A functional and environmentally green procedure for the design of novel pyridine - and - derivatives through two pathways is presented. The first pathway is via a one-pot, four-component reaction of -formylphenyl-4-toluenesulfonate (), ethyl cyanoacetate (), acetophenone derivatives or acetyl derivatives -, and ammonium acetate () under microwave irradiation in ethanol. The advantages of this method are an excellent yield (82%-94%), pure products, a short reaction time (2-7 min), and low-cost processing. The second pathway was obtained by the traditional method with treatment of the same mixture under refluxing in ethanol, which afforded the same products, - and -, in less yield (71%-88%) and over a longer reaction time (6-9 h). The constructions of the novel compounds were articulated via spectral and elemental analysis. Overall, the compounds have been designed, synthesized, and studied for their in vitro anti-inflammatory activity using diclofenac as a reference drug (5 mg/kg). The most potent four compounds, , , , and , showed promising anti-inflammatory activity.