A sensible alternative is to conduct virtual reactions (VR) . Here, reaction rules are applied recursively to matching building block molecules in the forward direction, until desired number of steps is reached. Most virtual screening libraries are generated this way. This approach has also been used for de novo design. In pioneering work, Vinkers et al. describe an algorithm combining VRs with simulated annealing and search to optimize given scoring functions . Approaches investigating different optimization strategies have been reported as well . Forward VR enumeration can also be combined with retrosynthesis planning to generate focused libraries close to target molecules .