1. Reactor latest ChemAxon User Group MeetingBudapest 2007 György Pirok

2. Content Elements of the Virtual Synthesis Encoding Synthetic Knowledge in Reactions Applications New Features Summary

3. 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 reaction applications –Reactor GUI, Metabolizer

4. Calculator Plugins acceptor acceptorCount acceptorSiteCount acidicpKa acidicpKaLargeModel aliphaticAtom aliphaticAtomCount aliphaticBondCount aliphaticRingCount angle aromaticAtom aromaticAtomCount aromaticBondCount aromaticElectrophilicityOrder aromaticNucleophilicityOrder aromaticRingCount array asymmetricAtom asymmetricAtomCount atno atomCount atomicPolarizability averagePolarizability balabanIndex basicpKa basicpKaLargeModel BCUT bond bondCount bondType canonicalResonant canonicalTautomer carboaromaticRingCount carboRingCount chainAtom chainAtomCount chainBond chainBondCount charge chiralCenter chiralCenterCount composition conformer conformerCount conformers connected connectedGraph connections count cxsmarts cxsmiles cyclomaticNumber dihedral dissimilarity distance distanceDegree donor donorCount donorSiteCount dotDisconnectedFormula doubleBondStereoisomer doubleBondStereoisomerCount doubleBondStereoisomers dreidingEnergy eccentricity electrophilicLocalizationEnergy enumeration enumerationCount enumerations exactMass field filter formalCharge formula fusedAliphaticRingCount fusedAromaticRingCount fusedRingCount hararyIndex hasValidConformer hydrogenCount heavy heteroaromaticRingCount heteroRingCount hyperWienerIndex isoelectricPoint isotopeComposition isotopeFormula largestAtomRingSize largestRingSize logD logP logPIncrement logS logSMicro logSNeutral logSTrue lowestEnergyConformer majorMicrospecies majorMs map mass match matchCount max maxAtom maxValue microspecies microspeciesCount microspeciesDistribution min minAtom minValue molBinFormat molecularPolarizability molFormat molImage name nucleophilicLocalizationEnergy pair piChargeDensity piEnergy piOrbitalElctronegativity pKa plattIndex polarizability property randicIndex refractivity refractivityIncrements resonant resonantCount resonants ringAtom ringAtomCount ringBond ringBondCount ringCount ringCountOfAtom rotatableBond rotatableBondCount shortestPath sigmaOrbitalElectronegativity smallestAtomRingSize smallestRingSize smarts smiles solubility solubilityAtIsoelectricPoint solubilityOfMicroSpecies solubilityOfNeutral solventAccessibleSurfaceArea sortAsc sortDesc stereoisomer stereoisomerCount stereoisomers stericEffectIndex stericHindrance sum szegedIndex tautomer tautomerCount tautomers tetrahedralStereoisomer tetrahedralStereoisomerCount tetrahedralStereoisomers topologicalPolarSurfaceArea totalChargeDensity traditionalName uniqueSmiles valence vanDerWaalsSurfaceArea wienerIndex wienerPolarity

5. Encoding Synthetic Knowledge in Reactions The Baeyer-Villiger carbonyl oxidation Victor Villiger 1868-1934 Johann Friedrich Wilhelm Adolf Ritter von Baeyer 1835-1917

6. Reaction Processing from Command Line react -r '[C:2][C:1](=O)C>>[C:2][O:3][C:1](=O)C' 'CC(=O)C1CCCCC1' CC(=O)OC1CCCCC1 COC(=O)C1CCCCC1 reaction reactant products

7. Batch Reaction Processing from Command Line react -r Baeyer-Villiger oxidation.mrv carbonyls.sdf CCc1oc2ccccc2c1OC(=O)c3ccc(O)cc3 OC(OC(=O)c1ccccc1)c2ccccc2 C[NH2+]C1(CCCCC(=O)O1)c2ccccc2Cl COc1ccc(OC(=O)c2ccc(C)cc2)c(O)c1 O=C(OCC[NH+]1CCC(C1)c2ccccc2)c3ccc4OCCOc4c3 Oc1cccc2Cc3cccc(O)c3C(=O)Oc12 C[NH+](C)CCOc1cc2oc(=O)c3ccccc3c2c4ccccc14 Oc1c(oc(=O)c2ccccc12)-c3ccc(Br)cc3 CC([NH3+])OC(=O)c1ccccc1 Oc1c(oc(=O)c2ccccc12)-c3ccc(Cl)cc3...

8. Problem Chemical reactions are selective!

9. Encoding Synthetic Knowledge in Reactions The Baeyer-Villiger oxidation: generic scheme The Baeyer-Villiger oxidation is an organic reaction in which a ketone or aldehyde is oxidized to an ester by treatment with peroxy acids or hydrogen peroxide. The stereo configuration remains intact during the reactions. Retretention L[H,C]carbon or hydrogen

10. Encoding Synthetic Knowledge in Reactions The Baeyer-Villiger oxidation: excluding compounds giving side reactions, destroying the catalyst EXCLUDE: match(reactant(0), "[H][#5,#14,#15,#16]") || match(reactant(0), "C=S") || match(reactant(0), "[H]OC=O") || match(reactant(0), "[O-]C=O") Exclude reagents containing BH, SiH, PH, SH or thiocarbonyl or carboxyl and carboxylate groups.

11. Encoding Synthetic Knowledge in Reactions The Baeyer-Villiger oxidation: finding reactive sites REACTIVITY: !match(ratom(2), "[H][C:1](C=O)C=O", 1) Beta diketones are able to enolize, they do not react on the carbon between the two carbonyl groups.

12. Encoding Synthetic Knowledge in Reactions The Baeyer-Villiger oxidation: finding the most reactive sites SELECTIVITY: -charge(ratom(2), "sigma") The oxygen goes between the carbonyl carbon and its neighbour having the lowest sigma charge value. δδ

13. Encoding Synthetic Knowledge in Reactions The Baeyer-Villiger oxidation as a selective reaction REACTIVITY: !match(ratom(2), "[H][C:1](C=O)C=O", 1) SELECTIVITY: -charge(ratom(2), "sigma") EXCLUDE: match(reactant(0), "[H][#5,#14,#15,#16]") || match(reactant(0), "C=S") || match(reactant(0), "[H]OC=O") || match(reactant(0), "[O-]C=O")

14. Reactor, the engine REACTOR ChemAxon Reaction Library... Angeli-Rimini hydroxamic acid synthesis Baeyer-Villiger carbonyl oxidation Baylis-Hillman vinyl alkylation Beckmann rearrangement Bischler-Napieralski isoquinoline synthesis Friedel-Crafts acylation... ReactantsProducts

15. Reactor the Application

16. The Reaction Editor Built in Reaction Library Editor

17. The Reaction Editor Chemical Terms Editor for Rule Design

18. The Reaction Editor Internal Example and Property Editors

19. The Reaction Editor Built-in Reactant Standardizer and Reaction Tester

20. What's new in Reactor Automapping reaction results Aromaticity is automatically detected (no standardization needed) Synthesis code generation for the products Bromination(Acylation(AMINE12, ACID37):1):2 New and enhanced reactions in the library Separate example reaction properties Reaction testing with the internal examples Rule Editor Automatic reactant standardization can be built-in the virtual reaction Product standardization is a runtime option The Reactor license will contain about 10 sample reactions The new reaction library and reaction capabilities in Cartridge will be included in the Reactor Pro license

21. Future Features Reactor module in Instant JChem working in database tables (new, simplifed interface) Processing multistep reactions Transition states and intermedier based calculations Simplified rules –simplified Chemical Terms language –new plugin functions for reactivity and selectivity predictions –named functional groups (SMARTS-less rules) Reaction library can be classified by several aspects Functional group name based reaction definition amine>>amide

22. Summary What is Reactor? –Reactor is an effective and selective virtual synthesis tool transforming molecules to products according to given reaction schemes. What is it good for? –combichem library enumeration –reaction prediction –other transformation based applications (xenobiotic biotransformation, bacterial biodegradation, random synthesis, generating chlick chemistry universe, etc.) How can I use it? –Off the shelf (Reactor Application) –Integrate into applications (Java/.NET API, Oracle Cartridge) –Reaction Library option with predefined synthetic reactions –FREE for Academics

23. Acknowledgements Nóra Máté, Zsolt Mohácsi Plugin system, Chemical Terms Evaluator, Reactor Jenő Varga, Erzsébet Czinege Reaction Library, Reactor József Szegezdi, Ferenc Csizmadia Property predictions, calculations István Cseh, Attila Szabó Reactor Application, Chemical Terms Editor Szilárd Dóránt, Szabolcs Csepregi Substructure searching functions, Pipeline Pilot integration Péter Kovács JChem Cartridge integration Miklós Vargyas Chemical Terms Evaluator