Handbook for Chemical Process Research and Development,

Cover
Half Title
Title Page
Copyright Page
Table of Contents
Preface
Author Biography
List of Abbreviations
Chapter 1 Reaction Solvent Selection
	1.1 Ethereal Solvents
		1.1.1 Cyclopentyl Methyl Ether
			1.1.1.1 Brook Rearrangement
			1.1.1.2 N-Alkylation Reaction
		1.1.2 Tetrahydrofuran
			1.1.2.1 Grignard Reagent Formation
			1.1.2.2 Bromination of Ketone
		1.1.3 2-Methyl Tetrahydrofuran
			1.1.3.1 Control of Impurity Formation
			1.1.3.2 Enhancing Reaction Rate
			1.1.3.3 Improving Layer Separation
		1.1.4 Methyl tert-Butyl Ether
			1.1.4.1 Chlorination Reaction
			1.1.4.2 Darzens Reaction
		1.1.5 Diethoxymethane and Dimethoxyethane
	1.2 Protic Solvents
		1.2.1 Methanol as a Solvent
			1.2.1.1 Leak of Palladium Catalyst
			1.2.1.2 Side Product Formation
			1.2.1.3 Palladium-Catalyzed Methylation Reaction
		1.2.2 Ethanol as a Solvent
			1.2.2.1 Catalytic Reduction of Diaryl Methanol
			1.2.2.2 SN2 Reaction
		1.2.3 2-Propanol as a Solvent
			1.2.3.1 Reaction of Acyl Hydrazine with Trimethylsilyl Isocyanate
			1.2.3.2 Classical Resolution of Racemic Acid
			1.2.3.3 Nickel-Catalyzed Addition Reaction
		1.2.4 1-Pentanol
		1.2.5 Ethylene Glycol
	1.3 Water as Reaction Solvent
		1.3.1 Iodination Reaction
		1.3.2 Synthesis of Quinazoline-2,4-dione
		1.3.3 Synthesis of Pyrrolocyclohexanone
		1.3.4 Synthesis of Thiourea
		1.3.5 Synthesis of Amide
		1.3.6 Synthesis of 1,3/1,4-Diketones
	1.4 Non-Polar Solvents
		1.4.1 Condensation of Ketone with tert-Butyl Hydrazine Carboxylate
		1.4.2 Acid-Catalyzed Esterification
	1.5 Polar Aprotic Solvents
		1.5.1 Acetone as a Solvent
			1.5.1.1 Michael Addition Reaction with Acetone Cyanohydrin
			1.5.1.2 SN2 Alkylation Reaction
			1.5.1.3 Multi-Component Reactions
			1.5.1.4 Amidation Reaction
		1.5.2 Acetonitrile as a Solvent
			1.5.2.1 Intramolecular Michael Addition Reaction
			1.5.2.2 Synthesis of Imidazolines
			1.5.2.3 Synthesis of α-Alkylated Ketones
			1.5.2.4 Chlorosulfonylation Reaction
		1.5.3 N,N-Dimethylformamide as a Solvent
			1.5.3.1 Preparation of Alkyl Aryl Ether
			1.5.3.2 Preparation of Bisaryl Ether
	1.6 Halogenated Solvents
		1.6.1 Dichloromethane
			1.6.1.1 Reaction with Pyridine
			1.6.1.2 Synthesis of Benzo[d]isothiazolone
		1.6.2 1,2-Dichloroethane
		1.6.3 Trifluoroacetic Acid
		1.6.4 (Trifluoromethyl)benzene
		1.6.5 Hexafluoroisopropanol
			1.6.5.1 Selective Oxidation of Sulfide
			1.6.5.2 Cycloaddition Reaction
	1.7 Carcinogen Solvent
	1.8 Other Solvents
		1.8.1 DW-Therm
		1.8.2 Dowtherm A
			1.8.2.1 Synthesis of 6-Chlorochromene
			1.8.2.2 Conrad–Limpach Synthesis of Hydroxyl Naphthyridine
			1.8.2.3 Conrad–Limpach Synthesis of Quinolone
		1.8.3 Polyethylene Glycol
		1.8.4 Propylene Glycol Monomethyl Ether
		1.8.5 Sulfolane
			1.8.5.1 Bromination/Esterification
			1.8.5.2 Fluorine-Exchange Reaction
		1.8.6 Ionic Liquids
	1.9 Mixture Of Solvents
		1.9.1 Aldol Condensation Reaction
		1.9.2 Visible-Light Mediated Redox Neutral Reaction
	1.10 Solvent-Free Reaction
Chapter 2 Reagent Selection
	2.1 Inorganic Base
		2.1.1 Sodium Bicarbonate
		2.1.2 Potassium Carbonate
			2.1.2.1 Boc Protection of Amino Group
			2.1.2.2 Ring-Opening Iodination
		2.1.3 Sodium Hydride
			2.1.3.1 SN2 Reaction
			2.1.3.2 Addition/Elimination Reaction
			2.1.3.3 Nucleophilic Addition Reaction
		2.1.4 LiOH/H2O2 Combination
			2.1.4.1 Hydrolysis of Chiral Pentanoate
			2.1.4.2 Hydrolysis of Chiral Propanoate
			2.1.4.3 Hydrolysis of Chiral Amide
	2.2 Organic Base
		2.2.1 Trialkylamine
			2.2.1.1 Diisopropylethylamine
			2.2.1.2 Triethylamine
		2.2.2 Imidazole
		2.2.3 2,6-Dimethylpiperidine
		2.2.4 2-(N,N-Dimethylamino)pyridine
		2.2.5 Metal Alkoxide Base
			2.2.5.1 Potassium tert-Pentylate
			2.2.5.2 Lithium tert-Butoxide
			2.2.5.3 Potassium tert-Butoxide
			2.2.5.4 Potassium Trimethylsilanoate
			2.2.5.5 Combination of Potassium tert-Butoxide with tert-Butyllithium
			2.2.5.6 Sodium Methoxide
	2.3 Reagents For Amide C(O)−N Bond Formation
		2.3.1 CDI-Mediated Amide Formation
			2.3.1.1 Preparation of Nicotinic Acid Amide
			2.3.1.2 Preparation of Ureas
		2.3.2 Thionyl Chloride-Mediated Amide Formation
			2.3.2.1 Tetramethylurea-Catalyzed Acid Chloride Formation
			2.3.2.2 N-Sulfinylaniline-Involved Amide Preparation
		2.3.3 Boc2O-Mediated Amide Formation
		2.3.4 Schotten–Baumann Reaction
		2.3.5 Other Amide Formation Methods
			2.3.5.1 Copper (II)-Catalyzed Transamidation
			2.3.5.2 Cross-Coupling between Acyltrifluoroborates and Hydroxylamines
			2.3.5.3 Catalytic Aminolysis of Ester
Chapter 3 Various Reagent Surrogates
	3.1 Ammonia Surrogates
		3.1.1 Ammonium Hydroxide
		3.1.2 Ammonium Acetate
			3.1.2.1 Condensation with β-Keto Amide
			3.1.2.2 Condensation with Cyclohexanones
			3.1.2.3 Consecutive Reductive Amination Reactions
		3.1.3 Ammonium Chloride
		3.1.4 Hydroxylamine Hydrochloride
			3.1.4.1 Reductive Amination
			3.1.4.2 Aromatization
		3.1.5 O-Benzylhydroxylamine
		3.1.6 Hydroxylamine-O-Sulfonic Acid
			3.1.6.1 SN2 Reaction with Sulfinate
			3.1.6.2 Reaction with Boronic Acid
		3.1.7 Hexamethylene Tetramine
		3.1.8 Acetonitrile
		3.1.9 Chloroacetonitrile
		3.1.10 tert-Butyl Carbamate
		3.1.11 Diphenylmethanimine
		3.1.12 α-Amino Acids
			3.1.12.1 Glycine Hydrochloride
			3.1.12.2 2,2-Diphenylglycine
		3.1.13 Silylated Amines
		3.1.14 Allylamines
		3.1.15 Isoamyl Nitrite
		3.1.16 1,2-Benzisoxazole
	3.2 Carbon Monoxide Surrogates
		3.2.1 N-Formylsaccharin
		3.2.2 Paraformaldehyde
		3.2.3 Molybdenum Carbonyl
		3.2.4 Phenyl Formate
		3.2.5 Benzene-1,3,5-Triyl Triformate (TFBen)
		3.2.6 Formic Acid
	3.3 Carbon Dioxide Surrogates
	3.4 α-Hydroxysulfonates as Aldehyde Surrogates
		3.4.1 Oxidation of Aldehyde to Acid
		3.4.2 Reductive Amination
		3.4.3 Diels–Alder Reaction
		3.4.4 Strecker Reaction
		3.4.5 Transaminase DKR of Aldehyde
		3.4.6 Reduction of Aldehyde to Alcohol
	3.5 Sulfur Dioxide Surrogate
		3.5.1 Synthesis of Sulfones
		3.5.2 Synthesis of Sulfoxides
		3.5.3 Synthesis of Sulfonamides
	3.6 Miscellaneous Surrogates
		3.6.1 Methyl Iodide Surrogate
		3.6.2 Cyanide Surrogates
			3.6.2.1 2-Methyl-2-Phenyl Malononitrile (MPMN)
			3.6.2.2 2-Cyanoisothiazolidine 1,1-Dioxide
		3.6.3 Ethylene Surrogates
Chapter 4 Modes of Reagent Addition: Control of Impurity Formation
	4.1 Direct Addition
		4.1.1 Sonogashira Reaction
		4.1.2 Michael Reaction
		4.1.3 Fisher Indole Synthesis
		4.1.4 Amide Formation
			4.1.4.1 EEDQ-Promoted Amide Formation
			4.1.4.2 CDI-Promoted Amide Formation
		4.1.5 Thioamide Formation
		4.1.6 C–O Bond Formation
			4.1.6.1 SRN2 Reaction
			4.1.6.2 Mitsunobu Reaction
	4.2 Reverse Addition
		4.2.1 Grignard Reaction
			4.2.1.1 Reaction with Alkyl Aryl Ketone
			4.2.1.2 Grignard Reaction with Aldehydes
			4.2.1.3 Reaction of Grignard Reagent with Ester
		4.2.2 Copper-Catalyzed Epoxide Ring Opening
		4.2.3 Nitration Reaction
		4.2.4 Cyclization Reaction
		4.2.5 Amide Formation
			4.2.5.1 CDI-Promoted Amide Formation
			4.2.5.2 Phenyl Chloroformate-Promoted Urea Formation
		4.2.6 Reduction of Ketone to Hydrocarbon
		4.2.7 1,3-Dipole-Involved Reactions
			4.2.7.1 Addition–Elimination/Cyclization
			4.2.7.2 [3+2] Cycloaddition
	4.3 Other Addition Modes
		4.3.1 Sequential Addition
		4.3.2 Portionwise Addition
			4.3.2.1 Cyclization
			4.3.2.2 Deoxychlorination
		4.3.3 Slow Release of Starting Material/Reagent
			4.3.3.1 Synthesis of Urea
			4.3.3.2 Preparation of Alkylamine
		4.3.4 Alternate Addition
		4.3.5 Concurrent Addition
			4.3.5.1 Bromination Reaction
			4.3.5.2 Difluoromethylation
			4.3.5.3 Diels–Alder Reaction
Chapter 5 Process Optimization with Additives
	5.1 Acid Additives
		5.1.1 Hydrochloric Acid
			5.1.1.1 SNAr Reaction
			5.1.1.2 Deoxychlorination
		5.1.2 Phosphoric Acid
		5.1.3 Sulfuric Acid
			5.1.3.1 Iodination Reaction
			5.1.3.2 Chlorination Reaction with N-Chlorosuccinimide
			5.1.3.3 Chlorination Reaction with Phosphorus Trichloride
			5.1.3.4 Hydrogenation Reaction
		5.1.4 Methanesulfonic Acid
		5.1.5 Acetic Acid
			5.1.5.1 Condensation Reaction
			5.1.5.2 SN2 Reaction
			5.1.5.3 Mitsunobu Reaction
		5.1.6 Benzoic Acid
		5.1.7 Trifluoroacetic Acid
		5.1.8 Toluenesulfonic Acid
	5.2 Base Additives
		5.2.1 Potassium Carbonate
		5.2.2 Sodium Hydrogen Carbonate
		5.2.3 Diisopropylethylamine
			5.2.3.1 Neutralizing AcOH/Replacing Ammonia
			5.2.3.2 Stabilizing Intermediate
		5.2.4 1,4-Diazabicyclo[2.2.2]octane
		5.2.5 N,N’-Dimethylethylenediamine
		5.2.6 Potassium tert-Butoxide
		5.2.7 Sodium Methoxide
			5.2.7.1 Increasing Reaction Rate
			5.2.7.2 Improving Product Yield
		5.2.8 Sodium Acetate
			5.2.8.1 Trapping Hydrogen Iodide
			5.2.8.2 Trapping Hydrogen Chloride
			5.2.8.3 Improving Conversion
		5.2.9 Sodium Acrylate
	5.3 Inorganic Salts
		5.3.1 Lithium Chloride
			5.3.1.1 Increasing Reaction Rate
			5.3.1.2 Improving Stereoselectivity
			5.3.1.3 Improving Conversion
		5.3.2 Lithium Bromide
		5.3.3 Sodium Bromide
			5.3.3.1 Lowering Reaction Temperature
			5.3.3.2 Improving Product Yield
		5.3.4 Magnesium Chloride
		5.3.5 Magnesium Bromide
		5.3.6 Calcium Chloride
			5.3.6.1 Reaction with NaBH4
			5.3.6.2 Trapping Fluoride
		5.3.7 Zinc Chloride
		5.3.8 Zinc Acetate
	5.4 Assortment of Scavengers
		5.4.1 Catechol as Methyl Cation Scavenger
		5.4.2 Anisole as Quinone Methide Scavenger
		5.4.3 Ethyl Acetate as Hydroxide Scavenger
		5.4.4 Ethyl Trifluoroacetate as Hydroxide Scavenger
		5.4.5 Ethyl Trifluoroacetate as Benzylamine Scavenger
		5.4.6 Ethyl Pivalate as Hydroxide Scavenger
		5.4.7 Trimethyl Orthoformate as Water Scavenger
		5.4.8 Thionyl Chloride as Water Scavenger
		5.4.9 1-Hexene
			5.4.9.1 As HCl Scavenger
			5.4.9.2 As Diimide (NH=NH) Scavenger
		5.4.10 Epoxyhexene as HBr Scavenger
		5.4.11 Acetic Anhydride as Aniline Scavenger
		5.4.12 Amberlite CG50 as Ammonia Scavenger
		5.4.13 3-Pentanone as HCN Scavenger
	5.5 Other Additives
		5.5.1 Imidazole
		5.5.2 Triethylamine Hydrochloride
		5.5.3 Methyl Trioctylammonium Chloride
		5.5.4 Chlorotrimethylsilane
			5.5.4.1 Julia Olefination
			5.5.4.2 Michael Addition
		5.5.5 Chlorotriethylsilane
		5.5.6 Bis(trimethylsilyl)acetamide
		5.5.7 Water
			5.5.7.1 Wadsworth–Emmons Reaction
			5.5.7.2 O-Alkyation
			5.5.7.3 Methylation Reaction
			5.5.7.4 Enolization Reaction
			5.5.7.5 Pyrazole Synthesis
			5.5.7.6 Copper-Mediated Intramolecular Cyclization
			5.5.7.7 Crystallization-Induced Dynamic Resolution of Amine
		5.5.8 Hydroquinone
			5.5.8.1 Preclusion of Oxidation
			5.5.8.2 Preclusion of Polymerization
		5.5.9 Trimethyl Borate
		5.5.10 Isobutanoic Anhydride
		5.5.11 1,1-Dimethyl-2-Phenylethyl Acetate
		5.5.12 Alcohols
			5.5.12.1 Ethanol
			5.5.12.2 2-Propanol
			5.5.12.3 tert-Butanol
			5.5.12.4 Ethylene Glycol
			5.5.12.5 1,2-Propanediol
			5.5.12.6 Neopentyl Glycol
		5.5.13 1,4-Dioxane
		5.5.14 Benzotriazole
		5.5.15 1-Hydroxybenzotriazole
		5.5.16 1,4-Dibromobutane
		5.5.17 Diethanolamine
			5.5.17.1 Improving Selectivity
			5.5.17.2 Boranate Ester Exchange
		5.5.18 Trimethyl Phosphite
		5.5.19 Diethyl Phosphite
		5.5.20 4-Trifluoromethyl Benzaldehyde
Chapter 6 Process Optimization of Catalytic Reactions
	6.1 Suzuki–Miyaura Reaction
		6.1.1 Catalyst Poisoning
			6.1.1.1 Catalyst Poisoning by Sulfhydryl Group
			6.1.1.2 Catalyst Poisoning by Unknown Impurities
		6.1.2 Catalyst Precipitation
		6.1.3 Instability of Arylboronic Acids
			6.1.3.1 Buchwald’s Precatalyst
			6.1.3.2 Tridentate Ligand
			6.1.3.3 Alternative Negishi Coupling Reaction
			6.1.3.4 Alternative Kumada Coupling Reaction
			6.1.3.5 Using Protecting Group
			6.1.3.6 Using Trifluoroborate Salt
		6.1.4 Problems Associated with Base
			6.1.4.1 Protodeboronation
			6.1.4.2 Formation of Carbamate
		6.1.5 Dimer Impurity
			6.1.5.1 Reducing Arylboronic Acid Concentration
			6.1.5.2 Reducing Free Pd(II) Concentration
	6.2 Negishi Reaction
		6.2.1 Poor Product Yield
		6.2.2 Thick Reaction Mixture
	6.3 Heck Reaction
		6.3.1 Enhancing Palladium-Catalyst Stability
		6.3.2 Improving Selectivity
	6.4 Sonogashira Reaction
		6.4.1 Reducing Palladium-Catalyst Loading
		6.4.2 Improving Reactivity
	6.5 Catalytic Deprotection
		6.5.1 Debenzylation
			6.5.1.1 Catalyst Poisoning
			6.5.1.2 Erosion of Chiral Purity
		6.5.2 Catalytic Removal of Cbz Group
			6.5.2.1 Impurity Formation
			6.5.2.2 Pd(OAc)2/Charcoal System
	6.6 Catalytic Hydrogenation
		6.6.1 Reduction of Nitro Group
			6.6.1.1 Palladium-Catalyzed Hydrogenation
			6.6.1.2 Nickel-Catalyzed Hydrogenation
			6.6.1.3 Platinum-Catalyzed Hydrogenation
			6.6.1.4 Catalytic Transfer Hydrogenation
		6.6.2 Reduction of Pyridine Ring
		6.6.3 Reduction of α,β-Unsaturated Compounds
		6.6.4 Enantioselective Reduction of Quinolines
		6.6.5 Reduction of Nitrile
		6.6.6 Reduction of Azide
	6.7 Other Catalytic Reactions
		6.7.1 Cu(I)-Catalyzed Reaction
		6.7.2 Decarboxylative Bromination
		6.7.3 Formation of Acid Chloride
		6.7.4 Catalytic Dechlorination
		6.7.5 Two-Phase Reactions
			6.7.5.1 Enhancement of Reaction Rate
			6.7.5.2 Suppressing Side Reactions
			6.7.5.3 Reducing the Amount of Toxic Sodium Cyanide
			6.7.5.4 Replacing DMSO Solvent in SNAr Reaction
			6.7.5.5 Two-Phase Reactions without PTC
		6.7.6 Deoxybromination
		6.7.7 Regioselective Chlorination
		6.7.8 Regioselective Magnesiation
		6.7.9 Amide Preparation
			6.7.9.1 NaOMe as Catalyst
			6.7.9.2 HOBt as Catalyst
		6.7.10 Synthesis of Indole
		6.7.11 N-Methylation Reaction
		6.7.12 Baylis−Hillman Reaction
		6.7.13 Catalytic Wittig Reaction
		6.7.14 Palladium-Catalyzed Rearrangement
Chapter 7 Process Optimization of Problematic Reactions
	7.1 Temperature Effect
		7.1.1 Metal–Halogen/Hydrogen Exchange
			7.1.1.1 Magnesium–Bromine Exchange
			7.1.1.2 Lithium–Bromine Exchange
			7.1.1.3 Lithium–Hydrogen Exchange
		7.1.2 Ring Expansion
		7.1.3 Synthesis of Pyrazole
		7.1.4 Synthesis of Oxadiazole
		7.1.5 Cross-Coupling Reaction
		7.1.6 Vilsmeier Reaction
		7.1.7 Oxidative Hydrolysis
	7.2 Pressure Effect
		7.2.1 Nitrile Reduction
		7.2.2 [3+2]-Cycloaddition
	7.3 Low Product Yields
		7.3.1 Incomplete Reactions
			7.3.1.1 Poor Mass Transfer
			7.3.1.2 Undesired Physical Properties
			7.3.1.3 High Flow Rate of Nitrogen
		7.3.2 Loss of Product During Isolation
		7.3.3 Side Reactions of Starting Materials
			7.3.3.1 Decomposition of N-Oxide
			7.3.3.2 Decomposition of Hydrazone
			7.3.3.3 Hydrolysis of Chlorotriazine
		7.3.4 Side Reactions of Intermediates
			7.3.4.1 Sandmeyer Reaction
			7.3.4.2 Hofmann Rearrangement
			7.3.4.3 Tosylation/Amination Reactions
			7.3.4.4 Synthesis of Cyclic Sulfimidate
			7.3.4.5 Cyclization/Ring Expansion
			7.3.4.6 Michael Addition
		7.3.5 Side Reactions of Products
			7.3.5.1 Decomposition of Amide
			7.3.5.2 Side Reactions of 1,4-Isochromandione
			7.3.5.3 Side Reactions of Oxirane
	7.4 Reaction Problems Associated with Impurities
		7.4.1 Residual MTBE
		7.4.2 Residual Water
			7.4.2.1 Bromination Reaction
			7.4.2.2 SNAr Fluorination Reaction
			7.4.2.3 Copper-Catalyzed C−N Bond Formation
		7.4.3 Residual Oxygen
			7.4.3.1 Oxidative Dimerization
			7.4.3.2 Oxidation of Phenylenediamine
		7.4.4 Residual Zinc
	7.5 Reactions with Poor Selectivity
		7.5.1 CIDR to Improve cis/trans Selectivity
		7.5.2 Two-Step Process to Mitigate Racemization
		7.5.3 Reduction of Carboxylic Acid
		7.5.4 Sacrificial Reagent in Regioselective Acetylation
		7.5.5 Converting Side Product to Product
		7.5.6 Enamine Exchange
		7.5.7 Carry-Over Approach
		7.5.8 Friedel–Crafts Reaction
		7.5.9 Reduction of Carbon–Carbon Double Bond
		7.5.10 Reduction of Nitrile
	7.6 Protecting Group
		7.6.1 Acetyl Group
		7.6.2 Trimethylsilyl Group
			7.6.2.1 Protection of Terminal Alkyne
			7.6.2.2 Protection of Enolate
			7.6.2.3 Protection of Hydroxyl Group
		7.6.3 Cyanoethyl Group
		7.6.4 Benzhdryl Group
	7.7 Polymerization Issues
		7.7.1 Polymerization of Chloroacetyl Chloride
		7.7.2 Polymerization of Acid Chloride
		7.7.3 Polymerization of Chloroacrylonitrile
		7.7.4 Polymerization of Enone
		7.7.5 Polymerization of Pentasulfide
	7.8 Activation of Functional Groups
		7.8.1 Activation of Aniline Nitrogen
		7.8.2 Activation of Amide
		7.8.3 Activation of Lactol
		7.8.4 C–H Bond Activation
	7.9 Deactivation of Functional Groups
		7.9.1 Deactivation of Amino Group
		7.9.2 Deactivation of Sulfonyl Chloride
	7.10 Optimization of Telescoped Process
Chapter 8 Hazards of Oxidation and Reduction Reactions
	8.1 Oxidation Reactions
		8.1.1 Oxidation of Olefins
			8.1.1.1 Oxidation with mCPBA
			8.1.1.2 Oxidation with Sodium Perborate
			8.1.1.3 Oxidation with Ozone
			8.1.1.4 Oxidation with KMnO4
			8.1.1.5 Oxidation with 9-BBN/H2O2-NaOH
		8.1.2 Oxidation of Alcohols
			8.1.2.1 Py·SO3/DMSO System
			8.1.2.2 Ac2O/DMSO System
			8.1.2.3 TFAA/DMSO/TEA System
			8.1.2.4 TEMPO/NaOCl System
			8.1.2.5 RuCl3/NaOCl System
			8.1.2.6 Sulfinimidoyl Chloride
			8.1.2.7 2-Amadamantane N-Oxide/CuCl
		8.1.3 Oxidation of Aldehydes to Acids
		8.1.4 Oxidation of Sulfides to Sulfoxides
		8.1.5 Oxidation of Sulfides to Sulfones
			8.1.5.1 Oxidation with Oxone
			8.1.5.2 Oxidation with Sodium Perborate
			8.1.5.3 Oxidation with Sodium Periodate
			8.1.5.4 Oxidation with NaOCl
			8.1.5.5 Oxidation with H2O2/Na2WO4
			8.1.5.6 Oxidation with TMSCl/KNO3
		8.1.6 Other Oxidative Reactions
			8.1.6.1 Dakin Oxidation
			8.1.6.2 Hydroxylation
			8.1.6.3 Oxidation of Phosphite
	8.2 Reduction Reactions
		8.2.1 Reduction with NaBH4-Based Agents
			8.2.1.1 Reduction of Acids
			8.2.1.2 Reduction of Esters
			8.2.1.3 Reduction of Amides
			8.2.1.4 Reduction of Imine
		8.2.2 Reduction with Borane
			8.2.2.1 BH3·THF Complex
			8.2.2.2 BH3·DMS Complex
			8.2.2.3 BH3·Amine Complex
		8.2.3 Reduction with Lithium Aluminum Hydride
Chapter 9 Other Hazardous Reactions
	9.1 Catalytic Cross-Coupling Reactions
		9.1.1 Heck Reaction
		9.1.2 Negishi Cross-Coupling Reaction
	9.2 Blaise Reaction
	9.3 Ritter Reaction
	9.4 Hydrogen–Lithium Exchange
	9.5 Halogenation Reactions
		9.5.1 Chlorination Reaction
		9.5.2 Fluorination Reactions
			9.5.2.1 Deoxyfluorination
			9.5.2.2 Hydrofluorination of Aziridines
			9.5.2.3 Electrophilic Fluorination
		9.5.3 Deoxychlorination
			9.5.3.1 Deoxychlorination of Triazinone
			9.5.3.2 Deoxychlorination of Quinazolone
			9.5.3.3 Deoxychlorination of Triazine
			9.5.3.4 Deoxychlorination of 4,6-Dihydroxypyrimidine
			9.5.3.5 Deoxychlorination of 6,7-D​ihydr​othie​no[3.​2-d]p​yrimi​dine-​2,4-d​iol
			9.5.3.6 Deoxychlorination of 6-Chlorophthalazin-1-ol
	9.6 Thiocyanation
	9.7 Gas-Involved Reactions
		9.7.1 Boc Protection
		9.7.2 N-Acetylation
		9.7.3 Boc Deprotection
			9.7.3.1 Selective Deprotection with TFA
			9.7.3.2 Deprotection with NaOH
		9.7.4 N-tert-Butylamide Formation
		9.7.5 Deprotection of N-tert-Butyl Group
		9.7.6 Decarboxylative Ethoxide Elimination
		9.7.7 Deprotonation
		9.7.8 SN2 Reaction
		9.7.9 Chlorination Reaction
	9.8 Darzens Reaction
	9.9 Hofmann Rearrangement
	9.10 Friedel–Crafts Reaction
Chapter 10 Hazardous Reagents
	10.1 Diazonium Salts
		10.1.1 Hydrolysis of Diazonium Salt
		10.1.2 Diazonium Salt-Involved Cyclization
		10.1.3 Nitroindazole Formation
		10.1.4 Synthesis of Trifluoromethyl-Substituted Cyclopropanes
		10.1.5 Sandmeyer Reaction
	10.2 Azide Compounds
		10.2.1 Nucleophilic Displacement
			10.2.1.1 Synthesis of 3,4-Dihydropyrrole
			10.2.1.2 Synthesis of 3-(1,2-Diarylbutyl) Azide
			10.2.1.3 Preparation of Aryl (Alkyl) Azides
		10.2.2 Nucleophilic Addition
			10.2.2.1 Synthesis of Tetrazole
			10.2.2.2 Synthesis of Triazole
			10.2.2.3 Synthesis of Carbamate
			10.2.2.4 Curtius Rearrangement
	10.3 Hydrazine
		10.3.1 Wolff–Kishner Reduction
			10.3.1.1 Reduction of Asymmetric Ketone
			10.3.1.2 Reduction of Symmetric Ketone
			10.3.1.3 Synthesis of Indazole
			10.3.1.4 Synthesis of Pyrazole
			10.3.1.5 Preparation of Alkylamine
		10.3.2 Preparation of Aryl (or Alkyl) Hydrazines and Related Reactions
			10.3.2.1 Preparation of 5-Hydrazinoquinoline
			10.3.2.2 Synthesis of Aminopyrazole
			10.3.2.3 Fischer Indole Synthesis
	10.4 Hydroxylamine
	10.5 Oxime
	10.6 N-Oxide
	10.7 Nitro Compounds
		10.7.1 Preparation of Nitro Compounds by Nitration
			10.7.1.1 NaNO3/TFA/TFAA Nitration System
			10.7.1.2 KNO3/TFA Nitration System
			10.7.1.3 Use of Acetyl Nitrate
			10.7.1.4 NaNO3/Py∙SO3 System
			10.7.1.5 Stepwise Nitration
			10.7.1.6 Use of Chlorotrimethylsilane and Nitrate Salt
			10.7.1.7 Metal-Catalyzed Nitration
			10.7.1.8 N-Nitro Intermediate Rearrangement
		10.7.2 Hazardous Reactions of Nitro Compounds
			10.7.2.1 Unstable Nitrophenate
			10.7.2.2 Accumulation of Reactant
	10.8 Volatile Organic Compounds
		10.8.1 Ethylene Oxide
		10.8.2 Acetylene
		10.8.3 Halogenated Methyl Ethers
			10.8.3.1 Bis(bromomethyl)ether
			10.8.3.2 Chloromethyl Ethyl Ether
		10.8.4 Methyl Iodide
			10.8.4.1 N-Methylation of Heterocycles
			10.8.4.2 N-Methylation of Amide
			10.8.4.3 N-Methylation of 2-Methoxypyridine Derivative
		10.8.5 Methyl Bromide
	10.9 High Energy Compounds
		10.9.1 5-Hydroxybenzofurazan
		10.9.2 1-Hydroxybenzotriazole (HOBt)
			10.9.2.1 Ethyl Acetate/Water Two-Phase System
			10.9.2.2 Replacement of HOBt with 2-Hydroxypyridine
			10.9.2.3 Replacement of HOBt with 2-Chloro-4,6-dimethoxy-1,3,5-triazine
	10.10 Toxic Compounds
		10.10.1 Zinc Cyanide
		10.10.2 Potassium Ferrocyanide
		10.10.3 Acetone Cyanohydrin
			10.10.3.1 Epoxide Opening
			10.10.3.2 Michael Addition
	10.11 Corrosive Reagent
Chapter 11 Grignard Reagent and Related Reactions
	11.1 Preparation Of Grignard Reagents
		11.1.1 Use of Chlorotrimethylsilane
			11.1.1.1 Preparation of 4-Fluoro-2-methylphenylmagnesium Bromide
			11.1.1.2 Preparation of (4-(2​-(Pyr​rolid​in-1-​yl)et​hoxy)​pheny​l)mag​nesiu​m Bromide
		11.1.2 Use of Diisobutylaluminum Hydride
		11.1.3 Use of Diisobutylaluminum Hydride/Iodine
		11.1.4 Use of Grignard Reagents
			11.1.4.1 Use of MeMgCl
			11.1.4.2 Use of EtMgBr
			11.1.4.3 Use of Heel
		11.1.5 Use of Alkyl Halides
			11.1.5.1 Use of Iodomethane
			11.1.5.2 Use of 1,2-Dibromoethane
		11.1.6 Halogen–Magnesium Exchange
			11.1.6.1 Preparation of Trifluoromethyl Substituted Aryl Grignard Reagents
			11.1.6.2 Preparation of N-Methylpyrazole Grignard Reagent
			11.1.6.3 Preparation of (4-Bromonaphthalen-1-yl)magnesium Chloride
			11.1.6.4 Magnesium-ate Complex
			11.1.6.5 Alkylmagnesium Alkoxides
	11.2 Reactions of Grignard Reagents
		11.2.1 Reactions with Ketones
			11.2.1.1 Vinyl Grignard Reagents
			11.2.1.2 Aryl Grignard Reagents
			11.2.1.3 Methylmagnesium Bromide
		11.2.2 Reaction with Acid Chloride
		11.2.3 Reaction with Dimethylformamide
		11.2.4 Reaction with Weinreb Amide
		11.2.5 Michael Addition
		11.2.6 Reaction with Epoxide
		11.2.7 Other Grignard Reagent-Involved Reactions
			11.2.7.1 Ramberg−Bäcklund Reaction
			11.2.7.2 Synthesis of Chiral δ-Ketoamides
			11.2.7.3 Access to o-Quinone Methide Intermediates
Chapter 12 Challenging Reaction Intermediates
	12.1 Effect of Intermediates
		12.1.1 In Telescoping Steps
		12.1.2 In Designing Synthetic Route
		12.1.3 In Agitation
		12.1.4 In Product Isolations/Purifications
			12.1.4.1 Pictet–Spengler Reaction
			12.1.4.2 Imide Reduction
		12.1.5 In Improving Product Yields
			12.1.5.1 Amide Formation
			12.1.5.2 Synthesis of Hydroxybenzisoxazole
			12.1.5.3 Synthesis of Vinyl Bromide
		12.1.6 In Improving Operational Profile
	12.2 MONITORING INTERMEDIATES
		12.2.1 Direct Monitoring Intermediate
		12.2.2 Indirect Monitoring Intermediates
			12.2.2.1 Derivatization of Acylimidazolide
			12.2.2.2 Derivatization of N-Methylene Bridged Dimer
Chapter 13 Protecting Groups
	13.1 Protection of Hydroxyl Group
		13.1.1 Prevention of Side Reactions
			13.1.1.1 Friedel–Crafts Alkylation
			13.1.1.2 Removal of Trifluoromethanesulfonyl Group
			13.1.1.3 SN2 Reaction
		13.1.2 Increasing Catalyst Activity
		13.1.3 Separation of Diol Diastereomers
		13.1.4 Developing Telescoped Process
	13.2 Protection of Amino Group
		13.2.1 Protection with (4-Nitrophenyl)sulfonyl Group
		13.2.2 Protection with 2,5-Hexanedione
		13.2.3 Protection with Aldehyde
		13.2.4 Protection with 4-Methyl-2-Pentanone
		13.2.5 Protection with Methylene Group
		13.2.6 Protection with tert-Butyloxycarbonyl Group
		13.2.7 Protection with 2,2,6​,6-Te​trame​thylp​iperi​din-1​-ylox​ycarb​onyl Group
		13.2.8 Protection with Trimethylsilyl Group
	13.3 Protection of Carboxylic Acid
	13.4 Protection of Aldehydes And Ketones
		13.4.1 Protection of Aldehyde
		13.4.2 Protection of Ketones
			13.4.2.1 Protection with Methanol
			13.4.2.2 Protection with Ethylene Glycol
			13.4.2.3 Using Internal Protection Approach
	13.5 Protection of Acetylene
	13.6 Unusual Protecting Groups
		13.6.1 Boron-Containing Protecting Groups
			13.6.1.1 Borane Complex
			13.6.1.2 Boronic Acids
		13.6.2 N-Nitro Protecting Group
			13.6.2.1 Regioselective Nitration
			13.6.2.2 Activation of Aniline
		13.6.3 Halogen as Protecting Group
			13.6.3.1 Bromine Protecting Group
			13.6.3.2 Chlorine Protecting Group
Chapter 14 Telescope Approach
	14.1 Improving Process Safety
		14.1.1 Chloroketone Intermediate
		14.1.2 Lachrymatory Chloromethacryate Intermediate
		14.1.3 Chloromethyl Benzoimidazole
		14.1.4 Pyridine N-Oxide
		14.1.5 Benzyl Bromide
		14.1.6 Methyl Iodide
	14.2 Processing Problematic Intermediates
		14.2.1 Oily Intermediates
		14.2.2 Hygroscopic Intermediate Solid
		14.2.3 Hygroscopic Amine Salt
		14.2.4 High Water-Soluble Intermediate
		14.2.5 Unstable Intermediates
			14.2.5.1 Heteroaryl Chloride
			14.2.5.2 Toluenesulfonate Intermediate
			14.2.5.3 Aldehyde Intermediates
			14.2.5.4 Unstable Alkene Intermediates
			14.2.5.5 Unstable β-Hydroxyketone
	14.3 Improving Filtration
		14.3.1 Preparation of Amide
		14.3.2 Synthesis of β-Nitrostyrene
	14.4 Telescoping Catalytic Reactions
		14.4.1 Imine Reduction/Debenzylation
		14.4.2 Debromination/Suzuki Cross-Coupling Reaction
	14.5 Improving Overall Product Yields
		14.5.1 Synthesis of Spirocyclic Hydantoin
		14.5.2 Transition Metal-Catalyzed Cross-Coupling Reaction
	14.6 Reduction In Processing Solvents
		14.6.1 Toluene as the Common Solvent
		14.6.2 DMF as the Common Solvent
		14.6.3 EtOAc as the Common Solvent
		14.6.4 THF as the Common Solvent
		14.6.5 EtOH/THF as the Common Solvent
	14.7 Other Telescope Processes
		14.7.1 Bromination/Isomerization Reactions
		14.7.2 Fisher Indole Synthesis/Ring Rearrangemet
		14.7.3 Ylide Formation/Wittig Reaction/Cycloaddition
		14.7.4 Overman Rearrangement
		14.7.5 Acyla​tion/​Reduc​tion/​O-Alk​ylati​on/Br​omina​tion
		14.7.6 Synthesis of (–)-Oseltamivir
	14.8 Limitation of the Telescope Approach
		14.8.1 Lack of Purity Control
		14.8.2 Poor Product Yield
		14.8.3 Lack of Compatibility
Chapter 15 Design of New Synthetic Route
	15.1 Improving Process Safety
		15.1.1 Toxic Reagents and Intermediates
			15.1.1.1 Trimethylsilyl Cyanide as Cyanide Source
			15.1.1.2 CuCN in Sandmeyer Reaction
			15.1.1.3 Toxic Reagent (HF)
			15.1.1.4 Toxic Benzyl Halides
			15.1.1.5 Phosphorus Oxychloride
			15.1.1.6 Sulfonyl Chloride Intermediate
		15.1.2 High Energy Reagents
			15.1.2.1 Azide-Involved Cycloaddition
			15.1.2.2 Diazonium Salt-Involved Indazole Formation
			15.1.2.3 Lithium Aluminum Hydride Reduction
		15.1.3 Undesired Reaction Conditions
			15.1.3.1 Acylation Reaction
			15.1.3.2 SNAr Reaction
	15.2 Improving Product Yield
		15.2.1 Cycloaddition Reaction
		15.2.2 Resolution/Amide Formation/Cyclization
		15.2.3 Chlorine Replacement
		15.2.4 Wittig Reaction
	15.3 Improving Reaction Selectivity
		15.3.1 Chlorination
		15.3.2 Iodination
		15.3.3 N-Alkylation Reaction
		15.3.4 Formation of Seven-Membered Ring
	15.4 Other Route Design Strategies
		15.4.1 Using Less Expensive Starting Material
		15.4.2 Using Convergent Approach
			15.4.2.1 Decarboxylative Cross-Coupling Reaction
			15.4.2.2 Synthesis of Chiral Amide
		15.4.3 Step-Economy Synthesis
			15.4.3.1 Synthesis of Keto–Sulfone Intermediate
			15.4.3.2 Synthesis of Bendamustine
		15.4.4 Atom-Economy Synthesis
			15.4.4.1 Synthesis of Carboxylic Acid
			15.4.4.2 Stereoselective Synthesis of Diol
		15.4.5 Alternating Bond-Formation Order
		15.4.6 Minimizing Oxidation Stage Change
			15.4.6.1 Minimizing Nitrogen Oxidation Stage Adjustment
			15.4.6.2 Minimizing Carbon Oxidation Stage Adjustment
		15.4.7 Coupling Reagent-Free Amide Formation
		15.4.8 Preventing Etching of Glass Reactor
Chapter 16 Stereochemistry
	16.1 Asymmetric Synthesis
		16.1.1 Asymmetric Catalysis
			16.1.1.1 Desymmetrization of Anhydride
			16.1.1.2 Asymmetric Reduction of Enone
			16.1.1.3 Sharpless Asymmetric Dihydroxylation
			16.1.1.4 Enantioselective Alkylation
			16.1.1.5 Enantioselective Protonation of Enamines
			16.1.1.6 CuH-Catalyzed Synthesis of 2,3-Disubstituted Indolines
			16.1.1.7 CuH-Catalyzed Synthesis of Chiral Amines
		16.1.2 Chiral Pool Synthesis
			16.1.2.1 Condensation of Indoline with Benzaldehyde
			16.1.2.2 Claisen Rearrangement
		16.1.3 Use of Chiral Auxiliaries
			16.1.3.1 Diastereoselective Diels–Alder Reaction
			16.1.3.2 Diastereoselective Synthesis of Boronic Acid
			16.1.3.3 Synthesis of Chiral (S)-Pyridyl Amine
			16.1.3.4 Synthesis of L-Carnitine
	16.2 Kinetic Resolution
		16.2.1 Hydrolytic Kinetic Resolution of Epoxide
		16.2.2 Resolution of Diol via Stereoselective Esterification
		16.2.3 Resolution of Phosphine Ligand via Stereoselective Ligand Exchange
		16.2.4 Resolution of Diastereomeric Mixture via Salt Formation
	16.3 Enzymatic Resolution
		16.3.1 Resolution of Esters
			16.3.1.1 Resolution of Methyl Piperidine-4-Carboxylate
			16.3.1.2 Resolution of Ethyl α-Amino Acetate
			16.3.1.3 Resolution of Diazepane Acetate
		16.3.2 Resolution of Amino Acids
		16.3.3 Resolution Secondary Alcohols
	16.4 Separation with Chiral Chromatography
	16.5 Classical Resolution
		16.5.1 Resolution of Racemic Acid
		16.5.2 Resolution of Racemic Bases
			16.5.2.1 Use of Optical Pure tert-Leucine Derivative
			16.5.2.2 Use of di-p-Toluoyl-D-Tartaric Acid
			16.5.2.3 Use of bis((S)-Mandelic Acid)-3-Nitrophthalate
		16.5.3 Resolution of Ketone
		16.5.4 Resolution of Racemic Ammonium Salt
		16.5.5 Diastereomer Salt Break
		16.5.6 Examples of Diastereomeric Salts
	16.6 Dynamic Kinetic Resolution
		16.6.1 DKR via Imine Intermediates
			16.6.1.1 3,5-Dichlorosalicylaldehyde Catalyst
			16.6.1.2 2-Hydroxy-6-(hydroxymethyl)benzaldehyde Catalyst
			16.6.1.3 Picolinaldehyde Catalyst
			16.6.1.4 DRK without Catalyst
			16.6.1.5 Iridium-Involved DKR
		16.6.2 DKR via Enolate Intermediates
			16.6.2.1 Enolization with Base
			16.6.2.2 Enolization without Base
		16.6.3 DKR via Diastereomeric Salt Formation
		16.6.4 DKR of Six-Membered Ring Systems
			16.6.4.1 Epimerization of cis-Isomer to trans-Isomer
			16.6.4.2 Isomerization of Cyclohexane Derivative
			16.6.4.3 Fischer Indole Synthesis
		16.6.5 DKR via Reversible Bond Formation
			16.6.5.1 Reversible C−C Bond Formation
			16.6.5.2 Reversible C−N Bond Formation
			16.6.5.3 Reversible C−O Bond Formation
			16.6.5.4 Reversible C−S Bond Formation
		16.6.6 Other DKR Methods
			16.6.6.1 Bromide-Catalyzed DKR
			16.6.6.2 Resolution of Sulfoxide
			16.6.6.3 Dynamic Kinetic Isomerization via Ir-Catalyzed Internal Redox Transfer Hydrogenation
			16.6.6.4 Vinylogous Dynamic Kinetic Resolution
		16.6.7 Various DKR Examples
Chapter 17 Various Quenching Strategies
	17.1 Acidic Quenching
		17.1.1 Removal of Magnesium Salts
			17.1.1.1 Reaction of Grignard Reagent with Weinreb Amide
			17.1.1.2 Weinreb Amide Formation
		17.1.2 Removal of Zinc
	17.2 Basic Quenching
		17.2.1 Suppressing Thiadiazole Isomerization
		17.2.2 Prevention of Etching Glass Reactor
			17.2.2.1 Quenching with Sodium Bicarbonate
			17.2.2.2 Quenching with Sodium Hydroxide
	17.3 Anhydrous Quenching
		17.3.1 Removal of Zinc By-Product
		17.3.2 Avoiding Insoluble Organic Mass
		17.3.3 Avoiding Degradation of Product
			17.3.3.1 Use of Ethyl Acetate
			17.3.3.2 Use of Diisopropylethylamine
		17.3.4 Decomposition of Excess Reagent
			17.3.4.1 Use of Methanol
			17.3.4.2 Use of Silicon Dioxide
	17.4 Oxidative Quenching
		17.4.1 Oxidation of Hydrogen Iodide
		17.4.2 Oxidation of Pinacol
	17.5 Reductive Quenching
		17.5.1 Restroying tert-Butyl Hydroperoxide
		17.5.2 Destroying Hydrogen Peroxide
		17.5.3 Destroying Oxone
		17.5.4 Destroying Halogens
			17.5.4.1 Use of Ascorbic Acid to Destroy Bromine
			17.5.4.2 Use of Ascorbic Acid to Destroy Iodine
	17.6 Disproportionation Quenching
	17.7 Reverse Quenching
		17.7.1 Control of Impurity Formation
			17.7.1.1 Preparation of Ketone
			17.7.1.2 Preparation of Aldehyde
			17.7.1.3 Grignard Reaction
		17.7.2 Removal of Excess Reagent
		17.7.3 Increase in Conversion
		17.7.4 Suppressing Product Hydrolysis
		17.7.5 Prevention of Product Decomposition
		17.7.6 Prevention of Emulsion
			17.7.6.1 Copper-Catalyzed Amination
			17.7.6.2 Lithium Aluminum Hydride Reduction
		17.7.7 Prevention of Exothermic Runaway
	17.8 Concurrent Quenching
	17.9 Double Quenching
		17.9.1 Acetone/HCl Combination
			17.9.1.1 Ketone Reduction
			17.9.1.2 SNAr Reaction
		17.9.2 Acetone/Citric Acid Combination
		17.9.3 Acetone/MeOH/H2O Combination
		17.9.4 Ethyl Acetate/Water Combination
		17.9.5 Ethyl Acetate/Tartaric Acid Combination
		17.9.6 Ethyl Acetate/Aqueous Sodium Bicarbonate Combination
		17.9.7 Isopropanol/Citric Acid Combination
		17.9.8 Methyl Formate/Aqueous HCl Combination
	17.10 Reactive Quenching
Chapter 18 Various Isolation and Purification Strategies
	18.1 Extraction
		18.1.1 Aqueous Extractions
			18.1.1.1 Use of Methyl tert-Butyl Ether
			18.1.1.2 Use of 2-Methyltetrahydrofuran
			18.1.1.3 Use of Ethyl Acetate
			18.1.1.4 Use of Dodecane
			18.1.1.5 Use of n-Butanol
		18.1.2 Anhydrous Extraction
			18.1.2.1 Heptane/Acetonitrile System
			18.1.2.2 Heptane–Cyclohexane/N-Methyl-2-pyrrolidone System
		18.1.3 Double Extraction
	18.2 Direct Isolation
		18.2.1 Use of Cooling
			18.2.1.1 Direct Isolation from Isopropanol
			18.2.1.2 Direct Isolation from Ethyl acetate
			18.2.1.3 Direct Isolation from Isopropyl Acetate
			18.2.1.4 Direct Isolation from Acetonitrile
		18.2.2 Use of Anti-Solvent
			18.2.2.1 Adding Water to Acetic Acid
			18.2.2.2 Addition of Water to Dimethylformamide
			18.2.2.3 Addition of Water to Dimethylacetamide
			18.2.2.4 Addition of Water to Dimethylsulfoxide
			18.2.2.5 Addition of Methanol to Dimethylsulfoxide
		18.2.3 Use of Cooling and Anti-Solvent
			18.2.3.1 Isolation of Sonogashira Product
			18.2.3.2 Isolation of 6-Chlorophthalazin-1-ol
			18.2.3.3 Isolation of SNAr Product
		18.2.4 Use of Neutralization
		18.2.5 Use of Salt Formation
		18.2.6 Other Direct Isolation Approaches
			18.2.6.1 Direct Drop Process
			18.2.6.2 Removal of By-Product by Direct Drop Approach
	18.3 Filtration Problems
		18.3.1 Metal-Related Filtration Problems
			18.3.1.1 Copper-Related Filtration Problems
			18.3.1.2 TiCl4-Related Problems
		18.3.2 Small Particle Size
			18.3.2.1 Addition of Acetic Acid
			18.3.2.2 Addition of Isopropanol
			18.3.2.3 Temperature Control
			18.3.2.4 Polymorph Transformation
		18.3.3 Low-Melting Solid
	18.4 Purification Strategies
		18.4.1 Use of Salt Formation
			18.4.1.1 Hydrochloric Acid Salts
			18.4.1.2 Acetic Acid Salt
			18.4.1.3 (R)-Mandelate Salt
			18.4.1.4 L-Tartaric Acid Salt
			18.4.1.5 2-Picolinic Acid Salt
			18.4.1.6 Toluenesulfonic Acid Salts
			18.4.1.7 Sodium Salt
			18.4.1.8 Potassium Salt
			18.4.1.9 Magnesium Salt
			18.4.1.10 Dicyclohexylamine Salts
			18.4.1.11 Quaternary Salt
		18.4.2 Derivatization
			18.4.2.1 Isolation/Purification of Aldehydes
			18.4.2.2 Isolation/Purification of Amine
			18.4.2.3 Isolation/Purification of Diol
			18.4.2.4 Isolation/Purification of Amino Diol
		18.4.3 Various Approaches for Impurity Removal
			18.4.3.1 Removal of Ammonium Chloride
			18.4.3.2 Removal of 9-BBN
			18.4.3.3 Removal of Acetic Acid
			18.4.3.4 Removal of (1E,3E)-Dienol Phosphate
	18.5 Crystallization
		18.5.1 Seed-Induced Crystallization
			18.5.1.1 Avoiding Uncontrolled Crystallization
			18.5.1.2 Avoiding Oiling Out
			18.5.1.3 Control of Exothermic Crystallization
			18.5.1.4 Control of Polymorph
		18.5.2 Reactive Crystallization
			18.5.2.1 Deprotection/Salt Formation
			18.5.2.2 Enamine Preparation
			18.5.2.3 Free Acid Formation
			18.5.2.4 Boc Protection
			18.5.2.5 Limitations of Reactive Crystallization
		18.5.3 Other Crystallization Approaches
			18.5.3.1 Addition of Water
			18.5.3.2 Addition of Polymer
			18.5.3.3 Crystallization from Extraction Solvent
			18.5.3.4 Three-Solvent System
			18.5.3.5 Derivatization
			18.5.3.6 Control of Crystal Size Distribution
			18.5.3.7 Cocrystallization
Chapter 19 Methods for Residual Metal Removal
	19.1 Removal of Residual Palladium
		19.1.1 Crystallization
			19.1.1.1 Crystallization in the Presence of Cysteine
			19.1.1.2 Crystallization in the Presence of N-Acetylcysteine
		19.1.2 Extraction
			19.1.2.1 Liquid–Liquid Transportation
			19.1.2.2 Extractive Precipitation
		19.1.3 Adsorption
			19.1.3.1 Activated Carbon
			19.1.3.2 MP–TMT
			19.1.3.3 Deloxan THP-II
			19.1.3.4 Smopex 110
		19.1.4 Distillation
		19.1.5 Other Methods
			19.1.5.1 Adsorption–Crystallization
			19.1.5.2 Adsorption–TMT Wash
			19.1.5.3 Protecting Group
			19.1.5.4 Salt Formation
		19.1.6 Conclusion
	19.2 Removal of Residual Copper
		19.2.1 Use of Aqueous Ammonia
		19.2.2 Use of Thiourea
		19.2.3 Use of 2,4,6-Trimercaptotriazine
	19.3 Removal of Residual Rhodium
		19.3.1 Use of Smopex-234
		19.3.2 Use of Ecosorb C-941
	19.4 Removal of Residual Ruthenium
		19.4.1 Use of Activated Carbon
		19.4.2 Use of Supercritical Carbon Dioxide
	19.5 Removal of Zinc
		19.5.1 Extraction with Trisodium Salt of EDTA
		19.5.2 Use of Ethylenediamine
	19.6 Removal of Magnesium
	19.7 Removal of Aluminum
		19.7.1 Use of Triethanolamine
		19.7.2 Use of Crystallization
	19.8 Removal of Iron And Nickel
		19.8.1 Removal of Iron
		19.8.2 Removal of Nickel
Chapter 20 Methods for Impurity Removal
	20.1 Removal of Fluoride
		20.1.1 Use of Aqueous Wash
		20.1.2 Use of CaCl2
		20.1.3 Use of CaCO3
	20.2 Removal of Iodide
	20.3 Removal of High-Boiling Dipolar Aprotic Solvents
		20.3.1 Wash with Aqueous Solution
		20.3.2 Extraction with Heptane
	20.4 Removal of Triphenylphosphine Oxide
		20.4.1 Wash with Ethyl Acetate
		20.4.2 Precipitation of Ph3PO with MgCl2
		20.4.3 Precipitation of Ph3PO with ZnCl2
		20.4.4 Precipitation of Ph3PO with Heptane
	20.5 Use of Sodium Bisulfate
		20.5.1 Removal of Methacrylic Acid from Acid Product
		20.5.2 Removal of Alcohol from Aldehyde Product
		20.5.3 Removal of Excess Formaldehyde
		20.5.4 Removal of Ketone Intermediate
	20.6 Removal of Excess Reagents
		20.6.1 Use of Dimethylamine to Remove Excess Formaldehyde
		20.6.2 Use of N-Methylpiperazine to Remove Boc Anhydride
		20.6.3 Use of CO2 to Remove Excess Piperazine
		20.6.4 Use of Succinic Anhydride to Remove 1-(2-Pyrimidyl)piperazine
		20.6.5 Use of Pivalaldehyde to Remove 4-Chlorobenzylamine
		20.6.6 Use of DABCO to Remove Benzyl Bromide
		20.6.7 Use of Aqueous Ammonia to Remove Diethyl Sulfate
		20.6.8 Use of Hydrogen Peroxide to Oxidize Ph3P
	20.7 Conversion of Impurity To Starting Material
	20.8 Conversion of Impurity To Product
		20.8.1 Deoxychlorination
		20.8.2 Cycloaddition Reaction
	20.9 Removal of Other Impurities
		20.9.1 Removal of Polymeric Material
		20.9.2 Use of Sodium Periodate to Remove Diol
		20.9.3 Use of Phenylboronic Acid to Remove Diol
		20.9.4 Use of Sodium Dithionate to Reduce Nitro Group
		20.9.5 Use of Polymeric Resin to Remove Hydrazide
Chapter 21 Pharmaceutical Salts
	21.1 Salts of Basic Drug Substances
		21.1.1 Hydrochloride Salts
		21.1.2 Hemisulfate Salt
		21.1.3 Citric Acid Salt
		21.1.4 Various Pharmaceutical Salts
	21.2 Salts of Acidic Drug Substances
		21.2.1 Use of Inorganic Bases
			21.2.1.1 Sodium Salts
			21.2.1.2 Potassium Salts
			21.2.1.3 Calcium Salts
			21.2.1.4 Various Inorganic Salts
		21.2.2 Use of Organic Bases
Chapter 22 Solid Form
	22.1 Polymorphism
		22.1.1 Control of Polymorph by Seeding
			22.1.1.1 Use of Direct Addition
			22.1.1.2 Use of Reverse Addition
		22.1.2 Control of Polymorph by Temperature
		22.1.3 Control of Polymorph by Slurrying
		22.1.4 Control of Polymorph by Aging
		22.1.5 Control of Polymorph by Adding Polymer
		22.1.6 Polymorph Transformation
	22.2 Cocrystals
		22.2.1 Cocrystal with L-Phenylalanine
		22.2.2 Cocrystal with L-Pyroglutamic Acid
		22.2.3 Cocrystal with Phosphoric Acid
		22.2.4 Cocrystal with L-Proline
		22.2.5 Cocrystal with Adipic Acid
	22.3 Api Particle Size
	22.4 Amorphous Solids
		22.4.1 Use of Spray Drying
		22.4.2 Use of Solvent-Induced Method
		22.4.3 Use of Hot-Melt Extrusion
Index