Reaction SMILES: [OH-].[K+].[C:3]1([C:9]2[S:16][C:15]3[CH:14]=[N:13][NH:12][C:11]=3[CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I:17]I.OS([O-])=O.[Na+]>O.CN(C)C=O>[I:17][C:14]1[C:15]2[S:16][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:10][C:11]=2[NH:12][N:13]=1
Reactant: II
Reactant: c1ccc(-c2cc3[nH]ncc3s2)cc1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1n[nH]c2cc(-c3ccccc3)sc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
1-(5-phenyl-thieno[3,2-c]pyrazol-1-yl)-ethanone [Intermediate (44), LC/MS: 243.1(M+H), RT=3.45 minutes; 1H NMR (300 Mhz, CDCl3): δ 7.84 (s,1H), 7.78 (s, 1H), 7.64 (m, 2H), 7.43-7.31 (m, 3H), 2.75 (s, 3H)] is prepared using procedures similar to those described hereinabove for Intermediate (25) substituting 2-phenyl-5-methyl-thiophene for 5-methylthiophene-2-carboxylic acid in step 1. Step 2. To a mixture of 1-(5-phenyl-thieno[3,2-c]pyrazol-1-yl)-ethanone [3.82 g, 15.8 mmol, Intermediate (44)] and ethanol (50 mL) was added 6 N hydrochloric acid (50.0 mL, 300 mmol) in one portion and the resulting mixture heated at 70° C. After 18 hours, the reaction was cooled to ambient temperature and neutralized with 25% aqueous potassium carbonate. The mixture was diluted with water (200 mL) and aged at 0° C. for 1 hour. The resulting solid was collected, washed three times with water (50 mL), and then dried under vacuum to give 5-phenyl-1H-thieno[3,2-c]pyrazole [2.93 g, 92%, Intermediate (45)] as a beige powder. LC/MS: 201.0 (M+H), RT=3.15 minutes). Step 3. Crushed KOH (1.09 g, 6.49 mmol) was added in one portion to a stirred mixture of 5-phenyl-1H-thieno[3,2-c]pyrazole [1.30 g, 6.49 mmol, Intermediate (45)], iodine (2.47 g, 9.73 mmol), and dimethylformamide (15 mL) under nitrogen at room temperature and the dark reaction was stirred at room temperature. After 3 hours, 10% aqueous NaHSO3 (40 mL) was added with stirring. The resulting slurry was diluted with water (40 mL) and the mixture stirred at room temperature for 5 minutes. The solid was colleted by filtration, washed three times with water (20 mL) and then dried under high vacuum at 40° C. to give 3-iodo-5-phenyl-1H-thieno[3,2-c]pyrazole [1.94 g 91%, Intermediate (46)] as a tan powder. TLC Rƒ 0.52 (silica, 70% ethyl acetate/heptane); LC/MS: 326.94 (M+H), RT=3.38 minutes; 1H NMR [600 Mhz, (CD3)2SO]: δ 13.51 (br s 1H), 7.73 (m, 2H), 7.69 (br s, 1H), 7.46 (m, 2H), 7.38 (m, 1 Hz). Step 4. 4-Dimethylaminopyridine (195 mg, 1.60 mmol) was added to a mixture of 3-iodo-5-phenyl-1H-thieno[3,2-c]pyrazole [2.60 g, 7.97 mmol, Intermediate (46)], di-tert-butyl dicarbonate (2.78 g, 12.7 mmol), and anhydrous dichloromethane (30 mL) at room temperature with stirring. The resulting solution was stirred at room temperature. After 16 hours, the reaction was diluted with dichloromethane (20 mL), washed with water (50 mL) and brine (40 mL) successively, dried over magnesium sulfate, and concentrated under reduced pressure to an amber oil. The crude product was chromatographed on silica, eluting with dichloromethane to give 3-iodo-5-phenyl-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester [2.56 g, 75%, Intermediate (47)] as an off-white solid. TLC Rƒ 0.41 (silica, dichloromethane); LC/MS: 449.0 (M+Na), RT=4.23 minutes). Step 5. A mixture of 5-(tert-butyl-dimethyl-silanyloxymethyl)-1H-indole-2-boronic acid 1-carboxylic acid tert-butyl ester [2.39 g, 6.11 mmol, Intermediate (8), prepared as described in Example 1-4 of International Patent Application Publication No. WO 02/32861], 3-iodo-5-phenyl-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester [2.00 g, 4.69 mmol, Intermediate (47)], cesium carbonate (6.11 g, 17.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (230 mg, 0.282 mmol), 1,4-dioxane (40 mL), and water (10 mL) was purged with nitrogen and then heated at 90° C. with stirring under nitrogen. After 1.5 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (125 mL), and washed twice with water (50 mL) and brine (50 mL) successively. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give a dark residue. The residue was chromatographed on silica, eluting with dichloromethane to give 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butyl ester [2.55 g, 84%, Intermediate (48)] as a tan foam. TLC Rƒ 0.31 (silica, dichloromethane); LC/MS: 646.2 (M+H), RT=3.05 minutes). Step 6. To a solution of 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butyl ester [2.44 g, 3.78 mmol, Intermediate (48)] in tetrahydrofuran (25 mL) at 0° C. was added tetrabutylammonium fluoride (4.20 mL of a 1M THF solution, 4.20 mmol) in one portion with stirring. After 40 minutes, the reaction was partitioned between ethyl acetate (75 mL) and 10% aqueous ammonium chloride (50 mL) and the layers separated. The organics were washed with water (50 mL) and brine (50 mL) successively, dried over magnesium sulfate, and the solvent removed under reduced pressure to give an amber foam. The crude product was chromatographed on silica, eluting with 10% ethyl acetate/dichloromethane, to yield 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [1.99 g, 99%, Intermediate (49)] as a tan foam. TLC Rƒ 0.31 (silica, 10% ethyl acetate/dichloromethane); LC/MS: 532.2 (M+H), RT=4.31 minutes; 1H NMR [300 Mhz, (CD3)2SO]: δ 9.73 (s, 1H) 7.84-7.81 (m, 2H), 7.76 (s, 1H), 7.61 (d, J=2 Hz, 1H), 7.56-7.44 (m, 4H), 7.07 (s, 1H), 6.84 (dd, J=2, 8 Hz, 1H), 1.71 (s, 9H), 1.40 (s, 9H). Step 7. A mixture of 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [950 mg, 1.79 mmol, Intermediate (49)], cesium carbonate (1.75 g, 5.37 mmol), and 1,3-dibromopropane (6.0 mL) was heated at 90° C. under nitrogen. After 1.5 hours, the mixture was cooled to ambient temperature, filtered, and the insolubles washed twice with dichloromethane (10 mL). The filtrate was concentrated in vacuo to yield a cloudy oil. The crude product was chromatographed on silica, eluting first with 80% dichloromethane/heptane and then 100% dichloromethane to give 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [760 mg, 65%, intermediate 50] as a white foam. TLC Rƒ 0.37 (silica, dichloromethane); LC/MS: 674 (M+Na), RT=2.60 minutes. Step 8. A mixture of 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [300 mg, 0.460 mmol, Intermediate (50)], 3-hydroxypiperidine (73.0 mg, 0.722 mmol), potassium carbonate (191 mg, 1.38 mmol), potassium iodide (39.0 mg, 0.235 mmol), and anhydrous acetonitrile (5 mL) was heated at 70° C. with shaking at 200 rpm. After 20 hours, the reaction was cooled to ambient temperature, filtered, the insolubles washed with dichloromethane/methanol (5:1), and the filtrate concentrated under reduced pressure to give a dark residue. The residue was chromatographed on silica, eluting with 20% methanol/dichloromethane (20 mL) followed by 1 M ammonia in methanol/dichloromethane 1:9 (30 mL), to give 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno [3,2-c]pyrazol-3-yl)-6-[3-(3-hydroxy-piperidin-1-yl)-propoxy]-indole-1-carboxylic acid tert-butyl ester (329 mg) as a brittle green foam. LC/MS: 673.3 (M+H), 74% UV purity). To a solution of 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-[3-(3-hydroxy-piperidin-1-yl)-propoxy]-indole-1-carboxylic acid tert-butyl ester (326 mg), anisole (1.0 mL), and dichloromethane (1.0 mL) at ambient temperature was added trifluoroacetic acid (1.0 mL) and the resulting amber solution heated at 45° C. After 2 hours, the reaction was cooled to ambient temperature and added to a Varian Mega Bond Elut SCX column (5 g) that was conditioned with methanol. The product was washed with methanol (30 mL) and eluted with a 1 M ammonia in methanol solution. Fractions with product were combined and concentrated under reduced pressure to give a white solid. Trituration of the solid with methanol/ether (1:4) provided 1-{3-[2-(5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-6-yloxy]-propyl}-piperidin-3-ol [163 mg, 75%, Example 56] as an off-white powder. TLC Rƒ0.55 (silica, 20% 1 M NH3 in methanol/80% dichloromethane); mp: 213-216° C.; LC/MS: 473.2 (M+H), RT=2.67 minutes; 1H NMR [300 Mhz, (CD3)2SO]: δ 13.31 (br s 1H), 11.39 (br s, 1H), 7.79 (m, 2H), 7.66 (s, 1H), 7.51-7.36 (m, 4H), 6.93 (d, J=2 Hz, 1H), 6.67 (dd, J=2, 8.5 Hz, 1H), 6.60 (d, J=1.5 Hz, 1H), 4.58 (d, J=5 Hz, 1H), 3.99 (t, J=6.5 Hz, 2H), 3.47 (m, 1H), 2.85 (dm, J=11 Hz, 1H), 2.68 (dm, J=11 Hz, 1H), 2.45 (m, 2H), 1.95-1.67 (m, 5H), 1.62 (dm, J=13.5 Hz,1H), 1.40 (m, 1H), 1.07 (m, 1H).