Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:25][CH2:24][CH2:23][CH2:22][C:21]([C:26]([O:28]CC)=[O:27])=[CH:20][C:19]=3[CH:31]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:25][CH2:24][CH2:23][CH2:22][C:21]([C:26]([OH:28])=[O:27])=[CH:20][C:19]=3[CH:31]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCO3)cc1
Reaction time: 8 h
Yield: 32.5 %

Procedure:
Ethyl 8-[4-(2-butoxyethoxy) phenyl]-3,4-dihydro-1-benzoxocin-5-carboxylate (527 mg) was dissolved in THF (40 ml) and methanol (40 ml). Aqueous 1N sodium hydroxide solution (12.4 ml) was added to the solution and the resulting solution was stirred overnight. After neutralization with 1N hydrochloric acid at 0° C., the solution was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from hexane-ethyl acetate to obtain colorless crystals of 8-[4-(2-butoxyethoxy)phenyl]-3,4-dihydro-2H-1-benzoxocin-5-carboxylic acid (160 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30].CO.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.O1CCCC1>[CH3:26][C:25]1[C:20]([C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]4[N:5]([CH:27]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[N:3]=4)[CH:6]=3)[CH:12]=2)=[O:19])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CCC(=O)Nc1cn2cc(Oc3cccc(NC(=O)c4ncccc4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 41.2 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (129 mg, 0.359 mmol) in N,N-dimethylacetamide (6 mL) was added propionylchloride (34.3 μL, 0.395 mmol), and the mixture was stirred at room temperature for 22 hr. Methanol, tetrahydrofuran and aqueous sodium carbonate solution were added to the reaction mixture, and the mixture was stirred at 60° C. for 22 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (61.4 mg, 41%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5]2.[C:15](Cl)(=O)C(Cl)=O.CC1(C)OC(=O)CC(=O)O1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12](=[O:14])[CH3:15])[CH:6]=[CH:5]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cn1ccc2cc(Cl)ccc21
Agent: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Cn1ccc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of acid from Step 1 (1.048 g, 5 mmol) in CH2Cl2 (45 mL) at r.t. there was added oxalyl chloride (762 mg, 6 mmol) and 2 drops of DMF. The mixture was stirred at r.t. for 1 hour, then it was added slowly to a cooled (0° C.) solution of 2,2-dimethyl-1,3-dioxan-4,6-dione (864 mg, 6 mmol) in CH2Cl2 (10 mL) and pyridine (1 mL). The resulting mixture was stirred at 0° C. for 30 minutes, then at r.t. for 1.5 hours. The CH2Cl2 was evaporated, there was added a mixture of HOAc (15 mL) and H2O (30 mL), and the mixture was heated at 90° C. for 45 minutes. After dilution with H2O, the mixture was extracted twice with EtOAc, and these combined extracts were washed with H2O, dried and evaporated to a residue which was chromatographed on silica gel, eluting with EtOAc-hexane (1:2) to afford the title compound as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][CH3:12])(=[O:10])[CH2:8][SH:9].[Br:13][C:14]1[C:15](F)=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH:17]=O.O>CC#N>[Br:13][C:14]1[C:15]2[S:9][C:8]([C:7]([O:11][CH3:12])=[O:10])=[CH:17][C:16]=2[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cc(C(F)(F)F)cc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc2cc(C(F)(F)F)cc(Br)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (1.44 g, 10.42 mmol) then methyl thioglycolate (0.487 g, 4.59 mmol) were added to a degassed solution of 3-bromo-2-fluoro-5-(trifluoromethyl)benzaldehyde (1.13 g, 4.17 mmol) in CH3CN (11 mL). The mixture was stirred at room temperature for 30 minutes then refluxed at 100° C. overnight. The mixture was allowed to cool to room temperature, then water (20 mL) was added. The resulting light yellow solid was collected by vacuum filtration, washed with water, then dried in vacuo. The resulting ester was used directly for the following step. 1H NMR (500 MHz, CDCl3) δ 8.24 (br s, 1H); 8.15 (br s, 1H); 7.86 (br s, 1H); 4.02 (br s, 3H). LC1: 4.00 min. Compound does not ionize.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:19][CH:20]=[CH2:21])[C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH:36]([C:39]1[CH:44]=[CH:43][C:42]([S:45]([NH:48][CH3:49])(=[O:47])=[O:46])=[CH:41][CH:40]=1)([CH3:38])[CH3:37].[H-].[Na+]>FC(F)(F)C1C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:19][CH:20]=[CH2:21])[C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:48]([S:45]([C:42]3[CH:43]=[CH:44][C:39]([CH:36]([CH3:38])[CH3:37])=[CH:40][CH:41]=3)(=[O:46])=[O:47])[CH3:49])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNS(=O)(=O)c1ccc(C(C)C)cc1
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(Br)ccc2C1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: FC(F)(F)c1ccccc1
Product: C=CCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(N(C)S(=O)(=O)c3ccc(C(C)C)cc3)ccc2C1
Reaction time: 0.08 h
Yield: 112.3 %

Procedure:
In an inert atmosphere (argon), allyl-((S)-6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (749 mg, 2.0 mmol) was dissolved in trifluortoluol (20 ml) at room temperature. Tris(dibenzylideneacetone)dipalladium (92 mg, 0.1 mmol) and tri-tert-butyl-phosphane (61 mg, 0.3 mmol) were added to the reaction mixture. In a separate flask, 4-Isopropyl-N-methyl-benzenesulfonamide (427 mg, 2 mmol) was dissolved in trifluortoluol (20 ml) at 65° C. Sodium hydride (50% in oil) (96 mg, 2 mmol) was added, stirred for 5 minutes and added to the reaction mixture. The reaction mixture was dispensed into 3 vials and stirred for 1 hour at 150° C. in the microwave (CEM). The combined reaction mixture was evaporated to dryness. H20 (50 ml) was added and extracted three times with 50 ml diethylether. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield crude product (1.12 g, 68%).
Reaction SMILES: C([Li])CCC.[Br-].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:41]1([CH2:47][CH2:48][CH:49]=O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[C:41]1([CH2:47][CH2:48][CH:49]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][O:7]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: c1ccc([P+](CCCCCCCCOC2CCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CCCc1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=CCCc1ccccc1)CCCCCCCOC1CCCCO1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6M solution in hexane, 20 ml) was added to a stirred solution of the product of step (a) (11.0 g) in dry tetrahydrofuran at -70° C. under nitrogen. The orange solution was stirred for 30 minutes at -70° C. then a solution of 3-phenyl-propionaldehyde (2.75 g) in tetrahydrofuran (7 ml) was added. The pale solution was allowed to warm to room temperature and then evaporated. The residue was extracted with ether and the extract again evaporated and the residue was chromatographed on silica-gel eluting with 1:1 ether:hexane to give the title compound as a pale oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:10]1[N:15]=[CH:14][C:13](/[C:16](/[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:18][CH3:19])=[CH:12][CH:11]=1>>[C:20]1(/[C:17](/[CH2:18][CH3:19])=[C:16](/[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)\[C:13]2[CH:14]=[N:15][C:10]([O:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Reactant: OCCN1CCCC1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCN2CCCC2)nc1)c1ccccc1
Yield: 113.4 %

Procedure:
Following the same procedure as described in example 3, 2-(pyrrolidin-1-yl)ethanol (343 mg, 10 eq) and (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (100 mg, 1 eq, prepared from example 1) were used as starting material to get the desired product (140 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.15-7.20 (m, 2H), 7.01-7.13 (m, 6H), 6.92 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.4 Hz, 2H), 5.68 (brs, 1H), 4.26 (bs, 2H), 2.91 (brs, 2H), 2.72 (brs, 4H), 2.50 (q, J=7.2 Hz, 2H), 1.89 (brs, 4H), 0.91 (t, J=7.6 Hz, 3H); m/z=415 [M+1]+.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([O-:13])(O)=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N+:16]=1[O-:22]>OS(O)(=O)=O>[Cl:14][C:15]1[CH:20]=[C:19]([N+:10]([O-:13])=[O:11])[C:18]([Cl:21])=[CH:17][N+:16]=1[O-:22]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1cc(Cl)ccc1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1cc(Cl)[n+]([O-])cc1Cl
Temperature: 25 °C

Procedure:
At 0° C., 30% oleum (13 mL) is added slowly to fuming HNO3 (22 mL) and the resulting mixture is added slowly to the solution of 2,5-dichloro-pyridine 1-oxide (5.2 g, 31 mmol) in concentrated H2SO4. After addition, the reaction mixture is warmed to room temperature over 1 hr, then heated to 80° C. for 2 hr. After cooling to room temperature, the mixture is poured into ice (120 g) and precipitate is formed gradually. The solid is collected by filtration and washed with water. The product is obtained as yellow solid. 1H NMR (CDCl3) δ 8.46 (s, 1H), 8.25 (s, 1).
Reaction SMILES: [CH3:1][N:2]([CH:6]1[CH2:19][C:18]2[C:9]([CH3:28])([CH:10]3[CH:15]([CH2:16][CH:17]=2)[CH:14]2[CH2:20][CH2:21][CH:22]4[CH:23]([CH3:27])[N:24]([CH3:26])[CH2:25][C:13]24[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](Cl)=[O:4].[CH2:29]([OH:33])[CH2:30][CH2:31][OH:32]>N1C=CC=CC=1>[OH:32][CH2:31][CH2:30][CH2:29][O:33][C:3](=[O:4])[N:2]([CH3:1])[CH:6]1[CH2:19][C:18]2[C:9]([CH3:28])([CH:10]3[CH:15]([CH2:16][CH:17]=2)[CH:14]2[CH2:20][CH2:21][CH:22]4[CH:23]([CH3:27])[N:24]([CH3:26])[CH2:25][C:13]24[CH2:12][CH2:11]3)[CH2:8][CH2:7]1
Reactant: CC1C2CCC3C4CC=C5CC(N(C)C(=O)Cl)CCC5(C)C4CCC32CN1C
Reactant: OCCCO
Solvent: c1ccncc1
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)OCCCO)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 26.9 %

Procedure:
Compound 189A (30 mg, 0.074 mmol) and 1,3-propanediol (54μL, 0.061 mmol), were dissolved in pyridine (1 mL). The mixture was stirred at room temperature for 5 days. Stripped of pyridine, the crude reaction mixture was purified on silica gel column using 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (7.3 mg, 22.8% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.Cl.[NH2:19][OH:20].C[O-].[Na+].C(OCC)(=O)C>CO.O>[OH:20][N:19]=[CH:1][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C=O)cc(-n2cccc2)c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(C=NO)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 79.3 %

Procedure:
Methyl 3-formyl-5-(pyrrol-1-yl)benzoate (2.0 g) was added to a mixture of hydroxylamine hydrochloride (0.61 g) and 28% methanolic sodium methoxide (1.8 ml) in methanol (20 ml) and the whole was stirred for 22 hours at ambient temperature. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and ethyl acetate (20:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-hydroxyiminomethyl-5-(pyrrol-1-yl)benzoate (1.69 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=[O:25])[C:14]2=[O:30])[CH:3]=1.C([O-])=[O:32].[NH4+]>CO>[CH3:11][N:8]1[C:9]2[C:5](=[C:4]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]([CH:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=[O:25])[C:14]3=[O:30])[CH:3]=[CH:2][CH:10]=2)[CH2:6][C:7]1=[O:32]
Reactant: O=C[O-]
Reactant: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3c2ccn3C)c2ccccc21
Agent: [NH4+]
Solvent: CO
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cccc3c2CC(=O)N3C)c2ccccc21
Reaction time: 60 h
Yield: 34.4 %

Procedure:
To a solution of 3-[3-(6-bromo-1-methyl-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (25 mg, 0.05 mmol) in methanol (2 mL) was added ammonium formate (150 mg, 2.4 mmol) and PdC 10% (5 mg). The resulting mixture was agitated for 60 h, filtered and concentrated. The resulting residue was dispersed in DCM (2 mL), filtered, and the filtrate was washed with DCM (1×2 mL). The mother liquors were concentrated and the residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient to provide 7 mg (35%) of the title compound. LCMS (ESMS): m/z 408 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH3:30].C(O)(C(F)(F)F)=O.[K+].[Br-]>C(#N)C.O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]([CH3:30])[CH:8]=3)=[CH:15][CH:16]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(OC)cc3)cc2)cc1C
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COc2ccc(CSc3ccc(OCC(=O)O)c(C)c3)cc2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 33C. mp 150-152° C.; HPLC: area %=96.69, r.t.=2.93 min., γ=214 nm, mobile phase=acetonitrile/water with 0.10% TFA; IR (KBr) cm−1: 2929, 1728, 1707, 1513, 1491, 1225; 400 MHz 1H NMR (DMSO-d6): δ 12.98 (br(s), 1H), 7.27-7.34 (m, 2H), 7.02-7.16 (m, 4H), 6.81-6.91 (m, 4H), 6.69 (d, 1H, J=8.6 Hz), 4.91 (s, 2H), 4.61 (s, 2H), 3.99 (s, 2H), 3.69 (s, 3H), 2.08 (s, 3H); MS m/z 423 (M−1). Anal. Calc'd for C24H24O5S: C, 67.90; H, 5.70. found: C, 67.48; H, 5.59.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C@H:10]([N:24]([CH3:35])[C:25](=[O:34])[CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:9][CH2:8][C@@:7]4([OH:36])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.Cl.C1(CN2CC[C@]34C5[C:51]6O[C@H]3[C@H](N(C)C(=O)C=CC3C=CC=CC=3)CC[C@@]4(O)[C@H]2CC=5C=C[C:52]=6[OH:57])CC1.C1(CN2CC[C@]34C5C6O[C@H]3[C@H](N(C)C(=O)C=CC3C=CC=C(C(F)(F)F)C=3)CC[C@@]4(O)[C@H]2CC=5C=CC=6O)CC1.C(C(C(C([O-])=O)O)O)([O-])=O>>[CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C@H:10]([N:24]([CH3:35])[C:25](=[O:34])[CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:9][CH2:8][C@@:7]4([OH:36])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][C:52](=[O:57])[CH3:51])[CH2:2][CH2:3]1
Reactant: CN(C(=O)C=Cc1ccccc1)[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: CN(C(=O)C=Cc1cccc(C(F)(F)F)c1)[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@H](N(C)C(=O)C=Cc4ccccc4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314

Procedure:
tartrate 140 (yield: 70%) and 17-cyclopropylmethyl-3-acetoxy-14β-hydroxy-4,5α-epoxy-6β-(N-methyl-3-trifluoromethylcinnamamido)morphinan.tartrate 141 (yield: 56%) were obtained by following the procedure of example 129 but using 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(N-methylcinnamamido)morphinan.tartrate 99 and 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(N-methyl-3-trifluoromethylcinnamamido)morphinan.tartrate 60 instead of 17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6α-(N-methyl-3,4-dichlorophenylacetamido)morphinan.hydrochloride 1.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:28][Mg]Br.CCOCC.[Cl-].[NH4+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])([CH3:28])[CH3:26])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: C[Mg]Br
Reactant: CCN1CCN(c2nc(-c3ccc(C(C)=O)cc3)cc3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCN1CCN(c2nc(-c3ccc(C(C)(C)O)cc3)cc3ccccc23)CC1

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(4-acetylphenyl)isoquinoline (0.10 g) was dissolved in tetrahydrofuran (10 ml) and stirred under ice-cooling, to which was then added 3.0M methylmagnesium bromide/ether solution (1.1 ml), and the mixture was further stirred for 1.5 hr. An aqueous solution of saturated ammonium chloride, a 10% aqueous solution of sodium carbonate and ethyl acetate were added to the resulting mixture, the mixture was stirred. The organic layer was separated, and then it was washed with brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.05 g of the free compound of the title compound as a pale brown amorphous.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([NH2:26])=[O:25])=[CH:27][CH:28]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: NC(=O)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Product: NC(=O)c1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3[nH]cnc23)cc1

Procedure:
800 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 289 mg of the product obtained in stage 1 above are added. 147 mg of the expected product are thus obtained.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]=1[CH2:25][S:26][C:27]1[CH2:31][C:30]([CH3:33])([CH3:32])[O:29][N:28]=1.O>C(Cl)(Cl)Cl>[Cl:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]=1[CH2:25][S:26]([C:27]1[CH2:31][C:30]([CH3:33])([CH3:32])[O:29][N:28]=1)=[O:9]
Reactant: Cn1nc(-c2ccccc2)c(CSC2=NOC(C)(C)C2)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2ccccc2)c(CS(=O)C2=NOC(C)(C)C2)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
0.87 g of m-chloroperbenzoic acid (purity: 70%, 3.54 mmoles) was added, with ice-cooling, to a solution of 0.85 g (2.53 mmoles) of 3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 30 ml of chloroform. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.48 g (yield: 53.9%) of 3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylsulfinyl)-5,5-dimethyl-2-isoxazoline as a transparent viscous substance.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[CH3:19])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N1C=CC=CC=1.FC(F)(F)C(O[C:33]1[C:38]([F:39])=[C:37]([F:40])[C:36]([F:41])=[C:35]([F:42])[C:34]=1[F:43])=O>CN(C)C=O.CCOCC>[F:39][C:38]1[C:33]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[C:3]([F:21])=[C:4]([F:20])[C:5]=2[NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[CH3:19])=[C:34]([F:43])[C:35]([F:42])=[C:36]([F:41])[C:37]=1[F:40]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)O)cc(Br)c(F)c1F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cc(I)ccc1Nc1c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc(Br)c(F)c1F
Yield: 90.5 %

Procedure:
To a solution of 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (prepared as described in WO 99/01426) (1.61 g, 3.4 mmol) and pyridine (0.31 mL, 3.83 mmol) in anhydrous dimethylformamide (7 mL) was added 10 pentafluorophenyl trifluoroacetate (0.71 mL, 4.13 mmol). The resultant solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with ether (100 mL) and washed with water (40 mL), 0.1 M aqueous hydrochloric acid (40 mL), saturated aqueous sodium bicarbonate (40 mL), and saturated brine (40 mL). The organics were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a foam that was purified on silica gel. Elution with hexanes-ethyl acetate (19:1) afforded 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid pentafluorophenyl ester (1.95 g, 89%) as a pale-yellow powder: 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.24 (d, J=5.8 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J=8.4 Hz, 1H), 6.70 (dd, J=8.4, 5.3 Hz, 1H), 2.26 (s, 3H).