Name: 1214325-21-9|Methyl 3-bromo-5-fluoroisonicotinate|97%
Brand: Ambeed
SKU: A169525
Price: 21.0 USD
Availability: InStock
Rating: 91 (30 reviews)

1
[ 955372-86-8 ]
[ 18107-18-1 ]
methyl 3-bromo-5-fluoroisonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With methanol; In tetrahydrofuran; at 0 - 20℃; for 3h;Inert atmosphere;	TMSCHN2 (180 mL, 360 mmol, 2 equiv) was added into a solution of 3-bromo-5- fluoroisonicotinic acid (40 g, 182 mmol, 1 equiv), THF (240 mL), and MeOH (80 mL) dropwise with stirring at 0 C under nitrogen. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1/9) to afford the title compound (35 g, 83%) as yellow oil.

Reference： [1]Patent: WO2018/96159,2018,A1 .Location in patent: Paragraph 0202; 0203; 0206; 0207

2
[ 1214325-21-9 ]
[ 2227201-50-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 3 h / 50 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; PARAZA PHARMA INC - WO2018/96159, 2018, A1

3
[ 1214325-21-9 ]
[ 2227201-51-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 3 h / 50 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere 3: ammonia / dimethyl sulfoxide / 12 h / 80 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; PARAZA PHARMA INC - WO2018/96159, 2018, A1

4
[ 1214325-21-9 ]
[ 1805106-63-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 3 h / 50 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere 3: ammonia / dimethyl sulfoxide / 12 h / 80 °C 4: hydrogen / methanol / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; PARAZA PHARMA INC - WO2018/96159, 2018, A1

5
[ 1214325-21-9 ]
[ 1393558-93-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 3 h / 50 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere 3: ammonia / dimethyl sulfoxide / 12 h / 80 °C 4: hydrogen / methanol / 0.5 h / 20 °C 5: sodium hydroxide; water / methanol / 12 h / 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; PARAZA PHARMA INC - WO2018/96159, 2018, A1

6
[ 1214325-21-9 ]
[ 2227201-52-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 3 h / 50 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere 3: ammonia / dimethyl sulfoxide / 12 h / 80 °C 4: hydrogen / methanol / 0.5 h / 20 °C 5: sodium hydroxide; water / methanol / 12 h / 20 °C 6: ethanol / 3 h / 80 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; PARAZA PHARMA INC - WO2018/96159, 2018, A1

7
[ 1214325-21-9 ]
[ 2227201-53-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 3 h / 50 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere 3: ammonia / dimethyl sulfoxide / 12 h / 80 °C 4: hydrogen / methanol / 0.5 h / 20 °C 5: sodium hydroxide; water / methanol / 12 h / 20 °C 6: ethanol / 3 h / 80 °C 7: tetra-(n-butyl)ammonium iodide; potassium carbonate / N,N-dimethyl-formamide / 3 h / 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; PARAZA PHARMA INC - WO2018/96159, 2018, A1

8
[ 1214325-21-9 ]
[ 2227201-54-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 3 h / 50 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere 3: ammonia / dimethyl sulfoxide / 12 h / 80 °C 4: hydrogen / methanol / 0.5 h / 20 °C 5: sodium hydroxide; water / methanol / 12 h / 20 °C 6: ethanol / 3 h / 80 °C 7: tetra-(n-butyl)ammonium iodide; potassium carbonate / N,N-dimethyl-formamide / 3 h / 20 °C 8: hydrazine hydrate / methanol / 1 h / 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; PARAZA PHARMA INC - WO2018/96159, 2018, A1

9
[ 1214325-21-9 ]
[ 2227201-55-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 3 h / 50 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere 3: ammonia / dimethyl sulfoxide / 12 h / 80 °C 4: hydrogen / methanol / 0.5 h / 20 °C 5: sodium hydroxide; water / methanol / 12 h / 20 °C 6: ethanol / 3 h / 80 °C 7: tetra-(n-butyl)ammonium iodide; potassium carbonate / N,N-dimethyl-formamide / 3 h / 20 °C 8: hydrazine hydrate / methanol / 1 h / 20 °C 9: N,N-dimethyl-formamide / 3 h / 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; PARAZA PHARMA INC - WO2018/96159, 2018, A1

10
[ 1214325-21-9 ]
[ 2227200-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 3 h / 50 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere 3: ammonia / dimethyl sulfoxide / 12 h / 80 °C 4: hydrogen / methanol / 0.5 h / 20 °C 5: sodium hydroxide; water / methanol / 12 h / 20 °C 6: ethanol / 3 h / 80 °C 7: tetra-(n-butyl)ammonium iodide; potassium carbonate / N,N-dimethyl-formamide / 3 h / 20 °C 8: hydrazine hydrate / methanol / 1 h / 20 °C 9: N,N-dimethyl-formamide / 3 h / 20 °C 10: tetra-(n-butyl)ammonium iodide; potassium carbonate / N,N-dimethyl-formamide / 5 h / 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; PARAZA PHARMA INC - WO2018/96159, 2018, A1

11
[ 1214325-21-9 ]
[ 544-97-8 ]
[ 1803821-90-0 ]

Yield	Reaction Conditions	Operation in experiment
69%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane at 50℃; for 3h; Inert atmosphere;	6.3 Step 3: Preparation of methyl 3-fluoro-5-methylisonicotinate Zn(CH3)2 (225 mL, 0.22 mol, 1.5 equiv) was added into a mixture of 3-bromo-5- fluoroisonicotinate (35 g, 0.15 mol, 1 equiv), dioxane (1 L), and Pd(dppf)Cl2 (11 g, 15 mmol, 0.1 equiv) at room temperature under nitrogen. The resulting solution was stirred for 3 h at 50 °C. The reaction was then quenched by the addition of methanol. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica column chromatography to give the product (17 g, 69%).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; PARAZA PHARMA INC - WO2018/96159, 2018, A1 Location in patent: Paragraph 0202; 0203; 0208; 0209

12
[ 407-20-5 ]
[ 1214325-21-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium; diisopropylamine / tetrahydrofuran / 1 h / -70 - 0 °C / Inert atmosphere 1.2: 0.5 h / Inert atmosphere 2.1: methanol / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: n-butyllithium

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; PARAZA PHARMA INC - WO2018/96159, 2018, A1
[2]Current Patent Assignee: ROCHE HOLDING AG - US2019/284179, 2019, A1

13
[ 1214325-21-9 ]
[ 136725-53-6 ]
[ 2324161-09-1 ]

Yield	Reaction Conditions	Operation in experiment
39%	Stage #1: methyl 3-bromo-5-fluoroisonicotinate; (S)-3-fluoropyrrolidine hydrochloride With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 12h; Stage #2: (S)-3-fluoropyrrolidine hydrochloride In dimethyl sulfoxide at 50℃; for 12h;	Step1: (S)-Methyl 3-bromo-5-(3-fluoropyrrolidin-1-yl)isonicotinate Amixture of methyl 3-bromo-5-fluoroisonicotinate (1.50 g, 5.64 mmol, 88% puritycalculated by LC-MS analysis, prepared in Step 1 for 24), (S)-3-fluoropyrrolidinehydrochloride (0.850 g, 6.77 mmol) and DIPEA (2.92 g, 22.6 mmol) in DMSO (25mL) was stirred at room temperature for 12 h. To the reaction mixture was added(S)-3-fluoropyrrolidine;hydrochloride (0.354 g, 2.82 mmol) at roomtemperature. The reaction mixture washeated to 50 °C and stirred for 12 h. The reaction mixture was diluted withEtOAc (30 mL). The mixture was washed with water (8 mL) and brine (15 mL),dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography in silica gel (Petroleum ether/EtOAc = 15/1) to afford (S)-methyl3-bromo-5-(3-fluoropyrrolidin-1-yl)isonicotinate (0.660 g, 39%) as a yellowoil. 1H NMR (400 MHz, CDCl3) δ 2.06-2.18 (1H, m), 2.33-2.39(1H, m), 3.50-3.67 (4H, m), 3.98 (3H, s), 5.27-5.40 (1H, m), 8.04 (1H, s), 8.10(1H, s). MS (ESI) m/z: 302.9[M+H]+.

Reference： [1]Miyazaki, Tohru; Kawasaki, Masanori; Suzuki, Atsushi; Ito, Yuki; Imanishi, Akio; Maru, Takamitsu; Kawamoto, Tomohiro; Koike, Tatsuki [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 6, p. 815 - 820]

14
[ 955372-86-8 ]
[ 74-88-4 ]
methyl 3-bromo-5-fluoroisonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 15h;	Amixture of <strong>[955372-86-8]3-bromo-5-fluoroisonicotinic acid</strong> (1.00 g, 4.55 mmol), iodomethane(0.774 g, 5.45 mmol) and K2CO3 (1.26 g, 9.09 mmol) in DMF(10 mL) was stirred at room temperature for 15 h. The reaction mixture wasdiluted with EtOAc (50 mL) andwater(50 mL). The organic phase was separatedand the aqueous phase was extracted with EtOAc (2 x 50 mL). The combinedorganic phase was washed with brine (50 mL), dried with anhydrous Na2SO4,filtered and concentrated in vacuo toafford methyl 3-bromo-5-fluoroisonicotinate (0.810 g, 67%) as a brown oil. 1HNMR (400 MHz, CDCl3) delta 4.02 (3H, s), 8.51 (1H, s), 8.63 (1H, s). MS(ESI) m/z: 233.9 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 815 - 820

15
[ 1214325-21-9 ]
[ 2332897-93-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 30 h / 20 - 50 °C 2: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 15 h / 90 °C

Reference： [1]Miyazaki, Tohru; Kawasaki, Masanori; Suzuki, Atsushi; Ito, Yuki; Imanishi, Akio; Maru, Takamitsu; Kawamoto, Tomohiro; Koike, Tatsuki [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 6, p. 815 - 820]

16
[ 1214325-21-9 ]
[ 2332897-94-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 30 h / 20 - 50 °C 2: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 15 h / 90 °C 3: sodium hydroxide / tetrahydrofuran; water; methanol / 15 h / 90 °C / Sealed tube

Reference： [1]Miyazaki, Tohru; Kawasaki, Masanori; Suzuki, Atsushi; Ito, Yuki; Imanishi, Akio; Maru, Takamitsu; Kawamoto, Tomohiro; Koike, Tatsuki [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 6, p. 815 - 820]

17
[ 1214325-21-9 ]
[ 2324158-76-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 30 h / 20 - 50 °C 2.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 15 h / 90 °C 3.1: sodium hydroxide / tetrahydrofuran; water; methanol / 15 h / 90 °C / Sealed tube 4.1: oxalyl dichloride / N,N-dimethyl-formamide; tetrahydrofuran / 1 h / 0 - 20 °C 4.2: 16 h / 20 °C

Reference： [1]Miyazaki, Tohru; Kawasaki, Masanori; Suzuki, Atsushi; Ito, Yuki; Imanishi, Akio; Maru, Takamitsu; Kawamoto, Tomohiro; Koike, Tatsuki [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 6, p. 815 - 820]

18
[ 1214325-21-9 ]
[ 2324158-40-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 12 h / 20 °C 1.2: 12 h / 50 °C 2.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 14 h / 90 °C

Reference： [1]Miyazaki, Tohru; Kawasaki, Masanori; Suzuki, Atsushi; Ito, Yuki; Imanishi, Akio; Maru, Takamitsu; Kawamoto, Tomohiro; Koike, Tatsuki [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 6, p. 815 - 820]

19
[ 1214325-21-9 ]
[ 2324156-85-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 12 h / 20 °C 1.2: 12 h / 50 °C 2.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 14 h / 90 °C 3.1: sodium hydroxide / tetrahydrofuran; water; 1,1,1-trideuteromethanol / 14 h / 90 °C / Sealed tube

Reference： [1]Miyazaki, Tohru; Kawasaki, Masanori; Suzuki, Atsushi; Ito, Yuki; Imanishi, Akio; Maru, Takamitsu; Kawamoto, Tomohiro; Koike, Tatsuki [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 6, p. 815 - 820]

20
[ 110-91-8 ]
[ 1214325-21-9 ]
[ 2332897-92-2 ]

Yield	Reaction Conditions	Operation in experiment
29%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20 - 50℃; for 30h;	Step2: Methyl 3-bromo-5-morpholinoisonicotinate Amixture of methyl 3-bromo-5-fluoroisonicotinate (0.810 g, 3.06 mmol, 88% puritycalculated by LC-MS analysis), morpholine (0.320 g, 3.67 mmol) and DIPEA (1.19g, 9.18 mmol) in DMSO (8 mL) was stirred at room temperature for 15 h. Thereaction mixture was heated to 50 °C and stirred for 15 h. The reaction mixture was diluted with EtOAc(20 mL) and water (20 mL). The organic phase was separated and the aqueousphase was extracted with EtOAc (2 x 20 mL).The combined organic phase was washed with brine (20 mL), dried withanhydrous Na2SO4, filtered and concentrated in vacuo to afford methyl3-bromo-5-morpholinoisonicotinate (400 mg, 29% for 2 steps) as a brown oil. 1HNMR (400 MHz, CDCl3) δ 3.10 (4H, t, J = 4.4 Hz), 3.79 (4H, t, J= 4.4 Hz), 3.98 (3H, s), 8.37 (1H, s), 8.47 (1H, s). MS (ESI) m/z: 301.1 [M+H]+.

Reference： [1]Miyazaki, Tohru; Kawasaki, Masanori; Suzuki, Atsushi; Ito, Yuki; Imanishi, Akio; Maru, Takamitsu; Kawamoto, Tomohiro; Koike, Tatsuki [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 6, p. 815 - 820]

21
[ 955372-86-8 ]
methyl 3-bromo-5-fluoroisonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%		Step 2: Preparation of methyl 3-bromo-5-fluoroisonicotinate TMSCHN2 (180 mL, 360 mmol, 2 equiv) was added into a solution of <strong>[955372-86-8]3-bromo-5-fluoroisonicotinic acid</strong> (40 g, 182 mmol, 1 equiv), THF (240 mL), and MeOH (80 mL) dropwise with stirring at 0 C. under nitrogen. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1/9) to afford the title compound (35 g, 83%) as yellow oil.

Reference： [1]Patent: US2019/284179,2019,A1

22
[ 1214325-21-9 ]
[ 2427609-43-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane / 18 h / 50 °C / Sealed tube 3.1: hydrogenchloride; sodium hydroxide; sodium cyanoborohydride / methanol / 120 h / 20 °C / Inert atmosphere 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 4.2: 18 h / 20 °C / Inert atmosphere 4.3: 18 h / -78 - 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane / 18 h / 50 °C / Sealed tube 3.1: hydrogenchloride; sodium cyanoborohydride / methanol; water / 120 h / 20 °C / Inert atmosphere 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 4.2: 36 h / -78 - 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane; water / 18 h / 50 °C 3.1: hydrogenchloride; sodium hydroxide; sodium cyanoborohydride / methanol; water / 120 h / 20 °C / Inert atmosphere 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.25 h / Inert atmosphere 4.2: 18 h / -78 °C / Inert atmosphere 4.3: 18 h / -78 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106304, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[3]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

23
[ 1214325-21-9 ]
[ 2427609-44-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane / 18 h / 50 °C / Sealed tube 2.2: 30 h / 50 °C 3.1: sodium hydroxide; sodium cyanoborohydride / methanol; water / 120 h / 20 °C / Inert atmosphere 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 4.2: 18 h / 20 °C / Inert atmosphere 4.3: 18 h / -78 - 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane / 48 h / 50 °C / Sealed tube 3.1: hydrogenchloride; sodium cyanoborohydride / methanol; water / 120 h / 20 °C / Inert atmosphere 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 4.2: 36 h / -78 - 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane; water / 48 h / 50 °C 3.1: hydrogenchloride; sodium hydroxide; sodium cyanoborohydride / methanol; water / 120 h / 20 °C / Inert atmosphere 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C 4.2: 18 h / -78 - 20 °C 4.3: 18 h / -78 - 20 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106304, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[3]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

24
[ 1214325-21-9 ]
[ 2427609-85-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride; triethylamine / 1,4-dioxane / 18 h / 50 °C / Sealed tube
	Multi-step reaction with 2 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride; triethylamine / 1,4-dioxane / 18 h / 50 °C / Sealed tube
	Multi-step reaction with 2 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride; triethylamine / 1,4-dioxane; water / 18 h / 50 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106304, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[3]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

25
[ 1214325-21-9 ]
[ 2427609-87-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride; triethylamine / 1,4-dioxane / 18 h / 50 °C / Sealed tube 3: hydrogenchloride; sodium hydroxide; sodium cyanoborohydride / methanol / 120 h / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride; triethylamine / 1,4-dioxane / 18 h / 50 °C / Sealed tube 3: hydrogenchloride; sodium cyanoborohydride / methanol; water / 120 h / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride; triethylamine / 1,4-dioxane; water / 18 h / 50 °C 3: hydrogenchloride; sodium hydroxide; sodium cyanoborohydride / methanol; water / 120 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106304, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[3]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

26
[ 1214325-21-9 ]
[ 2427609-89-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane / 18 h / 50 °C / Sealed tube 2.2: 30 h / 50 °C
	Multi-step reaction with 2 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride; triethylamine / 1,4-dioxane / 48 h / 50 °C / Sealed tube
	Multi-step reaction with 2 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride; triethylamine / 1,4-dioxane; water / 48 h / 50 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106304, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[3]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

27
[ 1214325-21-9 ]
[ 2427609-91-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane / 18 h / 50 °C / Sealed tube 2.2: 30 h / 50 °C 3.1: sodium hydroxide; sodium cyanoborohydride / methanol; water / 120 h / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride; triethylamine / 1,4-dioxane / 48 h / 50 °C / Sealed tube 3: hydrogenchloride; sodium cyanoborohydride / methanol; water / 120 h / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride; triethylamine / 1,4-dioxane; water / 48 h / 50 °C 3: hydrogenchloride; sodium hydroxide; sodium cyanoborohydride / methanol; water / 120 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106304, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[3]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

28
[ 1214325-21-9 ]
[ 2428506-37-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / 1,4-dioxane / 18 h / 45 °C 2.2: 72 h / 20 °C
	Multi-step reaction with 2 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride; triethylamine / 1,4-dioxane / 72 h / 20 °C
	Multi-step reaction with 2 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / 1,4-dioxane; water / 18 h / 45 °C 2.2: 72 h / 20 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106304, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[3]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

29
[ 1360111-87-0 ]
[ 1214325-21-9 ]
[ 2427610-02-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	With chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); caesium carbonate In tetrahydrofuran; water at 85℃; for 18h;	115.3 Step 3: Methyl 3-(2-ethoxwinyl)-5-fluoroisonicotinate (a compound of formula (104)) A degassed solution of methyl 3-bromo-5-fluoroisonicotinate (10 g, 42.70 mmol), 2-(2- ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (12.7 g, 64.05 mmol), CS2CO3 (48.7 g, 49.45 mmol) and PdXPhos G2 catalyst (3.4 g, 4.27 mmol) in THF/H2O (9: 1 v/v, 90: 10 mL) was stirred at 85°C for 18 h. The reaction mixture was diluted with EtOAc (100 mL) and filtered through a Celite pad. The organic filtrate was washed with H2O (100 mL), brine (100 mL), dried over Na2S04, and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-25% EtOAc in hexanes) to give the product (7.07 g, 74%) as a brown oil. UPLC-MS (Acidic Method, 2 min): rt 1.01 and 1.10 min, m/z 226.1 [M+H]+. 'H NMR (400 MHz, CDCI3): d ppm (Note: a mixture of E:Z isomers 1.15 : 1) 9.18 - 9.13 (m, 1H), 8.48 (s, 1.15H), 8.30 (dd, 7=5.2, 0.8 Hz, 2.15H), 7.03 (d, 7=12.9 Hz, 1.15H), 6.41 (dd, .7=7.1 , 0.7 Hz, (2119) 1H), 5.91 (d, .7=12.9 Hz, 1.15H), 5.27 (d, 7=7.1 Hz, 1H), 4.05 (q, 7=7.1 Hz, 2H), 4.01 - 3.90 (m, 8.75H), 1.37 (td, 7=7.1, 2.8 Hz, 6.5H).
74%	With chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); caesium carbonate In tetrahydrofuran; water at 85℃; for 18h;	101.3 Step 3: Methyl 3-(2-ethoxyvinyl)-5-fluoroisonicotinate (a compound of formula (104) A degassed solution of methyl 3-bromo-5-fluoroisonicotinate (10 g, 42.70 mmol), 2-(2- ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.7 g, 64.05 mmol), CS2CO3 (48.7 g, 49.45 mmol) and PdXPhos G2 catalyst (3.4 g, 4.27 mmol) in THF/H2O (9: 1 v/v, 90: 10 mL) was stin-ed at 85°C for 18 h. The reaction mixture was diluted with EtOAc ( 100 mL) and filtered through a Celite pad. The organic filtrate was washed with H2O (100 mL), brine (100 mL), dried over Na2SC>4, and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-25% EtOAc in hexanes) to give the product (7.07 g, 74%) as a brown oil. UPLC-MS (Acidic Method, 2 min): rt 1.01 and 1.10 min, m/z 226.1 [M+H]+. 'H NMR (400 MHz, CDCb): d ppm (Note: a mixture of E:Z isomers 1.15 : 1) 9.18 - 9.13 (m, 1H), 8.48 (s, 1.15H), 8.30 (dd, .7=5.2, 0.8 Hz, 2.15H), 7.03 (d, .7=12.9 Hz, 1 .15H), 6.41 (dd, 7=7.1 , 0.7 Hz,1H), 5.91 (d, 7=12.9 Hz, 1.15H), 5.27 (d, 7=7.1 Hz, 1H), 4.05 (q, 7=7.1 Hz, 2H), 4.01 - 3.90 (m, 8.75H), 1.37 (td, 7=7.1 , 2.8 Hz, 6.5H).
74%	With chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); caesium carbonate In tetrahydrofuran; water at 85℃; for 18h;	103.3 Step 3: Methyl 3-(2-ethoxyvinyl)-5-fluoroisonicotinate (a compound of formula (104)) [0629] A degassed solution of methyl 3-bromo-5-fluoroisonicotinate (10 g, 42.70 mmol), 2-(2- ethoxyvinyI)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.7 g, 64.05 mmol), CS2CO3 (48.7 g, 49.45 mmol) and PdXPhos G2 catalyst (3.4 g, 4.27 mmol) in THF/H2O (9:1 v/v, 90:10 mL) was stirred at 85°C for 1 8 h. The reaction mixture was diluted with EtOAc (100 mL) and filtered through a Celite pad. The organic filtrate was washed with H2O (100 mL), brine (100 mL), dried over Na2SC>4, and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-25% EtOAc in hexanes) to give the product (7.07 g, 74%) as a brown oil. UPLC-MS (Acidic Method, 2 min): rt 1.01 and 1.10 min, m/z 226.1 [M+H]+. 'H NMR (400 MHz, CDCI3): d ppm {Note: a mixture of E:Z isomers 1.15 : 1) 9.18- 9.13 (m, 1H), 8.48 (s, 1.15H), 8.30 (dd,.7=5.2, 0.8 Hz, 2.15H), 7.03 (d,.7=12.9 Hz, 1.15H), 6.41 (dd,.7=7.1, 0.7 Hz, 1H), 5.91 (d,.7=12.9 Hz, 1.15H), 5.27 (d,.7=7.1Hz, 1H), 4.05 (q, =7.1Hz, 2H), 4.01 - 3.90 (m, 8.75H), 1.37 (td,.7=7.1, 2.8 Hz, 6.5H).

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106304, 2020, A1 Location in patent: Paragraph 0815; 0817
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1 Location in patent: Paragraph 0613
[3]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1 Location in patent: Paragraph 0629

30
[ 407-20-5 ]
[ 79-22-1 ]
methyl 3-bromo-5-fluoroisonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		To a solution of dry diisopropylamine (8.8 mL, 62.5 mmol) in dry THF (300 mL) stirred at 0C -BuLi (2.5M in hexanes, 25 mL, 62.5 mmol) was added. The reaction mixture was stirred for 30 min at room temperature, then cooled down to -78C and a solution of 3- bromo-5-fluoropyridine (10 g, 56.8 mmol) in dry THF (300 mL) was added. The reaction mixture was stirred for 1 h and treated with methyl chloroformate (5.3 mmol, 68.2 mmol). The reaction mixture was stirred for 1.5 h and then was quenched with a saturated NH4CI aqueous solution at 0C, extracted with EtOAc (3 c 100 mL), washed with H2O (100 mL) and brine (100 mL), dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-7% EtOAc in hexanes) to give the product (10.43 g, 78%) as a yellowish liquid. UPLC-MS (Acidic Method, 2 min): rt 0.86 min, m/z 234.0/236.0 [M+H]+. 1H NMR (400 MHz, CDCl3): d ppm 8.69 (t, 7=0.5 Hz, 1H), 8.57 (d, 7=8.4 Hz, 1H), 4.08 (s, 3H).
78%		[0627] To a solution of dry diisopropylamine (8.8 mL, 62.5 mmol) in dry THF (300 mL) stirred at 0C -BuLi (2.5M in hexanes, 25 mL, 62.5 mmol) was added. The reaction mixture was stirred for 30 min at room temperature, then cooled down to -78C and a solution of 3- bromo-5-fluoropyridine (10 g, 56.8 mmol) in dry THF (300 mL) was added. The reaction mixture was stirred for 1 h and treated with methyl chloroformate (5.3 mmol, 68.2 mmol). The reaction mixture was stirred for 1.5 h and then was quenched with a saturated NH4CI aqueous solution at 0C, extracted with EtOAc (3 x 100 mL), washed with H2O (100 mL) and brine (100 mL), dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-7% EtOAc in hexanes) to give the product (10.43 g, 78%) as a yellowish liquid. UPLC-MS (Acidic Method, 2 min): rt 0.86 min, m/z 234.0/236.0 [M+H]+. NMR (400 MHz, CDCI3): d ppm 8.69 (t, -0.5 Hz, l H), 8.57 (d, 7=8.4 Hz, 1H), 4.08 (s, 3H).
78%		To a solution of dry diisopropylamine (8.8 mL, 62.5 mmol) in dry THF (300 mL) stirred at 0C n-BuLi (2.5M in hexanes, 25 mL, 62.5 mmol) was added. The reaction mixture was stirred for 30 min at room temperature, then cooled down to -78C and a solution of 3- bromo-5-fluoropyridine (10 g, 56.8 mmol) in dry THF (300 mL) was added. The reaction mixture was stirred for 1 h and treated with methyl chloroformate (5.3 mmol, 68.2 mmol). The reaction mixture was stirred for 1.5 h and then was quenched with a saturated NH4CI aqueous solution at 0C, extracted with EtOAc (3 x 100 mL), washed with H2O (100 mL) and brine (100 mL), dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-7% EtOAc in hexanes) to give the product (10.43 g, 78%) as a yellowish liquid. UPLC-MS (Acidic Method, 2 min): rt 0.86 min, m/z 234.0/236.0 [M+H]+. (2114) NMR (400 MHz, CDCh): d ppm 8.69 (t, 7=0.5 Hz, 1H), 8.57 (d, 7=8.4 Hz, 1H), 4.08 (s, 3H).

Reference： [1]Patent: WO2020/106303,2020,A1 .Location in patent: Paragraph 0627
[2]Patent: WO2020/106304,2020,A1 .Location in patent: Paragraph 0485; 0815
[3]Patent: WO2020/106307,2020,A1 .Location in patent: Paragraph 0611
[4]Patent: WO2020/106308,2020,A1 .Location in patent: Paragraph 0221

31
[ 1360111-87-0 ]
[ 1214325-21-9 ]
[ 2427609-68-3 ]
[ 2427610-04-4 ]

Yield	Reaction Conditions	Operation in experiment
	With chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); caesium carbonate In tetrahydrofuran; water at 85℃; for 18h; Inert atmosphere; Overall yield = 74 percent; Overall yield = 7.07 g;	1.3 Step 3: Methyl 3-(2-ethoxyvinvl)-5-fluoroisonicotinate (a compound of formula (104)) A degassed solution of methyl 3-bromo-5-fluoroisonicotinate (10 g, 42.70 mmol), 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.7 g, 64.05 mmol), CS2CO3 (48.7 g, 49.45 mmol) and PdXPhos G2 catalyst (3.4 g, 4.27 mmol) in THF/H2O (9: 1 v/v, 90: 10 mL) was stirred at 85°C for 18 h. The reaction mixture was diluted with EtOAc (100 mL) and filtered through a Celite pad. The organic filtrate was washed with H2O (100 mL), brine (100 mL), dried over Na2S04, and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-25% EtOAc in hexanes) to give the product (7.07 g, 74%) as a brown oil. UPLC-MS (Acidic Method, 2 min): rt 1.01 and 1.10 min, m/z 226.1 [M+H]+. 1H NMR (400 MHz, CDCl3): d ppm (Note: a mixture of E:Z isomers 1.15 : 1) 9.18 - 9.13 (m, 1H), 8.48 (s, 1.15H), 8.30 (dd, 7=5.2, 0.8 Hz, 2.15H), 7.03 (d, 7=12.9 Hz, 1.15H), 6.41 (dd, 7=7.1, 0.7 Hz, 1H), 5.91 (d, 7=12.9 Hz, 1.15H), 5.27 (d, 7=7.1Hz, 1H), 4.05 (q, 7=7.1Hz, 2H), 4.01 - 3.90 (m, 8.75H), 1.37 (td, 7=7.1, 2.8 Hz, 6.5H).

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106308, 2020, A1 Location in patent: Paragraph 0223

32
[ 1214325-21-9 ]
[ 2427609-70-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C
	Multi-step reaction with 2 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

33
[ 1214325-21-9 ]
[ 2427609-71-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C 3: methanol / 72 h / 80 °C
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C 3: methanol / 72 h / 80 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

34
[ 1214325-21-9 ]
[ 2428506-36-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 72 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C 4.2: -78 - 20 °C
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 72 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C 4.2: 0.25 h / -78 °C
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 72 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C 4.2: 0.25 h / -78 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1
[3]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

35
[ 1214325-21-9 ]
[ 2427609-35-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 72 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C 4.2: -78 - 20 °C 5.1: hydrogenchloride / 1,4-dioxane / 18 h / 20 °C
	Multi-step reaction with 5 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 72 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C 4.2: 0.25 h / -78 °C 5.1: hydrogenchloride / 1,4-dioxane; water / 18 h / 20 °C
	Multi-step reaction with 5 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 72 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C 4.2: 0.25 h / -78 °C 5.1: hydrogenchloride / 1,4-dioxane; water / 18 h / 20 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1
[3]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

36
[ 1214325-21-9 ]
[ 2427609-75-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C 3: methanol / 72 h / 80 °C
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C 3: methanol / 72 h / 80 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

37
[ 1214325-21-9 ]
[ 2427609-36-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 72 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C 4.2: -78 - 20 °C 5.1: hydrogenchloride / 1,4-dioxane / 18 h / 20 °C
	Multi-step reaction with 5 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 72 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C 4.2: 0.25 h / -78 °C 5.1: hydrogenchloride / 1,4-dioxane; water / 18 h / 20 °C
	Multi-step reaction with 5 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 72 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C 4.2: 0.25 h / -78 °C 5.1: hydrogenchloride / 1,4-dioxane; water / 18 h / 20 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1
[3]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

38
[ 1214325-21-9 ]
[ 2427609-77-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C 3: methanol / 18 h / 80 °C
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C 3: methanol / 18 h / 80 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

39
[ 1214325-21-9 ]
[ 2427609-78-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 18 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 18 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 4.2: 1 h / -7 - 20 °C 4.3: 1 h / -78 - 20 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

40
[ 1214325-21-9 ]
[ 2427609-38-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 18 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C / Inert atmosphere 5.1: hydrogenchloride / 1,4-dioxane / 19.5 h / 20 °C
	Multi-step reaction with 5 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: methanol / 18 h / 80 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 4.2: 1 h / -7 - 20 °C 4.3: 1 h / -78 - 20 °C 5.1: hydrogenchloride / 1,4-dioxane; water / 19.5 h / 20 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

41
[ 1214325-21-9 ]
[ 2427609-80-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C 3: triethylamine / methanol / 72 h / 80 °C
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C 3: triethylamine / methanol / 72 h / 80 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

42
[ 1214325-21-9 ]
[ 2427609-81-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C 3: triethylamine / methanol / 72 h / 80 °C 4: lithium hydroxide; water / methanol / 0 - 20 °C
	Multi-step reaction with 4 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C 3: triethylamine / methanol / 72 h / 80 °C 4: lithium hydroxide; methanol; water / 0.5 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

43
[ 1214325-21-9 ]
[ 2427609-39-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: triethylamine / methanol / 72 h / 80 °C 4.1: lithium hydroxide; water / methanol / 0 - 20 °C 5.1: lithium hexamethyldisilazane / tetrahydrofuran / -78 °C / Inert atmosphere 5.2: -78 - 20 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: triethylamine / methanol / 72 h / 80 °C 4.1: lithium hydroxide; methanol; water / 0.5 h / 0 - 20 °C 5.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C / Inert atmosphere 5.2: 2.5 h / -78 - 20 °C 5.3: 18 h / -78 - 20 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

44
[ 1214325-21-9 ]
[ 2427609-40-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: triethylamine / methanol / 72 h / 80 °C 4.1: lithium hydroxide; water / methanol / 0 - 20 °C 5.1: lithium hexamethyldisilazane / tetrahydrofuran / -78 °C / Inert atmosphere 5.2: -78 - 20 °C / Inert atmosphere 6.1: thionyl chloride / 18 h / 0 - 20 °C
	Multi-step reaction with 6 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: triethylamine / methanol / 72 h / 80 °C 4.1: lithium hydroxide; methanol; water / 0.5 h / 0 - 20 °C 5.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C / Inert atmosphere 5.2: 2.5 h / -78 - 20 °C 5.3: 18 h / -78 - 20 °C 6.1: thionyl chloride / 18 h / 0 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

45
[ 1214325-21-9 ]
[ 2427609-82-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C 3: hydroxylamine hydrochloride; triethylamine / methanol / 90 h / 20 - 80 °C / Molecular sieve
	Multi-step reaction with 3 steps 1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2: hydrogenchloride / water / 18 h / 100 °C 3: hydroxylamine hydrochloride; triethylamine / methanol / 90 h / 80 °C / Molecular sieve

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

46
[ 1214325-21-9 ]
[ 2427609-41-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: hydroxylamine hydrochloride; triethylamine / methanol / 90 h / 20 - 80 °C / Molecular sieve 4.1: lithium hexamethyldisilazane / tetrahydrofuran / -78 °C / Inert atmosphere 4.2: -78 - 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride / water / 18 h / 100 °C 3.1: hydroxylamine hydrochloride; triethylamine / methanol / 90 h / 80 °C / Molecular sieve 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C 4.2: 0.75 h / -78 - 20 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

47
[ 1214325-21-9 ]
[ 2427609-83-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane / 18 h / 50 °C 2.2: 0.5 h / 20 °C 2.3: 1.25 h / 20 °C
	Multi-step reaction with 2 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane; water / 0.25 h / 20 °C 2.2: 18 h / 50 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

48
[ 1214325-21-9 ]
[ 2427609-42-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane / 18 h / 50 °C 2.2: 0.5 h / 20 °C 2.3: 1.25 h / 20 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C
	Multi-step reaction with 3 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane; water / 0.25 h / 20 °C 2.2: 18 h / 50 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

49
[ 1214325-21-9 ]
[ 2427609-47-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane / 48 h / 50 °C / Sealed tube 3.1: hydrogenchloride; sodium cyanoborohydride / methanol; water / 120 h / 20 °C / Inert atmosphere 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C / Inert atmosphere 4.2: 36 h / -78 - 20 °C / Inert atmosphere 5.1: samarium diiodide / tetrahydrofuran / 0.08 h / 20 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: caesium carbonate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) / tetrahydrofuran; water / 18 h / 85 °C 2.1: hydrogenchloride; triethylamine / 1,4-dioxane; water / 48 h / 50 °C 3.1: hydrogenchloride; sodium hydroxide; sodium cyanoborohydride / methanol; water / 120 h / 20 °C / Inert atmosphere 4.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.25 h / -78 °C 4.2: 18 h / -78 - 20 °C 4.3: 18 h / -78 - 20 °C 5.1: samarium diiodide / tetrahydrofuran / 0.08 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: NFLECTION THERAPEUTICS INC - WO2020/106303, 2020, A1
[2]Current Patent Assignee: NFLECTION THERAPEUTICS INC; STANFORD UNIVERSITY - WO2020/106307, 2020, A1

50
[ 1214325-21-9 ]
[ 824-94-2 ]
[ 2573798-81-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 16h;	1.1C.1C.3 To a solution of methyl 3-bromo-5-fluoroisonicotinate (B, 4.0 g, 17.17 mmol) in dimethylformamide (15 mL), potassium carbonate (7.0 g, 51.51 mmol) is added followed by drop wise addition of 4-methoxy benzyl amine (3.52 mL, 25.0 mmol at room temperature The reaction mixture is stirred for 16 h at 50 °C. After completion, the reaction mass is diluted with ethyl acetate and washed with cold water. The organic layer is separated and dried over anhydrous sodium sulphate, filtered and concentrated to give crude. The crude is purified by flash column chromatography eluting the compound with ethyl acetate in hexanes (10-20 %). The desired fractions are concentrated under reduced pressure to afford methyl 3-bromo-5-((4- methoxybenzyl)amino)isonicotinate (C).

Reference： [1]Current Patent Assignee: EFFECTOR THERAPEUTICS INC; EFFECT THERAPY STOCK LTD COMPANY - WO2021/3157, 2021, A1 Location in patent: Paragraph 0169; 0269

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	Inquiry	{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price) ]}	{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate,item.pr_is_large_size_no_price) ]}	{[ item.pr_usastock ]}		{[ item.pr_chinastock ]}	{[ item.pr_remark ]}

CAS No. :	1214325-21-9	MDL No. :	MFCD14698118
Formula :	C₇H₅BrFNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	234.02	Pubchem ID :	-
Synonyms :

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	43.17
TPSA :	39.19 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.66 cm/s

Log Po/w (iLOGP) :	1.91
Log Po/w (XLOGP3) :	1.5
Log Po/w (WLOGP) :	2.19
Log Po/w (MLOGP) :	1.51
Log Po/w (SILICOS-IT) :	2.31
Consensus Log Po/w :	1.88

[ CAS No. 1214325-21-9 ] {[proInfo.proName]}

Quality Control of [ 1214325-21-9 ]

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Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1214325-21-9 ]

Application In Synthesis of [ 1214325-21-9 ]

[ 1214325-21-9 ] Synthesis Path-Downstream 1~50

Technical Information

Related Functional Groups of
[ 1214325-21-9 ]

Fluorinated Building Blocks

Bromides

Esters

Related Parent Nucleus of
[ 1214325-21-9 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Log S (ESOL) :	-2.47
Solubility :	0.786 mg/ml ; 0.00336 mol/l
Class :	Soluble
Log S (Ali) :	-1.93
Solubility :	2.74 mg/ml ; 0.0117 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.24
Solubility :	0.135 mg/ml ; 0.000575 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.75

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 1214325-21-9 ] {[proInfo.proName]}

Quality Control of [ 1214325-21-9 ]

Related Doc. of [ 1214325-21-9 ]

Product Details of [ 1214325-21-9 ]

Calculated chemistry of [ 1214325-21-9 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1214325-21-9 ]

Application In Synthesis of [ 1214325-21-9 ]

[ 1214325-21-9 ] Synthesis Path-Downstream 1~50

Technical Information

Related Functional Groups of [ 1214325-21-9 ]

Fluorinated Building Blocks

Bromides

Esters

Related Parent Nucleus of [ 1214325-21-9 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 1214325-21-9 ]

Related Parent Nucleus of
[ 1214325-21-9 ]