[ CAS No. 884494-81-9 ] {[proInfo.proName]}

Name: 884494-81-9|3-Bromo-5-fluoro-2-methoxypyridine|98%
Brand: Ambeed
SKU: A193712
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Quality Control of [ 884494-81-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 884494-81-9 ]

CAS No. :	884494-81-9	MDL No. :	MFCD04972397
Formula :	C₆H₅BrFNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HSWCOAGQYSBFAK-UHFFFAOYSA-N
M.W :	206.01	Pubchem ID :	40427006
Synonyms :

Calculated chemistry of [ 884494-81-9 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.39
TPSA :	22.12 Å²

Pharmacokinetics

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) :	-6.17 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.19
Log Po/w (XLOGP3) :	1.95
Log Po/w (WLOGP) :	2.41
Log Po/w (MLOGP) :	1.76
Log Po/w (SILICOS-IT) :	2.45
Consensus Log Po/w :	2.15

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.72
Solubility :	0.389 mg/ml ; 0.00189 mol/l
Class :	Soluble
Log S (Ali) :	-2.04
Solubility :	1.88 mg/ml ; 0.00914 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.29
Solubility :	0.106 mg/ml ; 0.000513 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.88

Safety of [ 884494-81-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P501-P210-P264-P280-P302+P352-P370+P378-P337+P313-P305+P351+P338-P362+P364-P332+P313-P403+P235	UN#:	N/A
Hazard Statements:	H315-H319-H227	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 884494-81-9 ]

* 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.

Upstream synthesis route of [ 884494-81-9 ]
Downstream synthetic route of [ 884494-81-9 ]

[ 884494-81-9 ] Synthesis Path-Upstream 1~4

1
[ 884494-81-9 ]
[ 351410-62-3 ]

Reference： [1] Patent: US9096593, 2015, B2,

2
[ 884494-81-9 ]
[ 874822-98-7 ]

Reference： [1] Patent: US9096593, 2015, B2,

3
[ 884494-94-4 ]
[ 74-88-4 ]
[ 884494-81-9 ]

Yield	Reaction Conditions	Operation in experiment
43.8%	With silver carbonate In toluene at 20℃;	Preparation J; (R)- 5 -fluoro-2-methoxy-3 -(pyrrolidin-2-yl)pyridine; Step A: Preparation of 3-bromo-5-fluoro-2-methoxypyridine.; 3-Bromo-5- fluoropyridin-2(lH)-one (10.0 g, 52.1 mmol) and Ag₂CO₃ (10.0 g, 36.5 mmol) were combined in toluene (100 mL) and iodomethane (3.89 mL, 62.5 mmol) was added drop-wise. The reaction was stirred at ambient temperature overnight, filtered through Celite and the solids were washed with toluene. The filtrate was concentrated and the residue was purified on a silica gel column (5-25percent EtOAc/hexanes) to afford 3-bromo-5-fluoro-2- methoxypyridine (4.70 g, 43.8percent) as a clear oil.

Reference： [1] Patent: WO2011/6074, 2011, A1, . Location in patent: Page/Page column 74-75

4
[ 884494-81-9 ]
[ 884494-82-0 ]

Reference： [1] Patent: US9096593, 2015, B2,

[ 884494-81-9 ] Synthesis Path-Downstream 1~88

1
[ 884494-81-9 ]
[ 149104-90-5 ]
[ 943153-14-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 150℃; for 0.333333h;Irradiation;	1-Methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid {1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-amide A mixture of <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxy-pyridine</strong> (1.0 g, 4.9 mmol), 4-acetylphenylboronic acid (1.59 g, 9.7 mmol), tetrakis(triphenylphosphine)palladium (0) (0.28 g, 0.24 mmol), 2M aqueous sodium carbonate solution (2.4 ml) and 1,2-dimethoxyethane (5 ml) was heated in a microwave oven at 150 C. for 20 min. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue chromatographed on silica gel eluting with 3:1 heptane/ethyl acetate to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanone (1.0 g, 4.0 mmol, 82%). 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanone (1.0 g, 4.1 mmol) was treated with sodium borohydride (4.0 eq) in tetrahydrofuran and dichloromethane at room temperature. The solvent was evaporated to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanol (0.51 g, 2.1 mmol, 51%). To a solution 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanol (0.5 g, 2.0 mmol) in tetrahydrofuran (5 ml) was added triphenylphosphine (0.63 g, 2.4 mmol) and pthalimide (0.35 g, 2.4 mmol). The reaction was cooled to below 5 C. before adding diethylazodicarboxylate (0.42 g, 2.4 mmol) in a dropwise manner maintaining the temperature below 5 C. The reaction mixture was stirred for 24 h at room temperature. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue chromatographed on silica gel to give to give 2-{1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.31 g, 0.82 mmol, 41%). To a solution of 2-{1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.31 g, 0.8 mmol) in dioxan/methanol (1:1, 10 ml) was added hydrazine hydrate (0.83 g, 46.5 mmol). The reaction was stirred at room temperature for 24 h. The solvent was evaporated and dichloromethane added. The resultant white solid was filtered off and dried to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethylamine (0.21 g, 0.8 mmol, 100%) as a clear oil. To a solution of 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethylamine (0.1 g, 0.4 mmol) in dichloromethane (2 ml) was added triethylamine (123 mg, 1.2 mmol) and 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonylchloride (111 mg, 0.45 mmol). The reaction mixture was agitated for 16 h and quenched with saturated aqueuos sodium bicarbonate solution. The organic phase was washed with water, brine and dried over anhydrous magneium sulfate. The residue was chromatographed on silica gel to give the title compound (42 mg, 0.1 mmol, 25%). 1H NMR (400 MHz, CDCl3): delta 8.00 (d, 1H), 7.45 (m, 3H), 7.35 (dd, 1H), 7.21 (d, 2H), 4.86 (d, 1H), 4.60 (q, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 1.50 (b, 3H) ppm; MS (ESI) m/z: 459.3 [M+H]+.

Reference： [1]Patent: US2007/149577,2007,A1 .Location in patent: Page/Page column 13

2
[ 884494-81-9 ]
[ 73183-34-3 ]
[ 1083168-95-9 ]

Yield	Reaction Conditions	Operation in experiment
81.4%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 0.75h;	3-Bromo-5-fluoro-2-methoxypyridine (250 mg, 1.21 mmol) was added to a stirred solution of 452 KOAc (238.2 mg, 2.42 mmol) in 115 dioxane (10 mL) followed by the addition of 456 bispinacolatodiborane (308.1 mg, 1.21 mmol). The reaction mixture was degassed with N2 for 10 mins and PdCl2(dppf).DCM (99.02 mg, 0.12 mmol) added and degassed for another 10 min. The reaction mixture was heated at 100 C. for 45 mins and evaporated to dryness under reduced pressure. The residue was dissolved in 50% 81 EtOAc in 82 hexane, filtered through Celite and evaporated to dryness in vacuo afford the 457 title compound (250 mg, 81.4%) which was used without further purification. LCMS m/z=254 [MH]+
60%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃;	AJ. 5-fluoro-2-methoxy-3-(4A5,5-tetramethyl-lJ,2-dioxaborolan-2-yl)pyridine; To a dry flask was added <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxypyridine</strong> (1.0 g, 5.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.6 g, 6.4 mmol), and Pd(dppf)Cl2 (0.2 g, 0.25 mmol). Potassium acetate (1.5 g, 15 mmol) was weighed directly into the flask. The flask was then evacuated and back filled with N2. Anhydrous N,N- dimethylformamide (30 mL) was added and the reaction was heated at 80 0C in an oil bath overnight. The reaction mixture was evaporated to dryness. The residue was dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting material was purified by silica gel chromatography eluting with 0-50% ethyl acetate in hexane to yield the product (1.0 g, 80%). ESI-MS m/z calc. 253.13, found 254.1 (MW+1)+. Retention time 1.72 minutes.

Reference： [1]Patent: US2018/141954,2018,A1 .Location in patent: Paragraph 0576; 0577
[2]Patent: WO2008/141119,2008,A2 .Location in patent: Page/Page column 105

3
[ 67-56-1 ]
[ 884494-81-9 ]
[ 124-41-4 ]
[ 1093951-75-7 ]

Yield	Reaction Conditions	Operation in experiment
35%	at 130℃; for 0.833333h;Microwave irradiation;	3-Bromo-2,5-dimethoxypyridineA stirred mixture of <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxypyridine</strong> (2.7 g, 13.1 mmol) and a solution of sodium methoxide in MeOH (6.0 ml, 25% wt) was subjected to 130 C under microwave conditions for 50 minutes. The cooled mixture was concentrated, partitioned between water and ether, and extracted with ether. The combined organics were washed with brine, dried, and concentrated to give the title compound as a white solid (1.0 g, 35%). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 7.77 (d, J=2.7 Hz, 1 H) 7.47 (d, J=2.7 Hz, 1 H) 3.96 (s, 3 H) 3.81 (s, 3 H). MS APCI, m/z=218/220. (M+H).

Reference： [1]Patent: US2008/318943,2008,A1 .Location in patent: Page/Page column 76

4
[ 884494-94-4 ]
[ 74-88-4 ]
[ 884494-81-9 ]

Yield	Reaction Conditions	Operation in experiment
43.8%	With silver carbonate; In toluene; at 20℃;	Preparation J; (R)- 5 -fluoro-2-methoxy-3 -(pyrrolidin-2-yl)pyridine; Step A: Preparation of 3-bromo-5-fluoro-2-methoxypyridine.; 3-Bromo-5- fluoropyridin-2(lH)-one (10.0 g, 52.1 mmol) and Ag2CO3 (10.0 g, 36.5 mmol) were combined in toluene (100 mL) and iodomethane (3.89 mL, 62.5 mmol) was added drop-wise. The reaction was stirred at ambient temperature overnight, filtered through Celite and the solids were washed with toluene. The filtrate was concentrated and the residue was purified on a silica gel column (5-25% EtOAc/hexanes) to afford 3-bromo-5-fluoro-2- methoxypyridine (4.70 g, 43.8%) as a clear oil.

Reference： [1]Patent: WO2011/6074,2011,A1 .Location in patent: Page/Page column 74-75

5
[ 884494-81-9 ]
[ 5419-55-6 ]
[ 957120-32-0 ]

Yield	Reaction Conditions	Operation in experiment
66%		PREPARATION 10; (5-Fluoro-2-methoxypyridin-3-yl)boronic acid n-Butyllithium (1.6 M solution in hexanes, 20 mL, 32 mmol) was slowly added (0.4 mL/min) to a solution of <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxypyridine</strong> (6.0 g, 29.12 mmol) and triisopropylborate (8.4 mL, 36.62 mmol) in dry tetrahydrofuran (70 mL) at -100 C under argon atmosphere. The reaction mixture was stirred at -100 C for 2 hours and afterwards the temperature was allowed to warm up slowly overnight to ambient temperature before being cooled down to 0 C. Aqueous hydrochloric acid (1 N solution, 120 mL) was slowly added and the mixture was stirred at 0 C for 1 hour. A solution of sodium hydroxide (32% in water) was then added until pH was around 6 and the resulting mixture was extracted with diethyl ether (chi3). The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure to yield the title compound (3.28 g, 66%) as a white solid. X LRMS (m/z): 172 (M+1)+.1H-NMR delta (300 MHz, CDCI3): 4.04 (s, 3H), 6.00 (s, 2H), 7.88 (dd, 1 H), 8.09 (d,1 H).
66%		PREPARATION 10; (5-Fluoro-2-methoxypyridin-3-yl)boronic acid n-Butyllithium (20 mL of a 1.6 M solution in hexanes, 32 mmol) was slowly added (0.4 mL/min) to a solution of <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxypyridine</strong> (6.0 g, 29.12 mmol) and triisopropylborate (8.4 mL, 36.62 mmol) in dry tetrahydrofuran (70 mL) at -100 ºC under argon atmosphere. The reaction mixture was stirred at -100 ºC for 2 hours and afterwards the temperature was allowed to warm up slowly overnight to room temperature before being cooled down to 0 ºC. Aqueous hydrochloric acid (120 mL of a 1 N solution) was slowly added and the mixture was stirred at 0 ºC for 1 hour. A solution of sodium hydroxide (32% in water) was then added until pH was around 6 and the resulting mixture was extracted with diethyl ether (x3). The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure to yield the title compound (3.28 g, 66%) as a white solid. LRMS (m/z): 172 (M+1)+. 1H-NMR delta (300 MHz, CDCl3): 4.04 (s, 3H), 6.00 (s, 2H), 7.88 (dd, 1H), 8.09 (d, 1H).

Reference： [1]Patent: WO2012/69202,2012,A1 .Location in patent: Page/Page column 52
[2]Patent: EP2463289,2012,A1 .Location in patent: Page/Page column 21

6
[ 884494-81-9 ]
[ 874822-98-7 ]

Reference： [1]Patent: US9096593,2015,B2
[2]Patent: WO2019/184955,2019,A1

7
[ 884494-81-9 ]
[ 1196662-32-4 ]

Reference： [1]Patent: US9096593,2015,B2

8
[ 884494-81-9 ]
6-[(5-fluoro-2-methoxypyridin-3-ylmethyl)amino]nicotinic acid methyl ester [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

9
[ 884494-81-9 ]
{6-[(5-fluoro-2-methoxypyridin-3-ylmethyl)amino]pyridin-3-yl}methanol [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

10
[ 884494-81-9 ]
6-[(5-fluoro-2-methoxypyridin-3-ylmethyl)amino]pyridine-3-carbaldehyde [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

11
[ 884494-81-9 ]
(5-fluoro-2-methoxypyridin-3-ylmethyl)-[3-methoxy-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyridin-2-yl]amine [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

12
[ 884494-81-9 ]
5-fluoro-N-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyridin-2-yl]-2-methoxynicotinamide [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

13
[ 884494-81-9 ]
[ 884494-82-0 ]

Reference： [1]Patent: US9096593,2015,B2
[2]Patent: WO2019/184955,2019,A1

14
[ 884494-81-9 ]
5-fluoro-2-methoxynicotinoyl chloride [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

15
[ 884494-81-9 ]
(5-fluoro-2-methoxypyridin-3-ylmethyl){6-fluoro-5-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]pyridin-2-yl}amine [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2
[2]Patent: US9096593,2015,B2

16
[ 884494-81-9 ]
[5-(1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoropyridin-2-yl](5-fluoro-2-methoxypyridin-3-ylmethyl)amine [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

17
[ 884494-81-9 ]
4-[4-(1-benzenesulfonyl-3-{2-fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)amino]pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

18
[ 884494-81-9 ]
[5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amine [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

19
[ 884494-81-9 ]
3-{2-fluoro-6-[(5-fluoro-2-methoxypyridin-3-ylmethyl)amino]pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methylamide [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

20
[ 67-56-1 ]
[ 884494-81-9 ]
[ 201230-82-2 ]
[ 122433-52-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; at 100℃; under 5171.62 Torr;	In a 2 L Parr bomb, <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxy-pyridine</strong> (34, 14 g, 68.0 mmol), triethylamine (19.10 mL, 136 mmol) and [1,1?-bis(diphenylposphino)ferrocene]-dichloropalladium(II) (1.443 g, 1.767 mmol) were combined with 300 mL of methanol and heated at 100 C. under 100 psi of carbon monoxide overnight. The reaction was concentrated under vacuum, the residue dissolved in dichloromethane, and passed through a plug of silica, eluting with ethyl acetate to provide the desired compound as a white solid (35, 10 g, 54.0 mmol, 79%).

Reference： [1]Patent: US9096593,2015,B2 .Location in patent: Page/Page column 98; 99

21
[ 884494-81-9 ]
4-[4-(3-{2-fluoro-6-[(5-fluoro-2-methoxypyridin-3-ylmethyl)amino]pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2
[2]Patent: US9096593,2015,B2

22
[ 884494-81-9 ]
N-(3-{2-fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

23
[ 884494-81-9 ]
[6-fluoro-5-(5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyridin-2-yl](5-fluoro-2-methoxypyridin-3-ylmethyl)amine [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

24
[ 884494-81-9 ]
3-{2-fluoro-6-[(5-fluoro-2-methoxypyridin-3-ylmethyl)amino]pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Patent: US9096593,2015,B2

25
[ 14396-90-8 ]
[ 884494-81-9 ]
2-(4-(5-fluoro-2-methoxypyridin-3-yl)but-3-ynyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In N,N-dimethyl-formamide; at 90℃; for 2h;Inert atmosphere;	A solution <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxypyridine</strong> (4.00 g, 19.4 mmol), 2-(but-3-ynyl)isoindoline-1,3-dione (3.87 g, 19.4 mmol) and TEA (10.8 mL, 78 mmol) in DMF (40 mL) was degassed with argon. After addition of Pd(PPh3)4 (1.12 g, 0.971 mmol) and CuI (0.370 g, 1.94 mmol), the reaction mixture was heated at 90 C. for 2 hours and cooled to room temperature. After addition of MeOH, a precipitated solid was collected by filtration. The solid was washed with MeOH and dried under vacuum to afford 2-(4-(5-fluoro-2-methoxypyridin-3-yl)but-3-ynyl)isoindoline-1,3-dione (5.80 g, 92%) as a white fluffy solid. 1H-NMR (CDCl3, Varian, 400 MHz): delta 2.90 (2H, t, J=6.8 Hz), 3.85 (3H, s), 3.99 (2H, t, J=6.8 Hz), 7.34 (1H, dd, J=7.6, 2.4 Hz), 7.73-7.75 (2H, m), 7.87-7.89 (3H, m).

Reference： [1]Patent: US2016/168156,2016,A1 .Location in patent: Paragraph 0183; 0187; 0188

26
[ 884494-81-9 ]
5-(5-fluoro-2-methoxypyridin-3-yl)-7-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ No CAS ]

Reference： [1]Patent: US2018/141954,2018,A1

27
[ 884494-81-9 ]
(+)-5-(5-fluoro-2-methoxypyridin-3-yl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ No CAS ]
(-)-5-(5-fluoro-2-methoxypyridin-3-yl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ No CAS ]

Reference： [1]Patent: US2018/141954,2018,A1

28
[ 884494-81-9 ]
7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ No CAS ]

Reference： [1]Patent: US2018/141954,2018,A1

29
[ 884494-81-9 ]
[ 1083168-36-8 ]

Reference： [1]Patent: WO2008/141119,2008,A2

30
[ 884494-81-9 ]
[ 1083168-37-9 ]

Reference： [1]Patent: WO2008/141119,2008,A2

31
[ 884494-81-9 ]
3-(2,4-dimethoxybenzyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione [ No CAS ]
C₂₂H₂₅FN₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 18.0 g (87.4 mmol) of <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxypyridine</strong> in 63 mL of anhydrous THF was added 67.0 mL (87.1 mmol, 1 .3 M in THF) of i-PrMgCI LiCI slowly at 0 C. The mixture was stirred at rt under Ar atmosphere for 4 h.To a stirred solution of 12.6 g (43.6 mmol) of compound 17-1 in 10 mL of DCM was added 130 mL of the above Grignard reagent (-0.4 M in THF) at -78 C. The mixture was stirred at rt under Ar atmosphere overnight, then quenched by addition of 200 mL of saturated NH4CI at 0 C. The organic phase was separated, dried over anhydrous Na2S04. After filtration, the filtrate was concentrated to afford a residue, which was purified by Ci8column eluting with 0 to 30 % gradient of ACN in H20 (0.5 % NH4HCO3) to afford compound 17-2. LC-MS: m/e = 417 [M+H]+.

Reference： [1]Patent: WO2019/94143,2019,A1 .Location in patent: Paragraph 194

32
[ 884494-81-9 ]
[ 73286-71-2 ]
C₁₅H₁₉FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; potassium carbonate; triphenylphosphine; In 1,4-dioxane; at 100℃;Inert atmosphere;	To a solution of 15.0 g (72.8 mmol) of <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxypyridine</strong> in 300 mL of dioxane were added 17.2 g (102 mmol) of terf-butyl 2,3-dihydro-1 H-pyrrole-1 -carboxylate,3.80 g (14.5 mmol) of PPh3, 30.30 g (219.2 mmol) of K2C03and 1 .6 g (7.3 mmol) of Pd(OAc)2. The solution was stirred at 100 C overnight under nitrogen atmosphere and cooled down to rt. The mixture was diluted with 1000 mL of water, extracted with three 300 mL portions of ethyl acetate. The combined organic layers were washed with 300 mL of brine, dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography eluting with 6 % ethyl acetate in petroleum ether to afford compound 18-1 . LC-MS: m/e = 295 [M+H]+.

Reference： [1]Patent: WO2019/94143,2019,A1 .Location in patent: Paragraph 205

33
[ 884494-81-9 ]
[ 73286-71-2 ]
C₁₆H₂₁FN₂O₃ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

34
[ 884494-81-9 ]
[ 943516-56-1 ]
C₁₃H₁₇FN₂O*(x)ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of 5.40 g (26.0 mmol) of <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxypyridine</strong> in 30 mL of THF was added 19.9 mL (26.0 mmol) of chloro(propan-2-yl)magnesium dropwise at 0 C under nitrogen atmosphere. The mixture was stirred at 0 C for 2 h and cooled to -78 C, a solution of 700 mg (6.40 mmol) of compound 24-1 in 10 mL of THF was added dropwise. The mixture was warm to RT and stirred for 2 h, and quenched with water at 0 C. It was adjusted to pH 6 with 1 N HCI, extracted with two 20 mL portions of ethyl acetate. The aqueous layer was concentrated under reduced pressure to obtain compound 24-2 as HCI salt, which was used in next step without further purification. LC-MS: m/e = 237 [M+H]+.

Reference： [1]Patent: WO2019/94143,2019,A1 .Location in patent: Paragraph 239

35
[ 884494-81-9 ]
C₁₄H₂₀FN₃O₃ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

36
[ 884494-81-9 ]
C₉H₁₂FN₃O*(x)ClH [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

37
[ 884494-81-9 ]
C₁₈H₁₉FN₆O₃ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

38
[ 884494-81-9 ]
C₁₇H₁₇FN₆O₃ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

39
[ 884494-81-9 ]
C₂₉H₂₈FN₇O₅ [ No CAS ]
C₂₉H₂₈FN₇O₅ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

40
[ 884494-81-9 ]
C₂₁H₂₆FN₇O₃ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

41
[ 884494-81-9 ]
C₁₉H₂₂FN₇O₃ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

42
[ 884494-81-9 ]
C₁₆H₂₂FN₃O₃ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

43
[ 884494-81-9 ]
C₁₀H₁₃FN₂O*2ClH [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

44
[ 884494-81-9 ]
C₁₉H₂₀FN₅O₃ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

45
[ 884494-81-9 ]
C₁₈H₁₈FN₅O₃ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

46
[ 884494-81-9 ]
C₁₉H₁₇F₄N₅O₅S [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

47
[ 884494-81-9 ]
C₂₇H₃₁FN₆O₄ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

48
[ 884494-81-9 ]
C₁₆H₁₆FN₅O [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

49
[ 884494-81-9 ]
C₁₆H₁₅FN₆O₃ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

50
[ 884494-81-9 ]
ethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1
[2]Patent: CN109575025,2019,A

51
[ 884494-81-9 ]
[ 870-46-2 ]
C₁₁H₁₆FN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In toluene; at 105℃; for 2h;Inert atmosphere;	To a stirred solution of 5.0 g (24 mmol) of <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxypyridine</strong> in 35 mL of toluene were added 3.2 g (24 mmol) of (tert-butoxy)carbohydrazide, 1 .0 g (1 .4 mmol) of Pd(dppf)CI2and 4.0 g (12 mmol) of Cs2C03. The mixture was stirred at 105 C for 2 h under nitrogen atmosphere and cooled to rt. The mixture was concentrated to afford a residue, which was purified by silica gel column chromatography eluting with 0 to 10 % gradient of ethyl acetate in petroleum ether to afford compound 2-1 . LC-MS: m/e = 258 [M+H]+.

Reference： [1]Patent: WO2019/94143,2019,A1 .Location in patent: Paragraph 080

52
[ 884494-81-9 ]
[ 135884-31-0 ]
C₁₅H₁₇FN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; palladium diacetate; XPhos; In tetrahydrofuran; water; at 70℃;Inert atmosphere;	To a solution of 5.0 g (24 mmol) of <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxypyridine</strong> in 100 mL of THF and 10 mL of H20 were added 5.1 g (24 mmol) of [1 -[(tert-butoxy)carbonyl]-1 H-pyrrol-2- yl]boronic acid, 0.27 g (1 .2 mmol) of Pd(OAc)2, 2.3 g (4.9 mmol) of XPhos and 15.4 g (72.8 mmol) of K3PO4 at rt. The mixture was stirred at 70 C for overnight under nitrogen atmosphere and cooled down to rt. It was diluted with 500 mL of water and extracted with 500 mL of ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated to afford a residue, which was purified by chromatography on silica gel column eluting with 0 to 100 % gradient of ethyl acetate in petroleum ether to afford compound 7-1 . LC-MS: m/e = 293 [M+H]+.

Reference： [1]Patent: WO2019/94143,2019,A1 .Location in patent: Paragraph 108

53
[ 884494-81-9 ]
[ 135884-31-0 ]
C₁₅H₂₁FN₂O₃ [ No CAS ]

Reference： [1]Patent: WO2019/94143,2019,A1

54
[ 884494-81-9 ]
C₁₈H₁₈FN₅O₃ [ No CAS ]