Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][CH2:25][C:26]1([CH2:30][NH:31][C:32]2[CH2:36][S:35][C:34](=[O:37])[N:33]=2)[CH2:29][CH2:28][CH2:27]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][CH2:30][C:26]3([CH2:25][OH:24])[CH2:29][CH2:28][CH2:27]3)=[N:33][C:34](=[O:37])[S:35]/2)[CH2:8][CH2:7]1
Reactant: O=C1N=C(NCC2(CO)CCC2)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCC2(CO)CCC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (500 mg) in 2-propanol (10 mL) were added 4-({[1-(hydroxymethyl)cyclobutyl]methyl}amino)thiazol-2(5H)-one (474 mg) and piperidinium acetate (218 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (258 mg).
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:17][CH2:18][C@H:19]([OH:22])[CH2:20][OH:21])C1C=CC=CC=1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1>CN(C)C=O.O.C(OCC)(=O)C.C(O)C.[Pd]>[Si:23]([O:21][CH2:20][C@@H:19]([OH:22])[CH2:18][CH2:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[OH:8])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: COc1cccc(CC[C@H](O)CO)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Pd]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cccc(CC[C@H](O)CO[Si](C)(C)C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To a solution of (2S)-4-[2-(benzyloxy)-3-methoxyphenyl]-1,2-butanediol (8.00 g, 26.5 mmol) in N,N-dimethylformamide (250 mL) cooled to 0° C. was added tert-butyldimethylsilyl chloride (4.39 g, 29.1 mmol) followed by imidazole (2.16 g, 31.8 mmol) and the reaction mixture was allowed to stir at room temperature for 4 h. The reaction mixture was diluted with water (500 mL) and ethyl acetate (200 mL). The aqueous phase was separated and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with aqueous hydrogen chloride (200 mL), water (4×200 mL), aqueous sodium chloride (300 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. The residue was dissolved in ethanol (300 mL), palladium on carbon (10 wt. %, 1.00 g) was added, and the reaction mixture was shaken under an H2 atmosphere (50 psi) for 6 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4) gave 7.33 g (85%, 40% ee) of 2-((3S)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxybutyl)-6-methoxyphenol as a colorless oil which crystallized upon standing. Rf=0.53 (silica, ethyl acetate:hexanes 1:4); mp 44-46° C.; Anal. Calcd. for C17H30O4Si: C, 62.54; H, 9.26. Found: C, 62.41; H, 9.19.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:16]>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:16])[CH:5]=[C:4]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: Nc1nc(O)cc(-c2ccco2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)cc(-c2ccco2)n1

Procedure:
A solution of 2-amino-4-hydroxy-6-(2-furyl)pyrimidine (1.40 g, 7.9 mmol) in POCl3 (4 mL) was refluxed under argon for 2 h. The POCl3 was distilled; the residue was diluted with EtOAc and poured over iced saturated NaHCO3. The layers were separated and the aqueous was extracted with EtOAc (100 mL). The combined extracts was washed with saturated NaCl, dried (MgSO4), and the solvent removed at reduced pressure to afford 0.5 g of crude product, which was used without further purification. TLC (20% EtOAc/80% hexane) Rf 0.26; 1H-NMR (DMSO-d6) δ 6.68 (dd, J=1.7, 3.4 Hz, 1H), 6.94 (s, 1H), 7.25 (dd, J=1, 3.7 Hz, 1H), 7.91 (dd, J=0.8, 1.9 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[CH3:15][N:14]1[C:10]([C:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:17][OH:18])=[N:11][N:12]=[N:13]1
Reactant: NO
Reactant: Cc1cccnc1C(=O)c1nnnn1C
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccnc1C(=NO)c1nnnn1C
Yield: 88 %

Procedure:
A solution of (3-methylpyridin-2-yl(1-methyltetrazol-5-yl)methanone (2.8 g, 13.8 mmol) and hydroxylamine hydrochloride (2.4 g, 34.4 mmol) in pyridine (30 ml) is stirred three hours at 50° C. and overnight at room temperature. The solvent is evaporated and water is added to the crude mixture. The resulting suspension is filtered. The solid is washed with water and dried to give 2.65 g of 1-methyl-5-[(3-methylpyridin-2-yl)carbohydroximoyl]tetrazole [yield 88.1%; 1H-NMR (DMSO-d6) δppm: 2.6 (s, 3H), 4.02 (s, 3H), 7.35 (dd, 1H), 7.82 (d, 1H), 8.34 (d, 1H), 13.1 (s, 1H)].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)([CH2:11][CH2:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[I-:29].[Na+].O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:28])[C:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][I:29])([CH2:11][CH2:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CCCCCCCl)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(CCCCCCI)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Yield: 89.4 %

Procedure:
To a solution of 6-chlorohexyl-(4,4,5,5,5-pentafluoropentyl)malonic acid diethyl ester (743 mg, 1.69 mmol) in acetone (5 ml) was added sodium iodide (761 mg, 5.08 mmol), which was then refluxed for 4 h. When the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. Then, the organic layer was washed with wafer and saturated sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=15:1) to give the title compound (801 mg, yield: 89%) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])=[C:8]2[CH3:29])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])=[C:8]2[CH3:29])=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccccc1Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(Cc1ccccc1C(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
To a solution of the product of Step 2 (300 mg, 0.62 mmol) in THF (2 mL) and MeOH (4 mL) was added NaOH (3N, 0.62 mL). The mixture was refluxed for 2.5 h and then cooled to r.t. Acidification with 1N HCl followed by extraction with EtOAc gave 148 mg of the title compound after evaporation of solvent. Anal. calcd. for C25H22NO3Br --H2O: C, 63.43, H, 4.90; N, 2.96; found: C, 63.77; H, 4.89; N, 3.12.
Reaction SMILES: O[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[N:14][OH:15])[CH3:13].C(N(S(F)(F)F)CC)C>C(Cl)Cl>[CH3:13][C:12]1[C:3]2[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=2[O:15][N:14]=1
Reactant: CCCc1c(O)ccc(C(C)=NO)c1O
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCCc1c(O)ccc2c(C)noc12
Temperature: -35 °C
Yield: 77.2 %

Procedure:
1-(2,4-dihydroxy-3-propylphenyl)ethanone oxime (400 mg, 1.91 mmol) (Example 66) was dissolved in CH2Cl2 and the solution was cooled to −35° C. under an atmosphere of argon. (Diethylamino)sulfur trifluoride (DAST) (647 mg, 4.01 mmol) was added dropwise and the solution was allowed to warm to −25° C. over 2 h. The mixture was quenched with NaHCO3 (saturated aqueous solution). The organic phase separated and the aqueous phase extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:3) gave 282 mg (77%) of the title compound as a faintly red-colored solid. 1H NMR (400 MHz, CDCl3): δ 0.95 (t, 3H), 1.67 (m, 2H), 2.56 (s, 3H), 2.79 (t, 2H), 6.76 (d, 1H), 7.19 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:41][CH:40]([OH:42])[CH2:39][NH:38][CH2:37][CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:35]4[CH2:41][CH:40]([OH:42])[CH2:39][NH:38][CH2:37][CH2:36]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: OC1CNCCNC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCNCC(O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and [1,4]Diazepan-6-ol following General Procedure B.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:24][CH2:25][N:26]([C:10]([C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)=[O:12])[CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc(N2CCCC2)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4)cc3)CC2)c(C)c1
Yield: 4.2 %

Procedure:
Using 4-(pyrrolidin-1-yl)benzoic acid (200 mg) and 1-(2,4-dimethylphenyl)piperazine (199 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (15.8 mg) was obtained.
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26](OC)=[O:27])=[CH:22][N:21]=1)=[O:19])=[O:9])([CH3:6])([CH3:5])[CH3:4].O.Cl>C1COCC1>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=1)=[O:19])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CO)cn1
Yield: 53 %

Procedure:
Under ice cooling, lithium tetrahydroborate (2.1 g, 100 mmol) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-5-methoxycarbonylpyridine-2-carboxylic acid amide (Reference Compound No. 2-1, 38 g, 100 mmol) in THF (400 mL), and then the reaction mixture was stirred for 3 hours. Under ice cooling, water (200 mL) and 1.0 M aqueous hydrochloric acid (300 mL) were added thereto, the whole was extracted with ethyl acetate (300 mL), and then the organic layer was washed with water (500 mL) and brine (400 mL). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. Ethyl acetate (20 mL) and hexane (30 mL) were added to the residue, and then the resulting solid was collected by filtration to give 18 g of the title reference compound as a white solid. (Yield 53%)
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([C:18]2[CH:19]=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1>[CH3:15][C:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][CH:11]([C:18]1[CH:19]=[N:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=2)=[CH:22][CH:23]=1)[O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:34])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OC(CCC(C)(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)CCC(Oc1ccc(C(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1

Procedure:
4-{4,4-Dimethyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-pentyloxy}-benzoic acid methyl ester (isomer 2) is taken into THF (1.0 mL) and treated with NaOH (1.0 mL, 5.0 N), then refluxed under nitrogen. The reaction mixture is neutralized with HCl (1.0 mL, 5.0 N), extracted with ethyl ether, dried over sodium sulfate. Concentration gives the title compound, (180 mg, 0.38 mmol), 55%.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[H-].[Na+].[Br:11][C:12]1[C:13]([C:24]([P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])([F:26])[F:25])=[CH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH2:22]Br)[CH:16]=2>C1(C)C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:22][C:17]1[CH:18]=[CH:19][C:20]2[C:15](=[CH:14][C:13]([C:24]([P:27]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:34])([F:26])[F:25])=[C:12]([Br:11])[CH:21]=2)[CH:16]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2cc(CBr)ccc2cc1Br
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc2cc(Br)c(C(F)(F)P(=O)(OCC)OCC)cc2c1)OCC
Reaction time: 1 h

Procedure:
To a solution of diethylphosphite (0.22 mL) in toluene (5 mL) at 0° C. was added NaH (60% in mineral oil, 20 mg). The reaction mixture was stirred for 1 hour and then a solution of diethyl [3-bromo-7-(bromomethyl)-2-naphthyl](difluoro)methylphosphonate (220 mg) in toluene (2 mL) was added dropwise. The reaction was stirred for 1 h at 0° C., quenched with a solution of saturated NH4Cl, extracted with EtOAc and dried over Na2SO4. The organic extracts were evaporated to dryness and the residue was purified by flash chromatography eluting with 50% EtOAc/hexanes to afford the titled compound.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])/[C:27]([OH:29])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])/[C:27]([OH:29])=[O:28])[N:25]=1
Reactant: O=C(O)/C(=N\OC1CCNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: CO
Product: Nc1nc(/C(=N/OC2CCNC2=O)C(=O)O)cs1
Yield: 60.8 %

Procedure:
49 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetic acid are suspended in a solution of one liter of methanol containing 40 ml of water, and the suspension is refluxed for 2 hours with heating. After cooling, crystalline precipitates are collected by filtration, and the crystals are washed with ethyl acetate. The crystals are recrystallized from a mixture of 500 ml of methanol and 50 ml of water, and dried at 70° C. under reduced pressure. 15.7 g of (Z)-2-(2-aminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetic acid are obtained as colorless prisms. The physico-chemical properties of this product are identical with those of the product obtained in Example 2-(4).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45]OS(C)(=O)=O)=[CH:41][C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[CH:52]=3)=[N:39]2)[CH2:36][CH2:35]1.CN1CCNCC1>>[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:41][C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([F:59])[CH:52]=3)=[N:39]2)[CH2:36][CH2:35]1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 73.8 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 73.8%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:10][C:11]1[NH:12][C:13](I)=[C:14]([CH2:16][CH3:17])[N:15]=1>CN(C)C=O>[CH3:10][C:11]1[NH:12][C:13]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:14]([CH2:16][CH3:17])[N:15]=1
Reactant: Sc1ccccc1
Reactant: CCc1nc(C)[nH]c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(C)[nH]c1Sc1ccccc1
Temperature: 130 °C
Yield: 64 %

Procedure:
To a solution of 2.24 g of thiophenol (20.3 mmol) in 16 ml of dry dimethylformamide is added 1.4 g of sodium hydride (60% oil suspension: 35 mmol) under ice cooling. Ten minutes later, 3.2 g of 2-methyl-4-ethyl-5-iodoimidazole (13.6 mmol) is added to the mixture, which is heated at 130° C. in a nitrogen atmosphere. Two hours later, the dimethylformamide is evaporated in vacuo. The residue is mixed with dry ice and extracted with methylene chloride. The extract is washed with water, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The crude product is chromatographed on a column of silica gel, eluting with 3% methanol/methylene chloride. The product is recrystallized from ethyl acetate/isopropyl ether to give 1.9 g of 2-methyl-4-ethyl-5-phenylthioimidazole 2. Yield, 64%: mp. 171° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[NH2:16][CH2:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccnc(Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Yield: 32 %

Procedure:
To a solution of 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine, 3, (300 mg, 1.25 mmol) and tert-butyl (2S)-2-(aminomethyl)pyrrolidine-1-carboxylate (500 mg, 2.50 mmol) in THF (10 mL) is added diisopropylethylamine (0.43 mL, 2.50 mmol). The reaction was heated at reflux for 18 hours and then cooled to room temperature. The crude reaction is then partitioned between EtOAc and sat. NaHCO3. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 160 mg (32% yield) of the desired product: MS (ESI, pos. ion) m/z: 404 (M+1).
Reaction SMILES: [CH2:1]=[N:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)#[N:12]>C1(C)C=CC=CC=1>[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:18][CH:1]=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: C=NCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncoc1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A solution of ethyl 2-(methylideneamino)acetate (1.7 g, 14.77 mmol, 1.00 equiv) was added dropwise to a stirred mixture of sodium hydride (60%, 722 mg, 18.05 mmol, 1.22 equiv) in toluene (30 mL) at 5° C. The mixture was stirred at room temperature for 30 min. 4-cyanobenzoyl chloride (3 g, 18.12 mmol, 1.22 equiv) was then added dropwise at 5° C. The reaction was stirred at room temperature for 12 h then quenched with 30 mL of ice-water mixture. The resulting mixture was extracted with 2×15 mL of ethyl acetate. The combined organic layers was washed with 1×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-30% of ethyl acetate in petroleum ether to give 1.3 g (36%) of ethyl 5-(4-cyanophenyl)oxazole-4-carboxylate as a red solid. 1H-NMR (300 MHz, CDCl3): δ 8.29-8.26 (m, 2H), 8.00 (s, 1H), 7.91-7.77 (m, 2H), 4.48-4.41 (m, 2H), 1.46-1.41 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH2:13][CH2:14][CH2:15]O)=[CH:10][CH:11]=2)[N:6]([CH3:17])[C:5]1=[O:18].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35]>O1CCOCC1>[CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH2:13][CH2:14][CH2:15][N:40]3[CH2:41][CH2:42][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:38][CH2:39]3)=[CH:10][CH:11]=2)[N:6]([CH3:17])[C:5]1=[O:18]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCO)nc21
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCN3CCN(S(C)(=O)=O)CC3)nc21
Temperature: 100 °C

Procedure:
To a stirred solution of 37-2 (0.05 g, 0.18 mmol) in dioxane (1 mL) was added triethylamine (0.10 mL, 0.72 mmol) and methanesulfonyl chloride (0.017 mL, 0.21 mmol). To this resulting mixture was added 1-methanesulfonyl-piperazine (0.09 g, 0.54 mmol) and the reaction was heated to 100° C. for 3 days. The reaction was concentrated and flash column separation using a 0-5% methanol/dichloromethane gradient gave 37-3. (0.025 g, 33%). HRMS (M+H)+: observed=424.2378, calculated=424.2377
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](N2CCCCCC2)[N:3]=1.F[C@@H]1[C@@H](CO)O[C@@H](N2C=CC(=O)NC2=O)C1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[N:3]1[CH:4]=[C:5]2[C:9]([NH:8][CH:7]=[N:6]2)=[N:10][CH:2]=1
Reactant: Nc1nc(N2CCCCCC2)c2nc[nH]c2n1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Solvent: CO
Product: c1ncc2nc[nH]c2n1
Temperature: 45 °C
Reaction time: 168 h
Yield: 19 %

Procedure:
2-Amino-6-hexahydroazepin-1-yl-9H-purine (0.60 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added and the suspension was stirred at 45° C. After 7 days, 100 ml MeOH was added to the reaction mixture. The resulting mixture was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone:methanol (97:2:1). Solvent was removed and lyophilization yielded 0.149 g of 2-amino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-hexahydroazepin-1-yl)-9H-purine (19%): mp 110°-114° C.: TLC Rf 0.70 (silica gel, MeCN:15N NH4OH:H2O/85:5:10); [α]D20 -16.6 (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 285 (17.6); at pH 13, 285 (17.3); 1H NMR (300 MHz, DMSO-d6) δ7.92 (s, 1H, H8), 6.21 (dd, 1H, H1', J=9.4 Hz, J=5.5 Hz), 5.72 (s, 2H, NH2), 5.45-5.49 (m, 1H, OH5'), 5.36 (dd, 1H, H3', J=53.7 Hz, J=4.3 Hz), 4.16 (dt, 1H, H4', J=27.2 Hz, J=4.4 Hz), 3.74-4.24 (b, 4H), 3.56 (t, 2H, H5' and H5", J=5.0 Hz), 2.75-2.95 and 2.40-2.60 (m, 2H, H2' and H2"), and 1.65-1.80 and 1.40-1.55 (b, 8H); MS (ci 351 (M+1), 331 (M-F), 233 (MH2 --C5H8FO2).