Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[C:15]1[C:16](=[O:30])[NH:17][CH:18]([CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([O:28][CH3:29])[CH2:24][CH2:23]2)[C:19]=1[OH:20].CCN(CC)CC>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:5]([O:4][C:2](=[O:3])[O:20][C:19]1[CH:18]([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([O:28][CH3:29])[CH2:26][CH2:27]2)[NH:17][C:16](=[O:30])[C:15]=1[C:9]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[CH3:7])[CH3:6]
Reactant: CON1CCC(CC2NC(=O)C(c3cc(C)ccc3C)=C2O)CC1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)NC1CC1CCN(OC)CC1
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (72 mg, 0.67 mmol) was added dropwise to a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-5-(1-methoxy-piperidin-4-ylmethyl)-1,5-dihydro-pyrrol-2-one (220 mg, 0.67 mmol), Et3N (94 mg, 0.9 mmol) and DMAP (30 mg, 0.25 mmol) in 10 ml of THF at room temperature. The mixture was stirred for 30 min and concentrated to dryness in vacuo. The residue was purified by column chromatography on silica gel. Yield: 150 mg of carbonic acid 4-(2,5-dimethyl-phenyl)-2-(1-methoxy-piperidin-4-ylmethyl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl ester ethyl ester (title compound P1.1) as a gum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CO[C:10](OC)([N:12]([CH3:14])[CH3:13])[CH3:11]>>[CH3:13][N:12]([CH3:14])[C:10](=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:11]
Reactant: COC(C)(OC)N(C)C
Reactant: Nc1ccccn1
Product: CC(=Nc1ccccn1)N(C)C

Procedure:
Compound 13 was obtained according to general procedure I with 2-aminopyridine in presence of dimethylacetamide-dimethylacetal instead of dimethylformamide-dimethyl-acetal, as an orange oil in a quantitative yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:2]=12.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[N+:1]1([O-:25])[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:2]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1c2ccccc2ccc2ncccc12
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2ccc2c1ccc[n+]2[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 2.07 grams (0.01 mole) of benzo[4,5]cyclohepta[1,2-b]pyridin-5-one in 25 milliliters of chloroform was added dropwise, a solution of 2.0 grams (0.01 mole) of m-chloroperbenzoic acid in 30 milliliters of chloroform and the resulting solution stirred for 7 hours at room temperature. At this time an additional 0.5 gram of m-chloroperbenzoic acid was added and the mixture stirred overnight at room temperature. The resulting reaction mixture was washed successively with two 100 milliliter portions of 10 percent aqueous sodium hydroxide and two 100 milliliter portions of water and then dried over magnesium sulfate. The dried solution was filtered to remove the drying agent and the chloroform was vaporized to obtain 2.23 grams of a benzo[4,5]cyclohepta[1,2-b]pyridin-5-one N-oxide intermediate.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].O>CN(C=O)C>[N+:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O-:23])=[O:22]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To phenol (6.5 g) in 20 ml DMF at room temperature was added K2CO3 (20 g) and this mixture stirred for 15 minutes at room temperature. Then 4-chloro-3-nitropyridine (10.0 g) in 60 ml DMF was added dropwise and the mixture stirred for two hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=3)[CH:13]=[O:14])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH2:13][OH:14])[CH:15]=[CH:16][CH:17]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc(-c2ccc3sccc3c2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1cccc(-c2ccc3sccc3c2)c1
Yield: 99 %

Procedure:
3-(1-Benzothien-5-yl)benzaldehyde (3.9 g, 16.4 mmol) was dissolved in ethanol (80 mL) and tetrahydrofuran (20 mL), and the mixture was ice-cooled. Sodium borohydride (0.62 g, 16.4 mmol) was added to this solution, and the mixture was stirred under ice-cooling for 3 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (3.9 g, yield 99%) as colorless prism crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2ccc(F)cc2)c1

Procedure:
4-Fluorophenylboronic acid (166 mg) and ethyl 2-chloroisonicotinate (200 mg) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:10](I)[CH2:9]1)[CH3:2].C(N(CC)CC)C.[H][H]>CO.[Pd]>[CH2:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](I)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 71.8 %

Procedure:
5-Ethyl-3'-iodo-2',3'-dideoxyuridine (432 mg, 0.87 mmole) is dissolved in methanol (40 ml) and triethylamine (0.5 ml) is added along with 10% Pd/C (200 mg). The mixture is then stirred in an atmosphere of hydrogen at room temperature for 30 min. After filtration of catalyst, the filtrate is evaporated to dryness. Purification of the product was achieved on silica gel plates using chloroform-methanol (20:1) to obtain a solid (150 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25]>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: Nc1ccc(C(=O)C(=O)c2ccc(N)cc2)cc1
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc3ccccc3nc2-c2ccc(N)cc2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 1.0 g (4.17 mmole) of 4,4′-diaminobenzil and 0.45 g of o-phenylenediamine in 250 ml glacial acetic acid was heated at 50° C. for 15 mins., then stirred for 16 hours at room temperature. The mixture was then heated to 80° C. and allowed to cool slowly. The solvent was removed under vacuum and the residue was redissolved in ethanol and that was removed under vacuum.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C=O)C>[CH3:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12]
Reactant: O=Cc1cccc(Br)n1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCN(c2cccc(C=O)n2)CC1
Temperature: 120 °C
Yield: 20.2 %

Procedure:
A suspension of 6-bromopicolinaldehyde (1.50 g, 8.10 mmol), 1-(methylsulfonyl)piperazine (9, 5.30 g, 32.2 mmol), potassium carbonate (4.45 g, 32.2 mmol) and anhydrous DMF (10 mL) was placed in a sealed vessel and the mixture was heated at 120° C. for 20 h. The mixture was diluted with water (50 mL) and brought to pH 7 using 2 N aq. HCl (15 mL). The resulting solution was extracted with CH2Cl2 (3×50 mL) and the combined extracts were washed with brine (200 mL). The solution was dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography eluting with 0-3% CH3OH in CH2Cl2 to afford the title compound (0.441 g, 20%) as an orange oil: 1H NMR (500 MHz, CDCl3) δ 9.90 (s, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.34 (d, J=7.0 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 3.80-3.78 (m, 4H), 3.37-3.33 (m, 4H), 2.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[H-].[Na+].[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25]Br>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:25][CH:24]([O:27][CH3:28])[O:23][CH3:22])[C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 27.1 g. (0.1 mole) of 7-chloro-1,3 -dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 300 ml. of dry dimethylformamide was added 4.6 g. (0.11 mole) of 57% sodium hydride in mineral oil, under nitrogen and with continuous stirring. After stirring one hour at room temperature, 25.4 g. (0.15 mol) of redistilled bromoacetaldehyde dimethylacetal in 10 ml. of dimethylformamide was added and the reaction mixture is kept at 100° C. with stirring during 16 hours. The mixture was then concentrated in vacuo to one-half the volume, well shaken with ice water and extracted with methylene chloride. The extract was washed with water, dried over Na2SO4 and evaporated at 25° C. and 0.2 mm.Hg pressure giving a brown oil which was crystallized from 2-propanol yielding 26.2 g. (73% of light brown crystals m.p. 115-117° C. A sample chromatographed on silica gel, eluted with 2% methanol-98% chloroform, evaporated in vacuo, and crystallized from 2-propanol gave 7-chloro -1,3-dihydro-1-(2,2-dimethoxyethyl)-5-phenyl-2H-1,4 -benzodiazepine-2-one of melting point 117° to 119° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3](=[O:13])[CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:7][CH:8]=1
Reactant: O=C(CCl)CCc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
1-Chloro-4-(4-chlorophenyl)-2-butanone (110 g) was added portionwise over half an hour to a stirred suspension of imidazole (175 g) in dimethylformamide (150 ml) at 0° C. and the mixture stirred overnight at ambient temperature. The resulting solution was poured into wate (1500 ml) with seeding at the first sign of turbidity, and the precipitate filtered off and washed well with water and hexane. Chromatography of the product on silica gel (1 Kg), eluting with 7% methanol in methylene chloride gave 100 g of 1-[4-(4-chlorophenyl) butan-2-on-1-yl]imidazole. The hydrochloride salt from acetone/methanol had a m.p. of 172.5°-174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[CH3:30][NH:31][CH2:32][CH3:33].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:31]([CH2:32][CH3:33])[CH3:30])=[O:18])=[N:14][CH:15]=1
Reactant: CCNC
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCN(C)C(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.7 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (126 mg, 0.30 mmol) obtained in Example 12 in methylene chloride (3 ml), N-methylethylamine (0.060 ml, 0.66 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (63 mg, 0.33 mmol) were added at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of diethyl ether and hexane, and was collected by filtration, to obtain the title compound (38 mg, 0.08 mmol, 27%) as a white solid.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[F:9][C:10](I)([F:12])[F:11].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:9][C:10]([F:12])([F:11])[C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: FC(F)(F)I
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Product: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
0.11 g (1.0 mmol) of uracil was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of a 1N dimethyl sulfoxide solution, 1.0 ml of a 2.1 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethyl uracil (19F-NMR yield: 94%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 5-Trifluoromethyluracil was obtained as a white solid (0.17 g, yield: 93%) by preparative thin-layer chromatography.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:5]1)[CH3:3].[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[Cl:13][C:7]1[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[CH:8]=1
Reactant: COC(=O)c1ccn(C(C)C)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C(C)C)cc1Cl
Temperature: 60 °C
Yield: 67.2 %

Procedure:
A solution of methyl 1-(1-methylethyl)-1H-pyrazole-3-carboxylate (0.13 g) in DMF (3 ml) was treated with N-chlorosuccinimide (0.103 g) and heated to 60° C. for 5 h under nitrogen. The cooled mixture was partitioned between diethyl ether (20 ml) and water (20 ml), separated, the organic extracts dried over sodium sulphate and evaporated to give the title compound as a pale yellow oil (0.105 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[O:12][CH:7](OC(=O)C)[C@H:6]([O:13][C:14](=[O:16])[CH3:15])[C@@H:5]1[O:17][C:18](=[O:20])[CH3:19].[Cl:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24]([Cl:31])[N:23]=1>C(Cl)(Cl)Cl>[C:14]([O:13][C@@H:6]1[C@H:5]([O:17][C:18](=[O:20])[CH3:19])[C@@H:4]([CH2:3][O:2][CH3:1])[O:12][C@H:7]1[N:28]1[CH:27]=[N:26][C:25]2[C:29]1=[N:30][C:22]([Cl:21])=[N:23][C:24]=2[Cl:31])(=[O:16])[CH3:15]
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: COC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClC(Cl)Cl
Product: COC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
5-O-Methyl-1,2,3-tri-O-acetyl-D-ribofuranose (5.0 g, 17 mmol) and 2,6-dichloropurine (3.3 g, 17 mmol) were thoroughly mixed. A catalytic amount of p-toluene sulfuric acid (50 mg) was added and the reaction mixture was heated to 140° C. at which point a homogeneous melt was obtained. The fusion was continued at 140° C. under oil pump vacuum for 0.5 h. The reaction mixture was dissolved in chloroform (200 ml) and washed with aqueous sodium bicarbonate (3×50 ml) and water (2×50 ml). The organic phase was dried (MgSO4), evaporated in vacuo and purified by flash chromatography eluting with a mixture of n-heptane and ethyl acetate (1:1) to provide 9-(2',3'-di-O-acetyl-5'-O-methyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.0 g, 14%) as an oil which crystallized from diethyl ether. A mixture of α/β-anomers (1.2 g, 17%) was also isolated, with mp 59°-61° C. 1H-NMR (400 MHz,CDCL3) δ2.06 (3H, s, --OCOCH3), 3.49 (3H, s, OCH3), 3.67, 3.72 (2H, ABX, H-5'a and H-5'b), 4.39 (1H, d, H-4'), 5.58 (1H, d, H-3'), 5.75 (1H, t, H-2'), 6.38 (1H, d, H-1'), 8.56 (1H, s, H-8). C15H16Cl2N4O6 requires C, 43.0; H, 3.9; N, 13.4. Found C, 43.1, H, 3.9, N, 13.2%.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=O.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:3]2[CH:1]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[O:5][C:4]=2[CH:11]=1
Reactant: COC(=O)COc1cc(OC)ccc1C=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc2ccc(OC)cc2o1
Yield: 56.1 %

Procedure:
A mixture of methyl 2-formyl-5-methoxyphenoxyacetate (27.7 g), 1,8-diazabicyclo[5.4.0]-7-undecene (40.8 g) and toluene (200 ml) was heated under refluxing conditions for 4 hours. The reaction mixture was concentrated under reduced pressure; after 6N hydrochloric acid was added, the residue was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off; 10% hydrochloric acid-methanol (30 ml) was added to the residue, followed by heating at 70° to 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure; water was added, followed by extraction with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off; the residue was subjected to silica gel column chromatography. From the fraction eluted with chloroform-hexane (1:2, v/v), methyl 6-methoxybenzofuran-2-carboxylate (14.3 g, 57%) was obtained, which was then recrystallized from dichloromethane-isopropyl ether to yield colorless prisms having a melting point of 97° to 98° C.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Sn](Cl)(Cl)(Cl)Cl>C(=S)=S>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1
Yield: 85 %

Procedure:
The known compound, 2-benzyl-benzo[b]thiophene (CA reg. no. 3407-15-6) was acylated with one equilvalent of anisoyl chloride using one equivalent of a tin (IV) chloride promoter in carbon disulfide solvent to afford (2-benzyl-benzo[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone (85% yield). This compound was demethylated using six equivalents of pyridinium hydrocholide at 228° C. to afford (2-benzyl-benzo[b]thiophen-3-yl)-(4-hydroxy-phenyl)-methanone (90% yield). This compound was brominated according to the procedure in Example 4 to afford the tide compound as a white solid (95% yield): mp 155.5-156.5; MS m/e 500 (M)+;
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH:21]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1>>[Cl:33][C:34]1[N:35]=[CH:36][C:37]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([N:18]5[CH2:19][CH2:20][CH:21]([N:24]6[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]6)[CH2:22][CH2:23]5)=[CH:14][C:13]=4[O:31][CH3:32])=[N:9]3)=[CH:4][CH:3]=2)=[CH:38][CH:39]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccc(Cl)nc3)n2n1
Temperature: 80 °C
Yield: 22.9 %

Procedure:
Following the example of 532 (D), (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.088 g, 0.00018 mol) and 2-Chloro-5-pyridineboronic acid (0.028 g, 0.00018 mol) were heated at 80° C. overnight. Purification by Gilson chromatography gave [7-(6-Chloro-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.022 g, 23%) as a tan solid. MP: 186-188° C.; 1H-NMR (DMSO-d6, 400 MHz) δ 9.18-9.17 (d, 1H, J=2.40 Hz), 8.98 (s, 1H), 8.64-8.61 (d, 1H, J=5.88 Hz), 8.05 (s, 1H), 7.61 (s, 1H), 7.59 (s, 1H), 7.34-7.32 (d, 1H, J=4.80 Hz), 6.97-6.95 (d, 1H, J=4.84 Hz), 6.77 (br, 1H), 6.63 (br, 1H), 3.83 (s, 1H), 3.46 (br, 2H), 2.78 (br, 2H), 2.08-2.01 (br, 3H), 1.66 (m, 2H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][CH:3]1[C:18](=O)[CH2:19][CH3:20].Cl.[C:23](=[NH:26])([NH2:25])[CH3:24]>>[CH2:19]([C:18]1[C:3]2[CH2:4][NH:5][CH2:6][CH2:7][C:2]=2[N:25]=[C:23]([CH3:24])[N:26]=1)[CH3:20]
Reactant: CCC(=O)C1CN(C(=O)OCc2ccccc2)CCC1=O
Reactant: CC(=N)N
Agent: Cl
Product: CCc1nc(C)nc2c1CNCC2

Procedure:
Benzyl 4-oxo-3-propanoylpiperidine-1-carboxylate, prepared in similar manner to C28 in Example 6, was condensed with ethanimidamide hydrochloride; deprotection afforded the requisite 4-ethyl-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[C:10]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=3)=[CH:16][CH:15]=2)=[O:13])[C:9]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:8][C:7]=1[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:2][CH2:3][CH3:4]>Cl.CO.O>[CH2:1]([O:5][C:6]1[N:11]=[C:10]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)=[O:13])[C:9]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:8][C:7]=1[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(C(=O)c2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C(=O)OCC)cc1C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCCOc1nc(C(=O)c2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(C(=O)OCC)cc1C(=O)OCC
Temperature: 20 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
One drop of concentrated hydrochloric acid is added to a solution of 30 mg (0.04 mmol) of the compound from Example 1 in 2 ml of methanol and the mixture is stirred at 20° C. for 3 hours. The reaction mixture is diluted with water and washed three times with ethyl acetate, the combined organic phases are washed with water and sodium chloride solution, dried over sodium sulphate and concentrated and the residue is chromatographed over 25 g of silica gel using methylene chloride/methanol 10:1 to give 15.9 mg of the title compound.