Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:26][CH2:27][CH2:28][OH:29])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12][CH3:13])=[CH:8][C:7]1([OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+]>ClCCl>[OH:1][CH:2]([CH2:26][CH2:27][CH2:28][OH:29])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12]([CH3:13])=[O:38])=[CH:8][C:7]1([OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CSC1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)C1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Reaction time: 3 h
Yield: 38 %

Procedure:
To a solution of 71 mg of 5-[(E)-4,7-dihydroxy-2-heptenylidene]-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 577 dissolved in 2 ml of dichloromethane was added a solution of 45 mg of 3-chloroperbenzoic acid in 2 ml of dichloromethane, and the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogencarbonate was added. The mixture was extracted twice with ethyl acetate, and the organic layers were combined, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration and concentration, the concentrate was subjected to silica gel column chromatography to give 27 mg (yield 38%) of low polarity isomer and 25 mg (yield 35%) of high polarity isomer of 5-[(E)-4,7-dihydroxyheptenylidene]-4-hydroxy-2-methylsulfinyl-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14]>CCCCCC>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[N:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NN=C1C2CC3CC(C2)CC1C3

Procedure:
A hexane solution containing 2-adamantanone (2 g) and tert-butyl carbazate (1.76) was heated to reflux for 3 hours. When the solution cooled, the title compound crystallized and was filtered (3.28 g). M. p. 175-177°.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]/[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>C1COCC1>[OH:24][C:23]1[N:8]2[C:9](=[O:15])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[N:16][N:17]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCCn1/c(=N\N)[nH]c(=O)c2[nH]cnc21
Solvent: C1CCOC1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(O)nnc12
Temperature: 100 °C
Yield: 103.7 %

Procedure:
A solution of (2z)-3-pentyl-3,7-dihydro-1h-purine-2,6-dione 2-hydrazone (200 mg, 0.846 mmol), N,N-carbonyldiimidazole (1.65 g, 10.2 mmol) in THF (10 ml) was stirred at 70° C. overnight. The reaction mixture was then heated in microwave reactor at 100° C. for 10 min. The reaction was completed checked by LCMS analysis. The reaction mixture was concentrated, diluted with EtOAc and washed with sat. NaHCO3. The aqueous was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and concentrated to yield the desired product (230 mg, 98.4%). LCMS calculated for C11H15N6O2 (M+H) 263.1. found: 263.1.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20]([CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:32]([O:34][C:35]([C:37]1[O:38][C:39]([CH2:42]Cl)=[CH:40][CH:41]=1)=[O:36])[CH3:33].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:12]([O:19][C:20]([CH:22]1[CH2:31][C:26]2[C:25](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][N:23]1[CH2:42][C:39]1[O:38][C:37]([C:35]([O:34][CH2:32][CH3:33])=[O:36])=[CH:41][CH:40]=1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OCc1ccccc1)C1NCCc2ccccc21
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1ccc(CN2Cc3ccccc3CC2C(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.8 %

Procedure:
To a solution of 1,2,3,4-tetrahydroisoquinolinecarboxylic acid benzyl ester p-toluenesulfonate (2.1 g, 4.9 mmol) in acetonitrile (15 mL) were added 5-chloromethylfuran-2-carboxylic acid ethyl ester (0.50 mL, 3.3 mmol) and N,N-diisopropylethylamine (1.4 mL, 8.1 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=92/8) to give the title compound (1.1 g, 2.6 mmol, 81%).
Reaction SMILES: [F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.C([N:25](CC)CC)C.O.NN>C(O)C>[F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:16])[NH:17][NH2:25])=[N:6]1
Reactant: CCN(CC)CC
Reactant: Cc1ncc2c(C(=N)N)nn(Cc3cccc(F)c3F)c2n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ncc2c(C(=N)NN)nn(Cc3cccc(F)c3F)c2n1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Under an argon atmosphere, 440 mg (1.237 mmol, purity 85%) of 1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were initially charged in 6 ml of ethanol and cooled to 0° C. 500 mg (4.49 mmol) of triethylamine and 85 mg (1.361 mmol) of 80% hydrazine hydrate were added, and the mixture was stirred at room temperature for 72 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, concentrated on a rotary evaporator and dried under high vacuum. 421 mg (purity 84%, 90% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:33]1COCO[CH2:34]1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@@H:15]([CH2:34][OH:33])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1OCOCO1
Reactant: O=C(CCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](CO)Cc1ccccc1
Reaction time: 0.33 h

Procedure:
1 M of titanium tetrachloride in DCM (43 mL) was added to a solution of intermediate (7b) (12.7 g, 41 mmol) in DCM (150 mL) at 0° C. under nitrogen. After 20 minutes, DIPEA (7.9 mL, 45.2 mmol) was added dropwise at 0° C. After 80 minutes, 1,3,5-trioxane (4.1 g, 45.2 mmol) in DCM (30 mL) was added, followed by a second equivalent of 1 M titanium tetrachloride in DCM after 10 minutes. After 2.5 hours at 0° C., the mixture was quenched with saturated aqueous NH4Cl (150 mL). The product was extracted with water (100 mL) and DCM (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield intermediate (7c), which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[CH:14][C:13]=1[NH:21][C:22]1[C:31]2[C:26](=[CH:27][C:28](F)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][C:23]=1[C:35]#[N:36].CS(C)=O>O1CCCC1>[CH2:3]([S:10][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:21][C:13]3[CH:14]=[C:15]([O:19][CH3:20])[C:16]([Cl:18])=[CH:17][C:12]=3[Cl:11])=[C:23]([C:35]#[N:36])[CH:24]=[N:25]2)=[CH:30][C:29]=1[O:32][CH3:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: SCc1ccccc1
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(SCc4ccccc4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
A mixture of sodium hydride (169 mg, 4.2 mmol), benzyl mercaptan (145 mg, 1.2 mmol) and 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (250 mg, 0.64 mmol) in 1 mL of tetrahydrofuran is heated at 70° C. for 1 hour, then stirred at room temperature overnight. Upon addition of 1 mL of dimethyl sulfoxide a solution is obtained. Additional amounts of sodium hydride and benzyl mercaptan are added and the reaction mixture is heated at 100° C. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative thin layer chromatography, eluting with 1:2 ethyl acetate:hexane to provide 150 mg of 7-benzylthio-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-quinolinecarbonitrile, mp 123-125° C.
Reaction SMILES: O.O.O.[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14]([OH:16])=O)[C:5]=1[C:17]([OH:19])=[O:18]>C(OC(=O)C)(=O)C>[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]2[C:14]([O:19][C:17](=[O:18])[C:5]=12)=[O:16]
Reactant: O=C(O)c1cc2ccccc2nc1C(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2nc3ccccc3cc21
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-quinolinedicarboxylic acid-trihydrate (0.141 mol) in acetic anhydride (125 ml) is heated at 85° C. for 1/2 hour and then at 100° C. for 1 hour. The reaction mixture is then cooled to room temperature, filtered and the solids washed with ethyl ether to afford the desired 2,3-quinolinedicarboxylic anhydride, mp 225°-228° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[CH:9][C@@H:8]([OH:12])[C@@H:7]1[OH:13])(=[O:3])[CH3:2].[CH3:14][O:15][CH2:16][C:17](OC=C)=[O:18]>C(COC)OC>[CH3:14][O:15][CH2:16][C:17]([O:12][C@H:8]1[C@H:7]([OH:13])[C@@H:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:11][CH:10]=[CH:9]1)=[O:18]
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Reactant: C=COC(=O)COC
Solvent: COCCOC
Product: COCC(=O)O[C@@H]1C=CO[C@H](COC(C)=O)[C@H]1O
Reaction time: 2 h
Yield: 93.8 %

Procedure:
325 mg (1.73 mmol) of 6-O-acetylglucal are dissolved in 1 ml of dimethoxyethane, 1 ml of vinyl methoxyacetate and 325 mg of lipase Fp (Pseudomonas fluorescens, Amano) are added, and the mixture is stirred at room tempera-tufa for 51/2hours. Filtering off the enzyme and flash chromatography on silica gel (ethyl acetate/hexane 1:2) result in 422 mg (1.62 mmol, 93.8% yield) of the desired 3-O-methoxyacetyl-6-O-acetylglucal.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][CH:13]1[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][N:15]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:14]1=[O:30])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][N:9]([CH2:12][CH:13]1[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][N:15]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:36][C:32]3[O:31][CH:35]=[CH:34][CH:33]=3)=[CH:25][CH:24]=2)[C:14]1=[O:30])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC1CN(Cc2ccc(O)cc2)C(=O)C1CN(C=O)OCc1ccccc1
Reactant: OCc1ccco1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC1CN(Cc2ccc(OCc3ccco3)cc2)C(=O)C1CN(C=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 318.5 %

Procedure:
To a solution of (+/−)-(3RS,4SR)-N-benzyloxy-N-[4-butyl-1-(4-hydroxybenzyl)-2-oxopyrrolidin-3-yl-methyl]formamide (0.1 g, 0.24 mmol) in tetrahydrofuran (3 mL) under argon was added furan-2-yl-methanol (0.041 mL, 0.048 mmol) and triphenylphosphine (0.07 g, 0.27 mmol). The solution was cooled to 0° C. and diethyl azodicarboxylate (0.042 mL, 0.27 mmol) was added dropwise. The reaction mixture was warmed up to rt and stirred overnight. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with dichloromethane (3×10 mL). The combined extractions were dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate/hexanes 1:1) to afford (+/−)-(3RS,4SR)-N-benzyloxy-N-{4-butyl-1-[4-(furan-2-yl- methoxy)benzyl]-2-oxopyrrolidin-3-yl-methyl}formamide as a colorless oil (0.075 g, 63%). MS(ES) m/e 491 [M+H]+.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3](O)[CH2:2]1.ClC(F)C(N(CC)CC)(F)F.C(O)C>CN(C)C=O>[CH3:16][C:15]1[C:13](=[O:14])[N:12]=[C:10]2[N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([O:11]2)[CH2:2]3)[CH:17]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CCN(CC)C(F)(F)C(F)Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Temperature: 70 °C
Yield: 60.3 %

Procedure:
Thymidine (85.4 g; 0.353 mol) was dissolved in 500 mL dry DMF (dimethyl formamide) and added to N-(2-chloro-1,1,2-trifluoroethyl)diethylamine (100.3 g; 0.529 mol) [prepared according to the method of D. E. Ayer, J. Med. Chem. 6, 608 (1963)]. This solution was heated at 70° C. for 30 minutes then poured into 950 mL ethanol with vigorous stirring. The product precipitated from this solution and was filtered. The ethanol supernatant was refrigerated then filtered to yield a total of 47.75 g (0.213 mol; 60.3%) of 2,3'-anhydrothymidine mp=228°-230° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)=[CH:4][C:3]=1[O:22][CH3:23].C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]([CH3:33])=[CH2:32]>C(O)C>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:32][C:31]([CH3:33])=[CH2:30])[CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: C=C(C)CCl
Reactant: COc1ccc(CC2NCCc3cc(OC)c(O)cc32)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C=C(C)CN1CCc2cc(OC)c(O)cc2C1Cc1ccc(OC)c(O)c1
Reaction time: 3 h

Procedure:
5.7 g. (18.07 mmol) (-)-7-Hydroxy-1-(3-hydroxy-4-methoxybenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and 3.7 g. (44 mmol) sodium bicarbonate in 120 ml. ethanol are mixed with 1.76 ml. (1.64 g., 18,07 mmol) 3-chloro-2-methylprop-1-ene. The mixture is allowed to react for 30 minutes at ambient temperature and thereafter for 3 hours at 80° C., while stirring. The usual working up and chromatographic purification on silica gel with chloroform as elution agent gives (+)-7-hydroxy-1-(3-hydroxy-4-methoxybenzyl)-6-methoxy-2-(2-methylprop-2-enyl)-1,2,3,4-tetrahydroisoquinoline in the form of a TLC-uniform yellowish foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]([OH:26])[C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23].[H-].[Na+].I[CH3:30]>CN(C=O)C.CCOC(C)=O>[CH3:24][C:21]([CH3:25])([CH2:22][CH3:23])[CH:20]([C:11]1[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])[O:26][CH3:30]
Reactant: CCC(C)(C)C(O)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(C)(C)C(OC)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of 66.62A (0.39 g, 1.1 mmol) in DMF (5 mL), was added NaH (0.034 g, 1.4 mmol). The mixture was stirred at room temperature for 10 minutes and then iodomethane (0.20 mL, 3.2 mmol) was added. The mixture was stirred at room temperature for 60 minutes and then it was diluted with EtOAc, washed with water and brine, and dried over anhydrous Na2SO4. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:9 EtOAc/hexane) and gave 66.62B, colorless oil, in 64% yield (260 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C=O)C.C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][C:2]2[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(O)c(CO)n1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C)nc2CO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
1.39 g (10 mmol) of the commercial 3-hydroxy-6-methyl-2-pyridinemethanol in 15 ml DMF was cooled (0° C.), treated with 0.52 g (13.00 mmol) of NaH (55% in oil) and after 30 min, with 1.35 mL (10.00 mmol) p-methoxybenzylchlorid. The suspension was stirred 1 h at 0° C. and 2 h at RT. The reaction mixture was diluted with CH2Cl2 and washed with 1M NaOH and brine. The organic layers were dried over magnesium sulfate, evaporated, purified by silica gel column (AcOEt) and crystallized (AcOEt/n-n-heptane) to give 1.55 g (60%) of the title compound as a white solid. MS: 260.0 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[N:6]=[C:5](F)[C:4]=1[F:12].[CH3:13][O-:14].[Na+].O>CO>[OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[N:6]=[C:5]([O:14][CH3:13])[C:4]=1[F:12]
Reactant: C[O-]
Reactant: OCc1c(F)c(F)nc(F)c1F
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(F)c(F)c(CO)c1F
Yield: 80 %

Procedure:
A mixture of 1.0 g (0.0055 mole) of 4-hydroxymethyl-2,3,5,6-tetrafluoropyridine (from Example 5) and 0.30 g (0.0055 mole) of sodium methoxide in 25 ml of methanol was refluxed for approximately twenty hours. After being cooled, the reaction mixture was poured into water. The aqueous solution was extracted with diethyl ether. The diethyl ether extract was dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure, yielding 0.85 g of 4-hydroxymethyl-2-methoxy-3,5,6-trifluoropyridine as a yellow oil. The structure and nmr spectra are set forth in Table 1C below.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.O.[C:11]1(C)[CH:16]=[CH:15][C:14]([S:17](O)(=O)=O)=[CH:13][CH:12]=1.C1(S)C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5]([S:17][C:14]2[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Sc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CC=C(Sc2ccccc2)CC1

Procedure:
A stirred solution of 4,4-dimethylcyclohexanone (1 g.), p-toluene sulphonic acid monohydrate (23 mg.) and thiophenol (0.81 ml.) in toluene (24 ml.) was heated at reflux for 9 hours with azeotropic removal of water using a Dean and Stark apparatus. The mixture was cooled, diluted with toluene (25 ml.) and extracted with saturated sodium bicarbonate solution (2×10 ml.), washed with water (3×10 ml.) and dried (MgSO4). Evaporation of the solvent gave (4,4-dimethylcyclohex-1-enyl)phenylsulphide as an oil (1.66 g.); NMR (CDCl3,90 MHz): 0.94 (6H,s), 1.45 (2H,t), 1.98 (2H,m), 2.18 (2H,m), 6.02 (1H,m) and 7.3 (5H,m).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O.C(Cl)(Cl)(Cl)Cl>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: C=C(C)C(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 57.9 %

Procedure:
4.2 g (0.03 mole) of 3-amino-5-t-butylpyrazole as prepared in Example 1 was dissolved in 50 ml of water, and 3.2 g of sodium carbonate was added thereto. To the resulting aqueous solution was added dropwise 3.2 g of methacryloyl chloride dissolved in 20 ml of carbon tetrachloride at 0° C. while cooling with ice for one hour. The reaction mixture was placed at room temperature (i.e., about 20° to 30° C.), followed by filtration and washing with water to obtain 3.6 g of 5-t-butyl-3-methacryloylaminopyrazole. The mass analysis showed the presence of a molecular ion peak at 207.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9](C(OCC)=O)[C:10](=[O:12])[NH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[K+].IC[CH2:22][CH2:23][C:24]([CH3:29])([N+:26]([O-:28])=[O:27])[CH3:25]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:8]2[NH:9][C:10](=[O:12])[N:11]([CH2:22][CH2:23][C:24]([CH3:29])([N+:26]([O-:28])=[O:27])[CH3:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)n1c(=O)[nH]c2cccc(OC)c21
Reactant: CC(C)(CCCI)[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1[nH]c(=O)n2CCC(C)(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.0 g (17 mmol) ethyl 7-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-carboxylate in DMF are combined with 85% potassium hydroxide solution (3.3 g, 51 mmol) while being cooled with the ice bath. After 30 minutes a solution of 5.2 g (21 mmol) 1-iodo-4-methyl-4-nitro-pentane in DMF is added and the mixture is stirred overnight at ambient temperature. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with water, dried and freed from the solvent. The oil remaining is purified by chromatography on a silica gel column (cyclohexane/ethyl acetate gradient). Yield: 0.5 g (8%); mass spectroscopy: [M+H]+=366.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=[O:14])[CH:8]=2)[C:3]=1[C:16]([NH2:18])=[O:17].[H][H]>CO.[Pt]=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][OH:14])[CH:8]=2)[C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: [H][H]
Reactant: NC(=O)c1c(-c2cccc([N+](=O)[O-])c2)nsc1N
Agent: O=[Pt]
Solvent: CO
Product: NC(=O)c1c(-c2cccc(NO)c2)nsc1N
Reaction time: 67 h
Yield: 67.3 %

Procedure:
A mixture of 5-amino-3-(3-nitrophenyl)isothiazole-4-carboxamide (50 mg, 0.19 mmol) and platinum oxide (20 mg, 0.088 mmol) in 5 mL MeOH was hydrogenated under 60 PSI hydrogen. After 5 hours an additional catalytic amount of platinum oxide was added and the reaction continued for 67 hours. The reaction mixture was filtered using Celite and the filter bed rinsed with 40% MeOH/CHCl3. The filtrate was evaporated to give 32 mg of yellow solid. Then 22 mg of this material was chromatographed eluting with CHCl3/MeOH to give the title compound as a pale yellow solid (10.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[NH:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:13])[C:6]=1[N:5]([C:18](=[O:19])[CH2:17][O:16][CH3:15])[NH:4][C:3]([O:2][CH3:1])=[O:14]
Reactant: COC(=O)NNc1c(C)cccc1C
Reactant: COCC(=O)Cl
Solvent: ClCCl
Product: COCC(=O)N(NC(=O)OC)c1c(C)cccc1C
Temperature: 25 °C

Procedure:
3 g of methyl-3-(2,6-dimethylphenyl)-carbazate were dissolved in 40 ml of methylene chloride (CH2Cl2). While stirring at room temperature, 1.7 g of methoxyacetyl chloride were gradually dropped into the solution. The reaction mixture was stirred at room temperature for 3 hours. It was then washed with 20 ml of H2O, 30 ml of a solution of NaHCO3 at 5% and 30 ml of H2O. It was anhydrified on anhydrous Na2SO4 and the solvent was removed by evaporation.