2-fluoro-1-iodo-4-methylbenzene

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: A mixture of (5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00007 mol) which was prepared using procedures analogous to those described in the synthesis of example 472-a and followed by standard hydrogenation to remove the carbobenzyloxy (Cbz) protecting and, 4-methyl-2-fluoro-1-iodobenzene (21 mg, 0.00009 mol), sodium tert-butoxide (9.98 mg, 0.000104 mol), 1,4,7,10,13,16-hexaoxacyclooctadecane (27.4 mg, 0.000104 mol), 2-(di-tert-butylphosphino)biphenyl (0.8 mg, 0.000003 mol), tris(dibenzylideneacetone)dipalladium(0) (1 mg, 0.000001 mol), in tert-butyl alcohol (1.0 mL, 0.010 mol) was stirred at rt for 18. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 361.1 (M+H)+. was prepared those described in the synthesis of example 472-a The crude product was purified by prep-HPLC

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

Procedure: A mixture of (5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00007 mol) which was prepared using procedures analogous to those described in the synthesis of example 472-a and followed by standard hydrogenation to remove the carbobenzyloxy (Cbz) protecting and, 4-methyl-2-fluoro-1-iodobenzene (21 mg, 0.00009 mol), sodium tert-butoxide (9.98 mg, 0.000104 mol), 1,4,7,10,13,16-hexaoxacyclooctadecane (27.4 mg, 0.000104 mol), 2-(di-tert-butylphosphino)biphenyl (0.8 mg, 0.000003 mol), tris(dibenzylideneacetone)dipalladium(0) (1 mg, 0.000001 mol), in tert-butyl alcohol (1.0 mL, 0.010 mol) was stirred at rt for 18. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 361.1 (M+H)+. was prepared those described in the synthesis of example 472-a The crude product was purified by prep-HPLC

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

Procedure: Prepared from 2-fluoro-1-iodo-4-methyl-benzene and 2-bromo-4-fluoro-benzenethiol.

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

Procedure: Prepared from 2-fluoro-1-iodo-4-methyl-benzene and 2-bromo-4-fluoro-benzenethiol.

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

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

Procedure: To a suspension of 2-fluoro-4-methylaniline (2.0 g, 16 mmol) in aqueous sulfuric acid (˜7 N) was added an aqueous solution of sodium nitrite (1.10 g, 16 mmol, 10 mL water) dropwise at 0° C. and the resulting light orange solution was stirred for 30 minutes. This solution was carefully poured into an aqueous solution of potassium iodide (3.98 g, 24 mmol, 16 mL water) at 80° C. and the resulting red mixture was stirred 1.5 hours at 80° C., and overnight at 50° C. The reaction was cooled to room temperature, poured into water (300 mL), and sodium bisulfite added until the light yellow color remained constant. The aqueous was extracted with diethyl ether (2×125 mL) and the organics were combined, washed with brine, dried (sodium sulfate), filtered, and the ether evaporated to give 2.5 g (66%) of crude product as a yellow green oil. Used without further purification. 1H NMR (CDCl3) δ2.32 (s, 3H,), 6.72 (dd, 1H, J=1.28 Hz, J=8.05 Hz), 6.88 (dd, 1H, J=1.28 Hz, JH=8.97 Hz), 7.58 (dd, 1H, J=1.08 Hz, J=6.78 Hz). the resulting red mixture was stirred 1.5 hours at 80° C. overnight at 50° C added until the light yellow color The aqueous was extracted with diethyl ether (2×125 mL) washed with brine dried (sodium sulfate) filtered the ether evaporated

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

Procedure: To a suspension of 2-fluoro-4-methylaniline (2.0 g, 16 mmol) in aqueous sulfuric acid (˜7 N) was added an aqueous solution of sodium nitrite (1.10 g, 16 mmol, 10 mL water) dropwise at 0° C. and the resulting light orange solution was stirred for 30 minutes. This solution was carefully poured into an aqueous solution of potassium iodide (3.98 g, 24 mmol, 16 mL water) at 80° C. and the resulting red mixture was stirred 1.5 hours at 80° C., and overnight at 50° C. The reaction was cooled to room temperature, poured into water (300 mL), and sodium bisulfite added until the light yellow color remained constant. The aqueous was extracted with diethyl ether (2×125 mL) and the organics were combined, washed with brine, dried (sodium sulfate), filtered, and the ether evaporated to give 2.5 g (66%) of crude product as a yellow green oil. Used without further purification. 1H NMR (CDCl3) δ2.32 (s, 3H,), 6.72 (dd, 1H, J=1.28 Hz, J=8.05 Hz), 6.88 (dd, 1H, J=1.28 Hz, JH=8.97 Hz), 7.58 (dd, 1H, J=1.08 Hz, J=6.78 Hz). the resulting red mixture was stirred 1.5 hours at 80° C. overnight at 50° C added until the light yellow color The aqueous was extracted with diethyl ether (2×125 mL) washed with brine dried (sodium sulfate) filtered the ether evaporated

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

Procedure: A mixture of (5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00007 mol) which was prepared using procedures analogous to those described in the synthesis of example 472-a and followed by standard hydrogenation to remove the carbobenzyloxy (Cbz) protecting and, 4-methyl-2-fluoro-1-iodobenzene (21 mg, 0.00009 mol), sodium tert-butoxide (9.98 mg, 0.000104 mol), 1,4,7,10,13,16-hexaoxacyclooctadecane (27.4 mg, 0.000104 mol), 2-(di-tert-butylphosphino)biphenyl (0.8 mg, 0.000003 mol), tris(dibenzylideneacetone)dipalladium(0) (1 mg, 0.000001 mol), in tert-butyl alcohol (1.0 mL, 0.010 mol) was stirred at rt for 18. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 361.1 (M+H)+. was prepared those described in the synthesis of example 472-a The crude product was purified by prep-HPLC

Conditions: temp:-72.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under dry nitrogen, a solution prepared by dissolving 4-bromo-3-fluorotoluene (10 g) in THF (50 mL) was cooled to −72° C. Then, a 1.6 mol/L n-butyl lithium hexane solution (35 mL) was added at −72° C. to the solution such a rate that the inside temperature was not more than −65° C., followed by further stirring at −72° C. for 1 hour. A solution prepared by dissolving iodine (14.8 g) in THF (30 mL) was added at −72° C. to the resultant mixture such a rate that the inside temperature was not more than −60° C., and the temperature was slowly increased to room temperature. Then, a saturated aqueous ammonium chloride solution and hexane were added at room temperature to separate an organic layer, and the organic layer was washed with a 10% aqueous sodium sulfite solution two times and saturated brine in that order, and then dried with sodium sulfate. The sodium sulfate was filtered off, and the organic solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to yield 13.0 g of 3-fluoro-4-iodotoluene as a yellow liquid. Under dry nitrogen, a solution prepared was not more than −65° C. A solution prepared was not more than −60° C. the temperature was slowly increased to room temperature to separate an organic layer the organic layer was washed with a 10% aqueous sodium sulfite solution two times and saturated brine in that order dried with sodium sulfate The sodium sulfate was filtered off the organic solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography

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

Procedure: A mixture of (5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00007 mol) which was prepared using procedures analogous to those described in the synthesis of example 472-a and followed by standard hydrogenation to remove the carbobenzyloxy (Cbz) protecting and, 4-methyl-2-fluoro-1-iodobenzene (21 mg, 0.00009 mol), sodium tert-butoxide (9.98 mg, 0.000104 mol), 1,4,7,10,13,16-hexaoxacyclooctadecane (27.4 mg, 0.000104 mol), 2-(di-tert-butylphosphino)biphenyl (0.8 mg, 0.000003 mol), tris(dibenzylideneacetone)dipalladium(0) (1 mg, 0.000001 mol), in tert-butyl alcohol (1.0 mL, 0.010 mol) was stirred at rt for 18. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 361.1 (M+H)+. was prepared those described in the synthesis of example 472-a The crude product was purified by prep-HPLC