Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-])=O)[C:5]=1[NH:17][CH3:18])([O-])=O.C(O)(=O)C>[Fe].C(O)C>[CH3:18][NH:17][C:5]1[C:4]([NH2:1])=[CH:9][C:8]([C:10]([F:11])([F:13])[F:12])=[CH:7][C:6]=1[NH2:14]
Reactant: CNc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1c(N)cc(C(F)(F)F)cc1N
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 80.1 %

Procedure:
To a mixture of (2,6-dinitro-4-trifluoromethyl-phenyl)-methyl-amine (5.0 g), acetic acid (11 mL), ethanol (100 mL), and ice (20 g), iron powder (6.4 g) was added under ice-cooling. The reaction mixture was stirred at 0° C. for 3.5 hours, and filtered through Celite®. The resulting filtrate was concentrated under reduced pressure, and diluted with 1N aqueous sodium hydroxide solution. The solution was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 3.1 g of N′-methyl-5-trifluoromethyl-benzene-1,2,3-triamine. N′-methyl-5-trifluoromethyl-benzene-1,2,3-triamine
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1)[NH2:18]
Reactant: FC(F)(F)c1nc(Cl)c2ccccc2n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nc(C(F)(F)F)nc2ccccc12

Procedure:
4-Chloro-2-trifluoromethylquinazoline (46.4 g, 0.2 mole) was taken up in ethanol (500 ml). Hydrazine hydrate (20 ml, 0.4 mole) was added and the contents refluxed for 2 hours. On cooling, the yellow precipitate was filtered and slurried in water (500 ml) to removed hydrazine hydrochloride. Filtration gave the product as a yellow crystalline solid, 34.5 g (76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:18]1([N:24]2[C:28]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[CH:27][C:26]([CH:34]=O)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:28]1[N:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:25]=[C:26]([CH2:34][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)[CH:27]=1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Product: COc1ccc(N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)cc1
Yield: 74.1 %

Procedure:
Compound 43 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][CH:7]=1.[F:24][C:25]([F:32])([F:31])[CH2:26][S:27](Cl)(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:27]([CH2:26][C:25]([F:32])([F:31])[F:24])(=[O:29])=[O:28])=[CH:10][CH:11]=1
Reactant: COc1ccccc1Oc1ccc(NCc2cccnc2)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: COc1ccccc1Oc1ccc(N(Cc2cccnc2)S(=O)(=O)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-(2-methoxyphenoxy)phenyl)pyridin-3-ylmethylamine (1.0 equiv.) in 2:1 DCE/Pyridine (0.15 M) was cooled to 0° C. and treated with 2,2,2-trifluoroethanesulfonyl chloride (1.8 equiv.). The mixture was allowed to warm to ambient temperature and stir overnight. The reaction was treated with anhydrous potassium carbonate, stirred for 40 min, and filtered. The filtrate was purified via preparative HPLC eluting with 98:2 to 96:4 DCM/MeOH to give the title compound. Anal Calcd for C21H19F3N2O4S: C, 55.75; H, 4.23; N, 6.19. Found: C, 55.65; H, 4.27; N, 6.19. MS found 4.53.0 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=S)[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[CH:25]=2)[CH2:17][CH2:16]1.[OH-].[Na+].OO.S([O-])([O-])(=[O:40])=S.[Na+].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[CH:25]=2)=[O:40])[CH2:17][CH2:16]1
Reactant: O=S([O-])([O-])=S
Reactant: COc1cc2ncnc(N3CCN(C(=S)NCc4ccc5c(c4)OCO5)CC3)c2cc1OC
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: COc1cc2ncnc(N3CCN(C(=O)NCc4ccc5c(c4)OCO5)CC3)c2cc1OC
Reaction time: 8 h
Yield: 20 %

Procedure:
In 10 ml of ethanol was suspended 152.7 mg (0.33 mmol) of 4-(6,7-dimethoxy-4-quinazolinyl)-N-(3,4-methylenedioxybenzyl)-1-piperazinethiocarboxamide obtained in Example 208, and 1 ml of a 10 N aqueous solution of sodium hydroxide and 1 ml of 30% aqueous hydrogen peroxide were added thereto, followed by overnight stirring. After addition of an aqueous solution of sodium thiosulfate, 4 N hydrochloric acid was added to the reaction mixture for neutralization. The resulting mixture was extracted with dichloromethane, and the organic layer was washed with water and dried over sodium sulfate. After the solvent was evaporated, the residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:19])[C:16]([OH:18])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[BH4-].[Na+].[OH-].[Na+]>C(OCC)C.O.C(O)C>[OH:19][CH:15]([C:13]1[N:14]=[C:10]([NH:9][C:7]([O:6][C:1]([CH2:4][CH3:5])([CH3:2])[CH3:3])=[O:8])[S:11][CH:12]=1)[C:16]([OH:18])=[O:17]
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)cs1
Agent: CCC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)O)cs1
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCC(C)(C)OC(=O)Nc1nc(C(O)C(=O)O)cs1

Procedure:
To a mixture of 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, (1.7 g.), sodium bicarbonate (0.5 g.), ethanol (10 ml.) and water (10 ml.) was added sodium borohydride (0.23 g.) under stirring and ice-cooling, and then the mixture was stirred for 1 hour at the same temperature. After the reaction, the reaction mixture was concentrated slightly. To the remaining reaction mixture were added 1 N sodium hydroxide aqueous solution (6 ml.) and diethyl ether (20 ml.), and then the aqueous layer was separated. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric acid and then the ethyl acetate layer was separated therefrom. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then treated with activated charcoal. The solvent was distilled off from the ethyl acetate layer to give brown powder of 2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, (1.5 g.).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]3[CH2:14][CH2:15][CH2:16][C@@H:9]23)=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[CH:18].C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:19]1([C:17]#[C:18][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12](=[O:13])[CH2:11][C@H:10]4[CH2:14][CH2:15][CH2:16][C@@H:9]34)=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1ccccc1
Reactant: O=C1C[C@H]2CCC[C@H]2N1c1ccc(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1C[C@H]2CCC[C@H]2N1c1ccc(C#Cc2ccccc2)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
In a 10 ml Pyrex tube were dissolved (3aR,6aR)-1-(5-iodopyridin-2-yl)hexahydro-cyclopenta[b]pyrrol-2(1H)-one (107 mg, 326 μmol) in 2 ml of THF. Argon was bubbled through the solution. Ethynylbenzene (59.9 mg, 64.5 μl, 587 μmol, 1.8 equiv.), triethylamine (99.0 mg, 136 μmol, 978 μmol, 3.0 equiv.), bis(triphenylphosphine)palladium(II) chloride (13.7 mg, 19.6 μmol, 0.06 equiv.), triphenylphosphine (1.71 mg, 6.52 μmol, 0.02 equiv.), and copper (I) iodide (1.86 mg, 9.78 μmol, 0.03 equiv.) were added. The dark brown solution was stirred at 50° C. for 2 h. The residue was taken up in ethyl acetate, the solids were filtered off and washed with ethyl acetate. The filtrate was concentrated in vaccuo and the residue was purified by flash chromatography (SiO2, 20 g) using a 0% to 60% ethyl acetate in heptane gradient. One obtained 95 mg (96%) of the title compound as a viscous yellow oil, MS: m/e=303.2 (M+H+).
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:24]=[O:25])=[CH:20]N(C)C)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[OH-:26].[Na+]>C(O)C>[CH2:1]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:24]=[O:25])=[CH:20][OH:26])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: [OH-]
Reactant: C=CCCCCCCCCCOc1ccc(C(C=O)=CN(C)C)cc1
Agent: [Na+]
Solvent: CCO
Product: C=CCCCCCCCCCOc1ccc(C(C=O)=CO)cc1
Temperature: 25 °C

Procedure:
A solution of 21 in ethanol (75 ml) was hydrolysed with aqueous sodium hydroxide solution (60 ml, 25%). The reaction mixture was stirred and heated under reflux (3 h), cooled to room temperature and the ethanol removed in vacuo to yield an off-white solid which was filtered and washed thoroughly with water. The solid was suspended in a 50% ethanol/water mixture (150 ml) and acidified with concentrated hydrochloric acid. The suspended solid whitened in colour and was collected by filtration, then recrystallised from petroleum ether (bp 60-80° C.). Yield=3.97 g (38%).
Reaction SMILES: [CH3:1][S:2]([C:5](=[CH:9][C:10]1[CH:11]=[N+:12]([O-:16])[CH:13]=[CH:14][CH:15]=1)[C:6]([CH3:8])=O)(=[O:4])=[O:3].[CH3:17][O:18][C:19](=[O:24])/[CH:20]=[C:21](\[NH2:23])/[CH3:22]>C(O)C>[CH3:17][O:18][C:19]([C:20]1[CH:9]([C:10]2[CH:11]=[N+:12]([O-:16])[CH:13]=[CH:14][CH:15]=2)[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]([CH3:8])[NH:23][C:21]=1[CH3:22])=[O:24]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1ccc[n+]([O-])c1)S(C)(=O)=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(S(C)(=O)=O)C1c1ccc[n+]([O-])c1

Procedure:
A mixture of 22.5 g of 1-methylsulphonyl-1-(1-oxido-3-pyridylmethylene)-acetone, 16.5 g of 3-aminocrotonic acid methyl ester and 45 g of molecular sieve (Union Carbide, 3 Å) in 250 ml of absolute ethanol is boiled under reflux for 18 hours. The resulting suspension is filtered, the filter residue is washed with chloroform and the filtrate is concentrated by evaporation under reduced pressure. The oily residue is dried by the addition of toluene and renewed concentration by evaporation under reduced pressure. The residue is chromatographed over approximately 50 to 100 times the amount of silica gel, a mixture of chloroform and methanol (9:1) being used as the liquid phase. Once the starting materials and intermediate have been removed by washing, the desired product is eluted; the corresponding fractions are combined and concentrated by evaporation and the residue is recrystallised from a mixture of isopropanol and diethyl ether. In this manner 2,6-dimethyl-5-methylsulphonyl-4-(1-oxido-3-pyridyl)-1,4-dihydropyridine-3-carboxylic acid methyl ester having a melting point of 236°-238° is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(B(O)O)C=CC=CC=1.O>O1CCOCC1>[C:18]1([N:13]2[C:12]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(-c3ccccc3)c2CC1
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)c1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
2,3-Diphenyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. To a solution of the above compound (0.28 g) in 5 mL of 1,4-dioxane was added 0.29 g of K3PO4, 104.3 mg of phenylboronic acid and 43.0 mg of PdCl2dppf. The mixture was heated at 80° C. for 3 h. More phenylboronic acid (0.10 g) and PdCl2dppf (26 mg) were added and the temperature was increased to 100° C. After an additional 12 h, the mixture was poured into water (100 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were filtered through diatomaceous earth and the filtrate was concentrated in vacuo. Chromatography on SiO2 (0 to 20% EtOAc/hexanes) afforded 158.8 mg of the desired compound. MS (ESI): exact mass calculated for C24H27N3O2, 389.21. found, m/z 390.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.[H-].[Na+].[CH2:16]1COCC1.IC>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:16])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1CO
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CI
Product: COCc1ccc(Br)cc1S(C)(=O)=O
Reaction time: 1 h

Procedure:
To a mixture of (4-bromo-2-methansulfonyl-phenyl)-methanol (0.73 g, 2.78 mmol), sodium hydride (0.030 g, 8.4 mmol), and THF (10 mL) was added iodomethane (0.21 mL, 3.36 mmol). After 1 h, the reaction was poured into water (40 mL), diluted in CH2Cl2, and washed with brine (40 mL). The organic layer was dried over (Na2SO4), filtered, concentrated and purified by silica gel column chromatography to give 600 mg of 4-bromo-2-methansulfonyl-1-methoxymethyl-benzene.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(N(C)C)=O.O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 130 °C
Reaction time: 18 h

Procedure:
Combine 4-hydroxy benzaldehyde (7.201 g, 59.0 mmol), 6-chloronicotinamide (9.605 g, 57.5 mmol), and potassium carbonate (19.86 g, 143.7 mmol) in dimethylacetamide (190 mL). Stir and heat at 130° C. After 18 h, cool to ambient temperature and dilute with water (600 mL). Extract aqueous layer with ethyl acetate (3×500 mL). Wash combined ethyl acetate extracts with water (1×) and brine (1×), successively, dry over anhydrous magnesium sulfate, filter, and concentrate. Purification by silica gel chromatography (1:1 ethyl acetate:hexanes→ethyl acetate) to provide 6.852 g (49%, 90% pure) of the title compound as a white solid: mass spectrum (electrospray): m/z=243.0 (M+1); 1H NMR (methanol-d4): 9.97 (s, 1H), 8.70 (d, 1H, J=2.4 Hz), 8.36 (dd, 1H, J=2.4, 8.8 Hz), 8.06-8.02 (m, 2H), 7.42-7.37 (m, 2H), 7.19 (d, 1H, J=9.3 Hz).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30].C(=O)(O)[O-].[Na+].S(Cl)(O[CH2:40][Cl:41])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl>[Cl:41][CH2:40][O:25][C:24](=[O:26])[CH2:23][CH2:22][C:17]12[CH2:20][CH2:21][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:27])[N:3]([CH2:28][CH2:29][CH3:30])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:19][CH2:18]1)[CH2:15][CH2:16]2
Reactant: O=S(=O)(Cl)OCCl
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)OCCl)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A mixture of 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid (208 mg, 0.5 mmol), sodium bicarbonate (168 mg, 2 mmol), and tetra-n-butylammonium hydrogensulfate (17 mg, 0.05 mmol) in water (5 ml) and dichloromethane (5 ml) was stirred vigorously at 0° C. After 10 min, to the reaction mixture was added a solution of chloromethyl chlorosulfate in dichloromethane (1 ml) and allowed to ambient temperature and continued to stir vigorously. After a couple of hours, the organic layer was separated and washed with brine. The organic extracts were dried over sodium sulfate. After the solvent was removed in vacuo, the residue was purified by column chromatography on SiO2 using ethyl/hexane (1:5) as an eluent to give (200 mg, yield 86%) 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid chloromethyl ester. MS (M+1 465)
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1)[OH:6])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl.CO>O1CCCC1.O>[NH2:1][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1)[OH:6]
Reactant: [N-]=[N+]=NC[C@H](O)c1ccc(Br)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: NC[C@H](O)c1ccc(Br)cn1
Temperature: 45 °C
Yield: 92.1 %

Procedure:
Compound 27c (4.8 g, 20 mmol) was dissolved in tetrahydrofuran (10 mL). Under the protection of argon, PPh3 (5.8 g, 22 mmol) was added, and the reaction mixture was heated to 45° C. to react for 2 hrs. Then water (7.86 mL) was added and the mixture was cooled to room temperature to react for 13 hrs. TLC (dichloromethane/methanol=20/1) was employed to monitor the reaction. After the reaction completed, the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then dried by rotary evaporation. Column chromatography afforded 4.0 g of white solid (compound 27d), yield 93.2%.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:24][CH2:25][C:26]1[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:32][C:31]1[CH:30]=[C:29]([CH3:33])[NH:28][C:27](=[O:34])[C:26]=1[CH2:25][NH:24][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=2[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:11]=1)=[O:15]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: COc1ccc(-c2cc(C(=O)O)c3cnn(C(C)C)c3n2)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: COc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3cnn(C(C)C)c3n2)cc1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1-(1-methylethyl)-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.225 mmol), DMSO(3 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (63.6 mg, 0.337 mmol) HCl salt, N-methylmorpholine (0.099 mL, 0.899 mmol), 1-hydroxy-7-azabenzotriazole (61.2 mg, 0.450 mmol), and EDC (86 mg, 0.450 mmol). The final product was collected as 89 mg (89%). LCMS E-S (M+H)=446.5. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=6.8 Hz, 6 H), 2.13 (s, 3 H), 2.23 (s, 3 H), 3.85 (s, 3 H), 4.41 (d, J=4.8 Hz, 2 H), 5.20-5.48 (m, 1 H), 5.91 (s, 1 H), 7.11 (d, J=8.8 Hz, 2 H), 8.11 (s, 1 H), 8.24 (d, J=8.8 Hz, 2 H), 8.34 (s, 1 H), 8.95 (m, 1 H), 11.58 (s, 1 H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Cl[C:11]1[C:20]([C:21]#[N:22])=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:29])[CH:17]=2)[N:12]=1>C1(C)C=CC=CC=1.O>[Cl:29][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9])[C:20]([C:21]#[N:22])=[C:19]2[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1CCCCN1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1c(N2CCCCC2=O)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 100 °C
Yield: 64.9 %

Procedure:
To a suspension of sodium hydride (31.5 mg, 55% in mineral oil, 0.723 mmol) in toluene (4 ml) was added piperidin-2-one (133 mg, 1.34 mmol) followed by 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) (200 mg, 0.669 mmol) and the mixture was heated to 100° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with water and extracted twice with DCM and twice with EtOAc. The combined extracts were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was triturated with cold diethyl ether to afford the title compound (157 mg, 62%) as light yellow solid. MS (ESI): 362.3 (M+H)+.
Reaction SMILES: Cl[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C@@H:22]1([N:30]2[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]1>N1C=CC=CC=1.C(Cl)Cl>[C:16]1([C:2]2([O:28][CH2:27][C@H:26]3[O:29][C@@H:22]([N:30]4[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]4=[O:32])[CH2:23][C@@H:24]3[OH:25])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=3[O:9][C:10]3[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClC1(c2ccccc2)c2ccccc2Oc2ccccc21
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC3(c4ccccc4)c4ccccc4Oc4ccccc43)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
585 mg (2 mmol) of 9-chloro-9-phenylxanthene were added to a solution of 484 mg (2 mmol) of thymidine in 20 ml of pyridine, and the resulting mixture was stirred at room temperature for 1 hour whilst shading it from light. The reaction mixture was then diluted with 200 ml of methylene chloride, and the diluted mixture was washed twice, each time with 200 ml of a 5% w/v aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 35 g of silica gel (70-230 mesh), using methylene chloride containing from 0 to 2.5% by volume of methanol as the eluent, to give 647.8 mg (yield 65%) of the title compound.