1. In Silico Synthesis György Pirok, Nóra Máté

2. Elements of the Virtual Synthesis Technology A language for describing chemical rules –Chemical Terms A library of selective reactions knowing chemistry –Chemaxon Reaction Library A reaction engine with high capacity and performance –Reactor Virtual synthesis applications –Synthesizer (combinatorial, random, exhaustive) –Retrosynthesizer

3. Chemical Terms, a Language for Cheminformatics structure search match("olefine.mol") && !match("c1ccncc1") && (atomCount(16) == 0) || (mass() < 300); goal function inhibitor = inhibitor.mol; similarity(inhibitor, chemical_tanimoto) - similarity(inhibitor, pharmacophore_tanimoto); drug likeness filter (mass() <= 500) && (logP() <= 5) && (donorCount() <= 5) && (acceptorCount() <= 10); structure matching functions (describing functional groups, reaction sites, similarity…) property calculations (partial charge distribution, pKa, logP, localization energy…) arithmetic and logic-operators Elements of the language Chemical Terms examples

4. Encoding Synthetic Knowledge in Reactions Friedel-Crafts acylation: generic scheme The hydrogen of an aromatic carbon atom is substituted with an acyl group of an acid halide during hydrogen halide elimination. C(a)aromatic carbon atom L[O, S]oxygen or sulfur atom L[Cl, Br, I]chlorine, bromine or iodine atom

5. Encoding Synthetic Knowledge in Reactions Friedel-Crafts acylation: finding reactive sites REACTIVITY: charge(ratom(1), "aromaticsystem") < -0.2 Friedel-Crafts acylation occurs only if the aromatic system is at least as activated as mono-halobenzenes.

6. Encoding Synthetic Knowledge in Reactions Friedel-Crafts acylation: finding the most reactive sites SELECTIVITY: -energyE(ratom(1)) TOLERANCE: 0.02 Directing rule: the electrophilic substitution takes place on the aromatic carbon atom with the lowest localization energy having an attached electrophile in the transition state. Aromatic carbon with the lowest localization energy provides the main product. Other aromatic carbons having similar localization energies (with less difference than 0.02) are also considered to lead to main products.

7. Encoding Synthetic Knowledge in Reactions Friedel-Crafts acylation: excluding compounds giving side reactions, destroying the catalyst EXCLUDE: match(ratom(2), "[C:1]C=C", 1) || match(reactant(0), "[#15][H]") || (max(pka(reactant(0), filter(reactant(0), "match('[O,S;H1]')"), "acidic")) > 14.5) || (max(pka(reactant(0), filter(reactant(0), "match('[#7:1][H]', 1)"), "basic")) > 0) Exclude aromatic compounds containing nucleophilic groups (but do not exclude phenols) and also exclude acrylic halides.

8. Encoding Synthetic Knowledge in Reactions Friedel-Crafts acylation as a smart reaction REACTIVITY: charge(ratom(1), "aromaticsystem") < -0.2 SELECTIVITY: -energyE(ratom(1)) TOLERANCE: 0.02 EXCLUDE: match(ratom(2), "[C:1]C=C", 1) || match(reactant(0), "[#15][H]") || (max(pka(reactant(0), filter(reactant(0), "match('[O,S;H1]')"), "acidic")) > 14.5) || (max(pka(reactant(0), filter(reactant(0), "match('[#7:1][H]', 1)"), "basic")) > 0)

9. Reactor, the engine Reactants REACTOR ChemAxon Reaction Library Baeyer-Villiger ketone oxidation Baylis-Hillman vinyl alkylation Beckmann rearrangement Bischler-Napieralski isoquinoline synthesis Friedel-Crafts reaction Friedlander quinoline synthesis Gabriel synthesis Grignard reaction Hell-Volhardt-Zelinski halogenation Products

10. Reactor, key features Effective –millions of compounds in a combinatorial reaction –up to 500,000 compounds / hour (P4 1.8 GHz) Compatible –reactions: MRV, RXN, RDF, SMARTS/SMIRKS –compounds: MRV, MOL, SDF, SMILES –mapping: MDL, Daylight, automapper Flexible –memory, file and database operations (even via Oracle Cartridge) –sequential or combinatorial mode –compound or reaction output type –reverse direction Smart –chemo-, regio- and stereospecific –customizable Available –Java API, command line tool, JSP –built-in reaction library –documentation and examples –free for the Academic community

11. Real Combinatorial Synthesis Derek S. Tan, Michael A. Foley, Matthew D. Shair, Stuart L. Schreiber*, J. Am. Chem. Soc., 1998, 120, 8565-8566 lacton aminolysisalkyne coupling esterification

12. Virtual Combinatorial Synthesis 540,600 compunds in the three steps in 2.5 hours (P4 3.0 GHz, Oracle 10g)

13. Building a Diverse Compound Space 1.2.3. 4.56.

14. Reactor API – part I. 1.Create a Reactor object: Reactor reactor = new Reactor(); 2.Set standardization (optional): reactor.setStandardizer(standardizer); reactor.setStandardizationType(Reactor.POST); 3.Set Reactor parameters (optional): reactor.setReverse(true); // reverse reaction reactor.setProductIndexes(new int[] {1}); // only first product

15. Reactor API – part II. 4.Set the reaction: reactor.setReaction(rmol); // rules in rmol or no rules reactor.setReaction(rmol, reactivity, selectivity); // rules reactor.setReactionString(rstr); // SMARTS (with rules) 5.Set the reactants: reactor.setReactants(new Molecule[] {r1, r2}); 6.Process the reaction: Molecule[] products = null; while ((products = reactor.react()) != null) { // do something with the products }

16. Reactor API – examples I.

17. Reactor API – examples II. Reactivity rule: !(match(ratom(3), '[#7:1]', 1) && pKa(ratom(3), 'basic') < 0.0) && !match(ratom(3), '[N,O,S:1][C,P,S]=[N,O,S]', 1)

18. Reactor API – examples III. Reactants:Product: Command line tool react:

19. Reactor API – examples IV.

20. Reactor API – examples V. Reactants: The reactivity rule excludes the N atom with negative basic pKa. reactive N atom

21. Reactor API – examples VI. The result reaction: Command line tool react:

22. Reactor API – examples VII. Processing reactants in combinatorial mode:

23. Reactor API – examples VIII. Time result for a 10x10 example, producing 120 products: Command line tool react: Observe the –m comb option for setting combinatorial mode.

24. Reactor speed test Time result for a 326x2955 example, producing over 1 million products in about 3 hours with the command line tool react: System configuration: CPU: intel P4 1.6 GHz RAM: 512 MB OS: RedHat 9, kernel 2.4.20-8 Java: 1.4.2

25. Reactor JSP application web: http://www.jchem.com/examples/reactor/jsp/index.jsp Graphical user interface Reaction / reactant setting: select from built-in reaction library load from file / SMARTS string draw in msketch set / modify reaction rules use example reactants from reaction Reaction processing: sequential or combinatorial mode product only or reaction form save results

26. Máramaros köz 3/a Budapest, 1037 Hungary info@chemaxon.com www.chemaxon.com Thank you for your attention