Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O.[NH2:10][NH2:11]>CO>[NH:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1)[NH2:11]
Reactant: Clc1cccc(Cl)n1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNc1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2 g of 2,6-dichloropyridine were dissolved in 60 ml of methanol and mixed with 10 ml of 80% hydrazine hydrate. The solution was firstly stirred for 3 days at room temperature and then refluxed for 10 days. Rotation in took place, the residue was taken up with methanol, followed by rotation in again and finally recrystallization from methanol/water. 0.25 g of 2-hydrazino-6-chloropyridine was obtained.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][O:10][C:8]2[CH:9]=[C:4]([CH:5]=[C:6]([O:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)[CH:7]=2)[C:3]([OH:44])=[O:2])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(OCCCOc2ccc(-c3ccccc3)cc2)cc(OCCCOc2ccc(-c3ccccc3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cc(OCCCOc2ccc(-c3ccccc3)cc2)cc(OCCCOc2ccc(-c3ccccc3)cc2)c1
Yield: 88.7 %

Procedure:
A solution of 1.5 g (2.55 mmol) of 3,5-bis[3-(1,1'-biphenyl-4-yloxy)propoxy]benzoic acid methyl ester and 15 mL (15 mmol) of 1N NaOH in 45 mL of methanol and 40 mL of dioxane was stirred at reflux for 6 hours. The reaction mixture was concentrated at reduced pressure, the residue was acidified and the product was filtered and recrystallized from ethyl acetate to give 1.3 g (89% yield, mp 186°-187°) of 3,5-bis[3-(1,1'-biphenyl-4-yloxy)propoxy]benzoic acid.
Reaction SMILES: [N:1]1([CH2:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>CC(C)=O>[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[O:9])[CH2:2][CH2:3]1)=[O:32]
Reactant: O=C1Cc2cc(C(=O)CN3CCNCC3)ccc2N1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1Cc2cc(C(=O)CN3CCN(C(=O)c4cccc(Cl)c4)CC3)ccc2N1
Temperature: 0 °C

Procedure:
To a suspension comprising 1.0 g of dihydrochloric acid salt of 5-[2-(1-piperazinyl)acetyl]oxindol, 0.63 gof potassium carbonate, 5 ml of water and 10 ml of acetone was added dropwise a solution of 0.63 g of m-chlorobenzoyl chloride in 2 ml of acetone under ice-cooling with stirring, and the mixture was stirred for 1.5 hours at the same temperature. After completion of reaction, the reaction mixture was poured into ice-water and extracted with chloroform. The chloroform layer was washed, in turn, with water and a saturated saline solution, and dried over sodium sulfate. The solvent was then distilled off under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent: chloroform:methanol=20:1) and recrystallized from a mixture of ethanol and chloroform to give 0.34 g of 5-[2-[4-(3-chlorobenzoyl)-1-piperazinyl]acetyl]oxindol.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([CH2:39][NH:40][C:41](=[O:45])[CH2:42][NH:43][CH3:44])[CH2:4][CH2:3]2.C=O.[C:48](O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:44][N:43]([CH3:48])[CH2:42][C:41]([NH:40][CH2:39][C@:5]12[CH2:35][CH2:34][C@@H:33]([C:36]([CH3:38])=[CH2:37])[C@@H:6]1[C@@H:7]1[C@@:2]([CH3:1])([CH2:3][CH2:4]2)[C@@:19]2([CH3:20])[C@@H:10]([C@:11]3([CH3:32])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)=[O:45]
Reactant: CC(=O)O
Reactant: C=C(C)[C@@H]1CC[C@]2(CNC(=O)CNC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(CNC(=O)CN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylamino)acetamido)methyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, example 139, (10 mg, 0.016 mmol) and formaldehyde (0.488 mg, 0.016 mmol) in MeOH (1 ml) was added acetic acid (1.860 mL, 0.033 mmol) and sodium cyanoborohydride (1.022 mg, 0.016 mmol). A clear solution was formed soon after mixing. The mixture was stirred at rt for 2 h, LC/MS showed the mass of the expected product. The mixture was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to afford the title compound as a white solid (2 mg, 18.6%). LCMS: m/e 629.4 (MH+), 2.72 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.90 (d, J=8.6 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 5.19-5.42 (m, 1H), 4.72 (d, J=1.8 Hz, 1H), 4.59 (s, 1H), 3.93 (s, 2H), 3.58 (br. s., 1H), 3.04-3.17 (m, 1H), 2.89 (s, 6H), 2.46-2.60 (m, 1H), 2.10-2.18 (m, 2H), 1.80 (br. s., 2H), 1.65-1.77 (m, 7H), 1.63 (s, 1H), 1.58 (br. s., 2H), 1.38-1.55 (m, 4H), 1.19-1.34 (m, 4H), 1.13-1.19 (m, 4H), 1.06-1.13 (m, 2H), 1.04 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: COC(=O)CCCCN
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCCCNC(=O)c1sc2ccc(OC)cc2c1OC(C)C
Temperature: 0 °C
Yield: 69.8 %

Procedure:
A solution of 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (500 mg, 2.00 mmoles) and 1,1'-carbonyldiimidazole (421 mg, 2.60 mmoles) in 20 mL of tetrahydrofuran is heated at reflux for 1 hour. After cooling to 0° C., the HCl salt of methyl 5-aminovalerate (787 mg, 4.7 mmoles) is added followed by triethylamine (836 μL, 6.0 mmoles). The mixture is heated at reflux overnight. The mixture is partitioned between ethyl acetate and 1N HCl. The organic layer is washed with 1N HCl, saturated NaHCO3, then brine. The organic layer is next dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography, eluting with 1:9 ethyl acetate:hexane to provide 530 mg (70%) of product; mp 82°-84° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[N+:10]([CH:13]([CH3:15])[CH3:14])([O-:12])=[O:11]>CO>[N+:10]([C-:13]([CH3:15])[CH3:14])([O-:12])=[O:11].[CH2:2]([NH3+:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CC(C)[N+](=O)[O-]
Reactant: CCCCCCCCN
Solvent: CO
Product: CCCCCCCC[NH3+]
Product: C[C-](C)[N+](=O)[O-]
Temperature: 40 °C
Yield: 97.6 %

Procedure:
Into a flask, 129 g (1.0 mole) of 1-aminooctane and 100 ml of methanol were charged, and then 89 g (1.0 mole) of 2-nitropropane were dropped into the flask maintained at about 40° C over a period of about 30 minutes. After that, upon maintaining the mixture at the same temperature for 30 minutes, crystals were precipitated to give slurry. The reaction mixture was cooled to a temperature of 5° C and then filtered. The filtered precipitates were washed with 30 ml of cold methanol and dried under reduced pressure to obtain 213 g of 1-octylammonium 2-nitropropan-2-ide with a yield of 97.7%.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][C:13]([C:17]#[N:18])=[N:14]2)=[CH:9][CH:8]=1)[CH:5]=C.CSC>C(OCC)(=O)C>[O:1]=[CH:5][CH2:4][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][C:13]([C:17]#[N:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc2c(-c3ccccc3)cc(C#N)nc2c1
Solvent: CSC
Solvent: CCOC(C)=O
Product: N#Cc1cc(-c2ccccc2)c2ccc(CC=O)cc2n1
Reaction time: 1 h

Procedure:
Ozone was bubbled into a solution of 7-allyl-4-phenylquinoline-2-carbonitrile (1.5 g, 5.6 mmol) in ethyl acetate (100 mL) at −78° C. for 1.5 h. Nitrogen was then bubbled into the solution and methylsulfide (2.1 mL, 28 mmol) was added. The reaction was brought back to room temperature, stirred for 1 h and concentrated to give the title compound. MS (+ESI): 273 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].C[O-].[Na+].[C:17](=[O:19])=[O:18]>>[CH:10]([C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:13])[C:17]([OH:19])=[O:18])([CH3:12])[CH3:11]
Reactant: O=C=O
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: C[O-]
Agent: [Na+]
Product: CC(C)c1cc(C(=O)O)cc(C(C)C)c1O

Procedure:
treating 2,6-diisopropylphenol with sodium methoxide and carbon dioxide to produce 3,5-diisopropyl-4-hydroxybenzoic acid;
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1COCC1.C(OC(=O)C)C>[Si:10]([O:8][CH:5]1[CH2:6][CH2:7][CH:3]([OH:9])[CH2:4]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: OC1CCC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
Sodium Hydride (3.77 g, 0.094 mol, 60% in mineral oil) was added to a solution of 1,3-cyclopentanediol (9.62 g, 0.094 mol) in 100 mL of THF. A slight generation of gas was observed. After stirring at room temperature for 1 h, tert-butyldimethylsilyl chloride (14.2 g, 0.094 mol) was added and the mixture was stirred at room temperature over night. The reaction mixture was diluted with 500 mL of ethylacetate and washed with 125 mL of 10% K2CO3, brine, and dried over Na2SO4. The solution was concentrated and dried in vacuo to give 20.3 g of crude product as a colorless oil. Further purification over SiO2 using a gradient elution 5% EtOAc/hexanes to 10% EtOAc/hexanes provided the desired compound as a colorless oil (7.1 g, 35% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:18][C:17]=1[C:26]([O:28][CH3:29])=[O:27].O>CN(C)C=O>[CH2:7]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:18][C:17]=1[C:26]([O:28][CH3:29])=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: CCC(=O)c1ccc(O)c(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Temperature: 60 °C

Procedure:
38 g of potassium carbonate and 12.65 ml, (14 g) of benzyl chloride are added to 20.8 g of 4'-hydroxy-3'-methoxycarbonylpropiophenone in 100 ml of dimethylformamide. The mixture is heated at 60° C. for 4 hours, with stirring. It is then poured into iced water, the mixture is extracted with ethyl acetate and the organic phase is washed with water, dried and evaporated to dryness. The residual oil crystallises on trituration with pentane. The crystals are filtered off and recrystallised from ethanol. 18 g of crystals melting at 76°-78° C. are collected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([C:14]#[N:15])=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:14]#[N:15])[N:8]=1
Reactant: COc1ccc2c(=O)[nH]c(C#N)c(-c3ccccc3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
A mixture of 6-methoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile (200 mg) and POCl3 (10 mL) was heated to 90 C for 18 h. The reaction was concentrated, and the residue was dissolve in EtOAc, cooled to 0 C, and quenched by careful addition of saturated aqueous sodium bicarbonate. The mixture was partitioned between saturated aqueous sodium bicarbonate and EtOAc. The aqueous solution was washed twice with EtOAc. The combined organic solutions were dried (Na2SO4) and concentrated. Flash chromatography (25 g silica, 3-30% EA/hex) gave a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C1C=CC=CC=1>[CH2:14]([NH+:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15].[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:31](=[O:32])[NH:30][C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=3)[C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1=NN(c2ccccc2)C(=O)C1C(=O)Nc1ccc([N+](=O)[O-])cc1
Product: CC[NH+](CC)CC

Procedure:
The suspension of 3.0 g of 1-phenyl-3-methyl-2-pyrazolin-5-one in 60 ml benzene is treated with 2.0 g of triethylamine, warmed until dissolution and combined with 2.8 g of p-nitrophenylisocyanate in 30 ml of benzene while stirring. After standing for several hours at room temperature, it is filtered and the residue washed with benzene to yield the 1-phenyl-3-methyl-4-(p-nitrophenylcarbamoyl)-2-pyrazolin-5-one triethylammonium salt melting at 185°-192°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].CN(C=O)C.CCN=C=NCCCN(C)C.Cl>O>[C:21]([CH2:23][C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)=[CH:6][CH:7]=1)=[O:25])#[N:22]
Reactant: COC(=O)c1ccc(CCCc2ccc(N)cc2)cc1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCc2ccc(NC(=O)CC#N)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
To a mixture of 16.0 g of methyl 4-[3-(4-aminophenyl)propyl]benzoate, 7.70 g of cyanoacetic acid, and 50 mL of DMF was added 17.1 g of EDCI/hydrochloride under ice-cooling. After stirring at room temperature for 18 hours, to the reaction mixture was added 200 mL of water at room temperature. After vigorous stirring at room temperature for 30 minutes, the precipitate was collected by filtration to obtain 19.3 g of methyl 4-(3-{4-[(cyanoacetyl)amino]phenyl}propyl)benzoate as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:9]2[CH2:11][CH2:10]2)[C:6]=1[C:7]#[N:8].[CH3:12][N:13]=[C:14]=[O:15].C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(COC)OC>[C:7]([C:6]1[C:5]([CH:9]2[CH2:10][CH2:11]2)=[CH:4][S:3][C:2]=1[NH:1][C:14]([NH:13][CH3:12])=[O:15])#[N:8]
Reactant: N#Cc1c(C2CC2)csc1N
Reactant: CN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: COCCOC
Product: CNC(=O)Nc1scc(C2CC2)c1C#N
Reaction time: 8 h

Procedure:
A solution of 10 g 2-amino-3-cyano-4-cyclopropylthiophene, 6.94 g methyl isocyanate and 0.1 g dibutyl tin dilaurate in 20 ml dimethoxyethane was refluxed for 7 hours and then allowed to stand at about 25°C. overnight. The reaction mixture was evaporated and the resulting residue was chromatographed on silica gel. The product, a pale-green solid melting at 169°-172°C., was eluted with 1:1 ether-hexane. Sulfur analysis for the product is tabulated in Table I.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].O1CCCC1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[C:24]2[Cl:30].C(N(CC)CC)C>O>[Cl:30][C:24]1[C:23]2[C:27](=[CH:28][CH:29]=[C:21]([NH:20][S:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[CH:22]=2)[NH:26][N:25]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(Cl)c2c1
Yield: 9.9 %

Procedure:
N-(3-Chloro-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained in the following way: a solution of 0.36 g of 2-methylsulfonylbenzenesulfonyl chloride and of 3.6 ml of tetrahydrofuran is added dropwise to a solution, cooled to 0° C., of 0.22 g of 5-amino-3-chloro-1H-indazole, of 15 ml of tetrahydrofuran and of 0.37 ml of triethylamine. After reacting for 30 minutes at a temperature in the region of 0° C. and 18 hours at a temperature in the region of 20° C., 30 ml of distilled water are added to the reaction medium. The medium is extracted with 30 ml and 15 ml of ethyl acetate. The organic phase is subsequently dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/methanol (99/1 by volume) mixture as eluent. The solid thus obtained is recrystallized from 45 ml of isopropanol. After drying under reduced pressure at 60° C., 0.05 g of N-(3-chloro-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide is thus obtained in the form of a white solid melting above 260° C. (analysis C14H12ClN3O4S2 % calculated C, 43.58; H, 3.13; Cl, 9.19; N, 10.89; O, 16.59; S, 16.62. % found C, 43.72; H, 2.88; Cl, 7.94; N, 10.63; S, 16.80).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[C:6]=1[I:7].I[CH3:20]>C(#N)C>[I-:1].[I:7][C:6]1[N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][NH+:3]([CH3:20])[C:2]=1[I:1]
Reactant: CI
Reactant: Ic1ncn(Cc2ccc3ccccc3c2)c1I
Solvent: CC#N
Product: C[NH+]1CN(Cc2ccc3ccccc3c2)C(I)=C1I
Product: [I-]

Procedure:
4,5-diiodoimidazole (5.0 mmol) and KOH (5.0 mmol) were placed in a round bottom flask with 50 mL THF. The mixture was brought to reflux and stirred 0.5 h until KOH was consumed. 2-bromomethylnapthalene (5.0 mmol) was added and the solution was stirred at reflux for 17 hours. KBr was removed by vacuum filtration and the filtrate was collected. The volatiles were removed by rotary evaporation to give 4,5-diiodo-1-(naphthalen-2-ylmethyl)-1H-imidazole as a off white solid. 4,5-diiodo-1-(naphthalen-2-ylmethyl)-1H-imidazole was dissolved in acetonitrile in a round bottom flask. The solution was brought to reflux and excess iodomethane was added. The reaction was stirred at reflux for overnight after which time it was cooled. The resulting yellow precipitate was collected by filtration and analyzed. 1H NMR (300 MHz, d6-DMSO): δ 3.88 (s), 5.64 (s), 7.47-7.60 (m), 7.89-8.02 (m), 9.57 (s) ppm.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.C1(CC([NH:22][CH:23]2[C:56](=[O:57])[N:25]3[C:26]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:27]([CH2:30][S:31][C:32]4[N:33]=[N:34][N:35]([CH2:37][C:38]#[CH:39])[N:36]=4)[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.CO>C(Cl)Cl>[NH2:22][CH:23]1[C:56](=[O:57])[N:25]2[C:26]([C:40]([O:42][CH:43]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:41])=[C:27]([CH2:30][S:31][C:32]3[N:33]=[N:34][N:35]([CH2:37][C:38]#[CH:39])[N:36]=3)[CH2:28][S:29][C@H:24]12
Reactant: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A mixture of phosphorus pentachloride (8.5 g) in methylene chloride (130 ml) was cooled to 5° C. and thereto was added pyridine (3.2 g). The mixture was stirred for 30 minutes at room temperature, cooled to 5° C. and thereto was added benzhydryl 7-(2-phenylacetamido)-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (13.0 g) to give a homogeneous solution. The obtained solution was stirred for 30 minutes at 5° C. and added to methanol (65.4 g) precooled to -30° C. The resulting mixture was stirred for 30 minutes without external cooling. The reaction mixture was evaporated and to the residue were added ethyl acetate and water. The mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium carbonate. The ethyl acetate layer was separated, washed with water (x3), dried over magnesium sulfate, treated with activated charcoal and evaporated under reduced pressure to give benzhydryl 7-amino-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (7.31 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CCN(CC)CC.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:21]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
Into a round bottom flask containing 3-hydroxybenzaldehyde (0.658 g, 5.23 mmol) and DMAP (0.0646 g, 0.52 mmol), first 10 mL of anhydrous CH2Cl2 and then 0.89 mL of NEt3 (0.634 g, 6.27 mmol) were added. After the reaction mixture was stirred under nitrogen at 0° C. for 10 minutes, 5 mL of a CH2Cl2 solution of TBSCl (0.976 g, 6.28 mmol) were added. The reaction mixture was stirred for 2.5 h at room temperature and, then it was filtered through silica gel-florisil, rinsed with CH2Cl2 and the organic phase dried under Na2SO4. After evaporating the solvent, 1.1308 g (4.79 mmol) of pure product was obtained in a 92% yield.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH:12]([SiH:15]([CH:17]([CH3:19])[CH3:18])Cl)([CH3:14])[CH3:13]>CCCCC>[CH:12]([SiH:15]([CH:17]([CH3:19])[CH3:18])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])([CH3:14])[CH3:13]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCC
Product: CC(C)[SiH](C#C[Si](C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A flame-dried 250-mL round-bottom flask was cooled under nitrogen and placed in an ice bath. Into this flask was added 30 mL pentane and 3.6 g (36 mmol) trimethylsilylacetylene. n-Butyllithium (13.2, 2.5 M in hexane) was added over 12 minutes, and the reaction was allowed to stir for one hour at 0° C. Diisopropylchlorosilane (5.1 g, 34 mmol) was then added, and the reaction stirred overnight. The solution was extracted with pentane (2×40 mL) and the organic layers were washed with water, dried over magnesium sulfate, filtered, then carefully concentrated using rotary evaporation (product was volatile). Chromatography on silica with pentane as an eluent yielded 6.9 g (33 mmol, 99%) the desired product as a clear oil.