Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:12]=2)=[CH:6][CH:5]=1
Reactant: CCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 221.9 %

Procedure:
A solution of N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)propionamide (0.513 g, 1.780 mmol) in MeOH (10 mL) and THF (10 mL) was treated with NH4Cl (3.81 g, 71.2 mmol) followed by zinc dust (1.164 g, 17.80 mmol) and stirred at RT overnight. Additional zinc dust (1 g) was added the mixture stirred at RT for 2 days. The solids were removed via filtration, washed with THF and filtrate concentrated to dryness. The material was suspended in THF, sonicated, the resulting solid removed via filtration and the filtrate concentrated to dryness to afford crude N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)propionamide (1.02 g, 222%) which was carried on without further purification. MS (ESI) m/z: 259.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:14])=[N:4][CH:5]=[C:6]([C:12]=1[OH:13])[C:7]([O:9]CC)=[O:8].[OH-].[K+].C>O>[Cl:1][C:2]1[C:3]([Cl:14])=[N:4][CH:5]=[C:6]([C:12]=1[OH:13])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc(Cl)c(Cl)c1O

Procedure:
114 g (0.483 mol) of ethyl 5,6-dichloro-4-hydroxy-nicotinate are boiled under reflux in 1200 ml of water with 58 g (1.03 mol) of potassium hydroxide for two hours. The cooled mixture is stirred with activated charcoal and filtered, and the filtrate is brought to a pH of 1 with half-concentrated hydrochloric acid, while cooling with ice. The product which precipitates is isolated, washed with water and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([F:13])[F:12])=[CH:4][C:3]=1[CH2:14][C:15]([OH:17])=O.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([F:13])[F:12])=[CH:4][C:3]=1[CH2:14][C:15]([Cl:21])=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(Br)c(CC(=O)O)cc1OC(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Br)c(CC(=O)Cl)cc1OC(F)F
Temperature: 25 °C

Procedure:
(2-Bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid (350 mg, 1.12 mmol) was dissolved in 6 ml dichloromethane and 0.1 ml oxalyl chloride and 0.01 ml DMF was added. The solution was stirred at room temperature until gas evolution stopped, then concentrated under reduced pressure. Dichloromethane (6 ml) was added to the residue and the solvent removed again to assure that all the oxalyl chloride was removed giving 118 mg of crude (2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid chloride.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[N:8][CH:9]=1.[CH3:16]I>CN(C)C=O>[Br:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:14][CH2:13][N:12]([CH3:16])[C:11]2=[O:15])=[N:8][CH:9]=1
Reactant: CI
Reactant: O=C1NCCN1c1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ncc(Br)cn2)C1=O
Reaction time: 0.5 h

Procedure:
NaH (10 mg) was added to a solution of 1-(5-bromopyrimidin-2-yl)imidazolidin-2-one (50 mg) in N,N-dimethylformamide (5 mL) under nitrogen at 0° C. After stirring for 30 min, MeI (36 mg) was added. The reaction mixture was stirred at room temperature until the starting material was completely consumed (TLC). The reaction mixture was then quenched with H2O (20 mL) and the resulting mixture was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with H2O (3×20 mL), dried (Na2SO4), and concentrated. The residue was purified by preparative TLC to afford the title compound. Yield: 10 mg (19% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:17])[C@@H:12]([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:20](=[O:26])[NH:21][C:22]([Br:25])=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[N:11]([C@H:12]([C:13](=[O:15])[NH:18][C:19]1[C:20](=[O:26])[NH:21][C:22]([Br:25])=[CH:23][CH:24]=1)[CH3:16])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)[nH]c1=O
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)Nc1ccc(Br)[nH]c1=O)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
To a solution of (S)-2-(benzyloxycarbonyl-methyl-amino)-propionic acid (2.7 g, 11.4 mmol) in 10 mL of CH2Cl2 at 0° C., is added 1-chloro-N,N-2-trimethyl-1-propenylamine (1.5 g, 11.4 mmol) drop wise. After being stirred at 0° C. for 20 minutes, the solution is added to a solution of 3-amino-6-bromo-1H-pyridin-2-one (1B) (1.8 g, 9.5 mmol) in 40 mL of CH2Cl2 at 0° C. slowly. Triethyl amine (3.2 ml, 22.8 mmol) is then added slowly. The reaction mixture is stirred at 0° C. for 1 hour, then washed with 2×15 ml of water, and concentrated. The crude product is purified by chromatography (CH2Cl2 95%, MeOH 5%) to give [(S)-1-(6-bromo-2-oxo-1,2-dihydro-pyridin-3-ylcarbamoyl)-ethyl]-methyl-carbamic acid benzyl ester (1C) (3.0 g, yield 79%) as purple solid. MS (ESI) m/e 408, 410 (M+H+).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:31][OH:32])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O>FC(F)(F)C(O)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH2:31][OH:32])[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CO)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CO)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.7 %

Procedure:
A solution of (5-(4-(bis (4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methanol (100.7 mg, 0.174 mmol) and trifluoromethanesulfonic acid (0.07 mL, 0.788 mmol) in 2,2,2-trifluoroacetic acid (3.5 mL) was stirred at 75° C. for 1 h. The mixture was subsequently cooled to 25° C. and concentrated in vacuo. NaOH (1.0 N, aq.; 2.0 mL) was added, followed by MeOH (1.0 mL) (final pH>10), and the resulting mixture was stirred at 25° C. for 5 min. MeOH was removed in vacuo, and the resulting mixture was vacuum filtered. The collected solid was sequentially washed with water (20 mL) and ethyl ether (6 mL) and then dried in vacuo. Chromatographic purification of this solid (ISCO, 4 g, 0 to 10% MeOH/DCM) furnished (5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methanol (41.8 mg, 0.123 mmol, 70.9% yield) as a yellow solid. 1H NMR (400 MHz, d4-MeOH) δ 8.94 (d, J=2.54 Hz, 1H); 8.48 (d, J=2.35 Hz, 1H), 8.25 (d, J=2.54 Hz, 1H); 8.07 (dd, J=8.80, 2.74 Hz, 1H); 6.85 (d, J=9.00 Hz, 1H); 4.60 (s, 2H); 3.94 (s, 3H); 3.38 (s, 2H); 2.52 (s, 3H). m/z (ESI, +ve ion) 340.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCN)CC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(CCCCCNC(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-(4-tert-Butoxycarbonylaminomethylpiperidin-1-yl)pentylamine (2.00 g) was dissolved in methylene chloride (80 ml) and phenyl isocyanate (0.80 ml) was dropwise added under ice-cooling. The mixture was stirred at room temperature for 15 hr, and the reaction mixture was concentrated under reduced pressure to give 4-tert-butoxycarbonylaminomethyl-1-(5-(3-phenylureido)pentyl)piperidine.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C1C=CC=CC=1.[OH-].[Na+]>[C:14]([O:13][C:11](=[O:12])[CH2:10][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CNCc1ccccc1
Reaction time: 1 h
Yield: 89 %

Procedure:
To 71.0 g of benzylamine in 100 ml of benzene was added with stirring 25.0 g of tert-butyl chloroacetate over a period of 30 minutes, while maintaining the temperature at 30°-70° C. The reaction mixture was held at 70° C for an additional 1 hour. At the end of this period, the reaction mixture was taken up in 70 ml of 2N NaOH solution and 80 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 32.7 g (89.0 percent) of N-benzylglycine tert-butyl ester, B.P. 120°-125° C/ 2 mmHg.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f54) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: CC(C1C=C(CC(N2CCN(C3C=CC([N+]([O-])=O)=CC=3)CC2)=O)C=C(C(C)(C)C)C=1O)(C)C.[CH3:34][C:35]([C:38]1[CH:43]=[C:42]([C:44]([N:46]2[CH2:51][CH2:50][N:49]([C:52]3[CH:57]=[CH:56][C:55]([N+:58]([O-])=O)=[CH:54][CH:53]=3)[CH2:48][CH2:47]2)=O)[CH:41]=[C:40]([C:61]([CH3:64])([CH3:63])[CH3:62])[C:39]=1[OH:65])([CH3:37])[CH3:36]>>[CH3:37][C:35]([C:38]1[CH:43]=[C:42]([CH2:44][N:46]2[CH2:47][CH2:48][N:49]([C:52]3[CH:53]=[CH:54][C:55]([NH2:58])=[CH:56][CH:57]=3)[CH2:50][CH2:51]2)[CH:41]=[C:40]([C:61]([CH3:64])([CH3:63])[CH3:62])[C:39]=1[OH:65])([CH3:34])[CH3:36]
Reactant: CC(C)(C)c1cc(C(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(CC(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(CN2CCN(c3ccc(N)cc3)CC2)cc(C(C)(C)C)c1O
Yield: 75 %

Procedure:
The experimental protocol used is the same as that described for intermediate 9.2, with 2,6-bis-(1,1-dimethylethyl)-4-{[[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl]-methyl }-phenol replacing the 2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol. A pale pink powder is obtained with a yield of 75%. Melting point: 152-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:14]2[N:15]=[C:16]([CH3:20])[CH:17]=[C:18](O)[C:13]2=[CH:12][C:11]=1[CH3:21].P(Br)(Br)[Br:23].C([O-])(O)=O.[Na+]>BrC1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:23][C:18]1[C:13]2[N:14]([C:10]([C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[Cl:1])=[C:11]([CH3:21])[CH:12]=2)[N:15]=[C:16]([CH3:20])[CH:17]=1
Reactant: COc1ccc(-c2c(C)cc3c(O)cc(C)nn23)c(Cl)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Brc1ccccc1
Product: COc1ccc(-c2c(C)cc3c(Br)cc(C)nn23)c(Cl)c1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A solution of 7-(2-chloro-4-methoxyphenyl)-2,6-dimethylpyrrolo[1,2-b]pyridazin-4-ol (2.89 g, 9.50 mmol) and phosphorus tribromide (4.20 mL, 12.0 g, 44.0 mmol) in bromobenzene (50.0 mL) was refluxed for 1 h. After cooling down to room temperature, the mixture was diluted with CHCl3. Saturated NaHCO3 solution was added to neutralize and separated immediately. The aqueous layer was extracted with CHCl3 (2×). The combined CHCl3 solution was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (silica gel, 1/5 EtOAc/heptane) to afford 3.13 g (90%) of yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=8.6 Hz, 1H), 7.13 (d, J=2.6 Hz, 1H), 6.98 (dd, J=8.6, 2.6 Hz, 1H), 6.73 (s, 1H), 6.60 (s, 1H), 3.91 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H); MS m/z 366.99 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13](Cl)(=[O:15])=[O:14])=[CH:5][CH:4]=1.[CH:17]12[CH2:25][CH2:24][CH:21](C[CH2:23]1)[CH2:20][NH:19][CH2:18]2.CCN(C(C)C)C(C)C>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13]([N:19]2[CH2:18][CH:17]3[CH2:23][CH:21]([CH2:24][CH2:25]3)[CH2:20]2)(=[O:15])=[O:14])=[CH:5][CH:4]=1
Reactant: C1CC2CCC1CNC2
Reactant: COc1ccc(S(=O)(=O)Cl)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CC3CCC(C3)C2)c2ccccc12

Procedure:
The title compound was prepared by reacting 4-methoxy-1-naphthalenesulfonyl chloride (0.27 g) with 3-azabicyclo[3.2.2]nonane (0.16 g) in the presence of DIEA (0.30 g) using a procedure similar to that of Example 5. Yield: 0.34 g of a white solid, mp: 136.2°-138.6° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][N:28]([CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1.[Br:52]N1C(=O)CCC1=O>CC#N>[CH3:49][Si:46]([CH3:48])([CH3:47])[CH2:45][CH2:44][O:43][CH2:42][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:50])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][N:28]([CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:9]=1[Br:52]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N(Cc1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccccc4c3)c2n1)C1CCOCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1nc2c(-c3cnc4ccccc4c3)cnn2c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To crude tert-butyl (7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl(tetrahydro-2H-pyran-4-yl)carbamate (Int-8d, 44 mg) in CH3CN (8 mL) was added N-bromosuccinimide (22 mg, 0.12 mmol), followed by additional CH3CN (4 mL). The reaction was then stirred at room temperature for 30 minutes, at which time LC/MS analysis confirmed full conversion of the starting material to the product. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give Int-8e as a yellow solid (8.7 mg, 0.02 mmol, 7% over three steps). LCMS: 0.82 mins, m/z=812.10 and 813.20 (MH+).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N:20]1([C:29]([C:31]2[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=2)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>CN(C=O)C.O>[N:20]1([C:29]([C:31]2[CH:32]=[CH:33][C:34]([CH2:35][N:10]3[C:11]4[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=4[N:8]=[CH:9]3)=[CH:37][CH:38]=2)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(CCl)cc1)n1ccc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)n3ccc4ccccc43)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 54.5 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-[(1-indolyl)carbonyl]benzyl chloride (2.70 g) and the mixture was stirred at room temperature for 22 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off to provide the title compound as colorless powder (2.25 g, 54%).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(Cl)(=O)C(Cl)=O.C([N:19]([CH2:22][CH3:23])CC)C.C(Cl)(=O)C1C=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>C(Cl)Cl.CN(C)C=O>[CH3:32][O:31][C:28]1[CH:29]=[CH:23][C:22]([NH:19][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccccc1O
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 0.65 h
Yield: 80.2 %

Procedure:
To a solution of salicylic acid (1.38 g, 10.0 mmol) in methylene chloride (100 mL) cooled to 0° C. was added a few drops of dry N,N-dimethylformamide, followed by oxalyl chloride (1.41 mL). After 39 min, the ice bath was removed, and the reaction mixture allowed to warm to room temperature over 2 h. The solvent was removed in vacuo, and the residue dissolved in dry methylene chloride (125 mL). After cooling the solution to 0° C., triethylamine (2.81 mL, 20.0 mmol) was added, followed by the dropwise addition of a solution of p-anisoyl chloride (2.46 g, 20.0 mmol) in methylene chloride (25 mL). After 1 h, the reaction mixture was washed twice with 1 N aqueous hydrochloric acid and once with cold saturated aqueous sodium bicarbonate solution. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. Trituration with hexane, produced 1.95 g (80%) of the title compound as a crystalline solid.
Reaction SMILES: [CH2:1]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH2:17]([O:19]C=C[Li])[CH3:18]>C1COCC1>[CH:4]1[C:3]2[C:2]3[CH2:1][CH2:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:9](=[CH:18][CH:17]=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: [Li]C=COCC
Solvent: C1CCOC1
Product: O=CC=C1C=CC2=C(CCC=C2)c2ccccc21

Procedure:
Dibenzosuberone (5.3 g, 0.026 mol) was reacted with 1-ethoxy-2-lithio ethylene in anhydrous THF in the manner of Preparation 1 to yield present title product as a yellow oily solid, 2.86 g (48%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[CH2:13](Br)[CH:14]=[CH2:15].[OH-].[Na+].C(OC(=O)C)C>CCCCCC>[CH2:15]([S:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=2[N:3]=1)[CH:14]=[CH2:13]
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCSc1nc2cc(C)c(C)cc2[nH]1
Yield: 93 %

Procedure:
2-Allylthio-5,6-dimethylbenzimidazole (III) was prepared as described above for I from 2,67 g (0,015 mol) 2-mercapto-5,6-dimethyl-benzimidazole, 2,1 g (0,017 mol) allylbromide in the presence 0,7 g (0,017 mol) sodium hydroxide, yield 2,5 g (76%), m.p. 119-120° C. (from mixture ethylacetate with hexane). 1H NMR (CDCl3), δ: 2,33 (6H, s, 2CH3); 3,89 (2H, d, CH2S); 5,10 (HB, d, CHC═CHAHB); 5,25 (HA,d, CHC═CHACHB); 7,30 (2H, broad s, ArH); 10,11 (1H, broad s, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20](Cl)=[N:21][C:22]([C:23]([NH2:25])=[O:24])=[C:11]2[CH2:10][N:9]=1.[CH3:27][O-:28].[Na+].[K+].[Br-]>CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]3[C:20]([O:28][CH3:27])=[N:21][C:22]([C:23]([NH2:25])=[O:24])=[C:11]3[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: NC(=O)c1nc(Cl)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reactant: C[O-]
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(N)=O)c2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A mixture of 0.3 g (0.00074 mole) of 6-(2-chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide, 1.15 g (0.0028 mole) of sodium methoxide and 15 ml of methanol was heated at 120°-125° in a steel bomb for 24 hrs. The solvent was evaporated in vacuo. The residue was dissolved in methylene chloride, washed with water, dried and evaporated at reduced pressure to give a tan, amorphous solid. After chromatography over silica gel using 5% (v/v) of ethanol in methylene chloride the solid was recrystallized from a solution of ethanol and methylene chloride to give off-white crystals with mp 235°-238° (dec). Uv λ max 216 l mμ (ε=41,000) sh 243 (22,600) max 264 (20,000); ir (KBr) 3445, 3330, 3280 cm-1 (NH2) 1675 (CON) nmr (d-DMSO) δ 4.0 ppm (d, 1) and 5.88 (d, 1) (AB-system, J=12 Hz, C4 -H) 4.06 (s, 3, OCH3) 6.9-7.9 (m, 9, aromatic H and NH2).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[Li][CH2:13][CH2:14][CH2:15]C.C(Br)C=C>C1COCC1>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([CH2:15][CH:14]=[CH2:13])[C:8]([O:10][CH3:11])=[O:9]
Reactant: [Li]CCCC
Reactant: COC(=O)CN1CCCC1=O
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(C(=O)OC)N1CCCC1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.2 %

Procedure:
Step A (1): To a solution of the methyl 2-(2-oxopyrrolidin-1-yl)acetate (15 g, 95.5 mmol, TCI-America) in THF (600 mL) at −78° C. was added n-BuLi (42.0 mL, 105 mmol, 2.5 M in hexane, Aldrich). After 10 min, allyl bromide (9.7 mL, 115 mmol, Aldrich) was added. The mixture was stirred at −78° C. for 1 h and warmed to room temperature over 2 h. The reaction was then quenched with saturated ammonium chloride. After 15 min the mixture was extracted with EtOAc (3×200 mL). The combined organic layers were dried with Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (20-80% EtOAc/hexanes linear gradient) to afford methyl 2-(2-oxopyrrolidin-1-yl)pent-4-enoate 4.0 g (21% yield) as pale yellow oil: LC-MS (M+H)+=198.2; 1H NMR (400 MHz, CDCl3) δ 5.67-5.69 (m, 1H), 5.04-5.14 (m, 2H), 4.88 (dd, J=10.70, 5.16 Hz, 1H), 3.70 (s, 3H), 3.44-3.69 (m, 1H), 3.34-3.37 (m, 1H), 2.68-2.75 (m, 1H), 2.36-2.46 (m, 3H), 1.94-2.07 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.C(O)(=O)C.O=[CH:34][C@@H:35]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:40]([O:39][C:38]([NH:37][C@@H:35]([CH3:36])[CH2:34][NH:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1)=[O:44])([CH3:43])([CH3:42])[CH3:41]
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](CNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 15 (92 mg) in MeOH (2 mL) was added TEA (70 μL), acetic acid (30 μL), (S)-tert-butyl 1-oxopropan-2-ylcarbamate (86 mg) and sodium triacetoxyborohydride (212 mg). The reaction mixture was stirred overnight at RT. Solvent was removed and the product was carried on to next step without further purification.