Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:14]([CH3:16])[CH3:15])[C:9]([F:13])=[C:10](F)[F:11])=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].Cl>O1CCCC1.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:14]([CH3:16])[CH3:15])[C:9]([F:13])=[CH:10][F:11])=[CH:6][CH:7]=1
Reactant: CC(C)C(C(F)=C(F)F)c1ccc(Cl)cc1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C(C(F)=CF)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A solution of 3-(p-chlorophenyl)-1,1,2-trifluoro-4-methyl-1-pentene (2.48 g, 0.01 mol) in tetrahydrofuran is cooled to −8° C., treated dropwise with a 3.4 M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (3.1 mL), stirred overnight at room temperature, diluted with water, acidified with 10% hydrochloric acid, and extracted with methylene chloride. The combined organic extracts are washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the title product as a yellow oil (2.10 g) which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[Cl:17]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Cl:17][C:12]1[CH:13]=[N:14][N:15]([CH3:16])[C:11]=1[C:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.75 g, 11.64 mmol) [Prepared in Example 99] and N-chlorosuccinimide (1.55 g, 11.64 mmol) in tetrahydrofuran (58 ml) was stirred in a sealed tube for 1 h at 70° C. Sodium hydroxide (9.70 ml, 58 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to 4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated then purified via column chromatography (silica, 20% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (2.3 g, 8.96 mmol, 77% yield) as a yellow oil: LCMS (ES) m/e 257, 259 (M, M+2)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO.Cl.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][N:25]3[CH2:26][CH2:27][N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2ccc(C=O)o2)cc1C
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2ccc(CN3CCN(c4ccccc4)CC3)o2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(3,4-Dimethylphenyl)-furan-2-carboxaldehyde (4.0g;0.02 mole), prepared by the method of C. S. Davis and G. S. Lougheed J.Het.Chem. 4,153, (1967), was added rapidly to a stirred solution of N-phenylpiperazine (3.2g; 0.02 mole) in methanol (30ml) adjusted to pH 7 (using MeOH/HCl). After 30 minutes a solution of sodium cyanoborohydride (0.48g; 0.0075 mole) in methanol (10ml) was added dropwise and the mixture stirred at room temperature for 2 hours. After removal of the methanol by evaporation, the resultant solid was purified by silica gel chromatography. The fractions containing the desired compound were combined, evaporated and the crystalline solid which formed was recrystallised from 60/80° C. petroleum ether to give the title compound, m.p. 110° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[N:15]=[C:14]([CH2:16]O)[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CS([Cl:31])(=O)=O>C(Cl)Cl>[Cl:31][CH2:16][C:14]1[N:15]=[C:10]([CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(CCCN2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: ClCc1cccc(CCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Additionally, to the solution of 495 mg of the resulting [6-(3-morpholin-4-ylpropyl)pyridin-2-yl]methanol and 104 mg of diisopropylethylamine in 20 mL of methylene chloride at ice temperature, 0.18 mL of methanesulfonyl chloride was added dropwise and the mixture was stirred at room temperature overnight. After the solvent was removed, the residue was purified by chromatography on silica gel (methylene chloride-ethanol=40:1) to give 290 mg of 4-[3-(6-chloromethylpyridin-2-yl)propyl]morpholine as a yellow powder.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]=1[C:22]([O:24]C)=[O:23])(=O)C.[OH-].[K+]>O1CCOCC1.O>[SH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]=1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)c1c(CCSC(C)=O)c2ccccc2n1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(CCS)c2ccccc2n1-c1ccccc1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a deoxygenated solution of 3-(2-acetylthioethyl)-1-phenyl-1H-indole-2-carboxylic acid, methyl ester in dioxane (5 mL) was added a deoxygenated solution of potassium hydroxide (0.168 g, 3.0 mmol) in water (5 mL). The reaction mixture was stirred overnight. Volatile solvent was removed under reduced pressure and the remaining mixture was poured into 1 N HCl (25 mL) containing ice chips. The resulting white precipitate was washed with H2O and dried under vacuum to give 0.110 g of 3-(2-mercaptoethyl)-1-phenyl-1H-indole-2-carboxylic acid (93% yield) as a white solid: 1H NMR (CDCl3) δ 1.52 (t, J=8.1 Hz, 1H), 2.91 (q, J=7.7 Hz, 2H), 3.49 (t, J=7.6 Hz, 2H), 7.08 (d, J=8.2 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.27–7.33 (m, 3H), 7.42–7.53 (m, 3H), 7.78 (d, J=8.0 Hz, 1H). Anal. Calcd. for C17H15N2O2S.0.25 H2O: C, 67.64, H, 5.18, N, 4.64, S, 10.62. Found: C, 67.77, H, 5.15, N, 4.69, S, 10.62.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][OH:15])=[CH:11][C:10]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[O:17])=[C:9]2[CH3:29])=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]=[O:15])=[CH:11][C:10]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[O:17])=[C:9]2[CH3:29])=[C:4]([C:30]([F:31])([F:33])[F:32])[CH:3]=1
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(CCO)n1-c1ccc(Cl)cc1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(CC=O)n1-c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of the compound (1.0 g, 2.0 mmol) of Example 1 in dichloromethane (10 mL), Dess-Martin reagent (1.3 g, 3.0 mmol) was added at 0° C. The reaction temperature was raised to room temperature, and after the mixture was further stirred for 1 hour, it was diluted with ethyl acetate and the organic layer was washed with an aqueous sodium hydrogencarbonate solution, an aqueous sodium thiosulfate solution, water and saturated brine. After the solution was dried with sodium sulfate, it was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 1-[4-chloro-2-(trifluoromethyl)phenyl]-2-methyl-N-[4-(methylsulfonyl)phenyl]-5-(2-oxoethyl)-1H-pyrrole-3-carboxamide (0.85 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.NC1C=CC=C(C)N=1.NC1C=CC([F:30])=C(C)N=1>>[F:30][C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(NC(=O)C(C)(C)C)n1
Reactant: Cc1nc(N)ccc1F
Agent: Cc1cccc(N)n1
Product: Cc1nc(NC(=O)C(C)(C)C)ccc1F

Procedure:
In a similar procedure, N-(6-methylpyridin-2-yl)-2,2-dimethylpropionamide was prepared from 2-amino-6-methylpyridine. 1H NMR (CDCl3) δ: 8.02-8.04 (1H, d), 7.95 (1H, broad s), 7.54-7.60 (1H, t), 6.86-6.88 (1H, d), 2.44 (3H, s), 1.31 (9H, s). Similarly, N-(5-fluoro-6-methylpyridin-2-yl)-2,2-dimethylpropionamide was prepared from 2-amino-5-fluoro-6-methylpyridine. 1H NMR (CDCl3) δ: 8.02 (1H, dd), 7.95 (1H, broad s), 7.35 (1H, t), 2.44 (3H, d), 1.32 (9H, s).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:8])[CH2:6][NH2:7])[CH2:3][CH2:2]1.S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[CH:1]1([NH:4][C:5](=[O:8])[CH2:6][NH:7][C:10]2[CH2:14][S:13][C:12](=[O:15])[N:11]=2)[CH2:3][CH2:2]1
Reactant: O=C1NC(=S)CS1
Reactant: NCC(=O)NC1CC1
Solvent: CCO
Product: O=C(CNC1=NC(=O)SC1)NC1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
To a solution of N-cyclopropylglycinamide (1.22 g) (J. Med. Chem. 2005, 48, 7808-7820) in ethanol (12 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.42 g), and the mixture was stirred at room temperature for 5 hr. The precipitate was collected by filtration, and the solid was washed with ethanol to give the title compound (2.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)=[C:11]([F:22])[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].N1C=CC=CC=1.[C:29](Cl)(=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:17][N:16]=2)=[C:11]([F:22])[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(-c2ccc(O)cn2)c(F)c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(OCCCCCCC)cc2F)nc1
Reaction time: 12 h

Procedure:
0.1 mol of 2-(4-heptyloxy-2-fluorophenyl)-5-hydroxypyridine (prepared from 4-heptyloxy-2-fluoroacetophenone in accordance with Example 1) is dissolved together with 0.12 mol of pyridine in toluene and 0.1 mol of nonanoyl chloride is then added at room temperature. Stirring is then carried out for 12 hours and standard working-up is carried out. 2-(4-Heptyloxy-2-fluorophenyl)5-nonanoyloxypyridine is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:9]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: OC(c1cccc(-c2cccnc2)c1)c1ncc[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(-c2cccc(Cc3ncc[nH]3)c2)c1

Procedure:
3-[3-(1H-Imidazol-2-ylmethyl)-phenyl]-pyridine was prepared from rac-(1H-imidazol-2-yl)-(3-pyridin-3-yl-phenyl)-methanol, triethylsilane and trifluoroacetic acid in analogy to Example 191e): white crystals; MS (ISP): 236.4 ([M+H]+, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]([CH:26]1[CH2:29][C:28](OC)([O:30]C)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C1C=CC=CC=1.CCCCCCC>[C:1]([NH:4][C:5]([CH:26]1[CH2:29][C:28](=[O:30])[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: COC1(OC)CC(C(CCCCB2OC(C)(C)C(C)(C)O2)(NC(C)=O)C(=O)NC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
2-Acetamido-N-tert-butyl-2-(3,3-dimethoxycyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (5.21 g, 11.10 mmol) was dissolved in acetone (110 mL) and treated with p-toluenesulfonic acid (106 mg, 0.56 mmol). The reaction was stirred overnight at room temperature, then diluted with benzene (500 mL) and heptane (250 mL), washed successively with water and saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 50-75% ethyl acetate in heptane to afford the desired product (3.40 g, 73%). Rf 0.31 (75% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 6.83 (br s, 1H), 5.84 (br s, 1H), 3.45-3.33 (m, 1H), 3.09-2.82 (m, 6H), 2.02 (s, 3H), 1.54-1.05 (m, 25H), 0.77 (t, J=7.4 Hz, 2H). ESI MS found for C22H39BN2O5 m/z [423.1 (M+1)].
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]([NH2:14])=O)=[CH:5][C:4]=2[N:3]1[CH2:15][CH:16]=[CH2:17].C(N(CC)CC)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]#[N:14])=[CH:5][C:4]=2[N:3]1[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCn1c(=O)ccc2ncc(C(N)=O)cc21
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCn1c(=O)ccc2ncc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a suspension of 6-oxo-5-(2-propen-1-yl)-5,6-dihydro-1,5-naphthyridine-3-carboxamide (0.69 g, 3 mmol) in DCM (30 ml) at 0° C. was added triethylamine (1.0 ml, 7.2 mmol) and trifluoromethanesulfonic anhydride (0.605 ml, 3.6 mmol) and the reaction was allowed warm to rt and stirred for 1 h at rt. Another four sequential treatments of triethylamine (1.0 ml, 7.2 mmol) and trifluoromethanesulfonic anhydride (0.605 ml, 3.6 mmol) over the next 6 h were necessary to drive the reaction almost to completion. The reaction mixture was treated with sat. aq NaHCO3 and the aqueous extracted twice more with DCM. The combined organic phases were then dried, evaporated and the residue was subjected to column chromatography on silica gel using a EtOAc:hexane gradient to provide the desired compound (0.570 g, 90%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][N:18]2[CH:22]=[N:21][N:20]=[CH:19]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]>N1C=CC=CC=1>[C:5]([N:17]([N:18]1[CH:22]=[N:21][N:20]=[CH:19]1)[C:14]1[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=1)(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(c1ccc([N+](=O)[O-])cc1)n1cnnc1
Reaction time: 2 h

Procedure:
2.8 Milliliters of acetic anhydride was added to 15 ml of a pyridine solution containing 0.62 g of 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole at room temperature and the mixture was stirred for about 2 hours. After completion of reaction, the solvent was removed by distillation under reduced pressure, and a proper amount of an aqueous sodium hydrogencarbonate solution was added to the residue obtained, which was then extracted several times each with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to give 0.52 g of 4-[N-acetyl-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole from the chloroform/methanol (100/1) eluate.
Reaction SMILES: [CH2:1]([Si](C)(C)C)[C:2](=[CH2:4])[CH3:3].[CH2:9]([O:16][C@@H:17]1[C@@H:22]([O:23][CH2:24]C2C=CC=CC=2)[C@H:21]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:20]([CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:19][C@:18]1([C:49]1[CH:54]=[C:53]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([CH2:62][CH3:63])=[CH:58][CH:57]=2)[C:52]([Cl:64])=[CH:51][C:50]=1[O:65][CH3:66])O)C1C=CC=CC=1>C(Cl)Cl>[CH2:9]([O:16][C@@H:17]1[C@@H:22]([O:23][CH2:24][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:21]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@@H:20]([CH2:39][O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[O:19][C@:18]1([C:49]1[CH:54]=[C:53]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([CH2:62][CH3:63])=[CH:58][CH:57]=2)[C:52]([Cl:64])=[CH:51][C:50]=1[O:65][CH3:66])[CH2:1][C:2]([CH3:3])=[CH2:4])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCc1ccc(Cc2cc([C@]3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OC)cc2Cl)cc1
Reactant: C=C(C)C[Si](C)(C)C
Solvent: ClCCl
Product: C=C(C)C[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2OC)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 104.4 %

Procedure:
To a mixture of methallyltrimethylsilane (185 μL, 1.05 mmol) and 23 (0.28 g, 0.35 mmol) in anhydrous methylene chloride (10 mL) at −20° C. was added BF3 OEt2 (88 μL, 0.70 mmol) in a drop-wise manner. The resulting light orange mixture was stirred for 1 hour, during which the temperature was allowed to rise to 0° C. The reaction mixture was quenched with 10% NaHCO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered, and evaporated to yield a residue which was purified by column chromatography eluting with 0-15% EtOAc in petroleum ether to give 24 (153 mg, 52%). 1H NMR (300 MHz, CDCl3) δ 7.18-7.30 (m, 20H), 7.00-7.05 (m, 1H), 6.98 (s, 4H), 6.69 (s, 1H), 4.67 (t, J=10.8 Hz, 1H), 4.49-4.60 (m, 8H), 4.24 (d, J=11.4 Hz, 1H), 4.12 (d, J=6.0 Hz, 1H), 3.67-4.00 (m, 7H), 3.54 (s, 3H), 3.07 (d, J=16.2 Hz, 1H), 2.79 (d, J=15.9 Hz, 1H), 2.55 (q, J=7.5 Hz, 2H), 1.54 (s, 3H), 1.17 (t, J=7.5 Hz, 3H). LC/MS m/z 860 (M+Na).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:32][OH:33].C(N(CC)C(C)C)(C)C>>[NH2:2][C:1](=[N:32][OH:33])[C:3]1[CH:4]=[C:5]([NH:20][C:21](=[O:30])[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)Nc2ccc(C#N)cc2NC(=O)c2ccc(OC)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2ccc(C(N)=NO)cc2NC(=O)c2ccc(OC)cc2)cc1
Yield: 93.3 %

Procedure:
To a stirred solution of 4-cyano-N1,N2-bis(4-methoxybenzoyl)-1,2-benzenediamine (750 mg, 1.9 mmol) was added hydroxylamine hydrochloride (130 mg, 1.9 mmol) and N,N-diisopropylethylamine (0.30 mL, 1.9 mmol). After heating at reflux for 12 h, the solution was cooled and the solvent was removed in vacuo. The residue was suspended in ethyl acetate and water, stirred vigorously, filtered, and dried in vacuo to give 770 mg (95%) of the title product as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1)([OH:14])[CH:10]=[C:11]([CH3:13])C.[CH3:22][S-].[Na+]>CN(C)C=O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1)([OH:14])[CH:10]=[CH:11][CH2:13][CH3:22]
Reactant: C[S-]
Reactant: COc1ccccc1C(O)(C=C(C)C)c1ncccc1C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC=CC(O)(c1ccccc1O)c1ncccc1C
Temperature: 120 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
7.13 g of 1-(2-methoxyphenyl)-3-methyl-1-(3-methyl-2-pyridyl)-2-buten-1-ol were dissolved in 100 ml of dimethylformamide at room temperature and 5.29 g of sodium methanethiolate were added. After stirring at 120° C. for 2 hours the mixture was allowed to cool to room temperature and then evaporated. Water and ethyl acetate were added, and the organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. There were obtained 4.53 g of 1-(2-hydroxyphenyl)-4-methyl-1-(3-methyl-2-pyridyl)-2-buten-1-ol in the form of an oil.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[S:14]([O-:18])([OH:17])(=[O:16])=[O:15].[Na+:19].C(O)(C)C>O>[Na+:19].[S:14]([O-:18])([O-:17])(=[O:16])=[O:15].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[Na+:19]
Reactant: O=S(=O)([O-])O
Agent: Cl
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=S(=O)([O-])[O-]
Reaction time: 4 h

Procedure:
Glucosamine hydrochloride (6.45 g, 0.03 mol) and sodium hydrogen sulphate (1.8 g, 0.015 mol) were taken in a flask and dissolved in water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol(150 ml) at room temperature over a period of one hour. The contents in the flask were further stirred for 4 hrs and then kept at 0° C.-5° C. for 16 hrs. The precipitate was filtered under vacuum (150 mm Hg). The product was washed twice (each time with 25 ml of isopropanol).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]([C:12](=[O:20])[N:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH3:14])=[C:10]([C:21](OC)=[O:22])[C:9]3[CH2:25][O:26][CH2:27][CH2:28][C:8]2=3)=[CH:4][CH:3]=1.[H-].[Na+].[NH4+].[Cl-]>CN(C)C=O>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:20])[N:13]([CH3:14])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:21]([OH:22])[C:10]=3[C:9]3[CH2:25][O:26][CH2:27][CH2:28][C:8]2=3)=[CH:4][CH:3]=1
Reactant: COC(=O)CN(C)C(=O)c1c(C(=O)OC)c2c(n1Cc1ccc(F)cc1)CCOC2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)c2c3c(n(Cc4ccc(F)cc4)c2c(=O)n1C)CCOC3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
An ice cold solution of methyl 1-(4-fluorobenzyl)-2-((2-methoxy-2-oxoethyl)(methyl)carbamoyl)-1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-3-carboxylate (3.2 g, 7.65 mmol) in N,N-Dimethylformamide (DMF) (38.2 ml) was treated with NaH (0.398 g, 9.94 mmol). After 5 min, the reaction mixture was warmed to ambient temperature. After 45 min, the reaction mixture was poured into sat. aq. NH4Cl and extracted with EtOAc. The organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford methyl 5-(4-fluorobenzyl)-9-hydroxy-7-methyl-6-oxo-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylate (2.54 g, 6.57 mmol, 86% yield) as a yellow solid. LCMS (m/z) ES+=387 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:3])[CH3:2].Cl.[Br:21][C:22]1[CH:27]=[CH:26][C:25](ON)=[C:24]([Cl:30])[CH:23]=1>>[C:1]([O:4][CH2:5][CH:6]1[N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH:9]2[C:26]3[CH:27]=[C:22]([Br:21])[CH:23]=[C:24]([Cl:30])[C:25]=3[O:12][CH:10]2[CH2:11]1)(=[O:3])[CH3:2]
Reactant: NOc1ccc(Br)cc1Cl
Reactant: CC(=O)OCC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)OCC1CC2Oc3c(Cl)cc(Br)cc3C2CN1C(=O)OC(C)(C)C
Yield: 8 %

Procedure:
The product obtained from step I (1.33 g, 4.9 mmol) was reacted with O-(4-bromo-2-chlorophenyl)hydroxylamine hydrochloride following the procedure of Example 29 step B. Purification by column chromatography (SiO2, 49:1 to 19:1 hexanes/ethyl acetate) afforded tert-butyl 3-(acetoxymethyl)-8-bromo-6-chloro-1,4,4a,9b-tetrahydrobenzofuro[3,2-c]pyridine-2(3H)-carboxylate (203 mg, 8%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.43 (s, 1H), 7.38 (d, J=1.8 Hz, 1H), 5.14 (br s, 2H), 4.10-4.07 (m, 3H), 3.16-3.14 (m, 1H), 2.80 (d, J=17.4 Hz, 1H), 2.04 (s, 3H), 1.52 (s, 9H).