Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[C:15]([C:16](Cl)=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]2[NH:26][N:27]=[N:28][C:24]=2[CH:23]=1.CN(C)C1C=CC=CC=1.O>O1CCCC1>[NH:26]1[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:16](=[O:17])[C:15]3[CH:19]=[C:11]([N:10]=[N:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH:12]=[CH:13][C:14]=3[OH:20])=[CH:23][C:24]=2[N:28]=[N:27]1
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Reactant: Nc1ccc2[nH]nnc2c1
Solvent: O
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)Nc3ccc4[nH]nnc4c3)c2)cc1

Procedure:
5-(4-Methoxyphenylazo)salicoyl chloride (1.46 g) in dry tetrahydrofuran (10 ml) was added dropwise with stirring to a solution of 5-aminobenzotriazole (0.67 g) in dry tetrahydrofuran (15 ml) and dimethylaniline (0.61 g). After 2-3 hours the mixture was poured into water and the solid removed by filtration. The product was crystallized in aqueous pyridine as yellow plates of the monohydrate (1.5 g, 81%), m.p. 275°-6°, λmax (methanol)=352 nm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:26][C:27]([O:29][CH:30]1[CH:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][CH:32]([CH3:39])[CH2:31]1)=[O:28]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]([C:15]#[N:16])([CH2:26][C:27]([O:29][CH:30]1[CH:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][CH:32]([CH3:39])[CH2:31]1)=[O:28])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC1CCC(C(C)C)C(OC(=O)CCl)C1
Reactant: CCOC(=O)C(C#N)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C#N)(CC(=O)OC1CC(C)CCC1C(C)C)NC(=O)OC(C)(C)C
Temperature: 15 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
Ethyl 2-(tert-butoxycarbonylamino)-2-cyanoacetate (1.20 g, 526 mmol) prepared in the same manner as Reference Example 1, acetone (2.3 ml), powdered potassium carbonate (872 mg, 6.31 mmol) and potassium iodide (175 mg, 1.05 mmol) were mixed, a solution of menthyl chloroacetate (1.22 g, 5.26 mmol) dissolved in acetone (1.1 ml) was added dropwise thereto at 10-20° C., and the mixture was stirred at the same temperature overnight. Insoluble materials were removed by filtration, the filtrate was concentrated in vacuo and toluene was added to the residue. The organic layer was washed with water and concentrated in vacuo to give ethyl 2-(tert-butoxycarbonylamino)-2-cyano-3-[(−)menthyloxycarbonyl]propionate (1.10 g, yield 49.3%) as a yellow oil.
Reaction SMILES: [C:1]([C:4]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(O)=[O:2].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[OH:2][CH2:1][C:4]1([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]1
Reactant: O=C1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(CO)(c2ccc(Cl)cc2)CC1
Reaction time: 6 h
Yield: 99 %

Procedure:
A solution of 19.26 g. (0.065 mole) of 4-carboxy-4-(4-chlorophenyl)cyclohexanone, ethylene ketal (prepared in Example 25) in 320 ml. of tetrahydrofuran is added to 5.9 g. (0.155 mole) of lithium aluminum hydride in 85 ml. of tetrahydrofuran. Following about 6 hours of heating at reflux, the mixture is cooled in ice and treated successively with 6 ml. of water, 6 ml. of 15% sodium hydroxide solution and 18 ml. of water. The resulting inorganic gel is collected on a filter and rinsed with ether. The combined filtrates are evaporated to dryness to give 19.23 g. (99% yield) of 4-hydroxymethyl-4-(4-chlorophenyl)cyclohexanone, ethylene ketal as an amorphous gum.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][N:20]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH2:13]OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:35].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][N:20]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH2:13][F:35])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: CS(=O)(=O)OCC1(CN(Cc2ccccc2)Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: FCC1(CN(Cc2ccccc2)Cc2ccccc2)CCN(Cc2ccccc2)C1
Reaction time: 16 h

Procedure:
A solution of 1-benzyl-3-(dibenzylaminomethyl)-3-mesyloxymethylpyrrolidine (6.90 g) in acetonitrile (70 ml) was added to 1N tetrabutylammonium fluoride in tetrahydrofuran (72 ml), and the mixture was starred at 40° C. for 16 hours. After concentration, the concentrate was poured into water (200 ml), and the mixture was made alkaline with aqueous ammonia and extracted with ether. The ether layer was washed with water, dried, concentrated and purified by silica gel column chromatography to give 4.37 g of the object compound as an oil.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C(=O)([O-])O.[Na+]>C(O)C>[Br:18][C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:1]=[C:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:11]=2)[CH:14]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc2nc(-c3ccccc3)cn2c1
Yield: 80.8 %

Procedure:
Dissolving 5.8 g (29 mmol) of phenacyl bromide and 5.0 g (29 mmol) of 2-amino-5-bromopyridine into 50 milliliter of ethanol, adding 3.6 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and ethanol, thereby obtaining 6.4 g of 6-bromo-2-phenyl-imidazo [1,2-a] pyridine (yield: 81%).
Reaction SMILES: [N+]([C:4]1[C:5](=O)[N:6](C)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.N.[CH3:16][N:17]1[CH2:22]CC(=O)[CH2:19][CH2:18]1>CO>[CH3:16][N:17]1[CH2:18][CH2:19][C:5]2[N:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[CH2:22]1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CN1CCC(=O)CC1
Agent: N
Solvent: CO
Product: CN1CCc2ncc([N+](=O)[O-])cc2C1
Reaction time: 72 h
Yield: 58.7 %

Procedure:
3,5-Dinitro-1-methyl-2-pyridone (5.97 g; 30 mmol) was treated with 1.22M ammonia in methanol (300 ml) then 1-methyl-4-piperidone (3.73 g, 33 mmol) and the mixture heated at 60° for 5 h, then allowed to stand at ambient temp for 72 h. Evaporation in vacuo gave an orange/red residue which was triturated in dichloromethane and diethyl ether, collected by filtration, washed with diethyl ether and dried in air. Chromatography through silica gel, eluting with ethyl acetate, gave the title compound as a red solid (3.4 g, 59%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[C:28]([NH2:31])(=[O:30])[CH3:29]>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([NH:31][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CC(N)=O
Product: CC(=O)Nc1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 72.7 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 186 and acetamide (89 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (294 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[Cl:18])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Nc1cc(NC(=O)c2ccnc(N3CCOCC3)c2)ccc1Cl
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
Using an analogous procedure to that described in Example 2, except that the reaction mixture was heated to 80° C. for 5 hours, 2-chloropyridine-4-carbonyl chloride was reacted with N-(3-amino-4-chlorophenyl)-2-morpholinopyridine-4-carboxamide to give the title compound in 95% yield; NMR Spectrum: (DMSOd6) 3.53 (m, 4H), 3.75 (m, 4H), 7.11 (d, 1H), 7.27 (s, 1H), 7.56 (d, 1H), 7.73 (d, 1H), 7.88 (d, 1H), 7.98 (s, 1H), 8.06 (s, 1H), 8.26 (d, 1H), 8.64 (d, 1H), 10.53 (m, 2H); Mass Spectrum: M+H+ 472.
Reaction SMILES: [O:1]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H][H]>C(O)C.[Pd]>[O:1]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][NH:14]2)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ncccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCCN2
Temperature: 25 °C
Yield: 81.9 %

Procedure:
5-(t-butyldimethylsiloxy)quinoline (1715 mg) was dissolved in ethanol (50 ml), and the air in a reactor was substituted by argon. 10% Pd—C (100 mg) was added to the resultant solution, and the mixture was stirred at room temperature in the reactor in which the atmosphere was replaced by hydrogen. After disappearance of the raw materials was confirmed, the solid was filtered off, and the filtrate was concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=10/1) to obtain the object compound (1426 mg, yield 82%).
Reaction SMILES: Cl[C:2]1[C:3]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CCO>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:3]3[S:11][C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH2:19][CH2:18]1
Reactant: Nc1nc(Cl)c2sc3ccccc3c2n1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(c2nc(N)nc3c2sc2ccccc23)CC1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A solution of crude 4-chloro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine (30 mg, 0.13 mmol) and N-methyl piperizine (0.03 mL, 0.27 mmol) in EtOH was heated at 70° C. for 1 h. The mixture was cooled to rt and concentrated and the crude residue purified by FCC to yield a white solid (9.8 mg, 26%). MS: 300.4. 1H NMR (CDCl3): 8.34-8.27 (m, 1H), 7.81-7.75 (m, 1H), 7.57-7.51 (m, 1H), 7.48-7.43 (m, 1H), 4.85 (s, 2H), 3.98 (t, J=4.9 Hz, 4H), 2.56 (t, J=4.9 Hz, 4H), 2.37 (s, 3H).
Reaction SMILES: [N:1]1([C:5]2[C:10]([CH:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:28])[C:17]=3[C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)[OH:12])=[C:9]([Cl:29])[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[N:1]1([C:5]2[C:10]([C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:28])[C:17]=3[C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][N:19]=3)=[O:12])=[C:9]([Cl:29])[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ncc(C(O)c2c(Cl)ncnc2N2CCC2)c1-c1ccc(C(F)(F)F)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cn1ncc(C(=O)c2c(Cl)ncnc2N2CCC2)c1-c1ccc(C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of [4-(azetidin-1-yl)-6-chloropyrimidin-5-yl]{1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (C15) (30 mg, 0.071 mmol) in dichloromethane (3 mL) was cooled to 0° C. and Dess-Martin periodinane (33.1 mg, 0.078 mmol) was added portion-wise. After completion of the addition, the reaction mixture was stirred for 1 hour at 0° C., then warmed to room temperature and stirred for an additional 18 hours. The reaction mixture was diluted with dichloromethane, and then quenched with aqueous sodium bicarbonate solution (1 mL) and aqueous sodium thiosulfate solution (1 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Chromatographic purification using silica gel [Gradient: 0% to 100% (95:2.5:2.5 ethyl acetate/methanol/triethylamine) in heptane] afforded the product. Yield: 29 mg, 0.069 mmol, 97%. LCMS m/z 423.1, 425.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.30-2.39 (m, 2H), 3.78 (s, 3H), 3.99-4.07 (m, 4H), 7.89 (d, J=8.2 Hz, 1H), 8.00-8.13 (m, 3H), 8.72 (br s, 1H).
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:19][CH3:20])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)C=CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/C(=O)c1ccccc1
Temperature: 85 °C
Reaction time: 0.67 h

Procedure:
A mixture of 3.00 g of β-benzoylacrylic acid (cis/trans =1/2 according to 1H NMR analysis), 10 ml of ethanol and 0.63 g of sulfuric acid was refluxed for 2 hours. A pressure was gradually reduced with the aspirator and ethanol was distilled away for 10 minutes. After a pressure was finally reduced to 20 mmHg, the resultant was stirred at 85° C. for 40 minutes and then cooled, followed by the procedure as in Example 1 to give 2.45 g of ethyl trans-β-benzoylacrylate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23][CH3:24])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:31](I)([CH3:33])[CH3:32].O>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:31]([CH3:33])[CH3:32])=[C:18]([S:23][CH3:24])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(O)c(SC)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC(C)C)c(SC)c1
Yield: 62.8 %

Procedure:
A suspension of the ethyl (RS)-(4-cyano-phenylamino)-(4-hydroxy-3-methylsulphanyl-phenyl)-acetate (198 mg, 0.58 mmol) described in Example 168.1, Cs2CO3 (227 mg, 0.64 mmol) and isopropyl iodide (58 μl, 0.58 mmol) in acetone (3 ml) was heated under reflux for 4 h. Water was added and the mixture was extracted with CH2Cl2. Die organic phase was dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 2:1). Ethyl (RS)-(4-cyano-phenylamino)-(4-isopropoxy-3-methylsulphanyl-phenyl)-acetate (140 mg, 63%) was obtained as a colorless oil; MS: 443 ([M+OAc]−).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]#[C:6][C:7]([CH3:14])([O:9][Si](C)(C)C)[CH3:8])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]#[C:6][C:7]([OH:9])([CH3:8])[CH3:14])[CH3:2]
Reactant: CCOC(=O)C#CC(C)(C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Product: CCOC(=O)C#CC(C)(C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 4-methyl-4-trimethylsilanyloxy-pent-2-ynoic acid ethyl ester (5.4 g, 23.7 mmol) in ethyl ether (50 mL) was added tetrabutylammonium fluoride (TBAF) (7.42 g, 28.4 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with H2O, and extracted with ethyl ether. The organic phase was washed with brine, dried (Na2SO4) and concentrated to afford 3.51 g of 4-hydroxy-4-methyl-pent-2-ynoic acid ethyl ester as yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8]2[C:9]([C:19]([OH:21])=O)=[N:10][C:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:12][N:13]=2)[CH:4]=[N:3][CH:2]=1.[CH3:22][NH:23][C:24]([C:26]1[N:27]([CH3:32])[N:28]=[CH:29][C:30]=1[NH2:31])=[O:25]>>[CH3:32][N:27]1[C:26]([C:24](=[O:25])[NH:23][CH3:22])=[C:30]([NH:31][C:19]([C:9]2[C:8]([NH:7][C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[N:13][CH:12]=[C:11]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[N:10]=2)=[O:21])[CH:29]=[N:28]1
Reactant: O=C(O)c1nc(N2CCCC2)cnc1Nc1cncnc1
Reactant: CNC(=O)c1c(N)cnn1C
Product: CNC(=O)c1c(NC(=O)c2nc(N3CCCC3)cnc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 3-(pyrimidin-5-ylamino)-6-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (30 mg, 94 μmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (19 mg, 123 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (10 mg, 26%).
Reaction SMILES: [NH2:1][C:2]([O:9][CH:10]([CH3:12])[CH3:11])=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].OO>C(O)(C)C>[NH2:5][C:4]1[S:6][N:1]=[C:2]([O:9][CH:10]([CH3:12])[CH3:11])[C:3]=1[C:7]#[N:8]
Reactant: CC(C)OC(N)=C(C#N)C(N)=S
Agent: OO
Solvent: CC(C)O
Product: CC(C)Oc1nsc(N)c1C#N
Yield: 89.1 %

Procedure:
In the manner of Example V C, 123 g of 3-amino-2-cyano-3-isopropoxy-2-propenethioamide in 500 ml of isopropanol were treated with 80 ml of 30% hydrogen peroxide (22.6 g of active H2O2). The residue from the reaction was recrystallized from toluene to yield 108.4 g of 5-amino-4-cyano-3-isopropoxyisothiazole, mp 146°-148°. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].I.[NH:10]([C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[NH2:11].[OH-].[K+].[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]\[C:22]([OH:24])=[O:23]>CCOCC.C(Cl)Cl.C1C=CC=CC=1.C(O)C>[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]\[C:22]([OH:24])=[O:23].[CH3:1][C:2]1[N:11]([NH:10][C:12]2[NH:16][CH2:15][CH2:14][N:13]=2)[C:5]([CH3:6])=[CH:4][CH:3]=1
Reactant: NNC1=NCCN1
Reactant: CC(=O)CCC(C)=O
Agent: I
Agent: O=C(O)/C=C\C(=O)O
Agent: [K+]
Solvent: CCO
Solvent: c1ccccc1
Solvent: ClCCl
Product: Cc1ccc(C)n1NC1=NCCN1
Temperature: 25 °C

Procedure:
To a boiling solution of 8.63 g. (0.0756 mole) of 2,5-hexanedione in 50 ml. of absolute ethanol, a solution of 14 g. (0.0614 mole) of 2-hydrazino-4,5-dihydro-1H-imidazole hydroiodide and 3.47 g. (0.0620 mole) of potassium hydroxide in 120 ml. of absolute ethanol and 60 ml. of anhydrous benzene is quickly added. The mixture is stirred under reflux for 30 minutes and at room temperature for 12 hours. The potassium iodide which forms is cast off by filtration, then the mixture is concentrated to small volume by evaporating off the solvent. A residue is obtained which is dissolved with methylene chloride. To the obtained solution an ether solution of maleic acid is added and a precipitate readily forms, which is recrystallized two times from absolute ethanol. Yield 1.3 g. M.p. 177°-8°C. The free base melts at 192°-3°C (from methanol.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:15]([CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][C@H:11]([O:12][CH3:13])[C@@H:10]1[OH:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:31][C@@H:10]1[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@:15]([CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:14][CH:11]1[O:12][CH3:13])(=[O:34])[CH3:33]
Reactant: CO[C@H]1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.8 %

Procedure:
To a stirred solution of 201 (287 mg, 1.52 mmol) in anhydrous pyridine (4 mL) at 0° C. was added dropwise acetic anhydride (0.43 mL, 4.56 mmol). The reaction mixture was stirred for 2 days at room temperature, quenched with saturated aqueous sodium hydrogen carbonate (75 mL) and extracted with dichloromethane (150+75 mL). The combined extract was dried (MgSO4), the solvent was removed by distillation under reduced pressure and the residue was purified by chromatography over silica gel with dichloromethane as eluent to give the product 209 as a clear oil (β:α˜3:1, 750 mg, 100%); MS FAB: 463 (M−OCH3, 100%), 517 (M+Na, 28%); Found: C, 58.53; H, 6.16; C24H30O9S requires C, 58.29; H, 6.11%. Methyl 2-O-acetyl-3,5-di-O-benzyl-4-C-methanesulfonyloxymethyl-β-D-ribofuranoside (209β). 1H NMR (CDCl3): δ7.36-7.18 (10H, m, Bn, 5.27 (1H, d, J 4.9 Hz, H-2), 4.88 (1H, s, H-1), 4.55-4.44 (6H, m, H-5′, Bn) 4.35 (1H, d, J 5.0 Hz, H-3), 3.73 (1H, d, J 9.2 Hz, H-5), 3.38 (1H, d, J 9.3 Hz, H-5), 3.30 (3H, s, OCH3), 2.95 (3H, s, SO2CH3), 2.11 (3H, s, OCCH3); 13C NMR (CDCl3): δ169.91 (C═O), 137.83, 137.28, 128.49, 128.44, 127.99, 127.87, 127.77 (Bn), 105.40 (C-1), 82.65, 81.05, 74.55, 73.62, 73.56, 71.86, 70.22 (C-2, C-3, C-4, C-5, C-5′, Bn), 55.03 (OCH3), 37.14 (SO2CH3), 20.37 (OCCH3). Methyl 2-O-acetyl-3,5-di-O-benzyl-4-C-methanesulfonyloxymethyl-α-D-ribofuranoside (209α). 1H NMR (CDCl3): δ7.36-7.18 (10H, m, Bn), 5.09 (1H, d, J 4.5 Hz, H-1), 4.95 (1H, dd, J 4.5, 6.8 Hz, H-2), 4.65-4.44 (6H, m, H-5′, Bn), 4.27 (1H, d, J 6.6 Hz, H-3), 3.49 (1H, d, J 9.9 Hz, H-5), 3.46 (3H, s, OCH3), 3.36 (1H, d, J 9.9 Hz, H-5), 2.92 (3H, s, SO2CH3), 2.14 (3H, s, OCCH3); 13C NMR (CDCl3): δ170.41 (C═O), 137.59, 137.28, 128.56, 128.51, 128.49, 128.44, 127.98, 127.88 (Bn), 102.35 (C-1), 84.25, 77.53, 74.66, 73.67, 72.12, 70.39, 70.28 (C-2, C-3, C-4, C-5, C-5′, Bn), 56.07 (OCH3), 36.94 (SO2CH3), 20.63 (OCCH3).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH2:18][C:19]([NH:21][CH:22]2[C:49](=[O:50])[N:24]3[CH:25]([C:33]([O:35][CH:36]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[C:26]([CH:29]=[C:30]([Cl:32])[Cl:31])=[CH:27][S:28][C@H:23]23)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[C:12]1([CH2:18][C:19]([NH:21][CH:22]2[C:49](=[O:50])[N:24]3[C:25]([C:33]([O:35][CH:36]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[O:34])=[C:26]([CH:29]=[C:30]([Cl:31])[Cl:32])[CH2:27][S:28](=[O:9])[C@H:23]23)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C=C(Cl)Cl)=CS[C@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Cl)Cl)CS(=O)[C@H]12
Yield: 42.6 %

Procedure:
A solution of m-chloroperbenzoic acid (7 g) in ethyl acetate (35 ml) was added to a solution of benzhydryl 7-phenylacetamido-3-(2,2-dichlorovinyl)-2-cephem-4-carboxylate (15 g) in ethyl acetate (75 ml) under ice-cooling and the mixture was stirred at the same temperature for an hour. The precipitates were collected by filtration to give benzhydryl 7-phenylacetamido-3-(2,2-dichlorovinyl)-3-cephem-4-carboxylate-1-oxide (6.57 g).
Reaction SMILES: [SH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([OH:5])=O.[CH:15](=[N:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:22]1[C:3](=[O:5])[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:1][CH:15]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCCCCCCC(S)C(=O)O
Reactant: CN(C)CCN=Cc1cccnc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCN(C)C)C1=O
Reaction time: 2 h
Yield: 89.6 %

Procedure:
2-Mercaptoundecanoic acid (2 g, 9.16 mmol) and N-nicotinylidene-N',N'-dimethylethylenediamine (1.62 g, 9.16 mmol) were dissolved in toluene (50 ml), and subjected to azeotropic dehydration for 2 hours. The solvent was removed from the product mixture by evaporation under reduced pressure The residue was purified by column chromatography, giving 3-(2-dimethylaminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (3.1 g, 90% yield).