Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31](=O)[C:32]([O:34]CC)=O.CC(O)=O>COCCO>[Cl:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[C:25]=1[C:31]1[C:32](=[O:34])[N:21]([CH3:22])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CNc1nc(Nc2ccc(N3CCOCC3)cc2)ncc1N
Reactant: CCOC(=O)C(=O)c1c(Cl)cccc1Cl
Solvent: CC(=O)O
Solvent: COCCO
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)nc2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Yield: 37.2 %

Procedure:
A mixture of 0.60 g (2 mmol) of 5-amino-4-(methylamino)-2-[[4-(morpholin-4-yl)phenyl]amino]pyrimidine, 0.74 g (3 mmol) ethyl 2-(2,6-dichlorophenyl)-2-oxoacetate (T. H. Kress and M. R. Leanna, Synthesis, 1988:803–805), and 0.3 mL HOAc in 25 mL of 2-methoxyethanol is heated under reflux for 16 hours before the solvent is removed under vacuum. The residue is extracted into EtOAc and, after being washed with water, the solution is dried over Na2SO4. Removal of the solvent and chromatography on silica, eluting with hexane/EtOAc 3:2 gives 0.36 g (37%) of the title compound (Compound 2 in Tables 1 and 2): mp (EtOH) 292–293° C.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:9]1[N:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1>>[CH3:1][NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:9]2[N:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=2)[CH2:4]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: CN[C@H]1CCNC1
Product: CN[C@H]1CCN(c2ncc([N+](=O)[O-])cn2)C1
Temperature: 110 °C

Procedure:
(S)—N-Methylpyrrolidin-3-amine (286 mg, 2.86 mmol) was added to 2-chloro-5-nitropyrimidine (415 mg, 2.60 mmol) slowly (CAUTION: extreme exotherm!!!). The resulting mixture was heated at 110° C. for 10 min. After cooling down to room temperature, another portion of amine (0.100 g) was added to the reaction mixture. The resulting mixture was heated at 110° C. for 10 min. After cooling down to room temperature, the obtained black solid product (Example 47A) was used for next step without further purification. LCMS (ES): m/z 252.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][C@H:9]([NH:26]C(OCC1C=CC=CC=1)=O)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][C@H:9]([NH2:26])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cccc(N2CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)CC2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(N2CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC2)c1
Reaction time: 12 h

Procedure:
To a solution of 4.00 g (S)-4-benzyloxycarbonylamino-5-[4-(3-methoxy-phenyl)-piperazin-1-yl]-5-oxo-pentanoic acid tert-butyl ester in 60 ml EtOH were added 0.7 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over Celite and washed with EtOH. The title compound was used without further purification after evaporation of the solvent. Yield: 2.90 g.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=O)[CH2:9][NH:8][C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:10](=[S:21])[CH2:9][NH:8][C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1N=C(c2ccc(Cl)c(Cl)c2)NCC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CCCCN1N=C(c2ccc(Cl)c(Cl)c2)NCC1=S
Temperature: 95 °C
Yield: 68.3 %

Procedure:
To a solution of 1.31 grams of 1-butyl-3-(3,4-dichlorophenyl)-4,5-dihydro-1,2,4-triazin-6-one (4.4 mmol) in 12 mL of toluene was added 0.37 gram of phosphorus pentasulfide (8.3 mmol). The reaction was heated to 95° C. for seven hours. After cooling 1.4 grams of flash grade silica gel was added. The reaction was filtered through Celite and concentrated under reduced pressure. The oil was chromatographed with 22% ethyl acetate/hexanes and 0.95 grams of 1-butyl-3-(3,4-dichlorophenyl)-4,5-dihydro-1,2,4-triazin-6-thione was isolated.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[S:15][CH:14]([N:16]2[CH:31]=[CH:30][C:20]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:19][C:17]2=[O:18])[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:1]([O:9][CH2:10][C@@H:11]1[S:15][C@H:14]([N:16]2[CH:31]=[CH:30][C:20]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:19][C:17]2=[O:18])[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccn(C2CO[C@H](COC(=O)c3ccccc3)S2)c(=O)n1)c1ccccc1
Solvent: CO
Product: O=C(Nc1ccn([C@@H]2CO[C@H](COC(=O)c3ccccc3)S2)c(=O)n1)c1ccccc1
Reaction time: 8 h

Procedure:
To the crude (S)-benzoyloxymethyl-4-(R,S)—(N-benzoylcytosin-1-yl)-1,3-oxathiolane (13.95 g) in a 250 mL round bottom flask, was added approximately 14.0 times (by volume) methanol (194.6 mL) and the mixture was refluxed till a clear solution could be seen. This was then allowed to cool without stirring overnight. The resulting crystallized product was then filtered, followed by washing with methanol (50 mL). Once all the mother liquor and the subsequent washing had passed through, the resulting crystallized white product was re-washed slowly with methanol (50 mL) and dried under vacuum. The resulting white crystalline solid on analyzing with NMR showed that it is >99% the cis isomer. Isolated yield, 4.8 g (34% yield for the recrystallization, based on the crude). Optical purity: RR/SS: 2.2/97.8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2.[C:17]1([CH2:23][CH:24]=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].N#CC#N.[Na+].[OH-].[Na+]>C(#N)C.C(O)(=O)C.C(O)(C)C>[CH3:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=CCc1ccccc1
Reactant: CCOC(=O)c1cc2cccc(N)c2n1C
Agent: N#CC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCOC(=O)c1cc2cccc(NCCc3ccccc3)c2n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.3 %

Procedure:
A mixture of 0.10 g (0.46 mmol) of ethyl 7-amino-1-methyl-2-indolecarboxylate, 0.12 g (0.50 mmol) of phenylacetaldehyde as 50% isopropanol solution, 0.043 g (0.69 mmol) of sodium cyanogen borohydride and 0.1 ml of acetic acid in 5 ml of acetonitrile was stirred at room temperature for 15 minutes. Thereafter 0.2 ml of acetic acid was added to the reaction mixture. The resulting mixture was allowed to stand at room temperature for 15 hours. After 1N sodium hydroxide solution was added to the reaction mixture, the mixture was extracted three times with diethyl ether. The combined extracts were then washed with 1N potassium hydroxide solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 0.045 g (30.5%) of ethyl 1-methyl-7-(2-phenylethylamino)-2-indolecarboxylate.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:4][N:3]=1.C(CN)O.[CH3:19][N:20](C)[CH:21]=O>>[CH3:19][N:20]([CH3:21])[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: NC(=O)Cc1cnc(Cl)c2ccoc12
Solvent: NCCO
Product: CN(C)c1ncc(CC(N)=O)c2occc12
Temperature: 130 °C
Yield: 43 %

Procedure:
Combine 2-(4-chlorofuro[3,2-c]pyridin-7-yl)acetamide (850 mg, 4.21 mmol), dimethylformamide (5 mL) and ethanolamine (0.76 mL, 12.63 mmol). Heat the reaction at 130° C. overnight. Add additional ethanolamine (0.25 ml) and heat at 130° C. overnight. Cool to room temperature, concentrate, and dilute with ethyl acetate. Wash with saturated aqueous sodium bicarbonate and concentrate. Subject to flash chromatography, eluting with ethyl acetate:methanol to provide the title compound as a white solid (400 mg, 43%).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH:14]1([O:19][C:20]2[C:21]([O:40][CH3:41])=[CH:22][CH:23]=[C:24]3[C:29]=2[O:28][C:27](=[O:30])[CH:26]=[C:25]3[NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[CH:34][C:33]=2[Cl:39])[CH2:18][CH2:17][CH2:16][CH2:15]1.NC(N)=O.OO.[O-]S([O-])(=S)=O.[Na+].[Na+]>Cl.ClCCl>[CH:14]1([O:19][C:20]2[C:21]([O:40][CH3:41])=[CH:22][CH:23]=[C:24]3[C:29]=2[O:28][C:27](=[O:30])[C:26]([OH:4])=[C:25]3[NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[CH:34][C:33]=2[Cl:39])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OC1CCCC1
Agent: Cl
Agent: NC(N)=O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)c(O)c(=O)oc2c1OC1CCCC1
Reaction time: 1.5 h

Procedure:
Trifluoroacetic anhydride (0.04 mL, 0.29 mmol) was added to a solution of 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (42 mg, 0.1 mmol, Example 3), urea•H2O2 (28.5 mg, 0.3 mmol), and dichloromethane (2 mL) at rt under N2. After 1.5 h, sat'd Na2S2O3 (8 mL) was added, and the mixture was stirred vigorously for 15 min. The reaction was then diluted with 0.5N HCl (40 mL), and extracted with dichloromethane (40 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (4:1→1:1; hexanes:ethyl acetate) to give 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-3-hydroxy-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.42 (s, 2H), 8.40 (s, 1H), 7.59 (d, 1H), 7.12 (d, 1H), 4.84 (m, 1H), 3.86 (s, 3H), 1.90-1.50 (m, 8H); MS (ESI): 436.9.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1.C(N(CC)CC)C.C(OCC)(=O)C>[CH3:29][S:30]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:20]([CH3:22])[CH3:21])[C:14](=[O:19])[C:15]([F:16])([F:18])[F:17])=[O:11])[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:4][CH:3]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NS(C)(=O)=O)c1=O)C(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.345 g) in tetrahydrofuran (7 mL) and triethylamine (0.36 mL) at 0° C. was added methanesulfonoyl chloride (0.19 mL) and the resulting solution was allowed to stir overnight. The mixture was diluted with ethyl acetate and the solution washed (1N hydrochloric acid, water, 5% sodium bicarbonate). The organic layer was dried and evaporated. The residue was dissolved in tetrahydrofuran (1 mL), and to it was added 3N aqueous potassium hydroxide (0.07 mL). The solution was allowed to stir for 12 h. The reaction was quenched by addition of 1N hydrochloric acid and the product was extracted into ethyl acetate. The organic layer was washed (water, brine), and the solution was dried and evaporated. The resulting material was purified by chromatography, with tetrahydrofuran:dichloromethane (10:90) as the eluent, to provide 2-(5-methylsulfonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a white solid (0.146 g); NMR (DMSO/D2O): 9.35 (s,1), 8.84 (d,1), 8.01 (s,1), 7.50 (m,5), 4.68 (m,2), 4.55 (d,1), 3.10 (s,3), 2.16 (m,1), 0.89 (d,3), 0.83 (d,3).
Reaction SMILES: [C:1]([CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])(OCC)=[O:2].O.[NH2:30][NH2:31].[OH:32][S:33]([OH:36])(=[O:35])=[O:34]>C(O)C>[S:33]([OH:36])([OH:35])(=[O:34])=[O:32].[NH:30]([C:1]([CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])=[O:2])[NH2:31]
Reactant: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: NN
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CN(C)CCC(=O)NN)[C@@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
Compound 13a (115 mg, 0.29 mmol) was dissolved in 10 mL of anhydrous ethanol and hydrazine monohydrate (73 mg, 0.07 mL, 1.46 mmol) was added to the solution. The reaction mixture was heated to reflux overnight. Hydrazine monohydrate (0.07 mL) was added again and heating was continued overnight. The resulting solution was evaporated to dryness. The crude product was purified by column chromatography (4:1:0.5 chloroform:methanol:NH4OH). The desired fractions were collected, concentrated, and dried in vacuo to yield a sticky solid. The product was dissolved in 8 mL of EtOH and 2N H2SO4 was added drop wise. The salt that was precipitated out was filtered and washed with EtOH. This salt, which was hygroscopic in nature, was dissolved in water (2 mL) and lyophilized to give a white solid: yield 71 mg (65%), MS: m/z 381 (M+H)+; 1HNMR (D2O) δ 8.44 (s, 1H, H-2), 6.09 (d, 1H, H-1′, J1′,2′=5.6 Hz), 5.10 (dd, 1H, H-2′, J2′,3′=4.5 Hz), 4.53-4.62 (bm, 2H, H-3′, H-4′), 3.86-3.94 (m, 1H, 5′-CH2), 3.52-3.66 (m, 3H, 5′-CH2, N(CH3)—CH2), 2.95 (s, 3H, N—CH3), 2.86 (t, 2H, NHCO—CH2), 2.70 (s, 3H, 8-CH3); UV λmax, nm, pH 1, 258.4 (∈ 15,000), pH 7, 259.3 (∈ 15,200), pH 13, 260.4 (∈ 15,700). Anal. (C15H24N8O4.2.0H2SO4.2.7H2O) C, H, N, S.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl.O>O1CCCC1>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)O1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOCC1COC(C)(C)O1
Reaction time: 3 h
Yield: 83 %

Procedure:
7(a) A solution of 9.25 g of (4RS)-2,2-dimethyl 1.3-dioxolane-4-methanol in 100 ml of tetrahydrofuran was added dropwise to a suspension of 3.36 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 300 ml of tetrahydrofuran at 20° to 24° C. over a period of 30 minutes. At the end of this time. 10.46 g of 2-methoxyethoxymethyl chloride in 50 ml of tetrahydrofuran were added dropwise to the mixture cooled on an ice bath. The reaction mixture was stirred at 0° to 2° C. for 3 hours, and then poured into water. It was then extracted twice with ethyl acetate. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 200 g of silica gel. 12.80 g of (4RS)-2,2-dimethyl-4-(2-methoxyethoxy)methoxymethyl-1,3-dioxolane were obtained as a colorless oil from the fractions eluted with mixtures of ethyl acetate and hexane ranging from 1:5 to 1:4 by volume.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[N:10]1([C:16]2[N:17]=[C:18]([CH2:23][C:24](OCC)=[O:25])[NH:19][C:20](=[O:22])[CH:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C[Al](C)C>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:24](=[O:25])[CH2:23][C:18]1[NH:19][C:20](=[O:22])[CH:21]=[C:16]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[N:17]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1Cc2ccccc2C1
Yield: 23.5 %

Procedure:
The product is prepared according to the procedure described in example 70, using 250 mg of isoindoline, 267 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 1 and 1.15 ml of a 2M solution of trimethylaluminium, in a mixture of 20 ml of toluene and 10 ml of tetrahydrofuran. 80 mg of 2-[2-(1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[O:12]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.FC1C=C([N+]([O-])=O)C=CC=1F.CN1CCNCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:19]1[CH2:20][CH2:21][C:16]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:17][CH2:18]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: CN1CCNCC1
Agent: O=[N+]([O-])c1ccc(F)c(F)c1
Product: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)c(Cl)c1

Procedure:
The title compound 3.05 g (quantitative) was obtained in a manner similar to the Manufacturing Example 25 by use of 3,4-dichloronitrobenzene and 1,4-dioxa-8-azaspiro[4.5]decane, instead of 3,4-difluoronitrobenzene and N-methylpiperazine, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19](OC)=[O:20]>C1COCC1>[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19](=[O:20])[CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccncc1
Reactant: COC(=O)c1sccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1sccc1Cl
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To a solution of 4-methylpyridine (1 eq, 75 mmol) in anhydrous THF (50 mL) was added n-butyl lithium 2.5 M solution (1.3 eq, 98 mmol) at −50° C. under nitrogen. The reaction mixture was stirred for 30 min at −50° C. To the mixture was slowly added a solution of methyl 3-chloro-2-thiophenecarboxylate (1 eq, 75 mmol, synthesis described in Heterocycles, 2007, 71(1), 87) in anhydrous THF (50 mL) at −50° C. The reaction mixture was stirred at −50° C. for 30 min, then allowed to warm to room temperature and stirred for 2 h. The mixture was quenched with aqueous saturated ammonium chloride solution (150 mL). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water, brine, dried over Na2SO4 and concentrated. The obtained dark brown residue was purified by column chromatography on silica gel (DCM:MeOH, 100:1 to 80:1) to afford 4 g of 1-(3-chloro-2-thienyl)-2-(pyridin-4-yl)ethanone (22% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][NH:16][NH2:17]>>[NH2:10][C:6]1[NH:17][N:16]([CH2:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[Cl:12])[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccccc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Product: Nc1cc(=O)n(Cc2ccccc2Cl)[nH]1
Yield: 40 %

Procedure:
35 g of β-amino-β-ethoxyacrylic acid ethyl ester and 32 g of 2-chlorobenzylhydrazine when reacted as described in Example 45 yield 17.5 g of the compound identified above as colorless crystals of melting point 153°. (Yield: 40% of theory)
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[C:41]([C:42](Cl)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[C:41]([C:42]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 617.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[CH3:20][O:19][C:13]1[CH:18]=[CH:17][C:16]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.5 h

Procedure:
The compound of formula 3a was prepared according to the procedure of Shani, J. et al., J. Med. Chem, 1985, 28, 1504. Thus, a mixture of 4-nitrobenzoyl chloride (90 g, 0.48 mol) and anisole (57.24 g, 0.53 mol) in carbon disulfide (450 mL) was stirred in a three neck round bottom flask equipped with nitrogen inlet, condenser and mechanical stirrer that was being cooled in an ice bath. Aluminum chloride (84.0 g, 0.63 mol) was added in portions and stirring continued at ice bath temperature for 30 minutes, then at room temperature for an additional 1 hour. The reaction mixture was cooled, treated with concentrated hydrochloric acid (150 mL), diluted with cold water (250 mL). The product was collected, filtered, washed, dried, and crystallized from ethyl acetate to give 4-(4-methoxybenzoyl)-nitrobenzene as an off-white solid, m.p. 120–122° C.; Analysis for C14H11NO4: Calc.: C, 65.3; H, 4.31; N, 5.44; Found: C, 65.22; H, 4.16; N, 5.69.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:23][CH2:24][OH:25].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:8]([CH2:9][C:10]1[CH:14]=[CH:13][O:12][CH:11]=1)[CH2:23][CH2:24][OH:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: c1ccc(CNCc2ccoc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCN(Cc1ccccc1)Cc1ccoc1

Procedure:
N-Benzyl-3-furylmethylamine (12 g, 64 mmol), triethylamine (18 ml, 130 mmol) and 2-bromoethanol (8.0 g, 64 mmol) were stirred at 60° C. to 70° C. for 16 hours in anhydrous N,N-dimethylformamide (120 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 7.1 g (31 mmol, 48% in yield) of the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C@@H:8]2[CH2:12][CH2:13][CH2:14][C@H:7]12)C.[NH3:16]>CO>[O:11]=[C:10]1[N:6]([CH2:5][C:4]([NH2:16])=[O:3])[C@H:7]2[CH2:14][CH2:13][CH2:12][C@H:8]2[CH2:9]1
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCC[C@@H]21
Reactant: N
Solvent: CO
Product: NC(=O)CN1C(=O)C[C@@H]2CCC[C@@H]21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of cis-hexahydro-2-oxo-cyclopenta-[b]pyrrole-1(2H)-acetic acid ethyl ester (3.25 g, 0.0154 mole) in methanol (200 ml) is saturated with anhydrous ammonia and stirred at ambient temperature 24 hours. The solution is concentrated at reduced pressure to yield a solid. Recrystallization from acetonitrile yields pure cis-hexahydro-2-oxo-cyclopenta[b]pyrrole-1(2H)-acetamide with a mp 142.5°-143.5° C.