Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:49]=[C:50]([CH:54]=[CH:55][CH:56]=1)[CH2:51][CH2:52][NH2:53]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:53][CH2:52][CH2:51][C:50]4[CH:54]=[CH:55][CH:56]=[C:48]([F:47])[CH:49]=4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: NCCc1cccc(F)c1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCCc2cccc(F)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-fluorophenethyl-amine (Aldrich) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-]>Cl>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCSC2)cc1
Agent: Cl
Agent: [Cl-]
Product: Nc1ccc(CN2CCSC2)cc1
Yield: 61.8 %

Procedure:
3-(4-nitrobenzyl)-thiazolidine (1.1 g, 5 mmoles) is put into solution in 10 ml concentrated hydrochloric acid at 0° C. Dihydrated in chloride (7.7g, 34 mmoles) is added in portions, the mixture is heated for 2 hours under reflux and the acid is evaporated off under reduced pressure. The residue is then taken up in 20 ml of water and. neutralized with a 2N soda solution (approximately 100 ml). 100 ml of dichloromethane is added to the medium and the whole is filtered on celite in order to eliminate the salts in suspension. The organic phase is extracted, washed 3 times with 50 ml of water, dried, filtered and evaporated to dryness under reduced pressure. The expected product is purified on silica gel in a dichloromethane/methanol (98/2) mixture and is obtained in the form of of a beige powder (0.6 g, 63%). Melting point: 73-74° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]=[C:9]([C:14]([CH3:16])=[O:15])[C:10]([O:12][CH3:13])=[O:11].[F:17][CH2:18]Br>CS(C)=O.CN(C)C=O>[F:17][CH2:18][O:7][N:8]=[C:9]([C:14]([CH3:16])=[O:15])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(=NO)C(C)=O
Reactant: FCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COC(=O)C(=NOCF)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
14.2 g of potassium carbonate was added to a solution of 14.5 g of methyl 2-hydroxyimino-acetoacetate in 50 ml of dimethylsulfoxide, and then 11.6 g of fluoro-bromomethane in 9 ml of N,N-dimethylformamide was added dropwise thereto. The mixture was stirred for 1 hour 30 minutes at room temperature, then poured into ice-water, and the resultant mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over Na2SO4 and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (120 g) with a mixture solvent of ethyl acetate and toluene (1/4 volume) as a eluent to give 4.7 g (27% yield) of methyl 2-fluoromethoxyiminoaceto-acetate (syn isomer).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1>[CH:23]1([NH:29][C:30]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:22])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)NC4CCCCC4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 50.8 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.00 g, 3.10 mmol) and cyclohexylisocyanate (0.39 g, 3.10 mmol) in THF (35 mL), was added triethylamine (0.88 mL, 6.20 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The mixture was filtered and the filtrate diluted with EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (100 mL), water (2×100 mL), dried (MgSO4) and concentrated. The crude product was purified by prep-HPLC (40/60 CH3CN/H2O). The product fractions were combined, concentrated and dried in vacuo to give 1-cyclohexyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.65 g, 77% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.16 min (99.05%); mp: 208-210° C.; 1H NMR (DMSO-d6) δ 1.01-1.36 (m, 5H), 1.46-1.83 (m, 5H), 2.00-2.14 (m, 1H), 2.53-2.66 (m, 2H), 2.79-3.01 (m, 1H), 3.34-3.44 (m, 1H), 4.36 (d, J=6.0 Hz, 2H), 5.14 (dd, J=5.3, 12.8 Hz, 1H), 6.00 (d, J=7.9 Hz, 1H), 6.42 (t, J=5.9 Hz, 1H), 7.67-7.79 (m, 2H), 7.87 (d, J=7.6 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.01, 24.50, 25.27, 30.93, 33.23, 42.67, 47.97, 48.97, 121.54, 123.39, 129.50, 131.53, 133.07, 149.49, 157.28, 167.05, 167.22, 169.83, 172.73; LCMS: MH=413; Anal Calcd for C21H24N4O5+0.2H2O: C, 60.76; H, 5.90; N, 13.47. Found: C, 60.61; H, 5.74; N, 13.31.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]3[C:12]([C:16](OC)=[O:17])=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[OH:17][CH2:16][C:12]1[C:10]2[S:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc2cc(-c3ccccc3)sc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2cc(-c3ccccc3)sc12
Yield: 85 %

Procedure:
20 g of the compound from Example VI are dissolved in 75 ml of tetrahydrofuran and the solution is added dropwise to 40 mmol of LiAlH4 in 50 ml of tetrahydrofuran. Customary working up gives 85% of the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([CH:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1)[CH3:10]>CN(C=O)C>[CH2:1]([N:15]1[CH2:14][CH2:13][NH:12][CH:11]([CH2:9][CH3:10])[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1CNCCN1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: CCC1CN(Cc2ccccc2)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Benzyl bromide (38.7 g, 0.22 mol) was added in portions to an ice cold (˜0° C.) solution of 2-ethylpiperazine (25 g, 0.22 mol) in DMF (150 mL) with such a rate that the temperature did not exceed 20° C. The mixture was stirred for 1 h, the solvent was evaporated and the residue was partitioned between CHCl3/0.5 M HCl. The aqueous phase was made alkaline (11M NaOH) and extracted three times with CHCl3. The combined organic phases were dried (MgSO4) and concentrated. The resulting oil was purified by column chromatography on silica using CHCl3, followed by CHCl3/MeOH/NH4OH (95:5:0.3) as eluents to give 31.6 g (70%) of the title compound as a yellowish oil. Anal. (C13H20N2) H, N; C: calc, 76.42 found 75.85; H, N.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].N1C=CC=CC=1.Cl[C:17]([C:19]1[C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[C:32]([C:35]#[N:36])[C:33]#[N:34])[C:23]=2[CH:22]=[CH:21][CH:20]=1)=[O:18]>ClCCl>[C:35]([C:32]([C:33]#[N:34])=[C:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:17]([O:2][C:1]3[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=3)=[O:18])[C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)#[N:36]
Reactant: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)Cl)cccc21
Reactant: Oc1cc(O)cc(O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)Oc3cc(O)cc(O)c3)cccc21
Yield: 58.3 %

Procedure:
A solution of 30.0 grams of phloroglucinol and 70 milliliters of pyridine in 300 milliliters of dichloromethane was stirred at room temperature under a nitrogen atmosphere. A solution of 8.0 grams of (4-chloroformyl-9-fluorenylidene)malononitrile in 400 milliliters of dichloromethane was added over a period of 1 hour. After addition, the reaction mixture was further stirred for another hour. The mixture was washed three times with dilute aqueous HCl solution, twice with dilute aqueous NaHCO3 solution, and once with water. The solution was dried, filtered and evaporated under reduced pressure to give the crude product. Recrystallization from methanol afforded 6.1 grams of (1b), mp., 255.5°-257° C.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.CN(C=O)C.[C:18](=[O:20])=[O:19]>O>[C:18]([C:4]1[C:3]([OH:2])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([OH:20])=[O:19]
Reactant: Oc1cccc2cccnc12
Reactant: O=C=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2cccnc2c1O
Yield: 30.4 %

Procedure:
Potassium salt of 8-hydroxyquinoline (25 mmol, 4.58 g), DMF (50 mL) and an excess of dry ice were heated in a pressure reactor at 120° C. for 12 hours. After cooling, water (150 mL) was added to the reaction mixture. The insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. To the residue, water was added again, and additional insoluble material was collected by filtration. The filtrate was acidified to pH 4 with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried to give 7-carboxy-8-hydroxyquinoline in 30.4% yield (1.44 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9]1)(=O)=O.[C:19]1(=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[NH:20]1.[K]>CN(C)C=O>[O:29]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]1[CH2:6][CH2:7][C:8]1([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(CCOS(C)(=O)=O)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 150 °C
Reaction time: 18 h
Yield: 49.1 %

Procedure:
To a solution of 2-{1-[(tert-butoxycarbonyl)amino]-cyclopropyl}ethyl methanesulfonate (9.5 g, 344.3 mmol) in anhydrous N,N-dimethylformamide (20 ml) was added potassium 2,3-dihydro-1H-isoindole-1,3-dione (7.0 g, 37 mmol). After being stirred at 150° C. for 18 hours, the resulting mixture was then filtered and washed with diethyl ether (50 mL). The filtrate was washed with brine (50 mL×3), dried over sodium sulfate and concentrated in vacuo. The residue was heated with stirring in water and the precipitate was collected by filtration and dried in vacuo to afford 6.0 g of the pure product as an orange solid (yield was 53%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][O:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][O:17][CH3:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
In DMF (255 ml) was dissolved 4-bromophenol (51.0 g). To the mixture was added at room temperature potassium carbonate (81.5 g) and then was added dropwise chloromethylmethyl ether (44.8 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-4-(methoxymethoxy)benzene (61.4 g). In ether (240 ml) was dissolved 1-bromo-4-(methoxymethoxy)benzene (30 g). To the mixture was added dropwise at −78° C. 1.6M n-butyllithium/hexane (90.7 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (43.1 g) in THF (43 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added water (150 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was stirred in methanol/water (2/1, 1000 ml) for 3 days. Under reduced pressure, methanol was removed, and the residue was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(methoxymethoxy)phenyl borate (2.4 g). 1H-NMR (200 MHz, CDCl3) δ 3.51 (3H, s), 5.26 (2H, s), 7.14 (2H, d, J=8.4 Hz), 8.15 (2H, d, J=8.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][NH:33][CH2:34][CH2:35][OH:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:33]([CH2:34][CH2:35][OH:36])[CH3:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CNCCO
Product: Cc1cc(F)ccc1-c1nc(N(C)CCO)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
Following the general procedure outlined in Example 126, the product of Example 48 (100 mg, 0.22 mmol), N-methylethanolamine (0.05 mL, 0.66 mmol) were reacted for 2 h to give the crude material, which was purified by preparative hplc to affored the title compound, 26 mg (27%). LC-MS: 441.2 (MH+, m/z), 2.19 (Rt, min).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:9][C:10]([OH:12])=[O:11])[CH2:5][C:6]([OH:8])=[O:7].Cl.[CH3:14][CH2:15]O>>[CH2:14]([O:12][C:10](=[O:11])[CH2:9][N:4]1[CH2:3][CH2:2][O:8][C:6](=[O:7])[CH2:5]1)[CH3:15]
Reactant: CCO
Reactant: O=C(O)CN(CCO)CC(=O)O
Agent: Cl
Product: CCOC(=O)CN1CCOC(=O)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To N-(2-hydroxyethyl)iminodiacetic acid (3.55 g, 20 mmol) in 500 mL EtOH was added concentrated HCl (1.7 mL, 21 mmol). The mixture was stirred for 24 h at rt and concentrated. The residue was partitioned in diethyl ether (200 mL) and NaHCO3 (150 mL, 10% wt). After layer separation, the organic phase was washed with aqueous NaHCO3 (2×100 mL) and dried over Na2SO4 and concentrated and dried under high vacuum. To this crude product in 250 mL of dioxane was added 1.5 mL of HCl and the mixture was heated to reflux for 24 h. After removal of the solvent, the residue was chromatographed (dichloromethane/methanol) to afford a dark yellow oil (1.45 g). 1H-NMR (CD3OD, 300 MHz) δ (ppm): 4.40 4.37 (m, 2H), 4.18-4.11 (m, 2H), 3.60 (s, 2H), 3.29 (s, 2H), 2.89-2.86 (m, 2H), 1.25-1.20 (m, 3H); 13C-NMR δ (ppm) 169.4, 167.0, 68.6, 60.9, 57.0, 54.5, 48.2, 14.2. (ESI) m/z: 188 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:6]([CH3:8])=O)[CH3:2].[CH3:18][N:19]1[C:23]([NH2:24])=[CH:22][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:20]1.[ClH:31].CO>C(O)C>[ClH:31].[CH2:1]([O:3][C:4]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:22]2[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:20][N:19]([CH3:18])[C:23]=2[NH:24][C:6]=1[CH3:8])=[O:17])[CH3:2]
Reactant: Cn1nc(-c2ccccc2)cc1N
Reactant: CCOC(=O)C(=Cc1ccccc1C)C(C)=O
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2c(c(-c3ccccc3)nn2C)C1c1ccccc1C
Temperature: 25 °C

Procedure:
Ethyl-2-(2-methylbenzyliden)acetoacetate (0.050 mol) is added to 1-methyl-3-phenyl-5-pyrazolamine (0.050 mol) in ethanol (50 ml) and refluxed for 90 minutes. The mixture is then cooled to room temperature, further ethyl-2-(2-methylbenzyliden)acetoacetate (0.050 mol) is added thereto, and the mixture refluxed for further 90 minutes. The reaction mixture is then cooled, the solvent is evaporated, and the residue is taken up in ethyl ether, collected by filtration, and dried. The product is dissolved in methanol and a mixture of hydrochloric acid and methanol (45 mmol of HCl) is added thereto. The product of the title precipitates by adding ethyl ether. M.p. 187° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[C:4]([CH3:17])[CH:3]=1.C([Li])CCC.CCCCCC.[NH:29]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32](=[O:33])[C:30]1=[O:31].[NH4+].[Cl-]>C1COCC1>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][C:5]1[C:14]([CH3:16])=[CH:15][C:2]([C:32]2([OH:33])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH:29][C:30]2=[O:31])=[CH:3][C:4]=1[CH3:17])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Cc1cc(Br)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C2(O)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 154.3 %

Procedure:
Dissolve (4-bromo-2,6-dimethyl-phenoxy)-tert-butyl-dimethyl-silane (15.77 g, 50 mmol) in anhydrous THF (250 mL) under nitrogen and cool in a dry ice/acetone bath. Add slowly at −75 to −70° C. 1.6M n-butyl lithium in hexane (31.3 mL, 55 mmol). Stir the resulting white precipitate at −75° C. for 30 min. Add isatin (3.68 g, 25 mmol) as a solid while maintaing positive nitrogen pressure. Remove some dry ice and allow the reaction to warm up slowly to −30 to −40° C. over 3 h and then to 15° C. over 1 h. Pour the reaction into NH4Cl solution and wash with EtOAc (2×500 mL, 250 mL). Wash combined organic portions with water (500 mL) and brine (500 mL). Dry (MgSO4), filter and concentrate in vacuo to give 14.8 g of a yellow solid. Triturate in hexane/ether/CH2Cl2, filter and air dry to give 6.0 g (63%) of the title compound as a pale yellow solid. MS (ES): m/z=383 (M−1); 1H NMR(DMSO-d6): δ10.14 (s, 1H), 7.07 (dt, J=1.1 Hz, J=7.6 Hz, 1H), 6.95 (d, J=7.0, 1H), 6.80 (t, J=7.3 Hz, 1H), 6.72 (m, 3H), 6.27 (s, 1H), 1.95 (s, 6H), 0.83 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH:14]2[CH:10]([CH:11]([CH3:25])[N:12]([CH3:24])[CH:13]2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu][C:28]#[N:29]>CN(C=O)C>[CH2:1]([N:8]1[C:9](=[O:26])[CH:10]2[CH:11]([CH3:25])[N:12]([CH3:24])[CH:13]([C:17]3[CH:22]=[CH:21][C:20]([C:28]#[N:29])=[CH:19][CH:18]=3)[CH:14]2[C:15]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: CC1C2C(=O)N(Cc3ccccc3)C(=O)C2C(c2ccc(Br)cc2)N1C
Solvent: CN(C)C=O
Product: CC1C2C(=O)N(Cc3ccccc3)C(=O)C2C(c2ccc(C#N)cc2)N1C
Yield: 84.9 %

Procedure:
400 mg (0.96 mmol) of (3aRS,4SR,6RS,6aSR)-2-benzyl-4-(4-bromo-phenyl)-5,6-dimethyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione and 360 mg (4.02 mmol) of copper(I) cyanide were suspended in 25 ml of DMF and heated under reflux and under argon for 18 hours. After cooling about 15 ml of DMF were removed, then 30 ml of dichloromethane and 20 ml of concentrated aqueous ammonia solution were added. The mixture was stirred vigorously for a few hours. The blue aqueous phase was separated and the organic phase was washed twice with ammonia solution and once with water. The solvent was removed and the residue was purified chromatographically (hexane/ethyl acetate 2:1+1% triethylamine). 293 mg of (1RS,3SR,3aRS,6aSR)-4-(5-benzyl-2,3-dimethyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile (85%) were isolated as colourless crystals. M.p.: 188°-190° C. (ethyl acetate). FAB-MS: 719 ([2M+H]+, 3); 512 (3); 360 ([M+H]+, 100); 344 (41); 289 (15); 107 (37); 91 (56).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)cc1

Procedure:
The alkylating agent used, cis-4-(tert.butyloxycarbonylamino)-1-(4-methylphenylsulphonyloxy)-cyclohexane (mass spectrum (ESI+): m/z=370 [M+H]+) was prepared by reacting cis-4-(tert.butyloxycarbonylamino)-cyclohexanol with 4-methylphenyl-sulphonyl chloride in pyridine.
Reaction SMILES: Br[C:2]1[CH:22]=[N:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7]3[N:16]=[CH:15][C:14](C)=[C:13](C)[C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:19]([N:6]1[C:5]2[N:21]=[CH:22][C:2]([C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:3][C:4]=2[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[CH:14][CH:15]=[N:16][C:7]1=2)[CH3:20]
Reactant: C#Cc1ccccc1
Reactant: CCN1c2ncc(Br)cc2C(=O)N(C)c2c1ncc(C)c2C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN1c2ncc(C#Cc3ccccc3)cc2C(=O)N(C)c2cccnc21
Yield: 120.9 %

Procedure:
To a solution of 8-bromo-5,11-dihydro-3,4-dimethyl-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.05 g, 0.14 mmol), phenylacetylene (0.03 g, 0.28 mmol), and triethylamine (3.5 mL) in 1.5 mL of acetonitrile was added tetrakis(triphenylphosphine)palladium(0) (10 mg) and copper(I) iodide (5 mg). The resultant mixture was heated at reflux for 2 hours. The solvent was removed at reduced pressure, and the residue was purified by preparative thin layer chromatography, eluting with ethyl acetate/hexanes. The product was recrystallized from ethyl acetate/petroleum ether to provide 60 mg of the title compound, m.p. 228°-229° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH2:18])=[N:9][C:5]=2[CH:4]=1.C([O:23]CC)C>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH2:18])=[O:23])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c(SCc3ccccc3N)nc2c1
Reactant: CCOCC
Product: COc1ccc2[nH]c(S(=O)Cc3ccccc3N)nc2c1

Procedure:
The title compound was prepared by the method of Example 3 using 1.20 g of the title product of Example 11 instead of the title product of Example 2. Trituration with diethylether gave 1.04 g of the title compound: m.p. 147-148° C. Anal. Calc'd. for C15H15N3O2S: C, 59.78; H, 5.02; N,13.94; S, 10.64. Found: C, 59.30; H, 4.95; N, 13.55; S, 10.73.