Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:46]2[CH2:51][CH2:50][CH:49]([C:52]3[CH:53]=[N:54][N:55](COCC[Si](C)(C)C)[CH:56]=3)[CH2:48][CH:47]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[NH:54]1[CH:53]=[C:52]([CH:49]2[CH2:50][CH2:51][C:46]([C:2]3[CH:7]=[C:6]([NH2:8])[N:5]4[N:25]=[CH:26][C:27]([C:28]5[CH:29]=[N:30][C:31]6[C:36]([CH:37]=5)=[CH:35][CH:34]=[CH:33][CH:32]=6)=[C:4]4[N:3]=3)=[CH:47][CH2:48]2)[CH:56]=[N:55]1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: CC1(C)OB(C2=CCC(c3cnn(COCC[Si](C)(C)C)c3)CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(C2=CCC(c3cn[nH]c3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 160 °C
Reaction time: 1 h

Procedure:
To a 2 mL microwave vessel was charged 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.043 mmol, 23.5 mg), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (0.047 mmol), K3PO4 (130 mmol, 27 mg), and PdCl2(dppf).CH2Cl2 (0.0043 mmol, 3.5 mg). To this mixture was added 9:1 dioxane:H2O (1 mL). The vessel was flushed with argon and heated to 160° C. for 30 minutes in microwave synthesizer. Upon completion, the reaction was concentrated in vacuo and the residue was dissolved in 1 mL TFA. This reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified via reverse-phase preparatory HPLC to yield 5-(4-(1H-pyrazol-4-yl)cyclohex-1-enyl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine as yellow solid. (m+H=408.30, retention time=3.16 min)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[CH:19][C:18]([S:21]([C:24]4[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:32]CCCl)[CH:25]=4)(=[O:23])=[O:22])=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=O)(C)(C)C.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH:44]([N:47]([CH2:51][CH3:52])[CH:48]([CH3:50])[CH3:49])([CH3:46])C.C(#N)C>>[F:30][C:28]1[CH:29]=[C:24]([S:21]([C:18]2[CH:19]=[CH:20][C:14]3[CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]4[O:16][C:15]=3[CH:17]=2)(=[O:23])=[O:22])[CH:25]=[C:26]([O:31][CH2:32][CH2:52][CH2:51][N:47]2[CH2:44][CH2:46][CH2:50][C@H:48]2[CH3:49])[CH:27]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(S(=O)(=O)c4cc(F)cc(OCCCCl)c4)cc3OC2C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCOc1cc(F)cc(S(=O)(=O)c2ccc3c(c2)OC2CNCCC32)c1
Temperature: 70 °C

Procedure:
A mixture of 7-[3-(3-chloro-propoxy)-5-fluoro-benzenesulfonyl]-3,4,4a,9a-tetrahydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (100 mg, 0.2 mmol), (R)-2-methyl-pyrrolidine, benzenesulfonic acid salt (92.5 mg, 0.380 mmol), sodium iodide (28.5 mg, 0.190 mmol), potassium carbonate (78.8 mg, 0.570 mmol), N,N-diisopropylethylamine (99.3 uL, 0.570 mmol) in acetonitrile (8.04 mL, 154 mmol) was heated at 70° C. After 3 days the reaction was cooled to room temperature, diluted with 10 mL solvent (MeOH:CH2Cl2 1:1) and filtered through a pad of silica-gel. The filtrate was concentrated. Purification by preparative TLC (MeOH:CH2Cl2 1:9) followed by removal of N-Boc protecting group with 4N HCl using the general procedure described afforded the desired product. mp 208-212° C., MS m/z 475 [M+H]+. 1H-NMR (400 MHz, DMSOd6): δ 10.58 (br s, 1H), 9.52 (br s, 1H), 8.84 (br s, 1H), 7.58 (m, 2H), 7.49 (s, 1H), 7.43 (d, J=6.82 Hz, 1H), 7.34 (s, 1H), 7.22 (d, J=9.92 Hz, 1H), 4.95 (s, 1H), 4.19 (s, 2H), 4.03 (m, 1H), 3.58-3.31 (overlapping m & s, 4H), 3.04 (s, 2H), 2.94 (s, 2H), 2.16 (br s, 4H), 1.99 (s, 1H), 1.94 (br s, 2H), 1.40 (d, J=5.33 Hz, 3H), 1.17 (m, 2H).
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[NH:3][CH:2]=1.C=O.[C:18]([BH3-])#N.[Na+].Cl>C(#N)C>[N:1]1[CH:5]=[C:4]([CH2:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[CH3:18])[NH:3][CH:2]=1
Reactant: COc1cccc(NCc2cnc[nH]2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc(N(C)Cc2cnc[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
(3H-Imidazol-4-ylmethyl)-(3-methoxy-phenyl)-amine (0.070 g, 0.34 mmol) was dissolved in acetonitrile (10 ml). Then formaldehyde (0.0.06 ml, 0.86 mmol, 37% aqueous solution) and sodium cyanoborohydride (0.065 g, 1.03 mmol) were added and the reaction mixture was allowed to stir at room temperature for 10 minutes. The reaction mixture was then acidified to pH 2-3 by dropwise addition of concentrated hydrochloric acid whereupon precipitation occurred. The mixture was stirred for a further 1 h at room temperature before being concentrated in vacuo. The residue was taken up in ethyl acetate, washed with 1 M aqueous sodium hydroxide solution and the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified using flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: methanol/dichloromethane gradient) to yield a white solid (0.056 g, 75%); MS (ISP): 218.3 ([M+H]+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][N:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:11]2.CN(C)[CH:24]=[O:25].Cl>CCCCCC.CCOCC>[C:16]1([N:10]2[CH2:9][C:8]3[C:7]([CH:24]=[O:25])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1cccc2c1CN(c1ccccc1)C2
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cccc2c1CN(c1ccccc1)C2
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
2.3 ml (3.7 mmol) of a 1.6 molar solution of butyllithium in hexane are added to 14 ml of dry ether in a dry apparatus under argon. A solution of 930 mg (3.4 mmol) of 4-bromo-2-phenylisoindoline in 10 ml of dry ether is then added dropwise at -70° C. The mixture is stirred at -70° C. for 30 minutes, and 0.3 ml of dry dimethylformamide in 0.5 ml of ether is added. The mixture is stirred at 70° C. for 3 hours and heated to -5° C., and 13.6 ml of 1N hydrochloric acid are added dropwise. 50 ml of ether are added and the mixture is separated. The aqueous phase is extracted by shaking with ether and the combined ether phases are washed once with water, dried and concentrated. 600 mg of yellowish crystals of melting point 120°-122° C. are obtained.
Reaction SMILES: [CH3:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][NH:20]C(OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1)[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[CH:31]([S:34](Cl)(=[O:36])=[O:35])([CH3:33])[CH3:32].C1CCN2C(=NCCC2)CC1>>[CH3:10][CH:8]([S:5]([NH:4][CH2:3][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][NH:20][S:34]([CH:31]([CH3:33])[CH3:32])(=[O:36])=[O:35])=[CH:15][CH:16]=1)[CH3:1])(=[O:6])=[O:7])[CH3:9]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(CCCNC(=O)OCc2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(CCCNS(=O)(=O)C(C)C)cc1
Yield: 42 %

Procedure:
Scheme Vc, step C: {2-[4-(3-Aminopropyl)phenyl]propyl}[(methylethyl)sulfonylamine (0.3 g, 1 mmol, prepared in example 10), isopropylsulfonyl chloride (0.12 mL, 1.06 mmol), and DBU (0.2 mL, 1.17 mmol) were combined and sulfonylation was carried out in a manner analogous to the procedure described in example 2 to provide the title compound, [(methylethyl)sulfonyl]{2-[4-(3-{[(methylethyl)sulfonyl]amino}propyl)phenyl]propyl}amine, (0.17 g, 42%) as a white crystalline solid. Electron spray M.S. 405 (M*+H). Analysis for C18H32N2O4S2:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][C:36]([CH3:47])([CH3:46])[CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]([CH3:47])([CH3:46])[CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(CBr)CO[Si](C)(C)C(C)(C)C
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (4.1 g), (3-bromo-2,2-dimethylpropoxy)(tert-butyl)dimethylsilane (2.36 g) and N,N-dimethylacetamide (10 mL) was stirred at 130° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 27%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]([NH:30][CH3:31])=[O:29]>CN(C)C=O>[N:11]1([CH2:10][C:2]2[N:1]([CH2:27][C:28]([NH:30][CH3:31])=[O:29])[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: c1ccc2[nH]c(Cn3nnc4ccccc43)nc2c1
Reactant: CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)Cn1c(Cn2nnc3ccccc32)nc2ccccc21
Reaction time: 8 h
Yield: 47.4 %

Procedure:
1-(1H-Benzimidazol-2-ylmethyl)-1H-benzotriazole (500 mg, 2.00 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). Potassium carbonate (1.11 g, 8.00 mmol) and 2-chloro-N-methylacetamide (237 mg, 2.20 mmol) were added. The reaction mixture was allowed to stir overnight at reflux. The solvent was evaporated under vacuum, and the white waxy residue taken up in methylene chloride (300 mL). The organic extract was washed with saturated aqueous sodium bicarbonate (2×100 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography (CH2Cl2/MeOH=15:1) to give 304 mg (47%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C>[CH3:1][NH:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNN
Reactant: O=Cc1ccccc1
Solvent: CCOCC
Product: CNN=Cc1ccccc1

Procedure:
18.4 g (0.4 mol) of methylhydrazine were initially charged in 248.7 g of diethyl ether. At 22-26° C., 42.4 g (0.4 mol) of benzaldehyde were added dropwise within 1.75 hours. The reaction mixture was then stirred at reflux temperature for 5 hours. The residue obtained after the solvent had been distilled off was taken up in diethyl ether and the solution was dried over sodium sulfate. After drying, the solution was concentrated under reduced pressure and the residue obtained was distilled at 78° C./0.5-1 mbar.
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:12](#[N:15])[CH:13]=[CH2:14].C(N(CC)CC)C.CN(C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:2]1([C:13](=[CH2:14])[C:12]#[N:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cccc2ccccc12
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(C#N)c1cccc2ccccc12
Yield: 90 %

Procedure:
Table 1, Entry 4. In the reaction tube were mixed 1-iodonaphthalene (0.254 g, 1.0 mmol), acrylonitrile (0.066 g, 1.25 mmol), palladium acetate (0.00225 g, 0.01 mmol), triethylamine (0.50 ml) and 0.50 ml DMF.under nitrogen. The contents of the flask were irradiated for 3.50 min with an effect of 80 W. After cooling, the product mixture was poured into 25 ml water and was extracted three times with 25 ml DCM. The combined extracts were washed with 25 ml water and concentrated to an oil. The crude product was purified by column chromatography on silica gel using i-hexane/diethyl ether (2/1) as the eluent. The yield was 90% (white solid, trans/cis 4/1).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5]OCC(O)=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH:38]1([CH2:37][C@H:13]([NH:12][C:29](=[O:30])[CH2:28][N:16]([CH3:14])[NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC1CCCCC1
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CC1CCCCC1)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC
Yield: 44.6 %

Procedure:
According to the procedure described in the synthesis method of Compound II-130, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 32 mg (0.18 mmol) was coupled with (S)-2-amino-3-cyclohexyl-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-23) 66 mg (0.15 mmol) to obtain the title compound 20 mg (23%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:12](=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:27])[N:5]=1)[CH3:3].Cl[C:29]1[C:30]2[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[F:27][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:12](=[O:26])[N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])[CH:15]=1)[C:4]([C@@H:2]([NH:1][C:29]1[C:30]3[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][NH:35][C:31]=3[N:32]=[CH:33][N:34]=1)[CH3:3])=[N:5]2
Reactant: FC(F)(F)c1c[nH]c2ncnc(Cl)c12
Reactant: C[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc2[nH]cc(C(F)(F)F)c12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (76 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.4 mL) at 23° C. was added 4-chloro-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (49 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 16 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 50 mg of the title compound (44% yield).
Reaction SMILES: [OH2:1].C[N+]1([O-])CCOCC1.C[N+]1([O-])CCOCC1.[C:18]([O:22][C:23]([NH:25][C@@:26]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:31]=[CH:30][C@@H:29]2[C@H:27]1[C@H:28]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])([CH3:21])([CH3:20])[CH3:19].CCCCCC.C(OCC)(=O)C.[OH2:58]>CC(C)=O.[Os](=O)(=O)(=O)=O>[C:18]([O:22][C:23]([NH:25][C@@:26]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:31]([OH:1])[C@H:30]([OH:58])[C@@H:29]2[C@H:27]1[C@H:28]2[C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C=C[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1O
Temperature: 23 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
Osmium tetraoxide (4% wt/wt in water, 231.78 mL, 241.05 g, 37.93 mmol,) is added at 23° C. to a solution of N-methylmorpholine-N-oxide hydrate (101.62 mL; 114.83 g, 424.78 mmol), N-methylmorpholine-N-oxide hydrate (116.88 g, 864.74 mmol), 4-methylmorpholine-4-oxide (198.88 mL; 195.50 g, 1.67 mol), and di-tert-butyl (1S,2S,5R,6S)-2-[(tert-butoxycarbonyl)amino]bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylate (600.00 g, 1.52 mol) in acetone (12.00 L) and water (1.80 L). The mixture is stirred at 23° C. overnight. Thin layer chromatograph (hexane/ethyl acetate 3:2; stain: PMA) analysis of the reaction mixture revealed complete consumption of di-tert-butyl (1S,2S,5R,6S)-2-[(tert-butoxycarbonyl)amino]bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylate. The reaction is quenched with saturated aqueous Na2S2O3 (1 L) and extracted with methyl tert-butyl ether (15 L). The organic phase is washed with an aqueous solution (1.5 L) prepared from 37% aqueous HCl (300 mL) and brine (1.2 L), dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue is slurried in heptane (1.5 L), filtered, washed with heptane (2×500 mL), and resulting solid. The solid is dried under vacuum to yield the title compound (450 g, 69% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])[CH:17]=1>CO.O1CCCC1>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])[CH:17]=1
Reactant: CNS(=O)(=O)c1cccc(C2=Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Solvent: CO
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Yield: 84.2 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(N-methylsulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate (175 mg, 0.438 mmol) in methanol/tetrahydrofuran (9.5 mL/9.5 mL) was treated with H2 at room temperature overnight. LC-MS showed the reaction was complete. The mixture was separated by filtration and the filtrate was concentrate in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to give 143.2 mg of methyl 3,3-dimethyl-2-(3-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate, yield: 81.2%.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(Cl)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2ccc(Cl)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-chlorophenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 7) 80.0 mg (0.181 mmol) in 3 ml of EtOH and 2 ml of THF was added 48.0 mg (1.20 mmol, 1.20 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (MSO): δ 7.90 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.51-7.48 (4H, m), 7.34 (2H, d, J=8.4 Hz), 6.97 (1H, s), 6.07 (1H, t, J=4.5 Hz), 2.34 (2H, d, J=4.6 Hz), 1.29 (6H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][O:22]S(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]1[O:31][C:30]2[CH:32]=[C:33](O)[CH:34]=[CH:35][C:29]=2[O:28]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][O:22][C:33]2[CH:34]=[CH:35][C:29]3[O:28][CH2:27][O:31][C:30]=3[CH:32]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC[C@@H]1CN(Cc2ccccc2)CC[C@@H]1c1ccc(F)cc1
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Fc1ccc([C@@H]2CCN(Cc3ccccc3)C[C@H]2COc2ccc3c(c2)OCO3)cc1
Yield: 64 %

Procedure:
To a solution containing 7.54 g (0.02 mol) of (+)-cis-1-benzyl-4-(4-fluorophenyl)-3-mesyloxymethylpiperidine in 120 ml of tertiary butanol, 3 g (0.022 mol) of sesamol and 3.35 g (0.03 mol) of potassium tertiary butoxide are added and the mixture is boiled under reflux for 12 hours. After completion of the reaction the mixture is evaporated and 100 ml of dichloromethane and 50 ml of water are added to the residue. After separation, the organic phase is washed with water until neutral, dried over a drying agent and after filtration the filtrate is evaporated to solvent-free. The evaporation residue is recrystallized from 25 ml of isopropanol. The precipitated product is filtered at 0° C. to obtain 5.37 g (64%) of title compound, m.p.: 98-100° C.; [α]D20−37.1° (c=1, chloroform).
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[C:15]([Br:26])[CH:14]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH:42]=[CH:43][CH2:44]O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH:42]=[CH:43][CH2:44][N:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:10][N:9]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:12]=2)=[CH:14][C:15]=1[Br:26])[C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Nc1ccc(-c2nc(Cc3ccccc3)no2)cc1Br)C(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCN(C(=O)C(F)(F)F)c1ccc(-c2nc(Cc3ccccc3)no2)cc1Br
Yield: 88 %

Procedure:
4-(3-Benzyl-1,2,4-oxadiazol-5-yl)-2-bromo-1-trifluoroacetylaminobenzene and (R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene were used. Chromatography using elution with 5% either in methylene chloride afforded the title compound (88%) as a thick yellow oil: R1 =0.32 (CHCl3); LRMS (m/z, relative intensity) 669 (M+, 25).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[C:5]([CH3:11])[C:4]=1[OH:12].[OH:13]O>CCOCC.O.C(O)(=O)C>[CH3:11][C:5]1[C:4](=[O:12])[C:3]([CH3:2])=[C:8]([CH3:9])[C:7](=[O:13])[C:6]=1[CH3:10]
Reactant: OO
Reactant: Cc1cc(C)c(C)c(O)c1C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: CC1=C(C)C(=O)C(C)=C(C)C1=O
Yield: 55 %

Procedure:
To 30 mg of the catalyst prepared in the same manner as in Example 19, 100 mg of water was added and stirred, and then 5 ml of an acetic acid solution containing 1% of hydrochloric acid was added. While cooling the mixture with water, 500 mg of 2,3,5,6-tetramethylphenol and 1 g of a 31% hydrogen peroxide aqueous solution were added, and the mixture was stirred for 2.5 hours. After the completion of the reaction, the mixture was diluted with ether, and the catalyst was filtered and washed successively with a NaHCO3 aqueous solution and a saturated sodium chloride aqueous solution. The filtrate was dried over MgSO4 and then concentrated, and the residue was purified by silica gel chromatography by eluting it with a solvent mixture of hexane-dichloromethane (1:1), whereby 300 mg (55% yield) of tetramethylbenzoquinone was obtained.