Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1C=CC=CC=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[CH2:29])=[CH:26][CH:25]=1>C(N(CC)CC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:28]([C:27]3[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:29][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1
Reactant: C=Cc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1=NN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)C1
Reaction time: 1 h

Procedure:
The compound of Example 6 (5.0 gm) was heated in refluxing benzene (30 ml) containing 4-chlorostyrene (7.0 ml). Addition of a benzene (10 ml) solution of triethylamine(7.5 ml) was followed by one hour of continued heating. The cooled mixture was filtered, rotovapped, and dried on the vacuum pump to remove excess styrene. The residual solid was recrystallized from hexane/benzene (charcoal) to give the title compound (6.3 gm); m.p.: 128° to 130° C. NMR (CDCl3) 7.3-6.9 (m, 8H, ArH), 5.4 (dd, 1H, CH), 4.3 (q, 2H, OCH2), 3.8 (m, 1H, CH), 3.0 (m, 1H, CH), 1.38 (t, 3H, CH3).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:8][C:9]([CH2:11][C:12]2[C:21]([F:22])=[C:20]([F:23])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([F:24])[C:13]=2[F:25])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:34](OCC)(=[O:36])C.O>CN(C)C=O.C[O-].[Na+]>[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]([CH:11]([C:12]2[C:13]([F:25])=[C:14]([F:24])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:20]([F:23])[C:21]=2[F:22])[CH2:34][OH:36])=[O:10])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1c(F)c(F)c(CC(=O)OC(c2ccccc2)c2ccccc2)c(F)c1F
Agent: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(F)c(F)c(C(CO)C(=O)OC(c2ccccc2)c2ccccc2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
In 486 ml of N,N-dimethylformamide was dissolved 8.6 g of methyl 4-diphenylmethoxycarbonylmethyl-2,3,5,6tetrafluorobenzoate. To the resulting solution were added 3.54 g of paraformaldehyde and 61 mg of sodium methylate in this order. The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 300 ml of ethyl acetate and 800 ml of water in this order. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 35.0 g (yield: 67.0%) of methyl 4-(1-diphenylmethoxycarbonyl-2-hydroxyethyl)-2,3,5,6-tetrafluorobenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[NH:5][CH:6]=[C:7]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1Cl)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:15]3[C:14](=[CH:19][CH:18]=[CH:17][N:16]=3)[C:13](=[O:21])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6]2)[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(=CNc1cccc(Br)c1)C(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The crude compound from Step 1 was dissolved in tetrahydrofuran (500 mL), the solution was cooled to 0° C., and sodium hydride (as a 60% dispersion in oil, 9.4 g, 235 mmol) was added in portions. After stirring at 0° for 1 hour, the mixture was allowed to warm up to room temperature. After 2 hours, water (400 mL) was added to the suspension and and the insoluble solid was filtered and washed copiously with water. When dry, the solid was stirred in ether (150 mL) at room temperature for 24 hours and filtered to afford the title compound as a cream-colored solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([NH:35]C(=O)OC(C)(C)C)[CH2:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:43]>ClCCl.O1CCOCC1.CCOCC>[ClH:43].[C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]3([NH2:35])[CH2:34][CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl (1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.55 g) in dichloromethane (50 mL) was added 4.0 M HCl in dioxane (5 mL). The reaction was stirred at room temperature for 6 hours and then diluted with ether (50 mL). The product was removed by filtration under reduced pressure and dried to give 1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutanamine hydrochloride as a pale yellow solid (0.52 g, 88% based on tris HCl salt). 1H NMR (DMSO-d6) 400 MHz δ 8.80 (bs, 3H), 8.68 (s, 1H), 8.12 (dd, JA=4.8 Hz, JB=1.6 Hz, 1H), 7.98-7.95 (m, 1H), 7.57-7.48 (m, 4H), 7.43-7.27 (m, 7H), 7.15 (t, J=7.2 Hz, 1H), 6.91-6.88 (m, 1H), 6.79-6.74 (m, 1H), 2.56 (t, J=8 Hz, 4H), 2.24-2.16 (m, 1H), 1.85-1.77 (m, 1H); LCMS: 456 [M+H]. Calc. for C30H25N5.3.07HCl.0.14 dioxane.0.28 diethylether: C, 63.36; H, 5.37; N, 11.66. Found C, 63.36; H, 5.50; N, 11.67.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:23][C@@H:24]([CH2:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:23][C@@H:24]([CH2:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)=[N:4][CH:3]=1)=[O:30]
Reactant: CC[C@H](C)CCCCC(=O)O
Reactant: CCCc1ccc(-c2ccc(-c3ncc(O)cn3)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(-c2ccc(-c3ncc(OC(=O)CCCC[C@@H](C)CC)cn3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
5-Hydroxy-2(4'-propyl-biphenyl-4-yl)pyrimidine (10 g, 0.034 mol) was dissolved in dichloromethane (100 ml), followed by adding (S)-6-methyloctanoic acid (7.9 g, 0.05 mol), DCC (20.6 g, 0.1 mol) and DMAP (3.3 g), agitating the mixture at room temperature for 2 hours, filtering off deposited crystals, washing the filtrate with 6N-HCl, then with 2N-NaOH and further with water until the washing water became neutral, drying the organic layer over anhydrous magnesium sulfate, distilling off dichloromethane and recrystallizing the residue from ethanol (150 ml) to obtain (S)-5-(6'-methyloctanoyloxy)-2-(4'-propylbiphenyl-4-yl)pyrimidine (9.9 g). This product was a liquid crystal and exhibited the following phase transition points (see also Table 1): ##STR88##
Reaction SMILES: [CH3:1][C:2]1([C:11]#[C:12][Si](C)(C)C)[CH2:7][CH2:6][C:5](=[O:8])[C:4]([C:9]#[N:10])=[CH:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(Cl)Cl.CCOCC>[C:11]([C:2]1([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[C:4]([C:9]#[N:10])=[CH:3]1)#[CH:12]
Reactant: CC1(C#C[Si](C)(C)C)C=C(C#N)C(=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: C#CC1(C)C=C(C#N)C(=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
A solution of 10 (20 mg, 0.086 mmol) in THF (0.6 mL) was degassed by gentle argon stream for 5 min. To the solution was added tetra-(n-butyl)ammonium fluoride (TBAF, 70 mg). The mixture was stirred at room temperature for 20 min. The mixture was diluted with methylene chloride/ether (1:2, 20 mL). The mixture was extracted with saturated aqueous sodium bicarbonate solution (10 mL×3). The basic extract was acidified with 5% aqueous HCl solution. The acidic mixture was extracted with methylene chloride/ether (1:2, 10 mL×4). The extract was washed with water (10 mL×2), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give a crystalline solid. The solid was purified by preparative TLC [hexanes-ethyl acetate (2.5:1)] to give MCE-3 as a crystalline solid (6.9 mg, 50%): 1H NMR (CDCl3) δ 7.39 (1H, d, J=1.8 Hz), 2.84 (1H, m), 2.62 (1H, m), 2.38 (1H, s), 2.32 (1H, m), 2.05 (1H, m), 1.55 (3H, s).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]#[N:20])[N:4]=1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[OH:25][NH:24][C:19]([C:5]1[N:4]=[C:3]([C:2]([F:21])([F:22])[F:1])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)[N:6]=1)=[NH:20]
Reactant: NO
Reactant: N#Cc1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A stirred mixture of 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (example B.2) (1.0 g, 3.15 mmol), hydroxylamine hydrochloride (0.81 g, 11.7 mol) and sodium carbonate (0.67 g, 6.32 mol) in water (15 mL) and ethanol (15 mL) was heated under reflux conditions for 2 h. The ethanol was removed partly and the mixture stirred at room temperature for 0.5 h. The precipitate was collected by filtration, washed with water and dried to yield the title compound (1.08 g, 98%) as a light brown solid. MS (ISP) 351.1 [(M+H)+]; mp 224° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][NH2:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][NH:17][C:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)=[O:13]
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Reactant: CC(C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CNC(=O)CCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.8 %

Procedure:
Combine 3-(4-cyanophenyl)-propionic acid (870 mg, 4.9 mmol), 2,2-dimethylpropylamine (0.6 mL, 5.4 mmol), EDCI (1.0 g, 5.4 mmol), HOBT (804 mg, 5.9 mmol), triethylamine (2 mL, 14.8 mmol) and DMAP (60.5 mg, 0.5 mmol) in anhydrous DCM (50 mL). Stir at room temperature for 1 day under nitrogen. Concentrate the mixture in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (1:1) to obtain the desired intermediate as a white solid (740 mg, 61%). MS (ES+) m/z: 245 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]I>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C#N)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of 2-(4-bromophenyl)acetonitrile (5.0 g, 25.5 mmol) in anhydrous THF (70 mL) was cooled to 0° C. and sodium hydride (60 wt %, 1.5 g, 38.3 mmol) added portion wise. The mixture was stirred at room temperature for 1 h. After which methyl iodide (1.$ mL, 28.1 mmol) was added and the mixture stirred for 14 h. The reaction mixture was carefully quenched with water at 0° C. and diluted with ethyl acetate (200 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue purified by column chromatography (silica, 0-30% ethyl acetate/heptane) to afford the desired product (3.8 g, 72%) as a yellow oil: ESI MS m/z 210 [C9H8BrN+H]+.
Reaction SMILES: CC(C)=O.N[C:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[C:19]([NH:21][CH3:22])=[O:20].Cl>O>[CH3:22][N:21]1[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]=2[C:19]1=[O:20]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C=C(N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Cn1c(-c2ccccc2)cc2onc(-c3ccccc3)c2c1=O
Reaction time: 8 h
Yield: 75.5 %

Procedure:
Under a nitrogen atmosphere, there is added 54 liters of acetone to 5.4 kilograms (16.9 mole) of 5-(2-amino-2-phenylethenyl)-N-methyl-3-phenyl-isoxazole-4-carboxamide at room temperature. To the resulting suspension, there is added 10.8 liters of approximately 5N hydrochloric acid while maintaining the temperature below 25° C. The mixture is then stirred overnight at 25° to 28° C. The resulting suspension is diluted with 16 liters of water at room temperature, and after mixing for 15 minutes, the solids are then filtered off and washed three times with a mixture of acetone/water (2:1). The resulting solids are then dried under reduced pressure at 45° C. to obtain 3.86 kilograms of 5-methyl-3,6-diphenyl-isoxazolo[4,5-c]pyridine-4(5H)-one; m.p. 145° to 148° C. The mother liquor is then concentrated under reduced pressure maintaining the temperature below 50° C. The mother liquor is then cooled to 20° C., the solids filtered off and washed three times with acetone/water (2:1) to obtain a second crop of 290 grams of 5-methyl-3,6-diphenyl-isoxazolo[4,5-c]pyridine-4(5H)-one; m.p. 140° to 145° C.; Yield 81%.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[CH3:25][S:26]([C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32])(=[O:28])=[O:27]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[S:26]([CH3:25])(=[O:28])=[O:27])=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Product: CS(=O)(=O)c1ccccc1C(=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1
Product: Cl

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 2-(methylsulfonyl)benzoic acid, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Methanesulfonyl chloride (966 μl, 12.5 mmol) was added dropwise to a solution of 1-benzylpiperazine (2 g, 11.3 mmol) and triethylamine (1.74 ml, 12.5 mmol) in dry methylene chloride (30 ml) cooled at 0° C. After stirring for 1 hour at ambient temperature, the mixture was partitioned between water and methylene chloride. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate (7/3) to give 1-benzyl-4-methylsulfonylpiperazine (2.5 g, 87%).
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[N:5][CH:4]=1.CS(O[CH2:18][C:19]1[O:20][C:21]2[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=2[C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)=O>CN(C=O)C>[C:24]1([C:23]2[C:22]3[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=3[O:20][C:19]=2[CH2:18][N:7]2[CH:8]=[N:9][C:10]3[C:6]2=[N:5][CH:4]=[N:3][C:11]=3[NH2:12])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)OCc1oc2ccccc2c1-c1ccccc1
Reactant: Nc1ncnc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1oc2ccccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of NaH (60% in mineral oil, 18 mg, 0.43 mmol) in DMF (5 mL) at 0° C. was added 9H-purin-6-ylamine (54 mg, 0.397 mmol). After 5 min stirring at 0° C., a solution of methanesulfonic acid 3-phenylbenzofuran-2-ylmethyl ester from Example 25 (100 mg, 0.331 mmol) in DMF (1 mL) was added dropwise and the mixture was slowly warmed to RT and stirred at RT for 2.5 h. The reaction mixture was then quenched by addition of water and diluted with DCM. The organic layer was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) and triturated form EtOAc with cyclohexane affording 163 as an off-white solid (33 mg, 29%). LCMS: RT 3.85 min [M+H]+ 342.1. 1H NMR (DMSO, 400 MHz): δ 8.21 (1H, s), 8.11 (1H, s), 7.79-7.74 (2H, m), 7.63-7.53 (4H, m), 7.50-7.44 (1H, m), 7.38-7.27 (2H, m), 7.23 (2H, s), 5.65 (2H, s)
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:47]=[C:46]2[C:42]([CH2:43][N:44]([CH3:49])[C:45]2=[O:48])=[CH:41][CH:40]=1.C([O-])(=O)C.[K+]>C(#N)C.O>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:39]2[CH:47]=[C:46]3[C:42](=[CH:41][CH:40]=2)[CH2:43][N:44]([CH3:49])[C:45]3=[O:48])=[CH:9][CH:10]=1
Reactant: CN1Cc2ccc(Br)cc2C1=O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1Cc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc2C1=O
Temperature: 25 °C
Yield: 64.3 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 300 mg), 6-bromo-2-methylisoindolin-1-one (Example 30, step (i), 131 mg) and potassium acetate (171 mg) in a mixture of acetonitrile (15 mL) and water (5 mL) was stirred under nitrogen at 90° C. with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (378 mg). After 4 h the reaction mixture was cooled to room temperature and diluted with water (50 mL). The products were extracted with ethyl acetate (3×50 mL) and the combined extracts dried over magnesium sulfate and concentrated to afford the sub-titled compound (200 mg).
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19]Br)=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O-:26])(=[O:25])[CH3:24].[K+].CN(C)C=O.[I-].[K+]>CCOCC>[C:1]([C:9]1[C:18]([CH2:19][O:26][C:23](=[O:25])[CH3:24])=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)OCc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of 3.0 g. (8.4 mmol.) of 2-benzoyl-3-bromomethylquinoxaline 1,4-dioxide and 0.90 g (9.2 mmol.) of potassium acetate in 40 ml. of N,N-dimethylformamide, was added 0.22 g. (1.3 mmol.) of finely ground potassium iodide. The reaction mixture was stirred for 1.5 hours at ambient temperature, and then it was poured into 1,000 ml. of ether. The solid which precipitated was removed by filtration and discarded. Evaporation of the filtrate in vacuo left a yellow solid which was washed with methanol and dried, to give 2.7 g (94% yield) of 2-benzoyl-3-acetoxymethylquinoxaline 1,4-dioxide, m.p. 164°-167° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[BH4-].ClCCl.[CH3:28][OH:29]>>[CH3:28][O:29][C:9]1[CH:8]=[CH:7][C:12]([CH2:4][NH:1][C@@H:2]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[CH:11][CH:10]=1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Reactant: CO
Agent: [BH4-]
Solvent: ClCCl
Product: COc1ccc(CN[C@H](Cc2c[nH]c3ccccc23)c2nc(-c3ccccc3)c[nH]2)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
2-{(1R)-1-Amino-2-[indol-3-yl]ethyl}-4-pheny-1H-imidazole (36.3 mg, 0.12 mmol) and panisaldehyde (12 μL, 0.1 mmol) in 1 mL of methanol were shaken for about 2 hours at about 22° C. Borohydride resin (76 mg, 2.5 mmol/g, AMBERLITE® IRA400) was then added and the slurry was stirred overnight before addition of dichloromethane (1 mL) and aldehyde Wang resin (31 mg, 3.22 mmol/g, Novabiochem). After about 8 hours of stirring, the slurry was then filtered and vaporated in vacuo to give a yellow solid (32.2 mg, 76%). 1H-NMR (CDCl3, 100 MHz) δ: 8.86 (br s, 1H); 7.73-6.68 (m, 15H); 4.62 (s, 1H); 4.33 (dd, J=4.7 and 8.5 Hz, 1H); 3.81 (s, 2H); 3.74 (s, 3H); 3.27 (ABX system, 2H); 2.26 (s, 1H). LC/MS: m/z=423 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH2:17][OH:18])[O:15][N:14]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Yield: 92.5 %

Procedure:
6-[3-(4-Chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (3.0 g, 8.0 mmol) in THF (20 mL), methanol (5.2 mL) and water (19 mL) was treated with lithium hydroxide monohydrate (678 mg, 16.0 mmol) for 8 h at room temperature. Hydrochloride acid (1 N, 25 mL) and water (200 mL) were added to the reaction mixture. The precipitate was filtered off and washed with water and ethyl acetate to afford the title compound (2.67 g, 93%) as a white solid. MS: m/e=359.0 [M−H]−.