4-[(4-iodophenyl)methyl]morpholine

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

Conditions: temp:195.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-butyl-7-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (59 mg, 0.14653 mmol) and 4-iodobenzyl morpholine (67 mg, 0.22 mmol) in NMP (1 mL) was added CuI (3 mg, 0.022 mmol) and N,N′-dimethylcyclohexane-1,2-diamine (2 mg, 0.044 mmol). The reaction mixture was stirred under microwave irradiation at 195° C. for 30 min. Then the reaction was diluted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product (85 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.36 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 7.17 (s, 1H), 4.86 (s, 1H), 3.71-3.52 (m, 4H), 3.44-3.38 (m, 4H), 3.32-3.17 (m, 1H), 2.81-2.71 (m, 2H), 2.45-2.33 (m, 4H), 2.15-2.04 (m, 2H), 1.96-1.83 (m, 2H), 1.61-1.29 (m, 8H), 0.94-0.75 (m, 12H), 0.00 (s, 6H). MS m/z 578.4 [M+H]+. The organic layer was dried (MgSO4) filtered concentrated The residue was purified by ISCO

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

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

Procedure: 3-amino-1-phenyl-1H-pyrazole-4-carbonitrile (100 mg, 0.543 mmol), 4-(4-iodobenzyl)morpholine (165 mg, 0.543 mmol), Pd2dba3 (24.86 mg, 0.027 mmol), K2CO3 (83 mg, 0.597 mmol) and X-Phos (64.7 mg, 0.136 mmol) were added to a 5 mL microwave vial. Degassed tert-amyl alcohol (0.8 mL) was added and the vial was evacuated and back-filled with N2 (×3). The resulting mixture was stirred at 100° C. for 24 hours. Room temperature was attained, MeOH was added and the solvent removed in vacuo while loading onto silica. Purification of the residue by MPLC (0-15% MeOH—CHCl3) gave 3-{[4-(morpholin-4-ylmethyl)phenyl]amino}-1-phenyl-1H-pyrazole-4-carbonitrile as a beige solid. the vial was evacuated back-filled with N2 (×3) Room temperature MeOH was added the solvent removed in vacuo Purification of the residue by MPLC (0-15% MeOH—CHCl3)

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

Procedure: 3-Prop-2-ynyl-1-oxa-3-aza-spiro[4.5]decan-2-one(55 mg, 0.284 mmol), 4-(4-iodo-benzyl)-morpholine(95 mg, 0.313 mmol), tetrakis(triphenylphosphine)palladium (17 mg, 0.0142 mmol), copper iodide (6 mg, 0.0284 mmol) and triethylamine (0.12 mL, 0.853 mmol) were mixed in acetonitrile (1 mL) under argon. The reaction mixture was stirred at room temperature for 1 hour and then diluted with dichloromethane (6 mL). The mixture was washed with water (4 mL), washed with brine (4 mL), dried over sodium sulfate and concentrated. The residue was purified on silica gel eluting with 10 to 25% ethyl acetate in hexanes. The isolated product was treated with 2M hydrochloric acid in diethyl ether to make the hydrochloric acid salt. The salt was then dissolved in water, washed with hexanes and the aqueous phase then made alkaline using aqueous saturated sodium bicarbonate. The aqueous mixture was then extracted with dichloromethane and the organic phase dried over sodium sulfate and concentrated to give the product as an off-white solid (43 mg, 41%). 1H NMR (300 MHz, CDCl3): δ 7.38 (d, 2H), 7.29 (d, 2H), 4.31 (s, 2H), 3.71 (t, 4H), 3.49 (s, 2H), 3.4 (s, 2H), 2.43 (t, 4H), 1.83 (m, 4H), 1.54 (m, 6H). The mixture was washed with water (4 mL) washed with brine (4 mL) dried over sodium sulfate concentrated The residue was purified on silica gel eluting with 10 to 25% ethyl acetate in hexanes The isolated product was treated with 2M hydrochloric acid in diethyl ether The salt was then dissolved in water washed with hexanes The aqueous mixture was then extracted with dichloromethane the organic phase dried over sodium sulfate concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Bromomethyl-4-iodo-benzene (320 mg, 1.08 mmol) and morpholine (1 mL, 11.47 mmol) were combined. The reaction mixture was heated at 70° C. for 4 hours and then diluted with ethyl acetate. The resulting mixture was filtered and the filtrate was concentrated and dried. The residue was then dissolved in dichloromethane (10 mL), washed with water (4 mL), washed with brine (4 mL), dried over sodium sulfate and concentrated to give the product as an off-white solid (300 mg, 92%). 1H NMR (300 MHz, CDCl3): δ 7.64 (d, 2H), 7.09 (d, 2H), 3.7 (t, 4H), 3.43 (s, 2H), 2.43 (t, 4H). The resulting mixture was filtered the filtrate was concentrated dried The residue was then dissolved in dichloromethane (10 mL) washed with water (4 mL) washed with brine (4 mL) dried over sodium sulfate concentrated

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

Procedure: 3-Prop-2-ynyl-1-oxa-3-aza-spiro[4.5]decan-2-one (55 mg, 0.284 mmol), 4-(4-iodo-benzyl)-morpholine (95 mg, 0.313 mmol), tetrakis(triphenylphosphine)palladium (17 mg, 0.0142 mmol), copper iodide (6 mg, 0.0284 mmol) and triethylamine (0.12 mL, 0.853 mmol) were mixed in acetonitrile (1 mL) under argon. The reaction mixture was stirred at room temperature for 1 hour and then diluted with dichloromethane (6 mL). The mixture was washed with water (4 mL), washed with brine (4 mL), dried over sodium sulfate and concentrated. The residue was purified on silica gel eluting with 10 to 25% ethyl acetate in hexanes. The isolated product was treated with 2M hydrochloric acid in diethyl ether to make the hydrochloric acid salt. The salt was then dissolved in water, washed with hexanes and the aqueous phase then made alkaline using aqueous saturated sodium bicarbonate. The aqueous mixture was then extracted with dichloromethane and the organic phase dried over sodium sulfate and concentrated to give the product as an off-white solid (43 mg, 41%). 1H NMR (300 MHz, CDCl3); δ 7.38 (d, 2H), 7.29 (d, 2H), 4.31 (s, 2H), 3.71 (t, 4H), 3.49 (s, 2H), 3.4 (s, 2H), 2.43 (t, 4H), 1.83 (m, 4H), 1.54 (m, 6H). The mixture was washed with water (4 mL) washed with brine (4 mL) dried over sodium sulfate concentrated The residue was purified on silica gel eluting with 10 to 25% ethyl acetate in hexanes The isolated product was treated with 2M hydrochloric acid in diethyl ether The salt was then dissolved in water washed with hexanes The aqueous mixture was then extracted with dichloromethane the organic phase dried over sodium sulfate concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Bromomethyl-4-iodobenzene (320 mg, 1.08 mmol) and morpholine (1 mL, 11.47 mmol) were combined. The reaction mixture was heated at 70° C. for 4 hours and then diluted with ethyl acetate. The resulting mixture was filtered and the filtrate was concentrated and dried. The residue was then dissolved in dichloromethane (10 mL), washed with water (4 mL), washed with brine (4 mL), dried over sodium sulfate and concentrated to give the product as an off-white solid ±300 mg, 92%). 1H NMR (300 MHz, CDCl3): δ 7.64 (d, 2H), 7.09 (d, 2H), 3.7 (t, 4H), 3.43 (s, 2H), 2.43 (t, 4H). The resulting mixture was filtered the filtrate was concentrated dried The residue was then dissolved in dichloromethane (10 mL) washed with water (4 mL) washed with brine (4 mL) dried over sodium sulfate concentrated

Conditions: temp:195.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-butyl-7-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (59 mg, 0.14653 mmol) and 4-iodobenzyl morpholine (67 mg, 0.22 mmol) in NMP (1 mL) was added CuI (3 mg, 0.022 mmol) and N,N′-dimethylcyclohexane-1,2-diamine (2 mg, 0.044 mmol). The reaction mixture was stirred under microwave irradiation at 195° C. for 30 min. Then the reaction was diluted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product (85 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.36 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 7.17 (s, 1H), 4.86 (s, 1H), 3.71-3.52 (m, 4H), 3.44-3.38 (m, 4H), 3.32-3.17 (m, 1H), 2.81-2.71 (m, 2H), 2.45-2.33 (m, 4H), 2.15-2.04 (m, 2H), 1.96-1.83 (m, 2H), 1.61-1.29 (m, 8H), 0.94-0.75 (m, 12H), 0.00 (s, 6H). MS m/z 578.4 [M+H]+. The organic layer was dried (MgSO4) filtered concentrated The residue was purified by ISCO