Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:24](N1CCCCC1)=[O:25]>O1CCCC1>[CH2:1]([O:8][CH2:9][C:10]1[S:11][C:12]([CH:24]=[O:25])=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1csc(COCc2ccccc2)c1
Reactant: O=CN1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1sc(COCc2ccccc2)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To (4-bromo-thiophen-2-yl)-methanol (18.8 g, 97.4 mmol, Intermediate (85)] in tetrahydrofuran (200 mL) was added sodium hydride (3.9 g, 97.4 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. Tetrabutylammonium iodide (3.6 g, 9.7 mmol) was added followed by benzyl bromide (11.6 mL, 97.4 mmol). The mixture was stirred at room temperature for 1 hour. Water was added. The resulting mixture was extracted with diethyl ether. The ether layer was dried over magnesium sulfate and concentrated. The residue was chromatographed through silica gel (n-heptane/ethyl acetate, 90/10 as eluant) to provide 2-benzyloxymethyl-4-bromo-thiophene [29.2 g, Intermediate (86)] (quantitative) as a yellow oil. LC/MS: 282.96 (M+H), RT=3.68 minutes. Step 2. To 2-benzyloxymethyl-4-bromo-thiophene (29.2 g, 103 mmol, Intermediate (86)] in tetrahydrofuran (100 mL) was added dropwise a 1. 8M solution of LDA in tetrahydrofuran (63 mL, 113 mmol) at 0° C. under nitrogen atmosphere. The solution was stirred at 0° C. for 30 minutes. Then N-formyl piperidine (13.75 mL, 127 mmol) was added and the reaction was stirred at 0° C. for 45 minutes, at room temperature for 15 minutes, and was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residual oil was chromatographed through silica gel (n-heptane/ethyl acetate, 90/10 as eluant) to afford 5-benzyloxymethyl-3-bromo-thiophene-2-carbaldehyde [23.3 g, Intermediate (87)] as an orange oil. Step 3. To (5-benzyloxymethyl-3-bromo-thiophene-2-carbaldehyde (23.2 g, 74.6 mmol, Intermediate (87)] in ethanol was added hydrazone benzophenone (16.1 g, 82 mmol). The mixture was stirred at 80° C. overnight. The solvent was removed. The residual oil was chromatographed through silica gel (n-heptane/ethyl acetate, 60/40 then 0/100 as eluant) to produce N-benzhydrylidene-N′-[1-(5-benzyloxymethyl-3-bromo-thiophen-2-yl)-methylidene]-hydrazine [34.1 g, 68%, 2 steps, Intermediate (88)] as a yellow waxy solid. LC/MS: 489.0 (M+H), RT=1.48min and 1.84 minutes. Step 4. To N-benzhydrylidene-N′-[1-(5-benzyloxymethyl-3-bromo-thiophen-2-yl)-methylidene]-hydrazine (34 g, 69.5 mmol, Intermediate (88)] in toluene (500 mL) were added hydrazone benzophenone (16.4, 83.4 mmol), cesium carbonate (38.4 g, 118.2 mmol), 1,1′diphenylphosphinoferrocene (5.8 g, 10.4 mmol), and palladium (II) acetate (1.17 g, 5.2 mmol). The suspension was stirred at 90° C. under nitrogen atmosphere until reaction is complete. The solvent was removed. The residual oil was chromatographed (ethyl acetate/n-heptane, 10/90 as eluant) to product an orange oil. It was dissolved in ethanol (350 mL). Concentrated hydrochloric acid (100 mL) was added. The dark mixture was stirred at 80° C. for hours then diluted with water. It was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed through silica gel (n-heptane/ethyl acetate, 80/20 then 50/50 as eluant) to afford 5-benzyloxymethyl-1H-thieno[3,2-c]pyrazole [5.2 g, 37%, Intermediate (89)] as an orange powder. LC/MS: 245.1 (M+H), RT=2.83 minutes. 1H NMR [300 Mhz, (CD3)2SO]: tautomer 1: δ 12.97 (s, 1H), 7.73 (s, 1H), 7.40-7.25 (m, 5H), 7.15-7.05 (m, 1H), 4.71 (s, 2H), 4.55 (s, 2H) tautomer 2: δ 13.27 (brs, 1H), 7.98 (s, 1H), 7.40-7.25 (m, 5H), 7.15-7.05 (m,1H), 4.71 (s, 2H), 4.55 (s, 2H). Step 5. 5-Benzyloxymethyl-3-iodo-1H-thieno[3,2-c]pyrazole [Intermediate (90), LC/MS: 371.0 (M+H), RT=3.49 minutes] was prepared in 77% yield using procedures similar to those of Example 5A, substituting 5-benzyloxymethyl-1H-thieno[3,2-c]pyrazole [Intermediate (89)] for 1H-thieno[3,2-c]pyrazole. Step 6. 5-Benzyloxymethyl-3-iodo-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester [Intermediate (91)] was prepared in 100% yield using procedures similar to those of Example 5B, substituting 5-benzyloxymethyl-3-iodo-1H-thieno[3,2-c]pyrazole [Intermediate (90)] for 3-iodo-1H-thieno[3,2-c]pyrazole. Step 7. 2-(5-Benzyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butyl ester [Intermediate (92)] was prepared in 39% yield using procedures similar to those of Example 5C, substituting 5-benzyloxymethyl-3-iodo-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester [Intermediate (91)] for 3-iodo-thieno[3,2c]pyrazole-1-carboxylic acid tert-butyl ester and 6-(tert-butyl-dimethyl-silanoxy)-1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid [Intermediate (74), prepared by the application of method described in Example 4-6 of International Patent Application Publication No. WO 02/32861] for 5-(tert-butyl-dimethyl-silanoxy)-1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid. Step 8. 2-(5-Benzyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [Intermediate (93), LC/MS: 576.2 (M+H), RT=4.0 minutes] was prepared in 33% yield using procedures similar to those of Example 5D, substituting 2-(5-benzyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butyl ester [Intermediate (92)] for 2-(1-tert-butoxycarbonyl-1H-thieno[3,2c]pyrazol-3-yl)-5-(tert-butyl-dimethyl-silanoxy)-indole-1-carboxylic acid tert-butyl ester. Step 9. 2-(5-Benzyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-bromo-propoxy)-indole-1-carboxylic acid tert-butyl ester [Intermediate (94), LC/MS: 696.0 (M+H), RT=4.82 minutes] was prepared in 72% yield using procedures similar to those of Example 5E, substituting 2-(5-benzyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [Intermediate (93)] for 2-(1-tert-butoxycarbonyl-1H-thieno[3,2c]pyrazol-3-yl)-5-hydroxy-indole-1-carboxylic acid tert-butyl ester. Step 10. 1-{3-[2-(5-Benzyloxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-6-yloxy]-propyl}-piperidin-4-ol [Example 69, LC/MS: 517.1 (M+H), RT=3.02 minutes; 1H NMR [300 Mhz, (CD3)2SO]: δ 13.17 (brs, 1H), 11.35 (brs, 1H), 7.45-7.25 (m, 6H), 7.20 (s, 1H), (s, 2H), 4.53 (m, 1H), 3.98 (t, J=6.4 Hz, 2H), 3.44 (m, 1H), 2.72 (m, 2H), 2.50 (m, 2H), 2.01 (m, 2H), 1.89 (m, 2H), 1.71 (m, 2H), 1.32 (m, 2H).] was prepared in 52% yield using procedures similar to those of Step 6 in Example 5, substituting 2-(5-benzyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-bromo-propoxy)-indole-1-carboxylic acid tert-butyl ester [Intermediate (94)] for 5-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester and 4-hydroxypiperidine for piperidine.