Tongshuang Li has extensive experience in synthetic organic chemistry and medicinal chemistry, with over 22 years in the pharmaceutical industry and 12 years in academia. Currently, he is working as a chemistry consultant for both biotech companies and academics. Dr. Li's work primarily focuses on the synthesis of target compounds for drug discovery, with two new drugs recently approved in China.

Preface xv
Abbreviations xix

1 Opinions and Suggestions 1
1.1 Be a "Doctor," Not Just a "Drug Fetcher" 1
1.2 Synthetic Organic Chemistry: Still as Much an Art as a Science 1
1.3 Synthetic Organic Chemistry Is an Experimental Science under the Guidance of Theory 2
1.4 Reduce Mistakes in Your Synthetic Work 2
1.5 Your Knowledge, Experience, and Skills Can Never Be Too Much 3
1.6 What Is a Mistake? 4
1.7 Beyond Experience: Combining Literature and Insight for Optimal Synthetic Design 6
1.8 Improve Your Decision-Making Ability 6
1.9 Know the Mechanism of the Reactions You Perform 7
1.10 Always Learn Something from the Reaction You Performed 8
1.11 Knowing Reaction Mechanisms Alone Doesn't Make an Excellent Chemist-But It's Essential 8
1.12 Patents Do Not Tell You the Full Story of Chemistry 8
1.13 Summarize Your Work After Completing a Synthesis 9
1.14 Two Examples 9

2 General Terms and Concepts in Synthetic Organic Chemistry 13
2.1 Reaction Mechanism 13
2.2 Approaches to Draw Reaction Mechanism 13
2.3 Desired Product 14
2.4 Unexpected Product 14
2.5 Side Reaction 15
2.6 Side Product and By-product 15
2.7 Impurity 15
2.8 Theoretical Yield, Percentage Yield (Yield), Net Yield, and Overall Yield 16
2.9 Intermediate 16
2.10 Transition State 17
2.11 Species 17
2.12 Free Radical 17
2.13 Stoichiometric Reaction 17
2.14 Catalytic Reaction 17
2.15 Material Balance 17
2.16 Electron Balance 18
2.17 Nucleophile 18
2.18 Electrophile 18
2.19 Acid 18
2.20 Base 18
2.21 Acidity and pKa 19
2.22 Acid-Base Reaction 19
2.23 Reaction Selectivity 20
2.24 Chemoselectivity 20
2.25 Regioselectivity 21
2.26 Stereoselectivity 21
2.27 Iteroselectivity 23
2.28 One-pot Synthesis/Telescoping Process 25
2.29 Cascade Reaction 27
2.30 Multicomponent Reaction 29
2.31 Flow Chemistry 29
2.32 Atom Economy 30
2.33 Green Chemistry 31
2.34 Partial Synthesis, Total Synthesis, and Formal Synthesis 32
2.35 Linear Synthesis and Convergent Synthesis 34
2.36 Divergent Synthesis 36
2.37 Click Chemistry 36
2.38 Parallel Synthesis 37
2.39 Solid-phase Synthesis 38
2.40 Combinatorial Chemistry 38
2.41 Process Chemist versus Medicinal Chemist 39

3 General Terms and Concepts in Medicinal Chemistry 43
3.1 What Is a Drug? 43
3.2 Drug Discovery 43
3.3 Medicinal Chemistry 44
3.4 Drug Target 45
3.5 Enzyme 45
3.6 Receptor 46
3.7 Inhibitor 47
3.8 Activator 48Table of Contents v
3.9 Drug Design 48
3.10 Ligand-based Drug Design 49
3.11 Structure-based Drug Design 50
3.12 Lipinski's Rule of Five 50
3.13 Lead Compound 51
3.14 Hit-to-Lead 52
3.15 High-Throughput Screening 52
3.16 Pharmacophore 52
3.17 Affinity, Efficacy, and Potency 53
3.18 Structure-Activity Relationship 54
3.19 Partition Coefficient and Log P/Clog P 54
3.20 Drug Candidate 55
3.21 Preclinical Studies 55
3.22 Toxicity 56
3.23 Pharmacokinetics and Pharmacodynamics 56
3.24 Absorption, Distribution, Metabolism, and Excretion 56
3.25 Bioavailability 57
3.26 Pharmacology 58
3.27 Formulation 58
3.28 Active Pharmaceutical Ingredient 59
3.29 Drug Stability 59
3.30 Prodrugs 60
3.31 Deuterium-containing Drug 61
3.32 Antibody Drug Conjugates 62
3.33 Good Laboratory Practice 62
3.34 Good Manufacturing Practice 63
3.35 Chemistry, Manufacturing, and Controls 64
3.36 Contract Research Organization 65
3.37 Investigational New Drug Application 65
3.38 Clinical Trials 65
3.39 New Drug Application 66

4 Mechanism Problems from Reactions Give Expected Products 71
4.1 Formation of Noncyclic Compounds 71
4.2 Formation of Hydrazine Derivatives 101
4.3 Formation of Cyclic Alkane and Derivatives 105
4.4 Formation of Aromatic Compounds 122
4.5 Formation of Nonaromatic Heterocycles 126
4.6 Formation of Monocyclic Aromatic Heterocycles 175
4.7 Formation of Bicyclic and Polycyclic Aromatic Heterocycles 248
4.8 Miscellaneous 277

5 Mechanism Problems from Reactions Give Unexpected, Undesired, or Side Products 305
5.1 Formation of Noncyclic Alkane and Derivatives 306
5.2 Formation of Cyclic Alkane and Derivatives 316
5.3 Formation of Aromatic Compounds 318
5.4 Formation of Nonaromatic Heterocycles 320
5.5 Formation of Monocyclic Aromatic Heterocycles 338
5.6 Formation of Bicyclic Aromatic Heterocycles 356
5.7 Miscellaneous 372

References 378
Index 383