Design rules (DRs) are the primary abstraction between design and manufacturing. The optimization of DRs to achieve the correct tradeoff between scaling and yield is a key step in developing a new technology node. In this work we propose a design-of-experiments based framework to optimize DRs, where layouts are generated for different DR values using compaction. By analyzing the impact of DRs on layout scaling, we propose a novel Boolean minimization based approach to reduce the number of layouts that need to be generated through compaction. This methodology provides an automated approach to analyze several DRs simultaneously and discover area-critical DRs and DR interactions. We apply this methodology to middle-of-line (MOL) and Metal1 layer design rules for a commercial 20nm process. Our methodology results in 10 − 10 5 × reduction in the number of layouts that need to be generated through compaction, and demonstrates the impact of MOL and Metal1 DRs on the area of some standard cell layouts.