The synthesis of uracil/thymine containing tetra/trisubstituted imidazole derivatives was demonstrated using Ugi/Passerini-reaction followed by a postcyclization reaction sequence. The approach enables the one-pot facile construction of diverse compounds in moderate to excellent yields (47–82%). The 5-fluorouracil and 5-methyluracil moieties afford potentially bioactive molecules with drug-like properties. These scaffolds are currently being utilized in the screening deck of the European Lead Factory.