Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4])=[CH2:24]
Reactant: C=COCCON
Reactant: COC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 60.5 %

Procedure:
To a mechanically stirred solution of 5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (82.17 g, 0.2 mol) and O-(2-vinyloxyethyl)hydroxylamine (40.73 g, 0.382 mol) in dry THF (1.27 L) at 5° C. under N2 atmosphere, was added lithium bis(trimethylsilyl)amide as a solution in THF (1 L, 1 M, 1 mol) over 1 hr, maintaining the temperature below 10° C. The reaction mixture was stirred at 0-5° C. for 20 minutes before being quenched with addition water (200 ml) and saturated saline (350 mL). Volatile solvents were removed in vacuo and the residue diluted with water (1.5 L) and extracted 2-methyl tetrahydrofuran (3×1 L). The organic layers were washed water (500 mL), saturated saline (500 mL), dried (Na2CO3) and absorbed onto silica gel (200 g) and purified on silica gel (400 g) using ethyl acetate as eluent. The resultant crude product was triturated with tert-butyl methyl ether (400 mL) to yield the title compound as a brown solid (58.36 g, 60%). LCMS (Method B): RT=2.79 min, [M+H]+=483.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10](=[O:11])[NH:9][N:8]=2)[CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=c1[nH]nc2ccc(Br)cn12
Temperature: 25 °C

Procedure:
A suspension of 40 g 5-bromo-2-hydrazinylpyridine (212 mmol) and 38 g 1,1′-Carbonyldiimidazole (234 mmol) in 500 mL acetonitrile was refluxed for 2 h. The reaction was then cooled to room temperature overnight. The precipitate was collect by filtration. 6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as a light brown solid was collected. m/z (ESI)=213.9 [M+H]+. 1H NMR (δ, d6-DMSO, 400 MHz) 12.59 (s, 1H), 8.04 (dd, 1H), 7.21 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.[CH3:14][C:15]([OH:19])([C:17]#[CH:18])[CH3:16]>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:18]#[C:17][C:15]([CH3:16])([OH:19])[CH3:14])[CH:7]=[CH:6]2
Reactant: C#CC(C)(C)O
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: COc1ccc2cc(C#CC(C)(C)O)ccc2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of 6-methoxy-2-bromonaphthalene (14.23 g, 60.0 mmol), copper (I) iodide (0.17 g, 0.90 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.63 g, 0.90 mmol), and 2-methyl-3-butyn-2-ol (8.7 mL, 90 mmol) in diethylamine (100 mL) was heated at reflux for 16 hours, cooled to room temperature and solvent evaporated. The residue was purified by flash chromatography using 15-25% ethyl acetate in hexane as an eluant. Drying at 80° C. for 20 minutes afforded 4-(6-methoxy-2-naphthyl)-2-methyl-3-butyn-2-ol as a light orange solid (14.4 g), mp: 118-119° C. 1HNMR (300 MHz, DMSO-d6): δ7.95 (s, 1H), 7.75-7.85 (m, 2H), 7.4 (dd, 1H, J=8.4 Hz and 1.5 Hz), 7.35 (d, 1H, J=2.4 Hz), 7.2 (dd, 1H, J=8.5 Hz and 1.5 Hz), 5.5 (s, 1H), 3.9 (s, 3H), and 1.5 ppm (s, 6H).
Reaction SMILES: [CH:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].N1C=CC=CC=1.[CH2:24]([O:30][C:31](Cl)=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CC(N(C)C)=O>[CH2:24]([O:30][C:31]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCOC(=O)Cl
Reactant: Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.5 %

Procedure:
To a solution of 4.0 g of arabinofuranosylcytosine dissolved in 50 ml of dimethylacetamide, there are added 3.0 g of pyridine and 4.06 g of n-hexylchloroformate. The reaction is carried out by stirring the mixture at room temperature for 3 hours. After the reaction is over, dimethylacetamide is evaporated under reduced pressure. The residue is diluted with 100 ml of cold water and the mixture is stirred under ice-cooling for one hour. The precipitated solids are filtrated and dried. The resultant white powders are washed with ethyl ether to obtain 2.9 g of N4 -hexyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:47%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].[C:17]1([CH3:29])[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1>C1(C)C=CC=CC=1>[C:17]1([CH3:29])[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:7]4=[N:6][C:5]=3[CH3:16])[CH2:27][CH2:28]2)[CH:18]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: Cc1ccc2nc(C)c(CCCl)c(=O)n2c1
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCN(CCc3c(C)nc4ccc(C)cn4c3=O)CC2)c1
Yield: 57.2 %

Procedure:
A mixture of 2.2 g of 3-(2-chloroethyl)-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 5 g of 1-(m-tolyl)piperazine and 25 ml of toluene was refluxed for 30 hours. After completion of the reaction, the reaction mixture was filtered while hot and the filtrate was concentrated under reduced pressure. The residue was purified by means of column chromatography using alumina and recrystallized from a mixture of ethanol and isopropyl ether to give 2 g of the desired compound as pale yellow prisms, m.p. 115 - 116°C.
Reaction SMILES: C(OC([P:9]([CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)(=[O:13])[O:10][CH2:11][CH3:12])(OCC)C)C.C(O)C.C[Si](Cl)(C)C>ClCCl>[CH2:11]([O:10][P:9]([CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)[OH:13])[CH3:12]
Reactant: CCOC(C)(OCC)P(=O)(OCC)C1CCCO1
Agent: C[Si](C)(C)Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOP(O)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 g of ethyl 1,1-diethoxyethyl(tetrahydrofuran-2-yl)-phosphinate in 10 ml of dichloromethane containing 1% (b.v.) of ethanol is treated with 0.71 g of trimethylsilylchloride. The faintly cloudy solution is stirred overnight at room temperature after which time thin layer chromatography indicates complete reaction. Removal of the solvent in vacuo affords a colourless oil which after distillation yields P-tetrahydrofuran-2-yl-phosphonous acid ethyl ester, b.p. 90°/8×10-2 mbar.
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20].Cl>CCOCC.CCCCCC>[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]([NH2:3])=[NH:20]
Reactant: COc1cccc(C#N)c1OC
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cccc(C(=N)N)c1OC
Reaction time: 0.17 h

Procedure:
To a solution of 20 g 1,1,1,3,3,3-hexamethyldisilazane in 150 mL dry ether was added 5 mL 2.4 M n-butyllithium in hexane. After 10 min at room temperature, 16.3 g 2,3-dimethoxybenzonitrile was added in one portion and the mixture was kept at room temperature for 16 h. The reaction mixture was then poured onto excess 3N HCl. The aqueous layer was separated, basified with 50% NaOH and the product was extracted three times with 10% methanol in methylene chloride. The combined organic extracts were dried over potassium carbonate and the solvents removed in vacuo to afford 2,3-dimethoxybenzamidine as a glassy solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=2)(C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC1C=CC=CC=1C.CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)(c2cncc(Cl)n2)C1
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCCC(c2cncc(Cl)n2)C1
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A solution of 3-(6-chloro-pyrazin-2-yl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (46 g) in o-xylene (300 mL) and DMA (30 mL) was heated under reflux for 5 hrs. After cooling to room temperature, it was washed with brine (200 mL×2). The organic layer was then dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The residue obtained was then purified on a silica gel column eluting with EA:DCM:Hex=1:1:3 to give the title compound (18 g) as a white solid. MS: 298.7 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:21]1([OH:24])[CH2:23][CH2:22]1)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:12][CH3:13].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([C:21]2([OH:24])[CH2:22][CH2:23]2)[CH2:12][CH3:13])=[CH:19][CH:18]=1
Reactant: CCC(c1ccc(Cl)cc1)(n1ccc2c(N)cccc21)C1(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(c1ccc(Cl)cc1)(n1ccc2c(NS(C)(=O)=O)cccc21)C1(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of compound from step B (83 mg, 0.22 mmol) and NMM (44 mg, 0.44 mmol) in DCM (5 mL) was added methylsulfonyl chloride (37 mg, 0.3 mmol) dropwise. Then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by Pre-HPLC to afford the title compound as a white solid. LC/MS m/z=419.1[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:18]([N+:28]([O-:30])=[O:29])=[C:19]([CH:25]=[CH:26][CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][CH:27]=[C:17]([O:16][CH3:15])[C:18]=3[N+:28]([O-:30])=[O:29])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COc1cccc(C=CC(=O)O)c1[N+](=O)[O-]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3[N+](=O)[O-])nc2n(CC)c1=O
Yield: 47 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.10 g (13.9 mmol) of 3-methoxy-2-nitrocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.28 g (yield 47%) of Compound 121 as orange needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[OH:11].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]#[N:20])[CH:13]=1.[OH-].[Na+]>CO>[C:19](/[C:18](/[C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1)=[CH:7]\[C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([OH:11])[CH:5]=1)#[N:20]
Reactant: COc1ccc(C=O)cc1O
Reactant: N#CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C(\C#N)c2cccnc2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
A mixture of 4-methoxy-3-hydroxybenzaldehyde (0.5 g, 3.3 mmoles), 3-pyridylacetonitrile (0.35 ml, 3.3 mmoles) and 50% w/v of aqueous NaOH (3 ml) in methanol (10 ml) was stirred at room temperature for 30 minutes. The yellow solid that precipitated was filtered, washed with cooled methanol (1 ml), cooled CH2Cl2 (5 ml) and dried under vacuum over P2O5 to yield 0.5 g (60%) of the title compound as a yellow solid. 1H-NMR (CD3OD) 8.8 (m, 1H), 8.5 (m, 1H), 8.1 (m, 1H), 7.7 (s, 1H), 7.5 (m, 1H), 7.3 (d, 1H), 7.2 (d, 1H), 6.8 (d, 1H). Mass Spectrum m/e (M+1) 253.
Reaction SMILES: [CH:1]1([NH:5][S:6]([N:9]2[C:14]3([CH2:16][CH2:15]3)[CH2:13][N:12]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:11][CH2:10]2)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[O:32](C(OC(C)(C)C)=O)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=O.O>CN(C=O)C>[CH:1]1([NH:5][S:6]([N:9]2[C:14]3([CH2:15][CH2:16]3)[CH2:13][N:12]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:32])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:11][CH2:10]2)(=[O:7])=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(NC1CCC1)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)NC4CCC4)C4(CC4)C3)ncnc21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
N-cyclobutyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8-diazaspiro[2.5]octane-8-sulfonamide (intermediate 30) (4.4 mmol) was dissolved in dry DMF (15 ml), added K2CO3 (5.28 mmol) and cooled to 0° C. A solution of BOC2O (1.06 g, 4.86 mmol) in dry DMF (5 mL) was added and the reaction mixture was allowed to warm up freely to rt and stirred at rt for 16 h. The crude mixture was treated with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [CH2:1]([CH:3]([C:11](=O)[C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])[C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].Cl.Cl.[NH2:24][NH2:25]>CCO>[CH2:1]([C:3]1[C:11]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])=[N:24][NH:25][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)C(CC)C(=O)c1c(C)cc(C)cc1C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1[nH]nc(-c2c(C)cc(C)cc2C)c1CC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of ethyl 3-ethyl-2,4-dioxo-4-(2,4,6-trimethylphenyl)butanoate (6.0 g, 20.7 mmol) and hydrazine dihydrochloride (2.17 g, 20.7 mmoL) in 100 mL of EtOH was stirred at 80° C. for 6 hours. The solvent was then removed from the mixture. 200 mL of water was added to the residue and mixture was neutralized by the addition of solid NaHCO3. The product was extracted into ether. The ether extract was dried over Na2SO4 and evaporated to give 5.8 g as an oil which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][N:14]([CH:18]([CH2:20][CH3:21])[CH3:19])[C:15](Cl)=[O:16])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH:18]([CH2:20][CH3:21])[CH3:19])[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])=[CH:22][CH:23]=1
Reactant: CCC(C)N(Cc1ccc(Cl)cc1)C(=O)Cl
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: CCC(C)N(Cc1ccc(Cl)cc1)C(=O)Nc1ccccc1
Yield: 83 %

Procedure:
19 g (0.2 mole) of aniline were dissolved in 300 ml of toluene. To the resulting solution, a solution of 26 g (0.1 mole) of N-[4-chlorobenzyl]-N-sec.-butyl-carbamoyl chloride in 70 ml of toluene was added dropwise, under cooling and stirring. After the dropwise addition, the temperature of the solution was gradually raised, and the the solution was stirred at a temperature of 70°-80° C for about 5 hours. The solution was cooled to precipitate aniline hydrochloride, which was then separated by filtration. The toluene layer was washed with 100 ml of water and dried with anhydrous sodium sulfate. Then, the toluene was distilled off. The residue was subjected to recrystallization from a mixture of hexane and ethyl alcohol, whereby 26.3 g of N-(4-chlorobenzyl)-N-sec.-butyl-N'-phenylurea were obtained. Yield: 83%. Melting point: 80°-81.5° C.
Reaction SMILES: [F-:1].[K+].O[CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=2[NH:6][C:5]1=[O:22].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[F:1][CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=2[NH:6][C:5]1=[O:22]
Reactant: [F-]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F

Procedure:
First, 1.2 of KF and then 2.9 g. of 3-hydroxy-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one are added to a mixture of 35 g. of HF and 15 ml. of pyridine and the mixture is stirred for 1 hour more. Working up in the customary manner using sodium carbonate solution/ethyl acetate gives 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one, m.p. 235° (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:30]2[N:29]=[C:28]([C:21]3[C:22]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[NH:19][CH:20]=3)[CH:33]=[CH:32][N:31]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: COc1cccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)c1
Yield: 29.2 %

Procedure:
Using the procedure of example 1, m-anisidine (100 mg) was reacted with compound 1f (100 mg) to provide compound 6 (25 mg, 29%). 1H NMR (400 MHz, CD3OD) δ 8.84 (d, J=8.0 Hz, 1H), 8.33 (d, J=5.2 Hz, 1H), 8.31 (d, J=4.8 Hz, 1H), 8.12 (s, 1H), 7.48 (m, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.23 (m, 2H), 7.13 (d, J=5.2 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 3.86 (s, 3H). MS (ESI) m/z: 318 (M+H)+.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C(O[C@H:13]1[O:35][C@H:34]([CH2:36][O:37]C(=O)C2C=CC=CC=2)[C@H:24]([O:25]C(=O)C2C=CC=CC=2)[C@H:14]1[O:15]C(=O)C1C=CC=CC=1)(=O)C.[Sn](Cl)(Cl)(Cl)Cl>C(#N)C>[C@@H:13]1([N:1]2[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]2=[O:3])[O:35][C@H:34]([CH2:36][OH:37])[C@H:24]([OH:25])[C@H:14]1[OH:15]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CC(=O)O[C@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@H](O)[C@H]2O)c(=O)n1

Procedure:
One equivalent of cytosine is condensed with one equivalent of 1-O-acetyl-2,3,5-tri-O-benzoyl-α-D-xylofuranose at ambient temperature, in anhydrous acetonitrile, in the presence of tin tetrachloride, SnCl4 (2 equivalents); the compound obtained is purified by chromatography on a silica column and debenzoylated using a methonal solution saturated with ammonia gas. This gives 1-(β-D-xylofuranosyl)-cytosine.
Reaction SMILES: [F:1][C:2]1([F:6])[CH2:5][NH:4][CH2:3]1.[CH:7]1([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[CH:27]=[N:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[O:17])[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1>>[F:1][C:2]1([F:6])[CH2:5][N:4]([C:21]([C:20]2[CH:24]=[CH:25][N:26]=[CH:27][C:19]=2[NH:18][C:16]([C:14]2[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=[C:10]([CH:7]3[CH2:9][CH2:8]3)[N:15]=2)=[O:17])=[O:22])[CH2:3]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: FC1(F)CNC1
Product: O=C(Nc1cnccc1C(=O)N1CC(F)(F)C1)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 26 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3,3-difluoroazetidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound as yellow powder (26%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH3:35][O:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:40]3[CH2:41][CH2:42][CH:37]([O:36][CH3:35])[CH2:38][CH2:39]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: COC1CCNCC1
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCC(OC)CC4)c(OC)cc23)c2c1OCO2
Yield: 78.9 %

Procedure:
This was prepared using the method described in example 13 using N-[5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (200 mg, 0.40 mmol) and 4-methoxypiperidine (246 mg, 2.14 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent. There was thus obtained the title compound (184 mg, 80%) as a pale yellow solid; NMR Spectrum:(CDCl3) 1.55-1.70 (m, 2H), 1.85-2.00 (m, 2H), 2.10 (quintet, 2H), 2.24 (m, 2H), 2.56 (t, 2H), 2.72 (t, 2), 2.78 (m, 2H), 3.24 (m, 1H), 3.34 (s, 3H), 3.42 (s, 3H), 3.62 (t, 2H), 3.98 (s, 3H), 4.24 (t, 2H), 6.05 (s, 2H), 6.90 (s, 1H), 7.04 (s, 1H), 7.09 (s, 1H), 7.28 (s, 1H), 8.61 (s, 1H); Mass Spectrum: M+H+ 583/585.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([N:22]2[CH:26]=[N:25][C:24]([C:27]#[N:28])=[N:23]2)=[N:10]1.Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH:32]([C:36]([OH:38])=[O:37])[CH2:31]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([N:22]2[CH:26]=[N:25][C:24]([C:27]#[N:28])=[N:23]2)[NH:12][C:13]([CH2:20][N:30]2[CH2:35][CH2:34][O:33][CH:32]([C:36]([OH:38])=[O:37])[CH2:31]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Yield: 42.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(3-cyano-1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (0.32 g, 0.63 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.13 g, 0.75 mmol) according to the procedure as described in Example 3 to give the title compound as a pale yellow solid (0.15 g, 42%). The compound was characterized by the following spectroscopic data: