A novel reaction discovery system that does not depend on DNA duplex formation is provided. The advantages of this system include exploring reactions conditions not possible where DNA hybridization is required. For example, the inventive reaction discovery system allows for reaction conditions using organic solvents, higher temperatures, and water-insoluble reagents, catalysts, and ligands. The invention also provides single-stranded oligonucleotide templates with substrate pairs covalently attached and methods of screening for reaction conditions that result in a direct covalent bond between the substrates. Kits are also provided for practicing this novel reaction discovery system.