3.1. Chemistry

All organic solvents used for the synthesis were analytical grade. Melting points were determined on a Stuart Scientific SMP3 apparatus. ¹H and ¹³C NMR spectra were obtained on a Bruker AM-400 spectrometer. The chemical shifts are expressed in ppm (δ scale) downfield from TMS, J value are given in Hertz for solutions in CDCl3 unless otherwise indicated. Column chromatography was performed on Merck silica gel 60 (70–230 mesh). Thin layer chromatographic separations were performed on Merk silica 60 (70–230 mesh) chromatofoils.

Cyanoacetic acid hydrazide was obtained by careful addition of 3.2 mL (30 mmol) of ethyl cyanoacetate to a solution of 1.8 mL (60 mmol) of hydrazine hydrate in ethanol (20 mL) with stirring at 0 °C. Then the mixture was heated to room temperature with stirring at room temperature for 2 h. The solid formed was filtered, washed with diethyl ether and dried obtain 2.82 g of product. Yield = 95%. White solid. This compound was used without previous purification at the next synthetic step.

2.8 g (28 mmol) of cyanoacetic acid hydrazide was dissolved in 100 mL of distilled water. To the mixture was added 1 mL of concentrated HCl. The solid was completely dissolved and then acetylacetone 2.93 mL (28 mmol) was added drop by drop with vigorous stirring at room temperature for 5 h. The resulting mixture was filtered and the solid obtain was washed with cold diethyl ether obtaining 3.38 g of white solid. Yield = 74%. m.p. 119–121 °C (CDCl₃, 400 MHz) δ 2.24 (s, 3H, CH₃), 2.54 (s, 3H, CH₃), 4.30 (s, 2H, CH₂-CN), 6.04 (s, 1H, pyrazole-H).

Equimolar amounts (6.9 mmol) of 1-cyanoacetyl-3,5-dimethylpyrazole and respective amine both they were placed in a reaction flask and dissolved with 40 mL of toluene and heated to reflux for 4 h with stirring. After completing the reaction, the mixture was cooled at room temperature and the solid was filtered and the solvent was recovered. The solid obtain was washed with ethanol and dried.

2-cyano-N-phenylacetamide (4a). Gray solid. Yield = 81%, mp 131 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 3.89 (s, 2H, CH₂), 7.09 (t, J = 7.4 Hz, 1H, C4 phenyl), 7.33 (t, J = 7.9 Hz, 2H, C3 C5 phenyl), 7.54 (d, J = 7.9 Hz, 2H, C2 C6 phenyl), 10.28 (s, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ 27.18, 116.38, 119.71, 124.37, 129.36, 138.82, 161.45.

2-cyano-N-(4-methylphenyl)acetamide (4b). Gray solid. Yield = 83%, mp 154 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.25 (s, 3H, CH₃ phenyl), 3.86 (s, 2H, CH₂), 7.13 (d, J = 8.4 Hz, 2H, C3 C5 phenyl), 7.42 (d, J = 8.4 Hz, 2H, C2 C6 phenyl), 10.19 (s, 1H, NH). ¹³C NMR (101 MHz, DMSO-d₆) δ 20.90, 27.09, 116.43, 119.72, 129.73, 133.37, 136.33, 161.17.

2-cyano-N-(4-hydroxyphenyl)acetamide (4c). purple solid. Yield = 84%. mp 229–231 °C. ¹H MR (400 MHz, DMSO-d₆) δ 4.44 (s, 2H, CH₂), 6.35–6.66 (m, 4H, H phenyl), 8.91 (s, 1H, OH). ¹³C NMR (101 MHz, DMSO-d₆) δ 114.91, 116.90, 119.97, 136.98, 144.44.

Equimolar amounts of acetylacetone and corresponding N-substituted cyanoacetamide (10 mmol) were heated under reflux in a water/ethanol mixture (20 mL) in the presence of a few drops of piperidine as catalyst for 4 h. Product was purified by crystallization from ethanol [29].

N-phenyl-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (5a). White solid. Yield = 85%. mp 255 °C, ¹H NMR (400 MHz, DMSO-d₆) δ 2.00 (s, 3H, CH₃, C6 pyridone), 2.40 (s, 3H, CH₃ C4 pyridone), 6.36 (s, 1H, H5 pyridone), 7.23–7.32 (m, 2H, C2 C6 phenyl), 7.45–7.60 (m, 3H, C3 C4 C5 phenyl). ¹³C NMR (101 MHz, DMSO-d₆) δ 20.36, 21.02, 100.38, 108.59, 115.30, 127.79, 128.84, 129.37, 137.46, 151.65, 159.11, 160.28.

N-(4-methylphenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (5b). White solid. Yield = 78%. mp 274–275 °C. ¹H NMR (400 MHz, DMSO-d6) δ 2.00 (s, 3H, CH₃ C6 pyridone), 2.40 (s, 6H CH₃, 4-methylphenyl, C4 pyridone), 6.34 (s, 1H, H5 pyridone), 7.13 (d, J = 7.8 Hz, 2H, C3 C5 phenyl), 7.34 (d, J = 7.8 Hz, 2H, C2, C6 phenyl). ¹³C NMR (101 MHz, DMSO-d₆) δ 20.30, 21.04, 100.30, 108.48, 127.48, 129.85, 134.90, 138.50, 151.88, 158.98, 160.35.

1-(4-hydroxyphenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (5c) White solid. Yield = 89%, mp 178–179 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 1.96 (s, 6H, CH₃, C4 C6 pyridone), 5.19 (s, 1H, H5 pyridone), 6.75–6.94 (m, 2H, C3 C5 phenyl), 6.98–7.19 (m, 2H, C2 C6 phenyl). ¹³C NMR (101 MHz, DMSO-d₆) δ 19.96, 29.33, 97.66, 116.23, 116.23, 119.51, 125.47, 126.60, 150.83, 160.48, 194.72.

4.9 mmol of the corresponding N-substituted dihydropyridine-3-carbonitrile were dissolved in 50 mL of distilled water. 49 mmol of KOH were placed in the reaction flask and the mixture was heated to reflux for 24 h with constant stirring. Then the reaction was cooled to room temperature and a HCl solution 1N was added dropwise until a pH equal to 1 was obtained. The mixture formed was placed into separating funnel and extracted with DCM (3 × 20 mL). The combined organic phases were dried and evaporated.

4,6-dimethyl-2-oxo-1-(4-methylphenyl)-1,2-dihydropyridine-3-carboxylic acid (6a) white solid. Yield = 85% mp 220–222 °C. ¹H NMR (400 MHz, Chloroform-d) δ 2.09 (s, 3H, CH₃ C6 pyridone), 2.77 (s, 3H, CH₃ C4 pyridone), 6.38 (s, 1H, H5 pyridone), 7.14–7.24 (m, 2H, C2 C6 phenyl), 7.47–7.68 (m, 3H, C3 C4 C5 phenyl), 14.94 (s, 1H COOH). ¹³C NMR (101 MHz, Chloroform-d) δ 21.55, 23.63, 113.12, 114.35, 127.12, 129.85, 130.27, 137.12, 149.27, 161.62, 166.07, 166.26.

4,6-dimethyl-2-oxo-1-(4-methylphenyl)-1,2-dihydropyridine-3-carboxylic acid (6b) white solid. Yield = 95%, 230–232 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.01 (s, 3H, CH₃ C6 pyridone), 2.39 (s, 3H, CH_3, 4-phenyl), 2.60 (s, 3H, CH₃ C4 pyridone), 6.65 (s, 1H, H5 pyridone), 7.24 (d, J = 8.2 Hz, 2H, C2 C6 phenyl), 7.37 (d, J = 8.2 Hz, 2H, C3 C5 phenyl). ¹³C NMR (101 MHz, DMSO-d6) δ 21.19, 21.54, 22.86, 113.14, 113.14, 127.73, 130.65, 135.14, 139.34, 150.99, 159.57, 165.72, 166.15.

4,6-dimethyl-2-oxo-1-(4-hydroxyphenyl)-1,2-dihydropyridine-3-carboxylic acid (6c) white solid. Yield = 82% 241–243 °C. ¹H NMR (400 MHz, Chloroform-d) δ 2.34 (s, 3H, CH₃ C6 pyridone), 2.87 (s, 3H, CH₃ C4 pyridone), 6.45 (s, 1H, H5 pyridone), 7.24–7.44 (m, 2H, C3 C5 phenyl), 7.57–7.78 (m, 2H, C2 C6 phenyl), 9.77 (s, 1H, OH), 14.98 (s, 1H COOH). ¹³C NMR (101 MHz, Chloroform-d) δ 21.55, 23.63, 112.26, 113.45, 127.12, 129.88, 130.30, 137.10, 149.26, 161.60, 166.08, 169.46.

1.0 mmol of the corresponding N-substituted dihydropyridine-3-carboxylic acid was dissolved in 2 mL of DMF. 2,0 mmol of Diisopropylamine (DIPEA) was added and subsequently 1.2 mmol of BOP reagent was placed in the reaction flask. The mixture was stirred to room temperature for 10 min. Then 1.1 mmol of respective amine was placed in the reaction flask. The mixture of reaction was stirred to room temperature for 2 h until the reaction is complete (monitored by TLC). The mixture was placed, drop by drop, into water-ice bath and solid obtained was filtrated and washed with ethyl ether.

N-(benzo[d]thiazol-2-yl)-4,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (7a) White solid. Yield = 71%. mp 163–165 °C. ¹H NMR (400 MHz, Chloroform-d) δ 2.19 (s, 3H: CH₃, C6 pyridone), 2.89 (s, 3H: CH₃ C4 pyridone), 6.51 (s, 1H: H5 pyridone), 7.28–8.01 (m, 9H: H aromatics), 12.52 (s, 1H, NH). ¹³C NMR (101 MHz, Chloroform-d) δ 20.08, 21.05, 109.90, 118.62, 119.90, 121.90, 122.82, 125.68, 128.11, 129.15, 130.05, 131.10, 139.31, 145.20, 151.95, 155.27, 160.10, 161.89, 166.58. LS-MS: [M + H] = 376.1.

N-(1H-benzo[d]imidazol-2-yl)-4,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (7b) White solid. Yield = 77%. mp 177–179 °C. ¹H NMR (400 MHz, DMSO-d6) δ 1.96 (s, 3H: CH₃, C6 pyridone), 2.37 (s, 3H: CH₃, C4 pyridone), 6.27 (s, 1H, H5 pyridone), 7.01–7.35 (m, 9H, H aromatics), 12.54 (s, 2H; NH). ¹³C NMR (101 MHz, DMSO-d6) δ 19.21, 21.69, 109.35, 111.89, 116.31, 120.32, 122.84, 124.76, 129.28, 129.99, 130.40, 137.97, 143.94, 149.29, 150.58, 154.63, 159.74, 162.34, 167.33. LS-MS: [M + H] = 359.2.

N-(benzo[d]oxazol-2-yl)-4,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (7c) White solid. Yield = 73%. mp 228–230 °C. ¹H NMR (400 MHz, DMSO-d6) δ 2.34 (s, 3H; CH₃, C6 pyridone), 2.61 (s, 3H: CH₃, C4 pyridone), 6.66 (s, 1H, H5 pyridone), 7.47–7.62 (m, 9H, H aromatics), 14.84 (s, 1H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ 20.88, 22.33, 109.81, 112.83, 113.43, 120.98, 127.54, 128.00, 128.54, 129.42, 129.68, 137.23, 138.42, 146.43, 150.20, 151.62, 159.00, 161.40, 167.28. LS-MS: [M + H] = 360.0.

N-(benzo[d]oxazol-2-yl)-4,6-dimethyl-2-oxo-1-(4-methylphenyl)-1,2-dihydropyridine-3-carboxamide (7d). ¹H NMR (400 MHz, DMSO-d6) δ 2.37 (s, 3H, CH₃, 4-phenyl), 2.39 (s, 3H, CH₃, C6 pyridone), 2.63 (s, 3H, CH₃, C4 pyridone), 6.57 (s, 1H, H5 pyridone), 7.03–7.42 (m, 8H, H aromatics), 14.98 (s, 1H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ 20.55, 21.42, 22.85, 109.82, 112.85, 113.48, 120.94, 127.71, 128.21, 128.64, 129.40, 135.41, 137.34, 138.44, 146.42, 150.21, 151.64, 159.47, 161.36, 167.57. LS-MS: [M + H] = 373.0.

N-(1H-benzo[d]imidazol-2-yl)-4,6-dimethyl-2-oxo-1-(4-methylphenyl)-1,2-dihydropyridine-3-carboxamide (7e) White solid. Yield = 79%. mp 198–200 °C. ¹H NMR (400 MHz, DMSO-d6) δ 1.96 (s, 3H: CH₃, C6 pyridone), 2.25 (s, 3H, CH₃ 4-phenyl), 2.37 (s, 3H: CH₃, C4 pyridone), 6.27 (s, 1H, H5 pyridone), 6.99–7.33 (m, 8H, H aromatics). 12.58 (s, 2H; NH). ¹³C NMR (101 MHz, DMSO-d6) δ 19.21, 21.69, 22.92, 109.35, 111.89, 116.31, 120.32, 122.84, 124.76, 129.28, 129.99, 130.40, 137.97, 143.94, 149.29, 150.58, 154.63, 159.74, 162.34, 167.33. LS-MS: [M + H] = 373.0–374.2.

N-(1H-benzo[d]imidazol-2-yl)-1-(4-hydroxyphenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide (7f). White solid. Yield = 72%. mp 176–178 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 2.03 (s, 3H, CH₃, C6 pyridone), 2.16 (s, 3H, CH₃, C4 pyridone), 6.43 (s, 1H, H5, pyridone), 6.74–7.22 (m, 8H, H aromatics), 9.78 (s, 1H, OH), 12.58 (s, 2H; NH). ¹³C NMR (101 MHz, DMSO-d6) δ 19.34, 22.84, 109.35, 111.89, 116.20, 116.24, 116.31, 120.32, 122.84, 125.01, 125.32, 137.97, 143.94, 149.29, 150.58, 154.63, 156.45, 159.74, 162.34, 167.33. LS-MS: [M + H] = 374.9.

N-(benzo[d]thiazol-2-yl)-1-(4-hydroxyphenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide (7g). ¹H NMR (400 MHz, Chloroform-d) δ 2.02 (s, 3H: CH₃, C6 pyridone), 2.21 (s, 3H: CH₃ C4 pyridone), 6.41 (s, 1H: H5 pyridone), 6.71–7.83 (m, 8H: H aromatics), 9.77 (s, 1H, OH), 12.03 (s, 1H; NH). ¹³C NMR (101 MHz, Chloroform-d) δ 20.05, 21.02, 109.85, 118.59, 119.84, 121.89, 122.78, 125.67, 128.09, 129.14, 131.08, 139.29, 145.17, 151.96, 155.30, 160.18, 161.92, 166.64. LS-MS: [M + H] = 391.9–393.9.

N-cyclohexyl-4,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (8a). White solid. Yield = 78%. mp 139–140 °C. ¹H NMR (400 MHz, DMSO-d6) δ 1.28–1.76 (m, 10H, CH₂ cyclohexyl), 1.89 (s, 3H, CH₃, C6, pyridone), 2.35 (s, 3H, CH₃, C4 pyridone), 3.83–3.96 (m, 1H, CH cyclohexyl), 6.21 (s, 1H, H5 pyridone), 7.18–7.28 (m, 2H, C2 C6 phenyl), 7.41–7.61 (m, 3H, C3 C4 C5 phenyl), 8.84 (d, J = 7.8 Hz, 1H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ 20.74, 20.86, 24.23, 25.64, 33.10, 49.38, 109.97, 120.77, 127.98, 128.54, 129.43, 138.38, 146.25, 151.64, 161.58, 164.01. LS-MS: [M + H] = 324.6.

N-cycloheptyl-4,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (8b). White solid. Yield = 80%. mp 138–140 °C. ¹H NMR (400 MHz, DMSO-d6) δ 1.34–1.77 (m, 12H, CH₂ cycloheptyl), 1.89 (s, 3H, CH₃, C6, pyridone), 2.34 (s, 3H, CH₃, C4 pyridone), 3.82–3.96 (m, 1H, CH cycloheptyl), 6.25 (s, 1H, H5 pyridone), 7.19–7.28 (m, 2H, C2 C6 phenyl), 7.41–7.61 (m, 3H, C3 C4 C5 phenyl), 8.85 (d, J = 7.8 Hz, 1H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ 20.74, 20.86, 23.67, 27.66, 34.20, 49.31, 109.97, 120.77, 127.98, 128.54, 129.43, 138.38, 146.25, 151.64, 161.58, 164.01. LS-MS: [M + H] = 339.1–341.1.

N-(adamantan-1-yl)-4,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (8c). White solid. Yield = 83%, mp 164–165 °C. ¹H NMR (400 MHz, DMSO-d6) δ 1.65–1.87 (m, 14H, H adamantyl), 1.94 (s, 3H, CH₃, C6, pyridone), 2.38 (s, 3H, CH₃, C4 pyridone), 6.24 (s, 1H, H5 pyridone), 7.08–7.43 (m, 4H, H phenyl), 7.91 (s, 1H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ 20.74, 20.86, 29.75, 36.10, 42.38, 51.32, 109.97, 120.77, 127.97, 128.53, 129.43, 138.38, 146.25, 151.63, 161.58, 164.01. LS-MS: [M + H] = 377.2.

N-(adamantan-1-yl)-4,6-dimethyl-2-oxo-1-(4-methylphenyl)-1,2-dihydropyridine-3-carboxamide (8d). White solid. Yield = 71%. mp 154–155 °C. ¹H NMR (400 MHz, DMSO-d6) δ 1.47–1.73 (m, 14H, H adamantyl), 1.96 (s, 3H, CH₃ C6 pyridone), 2.38 (s, 6H CH₃ 4-phenyl, C4 pyridone), 6.41 (s, 1H, H5 pyridone), 7.09 (d, J = 8.2 Hz, 2H, C2 C6 phenyl), 7.32 (d, J = 8.2 Hz, 2H, C3 C5 phenyl), 8.56 (s, 1H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ 20.65, 20.86, 28.80, 36.05, 41.06, 50.71, 109.98, 121.30, 127.67, 129.86, 135.82, 137.93, 146.20, 151.33, 161.68, 164.40. LS-MS: [M + H] = 391.1.

N-cycloheptyl-4,6-dimethyl-2-oxo-(4-methylphenyl)-1,2-dihydropyridine-3-carboxamide (8e). White solid. Yield = 74%. mp 238–240 °C. ¹H NMR (400 MHz, DMSO-d6) δ 1.34–1.77 (m, 12H, CH₂ cycloheptyl), 1.94 (s, 3H, CH₃, C6, pyridone), 2.33 (s, 3H CH₃ 4-phenyl)2.37 (s, 3H, CH₃, C4 pyridone), 3.45–3.65 (m, 1H, CH cycloheptyl), 6.26 (s, 1H, H5 pyridone), 7.20–7.29 (m, 2H, C2 C6 phenyl), 7.40–7.65 (m, 3H, C3 C4 C5 phenyl), 7.92 (s, 1H, NH). ¹³C NMR (101 MHz, DMSO-d6) δ 20.74, 20.86, 29.75, 36.10, 42.38, 51.32, 109.97, 120.77, 127.97, 128.53, 129.43, 138.38, 146.25, 151.63, 161.58, 164.01. LS-MS: [M + H] = 353.5.

N-cycloheptyl-1-(4-hydroxyphenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide (8f). White solid. Yield = 81%. mp 232–233 °C. ¹H NMR (400 MHz, DMSO-d6) δ 1.22–1.77 (m, 12H, H cycloheptyl), 1.90 (s, 3H, CH₃ C6 pyridone), 2.33 (s, 3H, CH₃ C4 pyridone), 6.21 (s, 1H, H5 pyridone), 6.86 (d, J = 8.7 Hz, 2H, C2 C6 pyridone), 6.99 (d, J = 8.7 Hz, 2H, C3 C5 pyridone), 8.91 (d, J = 7.8 Hz, 1H, NH), 9.75 (s, 1H, OH). ¹³C NMR (101 MHz, DMSO-d6) δ 20.82, 20.93, 23.66, 27.66, 34.20, 49.25, 109.87, 115.81, 120.41, 128.81, 129.42, 147.05, 151.58, 157.30, 161.92, 164.12. LS-MS: [M + H] = 354.9.

N-cyclohexyl-1-(4-hydroxyphenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide (8g) White solid. Yield = 78%. mp 139–140 °C. ¹H NMR (200 MHz, DMSO-d₆) δ 1.01–1.79 (m, 10H, CH cyclohexyl), 1.90 (s, 3H, CH₃ C6 pyridone), 2.33 (s, 3H, CH₃ C4 pyridone), 3.57–3.85 (m, 1H, CH cyclohexyl), 6.21 (s, 1H, H5 pyridone), 6.86 (d, J = 8.7 Hz, 2H, C2 C6 phenyl), 6.99 (d, J = 8.7 Hz, 2H, C3 C5 phenyl), 8.87 (d, J = 7.8 Hz, 1H, NH), 9.76 (s, 1H, OH). ¹³C NMR (101 MHz, DMSO-d6) δ 20.82, 20.93, 24.31, 25.21, 32.24, 47.05, 109.87, 115.81, 120.39, 128.81, 129.41, 147.08, 151.61, 157.30, 161.89, 164.36. LS-MS: [M + H] = 340.6.