[ CAS No. 77199-09-8 ] {[proInfo.proName]}

Name: 77199-09-8|Ethyl 5-bromopicolinate|98%
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SKU: A101561
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Quality Control of [ 77199-09-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 77199-09-8 ]

Product Details of [ 77199-09-8 ]

CAS No. :	77199-09-8	MDL No. :	MFCD00234415
Formula :	C₈H₈BrNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MVJPVDSRSXLJNQ-UHFFFAOYSA-N
M.W :	230.06	Pubchem ID :	12686158
Synonyms :

Calculated chemistry of [ 77199-09-8 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	48.02
TPSA :	39.19 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) :	-5.76 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.34
Log Po/w (XLOGP3) :	2.74
Log Po/w (WLOGP) :	2.02
Log Po/w (MLOGP) :	1.4
Log Po/w (SILICOS-IT) :	2.2
Consensus Log Po/w :	2.14

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.16
Solubility :	0.157 mg/ml ; 0.000685 mol/l
Class :	Soluble
Log S (Ali) :	-3.22
Solubility :	0.139 mg/ml ; 0.000606 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.37
Solubility :	0.099 mg/ml ; 0.000431 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.83

Safety of [ 77199-09-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 77199-09-8 ]

* 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 [ 77199-09-8 ]
Downstream synthetic route of [ 77199-09-8 ]

[ 77199-09-8 ] Synthesis Path-Upstream 1~10

1
[ 77199-09-8 ]
[ 30766-11-1 ]

Reference： [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020

2
[ 77199-09-8 ]
[ 75754-04-0 ]

Reference： [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020

3
[ 77199-09-8 ]
[ 88139-91-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: With sodium tetrahydroborate In methanol at 20 - 70℃; for 0.833333 h; Stage #2: With hydrogenchloride In water	Example 593-(((5-(l-(4-(2,3-Dimethylphenoxy)butanoyl)-l,2,3,4-tetrahydroquinolin-5-yl)pyridin-2- yl)methoxy)carbonylamino)propanoic acid[00204] To a solution of NaBH₄ (0.822 g, 21.73 mmol) in MeOH (25 mL) was added ethyl 5-bromopicolinate (1.0 g, 4.35 mmol) portion-wise over a period of 10 min at room temperature. The mixture was stirred at room temperature for 10 min and then heated to 70 °C for 30 min. The solvent was removed in vacuo, and the resulting residue was diluted with EtOAc and water. The aqueous phase was adjusted to pH 7 with 1 N aq. HCl, and extracted with EtOAc. The combined organic layer was dried over MgS0₄, filtered, and concentrated in vacuo to afford the title compound (0.65 g, 80percent yield) as a white solid. LCMS, [M+H]⁺ = 187.9.

Reference： [1] Patent: WO2012/149236, 2012, A1, . Location in patent: Page/Page column 162

4
[ 30766-11-1 ]
[ 64-17-5 ]
[ 77199-09-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 20℃; for 18 h;	(a) Preparation of ethyl 5-bromopyridine-2-carboxylate 2:To a suspension of 5-bromopyridine-2-carboxylic acid 1 (2.02 g, 10 mmol) in 50 mL of EtOH was added thionyl chloride (5 mL). The mixture was stirred at ambient temperature for 18 h. After removal of all solvent, the residue was purified by column (2: 1 of hexane/ethyl acetate) to give 2.3 g of ethyl 5-bromopyridine-2-carboxylate 2 as an oil. Yield: 2.3g, quantitative yield. ^.HNMR (CDCI_B) δ (ppm): 8.80 (d, 1 H), 8.00 (m, 2 H), 4.50 (m, 2 H), 1.44 (t, 3 H).
86%	at 75℃; for 2 h;	Reference Example 255 Production of ethyl 5-bromopyridine-2-carboxylate A mixture of 5-bromopyridine-2-carboxylic acid (35.0 g, 173 mmol), sulfuric acid (12.0 mL) and ethanol (300 mL) was stirred at 75°C for 2 hr. After cooling to 0°C, the mixture was neutralized with sodium hydrogen carbonate and diluted with water (150 mL). Ethanol was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (300 mL). The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained solid was collected by filtration, washed with hexane, and dried to give the title compound (34.5 g, 86percent) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ:1.33 (3 H, t, J = 7.1 Hz), 4.35 (2 H, q, J = 7.1 Hz), 7.99 (1 H, d, J = 8.3 Hz), 8.27 (1 H, dd, J = 2.3, 8.3 Hz), 8.86 (1 H, d, J = 2.3 Hz).
28%	Stage #1: for 2 h; Heating / reflux Stage #2: Heating / reflux Stage #3: With sodium carbonate In water; toluene	Pyridine (22) is obtained in two steps from 5-bromo-2-methyl-pyridine (20) by oxidation to 5-bromo-2-pyridinecarboxylic acid (21) as described in G. M. Sanders, M. van Dijk and H. C. van der Plas, Heterocycles 1981, 15, 213-223, and chlorination with SOCl₂followed by reaction with EtOH (see Scheme 6). 1.17 g of 5-bromo-2-pyridinecarboxylic acid (21), prepared according to G. M. Sanders, M. van Dijk and H. C. van der Plas, Heterocycles 1981, 15, 213-223, are placed in SOCl₂(6 ml) and the mixture is heated 2 h under reflux. After evaporation of SOCl₂the residue is treated under reflux with a mixture of toluene (3 ml) and absolute EtOH (6 ml). The pH is adjusted to 8 by addition of sat. aq. Na₂CO₃sol. and the product is extracted with Et₂O. The organic layer is washed to neutral pH with H₂O portions, dried over Na₂SO₄and the solvent is evaporated to obtain 377 mg of 5-bromo-pyridine-2-carboxylic acid ethyl ester (22) as a white powder, MS (ESI) 232.0 (M+H)⁺.

15 g

at 70℃; for 3 h;

Compound d-1-1 of 21g was dissolved in EtOH (ethanol) 300ml and 15ml of sulfuric acid was added, and the mixture was stirred for 3 hours at 70 . Then, by cooling the resulting solution, and then was neutralized with aqueous sodium hydrogen carbonate and ethyl acetate was added to extract fractions, it was carried out the concentration of the organic layer. Purification of the resultant concentrate by silica gel column chromatography to obtain 15g of the compound d-1-2.

Reference： [1] Patent: WO2012/76898, 2012, A1, . Location in patent: Page/Page column 58
[2] Patent: EP2471789, 2012, A1, . Location in patent: Page/Page column 115
[3] Patent: US2005/113374, 2005, A1, . Location in patent: Page/Page column 8; 12-13
[4] Heterocycles, 1981, vol. 15, # 1, p. 213 - 223
[5] Patent: WO2009/5645, 2009, A1, . Location in patent: Page/Page column 153
[6] Patent: WO2009/5646, 2009, A2, . Location in patent: Page/Page column 155
[7] Patent: WO2005/44814, 2005, A1, . Location in patent: Page/Page column 26
[8] Patent: KR2015/129778, 2015, A, . Location in patent: Paragraph 0567-570; 0574-0576

5
[ 624-28-2 ]
[ 667-27-6 ]
[ 77199-09-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: With copper In dimethyl sulfoxide at 20℃; for 1 h; Stage #2: at 20℃; for 15 h;	SYNTHESIS OF INTERMEDIATE KETONE B2-(5-Bromopyridin-2-yl)- 1-(2,4-difluorophenyl)-2,2-difluoroethanone (B) To a suspension of copper powder (2.68 grams (g), 42.2 millimoles (mmol)) in dimethyl sulfoxide(DMSO; 35 milliliters (mL)) was added ethyl 2-bromo-2,2-difluoroacetate (2.70 mL, 21.10mmol), and the mixture was stirred for 1 hour (h) at room temperature (RT). 2,5-Dibromopyridine(2.50 g, 10.55 mmol) was then added, and stirring was continued for 15 h at RT. The reactionmixture was quenched with aqueous (aq) ammonium chloride (NH4C1) and extracted withdichloromethane (CH2C12 3 x 25 mL). The combined organic layers were washed with water (H20), washed with brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure to afford the crude product mixture. Purification by column chromatography (eluting with ethyl acetate (EtOAc)/hexane) afforded the ethyl ester intermediate (2.40 g, 8.57mmol, 81percent) as a pale yellow oil. ‘H NMR (500 MHz, CDC13): ö 8.71 (s, 1H), 8.00 (d, J 9.0 Hz,1H), 7.64 (d, J= 9.0 Hz, 1H), 4.42-4.35 (m, 2H), 1.39-1.3 1 (m, 3H).

Reference： [1] Patent: WO2014/43376, 2014, A1, . Location in patent: Page/Page column 46; 47

6
[ 624-28-2 ]
[ 109-94-4 ]
[ 77199-09-8 ]

Yield	Reaction Conditions	Operation in experiment
46%	Stage #1: With trimethylsilylmethyllithium In toluene at -78 - 0℃; for 0.5 h; Stage #2: for 3 h; Stage #3: With iodine; potassium carbonate In toluene at 20℃; for 18 h;	General procedure: N,N-Dimethylaminoethanol (0.85 ml, 8.5 mmol, 1 equiv.) and(trimethylsilyl)methyllithium 1 M (25.3 ml, 25.3 mmol, 3 equiv.)was added dropwise to 25 ml of dry toluene at 0 °C and the solutionwas stirred for 30 min to form TMSCH2Li-LiDMAE (in situ). Then, Asolution of 2,5-dibromopyridine 1 (2 g, 8.5 mmol, 1 equiv.) in 9 mlof dry toluene was added dropwise. The reaction mixture wasstirred for 30 min, cooled to 78 °C and added methyl formate(5.2 ml, 85 mmol, 10 equiv.) or ethyl formate (6.9 ml, 85 mmol,10 equiv.) in 10 ml of toluene. The reaction mixture stirred for 3 h,and I2 (6.4 g, 25.5 mmol, 3 equiv.), K2CO3 (5.8 g, 42.5 mmol, 5 equiv.)and 20 ml methanol or ethanol were added. The mixture wasstirred at room temperature for 18 h and added 10 ml of a sat.aqueous Na2SO3 solution.Water (10 ml)was added and the mixtureextracted with dichloromethane (3x40 ml), washed with water(1 x 25 ml) and brine (1 x 25 ml). The residue was purified bysilica-gel flash column chromatography (eluent: heptane/diethylether 2: 1) to obtain 2a-b

Reference： [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020

7
[ 137178-88-2 ]
[ 64-17-5 ]
[ 77199-09-8 ]

Reference： [1] Patent: US2010/41642, 2010, A1, . Location in patent: Page/Page column 25

8
[ 624-28-2 ]
[ 64-17-5 ]
[ 201230-82-2 ]
[ 77199-09-8 ]

Reference： [1] Synthetic Communications, 1997, vol. 27, # 3, p. 515 - 520
[2] Dalton Transactions, 2011, vol. 40, # 29, p. 7534 - 7540

9
[ 64-17-5 ]
[ 29682-15-3 ]
[ 77199-09-8 ]

Reference： [1] Organic Letters, 2009, vol. 11, # 16, p. 3690 - 3693

10
[ 3430-13-5 ]
[ 77199-09-8 ]

Reference： [1] Heterocycles, 1981, vol. 15, # 1, p. 213 - 223

[ 77199-09-8 ] Synthesis Path-Downstream 1~88

1
[ 96-48-0 ]
[ 77199-09-8 ]
[ 77199-10-1 ]

Reference： [1]Heterocycles,1981,vol. 15,p. 213 - 223

2
[ 30766-11-1 ]
[ 64-17-5 ]
[ 77199-09-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; at 20℃; for 18h;	(a) Preparation of ethyl 5-bromopyridine-2-carboxylate 2:To a suspension of 5-bromopyridine-2-carboxylic acid 1 (2.02 g, 10 mmol) in 50 mL of EtOH was added thionyl chloride (5 mL). The mixture was stirred at ambient temperature for 18 h. After removal of all solvent, the residue was purified by column (2: 1 of hexane/ethyl acetate) to give 2.3 g of ethyl 5-bromopyridine-2-carboxylate 2 as an oil. Yield: 2.3g, quantitative yield. .HNMR (CDCIB) delta (ppm): 8.80 (d, 1 H), 8.00 (m, 2 H), 4.50 (m, 2 H), 1.44 (t, 3 H).
86%	With sulfuric acid; at 75℃; for 2h;	Reference Example 255 Production of ethyl 5-bromopyridine-2-carboxylate A mixture of 5-bromopyridine-2-carboxylic acid (35.0 g, 173 mmol), sulfuric acid (12.0 mL) and ethanol (300 mL) was stirred at 75C for 2 hr. After cooling to 0C, the mixture was neutralized with sodium hydrogen carbonate and diluted with water (150 mL). Ethanol was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (300 mL). The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained solid was collected by filtration, washed with hexane, and dried to give the title compound (34.5 g, 86%) as a white solid. 1H NMR (300 MHz, DMSO-d6) delta:1.33 (3 H, t, J = 7.1 Hz), 4.35 (2 H, q, J = 7.1 Hz), 7.99 (1 H, d, J = 8.3 Hz), 8.27 (1 H, dd, J = 2.3, 8.3 Hz), 8.86 (1 H, d, J = 2.3 Hz).
28%		Pyridine (22) is obtained in two steps from 5-bromo-2-methyl-pyridine (20) by oxidation to 5-bromo-2-pyridinecarboxylic acid (21) as described in G. M. Sanders, M. van Dijk and H. C. van der Plas, Heterocycles 1981, 15, 213-223, and chlorination with SOCl2 followed by reaction with EtOH (see Scheme 6). 1.17 g of 5-bromo-2-pyridinecarboxylic acid (21), prepared according to G. M. Sanders, M. van Dijk and H. C. van der Plas, Heterocycles 1981, 15, 213-223, are placed in SOCl2(6 ml) and the mixture is heated 2 h under reflux. After evaporation of SOCl2 the residue is treated under reflux with a mixture of toluene (3 ml) and absolute EtOH (6 ml). The pH is adjusted to 8 by addition of sat. aq. Na2CO3 sol. and the product is extracted with Et2O. The organic layer is washed to neutral pH with H2O portions, dried over Na2SO4 and the solvent is evaporated to obtain 377 mg of 5-bromo-pyridine-2-carboxylic acid ethyl ester (22) as a white powder, MS (ESI) 232.0 (M+H)+.

		To a cloudy suspension of the 5-bromopicolinic acid (5.0 g, 25 mmol) in EtOH (150 mL) was added a solution of HCI in dioxane (4M, 6.8 ml_, 27 mmol). The mixture was heated to reflux with stirring for 16 h. The mixture was then concentrated and the crude product was partitioned between EtOAc and NaHCO3 (aq.). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford the ester (4.91 g) as a white crystalline solid.
	With hydrogenchloride; In 1,4-dioxane; for 16h;Heating / reflux;	Step 1:To a cloudy suspension of the 5-bromopicolinic acid (5.0 g, 25 mmol) in EtOH (150 ml_) was added a solution of HCI in dioxane (4M, 6.8 ml_, 27 mmol). The mixture was heated to reflux with stirring for 16 h. The mixture was then concentrated and the crude product was partitioned between EtOAc and NaHCO3 (aq.). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford the ester (4.91 g) as a white crystalline solid.
		Example 13; 5-(3,3-Dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylethynyl)-pyridine-2- carboxylic acid ethyl ester; a) 5-Bromo-pyridine-2-carboxylic acid ethyl ester (22); 1.17 g of 5-bromo-2-pyridinecarboxylic acid (21), prepared according to G. M. Sanders, M. van Dijk and H. C. van der Plas, Heterocycles 1981,15, 213-223, are placed in SOC12 (6 ml) and the mixture is heated 2 h under reflux. After evaporation of SOC12 the residue is treated under reflux with a mixture of toluene (3 ml) and absolute EtOH (6 ml). The pH is adjusted to 8 by addition of sat. aq. Na2CO3 sol. and the product is extracted with Et20. The organic layer is washed to neutral pH with H20 portions, dried over Na2SO4 and the solvent is evaporated to obtain 377 mg of 5-bromo-pyridine-2- carboxylic acid ethyl ester (22) as a white powder, MS (ESI) 232.0 (M+H) +.
15 g	With sulfuric acid; at 70℃; for 3h;	Compound d-1-1 of 21g was dissolved in EtOH (ethanol) 300ml and 15ml of sulfuric acid was added, and the mixture was stirred for 3 hours at 70 . Then, by cooling the resulting solution, and then was neutralized with aqueous sodium hydrogen carbonate and ethyl acetate was added to extract fractions, it was carried out the concentration of the organic layer. Purification of the resultant concentrate by silica gel column chromatography to obtain 15g of the compound d-1-2.

Reference： [1]Patent: WO2012/76898,2012,A1 .Location in patent: Page/Page column 58
[2]Patent: EP2471789,2012,A1 .Location in patent: Page/Page column 115
[3]Patent: US2005/113374,2005,A1 .Location in patent: Page/Page column 8; 12-13
[4]Heterocycles,1981,vol. 15,p. 213 - 223
[5]Patent: WO2009/5645,2009,A1 .Location in patent: Page/Page column 153
[6]Patent: WO2009/5646,2009,A2 .Location in patent: Page/Page column 155
[7]Patent: WO2005/44814,2005,A1 .Location in patent: Page/Page column 26
[8]Patent: KR2015/129778,2015,A .Location in patent: Paragraph 0567-570; 0574-0576

3
[ 624-28-2 ]
[ 64-17-5 ]
[ 201230-82-2 ]
[ 77199-09-8 ]

Reference： [1]Synthetic Communications,1997,vol. 27,p. 515 - 520
[2]Dalton Transactions,2011,vol. 40,p. 7534 - 7540

4
[ 3430-13-5 ]
[ 77199-09-8 ]

Reference： [1]Heterocycles,1981,vol. 15,p. 213 - 223

5
[ 77199-09-8 ]
[ 77199-12-3 ]

Reference： [1]Heterocycles,1981,vol. 15,p. 213 - 223

6
[ 77199-09-8 ]
2,7-dibromoquinolizinium bromide [ No CAS ]

Reference： [1]Heterocycles,1981,vol. 15,p. 213 - 223

7
[ 77199-09-8 ]
7-bromo-1-oxo-1,2,3,4-tetrahydroquinolizinium bromide [ No CAS ]

Reference： [1]Heterocycles,1981,vol. 15,p. 213 - 223

8
[ 77199-09-8 ]
2,7-dibromo-1-oxo-1,2,3,4-tetrahydroquinolizinium bromide [ No CAS ]

Reference： [1]Heterocycles,1981,vol. 15,p. 213 - 223

9
[ 893420-22-9 ]
[ 77199-09-8 ]
[ 909711-94-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;	2-Amino-5-fluoro-4-(l-isopropyl-2-methyl-lH-imidazol-5-yl)pyrimidine (Method 1 ; 517mg, 2.2mmol), <strong>[77199-09-8]ethyl 5-bromopyridine-2-carboxylate</strong> (460.12mg, 2mmol), EPO <DP n="69"/>tris(dibenzylideneacetone)dipalladium(0) (18.31mg, lmol%), Xantphos (25.5mg, 2.2mol%) and caesium carbonate (912.3mg, 2.8mmol) in anhydrous 1,4-dioxane (8ml) were evacuated and refilled with nitrogen (3 times). The reaction was heated under nitrogen at 100C for 3.5h. Extra tris(dibenzylideneacetone)dipalladium(0) (18.31mg, lmol%) and Xantphos (25.5mg, 2.2mol%) were added and the reaction mixture was heated under nitrogen at 1000C overnight before evaporating under reduced pressure. The residue obtained was partitioned between DCM and water and the aqueous layer was extracted with DCM twice. The organics were combined, washed with brine, dried and the solvent was evaporated to give a foam which was purified by reverse phase chromatography (acidic prep HPLC system). The product containing fractions were passed through a pre-equilibrated Isolute SCX-2 column, eluted with MeOH, and a 7 molar solution of ammonia in MeOH. Evaporation of solvent gave the title compound as a solid which was dried in vac oven overnight at 5O0C (540mg, 70%). NMR (400MHz): 1.33 (t, 3H), 1.48 (d, 6H), 2.54 (s, 3H), 4.32 (q, 2H), 5.39 (septet, IH), 7.41 (d, IH), 8.02 (d, IH), 8.35 (dd, IH), 8.67 (d, IH), 8.91 (d, IH), 10.16 (s, IH); 17F NMR (400MHz): -145.98 (t, IF); m/z 385.

Reference： [1]Patent: WO2006/95159,2006,A1 .Location in patent: Page/Page column 67-68

10
[ 77199-09-8 ]
[ 848952-82-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine; In ethanol; at 90℃; for 1.16667h;	A suspension of 5-bromo-2-pyridinecarboxylic acid (1.0 g, 4.95 mmol) and thionyl chloride (1.4 mL, 19.8 mmol) was heated at 70 C. for 2 hours. The reaction was cooled to room temperature and the excess thionyl chloride was removed under a stream of nitrogen. Toluene (5 mL) and ethanol (2.91 mL, 49.5 mmol) were added and heated at 80 C. for 18 hours. Excess ethanol was removed under reduced pressure. Ethyl acetate was added and the mixture was neutralized with sat. NaHCO3. The organic layer was washed with water and sat. NaCl. Extract was dried over MgSO4, filtered and solvent removed under reduced pressure to give 1.07 g of <strong>[77199-09-8]ethyl 5-bromopicolinate</strong>.Ethyl 5-bromopicolinate (1.0 g, 4.35 mmol) was mixed with 4.3 mL hydrazine and 4 mL ethanol and heated at 90 C. for 70 minutes then the excess reagent and ethanol was removed with a stream of nitrogen. The wet solid was triturated with ether then 90:10 Ether:MeOH to give a gray/green solid which was dried on the vacuum pump. The yield of 5-bromopicolinohydrazide was 0.536 g.5-Bromopicolinohydrazide (0.2 g, 0.926 mmol) was mixed with 0.4 mL acetic acid and 4.0 mL phosphorus oxychloride and heated at 100 C. for 1 hour then at 120 C. for 1.5 hours. Excess reagents were removed with a stream of nitrogen. The residue was dissolved in ethyl acetate and sat. NaHCO3 was added until the mixture was slightly basic. The organic layer was washed again with sat. NaHCO3, water and finally sat. NaCl. The organic layer was dried over MgSO4, filtered and solvent was removed under reduced pressure to give 0.236 g of 2-(5-bromopyridin-2-yl)-5-methyl-1,3,4-oxadiazole.2-(5-Bromopyridin-2-yl)-5-methyl-1,3,4-oxadiazole e (0.222 g, 0.925 mmol) was mixed with 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.226 g, 0.971 mmol), palladium tetrakis triphenyl phosphine (0.012 g, 0.046 mmol), 2M K3PO4 (0.957 mL), and 3.2 mL dioxane. The reaction was purged with nitrogen, sealed in a tube and put in an oil bath at 95 C. under a balloon filled with nitrogen for 18 hours. The reaction was cooled to room temperature and filtered through a plug of Celite washing with water and ethyl acetate. The layers were separated and the water layer was extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with 20 mL sat. NaCl, dried with MgSO4, filtered and solvent removed under reduced pressure. The crude product was purified by column chromatography on 100 mL Silica Gel eluting with 100% ethyl acetate followed by 90:10 ethyl acetate:MeOH to give 0.147 g of 4-methyl-3-(6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)aniline.Phosgene solution (0.146 mL, 0.278 mmol) in 1 mL DCM was cooled to 0 C. A solution of 4-(2-amino-5-tert-butylthiophene-3-carbonyl)-1,3,3-trimethylpiperazin-2-one (0.030 g, 0.093 mmol) in 1 mL DCM was added to the cooled phosgene solution over 5 minutes. The ice bath was removed and after 20 minutes the reaction was checked by LC/MS. The excess phosgene and solvents were removed in a stream of Nitrogen and the residue was taken up in 1 mL of DCM. 4-Methyl-3-(6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)aniline (0.024 g, 0.090 mmol) and DIEA (0.019 mL, 0.107 mmol) were mixed with 1 mL DCM and cooled in salt ice bath. The carbamoyl chloride solution was added dropwise to the amine solution. LC/MS of the reaction mixture 20 minutes later showed completion of the reaction. The reaction was diluted with DCM and washed with sat. NaHCO3, water and sat. NaCl. The combined organic layers were dried over MgSO4, filtered and solvent removed under reduced pressure. Purification by column chromatography on silica gel eluting with 90:10 ethyl acetate:Hex then 100% ethyl acetate gave the material contaminated with some residual aniline. This material was dissolved in DCM and two drops of Acetyl chloride were added to form the acetate of the aniline impurity. The reaction was run for 30 minutes then it was diluted with DCM and washed with sat. NaHCO3 and sat. NaCl. The organic layers were dried over MgSO4, filtered and solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with 100% ethyl acetate to give 0.0168 g of 1-(5-tert-butyl-3-(2,2,4-trimethyl-3-oxopiperazine-1-carbonyl)thiophen-2-yl)-3-(4-methyl-3-(6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)phenyl)urea.H-1 NMR (400 MHz, CDCl3): (ppm) 10.05 (s, 1H), 8.70 (d, J=1.4 Hz, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.85 (dd, J=8.2, 2.1 Hz, 1H), 7.75 (s, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.30 (dd, J=8.2, 2.3 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.40 (s, 1H), 3.73 (t, J=5.0 Hz, 2H), 3.46 (t, J=5.0 Hz, 2H), 3.02 (s, 3H), 2.67 (s, 3H), 2.22 (s, 3H), 1.72 (s, 6H), 1.31 (s, 9H).

Reference： [1]Patent: US2010/41642,2010,A1 .Location in patent: Page/Page column 25

11
[ 137178-88-2 ]
[ 64-17-5 ]
[ 77199-09-8 ]

Yield	Reaction Conditions	Operation in experiment
		A suspension of 5-bromo-2-pyridinecarboxylic acid (1.0 g, 4.95 mmol) and thionyl chloride (1.4 mL, 19.8 mmol) was heated at 70 C. for 2 hours. The reaction was cooled to room temperature and the excess thionyl chloride was removed under a stream of nitrogen. Toluene (5 mL) and ethanol (2.91 mL, 49.5 mmol) were added and heated at 80 C. for 18 hours. Excess ethanol was removed under reduced pressure. Ethyl acetate was added and the mixture was neutralized with sat. NaHCO3. The organic layer was washed with water and sat. NaCl. Extract was dried over MgSO4, filtered and solvent removed under reduced pressure to give 1.07 g of ethyl 5-bromopicolinate.Ethyl 5-bromopicolinate (1.0 g, 4.35 mmol) was mixed with 4.3 mL hydrazine and 4 mL ethanol and heated at 90 C. for 70 minutes then the excess reagent and ethanol was removed with a stream of nitrogen. The wet solid was triturated with ether then 90:10 Ether:MeOH to give a gray/green solid which was dried on the vacuum pump. The yield of 5-bromopicolinohydrazide was 0.536 g.5-Bromopicolinohydrazide (0.2 g, 0.926 mmol) was mixed with 0.4 mL acetic acid and 4.0 mL phosphorus oxychloride and heated at 100 C. for 1 hour then at 120 C. for 1.5 hours. Excess reagents were removed with a stream of nitrogen. The residue was dissolved in ethyl acetate and sat. NaHCO3 was added until the mixture was slightly basic. The organic layer was washed again with sat. NaHCO3, water and finally sat. NaCl. The organic layer was dried over MgSO4, filtered and solvent was removed under reduced pressure to give 0.236 g of 2-(5-bromopyridin-2-yl)-5-methyl-1,3,4-oxadiazole.2-(5-Bromopyridin-2-yl)-5-methyl-1,3,4-oxadiazole e (0.222 g, 0.925 mmol) was mixed with 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.226 g, 0.971 mmol), palladium tetrakis triphenyl phosphine (0.012 g, 0.046 mmol), 2M K3PO4 (0.957 mL), and 3.2 mL dioxane. The reaction was purged with nitrogen, sealed in a tube and put in an oil bath at 95 C. under a balloon filled with nitrogen for 18 hours. The reaction was cooled to room temperature and filtered through a plug of Celite washing with water and ethyl acetate. The layers were separated and the water layer was extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with 20 mL sat. NaCl, dried with MgSO4, filtered and solvent removed under reduced pressure. The crude product was purified by column chromatography on 100 mL Silica Gel eluting with 100% ethyl acetate followed by 90:10 ethyl acetate:MeOH to give 0.147 g of 4-methyl-3-(6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)aniline.Phosgene solution (0.146 mL, 0.278 mmol) in 1 mL DCM was cooled to 0 C. A solution of 4-(2-amino-5-tert-butylthiophene-3-carbonyl)-1,3,3-trimethylpiperazin-2-one (0.030 g, 0.093 mmol) in 1 mL DCM was added to the cooled phosgene solution over 5 minutes. The ice bath was removed and after 20 minutes the reaction was checked by LC/MS. The excess phosgene and solvents were removed in a stream of Nitrogen and the residue was taken up in 1 mL of DCM. 4-Methyl-3-(6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)aniline (0.024 g, 0.090 mmol) and DIEA (0.019 mL, 0.107 mmol) were mixed with 1 mL DCM and cooled in salt ice bath. The carbamoyl chloride solution was added dropwise to the amine solution. LC/MS of the reaction mixture 20 minutes later showed completion of the reaction. The reaction was diluted with DCM and washed with sat. NaHCO3, water and sat. NaCl. The combined organic layers were dried over MgSO4, filtered and solvent removed under reduced pressure. Purification by column chromatography on silica gel eluting with 90:10 ethyl acetate:Hex then 100% ethyl acetate gave the material contaminated with some residual aniline. This material was dissolved in DCM and two drops of Acetyl chloride were added to form the acetate of the aniline impurity. The reaction was run for 30 minutes then it was diluted with DCM and washed with sat. NaHCO3 and sat. NaCl. The organic layers were dried over MgSO4, filtered and solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with 100% ethyl acetate to give 0.0168 g of 1-(5-tert-butyl-3-(2,2,4-trimethyl-3-oxopiperazine-1-carbonyl)thiophen-2-yl)-3-(4-methyl-3-(6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)phenyl)urea.H-1 NMR (400 MHz, CDCl3): (ppm) 10.05 (s, 1H), 8.70 (d, J=1.4 Hz, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.85 (dd, J=8.2, 2.1 Hz, 1H), 7.75 (s, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.30 (dd, J=8.2, 2.3 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.40 (s, 1H), 3.73 (t, J=5.0 Hz, 2H), 3.46 (t, J=5.0 Hz, 2H), 3.02 (s, 3H), 2.67 (s, 3H), 2.22 (s, 3H), 1.72 (s, 6H), 1.31 (s, 9H).

Reference： [1]Patent: US2010/41642,2010,A1 .Location in patent: Page/Page column 25

12
[ 1037746-91-0 ]
[ 77199-09-8 ]
[ 1180844-75-0 ]

Reference： [1]Organic Letters,2009,vol. 11,p. 3690 - 3693
[2]Beilstein Journal of Organic Chemistry,2017,vol. 13,p. 1407 - 1412

13
[ 64-17-5 ]
[ 29682-15-3 ]
[ 77199-09-8 ]

Reference： [1]Organic Letters,2009,vol. 11,p. 3690 - 3693

14
[ 23719-80-4 ]
[ 77199-09-8 ]
[ 1310948-09-4 ]

Yield	Reaction Conditions	Operation in experiment
87%		(1) A suspension of zinc chloride (27 g) in tetrahydrofuran (300 mL) was cooled to 0 C. in the presence of a nitrogen gas, and a 1 M solution of cyclopropanemagnesium bromide in tetrahydrofuran (186 mL) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was cooled to 0 C. Dichlorobis(triphenylphosphine)-palladium(II) (3.26 g) and a solution of <strong>[77199-09-8]ethyl 5-bromopyridine-2-carboxylate</strong> (21.4 g) in tetrahydrofuran (100 mL) were sequentially added, and the mixture was stirred at 0 C. for 30 minutes and at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1?1:1) to give ethyl 5-cyclopropylpyridine-2-carboxylate (15.5 g, 87%) as a pale brown oil.

Reference： [1]Patent: US2011/237791,2011,A1 .Location in patent: Page/Page column 47-48

15
[ 77199-09-8 ]
[ 1310948-10-7 ]

Reference： [1]Patent: US2011/237791,2011,A1

16
[ 77199-09-8 ]
[ 1310948-11-8 ]

Reference： [1]Patent: US2011/237791,2011,A1

17
[ 77199-09-8 ]
[ 1310948-12-9 ]

Reference： [1]Patent: US2011/237791,2011,A1

18
[ 77199-09-8 ]
[ 1310948-13-0 ]

Reference： [1]Patent: US2011/237791,2011,A1

19
[ 77199-09-8 ]
[ 1310948-14-1 ]

Reference： [1]Patent: US2011/237791,2011,A1

20
[ 77199-09-8 ]
[ 1310948-25-4 ]

Reference： [1]Patent: US2011/237791,2011,A1

21
[ 7486-35-3 ]
[ 77199-09-8 ]
[ 1269028-74-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere;	Reference Example 256 Production of ethyl 5-ethenylpyridine-2-carboxylate A mixture of the compound of Reference Example 255 (20.0 g, 86.9 mmol), tributylvinyltin (28.1 mL, 95.6 mmol), Pd(PPh3)4 (2.01 g, 1.74 mmol) and DMF (100 mL) was stirred at 100C for 2 hr under an argon atmosphere. To the reaction mixture was added water (200 mL), and the mixture was extracted with ethyl acetate (400 mL). The extract was washed with brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=98:2?20:80) to give the title compound (16.5 g, 100%) as a pale-yellow oil. 1H NMR (300 MHz, DMSO-d6) delta:1.33 (3 H, t, J = 7.1 Hz), 4.34 (2 H, q, J = 7.1 Hz), 5.56 (1 H, d, J = 11.1 Hz), 6.14 (1 H, d, J = 17.8 Hz), 6.87 (1 H, dd, J = 11.1, 17.8 Hz), 8.00-8.06 (1 H, m), 8.07-8.16 (1 H, m), 8.80 (1 H, d, J = 1.9 Hz).
100%	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere;	To a solution of 27 (20.0 g, 86.9 mmol) in DMF (100 mL) wereadded tributyl(vinyl)tin (28.1 mL, 95.6 mmol) and Pd(PPh3)4 (2.01 g, 1.74 mmol), and the mixture was stirred at 100 C for 2 hunder Ar atmosphere. The mixture was diluted with water(200 mL), and extracted with AcOEt (400 mL). The extracts werecombined, washed with brine (200 mL), dried over Na2SO4 andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (hexane/AcOEt = 49/1 to 4/1) to give ethyl5-ethenylpyridine-2-carboxylate (16.5 g, quant.) as pale yellowoil. To a solution of obtained compound above (7.71 g, 43.5 mmol)in EtOH (77 mL) was added 10% Pd-C (1.54 g) and the mixture wasstirred at room temperature for 3 h under H2 atmosphere. The mixturewas filtered through membrane filter, and the filtrate was concentratedin vacuo to give the title compound (7.92 g, quant.) aspale yellow oil. 1H NMR (DMSO-d6) d 1.22 (3H, t, J = 7.6 Hz), 1.33(3H, t, J = 7.1 Hz), 2.71 (2H, q, J = 7.6 Hz), 4.33 (2H, q, J = 7.1 Hz),7.83 (1H, dd, J = 8.0, 2.2 Hz), 7.98 (1H, d, J = 8.0 Hz), 8.58 (1H, d,J = 2.2 Hz).

Reference： [1]Patent: EP2471789,2012,A1 .Location in patent: Page/Page column 115
[2]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 4777 - 4791

22
[ 77199-09-8 ]
[ 13509-15-4 ]

Reference： [1]Patent: EP2471789,2012,A1
[2]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 4777 - 4791

23
[ 77199-09-8 ]
[ 1380672-04-7 ]

Reference： [1]Patent: WO2012/76898,2012,A1

24
[ 77199-09-8 ]
[ 1312903-94-8 ]

Yield	Reaction Conditions	Operation in experiment
20%	With sodium; In ethanol; for 3h;Reflux;	(b) Preparation of ethyl 5-ethoxypyridine-2-carboxylate 3 :To a solution of <strong>[77199-09-8]ethyl 5-bromopyridine-2-carboxylate</strong> 2 (1.5 g, 6.5 mmol) in 20 mL of EtOH was added a solution of sodium (0.18 g, 7.8 mmol) in 20 mL of EtOH. The mixture was stirred at reflux for 3 h. After removal of all solvent, the residue was purified by column (2: 1 of hexane/ethyl acetate) to give ethyl 5-ethoxypyridine-2-carboxylate 3 as an oil. Yield: 0.26 g, 20%. .HNMR (CDCI3) delta (ppm): 8.38 (d, 1 H), 8.10 (d, 1 H), 8.23 (d, 1 H), 7.22 (dd, 1 H), 4.45 (m, 2 H), 4.25 (m, 1 H), 1.40 (m, 6 H).

Reference： [1]Patent: WO2012/76898,2012,A1 .Location in patent: Page/Page column 58

25
[ 77199-09-8 ]
[ 1380672-69-4 ]

Reference： [1]Patent: WO2012/76898,2012,A1

26
[ 77199-09-8 ]
[ 1380672-70-7 ]

Reference： [1]Patent: WO2012/76898,2012,A1

27
[ 77199-09-8 ]
[ 1269028-78-5 ]

Reference： [1]Patent: EP2471789,2012,A1
[2]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 4777 - 4791

28
[ 77199-09-8 ]
[ 1269028-76-3 ]

Reference： [1]Patent: EP2471789,2012,A1
[2]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 4777 - 4791

29
[ 77199-09-8 ]
[ 88139-91-7 ]

Yield	Reaction Conditions	Operation in experiment
80%		Example 593-(((5-(l-(4-(2,3-Dimethylphenoxy)butanoyl)-l,2,3,4-tetrahydroquinolin-5-yl)pyridin-2- yl)methoxy)carbonylamino)propanoic acid[00204] To a solution of NaBH4 (0.822 g, 21.73 mmol) in MeOH (25 mL) was added <strong>[77199-09-8]ethyl 5-bromopicolinate</strong> (1.0 g, 4.35 mmol) portion-wise over a period of 10 min at room temperature. The mixture was stirred at room temperature for 10 min and then heated to 70 C for 30 min. The solvent was removed in vacuo, and the resulting residue was diluted with EtOAc and water. The aqueous phase was adjusted to pH 7 with 1 N aq. HCl, and extracted with EtOAc. The combined organic layer was dried over MgS04, filtered, and concentrated in vacuo to afford the title compound (0.65 g, 80% yield) as a white solid. LCMS, [M+H]+ = 187.9.

Reference： [1]Patent: WO2012/149236,2012,A1 .Location in patent: Page/Page column 162

30
[ 624-28-2 ]
[ 667-27-6 ]
[ 77199-09-8 ]

Yield	Reaction Conditions	Operation in experiment
81%		SYNTHESIS OF INTERMEDIATE KETONE B2-(5-Bromopyridin-2-yl)- 1-(2,4-difluorophenyl)-2,2-difluoroethanone (B) To a suspension of copper powder (2.68 grams (g), 42.2 millimoles (mmol)) in dimethyl sulfoxide(DMSO; 35 milliliters (mL)) was added ethyl 2-bromo-2,2-difluoroacetate (2.70 mL, 21.10mmol), and the mixture was stirred for 1 hour (h) at room temperature (RT). 2,5-Dibromopyridine(2.50 g, 10.55 mmol) was then added, and stirring was continued for 15 h at RT. The reactionmixture was quenched with aqueous (aq) ammonium chloride (NH4C1) and extracted withdichloromethane (CH2C12 3 x 25 mL). The combined organic layers were washed with water (H20), washed with brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure to afford the crude product mixture. Purification by column chromatography (eluting with ethyl acetate (EtOAc)/hexane) afforded the ethyl ester intermediate (2.40 g, 8.57mmol, 81%) as a pale yellow oil. ?H NMR (500 MHz, CDC13): oe 8.71 (s, 1H), 8.00 (d, J 9.0 Hz,1H), 7.64 (d, J= 9.0 Hz, 1H), 4.42-4.35 (m, 2H), 1.39-1.3 1 (m, 3H).

Reference： [1]Patent: WO2014/43376,2014,A1 .Location in patent: Page/Page column 46; 47

31
[ 77199-09-8 ]
[ 1416733-02-2 ]

Reference： [1]Patent: WO2014/43376,2014,A1

32
[ 77199-09-8 ]
[ 1581280-31-0 ]

Reference： [1]Patent: WO2014/43376,2014,A1

33
[ 77199-09-8 ]
[ 1581280-33-2 ]

Reference： [1]Patent: WO2014/43376,2014,A1

34
[ 348-57-2 ]
[ 77199-09-8 ]
[ 294182-06-2 ]