3-(chloromethyl)-4-methoxybenzaldehyde

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: In a ratio of 1:1 4-methoxy-3-chloromethylbenzaldehyde and triethyl phosphite were heated together until no more gas evolved. The reaction solution was then vacuum distilled to give the desired product. bp 172°-174° C. at 1 mm Hg. vacuum distilled

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-(chloromethyl)-4-methoxybenzaldehyde (91.0 mg, 0.5 mmol, 1.0 equiv) and 2,6-dimethylbenzenethiol (68.4 mg, 0.5 mmol, 1.0 equiv) in 4 mL acetonitrile was added potassium carbonate (0.55 g, 4.0 mmol, 8.0 equiv). The mixture was heated to 150° C. in the microwave for 10 min. After filtered off the solid and removed the solvent, 2-amino-N-(furan-2-ylmethyl)benzamide (107 mg, 0.5 mmol, 1.0 equiv) in 5 mL of EtOH was added followed by addition of Ytterbium trifluoromethanesulfonate (62 mg, 0.1 mmol, 0.2 equiv). The mixture was heated at 80° C. for 2 hours. Upon completion, the mixture was dried down and chromatographed on silica gel with 10-60% EtOAc/Hexanes gradient elution to give 2-(3-((2,6-dimethylphenylthio)methyl)-4-methoxyphenyl)-3-(furan-2-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one (101.4 mg, 42%) as a white solid after triturating with diethyl ether. 1HNMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 6 H), 3.56 (d, J=15.7 Hz, 1 H), 3.66 (s, 3 H), 3.72 (d, 1 H), 3.79 (d, 1 H), 5.12 (d, J=15.7 Hz, 1 H), 5.55 (d, J=2.2 Hz, 1 H), 6.25 (d, J=3.1 Hz, 1 H), 6.41 (dd, J=3.0, 1.9 Hz, 1 H), 6.59 (d, J=8.0 Hz, 1 H), 6.66 (t, J=7.5 Hz, 1 H), 6.78-6.94 (m, 2 H), 7.00-7.28 (m, 6 H), 7.59-7.66 (m, 2 H); LCMS: (electrospray+ve), m/z 485.2 (MH)+, tR=7.16 min, UV254=98%. HRMS (ESI): m/z calcd for C29H28N2O3S [M+H]+485.1905, found 485.1905. After filtered off the solid was added The mixture was heated at 80° C. for 2 hours Upon completion, the mixture was dried down chromatographed on silica gel with 10-60% EtOAc/Hexanes gradient elution

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2,6-dimethyl-4-nitrophenol (4a, 1.58 g, 9.45 mmol) in AcOH (20 ml), MeOH (15 ml), and THF (10 ml) in a hydrogenator vessel was treated with acetic anhydride (6 ml, 63.6 mmol) and PtO2 (200 mg, 0.881 mmol), pressurized to 50 p.s.i. with H2 and shaken for 24 h. The reaction mixture was returned to atmospheric pressure, diluted with EtOAc, washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. N-(4-hydroxy-3,5-dimethylphenyl)acetamide (4b) was isolated as a white solid that was pure based upon LCMS analysis and used without further purification. Potassium carbonate (810 mg, 5.34 mmol) was added to a solution of tetrabutylammonium iodide (78.9 mg, 0.534 mmol), 3-(chloromethyl)-4-methoxybenzaldehyde (5a, 197 mg, 1.07 mmol), and N-(4-hydroxy-3,5-dimethylphenyl)acetamide (4b, 211 mg, 1.18 mmol) in 20 ml of acetonitrile. The reaction mixture was heated to 150° C. in the microwave for 1 h, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with 5-50% EtOAc/DCM gradient to afford the desired product 6a (196 mg, 56%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H), 2.28 (s, 6 H), 3.93 (s, 3 H), 4.83 (s, 2 H), 7.02 (d, J=8.4 Hz, 1H), 7.13 (s, 1 H), 7.17 (s, 2 H), 7.89 (dd, J=8.4, 2.0 Hz, 1 H), 8.12 (d, J=1.8 Hz, 1H), 9.94 (s, 1 H); LCMS: (electrospray+ve), m/z 328.2 (MH)+, tR=3.16 min, UV254=>95%. N-(4-(5-formyl-2-methoxybenzyloxy)-3,5-dimethylphenyl)acetamide (6a, 145 mg, 0.441 mmol), 2-amino-N-(furan-2-ylmethyl)benzamide (3b, 105 mg, 0.486 mmol), and 0.2 equiv of Yb(OTf)3 in 5 ml of EtOH were heated at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica-gel using 7-60% ethyl acetate in hexanes to give the desired product 7a (40.9 mg, 0.078 mmol, 17.6% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H), 2.21 (s, 6 H), 3.77 (d, J=15.7 Hz, 1 H), 3.84 (s, 3 H), 4.41 (s, 1 H), 4.70-4.87 (m, 2 H), 5.35 (d, J=15.7 Hz, 1 H), 5.78 (s, 1 H), 6.20 (d, J=2.9 Hz, 1 H), 6.24-6.32 (m, 1 H), 6.53 (d, J=8.0 Hz, 1 H), 6.76-6.91 (m, 2 H), 7.03 (br. s., 1 H), 7.13 (s, 2 H), 7.30-7.37 (m, 2 H), 7.49 (d, J=2.0 Hz, 1 H), 7.92-8.03 (m, 1 H); LC/MS (electrospray+ve), m/z 526.2 (MH)+, Retention time t=5.71 min; Purity: UV220>98%, UV254>98%; HRMS (ESI): m/z calcd for C31H31N3O5 [M+H]+526.2351, found 526.2350. used without further purification filtered concentrated under reduced pressure The residue was purified by column chromatography on silica gel with 5-50% EtOAc/DCM gradient

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

Procedure: To a solution of 3-(chloromethyl)-4-methoxybenzaldehyde (300 mg, 1.625 mmol, 1.0 equivalent) and 2,6-dimethylphenol (218 mg, 1.787 mmol, 1.1 equivalent) in 10 ml acetonitrile was added potassium carbonate (1.1 g, 8.12 mmol, 5.0 equivalents). The mixture was heated to 150 C in a microwave for 30 min. Upon completion, the mixture was filtered and dried down to give 3-[(2,6-dimethylphenoxy)methyl]-4-methoxybenzaldehyde (400 mg, 91% yield) as a yellow solid. A portion of which (100 mg, 0.370 mmol, 1.0 equivalent) was taken up in ethanol (4 ml), and to it was added 2-amino-N-(pyridin-3-ylmethyl)benzamide (92 mg, 0.407 mmol, 1.1 equivalent) followed by ytterbium(III) trifluoromethanesulfonate (45.9 mg, 0.074 mmol, 0.2 equivalent). The mixture was heated to 80 C for 2 h. Upon completion, the mixture was dried down and chromatographed on silica gel with 0-30% EtOAc (ethyl acetate)/hexanes gradient elution to give the desired 2-{3-[(2,6-dimethylphenoxy)methyl]-4-methoxyphenyl}-3-(pyridin-3-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one (110 mg, 62.0% yield) as a tan solid. 1H nuclear magnetic resonance (400 MHz, DMSO-d6) δ ppm 8.39-8.45 (m, 2 H), 7.60-7.67 (m, 2 H), 7.48 (d, J=2.35 Hz, 1 H), 7.15-7.35 (m, 4 H), 6.94-7.02 (m, 3 H), 6.84-6.93 (m, 1 H), 6.60-6.69 (m, 2 H), 5.82 (d, J=2.35 Hz, 1 H), 5.07 (d, J=15.65 Hz, 1 H), 4.64 (d, J=2.74 Hz, 2 H), 3.99 (d, J=15.45 Hz, 1 H), 3.73 (s, 3 H), 2.12 (s, 6 H); liquid chromatography mass spectrometry: (electrospray+ve), m/z 480.2 (MH)+ (mass of molecular weight plus 1); HPLC: tR=5.05 min, UV254=100%. High-resolution mass spectroscopy (electrospray ionization): m/z calculated for C30H30N3O3 [M+H]+480.2282, found 480.2291. The mixture was heated to 150 C in a microwave for 30 min Upon completion, the mixture was filtered dried down

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-(chloromethyl)-4-methoxybenzaldehyde (85 mg, 0.46 mmol, 1.0 equiv) and 2,6-dimethylphenol (62 mg, 0.51 mmol, 1.1 equiv) in 3.0 mL of anhydrous acetonitrile, we added K2CO3 (320 mg, 2.3 mmol, 5.0 eq). The mixture was heated in a microwave reactor for 30 min at 150° C. After filtering off the solid and removing the solvent, 2-amino-N-(furan-2-ylmethyl)benzamide (110 mg, 0.51 umol, 1.1 equiv) in 5 mL of EtOH was added followed by addition of Ytterbium trifluoromethanesulfonate (57 mg, 0.02 umol, 0.2 equiv). The mixture was heated at 80° C. for 2 hours. The product was isolated via preparative HPLC purification and solvent was removed via reduced pressure lyophilization to give 2434(2,6-dimethylphenoxy)methyl)-4-methoxyphenyl)-3-(furan-2-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one (64.5 mg, 30%) as a white solid after triturating with diethyl ether. 1HNMR (400 MHz, DMSO-d6) δ ppm 2.16 (s, 6H), 3.77 (s, 3 H), 3.86 (d, J=15.6 Hz, 1 H), 4.69 (d, J=1.9 Hz, 2 H), 5.19 (d, J=15.4 Hz, 1 H), 5.75 (d, J=2.3, Hz, 1 H), 6.30 (d, J=3.2 Hz, 1 H), 6.39 (dd, J=3.2, 1.9 Hz, 1 H), 6.62-6.70 (m, 2 H), 6.86-6.97 (m, 1 H), 6.99-7.04 (m, 3 H), 7.19-7.29 (m, 2 H), 7.32 (d, J=2.3 Hz, 1 H), 7.49 (d, J=2.4, Hz, 1 H), 7.57 (dd, J=1.8, 0.7 Hz, 1 H), 7.68 (dd, J=7.9, 1.5 Hz, 1 H); HPLC: tR=6.88 min, UV254=97%; HRMS (ESI): m/z calculated for C29H28N2O4 [M+1]+469.2132, found 469.2138. After filtering off the solid was added The mixture was heated at 80° C. for 2 hours The product was isolated via preparative HPLC purification and solvent was removed via reduced pressure lyophilization