:34])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1
Reactant: CCOC(=O)C(Br)CC(C)C
Reactant: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2O)c1
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OC(CC(C)C)C(=O)OCC)c1
Yield: 81 %

Procedure:
Following the general method as outlined in Intermediate 268, starting from 4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenol (Intermediate 267) and 2-bromo-4-methyl-pentanoic acid ethyl ester, the title compound was obtained as a colorless sticky solid in 81% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.CC(O)CC>O>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: CN1CCNCC1
Solvent: CCC(C)O
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 118 °C
Yield: 84 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (100 g, 0.38 mol), N-methylpiperazine (250 mL, 2.5 vol) and 2-butanol (200 mL, 2 vol) were charged into a three-necked round bottom flask equipped with a reflux condenser, overhead stirrer, and thermometer. The reaction mixture was heated to reflux at 118° C. under a nitrogen atmosphere and refluxed overnight. The reaction mixture was allowed to cool to below 55° C. whereupon water (300 mL, 3 volumes) was added to precipitate out the solid. It was isolated by Buchner filtration and the light yellow solid was washed twice with 25% aqueous 2-butanol (100 mL) and then once with 2-butanol (100 mL) and dried to provide olanzapine in 84% yield (98.7 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]1
Reactant: OC1CCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-phenylcyclopentanol (142 mg) in dichloromethane (10 mL) at room temperature were added pyridinium chlorochromate (146 mg) and powdered 4 A° molecular sieves (146 mg), and the resulting mixture was stirred at room temperature for 1.5 h and then filtered through a small pad of silica gel. The filtrate was evaporated in vacuo and the residue was purified by preparative TLC eluting with 30% ethyl acetate/70% hexanes to give the title compound as an oily material (150 mg). 1H NMR (400 MHz, CDCl3) δ 2.3-2.6 (4H, m), 2.68 (1H, d, J=17.6 Hz), 2.76 (1H, d, J=17.6 Hz), 3.52 (1H, q, J=9.2 Hz), 3.58 (1H, d, J=9.2 Hz), 4.52 (2H, s), 7.2-7.4 (5H, m), 7.59 (2H, s), 7.76 (1H, s).
Reaction SMILES: O[CH2:2][C:3]1([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4]1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:23]=2)[CH:18]=[C:17]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:11]([O:10][C:9]([NH:8][CH2:7][C:3]1([CH2:2][N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:23]=3)[CH:18]=[C:17]2[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:6][CH2:5][CH2:4]1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: CC(C)(C)OC(=O)NCC1(CO)CCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CNC(=O)OC(C)(C)C)CCC3)c2c1
Reaction time: 60 h

Procedure:
To a solution of tert-butyl {[1-(hydroxymethyl)cyclobutyl]methyl}carbamate (12 g, 55.76 mmol), diethyl 1H-indole-2,6-dicarboxylate (14.56 g, 55.76 mmol) and triphenylphosphine (29.2 g, 111.5 mmol.) in THF (110 mL) is added diisopropyl azodicarboxylate (22.41 mL, 111.5 mmol) at room temperature and the reaction mixture is stirred for 60 h. The solvent is evaporated and the residue is purified by flash column chromatography using 12% EtOAc in petroleum ether to afford diethyl 1-[(1-{[(tert-butoxycarbonyl)amino]methyl}cyclobutyl)methyl]-1H-indole-2,6-dicarboxylate contaminated with un-reacted diethyl 1H-indole-2,6-dicarboxylate. The mixture is used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=1)=[O:5]>S(=O)(=O)(O)O>[O:5]=[C:4]1[C:6]2[C:7](=[CH:8][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1ccc(C(=O)CCCl)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc2c(c1)CCC2=O
Temperature: 20 °C
Yield: 58.4 %

Procedure:
(1-Oxoindan-5-yl)acetic acid can be obtained in the following way: a solution of 50.9 g of ethyl [4-(3-chloro-1-oxopropyl)phenyl]acetate in 950 ml of 95% sulphuric acid is heated for 1 hour at 100° C. The reaction mixture is cooled to a temperature in the region of 20° C. and then poured into 4 liters of ice-cold water. The mixture is extracted three times with 1.5 liter of dichloromethane. The organic phase is washed three times with 1 liter of water, then dried over magnesium sulphate and evaporated under reduced pressure. 22.2 g of (1-oxoindan-5-yl)acetic acid are thus obtained in the form of a cream solid melting at 141° C. (1H NMR spectrum in CDCl3, T=300 K, δ in ppm: 2.70 (2H, m, COCH2), 3.12 (2H, t, J=5 Hz, CH2), 3.68 (2H, s, CH2), 7.27 (1H, d, J=7 Hz, arom. CH), 7.45 (1H, s, arom. CH), 7.76 (1H, d, J=7 Hz, arom. CH)).
Reaction SMILES: C(O[C@@H:5]1[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[C@@H:8]([C:15]([O:17][CH2:18]C)=[O:16])[C:7]([CH3:20])=[CH:6]1)(=O)C.C1CCN2C(=NCCC2)CC1>Cl>[CH3:20][C:7]1[CH:6]=[CH:5][CH2:14][C:9]2([CH2:10][CH2:11][CH2:12][CH2:13]2)[C:8]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: CCOC(=O)[C@H]1C(C)=C[C@H](OC(C)=O)CC12CCCC2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=C(C)C=CCC12CCCC2
Temperature: 20 °C
Reaction time: 96 h
Yield: 27.3 %

Procedure:
A solution of a 30:70 mixture of cis-/trans-ethyl 9-acetoxy-7-methylspiro[4.5]dec-7-ene-6-carboxylate (2.7 g, 9.6 mmol) in DBU (15 ml, 97 mmol) was stirred for 4 d at 20° C. The reaction mixture was poured into cold 2N aqueous HCl (50 ml), and extracted twice with MTBE (50 ml). The combined organic phases were washed with 2N aqueous HCl (30 ml), with water (40 ml), with a saturated aqueous solution of NaCl (40 ml), dried (MgSO4), and concentrated. FC (250 g SiO2, pentane/Et2O 100:1) of the crude product (1.8 g) gave methyl 7-methylspiro[4.5]deca-6,8-diene-6-carboxylate (0.54 g, 25%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[OH-].[Na+]>O>[N:11]1[C:1](=[O:2])[N:12]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12
Reactant: Nc1ccccc1N
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1N=c2ccccc2=N1
Yield: 98 %

Procedure:
100 g (1.01 mol) of phosgene are passed into 108 g (1 mol) of o-phenylenediamine in 450 ml of water at 80° C. over a period of 4 hours, and the pH is kept constant at 10 by simultaneous metering in of 407 g (2.04 mol) of 20% strength aqueous sodium hydroxide solution. The end point of the reaction is determined by sampling for diazotizable amine. After cooling, the product which has precipitated is filtered off with suction, washed with water and dried. 131 g of benzimidazolone of melting point 308° C., which corresponds to a yield of 98% of theory, are obtained in this manner.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[S:23][C:24]=3[CH3:25])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:25][C:24]1[S:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:36])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], (6-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain (6-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-indol-1-yl)-acetic acid as off-white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CS(C)=O.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCNCC4)ccc23)CC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of piperazine (5 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (1 mmol) in DMSO (1 mL) was stirred at 120° C. for 1 h. It was then diluted with water and extracted with DCM. The combined extracts were washed with water, brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo to obtain 4-(7-piperazin-1-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester. This (0.1 mmol) was dissolved in anhydrous DCM (1 mL) and treated with Et3N (0.2 mmol) followed by 9-fluorenylmethyl chloroformate (FMOC-Cl, 0.2 mmol) and the mixture was stirred at rt overnight and then washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was then added 3M HCl/MeOH (2 mL) and stirred at rt for 2 h and then concentrated in vacuo. The crude residue was dissolved in a mixture of DCM:MeOH (1:1; 2 mL) and neutralized with excess Et3N and treated with (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride (0.11 mmol), as prepared by the method outlined in Example 66a, at rt overnight. It was then concentrated in vacuo and the crude product was dissolved in DCM and washed with water thrice, then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was then purified by Preparative TLC (silica gel; DCM:MeOH:NH4OH, 90:9:1) to obtain 5.6 mg (11%) of the title compound. 1H-NMR (300 MHz, CDCl3): 9.04 (s, 1H), 7.97 (d, 1H), 7.36-7.18 (m, 4H), 6.88 (d, 2H), 6.31 (s, 1H), 4.25 (m, 2H), 3.89-3.82 (m, 4H), 3.70-3.56 (m, 1H), 3.46-3.38 (m, 4H), 3.19-3.04 (m, 10H), 2.21-1.90 (m, 5H). LC/MS (ESI): 502.1 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:22][C@@H:21]3[CH2:23][C@@:18]2([CH3:25])[C:19](=[O:24])[O:20]3)[N:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[CH:14]1([C:11]2[CH:10]=[C:9]([NH:8][C:6]3[N:7]=[C:2]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:3]=[C:4]([N:17]4[CH2:22][C@@H:21]5[CH2:23][C@@:18]4([CH3:25])[C:19](=[O:24])[O:20]5)[N:5]=3)[NH:13][N:12]=2)[CH2:15][CH2:16]1
Reactant: C[C@@]12C[C@@H](CN1c1nc(Cl)nc(Nc3cc(C4CC4)n[nH]3)n1)OC2=O
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: C[C@@]12C[C@@H](CN1c1nc(Nc3cc(C4CC4)n[nH]3)nc(N3CCOCC3)n1)OC2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a solution of (1S,4S)-5-(4-chloro-6-(3-cyclopropyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-yl)-4-methyl-2-oxa-5-azabicyclo[2.2.1]heptan-3-one (365 mg, 1.01 mmol) in THF (10 ml) was added morpholine (0.2 ml, excess). The reaction mixture was stirred at RT for 4 h and concentrated. The residue was purified by prep. HPLC to give 105B (340 mg, 66%) as a TFA salt. LC/MS [M+H]+: 513; Ret time (Method F): 2.56 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C@@H:10]([C@@:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:20][CH2:19][C:18](=[O:21])[N:17]([CH3:22])[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]2=3)[C:11]([OH:13])=[O:12])[N:3]=1.[CH3:33]O>O.C=O.[Pd]>[CH3:22][N:17]1[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[C@:14]([C@H:10]([O:9][C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)[C:11]([OH:13])=[O:12])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:20]([CH3:33])[CH2:19][C:18]1=[O:21]
Reactant: CO
Reactant: Cc1cc(C)nc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCC(=O)N(C)c3ccccc32)n1
Agent: [Pd]
Agent: C=O
Solvent: O
Product: Cc1cc(C)nc(O[C@H](C(=O)O)[C@]2(c3ccccc3)c3ccccc3N(C)C(=O)CN2C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pd/C (100 mg, 10% Pd) is added to a solution of (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid (100 mg, 0.231 mmol, Example 49) in water (8 ml), methanol (8 ml) and aq. formaldehyde solution (0.2 ml, 36%). The mixture is stirred at rt under 3 atm H2 for 18 h before the catalyst is filtered off. The organic solvent of the filtrate is evaporated and the remaining aq. phase is extracted three times with DCM. The organic phase is evaporated and the product is purified by chromatography on prep. tlc-plattes with DCM:methanol 9:1 to give (±)-(S*)-((5S*)-1,4-dimethyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid (57 mg) as a white powder. LC-MS2: tR=3.40 min, [M+1]+=447.10, [M−1]−=445.14.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11](Br)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Li]CCCC.[CH:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH:25]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[OH:26])[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(C(O)c3cccnc3)cc3ccccc23)CC1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A solution of 1-(4-ethylpiperazin-1-yl)-3-bromoisoquinoline (0.39 g) obtained in Example 28-2, in tetrahydrofuran (10 ml) was cooled to −78° C., followed by the dropwise addition of 2.5M n-BuLi (0.6 ml). Fifteen minutes later, a solution of 3-formylpyridine (0.2 g) in tetrahydrofuran (3 ml) was added dropwise thereto. The temperature of the reaction solution was gradually raised to room temperature. The reaction solution was diluted with ethyl acetate, washed with brine, water and an aqueous solution of saturated sodium chloride, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound (0.15 g) as a pale yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:34])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[N+:31]([O-])=O)=[N:21][CH:22]=3)=[O:16])[CH2:6][C:5]=12.[H][H]>C(O)C.[Pd]>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:34])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[NH2:31])=[N:21][CH:22]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1

Procedure:
A room temperature solution of 1.0 g of N-[5-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-pyridinyl]-2-nitrobenzamide in 100 ml of ethyl alcohol is hydrogenated over 200 mg of 10% Pd/C in a Parr apparatus under 40 psi of hydrogen for 2 hours. The reaction mixture is filtered through diatomaceous earth and the cake washed with additional ethyl alcohol. The combined filtrates are concentrated in vacuo and the residue purified by crystallization from 2:1 ethyl acetate:hexane to give the desired product as pale yellow crystals: M+Na 445:M+ 423.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:22][O:23][NH2:24].C(O)(C)C.C(O)C>C(OCC)(=O)C>[CH3:22][O:23][N:24]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[C:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CON
Reactant: O=C(Nc1cnc2ccccc2c1Cl)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COn1c(-c2ccccc2)nc2cnc3ccccc3c21
Temperature: 80 °C

Procedure:
A mixture of N-(4-chloroquinolin-3-yl)benzamide (0.020 g, 1 eq), O-methylhydroxylamine hydrochloride (3 eq), and isopropanol was heated at 80° C. for 17 hours. The reaction was also run using ethanol in lieu of isopropanol. The two reaction mixtures were combined, diluted with ethyl acetate, washed sequentially with aqueous potassium carbonate (×2), water, and brine, dried over potassium carbonate, filtered, and then concentrated under reduced pressure. The resulting solid was dried at 80° C. for 3 days to provide 12.1 mg of 1-methoxy-2-phenyl-1H-imidazo[4,5-c]quinoline as a tan powder, mp 194.0-195° C. MS (APCI) m/z 276 (M+H)+; Anal. calcd for C17H13N3O.0.2H2O: C, 73.21; H, 4.84; N, 15.07. Found: C, 73.27; H, 4.61; N, 14.84.