ARChem Route Designer is a new retrosynthetic analysis package (1) that generates complete synthetic routes for target molecules from readily available starting materials. Rule generation from reaction databases is fully automated to insure that the system can keep abreast with the latest reaction literature and available starting materials. After these rules are used to carry out an exhaustive retrosynthetic analysis of the target molecules, special heuristics are used to mitigate a combinatorial explosion. Proposed routes are then prioritized by a merit ranking algorithm to present to the viewer the most diverse solution profile. Users then have the option to view the details of the overall reaction tree and to scroll through the reaction details. The program runs on a server with a web-based user interface. An overview of some of the challenges, solutions, and examples that illustrate ARChem's utility will be discussed.

1. ARChem Route Designer Antony Williams On behalf of A. Peter Johnson University of Leeds / SimBioSys Inc. Howard Y. Ando (Pfizer Inc.), Zsolt Zsoldos, Aniko Simon, James Law, Darryl Reid, Yang Liu, Sing Yoong Khew, Sarah Major

4. Typical Retrosynthetic Analysis Retrosynthetic analysis works backward from the target and generates increasingly simple precursors

9. System Design Overview Automatic Rule Extraction User input: Molecule Starting Materials: Aldrich, Acros Lancaster Reaction DB (MOS, Beilstein, CASREACT etc.) Reaction Rules Route Des. search Output: Reaction pathways

12. Route Designer Reaction Rules Reaction DB ( RDF format) Reaction Rules 1) The extraction process converts many reactions into a few rules. 2) The combinatorial explosion of the retrosynthetic search process is controlled. Generic leaving groups reduce the number of rules Cluster reactions by chemical equivalence Group identical reaction cores Find the core of the reaction Methods of Organic Synthesis ( MOS ) ~42k Reactions Large reaction DBs OK ( millions of reactions supported) 4k rules from 47k reactions

15. Reaction Core Extension Reaction Extracted Core Extended Core

16. Generic leaving groups Generic rule Reaction Rule Nucleofuge (NF) - a leaving group which carries away the bonding electron pair

18. Rule Generation Summary Other examples clustered: Reaction DB in RDF file format Esterification examples clustered: Esterification Reaction Rule: ...-> ... Some other rule

22. Top 5 Clusters (MOS example)

38. Acknowledgements Acknowledgements Pfizer Robert Wade Robert Dugger James Gage Peter Wuts David Entwistle Inaki Morano Richard Nugent Bryan Li Julian Smith Accelrys Rob Brown Eric Jamois Symyx-MDL Maurizio Bronzetti Jochen Tannemann