1,2,3,4,5-pentafluoro-6-iodobenzene

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

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

Procedure: A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled with dry ice-ethanol bath. A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C. After stirring the reaction mixture for 1 hour at the same temperature, pentafluoroiodobenzene (115 mL, 861 mmol) was added dropwise. The reaction-mixture was additionally stirred for 1 hour and 20 minutes, and then water/THF (1/1, v/v, 360 mL) was added thereto. Cooling was terminated, and then water (3600 mL) and heptane (3600 mL) were added to the reaction mixture, the aqueous layer was removed and the organic extract was washed with water (3600 mL). A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer and the aqueous layer was separated off. After cooling the aqueous layer in an ice bath and adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture and the organic layer was separated off. The aqueous layer was extracted with toluene (3600 mL), and both organic extracts were combined and concentrated to afford 220 g of the title compound as a dark green oil (87.3% yield). A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C was added dropwise Cooling was terminated water (3600 mL) and heptane (3600 mL) were added to the reaction mixture the aqueous layer was removed the organic extract was washed with water (3600 mL) A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer the aqueous layer was separated off After cooling the aqueous layer in an ice bath adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture the organic layer was separated off The aqueous layer was extracted with toluene (3600 mL) concentrated

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

Procedure: A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled with dry ice-ethanol bath. A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C. After stirring the reaction mixture for 1 hour at the same temperature, pentafluoroiodobenzene (115 mL, 861 mmol) was added dropwise. The reaction-mixture was additionally stirred for 1 hour and 20 minutes, and then water/THF (1/1, v/v, 360 mL) was added thereto. Cooling was terminated, and then water (3600 mL) and heptane (3600 mL) were added to the reaction mixture, the aqueous layer was removed and the organic extract was washed with water (3600 mL). A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer and the aqueous layer was separated off. After cooling the aqueous layer in an ice bath and adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture and the organic layer was separated off. The aqueous layer was extracted with toluene (3600 mL), and both organic extracts were combined and concentrated to afford 220 g of the title compound as a dark green oil (87.3% yield). A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C was added dropwise Cooling was terminated water (3600 mL) and heptane (3600 mL) were added to the reaction mixture the aqueous layer was removed the organic extract was washed with water (3600 mL) A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer the aqueous layer was separated off After cooling the aqueous layer in an ice bath adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture the organic layer was separated off The aqueous layer was extracted with toluene (3600 mL) concentrated

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

Procedure: A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled with dry ice-ethanol bath. A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C. After stirring the reaction mixture for 1 hour at the same temperature, pentafluoroiodobenzene (115 mL, 861 mmol) was added dropwise. The reaction-mixture was additionally stirred for 1 hour and 20 minutes, and then water/THF (1/1, v/v, 360 mL) was added thereto. Cooling was terminated, and then water (3600 mL) and heptane (3600 mL) were added to the reaction mixture, the aqueous layer was removed and the organic extract was washed with water (3600 mL). A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer and the aqueous layer was separated off. After cooling the aqueous layer in an ice bath and adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture and the organic layer was separated off. The aqueous layer was extracted with toluene (3600 mL), and both organic extracts were combined and concentrated to afford 220 g of the title compound as a dark green oil (87.3% yield). A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C was added dropwise Cooling was terminated water (3600 mL) and heptane (3600 mL) were added to the reaction mixture the aqueous layer was removed the organic extract was washed with water (3600 mL) A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer the aqueous layer was separated off After cooling the aqueous layer in an ice bath adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture the organic layer was separated off The aqueous layer was extracted with toluene (3600 mL) concentrated

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

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

Procedure: Compound 10 (11.3 g, 45.54 mmol, 1 equiv) and iodopentafluorobenzene (10.6 g, 36.2 mmol, 1 equiv) were dissolved in toluene (200 mL) and 1.0M potassium carbonate solution (200 mL). Tetrabutylammonium bromide (1.6 g, 5 mmol, 0.11 equiv) was added and the solution sparged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.63 g, 2.28 mmol, 0.05 equiv) was added and the reaction was refluxed for one day. The reaction was cooled to room temperature, then the layers were separated. The aqueous phase was back extracted with ethyl acetate (2×200 mL). Combined organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over silica gel (200 g), eluting with heptanes to give 2,3,4,5,6-pentafluoro-2′-methoxy-5′-methyl-1,1′-biphenyl (11) (9.7 g, 74% yield) as a pale-yellow oil. This material contained a small amount of unreacted iodopentafluorobenzene which was identified by 19F NMR. The material was used subsequently. the solution sparged with nitrogen for 10 minutes the reaction was refluxed for one day the layers were separated The aqueous phase was back extracted with ethyl acetate (2×200 mL) dried over sodium sulfate concentrated under reduced pressure The residue was purified over silica gel (200 g) eluting with heptanes

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

Procedure: A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(tetrahydro-2H-4-pyranylmethyl)amine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled in a dry ice-ethanol bath. Into the reaction mixture was dropped n-butyllithium (1.6M hexane solution; 538 mL, 854 mmol) at an inner temperature of −73° C. to −64.5° C. At the same temperature, the reaction mixture was stirred for 1 hour, and into the reaction mixture was dropped pentafluoroiodobenzene (115 mL, 861 mmol). The reaction mixture was further stirred for 1 hour and 20 minutes at the same temperature, and to the reaction mixture was added water/tetrahydrofuran (1/1, v/v, 360 mL). Into the reaction mixture was added water (3600 mL) and heptane (3600 mL). An aqueous layer was removed, and an organic layer was washed with water (3600 mL). Then, to the organic layer was added 5N hydrochloric acid (1800 mL) and the aqueous layer was separated. Then, the aqueous layer was cooled in an ice water bath, and a 5N sodium hydroxide aqueous solution (1620 mL) was added, then, toluene (3600 mL) was added, and an organic layer was separated. The remaining aqueous layer was further extracted with toluene (3600 mL), and both the organic layers were combined. The solution was concentrated under reduced pressure, to obtain 220 g of a title compound as deep green oil (yield: 87.3%). The reaction mixture was further stirred for 1 hour and 20 minutes at the same temperature An aqueous layer was removed an organic layer was washed with water (3600 mL) Then, to the organic layer was added 5N hydrochloric acid (1800 mL) the aqueous layer was separated Then, the aqueous layer was cooled in an ice water bath a 5N sodium hydroxide aqueous solution (1620 mL) was added toluene (3600 mL) was added an organic layer was separated The remaining aqueous layer was further extracted with toluene (3600 mL) The solution was concentrated under reduced pressure

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

Procedure: A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(tetrahydro-2H-4-pyranylmethyl)amine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled in a dry ice-ethanol bath. Into the reaction mixture was dropped n-butyllithium (1.6M hexane solution; 538 mL, 854 mmol) at an inner temperature of −73° C. to −64.5° C. At the same temperature, the reaction mixture was stirred for 1 hour, and into the reaction mixture was dropped pentafluoroiodobenzene (115 mL, 861 mmol). The reaction mixture was further stirred for 1 hour and 20 minutes at the same temperature, and to the reaction mixture was added water/tetrahydrofuran (1/1, v/v, 360 mL). Into the reaction mixture was added water (3600 mL) and heptane (3600 mL). An aqueous layer was removed, and an organic layer was washed with water (3600 mL). Then, to the organic layer was added 5N hydrochloric acid (1800 mL) and the aqueous layer was separated. Then, the aqueous layer was cooled in an ice water bath, and a 5N sodium hydroxide aqueous solution (1620 mL) was added, then, toluene (3600 mL) was added, and an organic layer was separated. The remaining aqueous layer was further extracted with toluene (3600 mL), and both the organic layers were combined. The solution was concentrated under reduced pressure, to obtain 220 g of a title compound as deep green oil (yield: 87.3%). The reaction mixture was further stirred for 1 hour and 20 minutes at the same temperature An aqueous layer was removed an organic layer was washed with water (3600 mL) Then, to the organic layer was added 5N hydrochloric acid (1800 mL) the aqueous layer was separated Then, the aqueous layer was cooled in an ice water bath a 5N sodium hydroxide aqueous solution (1620 mL) was added toluene (3600 mL) was added an organic layer was separated The remaining aqueous layer was further extracted with toluene (3600 mL) The solution was concentrated under reduced pressure

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

Procedure: A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(tetrahydro-2H-4-pyranylmethyl)amine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled in a dry ice-ethanol bath. Into the reaction mixture was dropped n-butyllithium (1.6M hexane solution; 538 mL, 854 mmol) at an inner temperature of −73° C. to −64.5° C. At the same temperature, the reaction mixture was stirred for 1 hour, and into the reaction mixture was dropped pentafluoroiodobenzene (115 mL, 861 mmol). The reaction mixture was further stirred for 1 hour and 20 minutes at the same temperature, and to the reaction mixture was added water/tetrahydrofuran (1/1, v/v, 360 mL). Into the reaction mixture was added water (3600 mL) and heptane (3600 mL). An aqueous layer was removed, and an organic layer was washed with water (3600 mL). Then, to the organic layer was added 5N hydrochloric acid (1800 mL) and the aqueous layer was separated. Then, the aqueous layer was cooled in an ice water bath, and a 5N sodium hydroxide aqueous solution (1620 mL) was added, then, toluene (3600 mL) was added, and an organic layer was separated. The remaining aqueous layer was further extracted with toluene (3600 mL), and both the organic layers were combined. The solution was concentrated under reduced pressure, to obtain 220 g of a title compound as deep green oil (yield: 87.3%). The reaction mixture was further stirred for 1 hour and 20 minutes at the same temperature An aqueous layer was removed an organic layer was washed with water (3600 mL) Then, to the organic layer was added 5N hydrochloric acid (1800 mL) the aqueous layer was separated Then, the aqueous layer was cooled in an ice water bath a 5N sodium hydroxide aqueous solution (1620 mL) was added toluene (3600 mL) was added an organic layer was separated The remaining aqueous layer was further extracted with toluene (3600 mL) The solution was concentrated under reduced pressure

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

Procedure: A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled with dry ice-ethanol bath. A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C. After stirring the reaction mixture for 1 hour at the same temperature, pentafluoroiodobenzene (115 mL, 861 mmol) was added dropwise. The reaction mixture was additionally stirred for 1 hour and 20 minutes, and then water/THF (1/1, v/v, 360 mL) was added thereto. Cooling was terminated, and then water (3600 mL) and heptane (3600 mL) were added to the reaction mixture, the aqueous layer was removed and the organic extract was washed with water (3600 mL). A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer and the aqueous layer was separated off. After cooling the aqueous layer in an ice bath and adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture and the organic layer was separated off. The aqueous layer was extracted with toluene (3600 mL), and both organic extracts were combined and concentrated to afford 220 g of the title compound as a dark green oil (87.3% yield) A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C was added dropwise Cooling was terminated water (3600 mL) and heptane (3600 mL) were added to the reaction mixture the aqueous layer was removed the organic extract was washed with water (3600 mL) A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer the aqueous layer was separated off After cooling the aqueous layer in an ice bath adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture the organic layer was separated off The aqueous layer was extracted with toluene (3600 mL) concentrated

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

Procedure: A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled with dry ice-ethanol bath. A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C. After stirring the reaction mixture for 1 hour at the same temperature, pentafluoroiodobenzene (115 mL, 861 mmol) was added dropwise. The reaction mixture was additionally stirred for 1 hour and 20 minutes, and then water/THF (1/1, v/v, 360 mL) was added thereto. Cooling was terminated, and then water (3600 mL) and heptane (3600 mL) were added to the reaction mixture, the aqueous layer was removed and the organic extract was washed with water (3600 mL). A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer and the aqueous layer was separated off. After cooling the aqueous layer in an ice bath and adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture and the organic layer was separated off. The aqueous layer was extracted with toluene (3600 mL), and both organic extracts were combined and concentrated to afford 220 g of the title compound as a dark green oil (87.3% yield) A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C was added dropwise Cooling was terminated water (3600 mL) and heptane (3600 mL) were added to the reaction mixture the aqueous layer was removed the organic extract was washed with water (3600 mL) A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer the aqueous layer was separated off After cooling the aqueous layer in an ice bath adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture the organic layer was separated off The aqueous layer was extracted with toluene (3600 mL) concentrated

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

Procedure: Compound 5 (11.3 g, 45.54 mmol, 1 equiv) and iodopentafluorobenzene (10.6 g, 36.2 mmol, 1 equiv) were dissolved in toluene (200 mL) and 1.0M potassium carbonate solution (200 mL). Tetrabutylammonium bromide (1.6 g, 5 mmol, 0.11 equiv) was added and the solution sparged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.63 g, 2.28 mmol, 0.05 equiv) was added and the reaction was refluxed for one day. The reaction was cooled to room temperature, then the layers were separated. The aqueous phase was back extracted with ethyl acetate (2×200 mL). Combined organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over silica gel (200 g), eluting with heptanes to give 2,3,4,5,6-pentafluoro-2′-methoxy-5′-methyl-1,1′-biphenyl (6) (9.7 g, 74% yield) as a pale-yellow oil. This material contained a small amount of unreacted iodopentafluorobenzene which was identified by 19F NMR. The material was used subsequently. the solution sparged with nitrogen for 10 minutes the reaction was refluxed for one day the layers were separated The aqueous phase was back extracted with ethyl acetate (2×200 mL) dried over sodium sulfate concentrated under reduced pressure The residue was purified over silica gel (200 g) eluting with heptanes