Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(OC(N1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])=O)C>C(#N)C.O>[CH:16]1([O:15][C:9]2[CH:8]=[C:7]([CH:2]([N:1]3[C:36](=[O:37])[C:35]4=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]4[C:33]3=[O:42])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
A mixture of 3-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)propanoic acid (3.00 g, 10.8 mmol) and sodium carbonate (1.20 g, 11.3 mmol) in acetonitrile (30 mL) and water (30 mL) under nitrogen was stirred at room temperature for 15 minutes. To the resulting solution was added N-ethoxycarbonyl phthalimide (2.36 g, 10.8 mmol). The resulting mixture was stirred at room temperature for 18 hours. Most of solvent was removed in vacuo. To the solution was added hydrochloric acid (6N) until the pH of solution <1 to give a suspension and stirring was continued for 1 hour. The suspension was filtered, the solid was washed with water (2×10 mL), and then was dried in a vacuum oven overnight (60° C., <1 torr) to afford 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phthalimidopropanoic acid as a white solid (3.0 g, 68% yield): mp, 168.0-169.0° C.; 1H NMR (DMSO-d6) δ1.55-1.88 (m, 8H, C5H8), 3.27 (dd, J=6.9, 16.5 Hz, 1H, CHH), 3.51 (dd, J=8.9, 16.5 Hz, 1H, CHH), 3.71 (s, 3H, CH3), 4.71-4.75 (m, 1H, CH), 5.61 (dd, J=6.9, 8.8 Hz, 1H, NCH), 6.87-6.95 (m, 2H, Ar), 7.03 (br s, 1H, Ar), 7.81-7.91 (m, 4H, Ar), 12.4 (br s, 1H, OH); 13C NMR (DMSO-d6) δ23.51, 32.14, 32.17, 36.07, 50.08, 55.52, 79.57, 112.15, 113.97, 119.39, 123.17, 131.09, 131.19, 134.66, 146.77, 149.16, 167.67, 171.72; Anal Calcd for C23H23NO6: C, 67.47; H, 5.66; N, 3.42. Found: C, 67.21; H, 5.46; N, 3.45.
Reaction SMILES: C(O)(=O)C.[C:5]([OH:12])(=O)[CH2:6][CH2:7][C:8]([OH:10])=[O:9].[C:13]1([C:19]([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C(C(C2C=CC=CC=2)O)=O)C=CC=CC=1.C([O-])(=O)C.[NH4+:49]>O>[C:13]1([C:19]2[N:49]=[C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[O:12][C:21]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: [NH4+]
Reactant: O=C(O)CCC(=O)O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 2 h

Procedure:
A clean dry reactor of 50 gallon capacity (227 liters) was charged with glacial acetic acid (92.0 kg.). With agitation benzoin hemisuccinate (25.3 kg.) prepared as described under part A and ammonium acetate (31 kg.) were added. The reaction mixture was heated to 90°-95° C. and stirred at this temperature range for 11/2 hours. Water (44.0 kg.) was carefully added to the reaction mixture and the mixture was reheated to 90°-95° C. The mixture was then transferred to another reactor of 50 gallon capacity (227 litres) through a pre-heated pressure filter. The first reactor and the filter were washed through with a mixture of glacial acetic acid (13.3 kg.) and water (6.2 kg.). The mixture in the reactor was then cooled to 10°-15° C. with agitation and the product was filtered on a ceramic filter. The product on the ceramic filter was then washed with a mixture prepared by adding glacial acetic acid (25.5 kg.) with agitation to water (12.5 kg.). The product on the filter was sucked well dry and then washed with demineralised water (10 kg.) and sucked well dry. The product was dried in a Mitchell oven at 80° C. for 16-18 hours. The yield of crude β-(4,5-diphenyloxazol-2-yl)propionic acid was 17.5 kg. (67% overall yield for parts A and B).
Reaction SMILES: [Cl:1][CH:2]1[C:10]2[C:5](=CC=CC=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.O[CH:24]1[C:32]2C(=NC=C[N:31]=2)C(=O)[N:25]1C1C=CC2C(=NC(OC)=CC=2)N=1.S(Cl)(Cl)=O>CN(C)C=O>[Cl:1][CH:2]1[C:10]2[C:5](=[N:25][CH:24]=[CH:32][N:31]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1
Reactant: COc1ccc2ccc(N3C(=O)c4nccnc4C3O)nc2n1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C1c2nccnc2C(Cl)N1c1ccc2ccc(Cl)nc2n1

Procedure:
5-Chloro-6-(7-chloro-1,8-naphthyridin-2-yl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazine is prepared in a manner similar to that described in Example 6 for the preparation of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone, but starting with 5-hydroxy-6-(7-methoxy-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (23.2 g), sulphinyl chloride (300 cc) and dimethylformamide (1 cc). 5-Chloro-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]-pyrazine (21 g ) m.p. 264° C., is thereby obtained.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]=[O:21].N(CCO)(CCO)C[CH2:24][OH:25]>O1CCOCC1.O>[OH:25][CH2:24][N:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8](=[O:13])[N:9]([CH2:20][OH:21])[C:10]1=[O:12]
Reactant: OCCN(CCO)CCO
Reactant: C=O
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Solvent: O
Solvent: C1COCCO1
Product: O=C1N(CO)C(=O)C(c2ccccc2)(c2ccccc2)N1CO
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In accordance with Example 5 of U.S. Pat. No. 3.595.862, 50.4 g (0.2 mole) of 5,5-diphenylhydantoin were suspended in a mixture of 50 ml of dioxan and 200 ml of water. To this suspension was added 88 ml of 37% aqueous formaldehyde solution and 10 ml of triethanolamine and the mixture was stirred for 7 hours at 92°-98° C. The resultant clear, colourless solution was cooled to 25° C., adjusted to a pH of 1 and extracted with ether (3×100 ml). The ethereal solution was washed with 50 ml of saturated saline solution and dried over anhydrous sodium sulphate. The ether was distilled off under reduced pressure (bath temperature 40° C.) and the 1,3-di-(hydroxymethyl)-5,5-diphenylhydantoin is obtained as an oil in a yield of 63.1 g (99.8% of theory).
Reaction SMILES: [N:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:23])[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:11]2[CH:15]2[CH2:17][CH2:16]2)=[CH:6][C:5]=1[F:24])=[N+]=[N-].C(O)C>CN(C)C=O.[Pd]>[NH2:1][C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:23])[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:11]2[CH:15]2[CH2:17][CH2:16]2)=[CH:6][C:5]=1[F:24]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N=[N+]=[N-])c(F)cc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N)c(F)cc2c1=O
Temperature: 5 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
A slurry of 1.20 kg of ethyl 7-azido-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 12 L of dimethylformamide was charged to a five gallon autoclave. After placing the vessel under nitrogen, a slurry of 76 g of 10% palladium-on-carbon in 700 ml of dimethylformamide was added. The mixture was hydrogenated at 48-50 p.s.i. and 600 r.p.m. for four hours. The reaction mixture was filtered and concentrated under aspirator pressure to give a thick but stirrable dark residue. Ethanol (3 L) was added and the suspension was briefly refluxed before allowing to cool. After cooling to 5° C., the product was collected, washed with 2×500 ml of cold ethanol and then dried at 65°-70° C. in vacuo overnight to give 962 g (86.7%) of product.
Reaction SMILES: ClC(OCC(C)C)=O.[O:9]=[C:10]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([OH:25])=O)[C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14].[NH3:26].C(O)C>C(Cl)Cl.O>[O:9]=[C:10]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([NH2:26])=[O:25])[C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: N
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.8 %

Procedure:
Isobutyl chloroformate (20 mmol, 2.7 mL) was added to a solution containing (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (4.89 g, 20 mmol) (from Example 1) in 50 mL methylene chloride at −10° C. with stirring. After 5 minutes, ammonia was added dropwise (20 mmol, 10 mL of 2 M ethyl alcohol solution). The reaction was warmed up to room temperature after stirring at −10° C. for 30 minutes. The mixture was diluted with water, and extracted into 200 mL methylene chloride. The organic extract was concentrated and further purified by silica gel to give 4.0 g of product as a white solid (81.8% yield). 1H NMR (CDCl3): δ0.91 (t, 3H, J=7.5); 1.28 (s, 6H, each); 1.63–1.84 (m, 2H); 1.95–2.22 (m, 3H); 2.46 (m, 1H); 3.55–3.67 (m, 2H); 4.67 (t, 1H, J=7.8); 5.51–5.53 (br, 1H, NH); 6.80 (br, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]1([C:15]([F:18])([F:17])[F:16])[CH2:14][O:13]1.C(=O)([O-])[O-:33].[Cs+].[Cs+]>CN(C=O)C.O.CS(C)=O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]([OH:33])([CH2:14][OH:13])[C:15]([F:16])([F:17])[F:18]
Reactant: COc1ccc(C(Nc2cc(F)cc3[nH]c(=O)ccc23)C2(C(F)(F)F)CO2)c(Cl)c1F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(Nc2cc(F)cc3[nH]c(=O)ccc23)C(O)(CO)C(F)(F)F)c(Cl)c1F
Yield: 379 %

Procedure:
250 mg (0.54 mmol) 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-on are stirred with 353 mg (1.1 mmol) Caesium carbonate in 3 ml DMF, 1.9 ml water and 0.5 ml DMSO. Water is added and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent flash chromatography on silica gel (methanol in dichloromethan 0 to 5%) yields 0.98 g of the title compound.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[C:15]([NH2:31])=[N:16][CH:17]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:24]=2)[CH:19]=1.C(N(CC)CC)C>CC(N(C)C)=O>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[C:15]([NH2:31])=[N:16][CH:17]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:26][CH2:27][N:28]([CH:2]([CH3:4])[CH3:3])[CH2:29][CH2:30]3)[CH:24]=2)[CH:19]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2o1
Reactant: CC(C)I
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
2-Iodopropane (0.029 ml) was added in one portion to 3-(1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.100 g) and triethylamine (0.05 8 ml) in DMA (3 ml) and the resulting solution was stirred for 30 minutes. A further portion of 2-iodopropane (0.029 ml) was added, the temperature was increased to 50° C. and the reaction mixture was stirred for a further 90 minutes. A third portion of 2-iodopropane (0.029 ml) was added, and then triethylamine (0.058 ml) was added and the reaction heated at 50° C. for a further hour. The reaction mixture was then evaporated to dryness and redissolved in DMSO (3.6 ml) and the crude product was purified by preparative X bridge HPLC (C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length using decreasingly polar mixtures of water containing 1% ammonia and MeCN as eluents). There was thus obtained 3-(1,3-benzoxazol-2-yl)-5-[1-(1-isopropyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.065 g); Mass Spectrum: M+H+ 403.17; RT 2.49 min; NMR Spectrum: (DMSOd6) 8.53 (1H, d), 8.44 (1H, d), 8.32 (1H, s), 7.90 (1H, s), 7.82-7.86 (1H, m), 7.77-7.81 (1H, m), 7.62 (2H, s), 7.41-7.49 (2H, m), 4.05-4.16 (1H, m), 2.91 (2H, d), 2.77 (1H, quintet), 2.29 (2H, t), 2.02-2.11 (2H, m), 1.94 (2H, qd), 1.01 (6H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].[CH3:18]N(C)CCN(C)C.C([Li])CCC.IC.Cl>CCCCCC.O1CCCC1>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)F)c(F)c1
Reactant: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc(C(F)(F)C(F)(F)F)c1F
Temperature: -40 °C
Reaction time: 4 h
Yield: 11.4 %

Procedure:
5.00 g (98% by weight; 19.0 mmol) of 3-fluoro-4-(pentafluoroethyl)benzoic acid were introduced into 40 ml of dry tetrahydrofuran. 4.73 g (40.7 mmol) of 1,2-bis(dimethyl-amino)ethane were added, and the mixture was then cooled to −40° C. Then 16.3 ml of a 2.5 M solution (40.7 mmol) of n-butyllithium in hexane were added dropwise at a rate such that the temperature was in a range from −33° C. to −35° C. The contents were stirred at a temperature of −35° C. for 4 hours. Then a solution of 8.25 g (58.1 mmol) of iodomethane in 10 ml of dry tetrahydrofuran was added dropwise, and the mixture was stirred at a temperature of −35° C. for 1 hour. Thereafter the contents were warmed to room temperature (RT) and stirred at this temperature for 16 hours. For working up, 50 ml of 2M hydrochloric acid were cautiously added, and then the aqueous phase was extracted with diethyl ether. The combined organic phases were dried and freed from the solvents on a rotary evaporator. The residue was stirred in n-heptane and subsequently filtered. This gave 2.33 g of residue as a clean product. The filtrate was freed from the solvent, and the residue was again stirred in n-heptane. Filtration produced 590 mg of residue, which was identified as a product with a purity of 70% by weight.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([CH:19]([CH3:21])[CH3:20])[CH:6]=1)(=O)C.[OH-].[Na+].CCCCCCC>O.CO>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][C:7]=1[CH:19]([CH3:21])[CH3:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)c(C(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCCCCCC
Product: CC(C)c1cc(O)ccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
4-Benzyloxy-3-isopropylphenyl acetate (5.59 kg, 19.7 mol) is added to a solution of sodium hydroxide (1.20 kg, 30.0 mol) in a mixture of water (30 L) and methanol (30 L). This solution is stirred at 24° for 1 hour. A black-colored solution develops. This is concentrated in vacuo (40°,3 Torr) to remove the methanol. This residue is then extracted with ethyl acetate (2×16 L) and the combined organic layers are washed with aqueous sodium hydroxide (1N, 2×10 L) and water (3×12 L). The solvent is stripped in vacuo (500, 3 Torr) to yield an amber oil. This oil is then triturted with heptane (10 L) for 4 hours and the allowed to stand overnight at room temperature at which time the solids are collected by filtration and washed with cold heptane (2×1 L). After air-drying, the product is further dried in vacuo (25°,120 Torr) for 72 hours to give 4-benzyloxy-3-isopropylphenol as a low melting solid, m.p. 39°-40°.
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:24])([CH3:23])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[C:12]([O:14]C)=[O:13])(=O)C.[OH-].[Li+].Cl>CO.C1COCC1.O>[C:19]([C:17]1[CH:16]=[C:11]([CH:10]=[C:9]([O:8][CH2:7][C:6]([CH3:24])([CH3:23])[CH2:5][OH:4])[CH:18]=1)[C:12]([OH:14])=[O:13])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1cc(OCC(C)(C)COC(C)=O)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(CO)COc1cc(C(=O)O)cc(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 112.8 %

Procedure:
Methyl 3-(3-acetoxy-2,2-dimethylpropoxy)-5-tert-butylbenzoate (O5.086; 1 g) was dissolved in methanol/THF (15/30 ml), and lithium hydroxide solution (11.89 ml, 1 M in water) was added. After stirring at 40° C. for 2 h, the organic solvent was drawn off, and the residue was diluted with water and adjusted to pH 3 with 1 N hydrochloric acid. Then it was extracted with EA, and the combined organic phases were dried, filtered and concentrated. 940 mg of the title compound were obtained. LC-MS rt: 1.45 min [M+H]+: 281.1 (met. a)
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C(N(CC)[CH:28]([CH3:30])[CH3:29])(C)C>C(#N)C>[Cl:1][C:29]1[CH:28]=[CH:30][C:19]([C:18]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:7]3=[O:23])=[O:21])=[CH:20][CH:15]=1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: CCN(C(C)C)C(C)C
Reactant: Cl
Solvent: CC#N
Product: Cc1nc2ccc(CNC(=O)c3ccc(Cl)cc3)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.54 g, 1.6 mmol) in acetonitrile (10 mL), was added 4-dichloro-benzoyl chloride (0.31 mL, 2.4 mmol) and N,N-diisopropyl ethylamine (0.66 mL, 4.0 mmol). The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 4-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-benzamide as a white solid (298 mg, 42% yield); HPLC, Waters Symmetry Cu, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.00 min (99.0%); mp, 267-269° C.; 1HNMR (DMSO-d6) δ 2.15-2.18 (m, 1H, CHH), 2.57-2.85 (m, 6H, CHCH2, CH3), 4.59 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.54-7.95 (m, 7H, Ar), 9.24 (t, J=5 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.91, 23.40, 30.60, 42.33, 56.52, 120.01, 123.89, 126.62, 128.44, 129.15, 132.84, 134.09, 136.16, 138.02, 145.83, 154.60, 160.43, 165.23, 169.45, 172.60. LCMS MH=439, 441; Anal Calcd For C22H19N4O4Cl+0.3H2O: C, 59.48; H, 4.45; N, 12.61; Cl, 7.98. Found: C, 59.32; H, 4.10; N, 12.50; Cl, 7.99.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12]O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CS(Cl)(=O)=O.C(N(CC)CC)C.[CH3:26][NH:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[CH3:26])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(CO)c1
Reactant: CCCCNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(C)Cc1cc(Br)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of methyl 3-bromo-5-(hydroxymethyl)benzoate (4.1 g, 16.8 mmol) in anhydrous methylene chloride (35 mL) at −30° C. is added methanesulfonyl chloride (1.82 mL, 23.5 mmol) followed by triethylamine (4.7 mL, 33.6 mmol). The reaction mixture is stirred for 45 min at 0° C., and then filtered. The filtrate is added to N-methylbutylamine (6 mL, 50.4 mmol) and stirred at room temperature for 16 h. The solution is concentrated under reduced pressure, and the residue is purified by flash column chromatography (silica, 8% ethyl acetate/hexanes) to give the title compound. ESI MS m/z 314.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]([CH3:20])[CH3:19])[C:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(O)[C:6]=2[N:7]=1.Cl>CC(O)C.CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([N:18]([CH3:20])[CH3:19])[C:5]2[CH2:10][CH:9]=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[N:7]=1
Reactant: CN(C)c1nc(Cl)nc2c1CCC2(O)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: CN(C)c1nc(Cl)nc2c1CC=C2c1ccccc1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
To a solution of 2-chloro-4-(dimethylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (85 mg) in i-PrOH (5 mL) was added HCl in ether (1M solution), and the reaction mixture was heated at 80° C. from 3 h. The solution was cloudy and turned to clear yellow solution by the end of the reaction. The solvents were removed, and the reaction mixture was worked up with EtOAc and saturated NaHCO3 to give the title compound as a brownish solid (50 mg). LC-MS (M−H2O+H)+=272.07.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:17]3[CH2:18][CH2:19][CH2:20][N:14]([CH3:13])[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1cc(C)c2oc(S)nc2c1
Reactant: CN1CCCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c2oc(N3CCCN(C)CC3)nc2c1

Procedure:
5,7-Dimethyl-2-mercaptobenzoxazole (220 mg) was dissolved in chloroform (20 ml), N-methylhomopiperazine (0.76 ml) was added dropwise to the solution and then the mixture was stirred with heating for 2 days. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound 5,7-dimethyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (110 mg).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])[CH:7]=[CH:6][N:5]=1.[SH:16][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1>C(O)C.[OH-].[Na+]>[Cl:15][CH2:14][CH2:13][CH2:12][S:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][S:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)[C:9]=1[CH3:10]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCCCCl)ccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
One equivalent of 2-chloromethyl-4-(3-chloropropylthio)-3-methylpyridine hydrochloride (dissolved in 10 ml of water) is added dropwise to a solution of 2-mercapto-1H-benzimidazole (1.5 g/10 mmol) in 40 ml of ethanol and 21 ml of 1N sodium hydroxide solution at 40° C. in the course of 20 min. The mixture is then stirred at 50°-60° C. for 2-3 hours and at room temperature for a further 3-4 hours, the ethanol is distilled off on a rotary evaporator (1 kPa/40° C.), the residue is extracted 3 times with 20 ml of methylene chloride each time and the extract is washed with 0.1N sodium hydroxide solution, dried over potassium carbonate and evaporated to dryness in vacuo. For purification, the crude product is chromatographed over silica gel (methylene chloride 20:1 to 3:1); the pure fractions collected are evaporated together in vacuo and the residue is crystallized from methylene chloride/diisopropyl ether. It is then recrystallized from methanol/toluene. Yield: 2.67 g (74%) of the title compound as a colorless solid of melting point 112°-114° C.