[ CAS No. 866775-09-9 ]

Name: 866775-09-9|Methyl 3-amino-6-bromopicolinate|97%
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Quality Control of [ 866775-09-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 866775-09-9 ]

CAS No. :	866775-09-9	MDL No. :	MFCD11656228
Formula :	C₇H₇BrN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FETASVOVQOWEBL-UHFFFAOYSA-N
M.W :	231.05	Pubchem ID :	45480453
Synonyms :

Calculated chemistry of [ 866775-09-9 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	47.62
TPSA :	65.21 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.34 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.64
Log Po/w (XLOGP3) :	1.93
Log Po/w (WLOGP) :	1.22
Log Po/w (MLOGP) :	0.51
Log Po/w (SILICOS-IT) :	1.17
Consensus Log Po/w :	1.29

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.73
Solubility :	0.434 mg/ml ; 0.00188 mol/l
Class :	Soluble
Log S (Ali) :	-2.92
Solubility :	0.276 mg/ml ; 0.00119 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.6
Solubility :	0.578 mg/ml ; 0.0025 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.99

Safety of [ 866775-09-9 ]

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:

Application In Synthesis of [ 866775-09-9 ]

* 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 [ 866775-09-9 ]
Downstream synthetic route of [ 866775-09-9 ]

[ 866775-09-9 ] Synthesis Path-Upstream 1~3

1
[ 36052-27-4 ]
[ 866775-09-9 ]

Yield	Reaction Conditions	Operation in experiment
74%	With sulfuric acid; bromine In water; acetic acid at 10 - 35℃; for 4 h;	(Step 2) (1071) To a mixture of methyl 3-aminopyridine-2-carboxylate (17 g, 111.8 mmol) in a mixed solvent of water (288 mL) and 2M sulfuric acid (58 mL) was added a solution of bromine (5.76 mL, 111.8 mmol) in acetic acid (43 mL) at room temperature, and the mixture was stirred at room temperature for 4 hr. The pH of the mixture was adjusted to 6 with 2N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (x2), the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; dichloromethane) to give methyl 3-amino-6-bromopyridine-2-carboxylate (19.2 g, 74percent) as a white solid. ¹H- NMR(300MHz,CDCl₃)δ3.94(3H,s),5.81(2H,brs),6.93(1H,d,J=8.72Hz), 7.32(1H,d,J=8.71Hz).
69%	Stage #1: With sulfuric acid; bromine; acetic acid In water	Step 2;. Preparation of 3-amino-6-bromo-pyridine-2-carboxylic acid methyl ester; Add a solution of 2 M sulfuric acid (2 mL) to a suspension of 3-amino-pyridine-2- carboxylic acid methyl ester (0.59 g, 3.88 mmol) in water (10 mL) and stir the mixture until the precipitate is dissolved. Add dropwise a solution of bromine (0.199 mL, 3.88 mmol) in acetic acid (1.5 mL). Add a solution of 2 M sodium hydroxide until pH = 6 and extract with ethyl acetate. Separate the organic layer and extract with ethyl acetate. Dry the combined organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue using silica gel chromatography eluting with ethyl acetate/hexanes to afford the title compound (0.616 g, 69percent). H-NMR (CDCl3,300 MHz) : No. 3.90 (s, 3 H) ; 6.90 (d, J = 8.5 Hz, 1H), 7.30 (d, J= 8.5 Hz, 1H).
54%	With N-Bromosuccinimide In acetonitrile at 20℃; for 2 h;	A solution of methyl 3-aminopyridine-2-carboxylate (1 g, 6.57 mmol, 1.00 equiv) and N-bromosuccinimide (1.29 g, 7.25 mmol, 1.10 equiv) in acetonitrile (25 mL) was stirred at room temperature. After being stirred for 2 h the mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to give the title compound (0.81 g, 54percent) as a yellow solid. LC-MS (ES, m/z): 231, 233 [M+H]⁺.

54%	With N-Bromosuccinimide In acetonitrile at 20℃; for 2 h;	A solution of methyl 3-aminopyridine-2-carboxylate (1 g, 6.57 mmol, 1.00 equiv) andN-bromosuccinimide (1.29 g, 7.25 mmol, 1.10 equiv) in acetonitrile (25 mL) was stirred at room temperature. After being stirred for 2 h the mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to give the title compound (0.81 g, 54percent) as a yellow solid. LC-MS (ES, mlz): 231, 233 [M+H].
50%	With sulfuric acid; bromine In water at 0 - 25℃; for 24 h;	4.1 Preparation of methyl 3-amino-6-bromopyridine-2-carboxylate 20 g of methyl 3-aminopyridine-2-carboxylate are suspended in 120 ml of water in a flask. After addition of 100 ml of sulfuric acid (2 mol/l), the mixture is cooled to 0° C., 6.73 ml of bromine are added dropwise, and the mixture is stirred at 25° C. until the acid has reacted completely (HPLC check, about 24 hours). A precipitate precipitates out of the reaction solution. This is filtered off, dissolved in EA, washed with sodium thiosulfate solution, the organic phase is dried and purified by means of column chromatography (gradient heptane: EA 5-100percent in 30 min.), giving 15 g of methyl 3-amino-6-bromo-pyridine-2-carboxylate as red-brown solid (yield 50percent, content 98percent); MS-FAB (M+H⁺)=232.9; R_f (polar method): 1.518 min.

Reference： [1] Patent: EP2975031, 2016, A1, . Location in patent: Paragraph 1071
[2] Patent: WO2005/97805, 2005, A1, . Location in patent: Page/Page column 54
[3] Patent: US2015/57260, 2015, A1, . Location in patent: Paragraph 0687; 0688
[4] Patent: WO2015/25026, 2015, A1, . Location in patent: Page/Page column 164
[5] Patent: US2013/210819, 2013, A1, . Location in patent: Paragraph 0252-0253
[6] Patent: US2017/190713, 2017, A1, . Location in patent: Paragraph 0261

2
[ 1462-86-8 ]
[ 866775-09-9 ]

Reference： [1] Patent: EP2975031, 2016, A1,
[2] Patent: US2017/190713, 2017, A1,

3
[ 866775-09-9 ]
[ 1052708-46-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: With methanol; lithium hydroxide; water In tetrahydrofuran for 16 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran; methanol	Example 314; Synthesis of 3-amino-6-bromopicolinic acid[0251] To a solution of methyl 3 -amino-6-bromopicolinate (2.3 Ig, lO mmoles) in 2:1 THF/MeOH (51 mL) was added 1.0 M LiOH (17 mL, 17 mmoles). After stirring <n="124"/>for 16 hours, 1 N HCl (17 mL, 17 mmoles) was added and the THF/MeOH was removed in vacuo. The resulting solid was filtered, rinsed with cold H₂O (4 x 20 mL) and pumped on yielding S-amino-β-bromopicolinic acid (97percent). LCMS (m/z): 216.9 (MH+); LC Rt = 1.93 min.
96%	With water; lithium hydroxide In tetrahydrofuran; methanol at 10 - 35℃; for 16 h;	(Step 3) (1072) To a solution of methyl 3-amino-6-bromopyridine-2-carboxylate (10 g, 43.28 mmol) in a mixed solvent of THF and methanol (2:1, v/v, 142 mL) was added 1M aqueous lithium hydroxide solution (71 mL) at room temperature, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 1N hydrochloric acid (71 mL), and the mixture was concentrated under reduced pressure. The precipitate was collected by filtration, and the crude crystals were washed with water to give to 3-amino-6-bromopyridine-2-carboxylic acid (9.0 g, 96percent) as a grayish white solid. ¹H-NMR(400MHz,DMSO-d₆):δ6.50-7.05(1H,brs),7.18(1H,d,J=8.76Hz),7.42(1H,d,J=8.76Hz),11.20-13.80(1H,brs). (the peak of CO₂H was not observed)

Reference： [1] Patent: WO2008/106692, 2008, A1, . Location in patent: Page/Page column 122-123
[2] Patent: EP2975031, 2016, A1, . Location in patent: Paragraph 1072

[ 866775-09-9 ] Synthesis Path-Downstream 1~69

1
[ 36052-27-4 ]
[ 866775-09-9 ]

Yield	Reaction Conditions	Operation in experiment
74%	With sulfuric acid; bromine; In water; acetic acid; at 10 - 35℃; for 4h;	(Step 2) (1071) To a mixture of <strong>[36052-27-4]methyl 3-aminopyridine-2-carboxylate</strong> (17 g, 111.8 mmol) in a mixed solvent of water (288 mL) and 2M sulfuric acid (58 mL) was added a solution of bromine (5.76 mL, 111.8 mmol) in acetic acid (43 mL) at room temperature, and the mixture was stirred at room temperature for 4 hr. The pH of the mixture was adjusted to 6 with 2N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (x2), the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; dichloromethane) to give methyl 3-amino-6-bromopyridine-2-carboxylate (19.2 g, 74%) as a white solid. 1H- NMR(300MHz,CDCl3)delta3.94(3H,s),5.81(2H,brs),6.93(1H,d,J=8.72Hz), 7.32(1H,d,J=8.71Hz).
69%		Step 2;. Preparation of 3-amino-6-bromo-pyridine-2-carboxylic acid methyl ester; Add a solution of 2 M sulfuric acid (2 mL) to a suspension of 3-amino-pyridine-2- carboxylic acid methyl ester (0.59 g, 3.88 mmol) in water (10 mL) and stir the mixture until the precipitate is dissolved. Add dropwise a solution of bromine (0.199 mL, 3.88 mmol) in acetic acid (1.5 mL). Add a solution of 2 M sodium hydroxide until pH = 6 and extract with ethyl acetate. Separate the organic layer and extract with ethyl acetate. Dry the combined organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue using silica gel chromatography eluting with ethyl acetate/hexanes to afford the title compound (0.616 g, 69%). H-NMR (CDCl3,300 MHz) : No. 3.90 (s, 3 H) ; 6.90 (d, J = 8.5 Hz, 1H), 7.30 (d, J= 8.5 Hz, 1H).
54%	With N-Bromosuccinimide; In acetonitrile; at 20℃; for 2h;	A solution of <strong>[36052-27-4]methyl 3-aminopyridine-2-carboxylate</strong> (1 g, 6.57 mmol, 1.00 equiv) and N-bromosuccinimide (1.29 g, 7.25 mmol, 1.10 equiv) in acetonitrile (25 mL) was stirred at room temperature. After being stirred for 2 h the mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to give the title compound (0.81 g, 54%) as a yellow solid. LC-MS (ES, m/z): 231, 233 [M+H]+.

54%	With N-Bromosuccinimide; In acetonitrile; at 20℃; for 2h;	A solution of <strong>[36052-27-4]methyl 3-aminopyridine-2-carboxylate</strong> (1 g, 6.57 mmol, 1.00 equiv) andN-bromosuccinimide (1.29 g, 7.25 mmol, 1.10 equiv) in acetonitrile (25 mL) was stirred at room temperature. After being stirred for 2 h the mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to give the title compound (0.81 g, 54%) as a yellow solid. LC-MS (ES, mlz): 231, 233 [M+H].
50%	With sulfuric acid; bromine; In water; at 0 - 25℃; for 24h;	4.1 Preparation of methyl 3-amino-6-bromopyridine-2-carboxylate 20 g of <strong>[36052-27-4]methyl 3-aminopyridine-2-carboxylate</strong> are suspended in 120 ml of water in a flask. After addition of 100 ml of sulfuric acid (2 mol/l), the mixture is cooled to 0 C., 6.73 ml of bromine are added dropwise, and the mixture is stirred at 25 C. until the acid has reacted completely (HPLC check, about 24 hours). A precipitate precipitates out of the reaction solution. This is filtered off, dissolved in EA, washed with sodium thiosulfate solution, the organic phase is dried and purified by means of column chromatography (gradient heptane: EA 5-100% in 30 min.), giving 15 g of methyl 3-amino-6-bromo-pyridine-2-carboxylate as red-brown solid (yield 50%, content 98%); MS-FAB (M+H+)=232.9; Rf (polar method): 1.518 min.
	With N-Bromosuccinimide; In acetonitrile; at 0 - 15℃; for 16h;	To a solution of <strong>[36052-27-4]methyl 3-aminopicolinate</strong> (50 g, 328 mmol, 1.0 eq.) in MeCN (600 mL) was added NBS (60 g, 337 mmol, 1.0 eq.) portionwise at 0 C. and the reaction mixture was stirred at 15 C. for 16 hr. The precipitate was collected by filtration to give methyl 3-amino-6-bromo-pyridine-2-carboxylate (48 g, 187 mmol, 56.9% yield, 90% purity) as a light yellow solid, which was used directly without further purification. 1H NMR (400 MHz, CDCl3) delta=7.35 (d, J=8.4 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 5.83 (br. s, 1H), 3.96 (s, 3H). ESI [M+H]=231.0/233.0

Reference： [1]Patent: EP2975031,2016,A1 .Location in patent: Paragraph 1071
[2]Patent: WO2005/97805,2005,A1 .Location in patent: Page/Page column 54
[3]Patent: US2015/57260,2015,A1 .Location in patent: Paragraph 0687; 0688
[4]Patent: WO2015/25026,2015,A1 .Location in patent: Page/Page column 164
[5]Patent: US2013/210819,2013,A1 .Location in patent: Paragraph 0252-0253
[6]Patent: US2017/190713,2017,A1 .Location in patent: Paragraph 0261

2
[ 866775-09-9 ]
[ 1052708-46-9 ]

Yield	Reaction Conditions	Operation in experiment
97%		Example 314; Synthesis of 3-amino-6-bromopicolinic acid[0251] To a solution of methyl 3 -amino-6-bromopicolinate (2.3 Ig, lO mmoles) in 2:1 THF/MeOH (51 mL) was added 1.0 M LiOH (17 mL, 17 mmoles). After stirring <n="124"/>for 16 hours, 1 N HCl (17 mL, 17 mmoles) was added and the THF/MeOH was removed in vacuo. The resulting solid was filtered, rinsed with cold H2O (4 x 20 mL) and pumped on yielding S-amino-beta-bromopicolinic acid (97%). LCMS (m/z): 216.9 (MH+); LC Rt = 1.93 min.
96%	With water; lithium hydroxide; In tetrahydrofuran; methanol; at 10 - 35℃; for 16.0h;	(Step 3) (1072) To a solution of <strong>[866775-09-9]methyl 3-amino-6-bromopyridine-2-carboxylate</strong> (10 g, 43.28 mmol) in a mixed solvent of THF and methanol (2:1, v/v, 142 mL) was added 1M aqueous lithium hydroxide solution (71 mL) at room temperature, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 1N hydrochloric acid (71 mL), and the mixture was concentrated under reduced pressure. The precipitate was collected by filtration, and the crude crystals were washed with water to give to 3-amino-6-bromopyridine-2-carboxylic acid (9.0 g, 96%) as a grayish white solid. 1H-NMR(400MHz,DMSO-d6):delta6.50-7.05(1H,brs),7.18(1H,d,J=8.76Hz),7.42(1H,d,J=8.76Hz),11.20-13.80(1H,brs). (the peak of CO2H was not observed)

Reference： [1]Patent: WO2008/106692,2008,A1 .Location in patent: Page/Page column 122-123
[2]Patent: EP2975031,2016,A1 .Location in patent: Paragraph 1072

3
[ 866775-09-9 ]
[ 162101-25-9 ]
[ 1052714-87-0 ]

Yield	Reaction Conditions	Operation in experiment
47%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 120℃; for 0.25h;microwave irradiation;	Method 1 Synthesis of methyl 3-amino-6-(2,6-difluorophenyl)picolinate A solution of <strong>[866775-09-9]methyl 3-amino-6-bromopicolinate</strong> (1.0 equiv.), 2,6-difluorophenyl-boronic acid (3.0 equiv), and Pd(dppf)Cl2-DCM (0.1 equiv.) in 3:1 DME/2M Na2CO3 (0.5 M) was subjected to microwave irradiation at 120 C. for 15 min intervals. The reaction was filtered and washed with EtOAc. The organic was partitioned with H2O (25 mL), was further washed with NaCl(sat.) (25 mL), was dried over MgSO4, and the volatiles were removed in vacuo. The residue was diluted in EtOAc and passed through a silica gel plug and the volatiles were removed in vacuo yielding methyl 3-amino-6-(2,6-difluorophenyl)picolinate (47%). LCMS (m/z): 265.1 (MH+); LC Rt=2.70 min
47%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 120℃; for 0.25h;Microwave irradiation;	Method 1Synthesis of methyl 3-amino-6-(2,6-diflurophenyl)picolinate[00152] A solution of <strong>[866775-09-9]methyl 3-amino-6-bromopicolinate</strong> (1.0 equiv.),2,6-difluorophenyl-boronic acid (3.0 equiv), and Pd(dppf)Cl2-DCM (0.1 equiv.) in 3: 1 DME/ 2M Na2C03 (0.5 M) was subjected to microwave irradiation at 120 C for 15 min intervals. The reaction was filtered and washed with EtOAc. The organic was partitioned with H20 (25mL), was further washed with NaCl(sat.) (25mL), was dried over MgS04, and the volatiles were removed in vacuo. The residue was diluted in EtOAc and passed through a silica gel plug and the volatiles were removed in vacuo yielding methyl 3-amino-6-(2,6-difiuorophenyl)picolinate (47%). LCMS (m/z): 265.1 (MH+); LC R, = 2.70 min.
47%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 120℃; for 0.25h;microwave irradiation;	A solution of <strong>[866775-09-9]methyl 3-amino-6-bromopicolinate</strong> (1.0 equiv.), 2,6-difluorophenyl-boronic acid (3.0 equiv), and Pd(dppf)Cl2-DCM (0.1 equiv.) in 3:1 DME/2M Na2CO3 (0.5 M) was subjected to microwave irradiation at 120 C. for 15 min intervals. The reaction was filtered and washed with EtOAc. The organic was partitioned with H2O (25 mL), was further washed with NaCl(sat.) (25 mL), was dried over MgSO4, and the volatiles were removed in vacuo. The residue was diluted in EtOAc and passed through a silica gel plug and the volatiles were removed in vacuo yielding methyl 3-amino-6-(2,6-difluorophenyl)picolinate (47%). LCMS (m/z): 265.1 (MH+); LC Rt=2.70 min.

47%

With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 0.25h;Microwave irradiation;

A solution of <strong>[866775-09-9]methyl 3-amino-6-bromopicolinate</strong> (1.0 equiv.), 2,6-difluorophenyl-boronic acid (3.0 equiv), and Pd(dppf)Cl2-DCM (0.1 equiv.) in 3:1 DME/ 2 M Na2CO3 (0.5 M) was subjected to microwave irradiation at 120 C for 15 min intervals. The reaction was filtered and washed with EtOAc. The organic was partitioned with H2O (25 mL), was further washed with NaCl(sat.) (25 mL),was dried over MgSO4, and thevolatiles were removed in vacuo. The residue was diluted in EtOAc and passed through a silica gel plug and the volatiles were removed in vacuo yielding methyl 3-amino-6-(2,6-difluorophenyl)picolinate (47%). LCMS (m/z): 265.1 (MH+); LC Rt = 2.70 min.

Reference： [1]Patent: US2010/56576,2010,A1 .Location in patent: Page/Page column 39-40
[2]Patent: WO2012/4217,2012,A1 .Location in patent: Page/Page column 66
[3]Patent: US2012/225061,2012,A1 .Location in patent: Page/Page column 25
[4]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1193 - 1197
[5]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2328 - 2332

4
[ 866775-09-9 ]
[ 162101-25-9 ]
[ 1052714-89-2 ]

Reference： [1]Patent: WO2012/4217,2012,A1
[2]Patent: US2012/225061,2012,A1

5
[ 866775-09-9 ]
[ 173382-28-0 ]
[ 1052714-92-7 ]

Yield	Reaction Conditions	Operation in experiment
51%	dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 80℃; for 1.5h;	solution of <strong>[866775-09-9]methyl 3-amino-6-bromopicolinate</strong> (1.0 equiv.),2-thiazolylzinc bromide 0.5 M solution in THF (3.0 equiv.), and Pd(dppf)Cl2-DCM (0.05 equiv.) was stirred at 80C for 1.5 hours. The reaction was filtered and washed with EtOAc. The organic was washed with H20 (lOOmL), and further washed with NaCl(sat.) (50mL), dried over MgS04, and the volatiles were removed in vacuo. The product was crystallized with hexane/EtOAc (1 : 1) to yield methyl 3-amino-6-(thiazol-2-yl)picolinate (51%). LCMS (m/z): 236.1 (MH+); LC R, = 2.3 min.
51%	dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 80℃; for 1.5h;	A solution of <strong>[866775-09-9]methyl 3-amino-6-bromopicolinate</strong> (1.0 equiv.), 2-thiazolylzinc bromide 0.5 M solution in THF (3.0 equiv.), and Pd(dppf)Cl2-DCM (0.05 equiv.) was stirred at 80 C. for 1.5 hours. The reaction was filtered and washed with EtOAc. The organic was washed with H2O (100 mL), and further washed with NaCl(sat.) (50 mL), dried over MgSO4, and the volatiles were removed in vacuo. The product was crystallized with hexane/EtOAc (1:1) to yield methyl 3-amino-6-(thiazol-2-yl)picolinate (51%). LCMS (m/z): 236.1 (MH+); LC Rt=2.3 min.
51%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 80℃; for 1.5h;	A solution of <strong>[866775-09-9]methyl 3-amino-6-bromopicolinate</strong> (1.0 equiv.), 2-thiazolylzinc bromide 0.5 M solution in THF (3.0 equiv.), and Pd(dppf)Cl2-DCM (0.05 equiv.) was stirred at 80 C for 1.5 hours. The reaction was filtered and washed with EtOAc. The organic was washed with H2O (100mL), and further washed with NaCl(sat.) (50mL), dried over MgSO4, and the volatiles were removed in vacuo. The product was crystallized with hexane/EtOAc (1:1) to yield methyl 3-amino-6-(thiazol-2-yl)picolinate (51%). LCMS (m/z): 236.1 (MH+); LC Rt = 2.3 min.

Reference： [1]Patent: WO2012/4217,2012,A1 .Location in patent: Page/Page column 71-72
[2]Patent: US2012/225061,2012,A1 .Location in patent: Page/Page column 24
[3]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2328 - 2332

6
[ 866775-09-9 ]
[ 1052714-95-0 ]

Reference： [1]Patent: WO2012/4217,2012,A1
[2]Patent: US2012/225061,2012,A1
[3]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2328 - 2332

7
[ 866775-09-9 ]
[ 874289-49-3 ]
[ 1052714-98-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 120℃; for 1.5h;	Synthesis of methyl 3-amino- -(2-fluoro-5-isopropylcabamoyl)phenyl)-picolinate[00160] A solution of <strong>[866775-09-9]methyl 3-amino-6-bromopicolinate</strong> (1.0 equiv.),N-isopropyl 3-borono-4-fluorobenzamide (1.1 equiv.), and Pd(dppf)Cl2-DCM (0.15 equiv.) in DME/2M Na2C03 (3 : 1), at a concentration of 0.5 M, was stirred at 120C for 1.5 hours. The reaction was filtered and washed with EtOAc. The organic was partitioned with H20 (25mL), washed with NaCl(sat.) (25mL), dried over MgS04, and the volatiles were removed in vacuo. The residue was diluted in EtOAc and passed through a silica gel plug and the volatiles were removed in vacuo yielding methyl 3-amino-6-(2- fluoro-5-isopropylcabamoyl)phenyl)picolinate (60%). LCMS (m/z): 332.2 (MH+); LC R, = 2.9 min.
60%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 1.5h;Microwave irradiation;	Synthesis of methyl 3-amino- -(2-fluoro-5-isopropylcabamoyl)phenyl)-picolinate A solution of <strong>[866775-09-9]methyl 3-amino-6-bromopicolinate</strong> (1.0 equiv.), N-isopropyl 3-borono-4- fiuorobenzamide (1.1 equiv.), and Pd(dppf)Cl2-DCM (0.15 equiv.) in DME/2M Na2C03 (3: 1), at a concentration of 0.5 M, was stirred at 120C for 1.5 hours. The reaction was filtered and washed with EtOAc. The organic was partitioned with H20 (25mL), washed with NaCl(sat) (25mL), dried over MgS04, and the volatiles were removed in vacuo. The residue was diluted in EtOAc and passed through a silica gel plug and the volatiles were removed in vacuo yielding methyl 3-amino-6-(2-fluoro-5-isopropylcabamoyl)- phenyl)picolinate (60%). LCMS (m/z): 332.2 (MH+); LC R, = 2.9 min.
60%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 1.5h;	Synthesis of methyl 3-amino-6-(2-fluoro-5-isopropylcabamoyl)phenyl)-picolinate A solution of <strong>[866775-09-9]methyl 3-amino-6-bromopicolinate</strong> (1.0 equiv.), N-isopropyl 3-borono-4- fiuorobenzamide (1.1 equiv.), and Pd(dppf)Cl2-DCM (0.15 equiv.) in DME/2M Na2C03 (3: 1), at a concentration of 0.5 M, was stirred at 120C for 1.5 hours. The reaction was filtered and washed with EtOAc. The organic was partitioned with H20 (25mL), washed with NaCl(sat) (25mL), dried over MgS04, and the volatiles were removed in vacuo. The residue was diluted in EtOAc and passed through a silica gel plug and the volatiles were removed in vacuo yielding methyl 3-amino-6-(2-fluoro-5-isopropylcabamoyl)- phenyl)picolinate (60%). LCMS (m/z): 332.2 (MH+); LC R, = 2.9 min.

Reference： [1]Patent: WO2012/4217,2012,A1 .Location in patent: Page/Page column 69-70
[2]Patent: WO2013/175388,2013,A1 .Location in patent: Page/Page column 80-81
[3]Patent: WO2014/33631,2014,A1 .Location in patent: Page/Page column 74-75

8
[ 866775-09-9 ]
[ 874289-49-3 ]
[ 1052715-01-1 ]

Reference： [1]Patent: WO2012/4217,2012,A1
[2]Patent: WO2013/175388,2013,A1
[3]Patent: WO2014/33631,2014,A1

9
[ 866775-09-9 ]
[ 1355011-11-8 ]
[ 1355011-12-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 80℃; for 0.166667h;Microwave irradiation; Sealed tube;	Synthesis of methyl 3-amino-6-(2,6-difluoro-3-(iso ropylcarbamoyl)-phenyl)picolinate[00167] To a microwave vessel, <strong>[866775-09-9]methyl 3-amino-6-bromopicolinate</strong> (700 mg, 1 equiv.), 2,4-difluoro-N-isopropyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide (2 equiv.), PdCl2(dppf) (0.1 equiv.), DME and 2 M Na2C03 solution (3: 1, 0.1 M solution) were added. The reaction mixture was degassed by N2 stream for 10 min. After sealed, the reaction mixture was heated at 80 C for 10 min in microwave. After 2 equiv. of bronic ester was added more, the reaction was repeated at microwave under the same condition. LCMS (m/z): 350.0 (MH+), R,=0.67 min. 1H-NMR (400 MHz, CDC13): delta 8.14 (m, 1H), 7.38 (m, 1H), 7.17 (m, 1H), 7.06 (m, 1H), 6.51 (m, 1H), 5.98 (s, 2H), 4.32 (m, 1H), 3.98 (s, 3H), 1.23 (s, 3H), 1.19 (s, 3H).

Reference： [1]Patent: WO2012/4217,2012,A1 .Location in patent: Page/Page column 73

10
[ 866775-09-9 ]
[ 1373621-95-4 ]
[ 1373622-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 90℃; for 7.0h;Inert atmosphere;	4.2 Preparation of methyl 3-amino-6-(1-triisopropylsilanyl-1H-pyrrolo-[2,3-b]pyridin-5-yl)pyridine-2-carboxylate 7.50 g of <strong>[866775-09-9]methyl 3-amino-6-bromopyridine-2-carboxylate</strong>, 12.10 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo-[2,3-b]pyridine, 8.18 g of sodium hydrogencarbonate and 2.27 g of PdCl2(PPh3)2 in 90 ml of dioxane and 15 ml of water are heated at 90 C. under nitrogen in a flask until the reaction is complete (HPLC check, about 7 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 25 min), giving 8.40 g of methyl 3-amino-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxylate as white solid (yield 56%, content 92%); MS-FAB (M+H+)=425.2; Rf (Esi1rod method): 3.10 min.

Reference： [1]Patent: US2013/210819,2013,A1 .Location in patent: Paragraph 0254-0255

11
[ 866775-09-9 ]
[ 1373622-03-7 ]

Reference： [1]Patent: US2013/210819,2013,A1

12
[ 866775-09-9 ]
[ 1373621-85-2 ]

Reference： [1]Patent: US2013/210819,2013,A1

13
[ 866775-09-9 ]
[ 1373621-86-3 ]

Reference： [1]Patent: US2013/210819,2013,A1

14
[ 866775-09-9 ]
[ 1373622-08-2 ]

Reference： [1]Patent: US2013/210819,2013,A1

15
[ 866775-09-9 ]
[ 1373621-89-6 ]

Reference： [1]Patent: US2013/210819,2013,A1

16
[ 866775-09-9 ]
[ 1373622-10-6 ]

Reference： [1]Patent: US2013/210819,2013,A1

17
[ 866775-09-9 ]
[ 1373621-90-9 ]

Reference： [1]Patent: US2013/210819,2013,A1

18
[ 866775-09-9 ]
[ 1373622-09-3 ]

Reference： [1]Patent: US2013/210819,2013,A1

19
[ 866775-09-9 ]
[ 956034-65-4 ]
[ 1373622-07-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With bis-triphenylphosphine-palladium(II) chloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 90℃; for 7.0h;Inert atmosphere;	8.1 Preparation of methyl 3-amino-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]pyridine-2-carboxylate 1.00 g of <strong>[866775-09-9]methyl 3-amino-6-bromopyridine-2-carboxylate</strong>, 2.00 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine, 1.00 g of sodium hydrogencarbonate and 0.30 g of PdCl2(PPh3)2 in 20 ml of dioxane and 2 ml of water are heated at 90 C. under nitrogen in a flask until the reaction is complete (HPLC check, about 7 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient EA: methanol 0-20% in 30 min), giving 1.00 g of methyl 3-amino-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo-[4,5-b]pyridin-6-yl]pyridine-2-carboxylate as white solid (yield 60%, content 98%); MS-FAB (M+H+)=414.2; Rf (polar method): 2.24 min.

Reference： [1]Patent: US2013/210819,2013,A1 .Location in patent: Paragraph 0283-0284

20
[ 866775-09-9 ]
[ 1052714-89-2 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1193 - 1197
[2]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2328 - 2332

21
[ 866775-09-9 ]
3-amino-N-(4-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)picolinamide [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1193 - 1197

22
[ 866775-09-9 ]
2-(5-bromo-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ No CAS ]
methyl 3-amino-6-(5-bromo-2,4-difluorophenyl)pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With bis-triphenylphosphine-palladium(II) chloride; cesium fluoride; In ethanol; water; at 90℃; for 1.0h;	General procedure: Aryl halide, palladium(II) bis(triphenylphosphine) dichloride or (triphenylphosphine) palladium (0.05eq), boronic acid or pinacol ester (1.1 eq) and cesium fluoride (2 eq) were weighed out into a microwave vessel or sealed tube. Ethanol (3 mL/mmol) and water (0.6 mL/mmol) were added. The vessel was capped and heated thermally or in a microwave vessel at 70-100 C. for 1 hour. The reaction mixture wasconcentrated under vacuum and the residue was purified by silica gel columnchromatography to afford the Suzuki coupling product.
49%	With bis-triphenylphosphine-palladium(II) chloride; cesium fluoride; In ethanol; water; at 90℃;Microwave irradiation;	Similar to as described in General Procedure X, <strong>[866775-09-9]methyl 3-amino-6-bromopyridine-2-carboxylate</strong> was reacted with 2- (5 -bromo-2,4-difluorophenyl)-4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolane to givethe title compound (0.08 g, 49%) as a white solid. LC-MS (ES, m/z): 343 [M+Hf?. Aryl halide, palladium (II) bis(triphenylphosphine) dichloride or tetrakis (triphenylphosphine) palladium (0.OSeq), boronic acid or pinacol ester (1. leq) and cesium fluoride (2eq) were weighed out into a microwave vessel or sealed tube. Ethanol (3 mL/mmol) and water (0.6 mL/mmol) were added. The vessel was capped and heated thermally or in a microwave vessel at 70-400 C for 1 hour. The reaction mixture was concentrated under vacuum and the residue was purified by silicagel column chromatography to afford the Suzuki coupling product.

Reference： [1]Patent: US2015/57260,2015,A1 .Location in patent: Paragraph 0548; 0549; 1119; 1120
[2]Patent: WO2015/25026,2015,A1 .Location in patent: Page/Page column 137; 246

23
[ 866775-09-9 ]
[ 112204-57-6 ]
methyl 3-amino-6-(5-bromo-2-fluorophenyl)pyrazine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With bis-triphenylphosphine-palladium(II) chloride; cesium fluoride; In ethanol; water;Microwave irradiation;	Similar to as described in General Procedure X, methyl 3-amino-6-bromopyrazine-2-carboxylatewas reacted with 5-bromo-2-fluorophenylboronic acid to give the title compound (0.26 g, 35%) asa yellow solid. LC-MS (ES, mlz): 326, 328 [M+H]. Aryl halide, palladium (II) bis(triphenylphosphine) dichloride or tetrakis (triphenylphosphine) palladium (0.OSeq), boronic acid or pinacol ester (1. leq) and cesium fluoride (2eq) were weighed out into a microwave vessel or sealed tube. Ethanol (3 mL/mmol) and water (0.6 mL/mmol) were added. The vessel was capped and heated thermally or in a microwave vessel at 70-400 C for 1 hour. The reaction mixture was concentrated under vacuum and the residue was purified by silicagel column chromatography to afford the Suzuki coupling product.

Reference： [1]Patent: WO2015/25026,2015,A1 .Location in patent: Page/Page column 137; 245

24
[ 866775-09-9 ]
C₂₇H₃₈N₆O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8373 - 8386

25
[ 866775-09-9 ]
C₃₁H₃₃N₅O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8373 - 8386

26
[ 866775-09-9 ]
3-amino-6-cyclohexylpicolinic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8373 - 8386

27
[ 866775-09-9 ]
(S)-3-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-cyclohexylpicolinamide trifluoroacetate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8373 - 8386

28
[ 866775-09-9 ]
3-amino-N-(4-((1R,3S)-3-aminocyclohexyl)pyridin-3-yl)-6-cyclohexylpicolinamide trifluoroacetate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8373 - 8386

29
[ 866775-09-9 ]
[ 7565-57-3 ]
methyl 3-amino-6-cyclohexylpicolinate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8373 - 8386

30
[ 1462-86-8 ]
[ 866775-09-9 ]

Reference： [1]Patent: EP2975031,2016,A1
[2]Patent: US2017/190713,2017,A1

31
[ 866775-09-9 ]
6-bromo-1,3-diethyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione [ No CAS ]

Reference： [1]Patent: EP2975031,2016,A1

32
[ 866775-09-9 ]
6-amino-1,3-diethyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione [ No CAS ]

Reference： [1]Patent: EP2975031,2016,A1

33
[ 866775-09-9 ]
N-(3-chloro-4-cyanophenyl)-N'-(1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-6-yl)-3-methylpentanediamide [ No CAS ]

Reference： [1]Patent: EP2975031,2016,A1

34
[ 866775-09-9 ]
[ 1380307-12-9 ]

Reference： [1]Patent: EP2975031,2016,A1

35
[ 866775-09-9 ]
6-bromo-3-ethyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione [ No CAS ]

Reference： [1]Patent: EP2975031,2016,A1

36
[ 866775-09-9 ]
C₂₃H₁₉FN₆O [ No CAS ]