1-(7-hydroxy-1-benzofuran-2-yl)ethanone

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

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

Procedure: DEAD (0.787 mL, 5.00 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.50 g, 4.63 mmol; prepared in Example 52, Step 2), 2-acetyl-7-hydroxybenzofuran (0.88 g, 5.0 mmol) and PPh3 (1.31 g, 5.0 mmol) in THF (3 mL) under gentle heating. After being stirred for 30 min at room temperature, the reaction mixture was poured into water, extracted with EtOAc, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica using toluene/EtOAc (7:3) as eluent. The pure fractions were combined and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature. The mixture was poured into 0.5 M aqueous HCl and washed with EtOAc. The aqueous layer was alkalinized, by addition of NaOH, to pH 12 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated. The residue (0.250 g, 0.65 mmol) and pyridinium hydrochloride (0.075 g, 0.65 mmol) was dissolved in MeOH. The mixture was and concentrated and the residue was re-dissolved in EtOH and concentrated three more times to give 0.27 g (14%) of the title product. Pos-EI-MS shows M+ and 19 ions supporting the stated structure. HRMS m/z calcd for C20H22N4O4 (M)+ 382.1641, found 382.1631. extracted with EtOAc dried (MgSO4) concentrated The residue was purified by column chromatography on silica treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature The mixture was poured into 0.5 M aqueous HCl washed with EtOAc The aqueous layer was alkalinized, by addition of NaOH, to pH 12 extracted with EtOAc The organic layer was dried (MgSO4) filtered concentrated concentrated the residue was re-dissolved in EtOH concentrated three more times

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

Procedure: DEAD (0.787 mL, 5.00 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.50 g, 4.63 mmol; prepared in Example 52, Step 2), 2-acetyl-7-hydroxybenzofuran (0.88 g, 5.0 mmol) and PPh3 (1.31 g, 5.0 mmol) in THF (3 mL) under gentle heating. After being stirred for 30 min at room temperature, the reaction mixture was poured into water, extracted with EtOAc, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica using toluene/EtOAc (7:3) as eluent. The pure fractions were combined and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature. The mixture was poured into 0.5 M aqueous HCl and washed with EtOAc. The aqueous layer was alkalinized, by addition of NaOH, to pH 12 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated. The residue (0.250 g, 0.65 mmol) and pyridinium hydrochloride (0.075 g, 0.65 mmol) was dissolved in MeOH. The mixture was and concentrated and the residue was re-dissolved in EtOH and concentrated three more times to give 0.27 g (14%) of the title product. Pos-EI-MS shows M+ and 19 ions supporting the stated structure. HRMS m/z calcd for C20H22N4O4 (M)+ 382.1641, found 382.1631. extracted with EtOAc dried (MgSO4) concentrated The residue was purified by column chromatography on silica treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature The mixture was poured into 0.5 M aqueous HCl washed with EtOAc The aqueous layer was alkalinized, by addition of NaOH, to pH 12 extracted with EtOAc The organic layer was dried (MgSO4) filtered concentrated concentrated the residue was re-dissolved in EtOH concentrated three more times

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

Procedure: DEAD (0.787 mL, 5.00 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.50 g, 4.63 mmol; prepared in Example 52, Step 2), 2-acetyl-7-hydroxybenzofuran (0.88 g, 5.0 mmol) and PPh3 (1.31 g, 5 0 mmol) in THF (3 mL) under gentle heating. After being stirred for 30 min at room temperature, the reaction mixture was poured into water, extracted with EtOAc, dried (MgSO 4) and concentrated The residue was purified b column chromatography on silica using toluene/EtOAc (7 ·3) as eluent. The pure fractions were combined and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature. The mixture was poured into 0.5 M aqueous HCl and washed with EtOAc. The aqueous layer was alkalinized, by addition of NaOH, to pH 12 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated The residue (0.250 g, 0.65 mmol) and pyridinium hydrochloride (0.075 g, 0.65 mmol) was dissolved in MeOH. The mixture was and concentrated and the residue was re-dissolved in EtOH and concentrated three more times to give 0.27 g (14 %) of the title product. Pos-EI-MS shows M+ and 19 ions supporting the stated structure. HRMS m/z calcd for C20H22N4O4 (M)+ 382.1641, found 382.1631. extracted with EtOAc dried (MgSO 4) concentrated The residue was purified b column chromatography on silica treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature The mixture was poured into 0.5 M aqueous HCl washed with EtOAc The aqueous layer was alkalinized, by addition of NaOH, to pH 12 extracted with EtOAc The organic layer was dried (MgSO4) filtered concentrated the residue was re-dissolved in EtOH concentrated three more times

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

Procedure: DEAD (0.787 mL, 5.00 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.50 g, 4.63 mmol; prepared in Example 52, Step 2), 2-acetyl-7-hydroxybenzofuran (0.88 g, 5.0 mmol) and PPh3 (1.31 g, 5 0 mmol) in THF (3 mL) under gentle heating. After being stirred for 30 min at room temperature, the reaction mixture was poured into water, extracted with EtOAc, dried (MgSO 4) and concentrated The residue was purified b column chromatography on silica using toluene/EtOAc (7 ·3) as eluent. The pure fractions were combined and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature. The mixture was poured into 0.5 M aqueous HCl and washed with EtOAc. The aqueous layer was alkalinized, by addition of NaOH, to pH 12 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated The residue (0.250 g, 0.65 mmol) and pyridinium hydrochloride (0.075 g, 0.65 mmol) was dissolved in MeOH. The mixture was and concentrated and the residue was re-dissolved in EtOH and concentrated three more times to give 0.27 g (14 %) of the title product. Pos-EI-MS shows M+ and 19 ions supporting the stated structure. HRMS m/z calcd for C20H22N4O4 (M)+ 382.1641, found 382.1631. extracted with EtOAc dried (MgSO 4) concentrated The residue was purified b column chromatography on silica treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature The mixture was poured into 0.5 M aqueous HCl washed with EtOAc The aqueous layer was alkalinized, by addition of NaOH, to pH 12 extracted with EtOAc The organic layer was dried (MgSO4) filtered concentrated the residue was re-dissolved in EtOH concentrated three more times

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture composed of 1.93 g (14.1 mM) of anhydrous zinc chloride, 1 g (5.7 mM) of 2-acetyl-7-hydroxybenzofuran and 2.2 g of molecular sieve 13× is stirred into 13 ml of toluene and 13 ml of acetonitrile. The mixture is brought to 90° C. and 1.42 g (14.1 mM) of triethylamine and 2.22 g (6.27 mM) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide are added, while maintaining the mixture at the temperature of 90° C. The mixture maintained at 90° C. is then stirred for 20 minutes. The mixture is subsequently cooled, 65 ml of a 0.5 N solution of sodium hydroxide are added, and the resulting mixture is stirred for one hour. The medium is filtered and the precipitate is washed with ethyl acetate. The filtrate is subsequently separated by settling out. The organic phase is washed with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The evaporation residue is purified by silica gel chromatography, elution being carried out with a cyclohexane/ethyl acetate mixture (7/3; v/v). The desired product is obtained in the form of a yellowish solid with a yield of 37%. is brought to 90° C. The mixture maintained at 90° C. The mixture is subsequently cooled the resulting mixture is stirred for one hour The medium is filtered the precipitate is washed with ethyl acetate The filtrate is subsequently separated The organic phase is washed with a saturated aqueous solution of ammonium chloride dried over magnesium sulfate concentrated under reduced pressure The evaporation residue is purified by silica gel chromatography, elution

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

Procedure: DEAD (0.787 mL, 5.00 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.50 g, 4.63 mmol; prepared in Example 52, Step 2), 2-acetyl-7-hydroxybenzofuran (0.88 g, 5.0 mmol) and PPh3 (1.31 g, 5.0 mmol) in THF (3 mL) under gentle heating. After being stirred for 30 min at room temperature, the reaction mixture was poured into water, extracted with EtOAc, dried (MgSO4) and concentrated. The residue was purified by column chromatography oil silica using toluene/EtOAc (7:3) as eluent. The pure fractions were combined and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature. The mixture was poured into 0.5 M aqueous HCl and washed with EtOAc. The aqueous layer was alkalinized, by addition of NaOH, to pH 12 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated. The residue (0.250 g, 0.65 mmol) and pyridinium hydrochloride (0.075 g, 0.65 mmol) was dissolved in MeOH. The mixture was and concentrated and the residue was re-dissolved in EtOH and concentrated three more times to give 0.27 g (14%) of the title product. Pos-EI-MS shows M+ and 19 ions supporting the stated structure. HRMS m/z calcd for C20H22N4O4(M)+382.1641, found 382.1631. extracted with EtOAc dried (MgSO4) concentrated The residue was purified by column chromatography oil silica treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature The mixture was poured into 0.5 M aqueous HCl washed with EtOAc The aqueous layer was alkalinized, by addition of NaOH, to pH 12 extracted with EtOAc The organic layer was dried (MgSO4) filtered concentrated concentrated the residue was re-dissolved in EtOH concentrated three more times

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

Procedure: Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(7-hydroxy-benzofuran-2-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (19 mg, 20% yield). MS: 504.22 (M+H+); HPLC Procedure A, retention time=12.20 min.

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 214 mg. of potassium salt of 2-acetyl-7-hydroxybenzofuran, 70 mg. of isopropylamine and 0.8 ml. of epichlorohydrin was suspended into 5 ml. of ethanol. After heating the suspension in a sealed tube at 100° C. for 20 hours, the reaction mixture was filtered and then the solvent was evaporated under a reduced pressure. The residue was subjected to thin layer chromatography (solid support: Kieselgel PF254 made by E. Merck, developer: benzene-chloroform-methanol-28 % aqueous ammonia (17:4:3:0.4), eluant: chloroform) for the purification to give 2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran having a melting point of 115° C. A mixture of 214 mg the reaction mixture was filtered the solvent was evaporated under a reduced pressure The residue was subjected to thin layer chromatography (solid support: Kieselgel PF254 made by E. Merck, developer: benzene-chloroform-methanol-28 % aqueous ammonia (17:4:3:0.4), eluant: chloroform) for the purification

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

Procedure: DEAD (0.787 mL, 5.00 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.50 g, 4.63 mmol; prepared in Example 52, Step 2), 2-acetyl-7-hydroxybenzofuran (0.88 g, 5.0 mmol) and PPh3 (1.31 g, 5.0 mmol) in THF (3 mL) under gentle heating. After being stirred for 30 min at room temperature, the reaction mixture was poured into water, extracted with EtOAc, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica using toluene/EtOAc (7:3) as eluent. The pure fractions were combined and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature. The mixture was poured into 0.5 M aqueous HCl and washed with EtOAc. The aqueous layer was alkalinized, by addition of NaOH, to pH 12 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated. The residue (0.250 g, 0.65 mmol) and pyridinium hydrochloride (0.075 g, 0.65 mmol) was dissolved in MeOH. The mixture was and concentrated and the residue was re-dissolved in EtOH and concentrated three more times to give 0.27 g (14%) of the title product. Pos-EI-MS shows M+ and 19 ions supporting the stated structure. HRMS m/z calcd for C20H22N4O4 (M)+ 382.1641, found 382.1631. extracted with EtOAc dried (MgSO4) concentrated The residue was purified by column chromatography on silica treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature The mixture was poured into 0.5 M aqueous HCl washed with EtOAc The aqueous layer was alkalinized, by addition of NaOH, to pH 12 extracted with EtOAc The organic layer was dried (MgSO4) filtered concentrated concentrated the residue was re-dissolved in EtOH concentrated three more times

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

Procedure: DEAD (0.787 mL, 5.00 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.50 g, 4.63 mmol; prepared in Example 52, Step 2), 2-acetyl-7-hydroxybenzofuran (0.88 g, 5.0 mmol) and PPh3 (1.31 g, 5 0 mmol) in THF (3 mL) under gentle heating. After being stirred for 30 min at room temperature, the reaction mixture was poured into water, extracted with EtOAc, dried (MgSO 4) and concentrated The residue was purified b column chromatography on silica using toluene/EtOAc (7 ·3) as eluent. The pure fractions were combined and treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature. The mixture was poured into 0.5 M aqueous HCl and washed with EtOAc. The aqueous layer was alkalinized, by addition of NaOH, to pH 12 and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated The residue (0.250 g, 0.65 mmol) and pyridinium hydrochloride (0.075 g, 0.65 mmol) was dissolved in MeOH. The mixture was and concentrated and the residue was re-dissolved in EtOH and concentrated three more times to give 0.27 g (14 %) of the title product. Pos-EI-MS shows M+ and 19 ions supporting the stated structure. HRMS m/z calcd for C20H22N4O4 (M)+ 382.1641, found 382.1631. extracted with EtOAc dried (MgSO 4) concentrated The residue was purified b column chromatography on silica treated with CH2Cl2/TFA/H2O (50:45:5; 5 mL) for 30 min at room temperature The mixture was poured into 0.5 M aqueous HCl washed with EtOAc The aqueous layer was alkalinized, by addition of NaOH, to pH 12 extracted with EtOAc The organic layer was dried (MgSO4) filtered concentrated the residue was re-dissolved in EtOH concentrated three more times