Note: Intro -- DIVERSITY-ORIENTED SYNTHESIS -- CONTENTS -- CONTRIBUTORS -- FOREWORD -- PREFACE -- ABBREVIATIONS -- 1 The Basics of Diversity-Oriented Synthesis -- 1.1 Introduction -- 1.2 What Is Diversity-Oriented Synthesis? -- 1.3 Small Molecules and Biology -- 1.4 Comparing DOS, TOS, and Combinatorial Chemistry: Focused Library Synthesis -- 1.5 Molecular Diversity -- 1.6 Molecular Diversity and Chemical Space -- 1.7 Synthetic Strategies for Creating Molecular Diversity -- 1.8 Reagent-Based Approaches to Diversity Generation -- 1.8.1 Use of Pluripotent Functional Groups -- 1.8.2 Use of Densely Functionalized Molecules -- 1.8.3 Twelve-fold Branching Strategy -- 1.9 Substrate-Based Approach to Skeletal Diversity Generation -- 1.10 Other Build/Couple/Pair Examples -- 1.11 Concluding Remarks -- References -- PART I CHEMICAL METHODOLOGY IN DIVERSITY-ORIENTED SYNTHESIS -- 2 Strategic Applications of Multicomponent Reactions in Diversity-Oriented Synthesis -- 2.1 Introduction -- 2.2 MCR Products for HTS -- 2.2.1 MCRs and HTS: The Real and the Virtual -- 2.2.2 Expanding Accessible Diversity: New MCRs -- 2.3 MCRs as Starting Points for DOS -- 2.4 Conclusions -- References -- 3 Cycloaddition Reactions in Diversity-Oriented Synthesis -- 3.1 Introduction -- 3.2 [4+2] Cycloaddition Reactions -- 3.2.1 Diels-Alder Reaction -- 3.2.2 Inverse Electron-Demand Diels-Alder Reaction -- 3.3 1,3-Dipolar Cycloaddition Reactions -- 3.4 Miscellaneous Cycloadditions -- 3.5 Conclusions -- References -- 4 Phosphine Organocatalysis as a Platform for Diversity-Oriented Synthesis -- 4.1 Introduction -- 4.2 DOS Using Phosphine Organocatalysis -- 4.2.1 Phosphine Organocatalysis of Allenes with Imines -- 4.2.2 Phosphine Organocatalysis of Allenes with Azomethine Imines -- 4.2.3 Phosphine Organocatalysis of Allenes with Electron-Deficient Olefins. , 4.2.4 Phosphine Organocatalysis of Allenes with Aldehydes -- 4.2.5 Phosphine Organocatalysis of Allenes with Aziridines -- 4.2.6 Phosphine Organocatalysis of Allenes with Dinucleophiles -- 4.2.7 Phosphine Organocatalysis of Acetylenes with Dinucleophiles -- 4.3 Skeletal Diversity Based on a Phosphine Catalysis/Combinatorial Scaffolding Strategy -- 4.4 A DOS Library Based on Phosphine Organocatalysis: Biological Screening, Analog Synthesis, and Structure-Activity Relationship Analysis -- 4.4.1 Protein Geranylgeranyltransferase Type I and Rab Inhibitors -- 4.4.2 Activators of Endothelium-Driven Innate Immunity of Macrophages -- 4.4.3 Cancer Cell Migration Assays -- 4.4.4 Aplexone Decreases Cellular Cholesterol Level -- 4.5 Conclusions -- References -- 5 Domino Reactions in Library Synthesis -- 5.1 Introduction -- 5.2 Pericyclic Domino Reactions -- 5.3 Anionic Domino Reactions -- 5.4 Transition-Metal-Mediated Domino Reactions -- 5.5 Radical Domino Reactions -- 5.6 Conclusions -- References -- 6 Diversity-Oriented Synthesis of Amino Acid-Derived Scaffolds and Peptidomimetics: A Perspective -- 6.1 Introduction -- 6.2 Definition and Classification of Peptidomimetics -- 6.3 Early Combinatorial Approaches to Peptidomimetic Scaffolds -- 6.4 Amino Acid-Derived Scaffolds -- 6.4.1 Scaffolds from-Amino Acids -- 6.4.2 Scaffolds Containing the Pyrrolidine Ring -- 6.4.3 Scaffolds from Amino Aldehyde Intermediates -- 6.4.4 Scaffolds from Amino Carbonyl and Sugar Derivatives -- 6.5 Macrocyclic Peptidomimetic Scaffolds -- 6.6 Conclusions -- References -- 7 Solid-Phase Synthesis Enabling Chemical Diversity -- 7.1 Introduction -- 7.2 Skeletal Diversity -- 7.2.1 Reagent-Based Strategy: Branching Process -- 7.2.2 Substrate-Based Strategy: Folding Process -- 7.3 Stereochemical Diversity -- 7.4 Appendage Diversity -- 7.5 Build/Couple/Pair Strategy -- 7.6 Scaffold Hopping. , 7.7 Conclusions -- References -- 8 Macrocycles as Templates for Diversity Generation in Drug Discovery -- 8.1 Introduction -- 8.2 Challenges Associated with Macrocycles -- 8.2.1 Synthetic Challenge -- 8.2.2 Assessment of Diversity -- 8.2.3 Macrocycles in Drug Discovery -- 8.3 Macrocyclic Peptides -- 8.3.1 Split-and-Pool Synthesis of Macrocyclic Peptides -- 8.3.2 Synthesis of Small-to-Medium-Sized Macrocycles Using Amphoteric Reagents -- 8.3.3 DNA-, RNA-, and Phage-Templated Synthesis of Peptidic Macrocycles -- 8.4 Peptidomimetic Macrocycles -- 8.4.1 Mimics of Peptide Secondary Structures -- 8.4.2 Diversity-Oriented Synthesis of Macrocyclic Peptidomimetics -- 8.4.3 Macrocyclic Peptoid Libraries -- 8.4.4 Semipeptidic Macrocycles -- 8.5 Diversity-Oriented Strategies Based on Nonpeptidic Natural Product Scaffolds -- 8.5.1 Diversification of Rapamycin -- 8.5.2 Diversification Strategies Based on Natural Macrolactones -- 8.5.3 Diversification on Macrolactam Scaffolds -- 8.5.4 Multicomponent Macrocyclization -- 8.6 Conclusions -- References and Notes -- PART II CHEMICAL LIBRARIES AND DIVERSITY-ORIENTED SYNTHESIS -- 9 Diversity-Oriented Synthesis of Natural Product-Like Libraries -- 9.1 Introduction -- 9.2 Libraries Inspired by Natural Product Scaffolds -- 9.3 Folding Pathways in the Synthesis of Natural Product-Like Libraries -- 9.4 Branching Pathways in the Synthesis of Natural Product-Like Libraries -- 9.5 Oligomer-Based Approaches to Natural Product-Like Libraries -- 9.6 Summary -- References -- 10 Chemoinformatic Characterization of the Chemical Space and Molecular Diversity of Compound Libraries -- 10.1 Introduction -- 10.2 Concept of Chemical Space -- 10.3 General Aspects of Chemoinformatic Methods to Analyze the Chemical Space -- 10.4 Chemoinformatic-Based Analysis of Libraries using Different Representations. , 10.4.1 Physicochemical Properties and Medicinally Relevant Chemical Spaces -- 10.4.2 Molecular Complexity -- 10.4.3 Scaffold Analysis -- 10.4.4 Structure Fingerprints and Multiple Representations -- 10.5 Recent Trends in Computational Approaches to Characterize Compound Libraries -- 10.6 Concluding Remarks -- References -- 11 DNA-Encoded Chemical Libraries -- 11.1 Introduction -- 11.1.1 Drug Discovery Today: A Formidable Challenge -- 11.1.2 Selecting Chemicals -- 11.1.3 Chapter Overview -- 11.2 DNA-Encoded Chemical Libraries -- 11.2.1 DNA Encoding -- 11.2.2 Single-Pharmacophore DNA-Encoded Chemical Libraries -- 11.2.3 Self-Assembled DNA-Encoded Chemical Libraries (Dual-Pharmacophore Libraries) -- 11.3 Selection and Decoding -- 11.3.1 In Vitro Selection Strategies -- 11.3.2 Decoding of DNA-Encoded Chemical Libraries -- 11.4 Drug Discovery by DNA-Encoded Chemical Libraries -- 11.5 DNA-Encoded Chemical Libraries: Prospects and Outlook -- 11.6 Conclusions -- References -- PART III SCREENING METHODS AND LEAD IDENTIFICATION -- 12 Experimental Approaches to Rapid Identification, Profiling, and Characterization of Specific Biological Effects of DOS Compounds -- 12.1 Introduction -- 12.2 Basic Principles of HTS -- 12.2.1 Specifics of HTS Assays -- 12.2.2 Assay Performance Measures -- 12.2.3 Primary Hit Selection Criteria -- 12.2.4 Quality Control of HTS Data -- 12.2.5 Stages of Lead Identification Projects -- 12.2.6 Special HTS Modalities -- 12.2.7 Principles of Assay Design -- 12.3 Common Assay Methods and Techniques -- 12.3.1 HTS Detection Approaches -- 12.3.2 The Great (Biological) Divide -- 12.3.3 Common Biochemical Screening Methods -- 12.3.4 Common Cell-Based Assays -- 12.3.5 Image-Based Screening -- 12.4 Future Perspectives -- References -- 13 Small-Molecule Microarrays -- 13.1 Introduction -- 13.2 Chemical Library Design and Synthesis. , 13.2.1 Diversity-Oriented Synthesis -- 13.2.2 Other Libraries -- 13.3 Fabrication of SMMs -- 13.3.1 Noncovalent Immobilization Approach -- 13.3.2 Covalent Immobilization Approach -- 13.3.3 In Situ Synthesis Approach -- 13.4 Applications of SMM -- 13.4.1 Protein Ligand Discovery -- 13.4.2 Enzyme Substrate/Inhibitor Profiling -- 13.4.3 Other Applications -- 13.5 Summary and Outlook -- References -- 14 Yeast as a Model in High-Throughput Screening of Small-Molecule Libraries -- 14.1 Introduction -- 14.1.1 The Quest for Rapid and Smart Biological Assays -- 14.1.2 Saccharomyces cerevisiae as a Model -- 14.2 Chemical Genetics and S. cerevisiae -- 14.2.1 Forward Chemical Genetics -- 14.2.2 Reverse Chemical Genetics -- 14.3 Chemical Genomics and S. cerevisiae -- 14.3.1 Competitive Growth Assay Based on Heterozygote Strains -- 14.3.2 Competitive Growth Assay Based on Haploid or Homozygous Strains -- 14.3.3 Comparative Expression Profiling -- 14.4 Conclusions: The Route of Drug Discovery with the Budding Yeast -- References -- 15 Virtual Screening Methods -- 15.1 Introduction -- 15.2 Basic Virtual Screening Concepts -- 15.2.1 Structure- and Ligand-Based Virtual Screening -- 15.2.2 Scaffold Analysis -- 15.2.3 Methodological Complexity -- 15.3 Molecular Similarity in Virtual Screening -- 15.3.1 Local vs. Global Similarity -- 15.3.2 Molecular Representations -- 15.4 Spectrum of Virtual Screening Approaches -- 15.5 Docking -- 15.6 Similarity Searching -- 15.6.1 Pharmacophores -- 15.6.2 Two-Dimensional Fingerprints -- 15.7 Compound Classification -- 15.7.1 Chemical Reference Spaces -- 15.7.2 Clustering and Partitioning -- 15.8 Machine Learning -- 15.8.1 Self-Organizing Maps vs. Decision Trees -- 15.8.2 Support Vector Machines -- 15.8.3 Bayesian Methods -- 15.9 Conclusions -- References. , 16 Structure-Activity Relationship Data Analysis: Activity Landscapes and Activity Cliffs.