Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH:15]([C:21]1[S:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:24][N:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CC(C)=O>[C:15]([C:21]1[S:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:24][N:25]=1)(=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC(O)c1ncc(S(N)(=O)=O)s1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCCC(=O)c1ncc(S(N)(=O)=O)s1
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
Jones' reagent (0.14 mL, 0.38 mmol, 2.67M) was added dropwise to a 0° C. solution of 2-(1-hydroxyhexyl)-5-thiazole sulfonamide (0.08 g, 0.32 mmol) in acetone (1 mL). The ice bath was removed and the solution stirred for 30 min. The reaction was quenched with a few drops of isopropanol and the acetone removed in vacuo. The residue was taken up in water and extracted with EtOAc. The combined extracts were dried (MgSO4), concentrated and recrystallized from EtOAc/hexane to give 0.031 g (38%) of 2-(1-hexanoyl)-5-thiazole sulfonamide as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=C(C)[N:6]=[C:5]([C:10]#N)[CH:4]=1.CO.C[CH2:15][O:16][C:17]([CH3:19])=[O:18].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH3:10])[N:6]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:8]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(CO)cc(C#N)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(CO)cc(C)n1
Temperature: 135 °C
Reaction time: 12 h

Procedure:
A mixture of 440 mg of the 4-(hydroxymethyl)-6-methylpicolinonitrile in 3 mL of concentrated H2SO4 and 1.8 mL of H2O was stirred at 135° C. for 12 h. The temperature was decreased to 95° C., 6 mL of MeOH was added, and the solution was stirred at 95° C. for 1 h. The solution was added to ice with H2O and EtOAc. Solid NaHCO3 and sat. NaHCO3 solution were added to a pH=8. The aqueous layer was extracted with EtOAc (2×). The combined extracts washed with brine (40 mL), dried over Na2SO4, filtered and concentrated to give 393 mg of methyl 4-(hydroxymethyl)-6-methylpicolinate which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:18]>ClCCl>[N+:1]1([O-:18])[C:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(-c2ccccn2)nc1
Solvent: ClCCl
Product: [O-][n+]1ccccc1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,2′-bipyridyl (1 mmole) in dichloromethane was treated with m-chloroperoxybenzoic acid (2 mmole) at 0° C., and the reaction mixture was stirred at 25° C. for 2 h. Extraction and chromatography gave 2,2′-bipyridyl-N-oxide.
Reaction SMILES: CCCCCCCCC.[CH2:10]([O:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:19][CH:20]=[CH2:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O:39]1CCCC1>>[CH2:10]([O:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:19][CH2:20][CH2:21][OH:39])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCC(CCCCCCCCCCCCCCCCC)OCc1ccccc1
Reactant: C1CCOC1
Solvent: CCCCCCCCC
Product: CCCCCCCCCCCCCCCCCC(CCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a 33 ml solution of a 0.5M solution of 9-borabicyclo[3:3:1]nonane in tetrahydrofuran was added dropwise, under nitrogen, a solution of 6.0 g of 4-benzyloxy-1-heneicosene in 30 ml of dry tetrahydrofuran. After stirring at room temperature for 3 hours, the reaction was quenched by successive addition of 9 ml of ethanol, 3 ml of 6N sodium hydroxide and 6.5 ml 30% hydrogen peroxide. The reaction mixture was heated at 50° for 90 minutes and then allowed to stand at ambient temperature overnight. Upon standing, the reaction mixture separated into aqueous and organic phases. The aqueous phase was saturated with potassium carbonate, and the organic phase was separated, washed with 15 ml of 10% solution of sodium sulfite and 20 ml of saturated solution of sodium chloride, dried over potassium carbonate, and concentrated. The residue was taken up in a mixture of 20% diethyl ether/hexane, filtered and concentrated to an oil. Flash chromatography of the oil on silica gel using hexane/diethyl ether (2:1 by volume) as the eluent gave 4.88 g (78%) of 4-benzyloxyheneicosan-1-ol.
Reaction SMILES: C(OC([NH:11][CH2:12][C@H:13]([OH:33])[CH2:14][C:15]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[O:16][PH2:17]=[O:18])=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:11][CH2:12][C@H:13]([OH:33])[CH2:14][C:15]([O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[O:16][PH2:17]=[O:18]
Reactant: CC(C)(C)C(=O)OC(CC1CCCCC1)(C[C@@H](O)CNC(=O)OCc1ccccc1)O[PH2]=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C(=O)OC(CC1CCCCC1)(C[C@@H](O)CN)O[PH2]=O
Yield: 94.9 %

Procedure:
2,2-Dimethyl-propionic acid ((R)-3-benzyloxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinoyloxymethyl ester (0.90 g, 0.39 mmol) was dissolved in ethanol (35 mL) and was hydrogenated via a hydrogen par shaker for 3 h at 50 psi with 10% Pd/C (0.09 g) as a catalyst. The reaction was filtered through celite and concentrated in vacuo to give 2,2-dimethyl-propionic acid ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinoyloxymethyl ester (130 mg, 0.37 mmol). 1H NMR (CDCl3, 300 MHz): δ 5.65 (m, 1H), 4.2 (m, 1H), 3.8 (m, 1H), 3.60 (m, 1H), 2.01-1.55 (m, 14H), 1.40-0.95 (m, 11H). 31P NMR (CDCl3, 300 MHz): 60.65, 59.20. LC/MS m/z: [M+H]+=350.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C@@H:5]2[O:7][C@H:8]([CH2:10][O:11][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9][C@@H:4]2[O:3]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][C:2]1([CH3:29])[O:6][C@@H:5]2[O:7][C@H:8]([CH2:10][OH:11])[CH2:9][C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C[C@@H]2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2O[C@H](CO)C[C@@H]2O1
Yield: 125.2 %

Procedure:
To a solution of [(3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methoxy-tert-butyl-diphenyl-silane (compound 25d, 11 g, 26.6 mmol) in THF (100 mL) was added TBAF solution (1M in THF, 6 mL, 6 mmol) with stirring. After being stirred at room temperature for 4 hours, the reaction solution was washed with saturated NH4Cl solution, dried over Na2SO4, concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:2 EtOAc in petroleum ether) to afford 5.8 g of [(3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanol (compound 25e).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH3:11].[ClH:12].C[OH:14]>CCOCC>[ClH:12].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[NH:8])[OH:14])=[CH:5][C:4]=1[CH3:11]
Reactant: COc1ccc(C#N)cc1C
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C(=N)O)cc1C
Reaction time: 3 h
Yield: 82 %

Procedure:
Under a nitrogen atmosphere was prepared a slurry of 21 (25.6 g, 0.174 mol) in a mixture of MeOH (10 ml) and Et2O (12 ml). With cooling, a stream of hydrogen chloride was passed through, giving a solution momentarily followed by a precipitate. The total uptake of HCl was 15 grams. The reaction mixture was refrigerated for 3 hours, and the solid collected and washed with Et2O to yield 31 grams (82%) of 4-methoxy-3-methylbenzimidate hydrochloride; m.p. 137°-140°.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:12])[CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.O=[C:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C)C=O>[OH:12][C@H:3]([CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][NH:1][CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:33]=[CH:32][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:22][CH:21]=2)[CH2:18][CH2:19]1
Reactant: NC[C@H](O)COc1cccnc1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4cccnc4)CC3)cc2)S1
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.8 %

Procedure:
(2S)-1-Amino-3-(3-pyridinyloxy)-2-propanol (0.21 g, 1.25 mmol) (which was obtained in Example 124) and 5-[4-(4-oxo-1-piperidineyl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) (0.413, 1.25 mmol) were mixed in N,N-dimethylformamide (12 mL) and then treated with sodium triacetoxyborohydride (0.56 g, 2.5 mmol) and acetic acid (0.26 mL). After stirring at room temperature under a nitrogen atmosphere for one day, the mixture was purified by column chromatography (dichloromethane/methyl alcohol 85/5) to give the title compound as a yellow solid (0.25 g, 56% yield); mp: 130-132° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.20-1.54 (m, 2H), 1.90-2.02 (m, 2H), 2.67 (t, 2H), 2.78-2.97 (m, 4H), 3.22-3.26 (m, 1 H), 3.35 (brs, 2H), 3.64-3.70 (d, 2H), 3.97-4.08 (m, 3H), 4.60-4.63 (m, 1H), 6.84-6.86 (m, 2 H), 7.03-7.05 (m, 2H), 730-7.36 (m, 1H), 7.38-7.40 (m, 1H), 8.16-8.17 (m, 1H), 8.8.29-8.30 (m, 1H); MS (ES) m/z: 457 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([Si:10]([CH3:27])([CH3:26])[O:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:13]1[CH2:24][OH:25])([CH3:9])[CH3:8].C(N(CC)CC)C>>[CH3:9][C:7]([Si:10]([CH3:27])([CH3:26])[O:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C@@H:13]1[CH2:24][O:25][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:6])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (3.85 mL, 39.29 mmol) was added to an ice cold methylene chloride solution of 1,1-dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy-}2-(hydroxymethyl)-1-pyrrolidinecarboxylate (6.05 g, 26.19 mmol) and triethylamine (7.28 mL, 52.38 mmol). The reaction was warmed to room temperature, stirred for 16 hours then concentrated under reduced pressure. The crude material was dissolved in ethyl acetate and washed with saturated NaHCO3, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to give the title compound as a yellow oil. (4.69 g, 11.4 mmol). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.1 (s, 6H), 0.8 (s, 9H), 1.4 (m, 9H), 1.7 (m, 1H), 2.0 (m, 1H), 3.2 (s, 3H), 3.3 (m, 2H), 3.7 (m, 1H), 4.0 (m, 1H), 4.2 (m, 1H), 4.3 (m, 1H). ES+=410.16.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([Si:15]([CH3:29])([CH3:28])[O:16][CH:17]1[CH:22]([O:23][CH3:24])[CH:21]([CH3:25])[CH2:20][O:19][CH:18]1[CH2:26][OH:27])([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl>[CH3:11][C:12]([Si:15]([CH3:29])([CH3:28])[O:16][CH:17]1[CH:22]([O:23][CH3:24])[CH:21]([CH3:25])[CH2:20][O:19][CH:18]1[CH:26]=[O:27])([CH3:13])[CH3:14]
Reactant: COC1C(C)COC(CO)C1O[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1C(C)COC(C=O)C1O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
Into a stirred solution of oxalylchloride (0.07 ml, 0.81 mmol) in dry dichloromethane (3 ml) was dropped a solution of dry dimethylsulfoxide (0.11 ml, 1.49 mmol) in dry dichloromethane at -60° C. and stirring was continued at this temperature (-60° C.) for 15 minutes. Then a solution of the title compound of Example 39 (180 mg, 0.62 mmol) in dry dichloromethane (1 ml) was added slowly. After being stirred for additional 15 minutes at -60° C. triethylamine (0.43 ml, 3.1 mmol) was added slowly, the mixture was stirred for 10 minutes at -60° C. and then allowed to come to ambient temperature and stirred for 40 minutes at this temperature. The solvent was removed on a rotary evaporator, and the residue was partitionated between ether and ice-water. The organic phase was separated, dried over sodium sulfate and evaporated in vacuo to leave an oil (157 mg) which was chromatographed on silica gel eluting with ethyl acetate/petroleum ether (1:4). The relevant fractions were combined and then evaporated in vacuo to yield the desired title aldehyde as a pale yellowish oil. Yield 108 mg.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[O:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[O:14][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:9]
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cc(Br)ccc1O

Procedure:
Using 5-bromosalicylic acid and 2-amino-4,5-diphenyloxazole as the raw materials, the same operation as the example 16 gave the title compound. (2-Amino-4,5-diphenyloxazole: refer to Zh. Org. Khim., 1980, 16, 2185.)
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Cl[C:29]1[C:30]2[C:37]([CH3:38])=[CH:36][S:35][C:31]=2[N:32]=[CH:33][N:34]=1.C1COCC1.[OH-].[Na+]>C(O)(C)C.Cl>[CH3:26][C:23]1[C:22]([NH:27][C:29]2[C:30]3[C:37]([CH3:38])=[CH:36][S:35][C:31]=3[N:32]=[CH:33][N:34]=2)=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]4)=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1Nc1ncnc2scc(C)c12
Temperature: 75 °C
Reaction time: 0.83 h

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.0583 g, 0.161 mmol) and 4-chloro-5-methyl-thieno[2,3-d]pyrimidine (0.0297 g, 0.161 mmol) were mixed in isopropyl alcohol (1 mL) and 1 drop of conc. HCl was added. The reaction was heated to 75° C. overnight, then THF (5 mL) was added, followed by NaOH (3N aq., 0.30 mL) and the reaction continued heating and stirring for 50 minutes. An additional portion of NaOH (3N aq., 0.10 mL) was added and the reaction was heated for 1 hour, then cooled. The reaction mixture was submitted to standard aqueous workup then purified on silica gel (30-100% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([O:17][C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(OC(C)(C)CO)cn2)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1nc(Cl)cc(Nc2ccc(OC(C)(C)C=O)cn2)c1=O
Reaction time: 0.67 h
Yield: 71.8 %

Procedure:
6-Chloro-4-(5-(1-hydroxy-2-methylpropan-2-yloxy)pyridine-2-ylamino)-2-methylpyridazin-3-(2H)-one (965 mg, 2.97 mmol) was taken up in a mixture of tetrahydrofuran (25 ml) and dichloromethane (15 ml). To the suspension was added Dess-Martin Periodinane (1.64 g, 3.86 mmol) and the flask was capped and stirred for 40 minutes. An aqueous saturated solution of sodium bicarbonate (50 ml) followed by the addition of an aqueous 10% solution of sodium thiosulfate (50 ml) and the material was stirred vigorously for 15 minutes. Ethyl acetate (50 ml) was added and the contents were shaken in a separatory funnel. The organic phase was collected and washed with brine solution (50 ml). The ethyl acetate phase was collected and the aqueous phases were back extracted with dichloromethane (2×40 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified via trituration from hot dichloromethane/hexanes to provide a brown solid (688 mg) (M+H)+=323 m/e.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClC(Cl)C.C1C=CC=CC=1.C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Solvent: CC(Cl)Cl
Solvent: c1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (1.0 g) in dichloroethane (10 ml) was added rhodium(II) octanoate (10 mg) under refluxing. After refluxing for 30 minutes, the reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in benzene (5 ml) and then evaporated in vacuo to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]-heptane-2-carboxylate.
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: O=C(O)C(F)(F)F
Solvent: ClCCl
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: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@H:15]3[O:27][C@@H:26]([CH2:28][O:29]C(=O)C)[C@H:21]([O:22]C(=O)C)[C@@H:16]3[O:17]C(=O)C)[C:6]=2[CH:5]=[C:4]([Cl:33])[C:3]=1[Cl:34].C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@H:15]3[O:27][C@@H:26]([CH2:28][OH:29])[C@H:21]([OH:22])[C@@H:16]3[OH:17])[C:6]=2[CH:5]=[C:4]([Cl:33])[C:3]=1[Cl:34]
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)C)nc3c(Br)c(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CC(C)Nc1nc2c(Br)c(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 70.3 %

Procedure:
4-Bromo-5,6-dichloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (1.16 g, 2.0 mmol), sodium carbonate (0.28 g, 2.64 mmol), water (4 mL), methanol (6 mL), and ethanol (8 mL) were used according to general procedure III. The product was purified by silica gel chromatography using 10:1 dichloromethane/methanol to afford 0.64 g (70%) of a white powder; m.p. 221-222° C. Anal. Calcd for C15H18BrCl2N3O4: C, 39.59; H, 3.99; N, 9.23. Found: C, 39.42; H, 4.20; N, 9.05.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)C1C=CC=CC=1.[N:25]1[C:34]2[C:29](=[N:30][C:31]([CH:35]=O)=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.N1CCCCC1>CC(O)C>[C:21]([O:20][C:18](=[O:19])[NH:17][C:12]1[NH:11][C:15](=[CH:35][C:31]2[CH:32]=[CH:33][C:34]3[C:29](=[CH:28][CH:27]=[CH:26][N:25]=3)[N:30]=2)[C:14](=[O:16])[N:13]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: O=Cc1ccc2ncccc2n1
Reactant: CC(C)(C)OC(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1=NC(=O)C(=Cc2ccc3ncccc3n2)N1
Temperature: 25 °C

Procedure:
To a mixture of 2-tert-butoxycarbonylamino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (53.3 mg, 0.16 mmol), 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 3 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration to give (5-[1,5]-naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-carbamic acid tert-butyl ester as a yellow solid, 29.8 mg (54.9%). HR-ES (+) m/e calcd. for C17H17N5O3: (M+H)+ 340.1404. Found: 340.1404.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]1C>C(O)CCC>[CH3:12][C:13]1[N:14]([C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CC1Cc2ccccc2N1C
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: Cc1cc2ccccc2n1-c1nc(Cl)nc2[nH]cnc12
Temperature: 100 °C

Procedure:
The same procedure as in stage 1 of Example 1 is carried out, mixing 378 mg of 2,6-dichloropurine, 10 ml of butanol and 0.32 of dimethylindoline. The mixture is heated at 100° C. for approximately 5 hours and allowed to return to ambient temperature. Partial drying and washing with isopropanol are carried out. The product is dried and 423 mg of expected product are thus obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[C:24]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=O)=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:22][C:23]1[C:24]([C:29]2[CH:37]=[CH:36][C:32]([C:33]3[NH:10][C:5]4[CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=[CH:7][C:6]=4[N:9]=3)=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, 1.0 mL (5.0 mmol) diisopropylethylamine and 1.1 g (6 mmol) O-(7-azabenzotriazol-yl)-N,N,N′,N′-tetramethyleuronium hexafluorophosphate were added to a solution of 0.59 g (2.5 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 25 mL dimethylformamide, which was then stirred at room temperature for 16 hours and vacuum concentrated. The concentrate thus obtained was dissolved in ethyl acetate, washed with saturated NaHCO3 and saturated NaCl, dried over magnesium sulfate, and concentrated in a vacuum. The residue was dissolved in acetic acid/toluene (15 mL/1.5 mL) and stirred at 75° C. for 3 hours, followed by vacuum concentration. Again, the concentrate was dissolved in ethyl acetate, washed with saturated NaHCO3 and saturated NaCl, dried over magnesium sulfate, and vacuum concentrated. The residue was separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.77 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 82%).