Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nccnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: BrCc1ccc2nccnc2c1
Temperature: 25 °C
Yield: 35.5 %

Procedure:
A mixture of 6-methylquinoxaline (2.0 g, 13.9 mmol), N-bromosuccinimide (3.0 g, 16.9 mmol), and benzoyl peroxide (411 mg, 1.7 mmol) in anhydrous carbon tetrachloride (50 mL) was stirred at reflux for 2 days. Dichloromethane (50 mL) was added after cooling to room temperature. The mixture was extracted with 1 N NaOH (1×100 mL) and brine (1×100 mL). The organic extract was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-30% EtOAc/hexanes), affording 6-(bromomethyl)quinoxaline (1.10 g, 35% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][C:11](=[O:17])[CH2:10][CH2:9]2)=[O:5])[CH3:2].[CH2:18](I)[CH3:19]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:18][CH3:19])[C:11](=[O:17])[CH2:10][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cc1C)NC(=O)CC2
Reactant: CCI
Product: CCOC(=O)c1cc2c(cc1C)N(CC)C(=O)CC2
Yield: 85.1 %

Procedure:
Using the compound (10.0 g, 42.9 mmol) obtained in step B and ethyl iodide (6.86 ml, 85.8 mmol), and according to the method of Reference Example 113, step B, the title compound (9.54 g, yield 85%) was obtained as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([F:34])[CH:28]=4)[C:22]3=[O:35])[CH2:17][C:16]2([F:37])[F:36])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[F:37][C:16]1([F:36])[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:20][CH2:19][N:18]([CH:21]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([F:34])[CH:28]=3)[C:22]2=[O:35])[CH2:17]1
Reactant: Cc1ccc(CN2CCC(N3CCC(c4ccc(OCc5ccccc5)cc4)C(F)(F)C3)C2=O)cc1F
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(CN2CCC(N3CCC(c4ccc(O)cc4)C(F)(F)C3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a stirred solution of 3-(4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (0.45 g, 0.89 mmol, mixture of diastereomers from step D) in MeOH (8 mL) at rt was added 0.56 g of 10% Pd/C and the reaction mixture was stirred at rt under a hydrogen atmosphere overnight. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo. The residue was subjected to HPLC purification (method E) to yield 200 mg of 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one as a mixture of four diastereoisomers.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:7]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]([CH:19]([CH3:21])[CH3:20])[C:11]3=[O:22])=[N:8][C:4]=2[CH:3]=1.[CH2:30](C([Sn])=C(CCCC)CCCC)[CH2:31]CC>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH:19]([N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][C:7]2[N:6]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:5]3[CH:28]=[CH:29][C:2]([CH:30]=[CH2:31])=[CH:3][C:4]=3[N:8]=2)[C:11]1=[O:22])([CH3:21])[CH3:20]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Yield: 32.3 %

Procedure:
A mixture of 1-[5-bromo-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (90 mg, 0.2 mmol), tributylvinyltin (76 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) in toluene (4 mL) was heated to reflux for 4 h. After cooling, the reaction mixture was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography (hexanes:EtOAc 4:1 to 2:1) to give 26 mg (32%) of 1-isopropyl-3-[1-(3-methyl-butyl)-5-vinyl-1H-benzoimidazol-2-ylmethyl]-1,3-dihydro-benzoimidazol-2-one as a off-white solid.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH:7]=[N:6][CH:5]=[N:4]1.CCN(CC)CC.[C:22]([O:26][C:27](ONC(C1C=CC=CC=1)C#N)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[N:3]1([CH2:8][CH:9]2[NH:10][CH2:11][CH2:12][N:13]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:14]2)[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: c1ncn(CC2CNCCN2)n1
Reactant: CC(C)(C)OC(=O)ONC(C#N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCNC(Cn2cncn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a suspension of 2-(1H-1,2,4-triazol-1-ylmethyl)piperazine dihydrochloride (104 mg, 0.39 mmol) and Et3N (157.7 mg, 1.56 mmol) in CH2Cl2 (3 ml) was added [{[(tert-butoxy-carbonyl)oxy]amino}(cyano)methyl]benzene (106.5 mg, 0.43 mmol). The mixture was stirred for 2 hours at room temperature. The solvent was evaporated in vacuo, and the residue was purified by column chromatography on silica gel (MeOH/CHCl3= 1/50- 1/10) to give tert-butyl 3-(1H-1,2,4-triazol-1-ylmethyl)-1-piperazinecarboxylate (50.9 mg, 48.9%): HPLC-MS (ESI): Calcd for C, H20N6O2 [M+H]+ 268, found: 268.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]#[N:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:16]1.N12CCCN=C1CCCCC2>C(#N)C>[C:13]([CH2:12][C:10]1([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16]2)[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)#[N:14]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cc[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2ccc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)c2)C1
Yield: 82.8 %

Procedure:
A 100 mL round bottom flask fitted with overhead stirring, septa and nitrogen inlet was charged with tert-butyl-3-(cyanomethylene)azetidine-1-carboxylate (1.8 g, 9.5 mmol), 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 9.5 mmol) and acetonitrile (60 mL). The resulting solution was heterogeneous. 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.5 mmol) was added portionwise via a syringe over 3 minutes at room temperature. The solution slowly becomes homogeneous and yellow in color. The reaction was allowed to stir at room temperature for 3 hours. The solution was concentrated by rotary evaporation to remove acetonitrile. EtOAc (100 mL) and brine (100 mL) were added. The organic phase was separated and the aqueous layer was extracted with 3×30 mL EtOAc. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield an orange oil which was purified by flash chromatography (120 grams silica, 30-55% EtOAc/hexane, loaded with CH2Cl2). Desired fractions were combined and concentrated to yield a yellow oil which was placed on a high vacuum pump to give 4 g (83%) of tert-butyl 3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidine-1-carboxylate as a white foam. LC-MS: [M+H]+=509.3.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[C:6]([C:8](=[O:24])[C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=2)[CH:7]=1.[H-].[Na+].[CH3:27]I>CN(C)C=O>[CH3:27][N:4]1[CH:5]=[C:6]([C:8](=[O:24])[C:9]2[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=2)[CH:7]=[C:3]1[S:2][CH3:1]
Reactant: CI
Reactant: CSc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cn1C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2-Methylthio-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (1 g) was added to a cooled, stirred suspension of 0.28 g of sodium hydride (50% in mineral oil) in 20 ml of anhydrous dimethylformamide under nitrogen. After 45 minutes at room temperature, the mixture was cooled to 0° C. and 0.25 ml of methyl iodide was added. After 30 minutes, the reaction mixture was poured into a 10% HCl-ice-water mixture, then extracted three times with 100 ml ethyl acetate. The organic layer was washed five times with 100 ml water, dried and evaporated to dryness. Crystallization of the residue from ethyl acetate-hexane gave 0.93 g of the title compound (mp 173°-175° C.).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.C(N(CC)CC)C.C(O)(=O)C(C)(C)C.CC(O[CH2:26][C:27]1[CH2:36][S:35][C@@H:30]2[C@H:31]([NH2:34])[C:32](=[O:33])[N:29]2[C:28]=1[C:37]([OH:39])=[O:38])=O>O>[NH2:34][CH:31]1[C:32](=[O:33])[N:29]2[C:28]([C:37]([OH:39])=[O:38])=[C:27]([CH2:26][S:7][C:5]3[S:6][C:2]([CH3:1])=[N:3][N:4]=3)[CH2:36][S:35][C@H:30]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1nnc(S)s1
Agent: CC(C)(C)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 82 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A mixture of 30 g of 5-methyl-2-mercapto,1,3,4-thiadiazole, 32 ml of triethylamine and 5 g of pivalic acid in 2 liters of water was heated to 82° C. Thereafter there was added in one shot 40 g of 7-aminocephalosporanic acid (92%) and 5 g of pivalic acid were added in one shot to the resulting solution. Precipitation started after a few minutes and increased with time. After 30 minutes of vigorous stirring at the same temperature, the mixture was cooled to 65° C. The solid was isolated by filtering, washed with water and acetone to give 35 g of the compound of the title. The liquors were cooled to 20° C. and filtered and gave a further 5 g fraction, with an overall yield of 87%. The infrared and proton magnetic resonance spectra are consistent with the technically pure product.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[F:18][C:19]1[C:24]2[B:25]([OH:28])[O:26][CH2:27][C:23]=2[CH:22]=[C:21]([OH:29])[CH:20]=1>>[Cl:1][C:2]1[C:3]([O:29][C:21]2[CH:20]=[C:19]([F:18])[C:24]3[B:25]([OH:28])[O:26][CH2:27][C:23]=3[CH:22]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(C)OCCOc1nc(Cl)c(Cl)cc1C#N
Reactant: OB1OCc2cc(O)cc(F)c21
Product: CC(C)OCCOc1nc(Oc2cc(F)c3c(c2)COB3O)c(Cl)cc1C#N

Procedure:
This compound was prepared from 5,6-dichloro-2-(2-isopropoxyethoxy)nicotinonitrile and 7-fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.01 (d, J=4.5 Hz, 6H), 3.45-3.48 (m, 1H), 3.51-3.53 (m, 2H), 4.11-4.14 (m, 2H), 5.03 (s, 2H), 7.14 (d, J=8.6 Hz, 1H), 7.22 (s, 1H), 8.62 (s, 1H), 9.35 (s, 1H).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][C:57](=[O:59])[CH3:58])=[CH:51][CH:50]=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1.C(OCC)(=O)C>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:48][C:49]2[CH:50]=[CH:51][C:52]([CH2:55][CH2:56][C:57](=[O:59])[CH3:58])=[CH:53][CH:54]=2)[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)CCc1ccc(OCCCc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol, 6 mmol of triphenylphosphine and 5 mmol of 4-(4-hydroxyphenyl)-2-butanone are dissolved under nitrogen in the cold. 6 mmol of diethyl azodicarboxylate, dissolved in 4 ml of THF, are added and the reaction mixture is stirred at room temperature for 48 hours. After evacuation of the solvent under reduced pressure and column chromatography (eluent: ethyl acetate), the residue is dissolved in 10 ml THF and 30 ml of 2N HCl and heated to 70° C. for 2 hours. The solvent is evaporated off under reduced pressure and triphenylmethanol is extracted using diethyl ether. The aqueous phase is neutralized with potassium carbonate and the product extracted with diethyl ether. The ethereal solution is dried and evaporated to obtain an oil, which is crystallized as hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30][NH2:31]>C(O)C>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:30][NH2:31])[CH:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(F)c2)cc1
Reactant: NN
Solvent: CCO
Product: NNc1cc(-c2c(-c3ccc(F)cc3)nn3c(NC4CCCC4)cccc23)ccn1
Yield: 65 %

Procedure:
In a similar manner as described in Example 29, from N-cyclopentyl-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine (45 mg, 0.12 mmol) and anhydrous hydrazine (0.5 mL) in ethanol (4 mL) at 100° C. for 13 hours was formed N-cyclopentyl-2-(4-fluorophenyl)-3-(2-hydrazino-4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine (30 mg, 65%) as a solid. 1H NMR (CDCl3): δ 8.05 (d, 1H), 7.61 (m, 2H), 7.20 (t, 1H), 7.09–6.99 (m, 4H), 6.71 (s, 1H), 6.63 (d, 1H), 6.03–5.96 (m, 3H), 4.01 (broad m, 2H), 2.14 (m, 2H), 1.84–1.68 (m, 6H); 19F NMR (CDCl3) δ −113.66; MS m/z 403 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.CCN=C=NCCCN(C)C.Cl.O>CO>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cnc(C=O)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 3.2 %

Procedure:
In methanol (15 ml), 5-methylpyrazine-2-carboxylic acid (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.25 g) was dissolved. Then, the solution was added with WSCI hydrochloride (2.59 g) and N,N-dimethylaminopyridine (1.65 g) in this order, followed by stirring at room temperature for 3 hours. The reaction solution was added with water and then extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. The solvent was distilled off and the resulting crude product was then purified through silica gel column chromatography (chloroform/methanol). The purified product was dissolved in ethanol (15 ml) and THF (8 ml) and added with calcium chloride (1.11 g). After that, the reaction solution was cooled to 0° C. and then gradually added with sodium borohydride (757 mg), followed by stirring at room temperature for 19 hours. The reaction solution was added with a 1 mol/l citric acid solution (40 ml), followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate, followed by distilling the solvent off. The residue was dissolved in chloroform (10 ml) and then added with manganese dioxide (chemically processed product) (2.2 g), followed by stirring at room temperature for 1 hour. After completion of the reaction, the catalyst was filtrated out through Celite and the solvent was then distilled off. The crude product obtained was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (35.9 mg) as a colorless oily substance.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[CH2:17][CH3:18])C>O1CCCC1>[CH2:17]([C:12]1[C:11]([CH2:10][OH:9])=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:18]
Reactant: CCOC(=O)c1cccnc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ncccc1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
To a suspension of LiAlH4 (0.83 g, 21.76 mmol) in tetrahydrofuran (50 ml) was added drop wise a solution of 2-ethyl-nicotinic acid ethyl ester (Breitmaier et al, Tetrahedron, 26, 1970, 5907-5910) (3 g, 16.74 mmol) in tetrahydrofuran (25 ml) at −50° C. After addition, the temperature was slowly allowed to increase to 0° C. After 3 h, the reaction was quenched with saturated NH4Cl, filtered and washed with 1M NaHCO3 (50 ml). The aqueous layer was extracted with ethyl acetate (3×50 ml). Combined organic extract were dried (Na2SO4), filtered and concentrated to yield 1.6 g (54%) of product as a yellowish liquid. MS (ESI+) m/z 138 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.[CH3:19]I.[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:19])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
2-Chloro-9-cyclopentyl-8,9-dihydro-5H-pyrimido[4.5-b][1,4]diazepin-6(7H)-one (474.7 mg, 1.78 mmol) and methyl iodide (0.122 ml, 1.96 mmol) in DMA (4.5 ml) stirred at −10° C. and treated with sodium hydride 60% oil dispersion (75 mg, 1.87 mmol). The mixture was warmed to 0° C. for 20 min and then to 20° C. for 40 min. A further 0.12 ml methyl iodide and 8 mg sodium hydride were added and the mixture stirred at ambient overnight. Ice was added and the mixture concentrated under reduced pressure. The residual oil was treated dropwise with water (6 ml), filtered and the buff solid dried under high vacuum at 60° C. (486 mg, 98%). NMR DMSO D6 1.45-1.72 (6H, m), 1.76-1.91 (2H, m), 2.61 (2H, d), 3.18 (3H, s), 3.64 (2H, d), 4.65-4.74 (1H, m), 8.15 (1H, s).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:13]=1[CH2:14][O:15][CH2:16][C@H:17]1[O:21][CH:20]([O:22][CH3:23])[C@H:19]([OH:24])[C@@H:18]1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:11][C:12]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:13]=1[CH2:14][O:15][CH2:16][C@H:17]1[O:21][CH:20]([O:22][CH3:23])[C:19](=[O:24])[C@@H:18]1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34]
Reactant: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of oxalyl chloride (2.15 ml, 25.1 mmol, 1.3 equiv.) in DCM (20 ml) at −78° C. is added a solution of DMSO (2.85 ml, 36.5 mmol, 1.9 equiv.) in DCM (30 ml) and stirred at −78° C. for 30 mins. Then a solution of (3R,4S,5R)-5-(2,4-Dichlorobenzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-2-methoxy-tetrahydrofuran-3-ol I-2 (9.6 g, 18.8 mmol, 1 equiv.) in DCM (50 ml) is added slowly and stirred at −78° C. for about 2 h. After that, triethylamine (15.8 ml, 114 mmol, 6.0 equiv.) is added to the reaction mixture and slowly brought to room temperature and stirred for 1 h. After the reaction is completed, the mixture is diluted with water (100 ml) and DCM (50 ml). The DCM layer is separated and washed with 1 N HCl solution and saturated brine, dried (anhyd Na2SO4), concentrated and purified by flash chromatography (hexane:ethyl acetate=70:30) to give (4R,5R)-5-(2,4-Dichlorobenzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-2-methoxy-dihydrofuran-3-one I-3 as slightly yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:10]1[CH:11]=[C:12](I)[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][N:16]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:15]2=[O:31])#[N:9]>>[C:8]([C:10]1[CH:11]=[C:12]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][N:16]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:15]2=[O:31])#[N:9]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3c(C#N)cc(I)cc3c2=O)c1
Product: COC(=O)c1ccc(C)c(-n2cnc3c(C#N)cc(N4CCN(C)CC4)cc3c2=O)c1

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting material N-methyl piperazine was reacted with methyl 3-(8-cyano-6-iodo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate to give methyl 3-[8-cyano-6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.24 (s, 3H), 2.49 (m, 4H, masked by DMSO), 3.36 (m, 4H), 3.88 (s, 3H), 7.63 (d, 1H), 7.70 (d, 1H), 8.03 (m, 2H), 8.13 (d, 1H), 8.28 (s, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[CH:1]1([NH:7][C:28]([C:17]2[N:18]([CH3:27])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=3)[N:16]=2)=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Cn1c(C(=O)O)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Product: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 20, Step B, but using cyclohexylamine (0.020 mL, 0.12 mmol), 4,5-di-(4-chlorophenyl)-1-methylimidazole-2-carboxylic acid (20 mg, 0.060 mmol) from Example 20, Step A was converted to the title compound.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:31]([Si:35]([CH3:52])([CH3:51])[O:36][CH:37]([C:39]1[O:40][C:41]([CH2:44][N:45]2[CH:49]=[CH:48][C:47]([NH2:50])=[N:46]2)=[CH:42][N:43]=1)[CH3:38])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl.O>[C:31]([Si:35]([CH3:52])([CH3:51])[O:36][CH:37]([C:39]1[O:40][C:41]([CH2:44][N:45]2[CH:49]=[CH:48][C:47]([NH:50][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])=[N:46]2)=[CH:42][N:43]=1)[CH3:38])([CH3:34])([CH3:33])[CH3:32]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ccc(N)n2)o1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-phenyl-oxazole-4-carboxylic acid (114 mg, 0.60 mmol) in CH2Cl2 (3.0 mL) was treated at rt with HOBt (98 mg, 0.72 mmol), EDC (289 mg, 1.51 mmol) DMAP (18 mg, 0.15 mmol) and the resulting mixture was stirred at rt for 30 min. 1-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-1H-pyrazol-3-ylamine (297 mg, 0.60 mmol) in CH2Cl2 (3.0 mL) was then added and the resulting mixture was stirred at rt for 16 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=1.17 min, [M+H]+=494.56.