Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C([O-])(=O)C.[Na+].Cl[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O>[C:21]1([CH2:20][CH2:19][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCCc1ccccc1
Reaction time: 8 h
Yield: 66 %

Procedure:
N-Hydroxyphthalimide (15.0 g, 92 mmol) and sodium acetate (7.5 g, 92 mmol) were stirred in dimethylsulfoxide (70 ml) at ambient temperature for 3 h. 2-Chloroethylbenzene (12.5 g, 89 mmol) was added and the reaction mixture was heated at reflux for 2 h. After cooling and standing overnight the reaction mixture was filtered and the flitrate was poured onto ice/water (300 ml). The mixture was extracted with dichloromethane (4×100 ml), the combined extracts were dried (MgSO4) and evaporated in vacuo to a residue. Purification by flash chromatography on a silica gel column eluting with heptane/ethyl acetate (1/1) afforded the title compound as a colourless foam (15.7 g, 33%); 1H NMR (DMSO-d6)γ 3.05 (2H, t, --OCH2 --), 4.39 (2H, t, --CH2Ph), 7.20-7.35 (5H, m, Ar-H), 7.85 (4H, s, Ar-H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:2][C:3]#[CH:4].I[C:19]1[C:27]2[O:26][CH2:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[O:29][CH3:30]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:30][O:29][C:20]1[CH:21]=[CH:22][C:23]2[C:24](=[O:28])[CH2:25][O:26][C:27]=2[C:19]=1[C:4]#[C:3][CH2:2][CH2:1][N:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: C#CCCN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc2c(c1I)OCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C#CCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 35.5 %

Procedure:
A solution of tert-butyl 4-(but-3-ynyl)piperazine-1-carboxylate (0.316 g, 1.33 mmol) in triethylamine (5 mL) was added with 7-iodo-6-methoxybenzofuran-3(2H)-one (0.385 g, 1.33 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.0933 g, 0.133 mmol) and copper(I) iodide (0.0127 g, 0.0665 mmol), and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated, and then added with water, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperazine-1-carboxylate (0.189 g, 35%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:12](Br)[C:13]#[CH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:14][C:13]#[CH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCOc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.9 %

Procedure:
To a solution of 2-(tert-butyl)phenol (21.0 g, 140 mmol) and propargyl bromide (18.8 mL, 168 mmol) in acetonitrile (250 mL) was added potassium carbonate (23.3 g, 168 mmol). The reaction was stirred at ambient temperature for two days. The reaction mixture was diluted with water (50 mL) and extracted diethyl ether (2×150 mL). The combined organic extracts were concentrated to provide 23.7 g (90%) of the title compound which was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ 7.26-7.14 (m, 2H), 7.02 (d, J=8.0 Hz, 1H), 6.94-6.86 (m, 1H), 4.83 (d, J=2.4 Hz, 2H), 3.55 (t, J=2.4 Hz, 1H), 1.34 (s, 9H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[N+](C)([O-])=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:13]([C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([F:9])[CH:11]=2)=[O:14])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2cccc(F)c2)cc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 50.8 %

Procedure:
To commercially available nitromethane (5 ml) were added commercially available anisole (541 mg), commercially available 3-fluorobenzoyl chloride (793 mg) and commercially available scandium(III) trifluoromethanesulfonate (49 mg), and the admixture was stirred at 60° C. for 3 days. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/acetone to obtain 585 mg of the title compound (yield: 51%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[N+:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])([O-:24])=[O:23]>>[N+:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:29])([O-:24])=[O:23]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3cccc([N+](=O)[O-])c3)CC1)O2

Procedure:
Compound 56 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-nitrobenzoyl chloride and conditions outlined in procedure N. M.p.=160-162° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.30 (m, 2H), 7.92 (m, 3H), 7.77 (t, 2H), 760 (m, 1H), 4.40 (m, 1H), 3.52 (brm, 2H), 3.24 (m, 1H), 3.12 (s, 2H), 2.08 (m, 1H), 1.90 (m, 3H); LCMS: 451 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH2:50]([SH:55])[CH2:51][CH2:52][CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:50]([S:55][C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:13][CH:14]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1)[CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCS
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 43 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g), pentylmercaptan (0.12 ml) and potassium carbonate (0.13 g) in acetonitrile (10 ml) was heated under reflux for 4 hours with stirring. The reaction mixture was allowed to cool and the precipitate was removed by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and then 1N hydrochloric acid (1.5 ml) was added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.16 g, 43%).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17](OS(C(F)(F)F)(=O)=O)=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:30])[C:11]1=[O:31])(=[O:3])[CH3:2].[CH3:33][NH2:34]>CO>[C:1]([O:4][C@H:5]([CH3:32])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([NH:34][CH3:33])=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:30])[C:11]1=[O:31])(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(OS(=O)(=O)C(F)(F)F)cc(C)nc2n(C)c1=O
Solvent: CO
Product: CNc1cc(C)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-1,7-dimethyl-5-trifluoromethanesulfonyloxypyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.062 mmol), methanol (1 ml), and 40% aqueous methylamine (1 ml) was stirred at room temperature for 10 minutes. Concentration under reduced pressure provided crude (R)-3-(5-acetoxyhexyl)-1,7-dimethyl-5-(N-methylamino)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione which was used immediately in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([Cl:28])=[C:10]([C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:13]2=[O:23])=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Br[CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43].Cl>CC(C)=O.C(Cl)Cl.CCOCC>[ClH:27].[CH:17]1([N:14]2[CH2:15][CH2:16][CH:12]([CH2:11][C:10]3[C:9]([Cl:28])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[CH:3][CH:4]=4)[CH:26]=[CH:25][C:24]=3[Cl:27])[C:13]2=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CN(C)CCCBr
Reactant: O=C1C(Cc2c(Cl)ccc(-c3ccc(O)cc3)c2Cl)CCN1C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(C)=O
Product: CN(C)CCCOc1ccc(-c2ccc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c2Cl)cc1
Yield: 65.1 %

Procedure:
Place 3-(3-(4-hydroxyphenyl)-2,6-dichlorobenzyl)-1-cyclohexylpyrrolidin-2-one (0.200 g, 0.478 mmol), sodium iodide (0.072 g, 0.478 mmol, and cesium carbonate (1.25 g, 3.82 mmol) in acetone (lOmL). Add 3-bromo-N,N-dimethylpropan-1-amine hydrochloride (0.194 g, 0.956 mmol) and stir at room temperature for 3 hours. Add water and extract with DCM. Dry, filter, and concentrate. Purify by silica gel to give the free base. Dissolve in DCM and add 2M HCl in ether. Concentrate to give 84 mg (33%) of the title compound as a tan solid. Mass spectrum (apci) m/z=503.3 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:14]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:12][C:11]3=[O:15].[BH4-].[Na+]>CCO>[CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:14]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:12][CH:11]3[OH:15]
Reactant: CSc1nccc2c1cc1n2CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CSc1nccc2c1cc1n2CCC1O
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(methylthio)-6,7-dihydro-8H-pyrido[3,4-b]pyrrolizin-8-one from Example 6 method-1 Step 5 (0.55 g, 2.2 mmol) in EtOH (10 mL)-TH (1 mL) was added NaBH4 (0.10 g, 2.6 mmol) at 0° C. After a period of 30 min. at room temperature, the reaction was quenched by the addition of acetone. The solvents were evaporated under reduced pressure and EtOAC and H2O were added to the residue. The organic phase was separated, dried over MgSO4 and evaporated. The title compound was washed with EtOAc/Hexane and filtered.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[N:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C=O)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:14][N:13]=[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: ON=C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(ON=C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
Following method A, potassium t-butoxide (37 g, 320 mmol) was added in portions to a cooled (2° C.) solution of cyclohexanone oxime (35 g, 300 mmol) in DMF (350 mL). The cooled reaction mixture was stirred for 20 minutes and then 1-chloro-4-nitrobenzene (50 g, 320 mmol) was added in portions. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure to remove the DMF and then treated with water (300 mL). The precipitate was collected by filtration and washed with water. Recrystallization of the crude material from isopropanol and column chromatography provided cyclohexanone O-(4-nitro-phenyl)-oxime (48 g). Cyclohexanone O-(4-nitro-phenyl)-oxime (48 g, 205 mmol) was dissolved in warm isopropanol (350 mL) and 12 N hydrochloric acid (94 mL) was added. The reaction mixture was heated to reflux for 3.5 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven to give 8-nitro-1,2,3,4-tetrahydro-dibenzofuran (33 g, 150 mmol). A mixture of 8-nitro-1,2,3,4-tetrahydro-dibenzofuran (11 g, 50 mmol) and Raney nickel (˜11 g wet weight) in ethanol (200 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was recrystallized from hexane to give 6,7,8,9-tetrahydro-dibenzofuran-2-YLAMINE (7.6 g). Mp 71-72° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O-:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].S(C1C=CC(C)=CC=1)(O[CH2:24][C@@H:25]1[O:27][CH2:26]1)(=O)=O.CN(C=O)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][CH2:24][C@H:25]1[CH2:26][O:27]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: O=[N+]([O-])c1ccc([O-])c(OCc2ccccc2)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
A 30 L jacketed reactor is charged with potassium 2-(benzyloxy)-4-nitrophenolate (1.31 kg, 4.62 mol), (R)-glycidyl tosylate (1.13 kg, 4.96 mol) and DMF (6.5 L). The resulting suspension is heated until an internal temperature of 65° C. is obtained, and is then stirred for 18 h. The solution is cooled to 20° C., and then water (2 L) is added over 30 min. The solution is seeded with 2 g of the desired product, and the addition of water is resumed (9 L over 1.25 h). The slurry is stirred for 2.5 h, and then collected by vacuum filtration. The reactor and filter cake are washed with water (5 L total) and suction dried to give the title compound (1370 g, 98%) as an off-white powder. LCMS (Standard Method): 2.74 min, 302 (M+H)−. 1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J=2.6, 9.0 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.48-7.34 (m, 5H), 6.98 (d, J=8.8 Hz, 1H), 5.19 (s, 2H), 4.43 (dd, J=2.7, 11.5 Hz, 1H), 4.08 (dd, J=5.8, 11.5 Hz, 1H), 3.43-3.39 (m, 1H), 2.95-2.91 (m, 1H), 2.81-2.78 (m, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH2:11][C:12]#[N:13].Br[CH:15]([CH3:17])[CH3:16].[OH-].[K+]>CS(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:11]([CH2:16][CH2:15][CH3:17])[C:12]#[N:13]
Reactant: CC(C)Br
Reactant: N#CCc1sccc1C1OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CS(C)=O
Product: CCCC(C#N)c1sccc1C1OCCO1
Reaction time: 0.42 h
Yield: 49 %

Procedure:
1.43 g (7.32 mmol) of 3-(1,3-dioxolan-2-yl)-2-thiopheneacetonitrile was dissolved in 2 ml of dimethyl sulfoxide, and 1.08 g (8.78 mmol) of 2-bromopropane, 100 mg (cat) of tetra-n-butylammonium iodide and 3 ml of 50% potassium hydroxide were successively added. After 25 minutes, 300 mg of 2-bromopropane, further after 50 minutes, 1 ml of 50% potassium hydroxide and 2 ml of DMSO were added. After completion of the reaction, brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to obtain a crude product. The crude product was subjected to 100 g of silica gel (ethyl acetate:hexane=1:8), to give 853 mg (3.59 mmol, 49.1%) of the title compound as a yellow oil.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([CH:3]=[O:2])[CH2:6][CH2:7]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: -60 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a solution of 1-benzyloxycarbonyl-piperidine-4-carboxylic acid methyl ester (2.0 g, 7.2 mmol) in anhydrous toluene (20 mL) at −78° C. was added DIBAL-H (15.2 mL of a 1 M solution in hexane, 15.2 mmol, 2 eq.) in a drop-wise fashion. The mixture was stirred at −60° C. for 2 h then quenched by addition of 1 N HCl. The resulting mixture was extracted with EtOAc (3×50 mL) and the combined organic extracts were washed with saturated brine (50 mL) then dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude residue was purified by flash column chromatography by eluting 9:1 toluene/EtOAc to give 1-benzyloxycarbonyl-piperidine-4-carboxaldehyde as a colorless gum (0.49 g, 2.09 mmol, 28%). 1H NMR (300 MHz, CDCl3): δ9.75 (s, 1H), 7.46 (m, 5H), 5.24 (s, 2H), 4.15 (m, 2H), 3.12 (t, 2H), 2.54 (m, 1H), 2.02 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:36]([O:1][CH:2]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[O:11])=[CH:7][CH:8]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1ccc(C(O)c2ccccc2)cc1)C1CC(c2cccnc2)=NO1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
) A suspension of compound (50) (0.021 mol), N,N-dimethyl-4-pyridinamine (0.042 mol) and triethylamine (catalytic quantity) in CH2Cl2 (100 ml) was stirred at RT. Acetic acid anhydride (0.042 mol) was added and the resulting reaction mixture was stirred and refluxed until a clear solution was obtained. The mixture was stirred and refluxed for an extra 30 minutes, then cooled to RT. Water was added. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure, yielding 8.0 g of (±)-[4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]phenyl]phenylmethyl acetate (compound 414).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH2:21])([CH3:3])[CH3:2].O1CCC[CH2:23]1.C[Mg]Br.C(OCC)(=O)C>C(OCC)C>[CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH2:23])[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH2:21])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=C(c1ccccc1)c1ccc2nc(N)n(C(C)C)c2c1
Reaction time: 8 h

Procedure:
Three grams (10.7 mmoles) of 1-isopropyl-2-amino-6-benzoylbenzimidazole were dissolved in 25 ml. of tetrahydrofuran, after which was added 27 ml. of a 2M solution of methyl magnesium bromide in ethyl ether. After stirring overnight, ethyl acetate was added, and the solution was washed three times with a saturated sodium chloride solution. The organic solution was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. One hundred milliliters of 98% formic acid were added to the residue. The solution was refluxed for 2 hours. The formic acid was evaporated under reduced pressure. Ethyl acetate was added, and the resulting solution was washed with a saturated sodium bicarbonate solution. After drying over magnesium sulfate, the solution was filtered and concentrated. Upon the addition of a small volume of ether, 2.0 g. of the title product solidified out of solution which was recovered by filtration, M+ =277.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][CH2:10][O-:11].[Na+]>CCO>[Cl:1][C:2]1[N:7]=[C:6]([O:11][CH2:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloropyrimidine (20 g, 0.13 mmol) in 240 mL of anhydrous EtOH was added slowly 1M NaOEt in EtOH over 2 hrs at −3° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The organic solvent was evaporated in vacuo and the residue was partioned between water and Et2O. The aqueous phase was extracted with Et2O and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH:13]([OH:16])[CH2:14][CH3:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1[N:21]=[CH:20][N:19]([C:22](N2C=NC=C2)=[O:23])[CH:18]=1>C(#N)C>[N:19]1([C:22]([O:16][CH:13]([C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[CH2:14][CH3:15])=[O:23])[CH:18]=[CH:17][N:21]=[CH:20]1
Reactant: CCC(O)c1ccc(-c2ccccc2)nc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CCC(OC(=O)n1ccnc1)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 44a (150 mg, 0.70 mmol), CDI (570 mg, 3.52 mmol) and acetonitrile (9 mL) according to Method E. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. White solid. Yield: 116 mg, 54%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.04 (t, J=7.4 Hz, 3H), 2.01-2.15 (m, 1H), 2.22 (dt, J=14.3, 7.2 Hz, 1H), 5.92 (t, J=7.1 Hz, 1H), 7.09 (dd, J=1.6, 0.6 Hz, 1H), 7.41-7.51 (m, 4H), 7.75-7.80 (m, 2H), 7.98-8.03 (m, 2H), 8.17-8.19 (m, 1H), 8.74-8.77 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=9.8, 28.7, 79.8, 117.0, 120.3, 126.9, 128.8, 129.3, 130.8, 132.3, 135.0, 137.0, 138.6, 148.0, 148.3, 158.0; MS (ESI): m/z=308.30 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]([CH:31]([CH3:33])[CH3:32])[C:8](=[O:30])[C:9]2[CH:14]=[CH:13][C:12]([CH:15](O)[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[C:11]([CH3:29])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.S(=O)(=O)(O)O.[Pd].C(OCC)(=O)C>[CH:1]1([N:7]([CH:31]([CH3:33])[CH3:32])[C:8](=[O:30])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[C:11]([CH3:29])[CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(O)c2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2C)cc(OC)c1OC
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(Cc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2C)cc(OC)c1OC

Procedure:
The compound of Example 47 (800 mg, 1.81 mmol) in EtOH (20 mL) containing concentrated sulfuric acid (4 drops) is hydrogenated at 60 psi and room temperature using 5% Pd/C as catalyst. The catalyst is filtered and the filtrate concentrated in vacuo to give the crude product. The crude product is dissolved in ethyl acetate and washed twice with aqueous NaHO3 solution and then with saturated aqueous NaCl solution. After drying (Na2SO4) the organic layer is filtered and concentrated in vacuo. Purification to give the title compound is carried out by chromatography of the residue on silica gel using mixtures of ethyl acetate and hexane as the eluents.