[ CAS No. 178876-83-0 ] {[proInfo.proName]}

Name: 178876-83-0|Methyl 6-amino-3-bromopicolinate|97%
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SKU: A224585
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Quality Control of [ 178876-83-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 178876-83-0 ]

CAS No. :	178876-83-0	MDL No. :	MFCD09800897
Formula :	C₇H₇BrN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YJUKTIBOUBUOJH-UHFFFAOYSA-N
M.W :	231.05	Pubchem ID :	10657127
Synonyms :

Calculated chemistry of [ 178876-83-0 ]

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) :	-6.73 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.55
Log Po/w (XLOGP3) :	1.38
Log Po/w (WLOGP) :	1.22
Log Po/w (MLOGP) :	0.91
Log Po/w (SILICOS-IT) :	1.17
Consensus Log Po/w :	1.25

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.38
Solubility :	0.963 mg/ml ; 0.00417 mol/l
Class :	Soluble
Log S (Ali) :	-2.35
Solubility :	1.03 mg/ml ; 0.00444 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 :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.84

Safety of [ 178876-83-0 ]

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 [ 178876-83-0 ]

* 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 [ 178876-83-0 ]
Downstream synthetic route of [ 178876-83-0 ]

[ 178876-83-0 ] Synthesis Path-Upstream 1~20

1
[ 36052-26-3 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Yield	Reaction Conditions	Operation in experiment
22%	With bromine In chloroform at 20℃; for 40 h;	d) 6-Amino-5-bromo-pyridine-2-carboxylic acid methyl ester; To a solution of 6-amino-pyridine-2-carboxylic acid methyl ester (10 g, 66.0 mmol) in chloroform (450 mL) was added bromine (3.4 mL, 66.0 mmol) in CHCl₃(100 mL) at room temperature and stirred for 40 hours. The reaction mixture was diluted with CHCl₃and washed with saturated sodium thiosulfate solution and water. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel column chromatography using ethyl acetate/hexane as eluent. The title compound obtained as yellow solid (3.3 g, 22percent).MS ESI (m/e): 231.0 [(M+H)⁺].¹H NMR (CDCl₃, 400 MHz): δ(ppm)=7.76 (d, J=7.88 Hz, 1H), 7.34 (d, J=7.92 Hz, 1H), 5.23 (s, 2H), 3.94 (s, 3H).d) 6-Amino-3-bromo-pyridine-2-carboxylic acid methyl esterIn step d) the isomeric 6-amino-3-bromo-pyridine-2-carboxylic acid methyl ester (3.0 g, 19percent) was isolated as side product.MS ESI (m/e): 231.2 [(M+H)⁺].¹H NMR (CDCl₃, 400 MHz): δ(ppm)=7.60 (d, J=8.72 Hz, 1H), 6.47 (d, J=7.88 Hz, 1H), 4.71 (s, 2H), 3.94 (s, 3H).
22%	With bromine In chloroform at 20℃; for 40 h;	To a solution of 6-amino-pyridine-2-carboxylic acid methyl ester (10 g, 66.0 mmol) in chloroform (450 mL) was added bromine (3.4 mL, 66.0 mmol) in CHC1₃ (100 mL) at room temperature and stirred for 40 hours. The reaction mixture was diluted with CHC1₃ and washed with saturated sodium thiosulfate solution and water. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel column chromatography using ethyl acetate/hexane as eluent. The title compound obtained as yellow solid (3.3g, 22percent). MS ESI (m/e): 231.0 [(M+H)⁺].1H NMR (CDC1₃, 400 MHz): <5 (ppm) = 7.76 (d, J = 7.88 Hz, 1H), 7.34 (d, J = 7.92 Hz, 1H), 5.23 (s, 2H), 3.94 (s, 3H).
22%	With bromine In chloroform at 20℃; for 40 h;	d) 6-Amino-5-bromo-pyridine-2-carboxylic acid methyl ester; To a solution of 6-amino-pyridine-2-carboxylic acid methyl ester (10 g, 66.0 mmol) in chloroform (450 mL) was added bromine (3.4 mL, 66.0 mmol) in CHCl₃(100 mL) at room temperature and stirred for 40 hours. The reaction mixture was diluted with CHCl₃and washed with saturated sodium thiosulfate solution and water. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel column chromatography using ethyl acetate/hexane as eluent. The title compound obtained as yellow solid (3.3 g, 22percent).MS ESI (m/e): 231.0 [(M+H)⁺].¹H NMR (CDCl₃, 400 MHz): δ (ppm)=7.76 (d, J=7.88 Hz, 1H), 7.34 (d, J=7.92 Hz, 1H), 5.23 (s, 2H), 3.94 (s, 3H).

22%

With bromine In chloroform at 20℃; for 40 h;

d) 6-Amino-5-bromo-pyridine-2-carboxylic acid methyl esterTo a solution of 6-amino-pyridine-2-carboxylic acid methyl ester (10 g, 66.0 mmol) in chloroform (450 mL) was added bromine (3.4 mL, 66.0 mmol) in CHC1₃ (100 mL) at room temperature and stirred for 40 hours. The reaction mixture was diluted with CHC1₃ and washed with saturated sodium thiosulfate solution and water. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel column chromatography using ethyl acetate/hexane as eluent. The title compound obtained as yellow solid (3.3 g, 22percent). MS ESI (m/e): 231.0 [(M+H)⁺].1H NMR (CDC1₃, 400 MHz): <5 (ppm) = 7.76 (d, J= 7.88 Hz, 1H), 7.34 (d, J= 7.92 Hz, 1H), 5.23 (s, 2H), 3.94 (s, 3H). d') 6-Amino-3-bromo-pyridine-2-carboxylic acid methyl esterIn step d) the isomeric 6-amino-3-bromo-pyridine-2-carboxylic acid methyl ester (3.0g, 19percent) was isolated as side product.MS ESI (m/e): 231.2 [(M+H)⁺].1H NMR (CDC1₃, 400 MHz): <5 (ppm) = 7.60 (d, J= 8.72 Hz, 1H), 6.47 (d, J= 7.88 Hz, 1H), 4.71 (s, 2H), 3.94(s, 3H).

Reference： [1] Journal of Organic Chemistry, 1996, vol. 61, # 14, p. 4623 - 4633
[2] Organic Process Research and Development, 2010, vol. 14, # 1, p. 263 - 271
[3] Tetrahedron Letters, 2010, vol. 51, # 38, p. 5035 - 5037
[4] Patent: US2011/190269, 2011, A1, . Location in patent: Page/Page column 61-62
[5] Patent: WO2011/92272, 2011, A1, . Location in patent: Page/Page column 129; 130
[6] Patent: US2011/201605, 2011, A1, . Location in patent: Page/Page column 45
[7] Patent: WO2011/101304, 2011, A2, . Location in patent: Page/Page column 92
[8] Patent: WO2009/140101, 2009, A2, . Location in patent: Page/Page column 42

2
[ 36052-26-3 ]
[ 178876-83-0 ]

Yield	Reaction Conditions	Operation in experiment
29%	Stage #1: at 10 - 35℃; for 7 h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate	Reference Example 17; methyl 6-amino-3-bromopyridine-2-carboxylate [Show Image]; To a suspension of methyl 6-aminopyridine-2-carboxylate (5.98 g, 39.5 mmol) and sodium carbonate (2.64 g, 24.9 mmol) in acetic acid (150 mL) was added bromine (7.89 g, 49.4 mmol), and the mixture was stirred at room temperature for 7 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. This was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70-->80/20) to give the title compound (2.67 g, yield 29percent). ¹H-NMR (CDCl₃) δ: 3.95 (3H, s), 4.74 (2H, brs), 6.49 (1H, d, J = 8.8 Hz), 7.62 (1H, d, J = 8.8 Hz), MS (ESI+): 231 (M+H).
11%	With bromine; sodium carbonate In acetic acid at 20℃; for 5 h;	To a 100 mL round bottom flask, were added methyl 6-aminopicolinate (6 g, 0.0394 mol), sodium carbonate (2.64 g, 0.0248 mol) and acetic acid (300 mL). The reaction mixture was cooled to 0 - 5 °C. To the same flask, bromine (2 mL, 0.039 mol) was slowly added. The reaction mixture was stirred at room temperature for 5 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 30 percent ethyl acetate in hexane to get the title compound [1 g, 11 percent]. ^{FontWeight="Bold" FontSize="10"}H NMR (400 MHZ, CDC1₃): δ 7.63 (d, / = 8.8 Hz, 1H), 6.51 (d, = 8.8 Hz, 1H), 4.80 (brs, 2H), 3.94 (s, 3H); LC-MS: 232.8 [M+2H]⁺.

Reference： [1] Patent: EP2098513, 2009, A1, . Location in patent: Page/Page column 49
[2] Patent: WO2014/125426, 2014, A1, . Location in patent: Page/Page column 59; 60

3
[ 36052-26-3 ]
[ 443956-21-6 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Yield	Reaction Conditions	Operation in experiment
18%	With bromine In chloroform at 20℃;	b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (Si0₂, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19percent) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29percent) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)
19%	With bromine In chloroform at 20℃;	b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (SiO₂, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19percent) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29percent) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)

Reference： [1] Patent: WO2011/75591, 2011, A1, . Location in patent: Page/Page column 95
[2] Patent: US2011/152312, 2011, A1, . Location in patent: Page/Page column 40

4
[ 1033201-61-4 ]
[ 18107-18-1 ]
[ 178876-83-0 ]

Reference： [1] Patent: US2013/96120, 2013, A1, . Location in patent: Paragraph 1079
[2] Patent: US2013/96121, 2013, A1, . Location in patent: Paragraph 1777

5
[ 1824-81-3 ]
[ 178876-83-0 ]

Reference： [1] Journal of Organic Chemistry, 1996, vol. 61, # 14, p. 4623 - 4633
[2] Patent: US2011/190269, 2011, A1,
[3] Patent: WO2011/92272, 2011, A1,
[4] Patent: WO2014/125426, 2014, A1,

6
[ 5327-33-3 ]
[ 178876-83-0 ]

Reference： [1] Journal of Organic Chemistry, 1996, vol. 61, # 14, p. 4623 - 4633
[2] Patent: US2011/190269, 2011, A1,
[3] Patent: WO2011/92272, 2011, A1,
[4] Patent: WO2014/125426, 2014, A1,

7
[ 26893-72-1 ]
[ 178876-83-0 ]

Reference： [1] Journal of Organic Chemistry, 1996, vol. 61, # 14, p. 4623 - 4633
[2] Patent: US2011/190269, 2011, A1,
[3] Patent: WO2011/92272, 2011, A1,

8
[ 1824-81-3 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Reference： [1] Patent: US2011/201605, 2011, A1,
[2] Patent: WO2011/101304, 2011, A2,

9
[ 5327-33-3 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Reference： [1] Patent: US2011/201605, 2011, A1,
[2] Patent: WO2011/101304, 2011, A2,

10
[ 26893-72-1 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Reference： [1] Patent: US2011/201605, 2011, A1,
[2] Patent: WO2011/101304, 2011, A2,

11
[ 23628-31-1 ]
[ 443956-21-6 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Reference： [1] Patent: US2011/152312, 2011, A1,
[2] Patent: WO2011/75591, 2011, A1,

12
[ 36052-26-3 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Yield	Reaction Conditions	Operation in experiment
22%	With bromine In chloroform at 20℃; for 40 h;	d) 6-Amino-5-bromo-pyridine-2-carboxylic acid methyl ester; To a solution of 6-amino-pyridine-2-carboxylic acid methyl ester (10 g, 66.0 mmol) in chloroform (450 mL) was added bromine (3.4 mL, 66.0 mmol) in CHCl₃(100 mL) at room temperature and stirred for 40 hours. The reaction mixture was diluted with CHCl₃and washed with saturated sodium thiosulfate solution and water. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel column chromatography using ethyl acetate/hexane as eluent. The title compound obtained as yellow solid (3.3 g, 22percent).MS ESI (m/e): 231.0 [(M+H)⁺].¹H NMR (CDCl₃, 400 MHz): δ(ppm)=7.76 (d, J=7.88 Hz, 1H), 7.34 (d, J=7.92 Hz, 1H), 5.23 (s, 2H), 3.94 (s, 3H).d) 6-Amino-3-bromo-pyridine-2-carboxylic acid methyl esterIn step d) the isomeric 6-amino-3-bromo-pyridine-2-carboxylic acid methyl ester (3.0 g, 19percent) was isolated as side product.MS ESI (m/e): 231.2 [(M+H)⁺].¹H NMR (CDCl₃, 400 MHz): δ(ppm)=7.60 (d, J=8.72 Hz, 1H), 6.47 (d, J=7.88 Hz, 1H), 4.71 (s, 2H), 3.94 (s, 3H).
22%	With bromine In chloroform at 20℃; for 40 h;	To a solution of 6-amino-pyridine-2-carboxylic acid methyl ester (10 g, 66.0 mmol) in chloroform (450 mL) was added bromine (3.4 mL, 66.0 mmol) in CHC1₃ (100 mL) at room temperature and stirred for 40 hours. The reaction mixture was diluted with CHC1₃ and washed with saturated sodium thiosulfate solution and water. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel column chromatography using ethyl acetate/hexane as eluent. The title compound obtained as yellow solid (3.3g, 22percent). MS ESI (m/e): 231.0 [(M+H)⁺].1H NMR (CDC1₃, 400 MHz): <5 (ppm) = 7.76 (d, J = 7.88 Hz, 1H), 7.34 (d, J = 7.92 Hz, 1H), 5.23 (s, 2H), 3.94 (s, 3H).
22%	With bromine In chloroform at 20℃; for 40 h;	d) 6-Amino-5-bromo-pyridine-2-carboxylic acid methyl ester; To a solution of 6-amino-pyridine-2-carboxylic acid methyl ester (10 g, 66.0 mmol) in chloroform (450 mL) was added bromine (3.4 mL, 66.0 mmol) in CHCl₃(100 mL) at room temperature and stirred for 40 hours. The reaction mixture was diluted with CHCl₃and washed with saturated sodium thiosulfate solution and water. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel column chromatography using ethyl acetate/hexane as eluent. The title compound obtained as yellow solid (3.3 g, 22percent).MS ESI (m/e): 231.0 [(M+H)⁺].¹H NMR (CDCl₃, 400 MHz): δ (ppm)=7.76 (d, J=7.88 Hz, 1H), 7.34 (d, J=7.92 Hz, 1H), 5.23 (s, 2H), 3.94 (s, 3H).

22%

With bromine In chloroform at 20℃; for 40 h;

13
[ 36052-26-3 ]
[ 443956-21-6 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Yield	Reaction Conditions	Operation in experiment
18%	With bromine In chloroform at 20℃;	b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (Si0₂, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19percent) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29percent) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)
19%	With bromine In chloroform at 20℃;	b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (SiO₂, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19percent) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29percent) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)

Reference： [1] Patent: WO2011/75591, 2011, A1, . Location in patent: Page/Page column 95
[2] Patent: US2011/152312, 2011, A1, . Location in patent: Page/Page column 40

14
[ 1824-81-3 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Reference： [1] Patent: US2011/201605, 2011, A1,
[2] Patent: WO2011/101304, 2011, A2,

15
[ 5327-33-3 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Reference： [1] Patent: US2011/201605, 2011, A1,
[2] Patent: WO2011/101304, 2011, A2,

16
[ 26893-72-1 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Reference： [1] Patent: US2011/201605, 2011, A1,
[2] Patent: WO2011/101304, 2011, A2,

17
[ 23628-31-1 ]
[ 443956-21-6 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Reference： [1] Patent: US2011/152312, 2011, A1,
[2] Patent: WO2011/75591, 2011, A1,

18
[ 36052-26-3 ]
[ 443956-21-6 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Yield	Reaction Conditions	Operation in experiment
18%	With bromine In chloroform at 20℃;	b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (Si0₂, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19percent) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29percent) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)
19%	With bromine In chloroform at 20℃;	b. A solution of bromine (2.57 ml) in chloroform (40 mL) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 mL). The mixture was stirred overnight at room temperature and then loaded on silica and purified by chromatography (SiO₂, Heptane/EA) to afford 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19percent) along with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29percent) and 6-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g, 18percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.97 (s, 3H), 5.22 (br. s., 2H), 7.38 (d, J=7.8 Hz, 1H) and 7.79 (d, J=7.8 Hz, 1H)

Reference： [1] Patent: WO2011/75591, 2011, A1, . Location in patent: Page/Page column 95
[2] Patent: US2011/152312, 2011, A1, . Location in patent: Page/Page column 40

19
[ 178876-83-0 ]
[ 443956-21-6 ]

Reference： [1] Patent: WO2003/87098, 2003, A1, . Location in patent: Page/Page column 98

20
[ 23628-31-1 ]
[ 443956-21-6 ]
[ 178876-83-0 ]
[ 178876-82-9 ]

Reference： [1] Patent: US2011/152312, 2011, A1,
[2] Patent: WO2011/75591, 2011, A1,

[ 178876-83-0 ] Synthesis Path-Downstream 1~88

1
[ 108-24-7 ]
[ 178876-83-0 ]
6-Acetylamino-3-bromo-pyridine-2-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 4623 - 4633

2
[ 1824-81-3 ]
[ 178876-83-0 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 4623 - 4633
[2]Patent: US2011/190269,2011,A1
[3]Patent: WO2011/92272,2011,A1
[4]Patent: WO2014/125426,2014,A1

3
[ 5327-33-3 ]
[ 178876-83-0 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 4623 - 4633
[2]Patent: US2011/190269,2011,A1
[3]Patent: WO2011/92272,2011,A1
[4]Patent: WO2014/125426,2014,A1

4
[ 26893-72-1 ]
[ 178876-83-0 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 4623 - 4633
[2]Patent: US2011/190269,2011,A1
[3]Patent: WO2011/92272,2011,A1

5
[ 71-41-0 ]
[ 178876-83-0 ]
[ 882499-92-5 ]

Yield	Reaction Conditions	Operation in experiment
45%	With copper(l) iodide; sodium iodide; at 135℃; for 20.0h;Product distribution / selectivity;	Compound 17 2-amino-5-iodo-6-n-pentyloxycarbonylpyridine (17); To a stirred solution of <strong>[178876-83-0]2-amino-5-bromo-6-methoxycarbonylpyridine</strong> (13.8 g, 59.3 mmol) in n-pentanol (75 mL) was added 1,3-diaminopropane (900 mg, 12.1 mmol), copper (I) iodide (1.15 g, 6.0 mmol) and sodium iodide (18.0 g, 120 mmol). The reaction mixture heated to 135 C. After 16 hours (HPLC analysis shows 70% conversion), further portions of copper (I) iodide (600 mg, 3.0 mmol), sodium iodide (9.0 g, 60 mmol) and 1,3-diaminopropane (450 mg, 6.0 mmol) were added. After a further 4 hours, the reaction mixture was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over magnesium sulphate and concentrated under reduced pressure. Filtration through a short plug of silica, washing with ethyl acetate:cyclohexane 1:2 affords 2-amino-5-iodo-6-npentyloxycarbonylpyridine (8.94 g, 26.7 mmol, 45%) as a pale yellow solid. 1H NMR (CDCl3) 7.82 (1 H, d, J 12 Hz, C4-H), 6.36 (1 H, d, J 12 Hz, C3-H), 4.65 (2H, m, NH2), 4.36 (2 H, d, J 8 Hz, COCH2), 1.87-0.89 (9 H, m, CH2CH2CH2CH3)

Reference： [1]Patent: US2006/84802,2006,A1 .Location in patent: Page/Page column 30; 33

7
[ 178876-83-0 ]
[ 140-88-5 ]
[ 615568-67-7 ]

Yield	Reaction Conditions	Operation in experiment
31%	With triethylamine;tris-(dibenzylideneacetone)dipalladium(0); tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; at 50℃; for 72.0h;	To a degassed solution of methyl 6-amino-5-bromopyridine-2-carboxylate (1.06 g), ethyl acrylate (2.49 ml), tri-o-tolylphosphine (280 mg), triethylamine (3.18 ml) in dimethylformamide (50 ml) was added tris (dibenzylideneacetone) palladium (0) (211 mg) and the resultant solution was heated at 50C for 72h. After stirring overnight, the mixture was evaporated and the residue treated with dichloromethane (50 ml) and washed with H20. The aqueous fraction was re-extracted with 10% methanol in dichloromethane and the combined organic fractions dried (MgS04) and evaporated. Chromatography of the residue (60-80 petroleum ether-ethyl acetate 4: 1) gave the product (360 mg, 31 %). MS (+ve ion electrospray) m/z 251 (MH+, 100%)

Reference： [1]Patent: WO2003/87098,2003,A1 .Location in patent: Page/Page column 103

8
[ 178876-83-0 ]
[ 577691-78-2 ]

Yield	Reaction Conditions	Operation in experiment
	With Selectfluor; In acetonitrile; at 40 - 80℃;	A mixture of methyl 6-amino-5-bromopyridine-2-carboxylate (19. 8 g) (T. R. Kelly and F. Lang, J ; Org. Chem. 61, 1996,4623-4633) and 1-chloromethyl-4-fluoro-1, 4- diazoniabicyclo [2.2. 2] octane bis (tetrafluoroborate) (34.3 g) in acetonitrile (340 ml) under argon was heated to 40C for 1 hour, 60C for 1 hour and then 80C overnight. After partitioning between EtOAc and water (500ml each) the aqueous fraction was re- extracted with EtOAc (300 ml) and the combined organic solution dried with MgS04 and evaporated. Chromatography (20% then 30% EtOAc in hexane) separated various byproducts from the required ester (2.09 g). MS (+ve ion electrospray) m/z 249 and 251 (MH+, 100%)

Reference： [1]Patent: WO2003/87098,2003,A1 .Location in patent: Page/Page column 104

9
[ 100-39-0 ]
[ 178876-83-0 ]
[ 1037840-90-6 ]

Yield	Reaction Conditions	Operation in experiment
73%	With sodium hydride; In N,N-dimethyl-formamide;Cooling with ice;	Reference Example 18; methyl 3-bromo-6-(dibenzylamino)pyridine-2-carboxylate [Show Image]; To a suspension of 60% sodium hydride (880 mg, 22.0 mmol) and benzyl bromide (6.24 mL, 52.5 mmol) in N,N-dimethylformamide (80 mL) was added a solution of <strong>[178876-83-0]methyl 6-amino-3-bromopyridine-2-carboxylate</strong> (2.42 g, 10.5 mmol) in N,N-dimethylformamide (25 mL) under ice-cooling and the mixture was stirred for 30 min. The reaction solution was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100?20/80) to give the title compound (3.16 g, yield 73%). 1H-NMR (CDCl3) delta: 3.96 (3H, s), 4.77 (4H, s), 6.39 (1H, d, J = 9.1 Hz), 7.18 - 7.37 (10H, m), 7.51 (1H, d, J = 9.1 Hz), MS (ESI+): 411 (M+H).

Reference： [1]Patent: EP2098513,2009,A1 .Location in patent: Page/Page column 49

10
[ 36052-26-3 ]
[ 178876-83-0 ]

Yield	Reaction Conditions	Operation in experiment
29%		Reference Example 17; methyl 6-amino-3-bromopyridine-2-carboxylate [Show Image]; To a suspension of methyl 6-aminopyridine-2-carboxylate (5.98 g, 39.5 mmol) and sodium carbonate (2.64 g, 24.9 mmol) in acetic acid (150 mL) was added bromine (7.89 g, 49.4 mmol), and the mixture was stirred at room temperature for 7 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. This was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70?80/20) to give the title compound (2.67 g, yield 29%). 1H-NMR (CDCl3) delta: 3.95 (3H, s), 4.74 (2H, brs), 6.49 (1H, d, J = 8.8 Hz), 7.62 (1H, d, J = 8.8 Hz), MS (ESI+): 231 (M+H).
11%	With bromine; sodium carbonate; In acetic acid; at 20℃; for 5.0h;	To a 100 mL round bottom flask, were added methyl 6-aminopicolinate (6 g, 0.0394 mol), sodium carbonate (2.64 g, 0.0248 mol) and acetic acid (300 mL). The reaction mixture was cooled to 0 - 5 C. To the same flask, bromine (2 mL, 0.039 mol) was slowly added. The reaction mixture was stirred at room temperature for 5 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60 - 120 silica gel and 30 % ethyl acetate in hexane to get the title compound [1 g, 11 %]. FontWeight="Bold" FontSize="10" H NMR (400 MHZ, CDC13): delta 7.63 (d, / = 8.8 Hz, 1H), 6.51 (d, = 8.8 Hz, 1H), 4.80 (brs, 2H), 3.94 (s, 3H); LC-MS: 232.8 [M+2H]+.

Reference： [1]Patent: EP2098513,2009,A1 .Location in patent: Page/Page column 49
[2]Patent: WO2014/125426,2014,A1 .Location in patent: Page/Page column 59; 60

11
[ 1113-59-3 ]
[ 178876-83-0 ]
[ 1195984-09-8 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile; at 85℃; for 12.0h;Sealed tube;	-amino-S-bromo-pyridine^-carboxylic acid methyl ester (1 eq.) is dissolved in acetonitrile (0.2 M). To this solution is added 3-bromopyruvic acid (1.1 eq.). The reaction is stirred at 85 0C in a sealed tube for 12 h and then cooled to room temperature. The resulting solid is collected and washed with acetonitrile to provide a yellow brown solid, m/z 301 (M+H)+.

Reference： [1]Patent: WO2009/140101,2009,A2 .Location in patent: Page/Page column 44

12
[ 823-96-1 ]
[ 178876-83-0 ]
[ 1319069-28-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 115℃; for 4.0h;Inert atmosphere;	a) 6-Amino-3-methyl-pyridine-2-carboxylic acid methyl ester; To a solution of <strong>[178876-83-0]6-amino-3-bromo-pyridine-2-carboxylic acid methyl ester</strong> (3 g, 12.99 mmol) and trimethyl boroxine (1.8 mL, 2.99 mmol) in 1,4 dioxane (30 mL) was added K2CO3 (3.5 g, 25.97 mmol) under an argon atmosphere. To this was added PdCl2 (dppf)2.CH2Cl2 (530 mg, 0.65 mmol) and stirred at 115 C. for 4 h. The reaction mixture was cooled to room temperature and water was added to residue. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as an off white solid (1.9 g, 88%).MS ESI (m/e): 166.8 [(M+H)+].1H NMR (DMSO, 400 MHz): delta(ppm)=7.31 (d, J=8.4 Hz, 1H), 6.53 (d, J=8.36 Hz, 1H), 5.99 (s, 2H), 3.77 (s, 3H), 2.21 (s, 3H).

Reference： [1]Patent: US2011/190269,2011,A1 .Location in patent: Page/Page column 73-74

13
[ 178876-83-0 ]
[ 1319069-29-8 ]

Reference： [1]Patent: US2011/190269,2011,A1
[2]Patent: WO2011/92272,2011,A1

14
[ 178876-83-0 ]
[ 1319069-33-4 ]

Reference： [1]Patent: US2011/190269,2011,A1

15
[ 178876-83-0 ]
[ 1319069-35-6 ]
C₉H₉BrN₄O [ No CAS ]

Reference： [1]Patent: US2011/190269,2011,A1

16
[ 178876-83-0 ]
[ 1319069-37-8 ]

Reference： [1]Patent: US2011/190269,2011,A1

17
[ 178876-83-0 ]
[ 1319069-31-2 ]

Reference： [1]Patent: US2011/190269,2011,A1

18
[ 102-24-9 ]
[ 178876-83-0 ]
[ 1319069-28-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 115℃; for 4.0h;Inert atmosphere;	To a solution of <strong>[178876-83-0]6-amino-3-bromo-pyridine-2-carboxylic acid methyl ester</strong> (3 g, 12.99 mmol) and trimethyl boroxine (1.8 mL, 2.99 mmol) in 1,4 dioxane (30 mL) was added K2CO3 (3.5 g, 25.97 mmol) under an argon atmosphere. To this was added PdCl2 (dppf) 2.CH2Cl2 (530 mg, 0.65 mmol) and stirred at 115C for 4 h. The reaction mixture was cooled to room temperature and water was added to residue. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as an off white solid (1.9 g, 88%).MS ESI (m/e): 166.8 [(M+H)+].1H NMR (DMSO, 400 MHz): <5 (ppm) = 7.31(d, J= 8.4 Hz, 1H), 6.53 (d, J= 8.36 Hz, 1H), 5.99 (s, 2H), 3.77 ( s, 3H), 2.21 (s, 3H).

Reference： [1]Patent: WO2011/92272,2011,A1 .Location in patent: Page/Page column 156

19
[ 330660-35-0 ]
[ 1226890-40-9 ]
[ 178876-83-0 ]
[ 1227001-99-1 ]

Yield	Reaction Conditions	Operation in experiment
34%	In dichloromethane; acetonitrile;	Example (Ik-127) N-{3-Bromo[2-(1R,2S)-2-fluorocycloprop-1-ylcarbamoyl]pyrid-6-yl}-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 528 mg (1.59 mmol) of 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride and a suspension of 214 mg of silver(I) cyanide in 13.4 ml of acetonitrile are added to a solution of 369 mg (1.59 mmol) of <strong>[178876-83-0]methyl 6-amino-3-bromopyridine-2-carboxylate</strong> (cf. WO 2008/084717) in 13.4 ml of dichloromethane. The reaction mixture is then stirred for 24 hours at room temperature. The reaction mixture is then filtered and the solvent mixture is stripped off in vacuo. The remaining residue is purified by means of column chromatography over silica gel using the eluent mixture cyclohexane:acetone (gradient). This gives 302 mg of methyl 3-bromo-6-([1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-yl]carbonyl}amino)pyridine-2-carboxylate (34%). HPLC-MSa): log P=4.06; mass (m/z)=527 [M+H]+.

Reference： [1]Patent: US2011/301181,2011,A1

20
[ 178876-83-0 ]
N-{3-Bromo[2-(1R,2S)-2-fluorocycloprop-1-ylcarbamoyl]pyrid-6-yl}-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide [ No CAS ]

Reference： [1]Patent: US2011/301181,2011,A1

21
[ 178876-83-0 ]
[ 1227002-00-7 ]

Reference： [1]Patent: US2011/301181,2011,A1

22
[ 178876-83-0 ]
[ 1446685-60-4 ]

Reference： [1]Arzneimittel-Forschung/Drug Research,2012,vol. 62,p. 537 - 544

23
[ 178876-83-0 ]
[ 1446685-56-8 ]

Reference： [1]Arzneimittel-Forschung/Drug Research,2012,vol. 62,p. 537 - 544

24
[ 178876-83-0 ]
[ 1446685-64-8 ]

Reference： [1]Arzneimittel-Forschung/Drug Research,2012,vol. 62,p. 537 - 544

25
[ 178876-83-0 ]
C₁₀H₁₀N₂O₃ [ No CAS ]

Reference： [1]Arzneimittel-Forschung/Drug Research,2012,vol. 62,p. 537 - 544

26
[ 292638-85-8 ]
[ 178876-83-0 ]
C₁₁H₁₂N₂O₄ [ No CAS ]

Reference： [1]Arzneimittel-Forschung/Drug Research,2012,vol. 62,p. 537 - 544

27
[ 1033201-61-4 ]
[ 18107-18-1 ]
[ 178876-83-0 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; hexane; ethyl acetate; for 72.0h;	Example 57C methyl 6-amino-3-bromopicolinate To a solution of 6-amino-3-bromopicolinic acid (30 g) in ethyl acetate (300 mL) and methanol (300 mL) was added TMS-diazomethane (70 mL, 2M in hexanes) and the reaction mixture was stirred for 3 days. The mixture was concentrated, taken up in ether (500 mL) and washed with aqueous Na2CO3 solution (twice), then washed with brine, dried over sodium sulfate, filtered and concentrated to provide the title compound.
	In methanol; ethyl acetate; for 72.0h;	Example 158C methyl 6-amino-3-bromopicolinate To a solution of 6-amino-3-bromopicolinic acid (30 g) in ethyl acetate (300 mL) and methanol (300 mL) was added TMS-diazomethane (70 mL, 2M in hexanes) and the reaction mixture was stirred for 3 days. The mixture was concentrated, taken up in ether (500 mL) and washed with aqueous saturated Na2CO3 solution (twice) and brine, then dried over sodium sulfate, filtered and concentrated to provide the title compound.

Reference： [1]Patent: US2013/96120,2013,A1 .Location in patent: Paragraph 1079
[2]Patent: US2013/96121,2013,A1 .Location in patent: Paragraph 1777

28
[ 178876-83-0 ]
[ 1430753-68-6 ]

Reference： [1]Patent: US2013/96120,2013,A1
[2]Patent: US2013/96121,2013,A1

29
[ 178876-83-0 ]
[ 1214324-98-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With nitrosonium tetrafluoroborate; In dichloromethane; at 0 - 20℃; for 16.0h;	At 0 C., to a solution of NOBF4 (2.28 g, 19.52 mmol) in dichloromethane (60 mL) was added a solution of <strong>[178876-83-0]methyl 6-amino-3-bromopyridine-2-carboxylate</strong> (3.45 g, 14.93 mmol) in dichloromethane (15 mL) slowly. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was then quenched by water (100 mL) and extracted with dichloromethane (120 mL*2). The combined organic phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with petroleum ether: ethyl acetate (10:1 to 7:3 gradient) to yield methyl 3-bromo-6-fluoropyridine-2-carboxylate (2.4 g, 69%) as light yellow oil. MS: m/z=233.8 [M+H]+.
	With nitrosonium tetrafluoroborate; In dichloromethane; at 5 - 20℃;	Example 57D methyl 3-bromo-6-fluoropicolinate To a solution of nitrosonium terafluoroborate (17.8 g) in dichloromethane (100 mL) at 5 C. was added EXAMPLE 57C (26.1 g) in dichloromethane (250 mL) over 1 hour. The reaction mixture was stirred an additional 30 minutes at 5 C., and allowed to warm to room temperature overnight. The reaction mixture was quenched with pH 7 buffer (100 mL), and neutralized with solid potassium carbonate. The resulting mixture was extracted with ether (twice), and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel using 1-10% ethyl acetate in hexanes to provide the title compound.
	With nitrosonium tetrafluoroborate; In dichloromethane; at 5 - 20℃;	Example 158D methyl 3-bromo-6-fluoropicolinate To a solution of nitrosonium terafluoroborate (17.8 g) in dichloromethane (100 mL) at 5 C. was added EXAMPLE 158C (26.1 g) in dichloromethane (250 mL) over 1 hour. The reaction mixture was stirred an for additional 30 minutes at 5 C., and then allowed to warm to room temperature overnight. The reaction mixture was quenched with pH 7 buffer (100 mL), and then neutralized with solid potassium carbonate. The resulting mixture was extracted with ether (twice), and the combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 1 to 10% ethyl acetate in hexanes to provide the title compound.

Reference： [1]Patent: US2016/75711,2016,A1 .Location in patent: Paragraph 0386-0387
[2]Patent: US2013/96120,2013,A1 .Location in patent: Paragraph 1080
[3]Patent: US2013/96121,2013,A1 .Location in patent: Paragraph 1778

30
[ 178876-83-0 ]
[ 1430749-96-4 ]

Reference： [1]Patent: US2013/96121,2013,A1

31
[ 178876-83-0 ]
[ 1430753-53-9 ]

Reference： [1]Patent: US2013/96121,2013,A1

32
[ 178876-83-0 ]
[ 1430753-54-0 ]

Reference： [1]Patent: US2013/96121,2013,A1

33
[ 178876-83-0 ]
[ 1430845-34-3 ]

Reference： [1]Patent: US2013/96120,2013,A1

34
[ 178876-83-0 ]
[ 1430846-79-9 ]

Reference： [1]Patent: US2013/96120,2013,A1

35
[ 178876-83-0 ]
[ 1430846-80-2 ]

Reference： [1]Patent: US2013/96120,2013,A1

36
[ 178876-83-0 ]
[ 1214342-46-7 ]

Reference： [1]Patent: WO2014/125426,2014,A1

37
[ 178876-83-0 ]
[ 1622243-02-0 ]

Reference： [1]Patent: WO2014/125426,2014,A1

38
[ 178876-83-0 ]
[ 1622243-03-1 ]

Reference： [1]Patent: WO2014/125426,2014,A1

39
[ 178876-83-0 ]
[ 1622242-69-6 ]

Reference： [1]Patent: WO2014/125426,2014,A1

40
[ 768-35-4 ]
[ 178876-83-0 ]
[ 1214359-92-8 ]

Yield	Reaction Conditions	Operation in experiment
57%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,3-dioxane; water; at 90℃; for 2.0h;	To a 25 mL round bottom flask, were added <strong>[178876-83-0]methyl 6-amino-3-bromopicolinate</strong> (1 g, 0.0043 mol), 3-fluorophenylboronic acid (0.72 g, 0.0052 mol), potassium carbonate (1.52 g, 0.011 mol), 1,4-dioxane (20 mL) and water (4 mL). The reaction mixture was degassed with nitrogen for 5 min. To the same flask, bis(triphenylphosphine)palladium(II) dichloride (0.14 g, 0.00022 mol) was added. The reaction mixture was again degassed with nitrogen for 5 min. The reaction mixture was stirred at 90 C for 2 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 20 - 40 % ethyl acetate in hexane to obtain the title compound [0.6 g, 57 %]. FontWeight="Bold" FontSize="10" H NMR (CDC13, 400 MHz): delta 7.68-7.63 (m, 1H), 7.48 (d, = 8.8 Hz, 1H), 7.36-7.31 (m, 1H), 7.05-6.97 (m, 2H), 6.67 (d, = Hz, 1H), 4.79 (brs, 2H), 3.72 (s, 3H); LC-MS: 247.1 [M+H]+.

Reference： [1]Patent: WO2014/125426,2014,A1 .Location in patent: Page/Page column 60

41
[ 594-27-4 ]
[ 178876-83-0 ]
6-amino-3-methylpicolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); lithium chloride; In N,N-dimethyl-formamide; at 110℃; for 9.0h;	10593] To <strong>[178876-83-0]methyl 6-amino-3-bromopicolinate</strong> (500 mg, 2.2 mmol), tetramethylstannane (900 pL, 6.5 mmol) and LiC1 (354 g, 8.7 mmol) in DMF (6 mE) was added Pd(PPh3)4 (76 mg, 10 mol %). The reaction mixture was heated at 1100 C. for 3 h. Additional tetramethylstannane, EiC1 and Pd(PPh3)4 were added and heating continued for 6 h. Purification via silica gel chromatography (0-20% MeOH in DCM) gave the title compound.

Reference： [1]Patent: US2016/46640,2016,A1 .Location in patent: Paragraph 0593

42
[ 178876-83-0 ]
(3-bromo-6-fluoropyridin-2-yl)methanol [ No CAS ]

Reference： [1]Patent: US2016/75711,2016,A1

43
[ 178876-83-0 ]
3-bromo-6-fluoropyridine-2-carbaldehyde [ No CAS ]

Reference： [1]Patent: US2016/75711,2016,A1

44
[ 178876-83-0 ]
6-fluoro-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]pyridine-2-carbaldehyde [ No CAS ]

Reference： [1]Patent: US2016/75711,2016,A1

45
[ 178876-83-0 ]
1-cyclohexyl-3-[6-fluoro-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]pyridin-2-yl]prop-2-en-1-one [ No CAS ]

Reference： [1]Patent: US2016/75711,2016,A1

46
[ 178876-83-0 ]
1-cyclohexyl-2-[10-fluoro-4,6,9-triazatricyclo[6.4.0.0^2,6]dodeca-1⁽⁸⁾,2,4,9,11-pentaen-7-yl]ethan-1-one [ No CAS ]

Reference： [1]Patent: US2016/75711,2016,A1

47
[ 178876-83-0 ]
1-cyclohexyl-2-[10-fluoro-4,6,9-triazatricyclo[6.4.0.0^2,6]dodeca-1⁽⁸⁾,2,4,9,11-pentaen-7-yl]ethan-1-ol [ No CAS ]

Reference： [1]Patent: US2016/75711,2016,A1

48
[ 178876-83-0 ]
10-fluoro-7-[2-(1-fluorocyclohexyl)ethyl]-4,6,9-triazatricyclo[6.4.0.0^2,6]dodeca-1⁽⁸⁾,2,4,9,11-pentaene [ No CAS ]

Reference： [1]Patent: US2016/75711,2016,A1

49
[ 178876-83-0 ]
6-methylimidazo[1,2-a]pyridine-5-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2016/46640,2016,A1

50
[ 107-20-0 ]
[ 178876-83-0 ]
C₉H₇BrN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2 g	With sodium hydrogencarbonate; In ethanol; at 95℃; for 5.5h;	To a solution of <strong>[178876-83-0]methyl 6-amino-3-bromopicolinate</strong> (2.00 g, 8.66 mmol, 1 eq) in EtOH (15 mL) was added chloroacetaldehyde (13.6 g, 86.58 mmol, 50% purity, 10 eq) and NaHC03 (1.24 g, 14.72 mmol, 1.7 eq). The mixture was stirred at 95 C for 5.5 hours (hr). The reaction mixture was filtered and concentrated under reduced pressure. The residue was adjusted to pH=9 with K2C03 aqueous solution and extracted with chloroform. The combined organic layers were washed with brine, and dried over MgS04. The concentrated residue was purified by flash chromatography (Si02, pentane/ethyl acetate/MeOH = 2: 1 :0.03). Example 1 A (2.0 g, 91% yield) was obtained as a brown solid. Mass spectrum (ESI), m/z 255.0 and 257.1 [M + H]+.

Reference： [1]Patent: WO2017/214413,2017,A1 .Location in patent: Paragraph 0101

51
[ 64-17-5 ]
[ 78-95-5 ]
[ 178876-83-0 ]
C₁₁H₁₁BrN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.3%	With sodium hydrogencarbonate; at 90℃; for 12.0h;	To a solution of <strong>[178876-83-0]methyl 6-amino-3-bromopicolinate</strong> (1.00 g, 4.33 mmol, 1 eq) in ethanol (50 mL) was added sodium bicarbonate (618 mg, 7.36 mmol, 1.7 eq) and 1- chloropropan-2-one (2.47 g, 26.7 mmol, 6.2 eq). The reaction was stirred at 90 C for 12 hr. The reaction was cooled to 25 C and concentrated in vacuo. To the residue was added water (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL3). The combined organic phases were washed with brine (50 mL2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-TLC. Example 119A (400 mg, yield=34.3%) was obtained as a brown solid. ESI m/z 283.0 [M + 1] +.

Reference： [1]Patent: WO2017/214413,2017,A1 .Location in patent: Paragraph 0209

52
[ 178876-83-0 ]
C₁₈H₁₉N₃O₄ [ No CAS ]