Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]3)=[CH2:8])[CH:2]=1.[H][H]>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]3)[CH3:8])[CH:2]=1
Reactant: C=C(c1cccnc1)c1ccc2cc(C(=O)OC)ccc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2cc(C(C)c3cccnc3)ccc2c1
Yield: 20 %

Procedure:
130 mg of Pd/C (10%) are added to 0.25 g (0.86 mmol) of methyl 6-[1-(3-pyridyl)ethenyl]-2-naphthoate in 25 ml of absolute methanol, and hydrogenation is carried out under atmospheric pressure (hydrogen uptake: 40 ml). The catalyst is then removed by filtration, and the solution is evaporated and chromatographed on silica gel using ethyl acetate. 50 mg (20%) of methyl 6-[1-(3-pyridyl)ethyl]-2-naphthoate are obtained as an oil. RF (ethyl acetate): 0.34.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:30]=[CH:29][N:13]([C@@H:14]2[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:31])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][S:33]([CH3:35])=O.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>CCOC(C)=O.C(O)(=O)C>[C:1]([NH:9][C:10]1[CH:30]=[CH:29][N:13]([C@@H:14]2[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:23])[CH3:22])[C@@H:16]([O:17][CH2:32][S:33][CH3:35])[CH2:15]2)[C:12](=[O:31])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)C[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CSCO[C@H]1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
3.5 g N4-benzoyl-5′-O-tert-butyldimethylsilyl-2′-deoxycytidine (5c) (7.65 mmol) was dissolved in a mixture consisting of 14.7 mL DMSO, 6.7 mL acetic acid, and 21.59 mL acetic anhydride and stirred for 48 h at room temperature. During this period of time, a complete conversion to product was observed by TLC(Rf=0.4, EtOAc:hex/10:1). The mixture was then neutralized with a saturated NaHCO3 solution and extracted with CH2Cl2 (3×100 mL). The combined organic extract was then washed with saturated solution of NaHCO3 and dried over Na2SO4, and concentrated under vacuum. The product was then purified by silica gel column chromatography (EtOAc:hex/2:1 to 9:1) to obtain N4-benzoyl-3′-O-(methylthiomethyl)-5′-O-(tert-butyldimethylsilyl)-2′-deoxycytidine (6c) as white powder in 73% yield (2.9 g, Rf=0.6, EtOAc:hex/9:1). HR-MS: obs. m/z 506.2134, cald. for C24H36O5N3SiS [M+H]+. 506.2145. 1H-NMR (CDCl3): δH 8.43 (d, J=7.1 Hz, 1H), 7.93 (m, 2H), 7.64 (m, 1H), 7.54 (m, 3H), 6.30 (m, 1H), 4.62 & 4.70 (2×d, J=11.59 Hz, 2H), 4.50 (m, 1H), 4.19 (m, 1H), 3.84 & 3.99 (2×dd, J=11.59 & 2.79 Hz, 2H), 2.72 (m, 1H), 2.21 (m, 1H), 2.14 (s, 3H), 0.99 (s, 9H), and 0.16 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([OH:17])(=[O:16])[CH2:12][CH2:13][C:14]#[CH:15].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[Cl-].[Na+]>C(O)(C)(C)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH:15]=[C:14]([CH2:13][CH2:12][C:11]([OH:17])=[O:16])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CCCC(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)CCc1cn(Cc2ccccc2)nn1
Reaction time: 8 h

Procedure:
Benzyl azide (2.82 ml, 21.18 mmol) was dissolved in tert-butanol (212 ml) and water (212 ml). Pent-4-ynoic acid (2.078 g, 21.18 mmol) was added followed by copper (II) acetate (385 mg, 2.118 mmol) and sodium L-ascorbate (837 mg, 4.24 mmol) and the reaction mixture was stirred vigorously overnight. Sodium chloride (solid) was added to the reaction mixture followed by EtOAc. The phases separated and the aqueous layer was further extracted with EtOAc. The organic phases were combined, dried over MgSO4 (anh), filtered and evaporated under reduced pressure and dried in a vacuum oven to afford the title compound;
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([CH2:9][S:10][CH3:11])=[C:7]([Cl:12])[CH:6]=[CH:5][C:4]=1[C:13](=[O:20])[CH2:14][C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[CH2:21]([O:23][CH:24](OCC)OCC)[CH3:22]>C(OC(=O)C)(=O)C>[CH3:1][S:2][C:3]1[C:8]([CH2:9][S:10][CH3:11])=[C:7]([Cl:12])[CH:6]=[CH:5][C:4]=1[C:13](=[O:20])[C:14](=[CH:24][O:23][CH2:21][CH3:22])[C:15]([CH:17]1[CH2:18][CH2:19]1)=[O:16]
Reactant: CCOC(OCC)OCC
Reactant: CSCc1c(Cl)ccc(C(=O)CC(=O)C2CC2)c1SC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(Cl)c(CSC)c1SC)C(=O)C1CC1

Procedure:
A mixture of 1-[2-(methylsulphenyl)-3-(methylsulphenylmethyl)-4-chlorophenyl]-3-cyclopropylpropan-1,3-dione (1.5 g) and triethylorthoformate (8 ml) in acetic anhydride (25 ml) was heated at reflux temperature for 4 hours. The excess reagent and solvent were evaporated under reduced pressure, yielding 1-[2-(methylsulphenyl)-3-(methylsulphenylmethyl)-4-chlorophenyl]-2-ethoxymethylene-3-cyclopropylpropan-1,3-dione as a brown oil (2.3 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:37][C:38]1[S:39][C:40]([CH2:43]Cl)=[CH:41][CH:42]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:24]=[N:25][N:26]([CH2:43][C:40]2[S:39][C:38]([Cl:37])=[CH:42][CH:41]=2)[CH:27]=1)[C:28]1[CH:29]=[N:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1ccc(Cl)s1
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccc(Cl)s3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 74.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.44 g) and 2-chloro-5-(chloromethyl)thiophene (0.79 g) as starting materials, 5-benzyloxy-N-({1-[(5-chlorothiophen-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.37 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 133, N-({1-[(5-chlorothiophen-2-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.37 g) was obtained. melting point: 98-101° C.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19](OC([C@H](O)[C@@H](NC(OC(C)(C)C)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2(O)[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4](O)[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2OC(C2C=CC=CC=2)=O)[C@:11]2(OC(C)=O)[CH2:50]O[C@@H:10]2[CH2:9][C@@H:8]1O)=O.CC1[C@@H](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)C[C@]2(O)C(C)(C)C=1[C@@H](OC(C)=O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O.CC1[C@@H](OC([C@H](O)[C@@H](NC(OC(C)(C)C)=O)C2C=CC=CC=2)=O)C[C@]2(O)C(C)(C)C=1[C@@H](OC)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1OC)=O.CC1[C@@H](OC([C@H](O)[C@@H](NC(OC(C)(C)C)=O)C2C=CC=CC=2)=O)C[C@]2(O)C(C)(C)C=1[C@@H](OC(C)=O)C([C@@]13[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1C3)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1(C)CCC(C(C)C)C(O)C1>C(O)C.OCC(CO)O>[CH3:50][C@H:11]1[C@H:12]2[CH2:13][C@H:14]3[C:15]([CH3:16])([CH3:17])[C@@H:3]([CH2:4][CH2:5][C@:7]2([CH3:57])[CH2:8][CH2:9][CH2:10]1)[C@H:2]([CH3:1])[CH2:19][CH2:18]3
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Agent: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: CC(=O)O[C@H]1C(=O)[C@]23C[C@H]2C[C@H]2OC[C@@]2(OC(C)=O)[C@H]3[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c3ccccc3)C(C)=C1C2(C)C
Agent: CC1CCC(C(C)C)C(O)C1
Solvent: CCO
Solvent: OCC(O)CO
Product: C[C@@H]1CCC[C@@]2(C)CC[C@H]3[C@H](C)CC[C@@H](C[C@H]12)C3(C)C
Reaction time: 0.05 h

Procedure:
200 mg of an active drug (docetaxel, paclitaxel, cabazitaxel, or larotaxel) is weighed into a 5 mL volumetric flask. 2 g polysorbate 80 is added to the flask and votexed for 3 minutes. Then glycerol (0.5 g), polyvinylpyrrolidone (0.5 g), citric acid (0.05 g), menthol (0.025 g) are added to the flask. Ethanol is then added to make the total volume of 5 mL. The solution is votexed for 5 minutes and mixed well. The final pH is 5.3 (range 5.0-6.0).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C1COCC1>[F:1][C:2]1[C:3]([NH:17][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(COc2ncc(F)c(N)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(COc2ncc(F)c(NS(=O)(=O)c3ccc(C)cc3)n2)cc1
Reaction time: 0.08 h
Yield: 45.2 %

Procedure:
To a magnetically stirred solution of 5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-amine (200 mg, 0.857 mmol) in sure seal THF (4 mL) was added 1M lithium bis(trimethylsilyl)amide (LiHMDS) solution in THF (1.28 mL, 1.28 mmol) causing a slight exotherm. After stirring for 5 min, p-toluenesulfonyl chloride (196.65 mg, 1.028 mmol) was added and after 10 min the orange solution turned light yellow and turbid. The mixture was stirred at room temperature for 4 h. The solvent was removed in vacuo and the resulting viscous gold oil was diluted in EtOAc (50 mL), poured into a separatory funnel containing EtOAc (75 mL) and washed with 1N HCl aqueous solution (4×75 mL) followed by brine solution (1×100 mL). The organic extract was dried over Na2SO4, filtered, and evaporated. To the crude oil material was added distilled water (150 mL) and the resulting mixture was vigorously stirred at room temperature over 72 h forming an off-white solid. The solid was collected by vacuum filtration and air dried for 1 hour followed by drying under vacuum for 24 hours. The white solid was then suspended in Et2O (2 mL) for 1 h, then collected by vacuum filtration washed with Et2O (1×1 mL), and air dried for 1 h to yield N-(5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-yl)-4-methylbenzenesulfonamide (150 mg, 45.2% yield) as a white solid: mp 120-122° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.28 (d, J=2.9 Hz, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.23 Hz, 2H), 7.16 (d, J=7.92 Hz, 2H), 5.08 (s, 2H), 2.33 (s, 3H), 2.29 (s, 3H) MS (ESI) m/z 386.3 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:20][C:21]([F:24])([F:23])[F:22])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:11]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:9]=[C:10]1[S:20][C:21]([F:23])([F:22])[F:24])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(-c2cc(SC(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Product: CC(=O)n1c(SC(F)(F)F)cc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Reaction time: 48 h

Procedure:
A mixture of 1.8 g. of 4,5-bis(4-fluorophenyl)-2-(trifluoromethylthio)pyrrole and 25 ml. of acetic anhydride was heated at reflux with stirring under nitrogen for 2 days and then concentrated under vacuum. The residue was purified by chromatography on Silic AR CC-7 (eluting with hexane and then hexane/toluene) to give 400 mg. of a colorless solid product. Recrystallization from ethanol/H2O gave an analytical sample, m.p. 75°-76° C.
Reaction SMILES: Cl[C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][B-](F)(F)F.[Na+].O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl.O>[Cl:15][C:13]1[CH:12]=[CH:11][C:3]2[CH2:4][O:5][CH2:6][C:2]=2[CH:14]=1
Reactant: F[B-](F)(F)COCc1ccc(Cl)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1ccc2c(c1)COC2
Temperature: 100 °C
Reaction time: 8.5 h
Yield: 4 %

Procedure:
To the mixture of sodium (((2,4-dichlorobenzyl)oxy)methyl)trifluoroborate (50 mg, 0.18 mmol) synthesized in Example 8 and 1,4-dioxane (1.5 ml), water (0.15 ml), cesium carbonate (170 mg, 0.53 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (15 mg, 0.036 mmol), and palladium(II) acetate (4.0 mg, 0.018 mmol) were added at room temperature, and the obtained reaction mixture was then stirred at 100° C. (an outer temperature) for 8.5 hours. The reaction mixture was cooled to room temperature, and then water and dichloromethane were added thereto, followed by filtration with Celite. The organic layer of the filtrate was separated and washed with saturated saline. The solvents were evaporated under reduced pressure from the organic layer, and then the obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=10:1), thereby obtaining the entitled compound (1.1 mg, 4%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13]([C:17]([OH:19])=O)[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23].CN1CCOCC1>ClCCl.C(OCC)C>[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH:23][C:17]([C:13]1[N:12]=[C:11]([S:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:16]=[N:15][CH:14]=1)=[O:19]
Reactant: O=C(O)c1cncc(Sc2cccc([N+](=O)[O-])c2)n1
Reactant: Nc1ccc(F)cc1F
Solvent: CN1CCOCC1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1F)c1cncc(Sc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
7 g (11 mmol) of a 50% strength solution of propanephosphonic anhydride in dichloromethane are added to a solution of 2.8 g (10 mmol) of 2-(3-nitrophenylthio)-6-pyrazinecarboxylic acid, 3.2 g (25 mmol) of 2,4-difluoroaniline and 3 g (30 mmol) of 4-methylmorpholine in dichloromethane at 0° C. The reaction mixture is heated to room temperature. After 12 hours, the solvent is istilled off under reduced pressure. The residue is taken up in diethyl ether and the solution is extracted with 10% strength, aqueous hydrochloric acid, washed with distilled water and with saturated, aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and freed from the solvent under reduced pressure. The crude product is purified by chromatography (silica gel, cyclohexane/ethyl acetate 4/1 (v/v)). Yield 1.6 g (40%); light yellow, crystalline solid, mp. 131-135° C.
Reaction SMILES: CO[C:3]1[CH:18]=[CH:17][C:6]2[CH2:7][CH:8]3[C:14](=[O:15])[C:13](C)([C:5]=2[CH:4]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3.BrCCCC1(C)C2C(=CC=CC=2)CCC1=O.[H-].[Na+]>>[CH3:12][C:13]12[C:14](=[O:15])[CH:8]([CH2:7][C:6]3[CH:17]=[CH:18][CH:3]=[CH:4][C:5]=31)[CH2:9][CH2:10][CH2:11]2
Reactant: COc1ccc2c(c1)C1(C)CCCCC(C2)C1=O
Agent: CC1(CCCBr)C(=O)CCc2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CC12CCCC(Cc3ccccc31)C2=O

Procedure:
Using a procedure analogous to that described in Example X for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one there is otained from 1-(3-bromopropyl)-1-methyl-2-tetralone (4.0 g.) treated with sodium hydride (1 g.); 1.4 g. of the title product, b.p. 122° to 130° C. (0.1 mm.). A sample is converted to the semicarbazone and crystallized from acetonitrile, m.p. 250° to 251° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:11]=1)=[O:9])=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:11]=1)=[O:9])([OH:4])=[O:2]
Reactant: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cccc(C(=O)OC)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(C(=O)c2cccc(C(=O)O)c2)n1
Yield: 77.7 %

Procedure:
Under the conditions of example 2, 20 mg of 2-(3-methoxycarbonylbenzoyl)-6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-pyridine in 1 ml of methanol is saponified with 2 ml of 1 n sodium hydroxide solution and worked up. 15 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[Br:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)[O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1>>[Br:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:15])[O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Reactant: Brc1cccc2oc(CC3CCCCN3)cc12
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3c(Br)cccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (0.45 g) was prepared from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (0.89 g) and 2-(4-bromo-benzofuran-2-ylmethyl)-piperidine, D72 (0.88 g) by a procedure similar to that described for Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].[N:22]#[C:23]Cl.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([O:20][C:23]#[N:22])=[C:15]([Cl:21])[CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8]
Reactant: CC(C)(c1cc(Cl)c(O)c(Cl)c1)c1cc(Cl)c(O)c(Cl)c1
Reactant: N#CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(c1cc(Cl)c(O)c(Cl)c1)c1cc(Cl)c(OC#N)c(Cl)c1
Yield: 99.7 %

Procedure:
36.6 g (0.1 mol) of 2,2-bis-(3,5-dichloro-4-hydroxyphenyl)-propane are suspended in 500 ml of water and 400 ml of methylene chloride. After cooling to about 0° to 3° C, 20 ml (0.4 mol) of cyanogen chloride are added. A solution of 10.6 g of Na2CO3 in 50 ml of water is added dropwise over the course of 90 minutes, with vigorous stirring, in such a way that the pH value of the reaction mixture is constantly kept in the range between 7.5 and 8.5. Thereafter, 1 N NaOH is added in such a way that a pH value of the reaction mixture of about 8.0 is maintained, and persists as the final value. Thereafter, the organic phase is separated off, washed with 100 ml of water and concentrated at room temperature. 39 g (99% of theory) of 2-(3,5-dichloro-4-hydroxyphenyl)-2-(3,5-dichloro-4-cyanatophenyl)-propane are obtained as the residue.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:22][CH2:21][CH2:20][C@H:2]1[C:3]([N:5]1[CH2:19][CH2:18][CH2:17][C@H:6]1[C:7]([O:9]N1C(=O)CCC1=O)=O)=[O:4].[NH2:30][C@H:31]([C:36]([OH:38])=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33].[CH3:39][N:40]1[C@@H:57]2[CH2:58][C:45]3[CH:46]=[CH:47][C:48]([O:59][CH3:60])=[C:49]4[O:50][C@H:51]5[C:52]([CH2:54][CH2:55][C@@H:56]2[C@:43]5([C:44]=34)[CH2:42][CH2:41]1)=[O:53]>>[NH:1]1[CH2:22][CH2:21][CH2:20][C@H:2]1[C:3]([N:5]1[CH2:19][CH2:18][CH2:17][C@H:6]1[C:7]([NH:30][C@H:31]([C:36]([OH:38])=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33])=[O:9])=[O:4].[CH3:39][N:40]1[C@@H:57]2[CH2:58][C:45]3[CH:46]=[CH:47][C:48]([O:59][CH3:60])=[C:49]4[O:50][C@H:51]5[C:52]([CH2:54][CH2:55][C@@H:56]2[C@:43]5([C:44]=34)[CH2:42][CH2:41]1)=[O:53]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1)C(=O)O

Procedure:
Pro-Pro-Ile-Hydrocodone was prepared by a similar method to Example 9 except the amino acid starting material was Boc-Pro-Pro-OSu and the conjugate starting material was Ile-Hydrocodone.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[I:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[S:32])[CH:27]=[CH:28][CH:29]=1>>[I:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:32])[CH:27]=[CH:28][CH:29]=1
Reactant: S=C=Nc1cccc(I)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(I)c4)CC3)nc21

Procedure:
Pipemidic acid (40 mg, 0.133 mmol) and 3-iodophenyl isothiocyanate (29 mg, 0.111 mmol) were used. Purification on silica yielded compound 29 in Table 1, below (57 mg, 90%). 1H NMR (250 MHz, CDCl3) δ 9.33 (s, 1H), 8.73 (s, 1H), 7.66-7.64 (m, 1H), 7.54-7.51 (m, 1H), 7.40-7.24 (m, 1H), 7.12-7.06 (m, 1H), 4.48-4.31 (m, 2H), 4.27-3.93 (m, 8H), 1.34-1.17 (m, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:13][CH3:14])[CH2:10][CH2:9][CH:8]=[C:7]([Br:11])[C:6]1=[O:12].[CH2:16]([Mg]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.[Br-].[Zn+2].[Br-]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:13][CH3:14])[CH2:10][CH2:9][CH:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]([Br:11])[C:6]1=[O:12]
Reactant: CCC1(CC(=O)OC)CCC=C(Br)C1=O
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC)CCC(Cc2ccccc2)C(Br)C1=O
Reaction time: 0.08 h

Procedure:
A solution of 3-bromo-1-ethyl-2-oxocyclohex-3-eneacetic acid methyl ester (10 g, 36.3 mmol, as prepared in Example 1) and copper (I) bromide-dimethyl sulfide complex (3.63 mmol, 746 mg) in 107 mL of dry tetrahydrofuran was stirred at 0° C. under nitrogen and treated with anhydrous zinc bromide (36.6 mmol, 8.17 g). After 5 minutes, the mixture was treated dropwise with 36.6 mmol of benzylmagnesium chloride (18.2 mL of 2M in THF). After 45 minutes, another 8 mmol of benzylmagnesium chloride were added followed by 350 mg of copper (I) bromide-dimethyl sulfide complex and then another 16 mmol of benzylmagnesium chloride. The reaction was quenched with 150 mL of 1M HCl and extracted with 4×50 ML of ether. The extracts were combined, dried over magnesium sulfate, and concentrated affording 3-bromo-1-ethyl-2-oxo-4-(phenylmethyl)cyclohexaneacetic acid methyl ester. This was then stirred in a solution of 74 mL of N,N-dimethylformamide and 35 mL of water and treated with 109 mmol (18.96 g) of sodium dithionite. The mixture was heated at 55° C. under nitrogen for 20 minutes, poured into 200 mL of water and extracted with 4×100 mL of 1:1 ether-petroleum ether. The extracts were combined, washed with 100 mL of water and 100 mL of saturated sodium bicarbonate (aq), dired over magnesium sulfate, and concentrated affording 10.48 g (36.6 mmol, 100% crude yield) of product as a pale yellow oil. Analysis by capillary GC demonstrated a 4.41:1 ratio of diastereomers, with the cis isomer predominating. The reduction of the intermediate 3-bromo-1-ethyl- 2-oxo-4-(phenylmethyl)cyclohexaneacetic acid methyl ester to the title compound can also be carried out as described in Example 3.