[ CAS No. 1214336-88-5 ]

Name: 1214336-88-5|Methyl 6-bromo-5-fluoronicotinate|98%
Brand: Ambeed
SKU: A267342
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Quality Control of [ 1214336-88-5 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 1214336-88-5 ]

CAS No. :	1214336-88-5	MDL No. :	MFCD14698110
Formula :	C₇H₅BrFNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PXHKAVXJQLVUBI-UHFFFAOYSA-N
M.W :	234.02	Pubchem ID :	46311203
Synonyms :

Safety of [ 1214336-88-5 ]

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

Application In Synthesis of [ 1214336-88-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 1214336-88-5 ]

[ 1214336-88-5 ] Synthesis Path-Downstream 1~37

1
[ 1214336-88-5 ]
[ 2165357-45-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2: Dess-Martin periodane / dichloromethane / 20 °C
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2: Dess-Martin periodane / dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2017/355693, 2017, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - EP3257847, 2017, A1

2
[ 1214336-88-5 ]
[ 2165357-46-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: isopropylmagnesium chloride; lithium chloride / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C
	Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: TurboGrignard / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2017/355693, 2017, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - EP3257847, 2017, A1

3
[ 1214336-88-5 ]
[ 18621-18-6 ]
[ 2165357-44-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 19h;	8.1 Step 1: methyl 5-fluoro-6-(3-hydroxyazetidin-1-yl)nicotinate Step 1: methyl 5-fluoro-6-(3-hydroxyazetidin-1-yl)nicotinate (0261) A mixture of 102 azetidin-3-ol hydrochloride (2.8 g, 26 mmol), 103 methyl 6-bromo-5-fluoronicotinate (5.0 g, 21 mmol), and 23 potassium carbonate (7.4 g, 53 mmol) up in 8 DMF (100 mL) was heated at 65° C. for 19 hours. The mixture was purified by flash chromatography (silica gel) to provide the desired 104 product. LCMS-ESI+(m/z): [M+H]+ calcd for C10H12FN2O3: 227.1; found: 227.0.
	With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 19h;	3.1 Step 1: methyl 5-fluoro-6-(3-hydroxyazetidin-1-yl)nicotinate (3a) Step 1: methyl 5-fluoro-6-(3-hydroxyazetidin-1-yl)nicotinate (3a) A mixture of azetidin-3-ol hydrochloride (2.8 g, 26 mmol), methyl 6-bromo-5-fluoronicotinate (5.0 g, 21 mmol), and potassium carbonate (7.4 g, 53 mmol) in DMF (100 mL) was heated at 65 °C for 19 hours. The mixture was purified by flash chromatography (silica gel) to provide the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C10H12FN2O3: 227.1; found: 227.0.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2017/355693, 2017, A1 Location in patent: Paragraph 0260; 0261
[2]Current Patent Assignee: GILEAD SCIENCES INC - EP3257847, 2017, A1 Location in patent: Paragraph 0156; 0157

4
[ 1214336-88-5 ]
[ 2165357-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: isopropylmagnesium chloride; lithium chloride / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: TurboGrignard / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2017/355693, 2017, A1
[2]Current Patent Assignee: GILEAD SCIENCES INC - EP3257847, 2017, A1

5
[ 1214336-88-5 ]
[ 2166106-19-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: isopropylmagnesium chloride; lithium chloride / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C 5.1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 18 h / 60 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2017/355693, 2017, A1

6
[ 1214336-88-5 ]
[ 2166106-00-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: isopropylmagnesium chloride; lithium chloride / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C 5.1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 18 h / 60 °C 6.1: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2017/355693, 2017, A1

7
[ 1214336-88-5 ]
[ 2165357-64-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: TurboGrignard / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C 5.1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 65 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - EP3257847, 2017, A1

8
[ 1214336-88-5 ]
[ 2165357-33-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 65 °C 2.1: Dess-Martin periodane / dichloromethane / 20 °C 3.1: TurboGrignard / 2-methyltetrahydrofuran / 1 h / Cooling with ice 3.2: 20 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C 5.1: potassium carbonate; sodium iodide / N,N-dimethyl-formamide / 65 °C 6.1: lithium hydroxide monohydrate / tetrahydrofuran; water / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - EP3257847, 2017, A1

9
[ 823-96-1 ]
[ 1214336-88-5 ]
[ 1253383-91-3 ]

Yield	Reaction Conditions	Operation in experiment
76%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane at 110℃; for 18h; Inert atmosphere; Sealed tube;	3.1 Step 1: Methyl 5-fluoro-6-methylnicotinate The commercially available methyl 6-bromo 5-fluoronicotinate (360 mg, 1.54 mmol) was mixed with trimethyl-1,3,5,2,4,6-trioxatriborinane (966 mg, 7.69 mmol), K2CO3 (319 mg, 2.31 mmol), and Pd(Ph3P)4 (196 mg, 0.169 mmol) in 1,4-dioxane (5 mL). The mixture was sparged with N2 and stirred at 110 o C in a sealed tube under N2 atmosphere for 18 h. After cooled, the reaction was added ethyl acetate and washed with water. The organic layer was dried (Na2SO4) and filtered through Celite. Solvent was evaporated and the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 1:1) to afford the title compound, 198 mg (76%). LC-MS: m/z [M+H]+ 170.1

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1 Location in patent: Paragraph 00161-00164

10
[ 1214336-88-5 ]
[ 73930-39-9 ]
[ 2637453-28-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1-Methylnaphthalene at 120℃; for 18h; Inert atmosphere;	8.1 Step 1: Methyl 6-((2.3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate General procedure: To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 o C under N2 for 18 h. After cooled and diluted with ethyl acetate, the organic layer was washed with water. Dried (Na2SO4), filtered and concentrated, the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as a brown oil, 38 mg (31%). LC- MS: m/z [M+H]+ 287.3

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1 Location in patent: Paragraph 00205-00208; 00215-00218

11
[ 1214336-88-5 ]
[ 2637453-23-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / 1,4-dioxane / 18 h / 110 °C / Inert atmosphere; Sealed tube 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 48 h / 75 °C

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1

12
[ 1214336-88-5 ]
[ 2637453-84-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 4.08 h / 110 °C / Inert atmosphere 2: hydroxylamine; potassium hydroxide / methanol; tetrahydrofuran; water / 0.17 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1

13
[ 1214336-88-5 ]
[ 2637453-24-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / 1,4-dioxane / 18 h / 110 °C / Inert atmosphere; Sealed tube 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 48 h / 75 °C 3: potassium carbonate / acetonitrile / 18 h / 77 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1

14
[ 1214336-88-5 ]
[ 2637453-52-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / 1,4-dioxane / 18 h / 110 °C / Inert atmosphere; Sealed tube 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 48 h / 75 °C 3: potassium carbonate / acetonitrile / 18 h / 77 °C / Inert atmosphere 4: sodium cyanoborohydride; acetic acid / water; acetonitrile / 0.25 h / 20 °C

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1

15
[ 2975-41-9 ]
[ 1214336-88-5 ]
[ 2637453-26-8 ]

Yield	Reaction Conditions	Operation in experiment
31%	With potassium carbonate In 1-Methylnaphthalene at 120℃; for 18h; Inert atmosphere;	7.1 Step 1: Methyl 6-((2.3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 o C under N2 for 18 h. After cooled and diluted with ethyl acetate, the organic layer was washed with water. Dried (Na2SO4), filtered and concentrated, the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as a brown oil, 38 mg (31%). LC- MS: m/z [M+H]+ 287.3

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1 Location in patent: Paragraph 00205-00208

16
[ 35386-24-4 ]
[ 1214336-88-5 ]
[ 2637453-30-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1-Methylnaphthalene at 120℃; for 18h; Inert atmosphere;	9.1 Step 1: Methyl 6-((2.3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate General procedure: To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 o C under N2 for 18 h. After cooled and diluted with ethyl acetate, the organic layer was washed with water. Dried (Na2SO4), filtered and concentrated, the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as a brown oil, 38 mg (31%). LC- MS: m/z [M+H]+ 287.3

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1 Location in patent: Paragraph 00205-00208; 00225-00228

17
[ 98-10-2 ]
[ 1214336-88-5 ]
[ 2637453-41-7 ]

Yield	Reaction Conditions	Operation in experiment
34%	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In 1,4-dioxane at 120℃; for 1h; Inert atmosphere; Sealed tube; Microwave irradiation;	15.1 Step 1: Methyl 5-fluoro-6-(phenylsulfonamido)nicotinate The commercially available methyl 6-bromo 5-fluoronicotinate (100 mg, 0.427 mmol) was mixed with benzenesulfonamide (67.2 mg, 0.427 mmol), sodium tert-butoxide (41.1 mg, 0.427 mmol), palladium acetate (2.4 mg, 0.0107 mmol) and Xantphos (12.4 mg, 0.0214 mmol) in 1,4-dioxane under N2 atomasphere in an oven-dried sealed tube, the reaction mixture was stirred and heated at 120 o C for 1 h under microwave. After cooled, the reaction was added saturated NaHCO3, and extracted with ethyl ester (X3). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by chromatography (Silica gel, DCM/15%MeOH in DCM, 1:0 to 0:1) to afford the title compound as a white solid, 45 mg (34%). LC-MS: m/z [M+H]+ 311.3

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1 Location in patent: Paragraph 00285-00288

18
[ 91-21-4 ]
[ 1214336-88-5 ]
[ 2637453-48-4 ]

Yield	Reaction Conditions	Operation in experiment
87.2%	With dmap In N,N-dimethyl-formamide at 80℃; for 3h; Microwave irradiation;	19.1 Step 1: Methyl 6-(3,4-dihydroisoquinolin-2(1H)-yl-5-fluoronicotinate To a solution of methyl 6-bromo-5-fluoropyridine-3-carboxylate (0.15 g, 0.64 mmol) in DMF was added 1,2,3,4-tetrahydroisoquinoline (0.17 g, 1.28 mmol) and DMAP (2.0 mg). The mixture was stirred and heated at 80 o C under microwave for 3 h. After cooled, the reaction was added saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as an oil, 160 mg (87.2%).

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1 Location in patent: Paragraph 00321-00324

19
[ 1214336-88-5 ]
[ 124-40-3 ]
[ 813425-23-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1-Methylnaphthalene at 120℃; for 18h; Inert atmosphere;	25.1 Step 1: Methyl 6-((2.3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate General procedure: To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 o C under N2 for 18 h. After cooled and diluted with ethyl acetate, the organic layer was washed with water. Dried (Na2SO4), filtered and concentrated, the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as a brown oil, 38 mg (31%). LC- MS: m/z [M+H]+ 287.3

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1 Location in patent: Paragraph 00205-00208; 00370-00374

20
[ 39093-93-1 ]
[ 1214336-88-5 ]
[ 2637453-57-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1-Methylnaphthalene at 120℃; for 18h; Inert atmosphere;	26.1 Step 1: Methyl 6-((2.3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate General procedure: To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 o C under N2 for 18 h. After cooled and diluted with ethyl acetate, the organic layer was washed with water. Dried (Na2SO4), filtered and concentrated, the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as a brown oil, 38 mg (31%). LC- MS: m/z [M+H]+ 287.3

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1 Location in patent: Paragraph 00205-00208; 00381-00385

21
[ 109-01-3 ]
[ 1214336-88-5 ]
[ 2637453-59-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1-Methylnaphthalene at 120℃; for 18h; Inert atmosphere;	27.1 Step 1: Methyl 6-((2.3-dihydro-1H-inden-2-yl)amino-5-fluoronicotinate General procedure: To a solution of methyl 5-fluoro-6-bromonicotinate (100 mg, 0.47 mmol) in NMP (2 mL) was added 2,3-dihydro-1H-inden-2-amine (62.6 mg, 0.47 mmol) and K2CO3 (195 mg, 1.41 mmol) in a vial. The reaction mixture was stirred and heated at 120 o C under N2 for 18 h. After cooled and diluted with ethyl acetate, the organic layer was washed with water. Dried (Na2SO4), filtered and concentrated, the resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 0:1) to afford the title compound as a brown oil, 38 mg (31%). LC- MS: m/z [M+H]+ 287.3

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1 Location in patent: Paragraph 00205-00208; 00393-00398

22
[ 1214336-88-5 ]
[ 411235-57-9 ]
[ 1354225-34-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane at 110℃; for 4.08h; Inert atmosphere;	A mixture of methyl 6-bromo-5-fluoropyridine-3-carboxylate (70 mg, 0.3 mmol), cyclopropylboronic acid (128 mg, 1.5 mmol), potassium carbonate (62.0 mg, 0.45 mmol) in 1,4- dioxane (1.5 mL) was flushed with nitrogen for 10 min. [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (43.8 mg, 0.06 mmol) was added and the mixture was flushed with nitrogen again for 5 min and heated in microwave at 110 °C for 4h. LCMS showed complete conversion. The mixture was partitioned in ethyl acetate and water. The layers were separated. The aqueous layer was extracted with ethyl acetate (2x) and the combined organic layers were filtered over a pad of celite. The filtrate was concentrated to half of the volume and washed with water (3x), brine and concentrated to give 169 mg crude volatile oil. This material was purified by column chromatography (4 g SiO2, 0-10% ethyl acetate in hexane). Fractions containing the desired product were combined and collected to 55.3 mg (95%) colorless oil. [00524] Methyl 6-cyclopropyl-5-fluoropyridine-3-carboxylate: [00525] LCMS m/z [M+H]+ C9H9FN2O2 requires: 195.07, found 195.1 [00526] 1H NMR (400 MHz, CDCl3) δ= 8.85 (s, 1 H), 7.85 (dd, J=9.90, 1.59 Hz, 1 H), 3.94 (s, 3 H), 2.35 - 2.45 (m, 1 H), 1.19 - 1.26 (m, 2 H), 1.09 - 1.15 (m, 2 H) ppm.

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1 Location in patent: Paragraph 00523-00526

23
[ 844470-80-0 ]
[ 1214336-88-5 ]
[ 2637453-37-1 ]

Yield	Reaction Conditions	Operation in experiment
15.5%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 1h; Microwave irradiation;	12.4 Step 4: Methyl (S )-6-((cyclopropyl(phenyl)methyl)amino)-5-fluoronicotinate The commercially available methyl 5-bromo-3-fluoronicotinate (50 mg, 0.214 mmol) was mixed with (S)-cyclopropyl(phenyl)methanamine hydrochloride (59 mg, 0.320 mmol) and diisopropylethylamine (166 mg, 1.28 mmol) in DMSO (2 mL). The mixture was stirred and heated under microwave at 100 o C for 1 h. After cooled, the reaction was added water and extracted with ethyl acetate. The organic layers were dried (Na2SO4), filtered and concentrated. The resulting residue was purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 1:1) to afford the title compound, 10 mg (15.5%). LC-MS: m/z [M+H]+ 301.3

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1 Location in patent: Paragraph 00255-00256; 00263-00264

24
[ 4248-19-5 ]
[ 1214336-88-5 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
72.1%	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In 1,4-dioxane at 75℃; for 5h; Sealed tube; Inert atmosphere;	4.1 Step 1: Tert-butyl-(3-fluoro-5-(hydroxycarbamoy)pyridine-2-yl)carbamate Methyl 6-bromo 5-fluoronicotinate (300 mg, 1.28 mmol) was mixed with tert-butyl carbamate (150 mg, 1.28 mmol), sodium tert-butoxide (123 mg, 1.28 mmol), palladium acetate (7.20 mg, 0.032 mmol) and Xantphos (37.1 mg, 0.064 mmol) in 1,4-dioxane in an oven-dried sealed tube. After evacuated and refilled with N2 (X3), the mixture was stirred and heated at 75 o C for 5 h. After cooled, the reaction was added ethyl acetate and washed with water. The organic layer was dried (Na2SO4), concentrated and purified by chromatography (Silica gel, hexane/ethyl acetate, 1:0 to 5:1) to afford a white solid as the title compound, 250 mg (72.1%). LC-MS: m/z [2M+Na]+ 563.5

Reference： [1]Current Patent Assignee: TENAYA THERAPEUTICS INC - WO2021/67859, 2021, A1 Location in patent: Paragraph 00171-00174

25
[ 1227068-84-9 ]
[ 1214336-88-5 ]
[ 2758440-93-4 ]

Yield	Reaction Conditions	Operation in experiment
2.2 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; Cs₂CO₃ In 1,4-dioxane; lithium hydroxide monohydrate at 90℃;	10.1 Step 1: methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (2.0 g, 8.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (2 mL) and water (2 mL), then Cs2CO3 (5.6 g, 17.1 mmol, 2.0 equiv.), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, 8.5 mmol, 1.0 equiv.) and Pd(dppf)Cl2CH2Cl2 (1.4 g, 1.7 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated overnight at 90 °C, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate (2.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 272.
2.2 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; Cs₂CO₃ In 1,4-dioxane; lithium hydroxide monohydrate at 90℃;	10.1 Step 1: methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (2.0 g, 8.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (2 mL) and water (2 mL), then Cs2CO3 (5.6 g, 17.1 mmol, 2.0 equiv.), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, 8.5 mmol, 1.0 equiv.) and Pd(dppf)Cl2CH2Cl2 (1.4 g, 1.7 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated overnight at 90 °C, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate (2.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 272.
2.2 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; Cs₂CO₃ In 1,4-dioxane; lithium hydroxide monohydrate at 90℃;	10.1 Step 1: methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate Methyl 6-bromo-5-fluoropyridine-3-carboxylate (2.0 g, 8.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (2 mL) and water (2 mL), then Cs2CO3 (5.6 g, 17.1 mmol, 2.0 equiv.), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, 8.5 mmol, 1.0 equiv.) and Pd(dppf)Cl2CH2Cl2 (1.4 g, 1.7 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated overnight at 90 °C, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give methyl 6-(4,4-difluorocyclohex-1-en-1-yl)-5-fluoropyridine-3-carboxylate (2.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 272.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2022/15957, 2022, A1 Location in patent: Page/Page column 122
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2022/15957, 2022, A1 Location in patent: Page/Page column 122
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2022/15957, 2022, A1 Location in patent: Page/Page column 122

26
[ 1214336-88-5 ]
[ 2758440-80-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: Cs₂CO₃; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct / lithium hydroxide monohydrate; 1,4-dioxane / 90 °C 2: hydrogen; Adams’s catalyst / dichloromethane / 20 °C 3: lithium aluminium hydride / tetrahydrofuran / 0.5 h / 0 °C 4: phosphorus tribromide / dichloromethane / 1 h / 0 °C 5: potassium carbonate / acetonitrile / 16 h / 20 °C