A convenient, efficient protocol to prepare diverse spiroisoxazolino-diketopiperazines via a parallel solid-supported synthesis was developed. The key steps are (1) a coupling reaction of an amino acid; (2) tosylation with concomitant β-elimination to form an α, β-unsaturated ester; (3) a 1,3-dipolar cycloaddition with an oxime to form isoxazoline rings; and (4) cyclic cleavage to release the product from the resin. All reaction steps and workup procedures were modified to allow the use of automated or semiautomated equipment. A 100-member demonstration library with two diversity sites was prepared in good purity and acceptable overall yields.