Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][O:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:8][C:7]=1[CH3:20])=[O:5])C.[OH-].[K+].Cl>O1CCCC1CCO>[C:16]([O:15][C:13]([O:12][NH:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:20])[N:8]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1sc(NOC(=O)OC(C)(C)C)nc1C
Agent: Cl
Agent: OCCC1CCCO1
Agent: [K+]
Product: Cc1nc(NOC(=O)OC(C)(C)C)sc1C(=O)O
Temperature: 55 °C

Procedure:
A stirred solution of ethyl-2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate (10 g, 34.95 mmol) in tetrahydrofuran-ethanol (250 mL, 2:3) was treated with a 6N KOH solution (250 mL). The mixture was heated to 55° C. overnight. The solution was cooled to 0° C. and acidified with concd. HCl to pH 1. The solvent was evaporated in vacuo. The residue was washed with water, diethyl ether, dried in vacuo over anhydrous phosphorous pentoxide to obtain the title acid (6 g, 89%) as a white solid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:9]([OH:10])[C:8]=1O>>[CH3:6][C:7]1[CH:8]=[C:9]([OH:10])[CH:11]=[C:12]([CH3:14])[C:13]=1[OH:2]
Reactant: Cc1cc(C)c(O)c(O)c1
Reactant: O=S(=O)(O)O
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following in the same manner as in Example 56 except that 0.11 g. of strong acidic sulfontype ion exchange resin Amberlyst 15 (manufactured by Rohm and Hass Co.) was used instead of sulfuric acid, 2.55 g. (18.5 m.moles) of 3,5-dimethylcatechol and 1.26 g. (9.1 m.moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 65.6%.
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[C:25](I)=[CH:24][NH:23][C:17]=4[N:18]=[C:19]([O:21][CH3:22])[N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]([OH:30])(=[O:29])[CH3:28]>C([O-])(=O)C.[Ag+]>[C:27]([O:30][C:25]1[C:16]2[C:15]([C:13]3[CH:12]=[N:11][N:10]([C@@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][C:8]#[N:9])[CH:14]=3)=[N:20][C:19]([O:21][CH3:22])=[N:18][C:17]=2[NH:23][CH:24]=1)(=[O:29])[CH3:28]
Reactant: COc1nc(-c2cnn(C(CC#N)C3CCCC3)c2)c2c(I)c[nH]c2n1
Reactant: CC(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Product: COc1nc(-c2cnn([C@H](CC#N)C3CCCC3)c2)c2c(OC(C)=O)c[nH]c2n1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-cyclopentyl-3-[4-(5-iodo-2-methoxy-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.25 g, 0.54 mmol) in acetic acid (3 mL) was treated with silver acetate (0.27 g, 1.6 mmol) and heated to 70° C. for 16 h. The mixture was filtered, rinsed with MeCN, water was added to the filtrate and this mixture was stirred for 20 min, Solid sodium chloride was added to this solution. The product was obtained by extraction of this aqueous mixture with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted and concentrated. A portion of the product was used in the hydrolysis step (Step 4) without further purification. 1H NMR (300 MHz, CDCl3): δ 9.87 (br s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 7.33 (s, 1H), 4.22 (dt, 1H), 4.06 (s, 3H), 3.14 (dd, 1H), 2.94 (dd, 1H), 2.64-2.47 (m, 1H), 2.36 (s, 3H), 2.03-1.86 (m, 1H), 1.79-1.12 (m, 7H); LCMS (M+H)+: 395.1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.P(Cl)(Cl)Cl>O>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(Br)c2cccnc2c1O
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Br)c2cccnc2c1O
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (2.68 g) of Preparation 2 and 4-chloroaniline (1.28 g) in 250 mL xylenes is heated to reflux. To this is added dropwise PCl3 (0.69 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The crude product is recrystallized from EtOAc/hexanes to yield 1.97 g of the title product as an orange solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[C:20]1([S:26]([O-])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:20]1([S:26]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)([O-])c1ccccc1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 43.7 %

Procedure:
Trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (13.0 g, 0.044 mole), sodium benzenesulfonate (7.25 g, 0.044 mole), 4,5-bis(diphenylphosphino,-9,9-dimethyl Xanthos (1.1 g, 0.004 mole), tris(dibenzylideneacetone) dipalladium(0) (1.0 g, 0.004 mole), cesium carbonate (5.0 g) and tetrabutylammonium fluoride (5 mL of 1M in THF) were all added to 100 mL toluene, and the reaction mixture was refluxed for four hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, and solvent was removed under reduced pressure. The resulting residue was purified by medium pressure chromatography eluting with methylene chloride to yield 5.5 g of 6-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one. Mp: 121° C. MS: 287 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][C:15]=2[F:21])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7]C)=[O:6].O1CCOCC1.[CH2:28]([Sn](CCCC)(CCCC)CCCC)[CH:29]=[CH2:30].Cl>CCO.[OH-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:30]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:3]2[C:2]([F:1])=[C:11]([F:12])[CH:10]=[CH:9][C:4]=2[C:5]([OH:7])=[O:6])=[C:15]([F:21])[CH:16]=1)[CH:29]=[CH2:28]
Reactant: COC(=O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: C=CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (1.00 g), 2.45 mmol) and (Ph3P)4Pd (568 mg, 0.49 mmol) were weighed into a dry flask which was fitted with a condensor and flushed with nitrogen. Dioxane (20 mL) and allyltributyltin (976 mg, 2.95 mmol) were added via syringe and the entire mixture heated at reflux overnight. All solvent was removed under reduced pressure and the residue loaded directly onto a silica gel column (10% EtOAc/PE as eluant). After chromatography, the crude methyl ester was obtained as a pale yellow oil which was dissolved in a mixture of EtOH (25 mL) and 1 M NaOH (25 mL) and stirred overnight at RT. The mixture was then diluted with water (70 mL) and acidified with 1 M HCl (approx. 30 mL), then extracted with EtOAc (3×100 mL). The combined EtOAc fractions were washed with water (100 mL), brine (100 mL), dried (Na2SO4), then the solvent removed under reduced pressure to afford a pale yellow solid which was purified by chromatography on silica gel (50% EtOAc/PE as eluant) to afford 2-(4-allyl-2-fluoroanilino)-3,4-difluorobenzoic acid as pale yellow needles (583 mg, 72%); m.p. (EtOAc/hexane) 199-201° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.68 (v br s, 1 H), 9.25 (br s, 1 H), 7.81 (ddd, J=8.3, 6.1, 2.0 Hz, 1 H), 7.07 (dd, J=12.2, 1.7 Hz, 1 H), 7.06-6.98 (m, 2 H), 6.93 (dd, J=8.2, 1.6 Hz, 1 H), 6.01-5.89 (m, 1 H), 5.13-5.03 (m, 2 H), 3.51-3.40 (m, 2H, obscured by H2O). Anal. calcd. for C16H12F3NO2: C, 62.5; H, 3.9; N, 4.6. Found C, 62.7; H, 4.1; N, 4.5.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:11]=1)[CH3:9])(C)(C)C.Cl>O1CCOCC1>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([C:12]2[CH:11]=[C:10]([C@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[CH2:17][CH2:18]1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(N2CCN(C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](N)c1cccc(N2CCN(C)CC2)c1
Temperature: 50 °C
Yield: 80.5 %

Procedure:
To a solution of {(R)-1-[3-(4-Methyl-piperazin-1-yl)-phenyl]ethyl}-carbamic acid tert-butyl ester (0.6 g, 1.87 mmol) in 1,4-Dioxane (1.5 mL), was added 4N HCl(aq) (2 mL) at room temperature. The resulting mixture was heated at 50° C. for 5 h. After completion of the reaction, the reaction mixture was concentrated and washed with diethyl ether (5.0 mL) to afford the title compound (0.330 g).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.Cl.[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([OH:24])[C:22]=1[OH:23])[C:16]([O:18][CH3:19])=[O:17]>CCCCCC>[OH:24][C:21]1[C:22]2[O:23][CH:1]=[N:12][C:13]=2[CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:20]=1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1cc(N)c(O)c(O)c1
Agent: Cl
Solvent: CCCCCC
Product: COC(=O)c1cc(O)c2ocnc2c1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To stirred triethyl orthoformate (35.0 mL, 210 mmol) was added methyl 3-amino-4,5-dihydroxybenzoate hydrochloride (6.30 g, 28.7 mmol). The stirred suspension was refluxed for 20 min (until a clear solution formed), cooled to room temperature, and poured into hexane (200 mL). The formed precipitate was separated by filtration and vacuum-dried to afford the desired benzoxazole (4.26 g, 22.05 mmol, 77% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (br. s, 1H), 8.79 (s, 1H), 7.80 (d, J=1.3 Hz, 1H), 7.50 (d, J=1.3 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3]1.C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C1COCC1>[CH2:21]([O:20][C:18]([NH:1][C@H:2]1[CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1CCCNC(=O)C1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1C[C@@H](NC(=O)OCc2ccccc2)CCCN1
Temperature: 5 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
(3S)-3-Amino-ε-caprolactam (25 g) and triethylamine (19.7 g) were dissolved in THF (200 ml) and cooled to 5° C. Benzyl chloroformate (33 g) in THF (50ml) was added dropwise over 30 minutes. The reaction mixture was stirred at ambient temperature for 18 hours and then poured into water (500 ml). The reaction mixture was extracted with ethyl acetate (3×100 ml). The combined extracts were dried (MgSO4) and evaporated. The residue was triturated with ether (40 ml) and filtered to give 20 g of (S)-3-benzyloxycarbonylamino-ε-caprolactam as a white solid; NMR (d6-DMSO): 1.1-2(m, 6H), 2.9-3.2(m, 2H), 4.1-4.25 (m, 1H), 5.0 (s, 2H), 7.25-7.4 (m, 5H), 7.75 (t, 1H).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]3[CH2:20][CH:19]([NH:21][C:22](=[NH:37])[CH2:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=4)=[O:25])[CH2:18]3)=[O:16])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C1(OC)C=CC=CC=1>[SH:8][CH:9]1[CH2:13][N:12]([CH3:14])[CH:11]([C:15]([N:17]2[CH2:20][CH:19]([NH:21][C:22](=[NH:37])[CH2:23][C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[O:25])[CH2:18]2)=[O:16])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=N)CC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN1CC(S)CC1C(=O)N1CC(NC(=N)CC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
610 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-[3-(N-4-nitrobenzyloxycarbonylacetimidoylamino)azetidin-1-ylcarbonyl]pyrrolidine [prepared as described in step (a) above] were dissolved in 1.19 ml of anisole, and 4.23 ml of trifluoroacetic acid and 193 μl of trifluoromethanesulfonic acid were added to the resulting solution, whilst ice-cooling. The mixture was then stirred for 1 hour under the same conditions and then at room temperature for a further 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was washed with hexane and with diethyl ether and dried by evaporation under reduced pressure, to convert it to the trifluoromethanesulfonate in the form of a powder. Ethyl acetate was added to the whole of this compound, followed by sufficient of a saturated aqueous solution of sodium hydrogencarbonate to make it alkaline. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure, to give 448 mg of the title compound as a powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][C:6]([CH3:14])([CH3:13])[CH2:5][C:4]=2[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.CCC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][C:6]([CH3:14])([CH3:13])[CH2:5][C:4]=3[N:3]=2)=[CH:19][CH:18]=1
Reactant: CC1(C)CC(=O)c2ccc(Cl)nc2C1
Reactant: COc1ccc(N)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2ccc3c(n2)CC(C)(C)CC3=O)cc1
Yield: 19.4 %

Procedure:
To a solution of 2-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one (0.35 g, 1.67 mmol) and 4-methoxyphenylamine (0.267 g, 2.2 mmol) in toluene (2 ml) under an argon atmosphere was added sodium tert-amylate (0.22 g, 2.0 mmol) and bis(tri-tert-butylphosphine)palladium (0.043 g, 0.084 mmol). The mixture was heated at reflux for 8 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.096 g, 19%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCCC1>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:4][C:3]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A solution of 0.09 moles of 2,6-dimethyl-aniline in 35 ml of tetrahydrofuran was added to 200 ml of 20% (w/v) aqueous potassium carbonate contained in a one liter flask. A solution of 20 g of p-nitrobenzoyl chloride in 35 ml of tetrahydrofuran was added dropwise. The resulting mixture was refluxed for 12 hours while the pH was maintained at or above pH 8. The solution was cooled to room temperature and extracted three times, each with 100 ml of chloroform. The extracts were combined, dried over magnesium sulfate, and evaporated in vacuo. The resulting residue was crystallized from petroleum ether/benzene affording 15 g of the desired subtitle intermediate, m.p. 192-194.
Reaction SMILES: C([Li])CCC.[C:6]1([S:12]([OH:15])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[P:17]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.FC(F)(F)C(O)=O>O1CCCC1>[CH:24]1([P:17]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:12]([OH:15])(=[O:14])=[O:13])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: O=S(=O)(O)c1ccccc1
Agent: [Li]CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=S(=O)(O)c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
n-Butyllithium (manufactured by Kanto Chemical Co., Inc., 1.65 M hexane solution, 5.1 ml, 8.4 mmol) was added to a tetrahydrofuran (THF) solution (20 ml) of benzenesulfonic acid (manufactured by Tokyo Chemical Industry Co., Ltd., 0.66 g, 4.2 mmol) at 0° C. under argon atmosphere and the mixture was stirred for 2.5 hours at room temperature. After cooling the reaction container to −78° C., chlorodicyclohexylphosphine (manufactured by Sigma-Aldrich, 0.89 mg, 3.8 mmol) was added thereto at −78° C. and stirred for 24 hours at room temperature. After ceasing the reaction with trifluoroacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd., 0.50 M THF solution, 8.4 ml, 4.2 mmol), the precipitate formed was collected by filtration and dried under reduced pressure to obtain 2-(dicyclohexylphosphino)benzenesulfonic acid (compound 1a). The yield was 0.66 g (85%).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH2:15][OH:16])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2C=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccnc2CO)cc1
Yield: 35.7 %

Procedure:
To a solution of the above aldehyde (1.53 g, 6.11 mmol) in CH2Cl2 (50 mL) at 0° C. was added TFA (5 mL) as described in J. Med. Chem. (1997) 40:2196. Purification by flash column chromatography using EtOAc/hexane (1:1) afforded [1-(toluene-4-sulfonyl)-1H-imidazol-2-yl]-methanol as a white solid (0.55 g, 36%). 1H NMR (CDCl3) δ 2.45 (s, 3H), 3.03 (br s, 1H), 4.84 (s, 2H), 6.99 (d, 1H, J=3.0 Hz), 7.35 (s, 1H), 7.39 (d, 2H, J=3.0 Hz), 7.83 (d, 2H, J=9.0 Hz).
Reaction SMILES: CC(C)(O)[C:3]#[N:4].[C-]#N.[K+].[CH3:10][C@:11]12[CH2:28][CH2:27][C@H:26]3[C@@H:16]([CH2:17][CH2:18][C:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][C:21](=[O:29])[CH:20]=4)[C@@H:15]1[CH2:14][CH2:13][C:12]2=[O:30]>CO.O>[C:3]([C@@:12]1([OH:30])[CH2:13][CH2:14][C@H:15]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:11]12[CH3:10])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3)#[N:4]
Reactant: CC(C)(O)C#N
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C#N
Reaction time: 3 h

Procedure:
Acetone cyanohydrin (82 ml), potassium cyanide (1 gm) and water (2 ml) are added to a slurry of androst-4-en-3,17-dione (0.80 g) in methanol (400 ml) and water (40 ml) at 35°. The reaction becomes homogeneous and on continued stirring a heavy slurry develops. After 3 hours, 120 ml of water is added dropwise, and the slurry allowed to stir overnight at 20°-25°. The slurry is then cooled in an ice bath, filtered, and the solids washed with methanol/water (1/1). The solvents are dried under reduced pressure to give 70.4 g of the title compound. An additional 13.17 g of product is isolated from the mother liquor on partial evaporation, m.p.=159°-160.5°; [α]D (c=1, CHCl3)=+145.9°; MS=313, 298, 286, 245 and 124 m/e; NMR (CDCl3)=1.00, 1.20, 3.5 and 5.72 δ.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([CH3:25])([CH3:24])[C:21](O)=[O:22])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.CCCCCCC>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([CH3:24])([CH3:25])[C:21]([N:35]3[CH:39]4[CH2:40][CH2:41][CH:42]3[CH2:43][CH2:38]4)=[O:22])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2CCNC(=O)OC(C)(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
To a stirred solution of 2-[3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid (247 mg in 3 mL dry methylene chloride) was added 1-hydroxybenzotriazole (111 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (126 mg) and the reagents allowed to mix for 1 hour. At this time a solution of 7-aza-bicyclo[2.2.]heptane hydrochloride (130 mg in 1.5 mL methylene chloride) was added followed by 0.15 mL triehtylamine and the reaction stirred at room temperature. After 20 hours, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 1:1) to give the title compound (252 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:29])[N:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:14]=1)[C:6]([CH3:12])=[N:7]2.[C:30]1(OB(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.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].O>[CH3:12][C:6]1[N:5]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:17][CH:18]=2)[C:4](=[O:29])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:7]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Cc1nc2cccc(Cl)c2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
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: C1COCCO1
Solvent: O
Product: Cc1nc2cccc(-c3ccccc3)c2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 18.4 %

Procedure:
5-chloro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone synthesized in Example 27 (100 mg, 0.24 mmol), phenylboric acid (90 mg, 0.73 mmol) and cesium carbonate (480 mg, 1.45 mmol) were mixed in 1,4-dioxane (1 mL), and the atmosphere in the system was replaced by nitrogen. Pd2 (dba)3 (15 mg, 0.012 mmol) and tri-t-butylphosphine (10 mg, 0.036 mmol) were added, and stirred at 100° C. for 12 hours. Distilled water was added to the reaction mixture, and the mixture extracted with chloroform. The organic phase was washed by saturated brine, and dried with anhydrous sodium sulfate. The product was purified by thin layer silica gel chromatography, and the title compound (20 mg, 18%) was obtained as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH:10](SC)[C:9]2[C:4](=[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:20])[CH:6]=[CH:7][CH:8]=2)[NH:3]1>[Ni].O1CCOCC1>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:20])[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: CSC1C(=O)Nc2c(Oc3ccccc3N)cccc21
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1ccccc1Oc1cccc2c1NC(=O)C2

Procedure:
A mixture of 2-oxo-3-methylthio-7-(2-aminophenoxy)indoline (4.5 g.), Raney nickel (W-2 type)(9 ml.) and dioxane (50 ml.) was treated in a similar manner to that of the Preparation 15-(2) to give the captioned compound (3.5 g.) mp 210° to 212° C.