Chematica is a sophisticated platform for fully automated design of pathways leading to arbitrary (i.e., both known and new) targets. The software combines elements of network theory with an expert knowledge-base of synthetic transformations as well as multiple reaction-evaluation routines (based on machine learning, quantum mechanics, and molecular dynamics ) to search over vast trees of synthetic possibilities. The reaction transforms (currently, ~ 100,000) are expert-coded based on the underlying reaction mechanisms and are broader than any specific literature precedents (for comparison with machine extraction of rules from reaction repositories, see ). Each rule specifies the scope of admissible substituents, accounts for stereo-and regiochemistry requirements, recognizes groups that must be protected under given reaction conditions, and identifies functionalities that are outright incompatible. The searches are guided by combinations of functions (either heuristic or best-in-class AI-based ) that score both synthetic positions as well as costs of individual reactions. The pathways identified by the program terminate in either commercially available chemicals (here, more than 200,000 molecules from Sigma-Aldrich catalogs, each with price per unit quantity; also see below for price re-scaling) or those already known in the literature (ca. 6 million substances, each accompanied by a measure of synthetic popularity , i.e., how many times a given substance was used in prior syntheses). Since the program typically identifies a large number of possible routes, the network of viable syntheses already found is queried by dynamic linear programming algorithms to select pathways with the lowest cost (propagated recursively from substrates to products with the consideration of estimated yields), and that offer diverse retrosynthetic strategies. In setting up a particular search, the user can specify parameters influencing the economy of the solutions, notably, the upper price threshold and/or the minimal synthetic popularity of the starting materials, the relative cost of performing a reaction operation, or the desired estimated yield. The user can also eliminate certain types of transformations or unwanted reagents (e.g., expensive catalysts). He/she is also able to "lock" certain bonds or fragments in the target such that they are not disconnected along the synthetic plan -as described in detail in , this functionality is useful in navigating around patented routes.