Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[N:10][N:11]([CH2:17][C:18]([OH:20])=O)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:33]1C=CN=C1)=O.[OH-].[NH4+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[N:10][N:11]([CH2:17][C:18]([NH2:33])=[O:20])[C:12]=2[C:13]([F:14])([F:16])[F:15])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2nn(CC(=O)O)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nn(CC(N)=O)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
To a solution of [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (Example 10) (0.24 g, 0.54 mmol) in THF (6 mL) was added 0.10 g of 1,1'-carbonyidiimidazole at 25° C. under nitrogen. After gas evolution had ceased (approx. 30 minutes), 6 mL conc. ammonium hydroxide was added and the mixture stirred at 25° C. for 18 hours. The reaction mixture was diluted with water, extracted with two portions ethyl acetate and the organic layer washed successively with dilute aqueous HCl and brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from chloroform/acetone gave [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide as a white crystalline solid (0.15 g, 34%). Elemental analysis for C19H15N3F4SO3Calc'd: C, 51.70, H, 3.42, N, 9.52. Found: C, 51.46, 3.35, N, 9.39.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=O)=[O:4].Cl.[CH2:15]([NH2:17])[CH3:16].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:15]([NH:17][C:8]([C:7]1[CH:11]=[CH:12][N:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1)=[O:10])[CH3:16]
Reactant: CCN
Reactant: COC(=O)c1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccnc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a mixture of 2-(methoxycarbonyl)isonicotinic acid (150 mg, 0.83 mmol), ethylamine hydrochloride salt (203 mg, 2.48 mmol), and diisopropylethylamine (0.72 mL, 4.14 mmol) in DMF is added HBTU (377 mg, 0.99 mmol) at 0° C. After stirring at room temperature for 1 hour, the mixture is poured onto water (30 mL). The aqueous phase is extracted with dichloromethane (30 mL×2). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (2:1˜1:1) to give 83 mg (48% yield) of the title compound as a white solid.
Reaction SMILES: C(O[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])C.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([C:16]([NH2:18])=[O:17])=[CH:12][CH:11]=1.O1CCOCC1>C(OCC)(=O)C>[CH3:19][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(C(N)=O)cc1
Reactant: CCOC(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A 500 mL round-bottom flask was charged with trifluoroacetaldehyde ethyl hemiacetal (12.3 g, 85.0 mmol), p-toluamide (10.0 g, 74.0 mmol), and dioxane (150 mL). The thick white slurry was stirred at ambient temperature for 3 hours, then heated at reflux for 44 hours. The homogeneous solution was cooled and concentrated in vacuo to provide a white solid. The crude material was dissolved in ethyl acetate (50 mL), adsorbed onto silica gel (50 g), and eluted through a medium porosity fritted filter funnel (elution with 25% ethyl acetate/hexanes, then ethyl acetate) to provide 14.1 g of the desired product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:20])=[C:17]([NH2:18])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 56 %

Procedure:
Upon boiling a solution of 7.6 g 2-nitrobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 142° C. (ethanol) is obtained.
Reaction SMILES: O.[NH2:2][NH2:3].CS[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]([NH2:13])[C:7]=1[N:14]=[O:15]>CN(C=O)C>[NH:2]([C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]([NH2:13])[C:7]=1[N:14]=[O:15])[NH2:3]
Reactant: NN
Reactant: CSc1nc(N)nc(N)c1N=O
Solvent: O
Solvent: CN(C)C=O
Product: NNc1nc(N)nc(N)c1N=O
Reaction time: 8 h

Procedure:
Hydrazine hydrate (55% solution, 14.5 mL) was added rapidly to a suspension of (12.0 g; 64.9 mmol) of 6-Methylthio-5-nitroso-pyrimidine-2,4-diamine 2 in DMF at room temperature. The mixture was allowed to stir overnight and then the bright pink mixture was filtered and the solid washed several times with DMF followed by ether and then air dried to give 9.53 g of 6-Hydrazino-5-nitroso-pyrimidine-2,4-diamine as bright pink solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:10][C:11](=[O:26])[NH:12][C@H:13]1[C@H:19]([CH3:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[NH:15][C:14]1=[O:25])([CH3:9])([CH3:8])[CH3:7].[C:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)(=[O:29])[CH3:28]>N1C=CC=CC=1.O>[C:6]([O:10][C:11](=[O:26])[NH:12][C@H:13]1[C@H:19]([CH3:20])[N:18]([C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([C:27](=[O:29])[CH3:28])=[CH:38][CH:37]=2)[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[NH:15][C:14]1=[O:25])([CH3:7])([CH3:8])[CH3:9]
Reactant: C[C@@H]1Nc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1ccc(C(=O)N2c3ccccc3NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]2C)cc1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
Phosphoryl chloride (0.16 ml, 1.72 mmol) was added to a solution of ((2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (0.5 g, 1.72 mmol) and 4-acetyl-benzoic acid (0.25 g, 1.54 mmol) in pyridine (15 ml) at 0° C., stirring continued for 2 h. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×60 mL). The organic layers were combined, washed with 10% aqueous citric acid (1×15 mL), water (1×15 mL) and a saturated aqueous solution of sodium hydrogen carbonate (1×15 mL) and brine. The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted with 10 to 60% v/v ethyl acetate hexanes to give [(2S,3S)-1-(4-acetyl-benzoyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester (0.45 g, 60%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:33])[N:10]=[C:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[CH:18][CH:17]=3)[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.CI.[CH3:36]CN(C(C)C)C(C)C>C(Cl)Cl>[CH3:36][N:12]1[CH:13]=[C:8]([CH2:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[C:9](=[O:33])[N:10]=[C:11]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)=[CH:20][CH:21]=1
Reactant: O=c1nc(CCc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: Cn1cc(Cc2cncnc2)c(=O)nc1CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.5 %

Procedure:
To the solution of 5-(pyrimidin-5-ylmethyl)-2-(4-(3-(trifluoromethyl)phenoxy)phenethyl) pyrimidin-4(1H)-one (200 mg, 0.442 mmol) in DCM (10 mL) was added MeI (4.42 mL, 4.42 mmol) (1.0 M in DCM) and DIPEA (0.772 mL, 4.42 mmol) at 25° C. The mixture was stirred at room temperature for 2 days. The solvent was removed in vacuo. Purification via MDAP then afforded the title compound (87.6 mg, 40.8% yield) as a white solid. LCMS: rt=1.59 min, [M+H+]=467.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]1[N:16]=[CH:15][C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][N:12]=1.C([C@H]([C@@H](C(O)=O)O)O)(O)=O.[CH2:32]([O:34][C:35]1[CH:47]=[CH:46][CH:45]=[CH:44][C:36]=1[O:37][C@@H:38]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39]1)[CH3:33]>O1CCCC1>[CH2:32]([O:34][C:35]1[CH:47]=[CH:46][CH:45]=[CH:44][C:36]=1[O:37][C@@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:11]2[N:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[CH:15][N:16]=2)[CH2:39]1)[CH3:33]
Reactant: CCOc1ccccc1O[C@@H]1CCCNC1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
N,N-Diisopropylethylamine (2.91 kg, 22.5 mol) was added to a mixture of ethyl 2-chloropyrimidine-5-carboxylate (1.20 kg, 6.43 mol) and (R)-3-(2-ethoxyphenoxy)piperidine D-tartrate (2.63 kg, 7.07 mol) in tetrahydrofuran (12.0 L) at 55° C., at a rate maintaining a temperature of 50-60° C. The mixture was held at that temperature for 1 hour, then was cooled to 30° C. The mixture was then partitioned between water (8.4 L) and 2-methyltetrahydrofuran (16.8 L). The organic layer was washed with aqueous 2M sodium chloride solution (6.8 L), and then was concentrated by distillation under reduced pressure. Tetrahydrofuran (12.0 L) and methanol (6.0 L) were added to the residue, and then an aqueous 8M potassium hydroxide solution was added at a rate to maintain the temperature below 55° C. The mixture was held at 50-55° C. for 1 hour, then was cooled to 30° C., and was partitioned between ethyl acetate (18.0 L) and aqueous 3M hydrochloric acid solution (8.86 L). The organic layer was washed with aqueous 2M sodium chloride solution (6.8 L), and was then distilled to a low volume. Ethyl acetate (22 L) was added and the resulting solution was distilled at ambient pressure and at constant volume with the addition of further ethyl acetate (25 L). The mixture was cooled to and held at 57° C. for 2 hours as crystallization initiated. n-Heptane (8.83 L) was added while maintaining temperature at 55-60° C. After 30 min, the slurry was cooled to 20-25° C. and was held at that temperature for 11 hours. The crystals were collected by filtration, rinsing with 2:1 ethyl acetate:n-heptane (8.0 L), to afford after drying (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (1.69 kg). MS (ES+) 344.3 (M+H). The mother liquors were concentrated and the resulting residue was recrystallized from ethyl acetate (4.2 L), with the addition of n-heptane (2.1 L) after crystallization initiated, to afford after filtering and drying an additional portion of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (0.370 kg).
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([CH2:25][CH3:26])[C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:18][C:12]=2[CH2:11]1)=[S:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:6][CH:7]([CH2:25][CH3:26])[C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:18][C:12]=2[CH2:11]1)=[S:9]
Reactant: CCC(O[Si](C)(C)C(C)(C)C)C(=S)N1CCc2nc(-c3ccccc3)oc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(O)C(=S)N1CCc2nc(-c3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
310.00 mg (744 μmol) 2-(tert-butyl-dimethyl-silanyloxy)-1-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl)-butan-1-thione are placed in 10 mL DCM, 2.50 mL TFA are added and the mixture is stirred for 4 h at RT. The solvent of the reaction mixture is eliminated in vacuo and the residue is purified on silica gel. (Eluant: cyclohexane/EA).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][C@H:15]([C:17]([NH:19][CH:20]1[C:26](=[O:27])[N:25]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:21]1=[O:40])=[O:18])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][C@H:15]([C:17]([NH:19][CH:20]2[C:21](=[O:40])[N:22]([CH2:36][CH:37]([CH3:38])[CH3:39])[C:23]3[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=3[N:25]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:26]2=[O:27])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)CN1C(=O)C(NC(=O)[C@H](C)N)C(=O)N(CC(C)C)c2ccccc21
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Product: CC(C)CN1C(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)C(=O)N(CC(C)C)c2ccccc21

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-S), the title compound was prepared as a white solid (melting point=197-198° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (2:1 gradient to 3:4). Rf=0.23 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].CI.[C:27](O)(=O)C>O1CCCC1.C(OCC)(=O)C>[CH3:1][C@@H:2]1[C@@H:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[C@@H:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH3:27]
Reactant: COc1ccccc1CC(=O)N1C(=O)O[C@H](c2ccccc2)[C@H]1C
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccccc1[C@@H](C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@H]1C
Reaction time: 0.75 h

Procedure:
To a solution, cooled to -50° C., of 22.82 g of (4R, 5R)-4-methyl-5-phenyl-3-[(2-methoxyphenyl)acetyl]-2-oxazolidinone in 190 cm3 of tetrahydrofuran are added 19.31 g of sodium 1,1,1,3,3,3-hexamethyldisilazide, and the mixture is stirred for 45 minutes at this temperature, followed by addition of 8.82 cm3 of methyl iodide. The reaction mixture is subsequently stirred for 15 hours at room temperature, and then 18.65 cm3 of acetic acid are added, and the mixture is diluted with 200 cm3 of ethyl acetate and washed with 200 cm3 of water and then with 250 cm3 of saturated aqueous sodium chloride solution, and dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized in isopropyl ether, filtered off and dried. 10.95 g of (4R, 5R)-4-methyl-5-phenyl-3-[(R)-2-(2-methoxyphenyl)propionyl]-2-oxazolidinone are obtained, in the form of a white solid melting at 110° C.
Reaction SMILES: CC#N.OOS([O-])=O.[K+].[C:10]([O-:13])(O)=[O:11].[Na+].[C:15]1(C=C[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC#N.O>[CH:23](=[O:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C:10]([OH:13])(=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccccc1
Product: O=Cc1ccccc1

Procedure:
The invention relates to a direct method of synthesis of aldehydes and ketones using nano-RuHAP as a general and effective catalyst for the oxidative cleavage of α,β-unsaturated alkenes. To a mixture of CH3CN (7.5 mL) and distilled water (5 mL) containing alkene (104 mg, 0.5 mmol) and nano-RuHAP (40 mg) was added a mixture Oxone (770 mg, 1.25 mmol) and NaHCO3 (330 mg, 2.3 mmol) over a period of 10 min at room temperature. Upon complete reaction based on TLC analysis, excess NaIO4 was quenched by a saturated Na2S2O3 solution. The catalyst was separated from the reaction mixture by centrifugation, and the recovered catalyst was washed with water and dried in vacuum before reuse. The supernatant liquid was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried over anhydrous Na2SO4. The reaction products were purified by flash chromatography and were characterized by IR, MS and NMR spectroscopies. “nano-RuHAP+Oxone” protocol would also effect oxidative cleavage of α,β-unsaturated alkenes. When chalcone (0.5 mmol) was treated with Oxone (1.25 mmol) and nano-RuHAP (4 mol %) in a NaHCO3 buffered MeCN—H2O (1.5:1 v/v) at room temperature for 3 h, benzaldehyde and benzoic acid were produced (entry 1). Similar oxidative cleavage products were found in isophorone and (+)-pulegone (entry 2,3). Notably, facile oxidative cleavage of C≡C bonds was also observed. For example, subjecting alkynes such as 1-phenyl-1-propyne to the Ru-catalyzed conditions produced benzoic acid in 82% yield (entry 4).
Reaction SMILES: C([O:5][C:6](=[O:34])[C@H:7]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:26])=[CH:17][N:18]=[C:19]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C.[C:35]([C:39]([OH:41])=[O:40])([F:38])([F:37])[F:36]>C(Cl)Cl.C1(C)C=CC=CC=1>[F:36][C:35]([F:38])([F:37])[C:39]([OH:41])=[O:40].[Cl:26][C:16]1[C:15]2[C:20](=[CH:21][C:12]([S:9]([NH:8][C@H:7]([C:6]([OH:34])=[O:5])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:10])=[O:11])=[CH:13][CH:14]=2)[C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@@H](Cc3ccccc3)C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-phenylalanine t-butyl ester (30 mg, 0.060 mmol) was dissolved in CF3CO2H (2.5 mL) and the mixture stirred at room temperature for 2.5 h. The mixture was diluted with CH2Cl2 and PhMe, concentrated in vacuo, azeotroping with PhMe, and the residue triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-phenylalanine trifluoroacetate (24.4 mg, 0.42 mmol) as a white solid.
Reaction SMILES: ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[C:25]3[N:26]([CH:39]([CH3:41])[CH3:40])[C:27]([C:29]4[C:30]([O:37][CH3:38])=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=4)=[CH:28][C:24]=3[C:23](=[O:42])[N:22]2[CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:17][CH:16]=1.C[CH2:50][N:51]([CH2:54]C)CC.CN>C(Cl)Cl.CCOC(C)=O>[CH3:50][NH:51][C:54]([N:46]1[CH2:47][CH2:48][CH:43]([N:22]2[C:23](=[O:42])[C:24]3[CH:28]=[C:27]([C:29]4[C:30]([O:37][CH3:38])=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=4)[N:26]([CH:39]([CH3:41])[CH3:40])[C:25]=3[CH:21]2[C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:44][CH2:45]1)=[O:3]
Reactant: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(C2CCNCC2)C3=O)c(OC)n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)N1CCC(N2C(=O)c3cc(-c4cnc(OC)nc4OC)n(C(C)C)c3C2c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
p-Nitrophenyl chloroformate [7693-46-1] (0.339 mmol) was added to a solution of 6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5-piperidin-4-yl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Example 106) (0.242 mmol) and Et3N (0.726 mmol) in CH2Cl2 (2 mL). After stirring at rt for 30 min, the reaction mixture was treated with methylamine (2M/THF) (3.63 mmol) and warmed to 35° C. After 20 h, the reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3 (3×). The organic phase was dried (MgSO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 4.93 min (HPLC 4); ESI-MS: tR=0.98 min, [M+H]+ 553/555 (LC-MS 1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N+:13]3([O-:41])[CH2:18][CH2:17][CH:16]([C:19]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[OH:20])[CH2:15][CH2:14]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH2:42]([I:44])[CH3:43]>C(#N)C>[I-:44].[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N+:13]3([O:41][CH2:42][CH3:43])[CH2:14][CH2:15][CH:16]([C:19]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][CH:32]=4)([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=4)[OH:20])[CH2:17][CH2:18]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: [O-][N+]1(Cc2ccc(OCC3CC3)cc2)CCC(C(O)(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)CC1
Reactant: CCI
Solvent: CC#N
Product: CCO[N+]1(Cc2ccc(OCC3CC3)cc2)CCC(C(O)(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)CC1
Product: [I-]
Temperature: 0 °C
Yield: 40.8 %

Procedure:
A stirred mixture of 1.0 gram (0.002 mole) of N-[4-(cyclopropylmethoxy)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxy-methyl]piperidine N-oxide, 0.3 gram (0.002 mole) of ethyl iodide, and about 5.0 mL of acetonitrile was heated at reflux for several hours. The reaction mixture was then cooled to 0° C., and petroleum ether was added. Upon completion of the addition the mixture was filtered and the filtrate was concentrated under reduced pressure, yielding 0.6 gram of N-[4-(cyclopropylmethoxy)phenylmethyl]-N-ethoxy-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]-piperidinium iodide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[CH:16]1([CH:21]=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.N1CCCC1>CO>[CH:16]1([CH:21]=[C:11]2[CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]=3[C:2]2=[O:1])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: O=CC1CCCC1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (3.4 g, 16.7 mmol) in methanol (30 mL) was added cyclopentanecarboxaldehyde (3.3 g, 33.3 mmol) and pyrrolidine (2.78 mL, 33.3 mmol). The solution was stirred for twenty hours at ambient temperature. The reaction was recharged with 0.5 mL of cyclopentanecarboxaldehyde. The resulting precipitate was collected by vacuum filtration to provide methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a solid (2.8 g, 60% yield). LC/MS on 4.6×50 mm C-18 column, tR=6.71 minutes (10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 285 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24-1.39 (m, 2H), 1.52-1.74 (m, 4H), 1.76-1.89 (m, 2H), 2.77 (t, J=5.77 Hz, 2H), 2.79-2.90 (m, 1H), 2.97 (t, J=6.44 Hz, 2H), 3.85 (s, 3H), 6.71 (d, J=9.94 Hz, 1H), 7.88 (d, J=6.44 Hz, 1H), 7.91 (s, 1H), 7.98 (d, J=8.06 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([C:12]1[CH:17]=[C:16]([SH:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:11])[CH3:10].[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[NH:34][C:35](=[O:38])[CH:36]=[CH2:37])[CH2:31]2>CO>[CH3:11][C:9]([C:12]1[CH:17]=[C:16]([S:18][CH2:37][CH2:36][C:35]([NH:34][CH:25]2[CH:26]3[CH2:32][CH:30]4[CH2:29][CH:28]([CH2:33][CH:24]2[CH2:31]4)[CH2:27]3)=[O:38])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:8])[CH3:10]
Reactant: C=CC(=O)NC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)c1cc(SCCC(=O)NC2C3CC4CC(C3)CC2C4)cc(C(C)(C)C)c1O

Procedure:
Following the procedure of Example 4, triethylamine (0.5 ml) was added to a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19g, 0.005 mole) and the N-tricyclo[3.3.1.13,7 ]dec-2-yl-2-propenamide (1.02 g, 0.005 mole) in methanol (100 ml) and the solution stirred ar room temperature for 12 hours. The solvent and triethylamine were removed on a rotary evaporator and the product purified by chromatography on silica, recrystallized from ethyl acetate/ethyl ether/hexane and dried, m.p. ca. 155.5°-156° C. Analysis calc. for C27H41NO2S(443.69):