This paper describes an adaptive algorithm for interpolation over a library of molecules subjected to synthesis and property assaying. Starting with a coarse sampling of the library compounds, the algorithm finds the optimal substituent orderings on all of the functionalized scaffold sites to allow for accurate property interpolation over all remaining compounds in the full library space. A previous paper introduced the concept of substituent reordering and a smoothness-based criterion to search for optimal orderings (Shenvi, N.; Geremia, J. M.; Rabitz, H. J. Phys. Chem. A 2003 107, 2066). Here, we propose a data-driven root-mean-squared (RMS) criteria and a combined RMS/smoothness criteria as alternative methods for the discovery of optimal substituent orderings. Error propagation from the property measurements of the sampled compounds is determined to provide confidence intervals on the interpolated molecular property values, and a substituent resealing technique is introduced to manage poorly designed/sampled libraries. Finally, various factors are explored that can influence the applicability and interpolation quality of the algorithm. An adaptive methodology is proposed to iteratively and efficiently use laboratory experiments to optimize these algorithmic factors, so that the accuracy of property predictions is maximized. The enhanced algorithm is tested on copolymer and transition metal complex libraries, and the results demonstrate the capability of the algorithm to accurately interpolate various properties of both molecular libraries.