Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:9])([O-])=O.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]2[NH:19][C:18]3[CH:17]=[CH:16][C:6]([NH:7][C:8](=[O:9])[C:10]4[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccncc1
Product: COc1ccc(-c2nc3cc(NC(=O)c4ccncc4)ccc3[nH]2)cc1

Procedure:
Compound 205 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(pyridin-4-oyl)aniline and 4-methoxybenzaldehyde. [M+H]+ calcd for C20H16N4O2: 345.13; found: 345.00.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([O:11]C)=[CH:4][CH:3]=1>Br>[F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(C(=O)O)c1
Agent: Br
Product: O=C(O)c1cc(O)ccc1F
Temperature: 100 °C

Procedure:
6-Fluoro-3-methoxybenzoic acid (500 mg, 2.94 mmol) was mixed with freshly distilled 48% HBr (20 mL) and heated at 100° C. for 14 h. Water and HBr were evaporated and the crude product (462 mg) was used without further purification. 1H NMR(CD3OD): δ 7.28-7.29 (m, 1H), 6.92-7.12 (m, 2 H); 13C NMR (CD3OD): δ 167.80, 157.26 (d, J=249 Hz), 154.77, 122.52 (d, J=10.4 Hz), 120.49 (d, J=11 Hz), 118.77 (d, J=19 Hz), 118.58.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]1=2.[C:19]([Cu])#[N:20]>C1C=CC=CC=1.CCCCCC>[C:19]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]1=2)#[N:20]
Reactant: N#C[Cu]
Reactant: COc1ccc2c(c1)C(Cl)c1ccccc1CO2
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COc1ccc2c(c1)C(C#N)c1ccccc1CO2

Procedure:
11-Chloro-2-methoxy-6,11-dihydrodibenz[b,e]oxepin (10.1 g; 0.038 mole) of Example 24A is dissolved in dry benzene (170 ml) and placed under a dry nitrogen atmosphere. To this solution is added in one portion, CuCN (8.5 g; 0.095 mole). The reaction is brought to reflux (twenty minutes), filtered while hot and the salts are washed with benzene. Removal of the solvent in vacuo yields an oil. The oil is dissolved in a minimal amount of benzene and hexane is added with cooling. The resulting solid is filtered and recrystallized from ethanol to give a solid of 11-cyano-2-methoxy-6,11-dihydrodibenz[b,e]oxepin, m.p. 120°-122° C.
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[Na+].N#N.C[SiH](O)C.C[Si](C)(C)C.C[Si](O)(C)C.[C:23]1(C)[CH:28]=[CH:27]C=[CH:25][CH:24]=1>Cl[Cu]>[C:2]1([CH3:4])[CH:3]=[C:28]([CH3:27])[CH:23]=[C:24]([CH3:25])[CH:1]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: Cl[Cu]
Agent: C[SiH](C)O
Agent: C[Si](C)(C)O
Solvent: C[Si](C)(C)C
Product: Cc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
General procedure for the kinetic resolution of racemic 3,5-dialkyl cyclopentenones. A flame dried Schlenk flask was charged with (S)-p-tol-BINAP (5 mol %) and toluene. To this solution CuCl (5 mol %) and NaOt-Bu (5 mol %) were added in a drybox (N2 atmosphere) and to the resulting light yellow solution PMHS (0.53 equiv.) was added at room temperature to give orange solution. Stirred for 20 minutes at room temperature then cooled down to the required temperature (see Kinetic Resolution Results table for reaction temperatures) and solution of substrate and mesitylene in toluene was dropwise added and stirred for 12 hours at the addition temperature. The optimal substrate's concentration is 0.1-0.4 M. The relative substrate and internal standard (mesitylene) amounts were determined by Hewlett-Packard 6890 gas chromatograph (50 to 250° C.). Reaction is quenched by addition of water and then stirring the organic phase with TBAF. Relative amounts of remaining starting material and internal standard were determined by gas chromatography and the conversion calculated. Then water added, extracted with diethyl ether, washed with brine, dried over anhydrous magnesium sulfate, and concentrated. Purified by flash chromatography. Eluent: hexane/ethyl acetate 8:1. The remaining starting was analyzed by HPLC and product was analyzed by HPLC or GC.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[NH2:9][C:10]1[C:22]([Br:23])=[CH:21][C:13]2[C:14]([C:17]([NH:19][CH3:20])=[O:18])=[CH:15][O:16][C:12]=2[CH:11]=1.[B:24](OC)([O:27]C)[O:25]C.[NH4+].[Cl-]>C1COCC1>[NH2:9][C:10]1[C:22]([Br:23])=[CH:21][C:13]2[C:14]([C:17](=[O:18])[NH:19][CH3:20])=[C:15]([B:24]([OH:27])[OH:25])[O:16][C:12]=2[CH:11]=1
Reactant: COB(OC)OC
Reactant: CNC(=O)c1coc2cc(N)c(Br)cc12
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC(=O)c1c(B(O)O)oc2cc(N)c(Br)cc12
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of LDA in THF (62.5 mmol, 70 mL, freshly prepared), 6-amino-5-bromo-N-methylbenzofuran-3-carboxamide (4 g, 14.86 mmol) in THF (60 mL) was added dropwise at −78° C. under N2. After the mixture was stirred for 1 hour, trimethyl borate (6.18 g, 59.5 mmol) was added dropwise at −78° C. After the mixture was stirred for 1 hour, NH4Cl (a.q.) was added, and the mixture was extracted with EtOAc (100 mL×3), dried over Na2SO4, filtrated and concentrated to give (6-amino-5-bromo-3-(methylcarbamoyl)benzofuran-2-yl)boronic acid (3.3 g, yield: 70%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.56 (s, 2H), 8.46 (d, J=4.8 Hz, 1H), 8.00 (s, 1H), 6.95 (s, 1H), 5.20˜5.82 (br s, 2H), 2.87 (d, J=4.8 Hz, 3H). MS (M+H)+: 313/315.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[CH3:29][C:30]1[O:34][C:33]([C@@H:35]([CH:37]2[CH2:41][CH2:40][CH2:39][O:38]2)O)=[CH:32][CH:31]=1.O>C1(C)C=CC=CC=1>[N:15]([C@H:35]([CH:37]1[CH2:41][CH2:40][CH2:39][O:38]1)[C:33]1[O:34][C:30]([CH3:29])=[CH:31][CH:32]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc([C@H](O)C2CCCO2)o1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1ccc([C@H](N=[N+]=[N-])C2CCCO2)o1
Temperature: 0 °C
Reaction time: 24 h
Yield: 62.8 %

Procedure:
11.9 ml (55.3 mmol; 1.2 eq) of diphenylphosphoryl azide and then 8.3 ml (55.3 mmol; 1.2 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added dropwise to a solution of 8.40 g (46.1 mmol; 1.0 eq) of (5-methylfuran-2-yl)-(R)-tetrahydrofuran-2-ylmethanol in 300 ml of toluene cooled to 0° C. The mixture was allowed to return to ambient temperature gently and was then stirred for 24 hours. The reaction medium was treated with water and extracted with ethyl acetate, The organic phases were combined, washed with a 1 M sodium dihydrogen phosphate solution, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (column puriFlash IR-50SI/300G, puriFlash) eluted with heptane/ethyl acetate (90/10). 6.0 g of 2-((R)-azidotetrahydrofuran-2-ylmethyl)-5-methylfuran were obtained (mixture of the 2 diastereoisomers). Yield=63%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:25]OS(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:25][N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: COC(=O)CCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(5-methoxycarbonylpentyl)propanamide (150.3 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(1H-imidazol-1-yl)propanamide (46.8 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: C([O:8][C:9]([C:18]1[N:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:49])[CH2:31][N:32]3[C:36](=[O:37])[C:35]([C:39]4[CH:40]=[CH:41][C:42]5[O:46][CH2:45][CH2:44][C:43]=5[CH:47]=4)([CH3:38])[NH:34][C:33]3=[O:48])[CH2:26][CH2:25]2)=[C:20]([CH2:50][CH2:51][CH3:52])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])C1C=CC=CC=1>CO.[C].[Pd]>[O:46]1[C:42]2[CH:41]=[CH:40][C:39]([C:35]3([CH3:38])[NH:34][C:33](=[O:48])[N:32]([CH2:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([C:21]5[CH:22]=[N:23][C:18]([C:9]([OH:8])([C:14]([F:15])([F:16])[F:17])[C:10]([F:11])([F:12])[F:13])=[CH:19][C:20]=5[CH2:50][CH2:51][CH3:52])[CH2:29][CH2:28]4)=[O:49])[C:36]3=[O:37])=[CH:47][C:43]=2[CH2:44][CH2:45]1
Reactant: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)CCO4)C2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)CCO4)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
3-[2-(4-{6-[2-(Benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-4-propylpyridin-3-yl}piperazin-1-yl)-2-oxoethyl]-5-(2,3-dihydrobenzofuran-5-yl)-5-methylimidazolidine-2,4-dione (13 mg, 0.0170 mmol) was dissolved in methanol (1.5 mL), added palladium carbon (2.0 mg), and the mixture was stirred at room temperature for 2 hours under a hydrogen atomosphere. The reaction solution was filtered through a pad of celite, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone), and the title compound (7.3 mg (yield 80%)) was obtained as a yellow oil.
Reaction SMILES: C(O)(=O)CCC(C)=O.C(O)=O.O.[C:13]12([CH2:23]S(O)(=O)=O)[C:20]([CH3:22])([CH3:21])[CH:17]([CH2:18][CH2:19]1)[CH2:16][C:14]2=[O:15].C(O)CCCO>>[C:13]12([CH3:23])[C:20]([CH3:22])([CH3:21])[CH:17]([CH2:18][CH2:19]1)[CH2:16][C:14]2=[O:15]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CC(=O)CCC(=O)O
Solvent: O=CO
Solvent: OCCCCO
Solvent: O
Product: CC12CCC(CC1=O)C2(C)C

Procedure:
A crude levulinic acid composition comprising 14.9 g (0.128 mol) levulinic acid, 0.449 g (9.76×10−3 mol) formic acid, 30 g (1.66 mol) DI water, and 0.3484 g (1.50×10−3 mol) camphor sulfonic acid was esterified with 2.89 g (3.21×10−2 mol) 1,4-butanediol. The procedure for Example 6 was followed, and analysis of the reaction mixture by GC-FID showed a peak corresponding to LA-BDO-LA.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20]P(=O)(OCC)OCC)=[CH:18][CH:17]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C1OCCOCCOCCOCCOC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:20][C:19]2[CH:29]=[CH:30][C:16]([F:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(F)cc1)OCC
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
A solution of 59.78 g of N-t-butoxycarbonylpiperidone and 81.25 g of diethyl 4-fluorobenzylphosphonate in 150 ml of tetrahydrofuran was added dropwise to a suspension of 13.20 g of 60% sodium hydride (in oil) containing 1.65 g of 15-crown-5 ether in 650 ml of tetrahydrofuran which was cooled in an ice bath over 20 minutes. After 1 day of stirring at room temperature, saturated aqueous sodium bicarbonate was carefully added to the reaction mixture which was subsequently extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine and dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and then the resulting filtrate was concentrated under reduced pressure and purified by a flash column chromatography (silica gel: Wako Gel C200 (manufactured by Wako Pure Chemical Industries), eluant: hexane-ethyl acetate=20.1) to obtain 55.23 g of N-t-butoxycarbonyl-4-(4-fluorobenzylidene)piperidine. The thus obtained oily product was crystallized after its overnight standing at room temperature.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[CH2:9]([OH:19])[C:10]1[CH:18]=[CH:17][C:16]2[O:15][CH2:14][O:13][C:12]=2[CH:11]=1.OO.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[O-][W]([O-])(=O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+].P([O-])([O-])(O)=O.[Na+].[Na+].O>[CH:18]1[C:10]([CH:9]=[O:19])=[CH:11][C:12]2[O:13][CH2:14][O:15][C:16]=2[CH:17]=1
Reactant: OCc1ccc2c(c1)OCO2
Agent: O=[W](=O)([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])(O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: O=Cc1ccc2c(c1)OCO2
Temperature: 94.5 °C
Yield: 90.2 %

Procedure:
In a glass-made reaction vessel equipped with a thermometer, a temperature controller, a dropping device and a stirring device were charged 220 ml of xylene, 76.01 g (500 mmol) of piperonyl alcohol, 1.65 g (5.0 mmol) of sodium tungstate.dihydrate (Na2WO4.2H2O), 1.70 g (5.0 mmol) of tetrabutyl ammonium hydrogen sulfate and 9.42 g of water. Then, to the mixture were added 2.34 g (1.6 mmol) of sodium dihydrogen phosphate.dihydrate and 3.56 g (1.0 mmol) of disodium hydrogen phosphate.1 dihydrate, and a pH of the reaction mixture was adjusted to pH 6.0. Next, an inner temperature of the reaction mixture was maintained from 94 to 95° C., 48.0 ml (991 mmol) of 60% aqueous hydrogen peroxide was added dropwise to the mixture with 141 mmol/hr, while maintaining the pH of the reaction mixture to 5.5 to 6.5 by using 8 mol/L aqueous sodium hydroxide solution. After completion of the reaction, the resulting reaction mixture was cooled to room temperature, and the organic layer was separated as a solution. The resulting organic layer solution was washed with 80 mL of 1 mol/L aqueous sodium hydroxide solution, and the solvent, xylene was distilled off with (1.3 kPa/132° C.) to obtain 67.7 g of piperonal as white solid (yield: 89.3%, based on piperonyl alcohol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:26][C:25]([C:27]([NH:29][CH:30]([CH:35]([CH3:37])[CH3:36])[C:31]([O:33][CH3:34])=[O:32])=[O:28])=[N:24][CH:23]=2)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:26][C:25]([C:27]([NH:29][C@@H:30]([CH:35]([CH3:37])[CH3:36])[C:31]([O:33][CH3:34])=[O:32])=[O:28])=[N:24][CH:23]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3Cl)cc2)o1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 1, using 2-chloro-4-(trifluoromethyl)-1-isocyanatobenzene (0.533 mmol) and intermediate 1. 1H NMR (DMSO-d6, 300 MHz): δ 9.883 (s, 1H), 9.025-8.998 (d, 1H), 8.707 (s, 1H), 8.498-8.469 (d, J=8.7 Hz, 1H), 7.904-7.898 (d, J=1.8 Hz, 1H), 7.842 (s, 1H), 7.837-7.807 (d, J=9 Hz, 2H), 7.723-7.688 (dd, J=1.8, 9 Hz, 1H), 7.653-7.624 (d, J=8.7 Hz, 2H), 4.332-4.2827 (m, 1H), 3.682 (s, 3H), 2.228-2.219 (m, 1H), 0.982-0.960 (d, J=6.6 Hz, 6H); MS (ESI) m/z 537 (M−H), 539 (M+H).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:14][C:15]1[C:20]2[C:21](=[O:33])[N:22]([CH3:32])[CH2:23][C:24]3[N:25]([CH:26]=[N:27][C:28]=3[C:29]([NH2:31])=O)[C:19]=2[CH:18]=[CH:17][CH:16]=1>O1CCOCC1.N1C=CC=CC=1>[F:14][C:15]1[C:20]2[C:21](=[O:33])[N:22]([CH3:32])[CH2:23][C:24]3[N:25]([CH:26]=[N:27][C:28]=3[C:29]#[N:31])[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CN1Cc2c(C(N)=O)ncn2-c2cccc(F)c2C1=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN1Cc2c(C#N)ncn2-c2cccc(F)c2C1=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 85.3 %

Procedure:
7.7 ml (55.3 mmol) of trifluoroacetic anhydride were added dropwise at 5°-8° to a suspension of 13.8 g (50.3 mmol) of 7-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxamide (EPA 150 040) in 80 ml of dioxan and 20 ml of pyridine. The beige solution obtained was stirred at 5° for 2.5 hours and subsequently poured into 220 ml of ice-water. The resulting precipitate was filtered off. After drying at 70°/10 Torr there were obtained 11 g (85%) of 7-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile as a white powder of m.p. >250°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)(=O)C.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC1(Cc2ccccc2)CCN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OCCC1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 1-benzyl-3-(phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine (1.19 g, 2.81 mmol) and tetrahydrofuran (20 mL). Cool in an ice bath. Add dropwise a solution of lithium aluminum hydride (2.81 mL, 1 M in THF, 2.81 mmol). After the addition is complete, warm to ambient temperature. After 2 hours, heat to reflux. After 1 hour, cool to ambient temperature and cautiously add water (0.11 mL), a solution of 1 M sodium hydroxide (0.11 mL), and water (0.32 mL). Stir vigorously. After 2 hours, filter through celite and rinse with dichloromethane. Dry the filtrate over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf=0.34 (silica gel, 2% triethylamine/30% methanol/ethyl acetate).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([CH3:18])=[C:8]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(OCC)(=O)C.[BrH:25]>S(=O)(=O)(O)O.C(O)(=O)C.O.[Cu]Br>[Br:25][C:6]1[C:7]([CH3:18])=[C:8]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1ccc(Cl)c(N)c1C
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(Cl)c(Br)c1C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of sodium nitrite (13 g) in concentrated sulphuric acid was added during 0.5 hours to a solution of ethyl 3-amino-4-chloro-2-methylbenzoate (22.4 g) in acetic acid, keeping the temperature below 15° C. After stirring for a further 1 hour at 5° C., the resulting diazonium mixture was added during 0.75 hours to a solution of copper (I) bromide (31 g) in hydrobromic acid (45%, 103 ml) and water. Heating to 40° C. was continued for a further 2 hours before addition of water and extraction (ethyl acetate). The extract was washed (sodium hydroxide solution), dried (magnesium sulphate) and evaporated to give ethyl 3-bromo-4-chloro-2-methylbenzoate (22.2 g) as a brown oil, NMR (CDCl3) 1.3 (t,3H), 2.65 (s,3H), 4.3 (q,2H), 7.45 (m,2H).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH:14]=[CH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH2:14][CH2:15][N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)Cc1ccccc1
Yield: 38 %

Procedure:
A solution of 1.0 g (4.44 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.24 ml (2.22 mmol) benzylamine in 25 ml acetonitrile was stirred for 16 h at 80° C. Concentration in vacuo and flash chromatography (gradient: 0-10% MeOH in EtOAc) afforded 470 mg (34%) of the title compound as a yellow oil. MS m/e (%): 558 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@:2]1([CH3:9])[C:3]([OH:5])=[O:4].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[OH-].[Na+].Cl>O1CCOCC1.O>[CH2:14]([O:13][C:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@@:2]1([CH3:9])[C:3]([OH:5])=[O:4])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@]1(C(=O)O)CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@]1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To the solution prepared by dissolving 500 mg of H-α-Me-Pro-OH (commercially available from Chem-Impex International Inc.) and 693 mg of benzyl chloroformate in 10 mL of 1,4-dioxane and 5 mL of water, a 1 M aqueous sodium hydroxide solution was added at room temperature so as to keep pH 10, and the solution was stirred at room temperature for 30 minutes. To the reaction solution, 5 M HCl was added so as to adjust the pH to 2, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure to obtain 842 mg of 1-[(benzyloxy)carbonyl]-2-methyl-L-proline [63-1] (hereinafter, referred to as the compound [63-1]).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:26]=[CH:25][C:10]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=2)=[O:12])=[CH:9][CH:8]=1.[H-].[Na+].[C:29]1([CH2:35][CH2:36][CH2:37][CH:38]([C:49]([O-:51])=[O:50])[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:29]1([CH2:35][CH2:36][CH2:37][C:38]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([CH2:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[C:10]3[CH:25]=[CH:26][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:8][CH:9]=3)=[CH:18][CH:19]=2)([C:49]([O:51][CH2:2][C:7]2[CH:26]=[CH:25][CH:10]=[CH:9][CH:8]=2)=[O:50])[C:39]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C([O-])C(CCCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(NCCCc1ccc(CCl)cc1)c1ccc(-c2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Product: O=C(NCCCc1ccc(CC(CCCc2ccccc2)(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1)c1ccc(-c2ccccn2)cc1
Yield: 133 %

Procedure:
In a similar manner to that described in Reference example 2(a), a reaction was carried out using 4-[3-(4-pyridine-2-ylbenzoylamino)propyl]benzylchloride (488 mg), which is the product of Reference example 50(c), sodium hydride (55% suspension in oil, 64 mg) and benzyl (3-phenylpropyl)malonate (540 mg) and the reaction mixture was treated to afford the title compound (0.65 g) as a syrup.
Reaction SMILES: [C:1]1([S:7][C:8](=[CH2:11])[CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[C:1]1([S:7]([C:8](=[CH2:11])[CH2:9][OH:10])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(CO)Sc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C=C(CO)S(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a stirred solution of 0.91 g (5.5 mmol) of 2-(phenylthio)-2-propenyl alcohol in 60 mL of CH2Cl2 at -78° C. was added 1.11 g (5.5 mmol) of 85% m-chloroperbenzoic acid. The reaction mixture was stirred for 1 hour at -78° C. The cooling bath was removed and the mixture allowed to warm to room temperature. The mixture was filtered, and then extracted with three 50-mL portions of saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. The residue was flash chromatographed on silica gel (230-400 mesh, 4×12-cm packed column) with 80% EtOAc/Skelly B as eluant, to give 0.57 g (57%) of the sulfoxide as a colorless oil; IR (neat) cm-1 3360, 1440, 1030, 990, 930, 750, 690; 1H NNR (CDCl3) δ4.00 (s, 1 H, allylic), 4.15 (s, 1H, allylic), 4.40 (bs, 1H, OH), 5.90 (t, J=1 Hz, 1H, vinyl), 6.05 (s, 1H, vinyl), 7.35-7.80 (m, 5H, phenyl).