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Scientific & technical presentation Virtual Synthesis - Reactor.

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1 Scientific & technical presentation Virtual Synthesis - Reactor

2 Elements of the Virtual Synthesis Technology Chemical property predictions –Calculator Plugins A language for describing chemical rules –Chemical Terms A library of selective reactions –Chemaxon Reaction Library A high performance reaction engine –Reactor Virtual reaction applications –Reactor (wizard, JChem for Excel, Instant Jchem) –Metabolizer

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

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 Applications of Chemical Terms CT virtual synthesis reaction and synthesis rules pharmacophore analysis pharmacophore definitions drug design goal functions structure searching advanced query expressions

6 Encoding Synthetic Knowledge in Reactions The Friedel-Crafts acylation James Mason Crafts Charles Friedel

7 Encoding Synthetic Knowledge in Reactions The 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

8 Encoding Synthetic Knowledge in Reactions The 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 monohalobenzenes.

9 Encoding Synthetic Knowledge in Reactions The 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 carbons having the lowest electrophilic localization energies provide the main product. Aromatic carbons having similar localization energies to the lowest one (within 0.02 tolerance range) are included.

10 Encoding Synthetic Knowledge in Reactions The Friedel-Crafts acylation: excluding compounds giving side reactions, destroying the catalyst EXCLUDE: match(reactant(1), "[Cl,Br,I]C(=[O,S])C=C") or match(reactant(0), "[H][O,S]C=[O,S]") or match(reactant(0), "[P][H]") or (max(pka(reactant(0), filter(reactant(0), "match('[O,S;H1]')"), "acidic")) > 14.5) or (max(pka(reactant(0), filter(reactant(0), "match('[#7:1][H]', 1)"), "basic")) > 0) Exclude aromatic compounds containing nucleophilic groups and acrylic halides. For example, phenols and indols are processed, but benzylalcohols or anilines are not.

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

12 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

13 Reactor the Application

14 The Reaction Editor

15 Reactor Module in Instant JChem The Reactor module of Instant JChem provides an easy to use virtual synthesis application for the scientists working in local or corporate database environments.

16 Reactor in JChem for Excel JChem for Excel is a new application bringing ChemAxons cheminformatics toolkit to Microsoft Excel. Reactor is integrated as one of the first features.

17 Reactor, key features Effective –millions of compounds in a combinatorial reaction –high performance (speed depends on the complexity of the reaction) Compatible –reactions: MRV, RXN, RDF, SMARTS/SMIRKS, CDX, SKC –compounds: MRV, MOL, SDF, SMILES, CDX, SKC –mapping: changing atoms, matching atoms, all atoms Flexible –memory, file and database operations –sequential and combinatorial modes –compound, reaction and fused reaction output types –reverse direction Smart –chemo-, regio- and stereospecific –customizable behaviour –reactant ratio to specify excess Available –Java and.NET API, command line tool, wizard, Jchem for Excel, Instant JChem –premade reaction library –documentation and examples –free for the Academic community

18 Visit other technical presentations MarvinSketch/View MarvinSpace Calculator Plugins JChem Base JChem Cartridge Standardizer Screen JKlustor Fragmenter Reactor

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