N,N-diethyl-2-hydroxybenzamide

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

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 25 g of N,N-diethylsalicylamide, 38.5 ml of 1-bromotetradecane, 22.35 g of potassium carbonate and 400 ml of 2-butanone is heated at reflux temperature for 16 hours. The reaction is cooled, filtered and concentrated in vacuo. The concentrate is dissolved in chloroform, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:0-30% ethyl acetate/hexane) to give 42.5 g of the desired product as colorless crystals. is heated at reflux temperature for 16 hours The reaction is cooled filtered concentrated in vacuo The concentrate is dissolved in chloroform dried concentrated in vacuo The residue is purified by column chromatography (silica gel:0-30% ethyl acetate/hexane)

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

Procedure: A mixture of 25 g of N,N-diethylsalicylamide, 38.5 ml of 1-bromotetradecane, 22.35 g of potassium carbonate and 400 ml of 2-butanone is heated at reflux temperature for 16 hours. The reaction is cooled, filtered and concentrated in vacuo. The concentrate is dissolved in chloroform, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:0-30% ethyl acetate/hexane) to give 42.5 g of the desired product as colorless crystals. is heated at reflux temperature for 16 hours The reaction is cooled filtered concentrated in vacuo The concentrate is dissolved in chloroform dried concentrated in vacuo The residue is purified by column chromatography (silica gel:0-30% ethyl acetate/hexane)

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

Procedure: CuI (10 mg, 0.05 mmol), N,N-diethylsalicylamide (10 mg, 0.05 mmol), 4-toluidine (161, 1.5 mmol) and K3PO4 (425 mg, 2.0 mmol) were put into a screw-capped test tube with a Teflon-lined septum. The tube was then evacuated and backfilled with argon (3 cycles). 5-Bromo-m-xylene (136 μL, 1.0 mmol) was added by a syringe. The reaction mixture was stirred at 100° C. for 20 h. The reaction mixture was allowed to reach room temperature. Ethyl acetate (˜2 mL), water (˜10 mL), ammonium hydroxide (˜0.5 mL) and dodecane (227 μL) were added. The organic phase was analyzed by GC and 22% conversion of 5-bromo-m-xylene and 9% GC yield of the desired product was obtained. The tube was then evacuated to reach room temperature

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

Procedure: CuI (10 mg, 0.05 mmol), N,N-diethylsalicylamide (39 mg, 0.20 mmol), 4-bromochlorobenzene (191 mg, 1.0 mmol) and K3PO4 (425 mg, 2.0 mmol) were put into a screw-capped test tube with a Teflon-lined septum. The tube was then evacuated and backfilled with argon (3 cycles). Piperidine (148 μL, 1.5 mmol) and DMF (0.5 mL) were added by syringes. The reaction mixture was stirred at 90° C. for 20 h. The reaction mixture was allowed to reach room temperature. Ethyl acetate (˜2 mL), water (˜10 mL), ammonium hydroxide (˜0.5 mL) and dodecane (227 μL) were added. The organic phase was analyzed by GC and GC-MS. A 75% conversion of 4-bromochlorobenzene and 29% calibrated GC yield was obtained. The tube was then evacuated to reach room temperature yield was obtained

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

Procedure: CuOAc (6 mg, 0.05 mmol), N,N-diethylsalicylamide (39 mg, 0.20 mmol) and K3PO4 (425 mg, 2.0 mmol) were put into a screw-capped test tube with a Teflon-lined septum. The tube was then evacuated and backfilled with argon (3 cycles). 5-Bromo-m-xylene (136 μL, 1.0 mmol), (R)-α-methylbenzylamine (193 μL, 1.5 mmol) and DMF (0.5 mL) were added by syringes. The reaction mixture was stirred at 100° C. for 30 h. The reaction mixture was allowed to reach room temperature. Ethyl acetate (˜2 mL), water (˜10 mL), ammonium hydroxide (˜0.5 mL) and dodecane (227 μL) were added. The organic phase was analyzed by GC or GC-MS. The reaction mixture was further extracted by ethyl acetate (4×10 mL). The combined organic phases were washed with brine and dried over Na2SO4. Solvent was removed in vacuo and the yellow residue was purified by column chromatography on silica gel using hexane/ethyl acetate (20:1) as eluent to afford the desired product as a colorless oil (160 mg, 71% yield, 98% ee). Rf=0.4 (hexane/ethyl acetate=20:1). HPLC conditions: (column: Daciel OD; flow rate: 0.7 mL/min; UV lamp: 254 nm; solvent system: hexane/2-propanol (9:1); retention time: 7.80 min). The tube was then evacuated to reach room temperature The reaction mixture was further extracted by ethyl acetate (4×10 mL) The combined organic phases were washed with brine dried over Na2SO4 Solvent was removed in vacuo the yellow residue was purified by column chromatography on silica gel

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

Procedure: 2.45 g (10.00 mmol) of potassium phosphate monohydrate was added under argon to a mixture of 1.42 g (5.00 mmol) of 1-bromo-4-iodobenzene, 1.00 g (5.00 mmol) of tert-butyl (S)-2-aminomethylpyrrolidine-1-carboxylate, 48 mg (0.25 mmol) of CuI, and 97 mg (0.50 mmol) of N,N-diethylsalicylamide in 5 mL of DMF and the mixture was stirred for 160 hours at 100° C. The reaction mixture was cooled to RT, combined with 100 mL of 4M aqueous HCl, and stirred for 1 hour at RT. The aqueous phase was washed with MTBE, made basic with concentrated aqueous ammonia, and exhaustively extracted with MTBE. The combined organic extracts were dried over magnesium sulfate, filtered through activated charcoal, and evaporated down in vacuo. The crude product was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). The eluates were evaporated down in vacuo and the residue was neutralized with sat. aqueous sodium bicarbonate solution. The aqueous phase was extracted with DCM, dried over magnesium sulfate and evaporated down in vacuo. Yield: 0.20 g (16% of theoretical); C11H15BrN2 (M=255.2); calc.: molpeak (M+H)+: 255/257 (Br); found: molpeak (M+H)+:255/257 (Br); HPLC-MS: 3.90 minutes (method B). The reaction mixture was cooled to RT stirred for 1 hour at RT The aqueous phase was washed with MTBE exhaustively extracted with MTBE The combined organic extracts were dried over magnesium sulfate filtered through activated charcoal evaporated down in vacuo The crude product was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v) The eluates were evaporated down in vacuo The aqueous phase was extracted with DCM dried over magnesium sulfate evaporated down in vacuo 3.90 minutes (method B)

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

Procedure: 4.90 g (20.00 mmol) of potassium phosphate monohydrate were added under argon to a mixture of 4.16 g (10.00 mmol) of 5-(4-chlorophenyl)-2-(4-iodophenylethynyl)pyridine, 3.10 g (15.00 mmol) of tert-butyl (S)-2-aminomethylpyrrolidine-1-carboxylate, 194 mg (1.00 mmol) of CuI, 0.77 g (4.00 mmol) of N,N-diethylsalicylamide in 10 mL of DMF and the mixture was stirred for 16 hours at 100° C. The reaction mixture was combined with 100 mL of 5% aqueous ammonia, stirred, and the precipitate was filtered off. The precipitate was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). 2 fractions were isolated. Fraction 1: yield: 0.48 g (10% of theoretical); C29H30ClN3O2 (M=488.020) molpeak (M+H)+: 488/490 (Cl); found: molpeak (M+H)+: 488/490 (Cl); Rf value: 0.60 (silica gel, PE/EtOAc 1:1). stirred the precipitate was filtered off The precipitate was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v) 2 fractions were isolated

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

Procedure: 4.90 g (20.00 mmol) of potassium phosphate monohydrate were added under argon to a mixture of 4.16 g (10.00 mmol) of 5-(4-chlorophenyl)-2-(4-iodophenylethynyl)pyridine, 3.10 g (15.00 mmol) of tert-butyl (S)-2-aminomethylpyrrolidine-1-carboxylate, 194 mg (1.00 mmol) of CuI, 0.77 g (4.00 mmol) of N,N-diethylsalicylamide in 10 mL of DMF and the mixture was stirred for 16 hours at 100° C. The reaction mixture was combined with 100 mL of 5% aqueous ammonia, stirred, and the precipitate was filtered off. The precipitate was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). 2 fractions were isolated. Fraction 1: yield: 0.48 g (10% of theoretical); C29H30ClN3O2 (M=488.020) molpeak (M+H)+: 488/490 (Cl); found: molpeak (M+H)+: 488/490 (Cl); Rf value: 0.60 (silica gel, PE/EtOAc 1:1). stirred the precipitate was filtered off The precipitate was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v) 2 fractions were isolated

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

Procedure: A mixture of 5-bromo-2-phenyl-pyrimidine (3.50 g, 14.89 mmol, 1.0 equiv), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.48 g, 22.33 mmol, 1.5 equiv), copper(I) iodide (0.28 g, 1.49 mmol, 0.1 equiv), N,N-diethylsalicylamide (0.58 g, 2.98 mmol, 0.2 equiv) and K3PO4 (3.16 g, 14.89 mmol, 1.0 equiv) in degassed DMF (30 mL) was heated under Ar to 90° C. for 24 h. The solvent was removed under reduced pressure and the crude reaction product extracted from water (300 mL) and 25% NH4OH (30 mL) with ethyl acetate (3×300 mL). The combined organic phases were dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a gradient of heptane/ethyl acetate (4:1→1:1) to provide 1.98 g (38%) of the title compound. MS (ESI): 377.1 [M+Na]+. The solvent was removed under reduced pressure the crude reaction product extracted from water (300 mL) and 25% NH4OH (30 mL) with ethyl acetate (3×300 mL) The combined organic phases were dried over Na2SO4 concentrated by evaporation under reduced pressure the crude material purified by silica column chromatography eluting with a gradient of heptane/ethyl acetate (4:1→1:1)