Quinolinones have various biological activities, including antibacterial, anticancer, and antiviral properties. The 3-substituted amide quinolin-2(1H)-ones not only show antibacterial activity, but also act as immunomodulators, 5-HT4 receptor agonists, cannabinoid receptor inverse agonists, and AchE and, BuchE inhibitors. To investigate the potent biological activity of 3-substituted amide quinolin-2(1H)-ones, a large number of 3,5-amide substituted-2-oxoquinolinones were prepared by parallel solid-phase synthesis. The compound 5-amino-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid was loaded onto 4-formyl-3,5-dimethoxyphenoxy (PL-FDMP) resin by reductive amination with high efficiency. Various building blocks were attached to the 3 and 5 positions to yield 3,5-disubstituted-2-oxoquinolinones with high purity and good yield. The ability some of these compound to inhibit the release of IL-1β, a cytokine involved in the immune response was measured, and they showed about 50% inhibition at 10 μM.