2-(oxan-4-yl)ethanol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-cold solution of 2-(tetrahydro-2H-pyran-4-yl)ethanol (1.00 g) in pyridine (6.5 mL) was added p-toluenesulfonyl chloride (1.5 g), followed by stirring at the same temperature for 30 minutes, and at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and then diluted aqueous hydrochloric acid (20 mL) was added to the residue, followed by twice extractions with ethyl acetate (20 mL). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20-50/50) to obtain p-toluenesulfonic acid 2-(tetrahydro-2H-pyran-4-yl)ethyl ester (450 mg). at room temperature for 18 hours The reaction mixture was concentrated under reduced pressure diluted aqueous hydrochloric acid (20 mL) was added to the residue followed by twice extractions with ethyl acetate (20 mL) washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20-50/50)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(tetrahydro-2H-pyran-4-yl)ethanol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 17 h, and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (33%). being purified by prep

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(tetrahydropyran-4-yl)-ethanol (1.5 g, 11.5 mmol) in 10 mL of CH2Cl2 and 7 mL of pyridine was added p-toluenesulfonyl chloride (2.4 g, 12.7 mmol) portion wise over 15 minutes. The mixture stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL of portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 302 (M+NH4)+. was quenched with 10 mL of saturated, aqueous NaHCO3 The layers were separated the aqueous layer was extracted with three 5 mL of portions of CH2Cl2 The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2-(tetrahydro-2H-pyran-4-yl)ethanol (3,3 g) in dry dichloromethane (100 ml) at 0° C. and under nitrogen was added triethylamine (4.6 ml), followed by methanesulphonyl chloride (2.6 ml) dropwise over 5 minutes. The reaction was stirred until the ice in the bath melted and left overnight at room temperature. The reaction was washed with saturated aqueous sodium bicarbonate (40 ml). The organic layer was dried by passing through a hydrophobic frit and concentrated in vacuo to yield the title compound as a yellow oil (5.4 g). The reaction was washed with saturated aqueous sodium bicarbonate (40 ml) The organic layer was dried concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2-(tetrahydro-2H-pyran-4-yl)ethanol (3,3 g) in dry dichloromethane (100 ml) at 0° C. and under nitrogen was added triethylamine (4.6 ml), followed by methanesulphonyl chloride (2.6 ml) dropwise over 5 minutes. The reaction was stirred until the ice in the bath melted and left overnight at room temperature. The reaction was washed with saturated aqueous sodium bicarbonate (40 ml). The organic layer was dried by passing through a hydrophobic frit and concentrated in vacuo to yield the title compound as a yellow oil (5.4 g). The reaction was washed with saturated aqueous sodium bicarbonate (40 ml) The organic layer was dried concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1.63 g (12.5 mmol) of 2-(tetrahydro-pyran-4-yl)-ethanol in pyridine (15 mL) are added 3.58 g (18.8 mmol) of p-toluenesulfonylchloride. The reaction is stirred at room temperature for 5 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved 2M aqueous HCl solution (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts are dried over Na2SO4, filtered and the solvent is removed to give 1.9 g of toluene-4-sulfonic acid 2-(tetrahydro-pyran-4-yl)-ethyl ester as off-white crystalline solid. Yield: 53%; ES-MS: m/z 285 [M+H] The reaction mixture is concentrated under reduced pressure The residue is dissolved 2M aqueous HCl solution (20 mL) extracted with ethyl acetate (3×50 mL) The combined organic extracts are dried over Na2SO4 filtered the solvent is removed

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 0.55 g of LiAlH4 (13.9 mmol) in THF (10 mL) is added dropwise a solution of 2 g (13.9 mmol) of (tetrahydro-pyran-4-yl)-acetic acid in THF (10 mL) under nitrogen atmosphere (CAUTION: highly exothermic reaction!). Upon complete addition, the reaction is stirred at room temperature for 18 h. The reaction is cooled in an ice-bath and quenched with addition of 1M aqueous NH4Cl solution (2 mL). The resulting precipitate is removed by filtration through Celite® and is rinsed with ethyl acetate (3×100 mL). The filtrate is dried over Na2SO4, filtered and concentrated under reduced pressure to afford 1.63 g of 2-(tetrahydro-pyran-4-yl)-ethanol as a colorless oil. Yield: 90%; ES-MS m/z 131 [M+H]. highly exothermic reaction Upon complete addition The reaction is cooled in an ice-bath quenched with addition of 1M aqueous NH4Cl solution (2 mL) The resulting precipitate is removed by filtration through Celite® is rinsed with ethyl acetate (3×100 mL) The filtrate is dried over Na2SO4 filtered concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-cold solution of 2-(tetrahydro-2H-pyran-4-yl)ethanol (1.00 g) in pyridine (6.5 mL) was added p-toluenesulfonyl chloride (1.5 g), followed by stirring at the same temperature for 30 minutes, and at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and then diluted aqueous hydrochloric acid (20 mL) was added to the residue, followed by twice extractions with ethyl acetate (20 mL). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20-50/50) to obtain p-toluenesulfonic acid 2-(tetrahydro-2H-pyran-4-yl)ethyl ester (450 mg). at room temperature for 18 hours The reaction mixture was concentrated under reduced pressure diluted aqueous hydrochloric acid (20 mL) was added to the residue followed by twice extractions with ethyl acetate (20 mL) washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20-50/50)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(tetrahydro-2H-pyran-4-yl)ethanol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 17 h, and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (33%). being purified by prep

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product of Example 8A (2.9 mmol), triethylamine (1.2 mL, 8.7 mmol) and methanesulfonyl chloride (0.34 mL, 4.4 mmol) in 10 mL tetrahydrofuran (THF) were reacted and the product isolated as in Example 1C to give the title compound that was used directly in the next reaction. the product isolated as in Example 1C