Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=3[O:14][C:10]=2[CH:9]=1.C1(=O)O[CH2:25][CH2:24][O:23]1>CN(C)C=O>[Cl:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH2:24][OH:23])=[CH:15][C:13]=3[O:14][C:10]=2[CH:9]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc2c(c1)oc1cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc2c(c1)oc1cc(Cl)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
83 g (0.6 mole) of potassium carbonate were added to a solution of 262 g (1.2 moles) of 7-chlorodibenzofuran-3-ol in 600 ml of dry dimethylformamide, and a solution of 212 g (2.55 moles) of ethylene carbonate in 300 ml of dimethylformamide was then added dropwise in the course of 90 minutes at 100° C. The mixture was stirred for 8 hours at 120° C. and was then filtered under suction at 100° C., and the filtrate was evaporated down. The residue was dissolved in 2.5 liters of ethyl acetate, the solution was washed with three times 300 ml of water, the organic layer was dried, decolorized with 10 g of animal charcoal and evaporated down to 500 ml, and the residue was cooled to 10° C. The precipitate was filtered off under suction, washed with 60 ml of methanol, 50 ml of ether and 200 ml of petroleum ether in succession at +5° C., and dried. 225 g (71.4% of theory) of 2-(7-chlorodibenzofuran-3-yloxy)-ethanol of melting point 118°-120° C. were obtained.
Reaction SMILES: BrBr.[C:3]([NH:11][C:12]1[CH:17]=[C:16]([CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=O)[CH:15]=[CH:14][N:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:29]([NH2:32])(=[S:31])[CH3:30].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[N:32]=[C:29]([CH3:30])[S:31][C:18]=2[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:17]=2)=[CH:22][CH:23]=1
Reactant: CC(N)=S
Reactant: COc1ccc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)cc1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(C)sc2-c2ccnc(NC(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
Bromine (0.18 mL, 3.5 mmol) was added to a solution of 2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (1.2 g, 3.4 mmol) in acetic acid (10 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated. The residue was dissolved in N,N-dimethylformamide (20 mL), thioacetamide (0.30 g, 19 mmol) was added to the solution and the mixture was stirred at room temperature for 20 hours. An aqueous saturated solution of sodium hydrogencarbonate (20 mL) was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate and the extract was washed with water. The extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 1:1) to obtain 0.68 g (yield 50%) of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:12]=2[CH:32]=1.O>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[CH:18]=[C:19]([CH2:21][OH:22])[N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:12]=2[CH:32]=1
Reactant: CCOC(=O)c1cn2c(n1)CN=C(c1ccccn1)c1cc(Br)ccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cn2c(n1)CN=C(c1ccccn1)c1cc(Br)ccc1-2
Temperature: -35 °C
Yield: 43.3 %

Procedure:
0.38 g of lithium aluminium hydride was added portionwise to a suspension of 2.06 g of ethyl 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylate in 250 ml of tetrahydrofuran at −40° C. while stirring vigorously. A dark green solution thereby formed and this was stirred at −7 to −10° C. for 45 min. Then, the mixture was cooled to −35° C. and treated dropwise with 2 ml of water. After stirring at room temperature for 2 h. a further 6.0 ml of water were added slowly. The reaction mixture was filtered clear over Dicalite and the filtrate was evaporated in a vacuum. The residue was partitioned between 100 ml of chloroform and 50 ml of saturated aqueous sodium hydrogen carbonate solution. The chloroform phase was separated, dried over sodium sulphate and evaporated in a vacuum. The residue (1.9 g) was dissolved in 100 ml of tert-butanol and 50 ml of pyridine, treated with 1.0 g of selenium dioxide and stirred at 65° C. for 30 min. The mixture was evaporated in a vacuum, the residue was dissolved in chloroform, with a small amount of insoluble impurity being filtered off. The solution was chromatographed over 250 g of aluminium oxide (activity 1). A small amount of impurity was eluted with dichloromethane/etanol 98:2, then 0.95 g of the desired 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol was eluted with dichloromethane/ethanol 95:5, 90:10 and 80:20. After recrystallization from ethyl acetate there was obtained 0.80 g of 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 176-178° C. which was converted into the hydrochloride (m.p. above 300° C.).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[C:26]([N:30]=[C:1]=[S:2])[N:27]=[CH:28][N:29]=2)=[CH:22][CH:23]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc(-c2ccc(Cl)cc2)ncn1
Product: S=C=Nc1cc(-c2ccc(Cl)cc2)ncn1
Temperature: 60 °C

Procedure:
To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.666 g, 2.87 mmol) dichloromethane/N,N-dimethylformamide at room temperature was added 6-(4-chlorophenyl)pyrimidin-4-amine (0.59 g, 2.87 mmol). The orange mixture was heated at 60° C. for 18 hours. The LC/MS showed the desired product peak as a major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-(4-chlorophenyl)-6-isothiocyanatopyrimidine (0.322 g, 1.300 mmol, 45% yield) as an orange oil. LCMS R.T.=2.82; [M]+=248.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:12])[CH2:9][CH2:10][OH:11])=[CH:4][C:3]=1[F:13].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl>[Si:19]([O:11][CH2:10][CH2:9][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:13])[CH:4]=1)[OH:12])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC[C@H](O)c1ccc(Cl)c(F)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC[C@H](O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
(S)-1-(4-Chloro-3-fluorophenyl)propane-1,3-diol (10.5 g, 51.3 mmol) was dissolved in dichloromethane (200 mL), and imidazole (8.73 g, 128 mmol) was added. The mixture was then cooled to 0° C., and tert-butyldimethylsilyl chloride (9.67 g, 64.1 mmol) was added. The mixture was agitated for 1 hour, diluted with dichloromethane to 250 mL and washed with water, sodium bicarbonate solution, dried and evaporated. Purified by chromatography on silica gel, eluted with 5-10% ethyl acetate/hexanes to give (S)-3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)propan-1-ol (8.40 g, 26.3 mmol, 51.3% yield) as an oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH:15]=O)=[C:12]([CH3:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.NO.C([N:23](CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]#[N:23])=[C:12]([CH3:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C=O
Reactant: CCN(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NO
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C#N

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10c) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-methylthiophene-2-carboxaldehyde (2.5 g, 9.2 mmol) that was obtained in Example 11 (11b), hydroxylamine hydrochloride (0.71 g, 10 mmol), triethylamine (2.6 mL, 18 mmol), and N,N′-dicyclohexylcarbodiimide (2.1 g, 10 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 5:95) as the eluent to afford the title compound (2.5 g) in a yield of 100% as a pale yellowish oily product.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>>[CH2:25]([O:24][C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)OCc1ccccc1
Product: CCOC(=NC(=O)OCc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6carboximidate and benzyl chloroformate, there is obtained ethyl N-benzyloxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e:M+ 400 (6), 371 (6), 309 (32), 263 (20), 194 (35), 179 (15), 167 (27), 108 (12), 91 (100);
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([NH2:17])=[CH:12][N:11]=1>CO>[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[N:17]=[C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])[S:8][C:14]=2[N:15]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1cnc(Cl)nc1Cl
Solvent: CO
Product: CCOC(=O)Nc1nc2cnc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
Ethoxycarbonyl isothiocyanate (4.32 mL, 36.6 mmol) and 2,4-dichloro-pyrimidin-5-ylamine (3.00 g, 18.29 mmol) were mixed neat and sonicated for 5 minutes to help dissolve. The mixture was stirred at ambient temperature for 10 minutes, at which time the entire mixture had solidified. Methanol (100 mL) was added and the mixture was refluxed for 30 minutes, cooled to ambient temperature and the solids were collected by filtration to afford ethyl 5-chlorothiazolo[5,4-d]pyrimidin-2-ylcarbamate (3.8 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.64 (s, 1 H) 9.05 (s, 1 H) 4.31 (q, J=7.19 Hz, 2 H) 1.32 (t, J=7.15 Hz, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)(O)[O-].[Na+].[C:22](Cl)(Cl)=[S:23]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([N:16]=[C:22]=[S:23])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: S=C(Cl)Cl
Reactant: Cc1cnc(N)c(-c2ccc(F)c(F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cnc(N=C=S)c(-c2ccc(F)c(F)c2)c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(3,4-difluorophenyl)-5-methylpyridin-2-amine (0.6 g, 2.7 mmol) in dichloromethane (15 mL) was added a solution of sodium bicarbonate (2.3 g, 26.7 mmol) in water (25 mL) followed by a solution of thiophosgene (0.25 mL, 3.2 mmol) in dichloromethane (1 mL) and the mixture stirred for 15 minutes. The phases were separated and the organic phase was dried with sodium sulfate and the solvent was evaporated in vacuo to afford the title compound was obtained as a crystalline yellow solid (0.7 g, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[N:25]([CH:28]([CH3:30])[CH3:29])=[C:26]=[O:27]>O1CCCC1>[CH:28]([NH:25][C:26]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)=[O:27])([CH3:30])[CH3:29]
Reactant: CC(C)N=C=O
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Benzyl 4-hydroxypiperidine-1-carboxylate (65 μL), is dissolved in tetrahydrofurane (2 mL), treated with triethylamine (890 μL) and 2-isocyanatopropane (420 μL) and the mixture is stirred for 12 hours at 80° C. Then the mixture is partitioned between saturated aqueous NH4Cl solution and ethylacetate and the organic phase is washed with brine and dried (MgSO4). The solvents are evaporated in vacuo and the residue is purified by HPLC on reversed phase to give the title compound. LC (method 1): tR=1.01 min; Mass spectrum (ESI+): m/z=321 [M+H]+.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Br)[N:18]=1>C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:18]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCCCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOc1cccc(Br)n1

Procedure:
Dodecanol (1.118 g, 6 mmol) was dissolved in toluene (2 mL) and sodium hydride (60% in mineral oil, 0.120 g, 3 mmol) was added. 2,6-Dibromopyridine (0.710 g, 3 mmol) was added and the reaction was heated to reflux for 16 hours. After cooling, the reaction mixture was filtered through Celite and purified on silica gel (0-5% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=1.[CH:17]1([Mg]Br)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]([CH:17]2[CH2:19][CH2:18]2)([OH:15])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=1
Reactant: Br[Mg]C1CC1
Reactant: O=C(Cn1ccnc1)c1cc(Cl)ccc1O
Product: Oc1ccc(Cl)cc1C(O)(Cn1ccnc1)C1CC1
Yield: 36 %

Procedure:
The general procedure of Example 1 was repeated using 1-(5-chloro-2-hydroxyphenyl)-2-(1H-1-imidazolyl)-1-ethanone [compound (5-1)] and cyclopropylmagnesium bromide, to thereby yield 4-chloro-2-(1-cyclopropyl-1-hydroxy-2-(1H-1-imidazolyl)ethyl)phenol as colorless crystals (yield: 36.0%).
Reaction SMILES: FCC[N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])(=[O:23])=[O:22])=[CH:18][CH:19]=3)[C:13](=[O:14])[C:11]2=[O:12])[N:6]=[N:5]1.[F:39][CH2:40][CH2:41][CH2:42][CH2:43]N=[N+]=[N-]>>[F:39][CH2:40][CH2:41][CH2:42][CH2:43][N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])(=[O:22])=[O:23])=[CH:18][CH:19]=3)[C:13](=[O:14])[C:11]2=[O:12])[N:6]=[N:5]1
Reactant: O=C1C(=O)N(Cc2cn(CCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21
Reactant: [N-]=[N+]=NCCCCF
Product: O=C1C(=O)N(Cc2cn(CCCCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
was prepared according to the procedure for compound 11, with the exception that 4-fluorobutylazide was used in place of the 2-fluoroethylazide.
Reaction SMILES: C[N:2]1C=CN=C1.P(Cl)(Cl)(Cl)=O.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH3:35])[O:23][C@H:22]1[N:36]1[CH:43]=[C:42]([F:44])[C:40](=O)[NH:39][C:37]1=[O:38])(=O)C1C=CC=CC=1.[OH-].[NH4+]>C(#N)C>[F:44][C:42]1[C:40]([NH2:2])=[N:39][C:37](=[O:38])[N:36]([CH:43]=1)[C@@H:22]1[O:23][C@H:24]([CH3:35])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: Cn1ccnc1
Reactant: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-methylimidazole (0.8 ml) and phosphoryl chloride (0.28 ml) in acetonitrile (20 ml) was added 2',3'-di-O-benzoyl-5'-deoxy-5-fluorouridine (500 mg) obtained above at 0° C. After stirring of the reaction mixture for 1.5 hours at room temperature 28% ammonium hydroxide (2.5 ml) was added to the mixture at 0° C., and the mixture was stirred for 1 hour at room temperature. Acetonitrile and ammonia were removed under reduced pressure. The residue was acidified with 1N-HCl and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 155 mg of 2',3'-di-O-benxoyl- 5'-deoxy-5-fluorocytidine, mp 192°~194° C.; MS 476 ((M+Na)+).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][CH2:8][CH:9](O)[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12]1)[CH3:6].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:3][CH:9]([CH2:8][O:7][CH2:5][CH3:6])[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12]1
Reactant: CCCCCCN1CCN(CC(O)COCC)CC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCN1CCN(CC(Cl)COCC)CC1

Procedure:
To 100 mL of chloroform is added 24 g (0.2 mol) of thionyl chloride and 27.2 g (0.1 mol) of 1-ethoxy-3-(4-hexylpiperazin-1-yl)-2-propanol. Reflux the reaction and monitor by thin-layer chromatography. Upon completion add saturated aqueous sodium bicarbonate until gas evolution ceases. Dry the organic phase over Na2SO4. Filter the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)[CH:5]=[CH:4][N:3]=1.[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>>[CH3:29][C:25]1[CH:24]=[C:23]([C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([S:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(F)c2)c1
Reactant: Sc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(Sc3ccccc3)c2)c1
Temperature: 150 °C
Reaction time: 10 h
Yield: 70.3 %

Procedure:
A mixture of 5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole (0.40 g, 0.94 mmol) and thiophenol (1.0 mL, 9.7 mmol) was stirred at 150° C. for 10 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added, the resulting mixture was extracted with ethyl acetate and washed with water. This extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 1:1) and recrystallized from ethanol to obtain 0.34 g (yield 70%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].Br[CH:21]([CH3:23])[CH3:22].Cl>CN(C)C=O.C(#N)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]([CH:21]([CH3:23])[CH3:22])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1
Reactant: Clc1ccc2c(Nc3ccncc3)csc2c1
Reactant: CC(C)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)N(c1ccncc1)c1csc2cc(Cl)ccc12
Temperature: 50 °C
Yield: 76.1 %

Procedure:
A solution of 6-chloro-3-(4-pyridinylamino)benzo[b]thiophene (2.43 g, 9.3 mmole) in 20 mL of dimethylformamide was added to a suspension of NaH (0.48 g of 60% in oil, 12.1 mmole) in DMF. To this was added 2-bromopropane (1.26 g, 10.2 mmole) and the reaction mixture was heated to 50° C. During the next 5 hours, an additional 200 mg of NaH and 1 g of the bromo compound were added three separate times. The reaction mixture was then quenched into water and extracted with ethyl acetate (3×). The combined organics were washed with water (3×), dried (MgSO4), filtered and concentrated. Purification of the residue via flash chromatography (C6H5CH3 →5%Et3N/C6H5CH3) gave 1.57 of an oil. This was dissolved in acetonitrile, treated with ethereal HCl and the salt was crystallized out with additional ether to give 1.20 g of a yellowish powder, mp: 244°-246° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:22][CH2:23][C:24]4[NH:25][N:26]=[CH:27][N:28]=4)[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:32][C:33]#[N:34].O>CN(C=O)C>[C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:22][CH2:23][C:24]4[N:28]=[CH:27][N:26]([CH2:32][C:33]#[N:34])[N:25]=4)[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCl
Reactant: c1ccc(-c2cc3nnc(-c4ccccc4)n3nc2OCc2ncn[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCn1cnc(COc2nn3c(-c4ccccc4)nnc3cc2-c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
The product from Example 72 Step c) (0.10 g) was suspended in DMF (5 ml). Sodium hydride (15 mg of a 60% dispersion in mineral oil) was added, and the mixture strrred at room temperature for 15 min. Chloroacetonitrile (41 μl) was added, and the mixture stirred as before for 2 days. Water (25 ml) was added, and the resultant precipitate filtered off and purified by flash chromatography (silica gel, 0 to 3% methanol in dichloromethane). The product was recrystallised from ethyl acetate/ethanol to yield colourless crystals (17 mg). 1H NMR (360 MHz, d6-DMSO) δ5.60 (2 H, s), 5.61 (2 H, s), 7.58 (6 H, m), 7.76 (2 H, m), 8.41 (1 H, s), 8.44 (2 H, m), 8.68 (1 H, s); MS (ES+) m/e 409 [MH+]. Anal. Found C, 64.62; H, 3.74; N, 26.82. C22H16N8O. 0.1 C4H8O2 requires C, 64.62; H, 4.06; N, 26.87%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12](=[O:14])[NH2:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:15])[CH:3]=1.[CH:16](O)=O>>[OH:15][C:4]1[CH:3]=[C:2]2[C:11]([C:12](=[O:14])[NH:13][CH:16]=[N:1]2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=CO
Reactant: COC(=O)c1cc(C(N)=O)c(N)cc1O
Product: COC(=O)c1cc2c(=O)[nH]cnc2cc1O

Procedure:
A mixture of methyl 4-amino-5-carbamoyl-2-hydroxybenzoate (5.4 g) and formic acid (50 ml) was heated to reflux for 1 hour. The mixture was evaporated. Toluene (75 ml) was added and the mixture was evaporated. The solid residue was washed with methanol and diethyl ether and dried to give methyl 7-hydroxy-4-oxo-3,4-dihydroquinazolin-6-carboxylate (5.2 g); NMR Spectrum: (DMSOd6) 4.9 (s, 3H), 7.09 (s, 1H), 7.39 (s, 1H), 8.5 (s, 1H).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:4]1=2.CC1(C)C(C)(C)OB([C:27]2[CH:36]=[CH:35][C:30]3[NH:31][C:32](=[O:34])[NH:33][C:29]=3[CH:28]=2)O1>>[F:18][C:15]1[CH:16]=[CH:17][C:4]2[C:3](=[CH:2][C:27]3[CH:36]=[CH:35][C:30]4[NH:31][C:32](=[O:34])[NH:33][C:29]=4[CH:28]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][O:6][C:5]=2[CH:14]=1
Reactant: Fc1ccc2c(c1)OCc1ccccc1C2=CBr
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Product: O=c1[nH]c2ccc(C=C3c4ccccc4COc4cc(F)ccc43)cc2[nH]1

Procedure:
Following procedures essentially as described in Example 219, using 11-bromomethylene-3-fluoro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 1.05 eq.) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (1 eq.). Purify crude product on silica gel, eluting with 60% to 100% ethyl acetate/CHCl3 to afford a light yellow solid. Triturate with acetone to afford the title compound as a white solid. HPLC (ISO60-10) t=4.09 min, 100%; MS [ES] 357 (M−H), 359 M+H); 1H-NMR (DMSO-d6) δ 10.56 (s, 1H), 10.46 (s, 1H), 7.56 (m, 2H), 7.35 (t, 1H, J=7.5 Hz), 7.23 (t, 1H, J=7.5 Hz), 6.99 (d, 1H, J=7.5 Hz), 6.94 (s, 1H), 6.78 (td, 1H, J=12.0, 4.2 Hz), 6.71 (d, 1H, J=8.4 Hz), 6.66 (d, 1H, J=8.4 Hz), 6.59 (dd, 1H, J=10.6, 2.6 Hz), 6.57 (s, 1H), 5.83-4.71 (br d, 2H).