6-chloro-1-benzofuran-3-one

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

Procedure: Prepared in an analogous manner as described for intermediate A22A from (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (intermediate A19B) (96 mg, 302 μmol) and commercially available 6-chlorobenzofuran-3(2H)-one [CAS no 3260-78-4] (61.0 mg, 362 μmol) The (5R)-5-(5-(6-chloro-2,3-dihydrobenzofuran-3-ylamino)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (72 mg, 153 μmol, 50.7% yield) was obtained as a light yellow foam. MS (ISN): m/z=469.1 [(M−H)−] and 471.2 [(M+2-H)−]. Prepared in an analogous manner

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

Procedure: Prepared in an analogous manner as described for intermediate A22A from (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (intermediate A19B) (96 mg, 302 μmol) and commercially available 6-chlorobenzofuran-3(2H)-one [CAS no 3260-78-4] (61.0 mg, 362 μmol) The (5R)-5-(5-(6-chloro-2,3-dihydrobenzofuran-3-ylamino)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (72 mg, 153 μmol, 50.7% yield) was obtained as a light yellow foam. MS (ISN): m/z=469.1 [(M−H)−] and 471.2 [(M+2-H)−]. Prepared in an analogous manner

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

Procedure: The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 6-chloro-benzofuran-3-one using decaborane yielded a mixture of epimers of the title compound as a white foam. MS (ESI): m/z=431.3 [M+H]+. yielded

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

Procedure: The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 6-chloro-benzofuran-3-one using decaborane yielded a mixture of epimers of the title compound as a white foam. MS (ESI): m/z=431.3 [M+H]+. yielded

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

Procedure: A mixture of 6-chloro-benzofuran-3 (2H)-one (1.68 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, the reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, ethyl(6-chloro-1-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 2.1 g (87%); 239 (M+H). At the end, the reaction mixture was concentrated The column was eluted with hexane (500 ml) and later with 25% ethyl acetate

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

Procedure: To a solution of 6-chloro-2,3-dihydro-1-benzofuran-3-one (2.5 g, 14.83 mmol) in methanol (50 mL) was treated with NaBH4 (1.2 g, 31.58 mmol) in four equivalent portions at room temperature, until the reaction was complete, as monitored by TLC (1 h). The reaction mixture was quenched by the addition of acetone (10 mL). This mixture was then treated with HCl (3N, 20 mL). After stirring for another 1 h, the resulting solution was extracted with ethyl acetate (3×50 mL) dried over anhydrous magnesium sulfate and concentrated under vacuum to give 6-chloro-1-benzofuran as oil (2 g, crude). as monitored by TLC (1 h) The reaction mixture was quenched by the addition of acetone (10 mL) This mixture was then treated with HCl (3N, 20 mL) the resulting solution was extracted with ethyl acetate (3×50 mL) dried over anhydrous magnesium sulfate concentrated under vacuum

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

Procedure: A mixture of 6-chloro-benzofuran-3 (2H)-one (1.68 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. Afterwards, the reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and then with 25% ethyl acetate. The product, ethyl(6-chloro-1-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 2.1 g (87%); (M+H): 239. Afterwards, the reaction mixture was concentrated The column was eluted with hexane (500 ml)

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

Procedure: Prepared in an analogous manner as described for intermediate A22A from (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (intermediate A19B) (96 mg, 302 μmol) and commercially available 6-chlorobenzofuran-3(2H)-one [CAS no 3260-78-4] (61.0 mg, 362 μmol) The (5R)-5-(5-(6-chloro-2,3-dihydrobenzofuran-3-ylamino)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (72 mg, 153 μmol, 50.7% yield) was obtained as a light yellow foam. MS (ISN): m/z=469.1 [(M−H)−] and 471.2 [(M+2-H)−]. Prepared in an analogous manner