Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[CH:8]1[C:13]([Cl:14])=[C:12]([CH2:15][CH3:16])[C:11](Br)=[C:10]([Cl:18])[C:9]1([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH3:20]>C(NC(C)C)(C)C.C1(C)C=CC=CC=1.O.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>[Cl:18][CH:10]1[C:11]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[C:12]([CH2:15][CH3:16])[C:13]([Cl:14])=[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:9]1([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCCOC1(CC)C(Cl)=C(Br)C(CC)=C(Cl)C1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOC1(CC)C(C#C[Si](C)(C)C)=C(Cl)C(CC)=C(C#C[Si](C)(C)C)C1Cl
Yield: 53.5 %

Procedure:
Trimethylsilylacetylene (3.1 mL, 21.43 mmol), PdCl2(PPh3)2 (400 mg, 0.6 mmol), and CuI (235 mg, 0.79 mmol) were added successively to a deaerated solution of 2,5-dibromo-3,6-dichloro-1,4-diethylhexyloxybenzene (10) (4.00 g, 7.14 mmol) in diisopropylamine (25 mL) and toluene (55 mL). The resulting mixture was refluxed for 48 hours, then diluted with water (150 mL), and extracted with hexane (2×80 mL). The extract was washed with water (2×80 mL) and dried (MgSO4). Evaporation of the solvent gave an oily residue, which was purified by column chromatography (hexane:CH2Cl2, 98:2) to give an orange-red solid (1.90 gm, 45%). 1H-NMR(CDCl3): δ 3.87 (m, 4H), 1.81 (m, 2H), 1.31-1.64 (m, 12H), 0.97 (t, J=7.5 Hz, 6H), 0.92 (t, J=7.5 Hz, 6H). MS (EI): Calculated. 595.8. found [M+I]+, 596.8.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:14][NH:15][CH3:16]>O1CCOCC1.O>[CH3:14][N:15]([CH3:16])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccc2ncnc(Cl)c2c1
Reactant: CNC
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1ncnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-quinazoline-6-carbaldehyde (200 mg, 1 mmol) was dissolved in 10 ml dioxane. To this solution was added a solution of dimethylamine in water (Seq.). The mixture was stirred during 2 h at r.t. Evaporation of the solvents and remaining amine under high vacuum afforded pure 4-Dimethylamino-quinazoline-6-carbaldehyde as a yellow solid, which was used for the next step without further purification (190 mg=91%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](SC)=S)[CH3:2].[NH:10]([C:12]([S-:14])=[S:13])[NH2:11].[K+]>C(O)C>[SH:13][C:12]1[S:14][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])=[N:11][N:10]=1
Reactant: CCOC(=O)C(=S)SC
Reactant: NNC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1nnc(S)s1

Procedure:
Ethyl(methylthio)(thioxo)acetate (20.0 g, 122 mmol) and potassium hydrazinecarbodithioate (R. S. Drago et al., JACS (1983) 105, 2287) (17.8 g, 122 mmol) were reflux overnight in ethanol (500 ml). The solution was concentrated and EtOAc was added. The organic phase was washed with 1M HCl, brine and dried over anhydrous Na2SO4. The solvent was evaporated and the residue purified on silica gel (hexanes-acetone, 80:20) to give the title compound. 1H NMR (400 MHz, acetone-d6): 4.43 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)([O-:3])=O.[C:13]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)#[CH:14].N(C1C=CC=CC=1)=C=O.O>C(#N)C>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][CH2:5][C:4]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=2)[O:3][N:1]=1
Reactant: O=[N+]([O-])CCOC1CCCCO1
Reactant: C#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: CC#N
Solvent: O=C=Nc1ccccc1
Product: FC(F)(F)c1cc(-c2cc(COC3CCCCO3)no2)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
To a solution of 2-[(2-nitroethyl)oxy]tetrahydro-2H-pyran (483 μL, 3.15 mmol) and 1-ethynyl-3,5-bis(trifluoromethyl)benzene (3.0 g, 12.6 mmol) in dry acetonitrile (15 mL) were added TEA (4.4 ml, 31.5 mmol) and isocyanatobenzene (3.4 mL, 31.5 mmol) at rt. The reaction is stirred at 50° C. for 5 h. Water was added and the mixture was extracted with Et2O three times. The combined organic layers were then washed with brine once, dried over MgSO4 and concentrated in vacuo. The residue was purified by radial chromatography (0-40% EtOAc-hexanes gradient) to afford the title compound (0.51 g, 41% yield): MS (ES) m/z 418 (M+Na+).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1C#CCCCCCCC1CCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1CCCCCCCCC1CCCCC1

Procedure:
To an ice cold solution of 1-hexyne (49.6 mmoles) in freshly distilled tetrahydrofuran (50 ml) containing a trace of triphenylmethane was added dropwise n-butyl lithium in hexane (49.5 mmoles). About 10 minutes after the addition was stopped, sieve dried hexamethylphosphoramide (57.5 mmoles) was added and the solution stirred for 10 minutes. A solution of 2-cyclohexylethyl bromide (51.3 mmoles) in tetrahydrofuran (10 ml) was added and the reaction mixture was stirred for about 3 hours as the temperature rose to room temperature. The mixture was taken up in ether (100 ml) and washed with water (3×100 ml) and sodium chloride solution (100 ml). The organic phase was dried over magnesium sulfate and evaporated to leave an oil which was purified by flash chromatography to give 1-cyclohexyloct-3-yne. This compound (20.8 mmoles) was treated with potassium hydride (36.8 mmoles) in propylene diamine to obtain the isomeric 8-cyclohexyloct-1-yne as an oil. A mixture of 2-bromobenzaldehyde (12.59 mmoles), 8-cyclohexyloct-1-yne (14.87 mmoles), cuprous iodide (0.17 mmoles) and bis(triphenylphosphine) palladium (II) chloride (0.26 mmoles) in triethylamine (35 ml) was refluxed under argon for 1.5 hours. The reaction mixture was cooled, filtered and the filtrate evaporated. The resulting residue was dissolved in ether (100 ml), washed with 3N hydrochloric acid (50 ml) and saturated sodium chloride solution (50 ml) and then dried over anhydrous magnesium sulfate and charcoal. The solution was evaporated to afford an oil which was purified by flash chromatography (2% ether/hexane) to yield 2-(8-cyclohexyl-1-octynyl)benzaldehyde as an oil. This benzaldehyde (10.22 mmoles) was hydrogenated with 10% palladium on charcoal in ethyl acetate to give the desired product as an oil, after chromatography (3% ether/hexane).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:14][C:13]=1[N+:31]([O-:33])=[O:32].NN.CCOC(C)=O.O>C1COCC1>[NH2:3][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][CH2:23]2)=[CH:14][C:13]=1[N+:31]([O-:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C(=O)c4ccccc4C3=O)c([N+](=O)[O-])c2)CC1
Agent: NN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a suspension of tert-butyl 4-(4-(1,3-dioxoisoindolin-2-yl)-3-nitrophenyl)piperazine-1-carboxylate (275.4 g, 0.6 mmol) in THF (5.0 ml) was added 1.0M Hydrazine in THF (1.8 ml, 1.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into EtOAc/water and organic layer was washed with brine, dried over MgSO4 and evaporated. The resulting oil was purified by flash chromatography on silica eluting with 20% to 70% EtOAc/Hexane to afford the title compound (182 mg, 93% yield). 1H-NMR (400 MHz, DMSO-d6) δ 1.42 (s, 9H) 2.89-2.99 (m, 4H) 3.44 (d, 4H) 6.98 (d, 1H) 7.22 (s, 2H) 7.26-7.38 (m, 2H)
Reaction SMILES: [Li]C(C)(C)C.[O:6]([S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8].C([C:25]1[C:30]([F:31])=[C:29]([F:32])[C:28]([CH:33]([S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42])[S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[C:27]([F:48])[C:26]=1[F:49])(C)(C)C>>[F:48][C:27]1[C:28]([CH:33]([S:41]([C:44]([F:45])([F:46])[F:47])(=[O:42])=[O:43])[S:34]([C:37]([F:39])([F:40])[F:38])(=[O:35])=[O:36])=[C:29]([F:32])[C:30]([F:31])=[C:25]([F:11])[C:26]=1[F:49].[O:6]([S:7]([C:10]([F:13])([F:11])[F:12])(=[O:9])=[O:8])[S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15]
Reactant: CC(C)(C)c1c(F)c(F)c(C(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c(F)c1F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Li]C(C)(C)C
Product: O=S(=O)(C(c1c(F)c(F)c(F)c(F)c1F)S(=O)(=O)C(F)(F)F)C(F)(F)F

Procedure:
As it is described in Table 2 that the yield of pentafluorophenylbis(triflyl)methane is 45%, it was revealed that when pentafluorophenylbis(triflyl)methane is produced using a pentafluoromethylbromide, both of pentafluorophenylbis(triflyl)methane and 4-tert-butyl-2,3,5,6-tetrafluorophenylbis(triflyl)methane can be obtained at a ratio of 1:1 (45% yield, respectively). However, it was found out that when 1.0 equivalent weight of t-BuLi and 0.5 equivalent weight of Tf2O are used, the production of 4-tert-butyl-2,3,5,6-tetrafluorophenylbis(triflyl)methane is completely suppressed, and pentafluorophenylbis(triflyl)methane can be obtained at 95% yield with Tf2O as a base. Consequently, the reactions of pentafluorophenylbis(triflyl)methane with the various types of alkyl lithium reagents were examined, in order to determine the generality and range of the nucleophilic substitution specific to the para position of pentafluorophenylbis(triflyl)methane. Table 3 shows the types of alkyl lithium reagents, the reaction conditions and the yield of the para position substituents of pentafluorophenylbis(triflyl)methane. The para position substituents of pentafluorophenylbis(triflyl)methane shown in Table 3 are obtained by washing the reaction product obtained by reacting pentafluorophenylbis(triflyl)methane with alkyl lithium reagent, with a hydrochloric solution. The “Bn” shown in Table 3 represents a benzyl group.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][NH2:12].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][CH2:11][NH2:12]
Reactant: NCCc1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NCCC1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.6 %

Procedure:
To a solution of 2-(indol-2-yl)ethylamine (2.7 g) in acetic acid (25 ml) at 15° C. was added sodium cyanoborohydride (2.22 g) in one portion. The solution was stirred at room temperature for 15 hours and diluted with chilled water. The mixture was made basic with sodium hydroxide pellets and extracted three times with ether. The ether layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give 2-(2,3-dihydroindol-2-yl)ethylamine (1.41 g) as an oil. The oil was dissolved in tetrahydrofuran (50 ml) and treated with 1,1'-carboxyldiimidazole (1.13 g) at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (30%-ethyl acetate-chloroform) to give crystals. The crystals were washed with ether to give 3,4,4a,5-tetrahydropyrimido[1,6-a]indol-1(2H)-one (0.74 g).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH:15]([CH3:26])[CH2:16][N:17]2[CH2:22][CH2:21][CH:20]=[C:19]([CH2:23][O:24][CH3:25])[CH2:18]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>C(O)C.[C].[Pd]>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH:15]([CH3:26])[CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][O:24][CH3:25])[CH2:18]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC1=CCCN(CC(C)Cc2cccc(Oc3ccccc3)c2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COCC1CCCN(CC(C)Cc2cccc(Oc3ccccc3)c2)C1
Yield: 94.5 %

Procedure:
N-[3-(m-Phenoxyphenyl)-2-methylpropyl]-3-methoxymethyl-1,2,5,6-tetrahydropyridine (0.2 g) was dissolved in ethanol (20 ml), followed by addition of acetic acid (1 ml) thereto. To the resultant mixture, 5% palladium-carbon (0.2 g) was added at room temperature under nitrogen stream, and then hydrogenation was carried out under nitrogen stream. After absorption of hydrogen was completed, the catalyst was removed by filtration, and the filtrate was combined with 15% aqueous sodium hydroxide solution (20 ml) and extracted with diethyl ether. The ether extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give N-[3-(m-phenoxyphenyl)-2-methylpropyl]-3-methoxymethylpiperidine (0.19 g).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])([CH3:8])[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])([CH3:1])[CH:3]=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C)cc1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1ccc(OC(C)(C)C=O)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
A solution of ethyl 2-methyl-2-(2-nitro-4-methylphenoxy)propionate (4.47 g) in toluene (50 ml) was cooled to -78° C. and treated dropwise with diisobutylaluminium hydride (DIBAL, 11.3 ml, 1.5M solution in toluene). The mixture was stirred for 2 hours and then additional DIBAL was added until reaction was complete, (ca. 4.4 ml) as monitored by thin layer chromatographic (tlc). The reaction was quenched by addition of aqueous ammonium chloride solution and ether. The resulting mixture was clarified by filtration through kieselguhr. The organic phase was separated, dried (MgSO4) and concentrated to give an oil. Purification by flash column chromatography, eluting with a mixture of ethyl acetate and hexane (increasing from 10:90 v/v to 15:85 v/v), gave 2-methyl-2-(2-nitro-4-methylphenoxy)propanal as an oil, (1.89 g); NMR: 1.45(6H, s), 2.35(3H, s), 6.8-7.6(3H, m) and 9.85(1H, s).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[O:13][C:14]([O:16][CH3:17])=[O:15]>S(=O)(=O)(O)O>[F:12][C:10]1[CH:11]=[C:6]([F:5])[C:7]([O:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:9]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Oc1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A mixture of concentrated nitric acid (4 ml) and concentrated sulphuric acid (4 ml) was added slowly to a cooled mixture of 2,4-difluoro-1-methoxycarbonyloxybenzene (50 g, 0.027 mol) in concentrated sulphuric acid (4 ml) such that the reaction temperature was maintained below 30° C. The mixture was stirred for a further 3 hours, diluted with ice/water and the precipitated product collected by filtration washed with water and dried to give 2,4-difluoro-5-methoxycarbonyloxy-1-nitrobenzene (2.8 g, 45%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[N:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][CH:14]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)nc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 6-chloropyridin-3-ol.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:9]([O:11]C)=[O:10])[S:8][C:4]=2[CH:3]=[N:2]1.O[Li].O.Cl>CO.O>[NH:1]1[C:5]2[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[S:8][C:4]=2[CH:3]=[N:2]1
Reactant: COC(=O)c1cc2[nH]ncc2s1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2[nH]ncc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1H-thieno[3,2-c]pyrazole-5-carboxylate (F-5) (4.2 g, 18.7 mmol) in MeOH (50 mL) was added a solution of LiOH.H2O (3.1 g, 74.8 mmol) in water (5 mL). The reaction mixture was stirred at room temperature overnight. Then 1N HCl was added to adjust to pH to ˜5, the resulting precipitate was collected and dried to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1CCNC1
Reactant: COc1cccc(C2CCCCC2=O)c1
Agent: Cl
Product: COc1cccc([C@H]2CCCC[C@H]2N2CCCC2)c1

Procedure:
2-(3-Methoxyphenyl) cyclohexanone (30g), pyrrolidine (20g) and 98 to 100% formic acid (20g) were heated under reflux at 130° to 140° C for 18 hours. The cooled mixture was poured into dilute hydrochloric acid, washed with ether, basified and ether extracted. The dried extract was evaporated to give cis-2-(3-methoxyphenyl)-1-pyrrolidinocyclohexane (19g) as a colourless oil. A sample distilled at 150° to 154° C/1 mm gave a hydrochloride m.p. 145° to 147° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]>CC(C)=O>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(-c2ccc(O)cc2)n1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(-c2ccc(OCc3ccccc3F)cc2)n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 73.1 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-pyridinecarboxylate (D80, 650 mg, 2.84 mmol) in acetone (8 ml) were added K2CO3 (780 mg, 5.67 mmol) and 1-(bromomethyl)-2-fluorobenzene (805 mg, 4.26 mmol). The mixture was stirred at 60° C. under nitrogen atmosphere for 6 h. Solvent was removed under reduced pressure and the residue was dissolved in AcOEt. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated to dryness. The crude compound was purified by flash chromatography on 25 g silica gel cartridge, using a gradient of cyclohexane/ethylacetate 10/0 to 8/2 as eluent, to give the title compound (700 mg, 73%).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)=[CH:14][N:13]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:10]2=[N:11][CH:12]=1)=[NH:6])C.[CH:30]([NH:32][NH2:33])=O.CCN(CC)CC>CCO>[C:24]1([S:21]([N:13]2[C:10]3=[N:11][CH:12]=[C:7]([C:5]4[NH:6][CH:30]=[N:32][N:33]=4)[CH:8]=[C:9]3[C:15]([C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)=[CH:14]2)(=[O:22])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=N)c1cnc2c(c1)c(-c1ccoc1)cn2S(=O)(=O)c1ccccc1
Reactant: NNC=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccoc2)c2cc(-c3nnc[nH]3)cnc21
Temperature: 75 °C
Yield: 48.4 %

Procedure:
A mixture of 39 (300 mg, 0.70 mmol), formic hydrazide (209 mg, 3.47 mmol) and Et3N (759 μM, 6.95 mmol) in EtOH (10.4 mL) was heated at 75° C. overnight. After cooling, the solvent was evaporated and the residue purified by silicagel chromatography using 80% ethyl acetate in hexane (gradient elution) then preparative TLC (1 mm plates, EtOAc eluent) to give 40 as a white solid (132.6 mg, 76%); 1H NMR (400 MHz, CDCl3+2 drops CD3OD) δ 6.71 (m, 1H), 7.40-7.70 (m, 5H), 7.84 (s, 1H), 7.93 (t, J=1.0 Hz, 1H), 8.10-8.30 (m, 3H), 8.63 (d, J=2.0 Hz, 1H), 9.10 (bs, NH); MS (CI) m/z 391.9 (MH+), 433.1 (M+MeCN).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[H-].[Na+].[NH:10]1[C:21](=[O:22])[C:20]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12].O>CS(C)=O>[CH2:2]([N:10]1[C:21](=[O:22])[C:20]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 43 h
Yield: 98.2 %

Procedure:
1-(5,6-Oxidohexyl)-3,7-dimethylxanthine (CT1541) was synthesized and used as an intermediate for synthesizing CT1517 and CT1595 as described in examples 2 and 3 below. A mixture of 1-bromo-5-hexene (10.7 g, 66 mmol), sodium hydride (1.58 g, 66 mmol), and theobromine (11.9 g, 66 mmol) in dimethylsulfoxide (100 ml) was stirred for 43 hr. The solution was treated with water (200 ml) and then extracted with dichloromethane (3×80 ml). The combined extracts were washed with water (3×100 ml), dried over magnesium sulfate, and then the solvent was evaporated under vacuum to give 1-(5-hexenyl)-3,7-dimethylxanthine (CT1539) (17 g, 98% yield) as a white powder.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[O:15]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16]1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[O:15]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=2)=[CH:16]1
Reactant: Clc1nc(SCc2ccccc2)ns1
Reactant: OCc1ccoc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CSc2nsc(OCc3ccoc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To 2 g of N,N-dimethylformamide, 0.243 g of 5-chloro-3-benzylthio-1,2,4-thiadiazole and 0.098 g of 3-furanmethanol were dissolved, and added 0.045 g of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 1 hour and at room temperature for 2 hours. Then, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with tert-butylmethylether. The organic layer was concentrated, and the residue obtaind was subjected to silica gel column chromatography to obtain 0.17 g of 5-(3-furyl)methoxy-3-benzylthio-1,2,4-thiadiazole.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[S:15][CH:14]=[N:13][C:12]=2[CH3:16])=[CH:4][C:3]=1[CH3:18].[NH2:19][C:20]([NH2:22])=[O:21]>Cl.O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[S:15][CH:14]=[N:13][C:12]=3[CH3:16])[NH:22][C:20](=[O:21])[N:19]=2)=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(C(=O)/C=C/c2scnc2C)ccc1O
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3scnc3C)[nH]c(=O)n2)ccc1O
Temperature: 120 °C
Yield: 3.3 %

Procedure:
(((E)-1-(4-hydroxy-3-methylphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (200 mg, 0.77 mmol) and urea (0.23 g, 3.8 mmol) were suspended in 5 mL of 4N HCl solution in dioxane (Aldrich), and the reaction mixture was heated in a sealed vessel to 120° C. for 20 h. After cooling to room temperature, the resulting mixture was concentrated in vacuo to remove dioxane. The residue was dissolved in 5 mL of methanol, and the product was purified by preparative HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to yield 7.7 mg of 4-(4-hydroxy-3-methylphenyl)-6-(4-methyl-1,3-thiazol-5-yl)pyrimidin-2(1H)-one. 1H NMR (400 MHz, d6-DMSO): δ 9.11 (s, 1H), 7.81 (d, 1H), 7.72 (dd, 1H), 7.07 (s, 1H), 6.90 (d, 1H), 2.73 (s, 3H), 2.17 (s, 3H). MS (EI) for C15H13N3O2S: 300.4 (MH+).