Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[C:12]=2[OH:19])[CH:3]=1.Br[CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[C:12]=2[O:19][CH2:21][CH2:22][OH:23])[CH:3]=1
Reactant: OCCBr
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1OCCO
Reaction time: 22 h
Yield: 83 %

Procedure:
A solution of 4-chloro-2-(3-formyl-2-hydroxyphenoxy)benzonitrile (0.30 g, 1.1 mmol), 2-bromoethanol (0.10 mL, 0.18 g, 1.4 mmol) and cesium carbonate (0.43 g, 1.3 mmol) were heated with stirring in dry DMF (3 mL) at 50° C. After 22 h, 2-bromoethanol (0.19 mL, 0.33 g, 2.7 mmol) was added, and stirring continued for an additional 24 h at 50° C. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (3×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-[3-formyl-2-(2-hydroxyethoxy)phenoxy]benzonitrile (0.29 g, 83%) as a tan oil, which was used without further purification.
Reaction SMILES: ClC1C=CC(C(C(C)C)C([O:11][CH2:12][C:13]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])([OH:20])[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=O)=CC=1.[OH-].[Na+]>C(O)C.O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:13]([OH:20])([CH2:12][OH:11])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CC(C)C(C(=O)OCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of (-)-3-[2-(4-chlorophenyl)isovaleroyloxy]-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2-propanol (6.85 g; M.P., 174°-175° C.) in ethanol (60 ml) was added a solution of sodium hydroxide (1.8 g) in water (10 ml), and the mixture was heated with stirring at 80° C. for 4 hours. The solvent was removed in vacuo and the residue was dissolved in 6N hydrochloric acid (70 ml). The acidic aqueous solution was washed with chloroform (20 ml×2) and then neutralized with a 28% aqueous ammonia solution. The resulting crystals were collected by filtration to give (-)-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2,3-propanediol. Yield, 3.6 g; 88%. M.P., 138.5°-141° C. [α]D24, -108.5° (C=1.0, MeOH).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH:14]=O)=[CH:8]2)[C:2]([CH3:4])=[O:3].C[O:17][C:18](=[O:39])[CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH:14]=[CH:19][C:18]([OH:39])=[O:17])=[CH:8]2)[C:2]([CH3:4])=[O:3]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1ccc2[nH]c(C=O)cc2c1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc2[nH]c(C=CC(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
16 (340 mg, 0.7 mmol) was added to a solution of methyl(triphenylphosphoranylidene)acetate (2|57 mg, 0.77 mmol) in toluene (30 mL) and the reaction mixture was heated to reflux for 3 days. The solvent was removed after cooled to room temperature. Ethyl acetate (10 mL) was added to the residue and the resulted precipitate 17 was filtered. MS (ion spray) (M+H) 259. Without further purification 17 was dissolved in DMF (3 mL) and methanol (5 mL) was added. 3N NaOH solution (2 mL) was added and the reaction mixture was stirred overnight. The solvent was removed and water (10 mL) was added. The solution was neutralized using 20% HCl. The resulting precipitate was filtered and washed with water. 44 mg (26% yield) of yellow solid 18 was obtained. mp: 238°-239° C. 1H NMR (DMSO-d6, ppm): 12.25 (brs, 1 H, COOH), 11.42 (s, 1 H, NH), 9.74 (s, 1 H, NH), 7.88 (s, 1 H, Ar--H), 7.55-7.50 (d, 1 H, J=16.0 Hz, CH=CH), 7.28 (s, 2 H, Ar--H) 6.80 (d, 1 H, J=2.0 Hz, Ar--H), 6.44-6.40 (d, 1 H, J=15.8 Hz, CH=CH), 2.03 (s, 3 H, CH3), Anal. (C13H12N2O3 0.3H2O), C, H, N.
Reaction SMILES: CS/[C:3](=[N:9]\[C:10](=O)[CH:11]=[C:12]([CH3:14])[CH3:13])/[N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[CH3:13][C:12]([CH3:14])=[CH:11][C:10]1[N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]=[C:3]([N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)[N:9]=1
Reactant: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Reactant: NNc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)=Cc1nc(N2CCCC2)nn1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
A mixture of 3-methyl-but-2-enoic acid 1-methylsulfanyl-1-pyrrolidin-1-yl-meth-(Z)-ylideneamide (130 mg, 0.575 mmol) and phenyl hydrazine (0.6 ml, 5.75 mmol) was stirred for 3 hours at 100° C. The mixture was cooled, diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography using 50% ethyl acetate in hexane affording 5-(2-methyl-propenyl)-1-phenyl-3-pyrrolidin-1-yl-1H-[1,2,4]triazole (60 mg, 38.87%) as colorless liquid. MS: m/z=268.8 (M+H+)
Reaction SMILES: Cl[O-:2].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+].[CH2:11]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][C:21]([CH3:27])([CH3:26])[CH:20]=[CH:19]2)[CH2:12][CH2:13][CH3:14]>C(Cl)Cl>[CH2:11]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][C:21]([CH3:26])([CH3:27])[C@H:20]1[O:2][C@@H:19]21)[CH2:12][CH2:13][CH3:14]
Reactant: [O-]Cl
Reactant: CCCCOc1ccc2c(c1)C=CC(C)(C)O2
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOc1ccc2c(c1)[C@@H]1O[C@@H]1C(C)(C)O2
Reaction time: 3 h

Procedure:
(3S, 4S)-(-)-6-Butoxy-2,2-dimethyl-3,4-epoxychroman At 0° C., 76 ml (42 mmol) of a 0.55 M sodium hypochlorite solution which had been adjusted to pH 11.3 using disodium hydrogen phosphate were added to a solution of 4.6 g (20 mmol) of 6-butoxy-2,2-dimethyl-2H-chromen (Example 5b) and 0.5 g (0.8 mmol) of (S,S)-(+)-N,N'-bis-(3,5-di-tert-butylsalicylidene)-1,2-diaminocyclohexanemanganese(III) chloride (Jacobsen's catalyst) in 20 ml of methylene chloride. The reaction mixture was stirred vigorously for 3 h and the organic phase was then separated off and the aqueous phase was extracted twice with methylene chloride. Silica gel chromatography of the crude product using cyclohexane/EA 9:1 gave 1.6 g of (3S, 4S)-(-)-6-butoxy-2,2-dimethyl-3,4-epoxychroman; optical rotation -14.9° (c=0.6; methanol).
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C:8](=[CH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:2]=[CH2:3].N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:36]([CH3:39])([O-:38])=[O:37]>>[CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C@@:8]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH2:39][N+:36]([O-:38])=[O:37])[CH2:7]2)[CH:2]=[CH2:3]
Reactant: C[N+](=O)[O-]
Reactant: C=CCC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 7 h

Procedure:
Tert-butyl(±)-(1S,5R)-3-allylbicyclo[3.2.0]hept-3-en-6-ylideneacetate (0.63 g, 2 mmol) was dissolved in nitromethane (5 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL, 3 mmol) was added, and the mixture was heated with stirring at 50 to 60° C. for 7 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (367.0 mg, 60%).
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][SH:25])=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>C(Cl)(Cl)Cl>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][S:25][CH:10]=[CH:9][C:8](=[N:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(CS)cc1
Reactant: C#CC(=Nc1ccccc1)SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Fc1ccc(CSC=CC(=Nc2ccccc2)SCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Benzyl N-phenylpropynthioimidate (0.30 g) and 4-fluorobenzylmercaptan were dissolved to chloroform (15 ml), catalytic amount of potassium t-butoxide was added thereto under ice-cooling and stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to obtain benzyl 3-(4-fluorobenzylthio)-N-phenyl-thioacrylimidate (0.15 g) as light yellow oil.
Reaction SMILES: CC([N:5]([C@@H:9]([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][C@H:9]([CH2:10][CH3:11])[C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13]
Reactant: CC[C@H](C(=O)Nc1ccc(Oc2cccc(C(C)C)c2)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc(C(C)C)c2)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1,1-dimethylethyl((1R)-1-{[(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 69, 1.28 g) was dissolved in 18 mL of dry dichloromethane. To this solution at 0° C. under argon was added dropwise 30 equivalents of TFA (7.15 mL, 93 mmol). The reaction was stirred during 3 hours at 0° C. The reaction mixture was evaporated. The residue obtained was purified by SCX on a 50 g cartridge. The cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N). After evaporation of the volatiles, the title compound was obtained (932 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:34])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])[CH2:13][CH2:12]3)=[N:9][C:10]=2[I:34])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(OCc1ccccc1)N1CCC(c2ncc3c(Cl)nccn23)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(c2nc(I)c3c(Cl)nccn23)CC1
Temperature: 55 °C
Reaction time: 20 h

Procedure:
To a solution of benzyl 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (1.31 g, 0.00354 mol) in DMF (0.6 mL) was added NIS (1.6 g, 0.0071 mol). The reaction mixture was left to stir at 55° C. for 20 h. then the mixture was diluted with EtOAc (20 mL), washed with water (2×40 mL) and brine, then dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was chromatographed over silica gel eluting with hexane→hexane:EtOAc 1:1 yielding 1.63 g of desired product. 1H NMR (400 MHz, CDCl3): δ 1.95-2.04 (m, 4H), 3.02-3.15 (m, 3H), 4.29-4.32 (m, 2H), 5.15 (s, 2H), 7.32 (d, J=5.2 Hz, 1H), 7.34-7.37 (m, 5H), 7.66 (d, J=5.2 Hz, 1H). MS (ES+): m/z 497.03 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:5]\[O:6][CH3:7].Cl>CO>[CH3:1][O:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[N:5]/[O:6][CH3:7]
Reactant: CO/N=C(\C(=O)OC)c1ccccc1Oc1ccccc1
Agent: Cl
Solvent: CO
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1ccccc1

Procedure:
To Z-α-methoxyimino-2-phenoxyphenylacetic acid methylester acid VI' (0.29 g, 1.0 mmole) were added dried methanol (3 ml) and 10% hydrochloric acid solution in methanol (0.36 g, 1.0 mmole) and the mixture was heated under reflux for 6 hours to conduct isomerization.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8](Br)[CH:7]=1)=[O:5])C.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.Cl.C(=O)(O)[O-].[Na+]>CS(C)=O.O>[CH2:19]([NH:18][C:16]([NH:15][C:13]1[N:14]=[C:10]2[CH:9]=[C:8]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:7]=[C:6]([C:4]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:5])[N:11]2[N:12]=1)=[O:17])[CH3:20]
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Reactant: C1CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(N3CCCC3)cc(C(=O)N3CCCC3)n2n1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (which may be produced as in Example 6) (0.080 g, 0.22 mmol) in dimethylsulfoxide (1 mL) was added pyrrolidine (0.2 mL). The reaction was stirred at 23° C. for 30 minutes then 80° C. for 3 days. The reaction was then diluted with water (2 mL), acidified with 1N aqueous hydrogen chloride, then neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give a solid that was purified by silica gel chromatography (gradient elution: 0-20% isopropanol/dichloromethane) to give the title compound as a solid. MS (APCI)=372.2 [M+H]
Reaction SMILES: O.[ClH:2].Cl.[NH:4]1[CH2:8][CH2:7][N:6]=[C:5]1[C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)[CH3:17]>CN(C)C=O>[ClH:2].[NH:6]1[CH2:7][CH2:8][N:4]=[C:5]1[C:9]1[CH:10]=[C:11]([NH:12][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[O:27])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(C2=NCCN2)c1
Reactant: CCOc1ccc(N=C=O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(NC(=O)Nc2cccc(C3=NCCN3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 3-(4,5-dihydro-1H-imidazol-2-yl) aniline dihydrochloride monohydrate (stored with 4 A molecular sieves, 48 mg, 0.19 mmol) and 4-ethoxyphenyl isocyanate (33 mg, 0.20 mmol) in dimethylformamide (2 ml) was stirred at room temperature overnight. After removal of the solvent, water (2 ml) was added and the resulting precipitate was collected (18 mg, 64% yield) by filtration. 1H NMR (600 MHz, DMSO-d6) δ 10.5 (br s, 1H), 9.12 (br s, 1H), 8.11 (s, 1H), 7.68 (d, 1H, J=8.4 Hz), 7.52 (t, 1H, 8.4 Hz), 7.47 (d, 1H, J=7.2 Hz), 7.35 (d, 2H, J=7.2 Hz), 6.86 (d, 2H, J=7.2 Hz), 3.98 (s, 4H). MS: m/z Calcd 324.4 Found MH+ 325.5
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:8]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:7]2[CH:8]=[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:4]=[N:5][CH:6]=[C:7]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)[CH:8]=4)[CH2:23][CH2:22]3)[CH:4]=[N:5][CH:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2cncc(CN3CCN(Cc4cncc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC

Procedure:
3-Chloromethyl-5-(3,4,5-trimethoxyphenyl)pyridine (70 mg) and piperazine (10 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:42])=[O:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:49]3[CH2:48][CH2:47][N:46]([CH2:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:51][CH2:50]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-isopropyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OJ-H 3×25 cm, 35° C. at 100 bar, eluting with 15% of 1:1 ethanol/acetonitrile in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C37H47N4O4SCl2 [(M+H)+] 713.2690, observed 713.2692.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl:21][Ti:22](Cl)([Cl:33])[C:23]1([CH3:32])[C:27]([CH3:28])=[C:26]([CH3:29])[C:25]([CH3:30])=[C:24]1[CH3:31]>C(OCC)C>[Cl:21][Ti:22]([Cl:33])([C:23]1([CH3:32])[C:24]([CH3:31])=[C:25]([CH3:30])[C:26]([CH3:29])=[C:27]1[CH3:28])[O:15][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1=C(C)C(C)([Ti](Cl)(Cl)Cl)C(C)=C1C
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC1=C(C)C(C)([Ti](Cl)(Cl)Oc2c(C(C)(C)C)cccc2C(C)(C)C)C(C)=C1C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
After 600 mg of 2,6-di-tert-butylphenol (2.91 mmol) (Aldrich, 99%) were dissolved in 30 mL of diethylether, 1.28 mL of butyl lithium (2.5 M hexane solution) were slowly dropped thereonto at −31° C. After 1 hour, agitation was conducted at normal temperature for 6 hours. The resulting mixture was dissolved in diethylether, and a solution in which (trichloro)(pentamethylcyclopentadienyl)titanium(IV) (752 mg, 2.60 mmol) was dissolved in 10 mL of diethylether was slowly dropped thereonto at −30° C. After 1 hour, agitation was conducted at normal temperature for 6 hours. The solvent was removed from the resulting product, and the solvent-free product was dissolved in 10 mL of toluene and then recrystallized to produce 829 mg of red solid component.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]1=[O:26].[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1>ClCCl>[CH2:24]([O:23][C:21]([CH2:20][N:4]1[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:8][CH:2]([NH:1][C:34]([NH:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH3:36])[CH:28]=2)=[O:35])[C:3]1=[O:26])=[O:22])[CH3:25]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCOC(=O)CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)C(NC(=O)Nc2cccc(C)c2)N=C(c2ccccc2F)c2ccccc21
Yield: 56.6 %

Procedure:
To a solution of (3RS)-3-amino-2,3-dihydro-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.972 g) in dichloromethane (15 ml) was added dropwise a solution of m-tolyl isocyanate (0.884 g) in dichlromethane (5 ml) under stirring. After completion of the addition, the mixture was stirred for 4 hours at ambient temperature. The resultant white precipitates were collected by suction to give N-[(3RS)-2,3-dihydro-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea as a colorless crystalline solid (1.533 g). The filtrate was concentrated in vacuo. The residue was treated with chloroform and isopropyl ether to recover the desired compound (0.897 g).
Reaction SMILES: [CH2:1]([NH2:9])[C:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3].[CH3:10][C:11]([O:14][C:15](ON=C(C1C=CC=CC=1)C#N)=[O:16])([CH3:13])[CH3:12].CCN(CC)CC>O1CCOCC1>[NH:9]([C:15]([O:14][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:16])[CH2:1][C:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3]
Reactant: NCC(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Yield: 56.4 %

Procedure:
An oven-dried 20 mL vial equipped with septum and stir bar was charged with 6 mL dioxane, Gly—Gly (1.325 g, 10.0 mmol), BOC—ON (2.714 g, 11.0 mmol), and Et3N (2.10 mL, 15 mmol). The mixture was stirred for 2 hours during which time a clear yellow solution formed. The mixture was extracted with EtOAc (20 mL) and H2O (15 mL). The aqueous layer was collected, washed with EtOAc and added to 50 mL 5% citric acid. The t-BOC-GlyGlyOH was extracted with EtOAc (200 ml) and dried over anhydrous Na2SO4. The EtOAc was removed in vacuo and triturated with hot Et2O. White crystals were collected, washed with Et2O and dried to give 1.309 g of the title compound: 1H NMR (300 MHz, DMSO-d6): δ 12.3 (bs 1H, CO2H), 8.04 (t, 1, NH), 6.98 (t, 1H, NH), 3.75 (d, 2H, CH2), 3.56 (d, 2H, CH2), and 1.38 (s, 9H, C(CH3)3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]=[CH:5][C:6]1[N:7]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[O:29][CH2:30][O:31][C:27]=3[CH:26]=2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12](Br)=[CH:11][CH:10]=2.CO>[Ni].C1COCC1>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[N:7]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[O:29][CH2:30][O:31][C:27]=3[CH:26]=2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC(=O)C=Cc1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
A mixture of 3-[2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl]acrylic acid methyl ester (100 mg), Raney-nickel (suitable amount), methanol (2.0 ml) and THF (2.0 ml) was stirred at room temperature under a hydrogen atmosphere for 3 hrs. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (55 mg) as a colorless powder.