883502-14-5

Basic information

• Product Name: 3-FLUORO-2-IODOTOLUENE
• Synonyms: 1-Fluoro-2-iodo-3-methylbenzene;2-Iodo-3-fluorotoluene
• CAS NO: 883502-14-5
• Molecular Formula: C7H6FI
• Molecular Weight: 236.03
• Mol File: 883502-14-5.mol
• Article Data: 23

Chemical Properties

• Boiling Point: 212℃
• Flash Point: 85℃
• Appearance: /
• Density: 1.788
• Vapor Pressure: 0.258mmHg at 25°C
• Refractive Index: 1.58
• Storage Temp.: 2-8°C(protect from light)
• CAS DataBase Reference: 3-FLUORO-2-IODOTOLUENE(CAS DataBase Reference)
• NIST Chemistry Reference: 3-FLUORO-2-IODOTOLUENE(883502-14-5)
• EPA Substance Registry System: 3-FLUORO-2-IODOTOLUENE(883502-14-5)

Safety Data

• Hazardous Substances Data: 883502-14-5(Hazardous Substances Data)

Usage

General Description

3-Fluoro-2-iodotoluene is a chemical compound that consists of a benzene ring substituted with a fluorine atom and an iodine atom. It is commonly used as a building block in the synthesis of pharmaceuticals, agrochemicals, and materials. 3-FLUORO-2-IODOTOLUENE is also utilized as an intermediate in the production of dyes, pigments, and other fine chemicals. It is important to handle 3-fluoro-2-iodotoluene with caution as it may be harmful if swallowed, inhaled, or in contact with skin, and it can cause irritation to the respiratory system. Due to its potential toxicity and reactivity, proper safety precautions and handling procedures should be followed when working with this chemical.

InChI:InChI=1/C7H6FI/c1-5-3-2-4-6(8)7(5)9/h2-4H,1H3

Synthetic route

2-fluoro-6-methylaniline (443-89-0) → 1-fluoro-2-iodo-3-methylbenzene (883502-14-5)

Conditions	Yield
Stage #1: 2-fluoro-6-methylaniline With hydrogenchloride In water at 0℃; for 0.25h; Stage #2: With sodium nitrite In water at 0℃; for 1.67h; Stage #3: With potassium iodide In water at 0℃; for 2.17h;	73%

NH-pyrazole (288-13-1) + 1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → 1-(2-iodo-3-methylphenyl)-1H-pyrazole

Conditions	Yield
With potassium phosphate In N,N-dimethyl-formamide at 150℃; for 2h; Microwave irradiation; Inert atmosphere; Schlenk technique;	70%

benzimidazole (271-44-3) + 1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → 1-(2-iodo-3-methylphenyl)-1H-indazole

Conditions	Yield
With potassium phosphate In N,N-dimethyl-formamide at 150℃; for 2h; Microwave irradiation; Inert atmosphere; Schlenk technique;	48%

1,2,4-Triazole (288-88-0) + 1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → 1-(2-iodo-3-methylphenyl)-1H-1,2,4-triazole

Conditions	Yield
With potassium phosphate In N,N-dimethyl-formamide at 150℃; for 6h; Microwave irradiation; Inert atmosphere; Schlenk technique;	31%

1,2,3-Benzotriazole (95-14-7) + 1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → 1-(2-iodo-3-methylphenyl)-1H-benzo[d][1,2,3]triazole

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 5h; Sealed tube; Inert atmosphere; Schlenk technique;	19%

zinc(II) cyanide (557-21-1) + 1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → 2-fluoro-6-methyl-benzonitrile (198633-76-0)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl acetamide at 80℃; for 16h; Inert atmosphere;
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl acetamide at 80℃; for 16h; Inert atmosphere;
With tetrakis(triphenylphosphine) palladium(0) In dimethyl amine at 80℃; Inert atmosphere;

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → 3-bromo-6-fluoro-2-methyl-benzonitrile (1255207-47-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 0 - 20 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → 3-ethenyl-6-fluoro-2-methylbenzonitrile (1255207-48-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / ethanol / 4 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 0 - 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → 6-fluoro-2-methyl-3-(oxiran-2-yl)benzonitrile (1255207-46-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C View Scheme
Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / ethanol / 4 h / Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 0 - 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → tert-butyl (3S)-4-[2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl]-3-(hydroxymethyl)piperazine-1-carboxylate (1426071-25-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5: ethanol / 0.5 h / 150 °C / Microwave irradiation View Scheme
Multi-step reaction with 5 steps 1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / ethanol / 4 h / Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C 5: ethanol / 0.5 h / 150 °C / Microwave irradiation View Scheme
Multi-step reaction with 5 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 0 - 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5: ethanol / 0.5 h / 150 °C / Microwave irradiation View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → tert-butyl (3R,9aS)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1426072-82-3)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4.1: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6.1: trifluoroacetic acid; triethylsilane / dichloromethane / 24 h / 20 °C 6.2: 2 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5: ethanol / 0.5 h / 150 °C / Microwave irradiation 6: cyanomethylenetributyl-phosphorane / benzene / 16 h / 100 °C / Inert atmosphere View Scheme
Multi-step reaction with 8 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6: triethylamine 7: ethyl acetate; hexane / 50 °C 8: hydrogen; 5% Pd-CaCO3 / methanol / 38 h / 40 °C / Inert atmosphere View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → tert-butyl (3S,9aS)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1426071-26-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4.1: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6.1: trifluoroacetic acid; triethylsilane / dichloromethane / 24 h / 20 °C 6.2: 2 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5: ethanol / 0.5 h / 150 °C / Microwave irradiation 6: cyanomethylenetributyl-phosphorane / benzene / 16 h / 100 °C / Inert atmosphere View Scheme
Multi-step reaction with 8 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6: triethylamine 7: ethyl acetate; hexane / 50 °C 8: hydrogen; 5% Pd-CaCO3 / methanol / 38 h / 40 °C / Inert atmosphere View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → 3-(2-bromo-acetyl)-6-fluoro-2-methyl-benzonitrile (1426073-08-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 3.2: 0.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 0 - 20 °C 3.1: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 20 - 100 °C 3.2: 0.75 h / 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / 16 h / 80 °C / Inert atmosphere 2.1: sulfuric acid; N-Bromosuccinimide / 3 h / 0 °C 3.1: bis(triphenylphosphine)palladium(II) dichloride / 1,4-dioxane / 22 h / 100 °C 3.2: 0.75 h / 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide; trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 3.2: 0.5 h / 0 - 5 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → C12H12FNO

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → (3R,9aS)-3-(3-cyano-4-fluoro-2-methyl-phenyl)-3-hydroxy-hexahydro-pyrazino[2,1-c][ 1,4]oxazine-8-carboxylic acid tert-butyl ester (1426073-09-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 3.2: 0.5 h / 0 - 5 °C 4.1: diisopropylamine / tetrahydrofuran / 18 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 3.2: 0.5 h / 0 - 5 °C 4.1: diisopropylamine / tetrahydrofuran / 18 h / 20 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → (S)-3-(3-cyano-4-fluoro-2-methyl-phenyl)-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester (1426073-10-0)

Conditions	Yield
Multi-step reaction with 7 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6: triethylamine 7: ethyl acetate; hexane / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 3.2: 0.5 h / 0 - 5 °C 4.1: diisopropylamine / tetrahydrofuran / 18 h / 20 °C 5.1: triethylamine / dichloromethane / 0.5 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 3.2: 0.5 h / 0 - 5 °C 4.1: diisopropylamine / tetrahydrofuran / 18 h / 20 °C 5.1: triethylamine / dichloromethane / 0.5 h / 20 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → C21H28FN3O6S

Conditions

Yield

Multi-step reaction with 6 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6: triethylamine View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → tert-butyl (3R)-4-[2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxylethyl]-3-(hydroxymethyl)piperazine-1-carboxylate (1426071-27-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5: ethanol / 1 h / 150 °C / Microwave irradiation View Scheme
Multi-step reaction with 5 steps 1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / ethanol / 4 h / Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C 5: ethanol / 1 h / 150 °C / Microwave irradiation View Scheme
Multi-step reaction with 5 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 0 - 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5: ethanol / 1 h / 150 °C / Microwave irradiation View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → tert-butyl (3S,9aR)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1426072-83-4) + tert-butyl (3R,9aR)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1426072-84-5)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4.1: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6.1: trifluoroacetic acid; triethylsilane / dichloromethane / 12 h / 20 °C 6.2: 2 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5: ethanol / 1 h / 150 °C / Microwave irradiation 6: cyanomethylenetributyl-phosphorane / benzene / 100 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → (3S,9aR)-3-(3-cyano-4-fluoro-2-methyl-phenyl)-3-hydroxy-hexahydro-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester (1426073-11-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / 16 h / 80 °C / Inert atmosphere 2.1: sulfuric acid; N-Bromosuccinimide / 3 h / 0 °C 3.1: bis(triphenylphosphine)palladium(II) dichloride / 1,4-dioxane / 22 h / 100 °C 3.2: 0.75 h / 0 - 5 °C 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: bis-triphenylphosphine-palladium(II) chloride; N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: N-Bromosuccinimide; trifluorormethanesulfonic acid / 1 h / 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C 5: 18 h / 20 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → (3S)-benzyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (1426071-28-4)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C View Scheme
Multi-step reaction with 6 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: dichloromethane; trifluoroacetic acid / 1 h / 20 °C 6.2: 1 h / 0 °C View Scheme
Multi-step reaction with 6 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 0 - 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → (7R,9aR)-benzyl 8-allyl-7-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (1426072-85-6)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: thionyl chloride / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube View Scheme
Multi-step reaction with 7 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: dichloromethane; trifluoroacetic acid / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: sulfuryl dichloride / 1 h / 90 °C 7.2: 1 h / 90 °C / Sealed tube View Scheme
Multi-step reaction with 7 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 0 - 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube View Scheme
Multi-step reaction with 7 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / 16 h / 80 °C / Inert atmosphere 2.1: sulfuric acid; N-Bromosuccinimide / 3 h / 0 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: chlorosulphone / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube View Scheme
Multi-step reaction with 7 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / 16 h / 80 °C / Inert atmosphere 2.1: sulfuric acid; N-Bromosuccinimide / 3 h / 0 °C 3.1: lithium chloride; tetrakis(triphenylphosphine) palladium(0) / toluene / 100 - 110 °C / Inert atmosphere 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: chlorosulphone / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → (7S,9aR)-benzyl 8-allyl-7-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (1426072-86-7)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: thionyl chloride / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube View Scheme
Multi-step reaction with 7 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: dichloromethane; trifluoroacetic acid / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: sulfuryl dichloride / 1 h / 90 °C 7.2: 1 h / 90 °C / Sealed tube View Scheme
Multi-step reaction with 7 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / 16 h / 80 °C / Inert atmosphere 2.1: sulfuric acid; N-Bromosuccinimide / 3 h / 0 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: chlorosulphone / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube View Scheme
Multi-step reaction with 7 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / 16 h / 80 °C / Inert atmosphere 2.1: sulfuric acid; N-Bromosuccinimide / 3 h / 0 °C 3.1: lithium chloride; tetrakis(triphenylphosphine) palladium(0) / toluene / 100 - 110 °C / Inert atmosphere 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: chlorosulphone / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → (3R,9aS)-8-benzyl 2-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)tetrahydro-1H-pyrazino[1,2-a]pyrazine-2,8-(9H,9aH)-dicarboxylate (1426071-29-5)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: thionyl chloride / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube 8.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 35 °C 8.2: 20 °C View Scheme
Multi-step reaction with 8 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: dichloromethane; trifluoroacetic acid / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: sulfuryl dichloride / 1 h / 90 °C 7.2: 1 h / 90 °C / Sealed tube 8.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 35 °C 8.2: 20 °C View Scheme
Multi-step reaction with 8 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 0 - 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube 8.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 35 °C 8.2: 20 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → (3R,9aS)-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino [1,2-a]pyrazine-2(6H)-carboxylate (1426071-30-8)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: thionyl chloride / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube 8.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 35 °C 8.2: 20 °C 9.1: hydrogen; palladium 10% on activated carbon / methanol / 20 °C View Scheme
Multi-step reaction with 9 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: dichloromethane; trifluoroacetic acid / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: sulfuryl dichloride / 1 h / 90 °C 7.2: 1 h / 90 °C / Sealed tube 8.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 35 °C 8.2: 20 °C 9.1: palladium 10% on activated carbon / methanol / 20 °C View Scheme
Multi-step reaction with 9 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 0 - 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube 8.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 35 °C 8.2: 20 °C 9.1: palladium 10% on activated carbon; hydrogen / methanol / 20 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → (3S,9aS)-8-benzyl 2-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)tetrahydro-1H-pyrazino[1,2-a]pyrazine-2,8 (9H,9aH)-dicarboxylate (1426071-31-9)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: thionyl chloride / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube 8.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 35 °C 8.2: 20 °C View Scheme
Multi-step reaction with 8 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: dichloromethane; trifluoroacetic acid / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: sulfuryl dichloride / 1 h / 90 °C 7.2: 1 h / 90 °C / Sealed tube 8.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 35 °C 8.2: 20 °C View Scheme
Multi-step reaction with 8 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / 16 h / 80 °C / Inert atmosphere 2.1: sulfuric acid; N-Bromosuccinimide / 3 h / 0 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: chlorosulphone / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube 8.1: tetrakis(triphenylphosphine) palladium(0); 1,3-dimethylbarbituric acid / dichloromethane / 4 h / 35 °C 8.2: 20 °C View Scheme
Multi-step reaction with 8 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / 16 h / 80 °C / Inert atmosphere 2.1: sulfuric acid; N-Bromosuccinimide / 3 h / 0 °C 3.1: lithium chloride; tetrakis(triphenylphosphine) palladium(0) / toluene / 100 - 110 °C / Inert atmosphere 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: chlorosulphone / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube 8.1: tetrakis(triphenylphosphine) palladium(0); 1,3-dimethylbarbituric acid / dichloromethane / 4 h / 35 °C 8.2: 20 °C View Scheme
Multi-step reaction with 8 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide; trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: thionyl chloride / 1 h / 90 °C 7.2: 1 h / 90 °C / Sealed tube 8.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 34 °C 8.2: 20 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → (3S,9aS)-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a ]pyrazine-2(6H)-carboxylate (1426071-32-0)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: thionyl chloride / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube 8.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 35 °C 8.2: 20 °C 9.1: hydrogen; palladium 10% on activated carbon / methanol / 20 °C View Scheme
Multi-step reaction with 9 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / dimethyl amine / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide / trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: dichloromethane; trifluoroacetic acid / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: sulfuryl dichloride / 1 h / 90 °C 7.2: 1 h / 90 °C / Sealed tube 8.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 4 h / 35 °C 8.2: 20 °C 9.1: palladium 10% on activated carbon / methanol / 20 °C View Scheme
Multi-step reaction with 9 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / 16 h / 80 °C / Inert atmosphere 2.1: sulfuric acid; N-Bromosuccinimide / 3 h / 0 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: chlorosulphone / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube 8.1: tetrakis(triphenylphosphine) palladium(0); 1,3-dimethylbarbituric acid / dichloromethane / 4 h / 35 °C 8.2: 20 °C 9.1: hydrogen; palladium 10% on activated carbon / methanol / 20 °C View Scheme
Multi-step reaction with 9 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / 16 h / 80 °C / Inert atmosphere 2.1: sulfuric acid; N-Bromosuccinimide / 3 h / 0 °C 3.1: lithium chloride; tetrakis(triphenylphosphine) palladium(0) / toluene / 100 - 110 °C / Inert atmosphere 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: chlorosulphone / 1 h / 90 °C 7.2: 1 h / 0 - 90 °C / Sealed tube 8.1: tetrakis(triphenylphosphine) palladium(0); 1,3-dimethylbarbituric acid / dichloromethane / 4 h / 35 °C 8.2: 20 °C 9.1: hydrogen; palladium 10% on activated carbon / methanol / 20 °C View Scheme
Multi-step reaction with 9 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: N-Bromosuccinimide; trifluorormethanesulfonic acid / 1 h / 20 °C 3.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 20 °C 5.1: ethanol / 0.5 h / 150 °C / Microwave irradiation 6.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.2: 1 h / 0 °C 7.1: thionyl chloride / 1 h / 90 °C 7.2: 1 h / 90 °C / Sealed tube 8.1: 1,3-dimethylbarbituric acid; tetrakis(triphenylphosphine) palladium(0) / dichloromethane / 34 °C 8.2: 20 °C 9.1: palladium 10% on activated carbon; hydrogen / methanol / 20 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → 6-fluoro-2-methyl-3-[(3S,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile 2,2,2-trifluoroacetate (1426072-49-2)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4.1: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6.1: trifluoroacetic acid; triethylsilane / dichloromethane / 24 h / 20 °C 6.2: 2 h / 20 °C 7.1: 1 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4.1: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6.1: trifluoroacetic acid; triethylsilane / dichloromethane / 24 h / 20 °C 6.2: 2 h / 20 °C 7.1: 1 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / ethanol / 4 h / Inert atmosphere; Reflux 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 72 h / 0 - 20 °C 5: ethanol / 0.5 h / 150 °C / Microwave irradiation 6: cyanomethylenetributyl-phosphorane / benzene / 16 h / 100 °C / Inert atmosphere 7: 1 h / 20 °C View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → 3-((3S,9aS)-8-(2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)acetyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-fluoro-2-methylbenzonitrile (1443735-03-2)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4.1: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6.1: triethylamine 7.1: ethyl acetate; hexane / 50 °C 8.1: hydrogen; 5% Pd-CaCO3 / methanol / 38 h / 40 °C / Inert atmosphere 9.1: 1 h / 20 °C 10.1: triethylamine / dichloromethane / 0.08 h 10.2: 2 h View Scheme
Multi-step reaction with 10 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4.1: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6.1: triethylamine 7.1: ethyl acetate; hexane / 50 °C 8.1: hydrogen; 5% Pd-CaCO3 / methanol / 38 h / 40 °C / Inert atmosphere 9.1: 1 h / 20 °C 10.1: triethylamine / dichloromethane / 0.08 h 10.2: 2 h View Scheme
Multi-step reaction with 8 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4.1: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6.1: trifluoroacetic acid; triethylsilane / dichloromethane / 24 h / 20 °C 6.2: 2 h / 20 °C 7.1: 1 h / 20 °C 8.1: triethylamine / dichloromethane / 0.08 h 8.2: 2 h View Scheme

1-fluoro-2-iodo-3-methylbenzene (883502-14-5) → 6-fluoro-2-methyl-3-[(3S,9aS)-8-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile (1443735-04-3)

Conditions	Yield
Multi-step reaction with 10 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6: triethylamine 7: ethyl acetate; hexane / 50 °C 8: hydrogen; 5% Pd-CaCO3 / methanol / 38 h / 40 °C / Inert atmosphere 9: 1 h / 20 °C 10: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / dichloromethane / 4 h / 20 °C View Scheme
Multi-step reaction with 10 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6: triethylamine 7: ethyl acetate; hexane / 50 °C 8: hydrogen; 5% Pd-CaCO3 / methanol / 38 h / 40 °C / Inert atmosphere 9: 1 h / 20 °C 10: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / dichloromethane / 4 h / 20 °C View Scheme
Multi-step reaction with 8 steps 1.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl acetamide / 16 h / 80 °C / Inert atmosphere 2.1: trifluorormethanesulfonic acid; N-Bromosuccinimide / 1 h / 0 - 20 °C 3.1: bis(triphenylphosphine)palladium(II) chloride / 1,4-dioxane / 22 h / 100 °C 4.1: N-Bromosuccinimide; water / tetrahydrofuran; 1,4-dioxane / 0.5 h / 0 - 5 °C 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 18 h / 20 °C 6.1: trifluoroacetic acid; triethylsilane / dichloromethane / 24 h / 20 °C 6.2: 2 h / 20 °C 7.1: 1 h / 20 °C 8.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / dichloromethane / 4 h / 20 °C View Scheme

Upstream product

• 443-89-0 2-fluoro-6-methylaniline 
• 3739-67-1 bisphenol A diallyl ether 
• 80-05-7 BPA 
• 106-95-6 allyl bromide 
• 107-05-1 3-chloroprop-1-ene 
• 95-50-1 1,2-dichloro-benzene 
• 107-18-6 allyl alcohol 
• 591-87-7 Allyl acetate 
• 557-40-4 Allyl ether 

Downstream Products

• 1255207-47-6 3-bromo-6-fluoro-2-methyl-benzonitrile 
• 198633-76-0 2-fluoro-6-methyl-benzonitrile 

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