3-ethoxy-5-formyl-2-hydroxybenzonitrile

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

Procedure: A mixture of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (200 mg, 0.82 mmol) and copper (I) cyanide in DMF (5 mL) was refluxed overnight. The reaction mixture was diluted with water (20 mL), extracted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. Purified by column chromatography on silica gel to afford Intermediate 51 (70 mg, yield 45%). was refluxed overnight extracted with EtOAc dried over Na2SO4 concentrated under reduced pressure Purified by column chromatography on silica gel

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (600 mg, 2.1 mmol) and CuCN (280 mg, 3.1 mmol) in DMF (10 mL) was heated at 180° C. for 4 hours. TLC (PE:EtOAc=1:1) indicated that the most of the starting material was consumed. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the 3-ethoxy-5-formyl-2-hydroxybenzonitrile (200 mg, yield: 50.0%). was consumed The solvent was removed in vacuo the residue was purified by column chromatography

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (600 mg, 2.1 mmol) and CuCN (280 mg, 3.1 mmol) in DMF (10 mL) was heated at 180° C. for 4 hours. TLC (PE:EtOAc=1:1) indicated that the most of the starting material was consumed. The solvent was removed in vacuo, and the residue was purified by column chromatograph to afford 3-ethoxy-5-formyl-2-hydroxybenzonitrile (200 mg, yield: 50.0%). was consumed The solvent was removed in vacuo the residue was purified by column chromatograph

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

Procedure: To a solution of 3-ethoxy-5-formyl-2-hydroxybenzonitrile (Intermediate 51) (70 mg, 0.37 mmol), 1-phenyl-2-(thiophen-3-yl)ethanone (Intermediate 2) (50 mg, 0.28 mmol) and urea (71 mg, 1.1 mmol) in 3 mL of ethanol was added 0.2 mL of concentrated HCl. Refluxed for 2 days. Solvent removed and resulting residue was purified by prep-HPLC (0.1% TFA as additive) to give Compound 105 (18 mg, yield 12%). 1H NMR (DMSO-d6 300 MHz): δ 10.33 (s, 1H), 8.70 (s, 1H), 7.51 (s, 1H), 7.37-7.10 (m, 8H), 6.84 (s, 1H), 6.22 (d, J=4.8 Hz, 1H), 5.16 (d, J=2.4 Hz, 1H), 4.07 (q, J=6.9 Hz, 2H), 1.35 (t, J=6.9 Hz, 3H). MS (ESI): m/z 418.0 [M+1]+. Refluxed for 2 days Solvent removed resulting residue was purified by prep-HPLC (0.1% TFA as additive)

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

Procedure: A mixture of 3-ethoxy-5-formyl-2-hydroxybenzonitrile (285 mg, 1.5 mmol), 1,2-diphenylethanone (320 mg, 1.6 mmol), and urea (270 mg, 4.5 mmol) in anhydrous EtOH (5 mL) was added concentrated HCl solution (0.5 mL). The reaction mixture was refluxed overnight. TLC (EtOAc:MeOH=10:1) showed 40% of the starting materials were consumed. The reaction mixture was concentrated, and purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 69 as a yellow solid (280 mg, yield: 45.7%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.30 (s, 1H), 8.70 (d, J=1.2 Hz, 1H), 7.47 (s, 1H), 7.20-7.27 (m, 5H), 7.16 (d, J=1.6 Hz, 1H), 6.98-7.06 (m, 4H), 6.80-6.82 (m, 2H), 5.14 (d, J=2.4 Hz, 1H), 4.00-4.10 (m, 2H), 1.33 (t, J=7.2 Hz, 3H); MS (ESI): m/z 412.1 [M+1]+. The reaction mixture was refluxed overnight were consumed The reaction mixture was concentrated purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC

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

Procedure: A mixture of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (200 mg, 0.82 mmol) and copper (I) cyanide in DMF (5 mL) was refluxed overnight. The reaction mixture was diluted with water (20 mL), extracted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. Purified by column chromatography on silica gel to afford Intermediate 51 (70 mg, yield 45%). was refluxed overnight extracted with EtOAc dried over Na2SO4 concentrated under reduced pressure Purified by column chromatography on silica gel

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

Procedure: A mixture of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (200 mg, 0.82 mmol) and copper (I) cyanide in DMF (5 mL) was refluxed overnight. The reaction mixture was diluted with water (20 mL), extracted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. Purified by column chromatography on silica gel to afford Intermediate 51 (70 mg, yield 45%). was refluxed overnight extracted with EtOAc dried over Na2SO4 concentrated under reduced pressure Purified by column chromatography on silica gel

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (600 mg, 2.1 mmol) and CuCN (280 mg, 3.1 mmol) in DMF (10 mL) was heated at 180° C. for 4 hours. TLC (PE:EtOAc=1:1) indicated that the most of the starting material was consumed. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the 3-ethoxy-5-formyl-2-hydroxybenzonitrile (200 mg, yield: 50.0%). was consumed The solvent was removed in vacuo the residue was purified by column chromatography

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (600 mg, 2.1 mmol) and CuCN (280 mg, 3.1 mmol) in DMF (10 mL) was heated at 180° C. for 4 hours. TLC (PE:EtOAc=1:1) indicated that the most of the starting material was consumed. The solvent was removed in vacuo, and the residue was purified by column chromatograph to afford 3-ethoxy-5-formyl-2-hydroxybenzonitrile (200 mg, yield: 50.0%). was consumed The solvent was removed in vacuo the residue was purified by column chromatograph

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

Procedure: To a solution of 3-ethoxy-5-formyl-2-hydroxybenzonitrile (Intermediate 51) (70 mg, 0.37 mmol), 1-phenyl-2-(thiophen-3-yl)ethanone (Intermediate 2) (50 mg, 0.28 mmol) and urea (71 mg, 1.1 mmol) in 3 mL of ethanol was added 0.2 mL of concentrated HCl. Refluxed for 2 days. Solvent removed and resulting residue was purified by prep-HPLC (0.1% TFA as additive) to give Compound 105 (18 mg, yield 12%). 1H NMR (DMSO-d6 300 MHz): δ 10.33 (s, 1H), 8.70 (s, 1H), 7.51 (s, 1H), 7.37-7.10 (m, 8H), 6.84 (s, 1H), 6.22 (d, J=4.8 Hz, 1H), 5.16 (d, J=2.4 Hz, 1H), 4.07 (q, J=6.9 Hz, 2H), 1.35 (t, J=6.9 Hz, 3H). MS (ESI): m/z 418.0 [M+1]+. Refluxed for 2 days Solvent removed resulting residue was purified by prep-HPLC (0.1% TFA as additive)

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

Procedure: A mixture of 3-ethoxy-5-formyl-2-hydroxybenzonitrile (285 mg, 1.5 mmol), 1,2-diphenylethanone (320 mg, 1.6 mmol), and urea (270 mg, 4.5 mmol) in anhydrous EtOH (5 mL) was added concentrated HCl solution (0.5 mL). The reaction mixture was refluxed overnight. TLC (EtOAc:MeOH=10:1) showed 40% of the starting materials were consumed. The reaction mixture was concentrated, and purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 69 as a yellow solid (280 mg, yield: 45.7%). 1H NMR (DMSO-d6 400 MHz TMS): δ 10.30 (s, 1H), 8.70 (d, J=1.2 Hz, 1H), 7.47 (s, 1H), 7.20-7.27 (m, 5H), 7.16 (d, J=1.6 Hz, 1H), 6.98-7.06 (m, 4H), 6.80-6.82 (m, 2H), 5.14 (d, J=2.4 Hz, 1H), 4.00-4.10 (m, 2H), 1.33 (t, J=7.2 Hz, 3H); MS (ESI): m/z 412.1 [M+1]+. The reaction mixture was refluxed overnight were consumed The reaction mixture was concentrated purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC

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

Procedure: A mixture of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (200 mg, 0.82 mmol) and copper (I) cyanide in DMF (5 mL) was refluxed overnight. The reaction mixture was diluted with water (20 mL), extracted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. Purified by column chromatography on silica gel to afford Intermediate 51 (70 mg, yield 45%). was refluxed overnight extracted with EtOAc dried over Na2SO4 concentrated under reduced pressure Purified by column chromatography on silica gel