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While generative models have recently become ubiquitous in many scientific areas, less attention has been paid to their evaluation. For molecular generative models, the state-of-the-art examines their output in isolation or in relation to its input. However, their biological and functional properties, such as ligand-target interaction is not being addressed. In this study, a novel biologically-inspired benchmark for the evaluation of molecular generative models is proposed. Specifically, three diverse reference datasets are designed and a set of metrics are introduced which are directly relevant to the drug discovery process. In particular we propose a recreation metric, apply drug-target affinity prediction and molecular docking as complementary techniques for the evaluation of generative outputs. While all three metrics show consistent results across the tested generative models, a more detailed comparison of drug-target affinity binding and molecular docking scores revealed that unimodal predictiors can lead to erroneous conclusions about target binding on a molecular level and a multi-modal approach is thus preferrable. The key advantage of this framework is that it incorporates prior physico-chemical domain knowledge into the benchmarking process by focusing explicitly on ligand-target interactions and thus creating a highly efficient tool not only for evaluating molecular generative outputs in particular, but also for enriching the drug discovery process in general., 59 pages, 26 figures Project GitHub repository, https://gitlab.com/cheml.io/abraham

ispartof: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY vol:2020 issue:23 pages:3378-3389 status: published

© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim A one-pot procedure involving a four-component Ugi reaction followed by an intramolecular Diels–Alder reaction/HCl elimination cascade has been developed to provide rapid access to the isoindolinone framework in a diversity-oriented fashion. The scope of the process has been investigated with respect to all four components, and a comparison between the one-pot and sequential approaches is given. The possibility of a late-stage one-pot functionalization through Suzuki coupling has been explored. ispartof: European Journal of Organic Chemistry vol:30 issue:30 pages:4379-4388 status: published

A new protocol for the one-pot synthesis of pyrrolones and butenolides involving an isocyanide-based multicomponent reaction (Ugi or Passerini) followed by a triethylamine-promoted cycloisomerization is described. ispartof: Synthesis vol:48 issue:14 pages:2280-2286 status: published

Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. A comprehensive study on gold- and silver-catalyzed cycloisomerizations of hydroxypropargylamides into oxazepines is described. Three different types of hydroxypropargylamide substrates derived from either amide coupling or Ugi reactions have been validated resulting in establishment of selective and general access to a medium-ring oxazepine core. A comprehensive study on gold- and silver-catalyzed cycloisomerizations of hydroxypropargylamides into oxazepines is described. ispartof: European Journal of Organic Chemistry vol:19 issue:19 pages:4190-4197 status: published

Normal 0 false false false MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Обычная таблица"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0pt 5.4pt 0pt 5.4pt; mso-para-margin:0pt; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman"; mso-ansi-language:#0400; mso-fareast-language:#0400; mso-bidi-language:#0400;}Thisthesis is devoted to the exploration of the strategies for the synthesis ofnitrogen-containing medium-sized rings fused with benzene or indole. Theimplemented approaches are based on several carbocyclization reactionsdeveloped previously in our laboratory which involve the construction of thekey C-C bond with the simultaneous assembly of the medium-sized ring. The elaboratedprotocols rely on modern transition metal catalysis and utilize readilyavailable starting materials.Chapter 1 serves as anintroduction into the chemistry of the title heterocycles, highlighting theiroccurrence in nature, biological properties and existing methodologies fortheir synthesis. The goals of the current research are also summarized in thischapter.Chapter 2 is dedicatedto the diversification of the 3-benzazepine scaffold using A3-couplingas a tool for the generation of propargylamine precursors for furtherPd-catalyzed intramolecular alkyne hydroarylation (reductive Heck reaction).Chapter 3 describesthe development of a novel protocol for a tandem Heck-Suzuki reaction and itsfurther application for diversification of the 3-benzazepine scaffold. A broadoptimization survey as well as detailed studies on the scope and limitations ofthis procedure are included.Chapter 4 deals withthe application of the Pd-catalyzed intramolecular alkyne hydroarylationreaction for the construction of the azocino[4,5,6-cd]indole framework. Some interesting structural features of thetitle heterocycles are commented.Chapter 5 discussesthe elaboration of the AuPPh3Cl/AgOTf-catalyzed protocol for the intramolecular alkyne hydroarylation processleading to azocino[5,4-b]indoles. A close look on thereactions with terminal propargylic amides resulted in the isolation and characterizationof hitherto unknown cyclized products interesting for the mechanisticunderstanding of such processes.Finally, General conclusions and perspectives arehighlighted. status: published