[ CAS No. 148038-83-9 ] {[proInfo.proName]}

Name: 148038-83-9|6-Bromo-1H-imidazo[4,5-b]pyridin-2(3H)-one|95%
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Quality Control of [ 148038-83-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 148038-83-9 ]

Product Details of [ 148038-83-9 ]

CAS No. :	148038-83-9	MDL No. :	MFCD00763285
Formula :	C₆H₄BrN₃O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VHCRLTJPUNUZRN-UHFFFAOYSA-N
M.W :	214.02	Pubchem ID :	1924413
Synonyms :

Calculated chemistry of [ 148038-83-9 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	44.41
TPSA :	61.54 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) :	-7.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.16
Log Po/w (XLOGP3) :	0.52
Log Po/w (WLOGP) :	1.01
Log Po/w (MLOGP) :	0.42
Log Po/w (SILICOS-IT) :	2.39
Consensus Log Po/w :	1.1

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.1
Solubility :	1.7 mg/ml ; 0.00794 mol/l
Class :	Soluble
Log S (Ali) :	-1.38
Solubility :	8.86 mg/ml ; 0.0414 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.31
Solubility :	0.106 mg/ml ; 0.000495 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.78

Safety of [ 148038-83-9 ]

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 [ 148038-83-9 ]

* 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 [ 148038-83-9 ]
Downstream synthetic route of [ 148038-83-9 ]

[ 148038-83-9 ] Synthesis Path-Upstream 1~4

1
[ 38875-53-5 ]
[ 530-62-1 ]
[ 148038-83-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	at 80℃; for 16 h;	To a solution of 2,3-diamino-5-bromopyridine (5 g, 27 mmol) in THF (87 mL) was added CDI (3.02 g, 18.6 mmol), and the reaction mixture was stirred at 80 °C for 16 h. Then, water was added, and the mixture was filtered. The solids were collected by filtration, washed with water and Et2O, and dried under vacuum to afford the title compound (5.3 g, 25 mmol, 93percent), which was used in the next step without further purification. MS (ESI): mass calcd. for C₆H₄BrN₃O, 212.95; m/z found, 214 [M+H]⁺.
92%	at 20℃; Inert atmosphere	Step 2 6-Bromo-lH-imidazo[4,5-b]pyridin-2(3H)-one. 5-Bromopyridine-2,3-diamine (2.45 g) was dissolved in THF (25 niL) and l,l'-carbonyldiimidazole (2.54 g, 1.2 eq) was added. The reaction was stirred at room temperature under nitrogen gas overnight. Water was then added to the mixture and the product was collected by filtration. The solid was dried under vacuum delivering product (2.57 g, 92percent yield). ¹H-NMR (300 MHz, DMSOd₆) δ 11.50 (s, IH), 11.00 (s, IH), 7.93 (s, 1 H), 7.39 (s, IH). MS (ES+) m/z 213.1 (M + 1).

Reference： [1] Patent: WO2018/67786, 2018, A1, . Location in patent: Page/Page column 106
[2] Patent: WO2010/121164, 2010, A2, . Location in patent: Page/Page column 61
[3] Patent: WO2011/149950, 2011, A2, . Location in patent: Page/Page column 104-105

2
[ 38875-53-5 ]
[ 57-13-6 ]
[ 148038-83-9 ]

Yield	Reaction Conditions	Operation in experiment
36%	at 100℃; for 16 h;	A mixture of 5-bromopyridine-2,3 -diamine (2 g, 10.6 mmol) and urea (2.5 g, 41.6 mmol) was dissolved in DMF and heated to 100 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over a2S0₄ then concentrated to provide 6-bromo-lH-imidazo[4,5- b]pyridin-2(3H)-one (0.80 g, 36 percent) as an off white solid which was used without further purification. LCMS Method W: retention time 0.98 min; [M+2] = 212, 214.0.
9 g	at 180℃; for 16 h;	To a stirred solution of compound 1(10 g) in DMF was added urea (8g) and the total reaction mass stirred at 180° c for 16hrs.cooled to RT and concentrated under vacuum to get desired compound 2 (9 g )
9 g	at 180℃; for 16 h;	Step-1 [0065] To a stirred solution of compound 1 (10 g) in DMF was added urea (8 g) and the total reaction mass stirred at 180° c. for 16 hrs. cooled to RT and concentrated under vacuum to get desired compound 2 (9 g)

Reference： [1] Patent: WO2011/28741, 2011, A1, . Location in patent: Page/Page column 284-285
[2] Journal of the Chemical Society, 1948, p. 1389,1392
[3] Patent: WO2013/42035, 2013, A1, . Location in patent: Page/Page column 16
[4] Patent: US2014/249170, 2014, A1, . Location in patent: Paragraph 0064; 0065

3
[ 38875-53-5 ]
[ 74124-79-1 ]
[ 148038-83-9 ]

Reference： [1] Patent: WO2004/35549, 2004, A1, . Location in patent: Page 200

4
[ 273-21-2 ]
[ 148038-83-9 ]

Reference： [1] Russian Journal of Organic Chemistry, 2003, vol. 39, # 2, p. 280 - 281

[ 148038-83-9 ] Synthesis Path-Downstream 1~76

1
[ 38875-53-5 ]
[ 57-13-6 ]
[ 148038-83-9 ]

Yield	Reaction Conditions	Operation in experiment
36%	In N,N-dimethyl-formamide; at 100℃; for 16.0h;	A mixture of 5-bromopyridine-2,3 -diamine (2 g, 10.6 mmol) and urea (2.5 g, 41.6 mmol) was dissolved in DMF and heated to 100 C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over a2S04 then concentrated to provide 6-bromo-lH-imidazo[4,5- b]pyridin-2(3H)-one (0.80 g, 36 %) as an off white solid which was used without further purification. LCMS Method W: retention time 0.98 min; [M+2] = 212, 214.0.
9 g	In N,N-dimethyl-formamide; at 180℃; for 16.0h;	To a stirred solution of compound 1(10 g) in DMF was added urea (8g) and the total reaction mass stirred at 180 c for 16hrs.cooled to RT and concentrated under vacuum to get desired compound 2 (9 g )
9 g	In N,N-dimethyl-formamide; at 180℃; for 16.0h;	Step-1 [0065] To a stirred solution of compound 1 (10 g) in DMF was added urea (8 g) and the total reaction mass stirred at 180 c. for 16 hrs. cooled to RT and concentrated under vacuum to get desired compound 2 (9 g)

Reference： [1]Patent: WO2011/28741,2011,A1 .Location in patent: Page/Page column 284-285
[2]Journal of the Chemical Society,1948,p. 1389,1392
[3]Patent: WO2013/42035,2013,A1 .Location in patent: Page/Page column 16
[4]Patent: US2014/249170,2014,A1 .Location in patent: Paragraph 0064; 0065

2
[ 148038-83-9 ]
[ 77-78-1 ]
[ 234771-64-3 ]

Reference： [1]Russian Journal of Organic Chemistry,1998,vol. 34,p. 1363 - 1364

3
[ 273-21-2 ]
[ 148038-83-9 ]

Reference： [1]Russian Journal of Organic Chemistry,2003,vol. 39,p. 280 - 281

4
[ 148038-83-9 ]
[ 361365-08-4 ]

Reference： [1]Russian Journal of Organic Chemistry,2005,vol. 41,p. 575 - 579

5
[ 148038-83-9 ]
[ 624723-95-1 ]

Reference： [1]Russian Journal of Organic Chemistry,2005,vol. 41,p. 575 - 579

6
[ 148038-83-9 ]
6-bromo-5-nitro-1,3-dihydro-imidazo[4,5-b]pyridin-2-one [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2007,vol. 43,p. 417 - 421

7
[ 38875-53-5 ]
[ 74124-79-1 ]
[ 148038-83-9 ]

Yield	Reaction Conditions	Operation in experiment
60%	In chloroform; for 48.0h;Reflux; Inert atmosphere;	General procedure: 136 (360mg, 2.92mmol) and disuccinimido carbonate (749mg, 2.92mmol) were dissolved in chloroform (5mL) and heated at reflux for 48h under N2. The reaction was then concentrated, and the residue dissolved in a 1:3 mixture of CyHex/EtOAc (200mL) and heated to reflux for 10min. The reaction was then cooled and the precipitate filtered and dried to obtain 145 as a solid (210mg, 48%).
	In chloroform; for 12.0h;Heating / reflux;	Example 203 [5-BROMO-2-F 4- [3- (TRIFLUOROMETHYL)] pyridin-2-yl] piperazin-1-yl}-lH-imidazo [4,5- b] pyridine. (a) [6-BROMO-1,] 3-dihydro-2H-imidazo [4,5-b] [PYRIDIN-2-ONE.] A mixture of 2, 3-diamino-5-bromopyridine (0.94 g, 5 mmol, Aldrich) and disuccinimido carbonate (1. 28 g, 5 mmol, Aldrich) in chloroform (50 mL) was heated at reflux for 12 h. The solvent was removed in vacuo and the residue was purified by recrystallization from 40% [ETOAC/HEXANE] to give the title compound as a brown solid. MS (ESI, pos. ion) [M/Z] : 214 (M+1).

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 195
[2]Patent: WO2004/35549,2004,A1 .Location in patent: Page 200

8
[ 148038-83-9 ]
[ 438190-89-7 ]

Yield	Reaction Conditions	Operation in experiment
59%	With trichlorophosphate; for 12.0h;Reflux;	General procedure: 145 (210mg, 1.41mmol) was dissolved in POCl3 (4mL) and stirred at reflux for 12h. The mixture was concentrated, and the residue was dissolved in EtOAc (30mL). The organic layer was then washed successively with saturated NaHCO3 (2×20mL), water (20mL) and brine (20mL), dried with Na2SO4 and concentrated. The crude residue was then purified by column chromatography (100% CyHex to 80% EtOAc/CyHex) to obtain the 146 as a solid (71mg, 30%).
	In trichlorophosphate;	A. 6-Bromo-2-chloro-3H-imidazo[4,5-b]pyridine Reflux <strong>[148038-83-9]6-bromo-1,3-dihydro-imidazo[4,5-b]pyridin-2-one</strong> (5 g) for 14 h in POCl3 (50 mL). Evaporate the solvent in vacuo, then carefully neutralize with saturated NaHCO3, and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, and purify by flash chromatography (1:1 hexanes/EtOAc) to obtain 6-bromo-2-chloro-3H-imidazo[4,5-b]pyridine.

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 195
[2]Patent: US2003/36652,2003,A1

9
[ 148038-83-9 ]
[ 1066-54-2 ]
C₁₁H₁₃N₃OSi [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 4701 - 4719

10
[ 38875-53-5 ]
[ 530-62-1 ]
[ 148038-83-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	In tetrahydrofuran; at 80℃; for 16.0h;	To a solution of 2,3-diamino-5-bromopyridine (5 g, 27 mmol) in THF (87 mL) was added CDI (3.02 g, 18.6 mmol), and the reaction mixture was stirred at 80 C for 16 h. Then, water was added, and the mixture was filtered. The solids were collected by filtration, washed with water and Et2O, and dried under vacuum to afford the title compound (5.3 g, 25 mmol, 93%), which was used in the next step without further purification. MS (ESI): mass calcd. for C6H4BrN3O, 212.95; m/z found, 214 [M+H]+.
92%	In tetrahydrofuran; at 20℃;Inert atmosphere;	Step 2 6-Bromo-lH-imidazo[4,5-b]pyridin-2(3H)-one. 5-Bromopyridine-2,3-diamine (2.45 g) was dissolved in THF (25 niL) and l,l'-carbonyldiimidazole (2.54 g, 1.2 eq) was added. The reaction was stirred at room temperature under nitrogen gas overnight. Water was then added to the mixture and the product was collected by filtration. The solid was dried under vacuum delivering product (2.57 g, 92% yield). 1H-NMR (300 MHz, DMSOd6) delta 11.50 (s, IH), 11.00 (s, IH), 7.93 (s, 1 H), 7.39 (s, IH). MS (ES+) m/z 213.1 (M + 1).
	In tetrahydrofuran; at 60℃;	Preparation of l-(lH-indol-5-yl)-6-(3,4,5-trimethoxyphenyl)-lH-imidazo[4,5-6]pyridin- 2(3H)-one (Compound BS)[0344] Commercially available 5-bromopyridine-2,3-diamine 3 was converted to 6-bromo- lH-imidazo[4,5-¾]pyridin-2(3H)-one via treatment with carbonyl diimidazole in THF at 60C, which was then protected as the monoethoxy carbonyl derivative 4 in a fashion similar to that described in J. Org. Chem., 1995, 1565-1582. Intermediate 4 was subjected to an NOE analysis, and interactions between the 7-position hydrogen and the carbamate ethyl group were apparent, supporting the structure that is shown above. Following protection of the 3 -position amine with a tert-butyl carboxylate group and deprotection of the ethyl carboxylate group using isopropyl amine, intermediate 6 was coupled to indole-5-boronic acid using copper acetate in a mixture of DCM/pyridine, after which it was deprotected using TFA/CH2C12. To the resulting 6-bromo-l- (lH-indol-5-yl)-lH-imidazo[4,5-¾]pyridin-2(3H)-one in CH3CN (1 mL) in a microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol),bis(triphenylphosphine)-palladium(II) dichloride (7.0 mg, 0.010 mmol), and 1 M Na2C03 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150C for 10 min in a Personal Chemistry Optimizer. The resulting mixture was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSC^, filtered, and stripped to give a residue that was purified via preparatory HPLC to give 1.8 mg of the title compound. HPLC retention time: 2.36 minutes; MS ESI (m/z): 417.4 (M+l) +, calc. 416.

Reference： [1]Patent: WO2018/67786,2018,A1 .Location in patent: Page/Page column 106
[2]Patent: WO2010/121164,2010,A2 .Location in patent: Page/Page column 61
[3]Patent: WO2011/149950,2011,A2 .Location in patent: Page/Page column 104-105

11
[ 148038-83-9 ]
[ 24424-99-5 ]
[ 1251948-79-4 ]

Yield	Reaction Conditions	Operation in experiment
37%	With dmap; In tetrahydrofuran;Reflux;	Step 3; di-tert-Butyl-6-bromo-2-oxo-lH-imidazo[4,5-b]pyridine-l,3(2H)-dicarboxylate. A THF(10 mL) solution of di-tert butyl dicarbonate (4.69 g, 2.2 eq) was added dropwise to a solution of 6-bromo-lH-imidazo[4,5-b]pyridin-2(3H)-one (2.09 g) and DMAP (119 mg, 0.1 eq) in THF (40 mL). The reaction was stirred at reflux for 1 h, then cooled and concentrated. The product was purified by chromatography (gradient: 95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) delivering the product (1.48 g, 37% yield). 1H-NMR (300 MHZ, CDCl3) delta 8.32 (s, IH), 8.24 (s, IH), 1.65 (s, 20 H).

Reference： [1]Patent: WO2010/121164,2010,A2 .Location in patent: Page/Page column 61

12
[ 503-29-7 ]
[ 148038-83-9 ]
[ 1256784-36-7 ]

Yield	Reaction Conditions	Operation in experiment
31%	In ethanol; at 100℃; for 0.5h;Microwave irradiation;	STEP 1 : A mixture of 6-bromo- 1 ,3-dihydro-2H-imidazo[4,5-6]pyridine-2-one (400 mg, 1.7 mmol, WO 2004035549) and azetidine (450 mg, 7.9 mmol) in ethanol (2 mL) was heated at 100 0C with microwave irradiation for 30 min. Concentration and column chromatography on silica (95:5 dichloromethane/methanol) gave 2-azetidin-l-yl- 6-bromo-lH-imidazo[4,5-6]pyridine (135 mg, 31% yield) as a yellow solid. MS (EI) for C9H9BrN4: 254 (MH+).

Reference： [1]Patent: WO2010/135568,2010,A1 .Location in patent: Page/Page column 31

13
[ 148038-83-9 ]
[ 73183-34-3 ]
[ 1209485-79-9 ]

Yield	Reaction Conditions	Operation in experiment
49%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 120℃; for 0.75h;Inert atmosphere; Microwave irradiation;	A mixture of 6-bromo-lH-imidazo[4,5-b]pyridin-2(3H)-one (0.500 g, 2.35 mmol), bis(pinacolato)diboron (0.895 g, 3.53 mmol) and potassium acetate (0.924 g, 9.42 mmol) in 1,4-dioxane (10 mL) was degassed with nitrogen for 15 min. (1, 1'- Bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (0.192 g, 0.23 mmol) was added and the reaction mixture was again degassed for 10 min. with nitrogen. The reaction mixture was heated in the microwave reactor at 120 C for 45 min. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to provide 6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one (0.3 g, 49 %) which was used without further purification. LCMS Method Y: retention time 1.5 min; [M+l] = 261.7.

Reference： [1]Patent: WO2011/28741,2011,A1 .Location in patent: Page/Page column 285

14
[ 148038-83-9 ]
[ 1272355-07-3 ]

Reference： [1]Patent: WO2011/28741,2011,A1

15
[ 148038-83-9 ]
[ 1021919-65-2 ]

Reference： [1]Patent: WO2011/149950,2011,A2

16
[ 148038-83-9 ]
[ 1229584-05-7 ]

Reference： [1]Patent: WO2011/149950,2011,A2

17
[ 148038-83-9 ]
[ 1229584-06-8 ]

Reference： [1]Patent: WO2011/149950,2011,A2

18
[ 148038-83-9 ]
[ 1229583-25-8 ]

Reference： [1]Patent: WO2011/149950,2011,A2

19
[ 148038-83-9 ]
[ 1229583-26-9 ]

Reference： [1]Patent: WO2011/149950,2011,A2

20
[ 148038-83-9 ]
C₁₅H₁₈BrN₃O₃ [ No CAS ]

Reference： [1]Patent: WO2011/149950,2011,A2

21
[ 148038-83-9 ]
[ 1207623-66-2 ]

Reference： [1]Patent: WO2011/149950,2011,A2

22
[ 7325-39-5 ]
[ 148038-83-9 ]
[ 1021919-64-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 3.0h;	A mixture of <strong>[148038-83-9]6-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one</strong> (5.3 g, 25 mmol), ethyl pyridin-2-yl carbonate (5.36 g, 27.2 mmol) and K2CO3 (3.77 g, 27.2 mmol) in DMF (245 mL) was heated to 75 C for 3 h. The crude reaction mixture was concentrated in vacuo and diluted with water and 1 M HCl until the mixture reached pH 1. The solution was filtered and triturated with Et2O to afford the title compound (6.6 g, 23 mmol, 93%), which was used in the next step without further purification. MS (ESI): mass calcd. for C9H8BrN3O3, 284.97; m/z found, 286 [M+H]+.
	With potassium carbonate; In acetonitrile;	Preparation of l-(lH-indol-5-yl)-6-(3,4,5-trimethoxyphenyl)-lH-imidazo[4,5-6]pyridin- 2(3H)-one (Compound BS)[0344] Commercially available 5-bromopyridine-2,3-diamine 3 was converted to 6-bromo- lH-imidazo[4,5-¾]pyridin-2(3H)-one via treatment with carbonyl diimidazole in THF at 60C, which was then protected as the monoethoxy carbonyl derivative 4 in a fashion similar to that described in J. Org. Chem., 1995, 1565-1582. Intermediate 4 was subjected to an NOE analysis, and interactions between the 7-position hydrogen and the carbamate ethyl group were apparent, supporting the structure that is shown above. Following protection of the 3 -position amine with a tert-butyl carboxylate group and deprotection of the ethyl carboxylate group using isopropyl amine, intermediate 6 was coupled to indole-5-boronic acid using copper acetate in a mixture of DCM/pyridine, after which it was deprotected using TFA/CH2C12. To the resulting 6-bromo-l- (lH-indol-5-yl)-lH-imidazo[4,5-¾]pyridin-2(3H)-one in CH3CN (1 mL) in a microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol),bis(triphenylphosphine)-palladium(II) dichloride (7.0 mg, 0.010 mmol), and 1 M Na2C03 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150C for 10 min in a Personal Chemistry Optimizer. The resulting mixture was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSC^, filtered, and stripped to give a residue that was purified via preparatory HPLC to give 1.8 mg of the title compound. HPLC retention time: 2.36 minutes; MS ESI (m/z): 417.4 (M+l) +, calc. 416.

Reference： [1]Patent: WO2018/67786,2018,A1 .Location in patent: Page/Page column 106
[2]Patent: WO2011/149950,2011,A2 .Location in patent: Page/Page column 104-105

23
[ 148038-83-9 ]
[ 24424-99-5 ]
[ 1428799-47-6 ]

Yield	Reaction Conditions	Operation in experiment
9 g	With dmap; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	To a stirred solution of compound 2(9 g) in DMF was added BOC-anhydride (8g), DMAP and the total reaction mass stirred at RT for 16h. Water and AcOEt were added, seprated organic layer and concentrated under vacuum to get desired compound 3 (9 g)
9 g	With dmap; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	Step-1 [0106] To a stirred solution of compound 2 (9 g) in DMF was added BOC-anhydride (8 g), DMAP and the total reaction mass stirred at RT for 16 h. Water and AcOEt were added, separated organic layer and concentrated under vacuum to get desired compound 3 (9 g)

Reference： [1]Patent: WO2013/42035,2013,A1 .Location in patent: Page/Page column 25
[2]Patent: US2014/249170,2014,A1 .Location in patent: Paragraph 0105; 0106

24
[ 148038-83-9 ]
[ 1428799-48-7 ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

25
[ 148038-83-9 ]
[ 1428799-49-8 ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

26
[ 148038-83-9 ]
[ 1428799-50-1 ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

27
[ 148038-83-9 ]
6-bromo-3-methyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one [ No CAS ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

28
[ 148038-83-9 ]
[ 1428799-01-2 ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

29
[ 148038-83-9 ]
[ 1428799-51-2 ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

30
[ 148038-83-9 ]
[ 1428799-52-3 ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

31
[ 148038-83-9 ]
[ 1428799-02-3 ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

32
[ 148038-83-9 ]
[ 1428799-56-7 ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

33
[ 148038-83-9 ]
[ 1428799-57-8 ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

34
[ 148038-83-9 ]
[ 1428799-04-5 ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

35
[ 148038-83-9 ]
[ 1428799-05-6 ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

36
[ 148038-83-9 ]
[ 1428799-07-8 ]

Reference： [1]Patent: WO2013/42035,2013,A1
[2]Patent: US2014/249170,2014,A1

37
[ 335033-27-7 ]
[ 148038-83-9 ]
[ 1428798-93-9 ]

Yield	Reaction Conditions	Operation in experiment
10 mg	With palladium diacetate; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; for 16.0h;Reflux;	A mixture of 2 (50mg), A (60mg), Pd(OAc)2 (19.7mg), P(o-tol)3 (53.6mg), DIPEA(142mg) in EtCN (0.8mL) and DMF (0.2mL) was refluxed forl6 h, the reaction cooled to room temperature. The solution was concentrated to dryness. The residue was purified by prepared HPLC to obtain the desired VT-02- 00002 (lOmg) as solid.MS (ESI): m/z 362(M+H)+ .
10 mg	With palladium diacetate; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; for 16.0h;Reflux;	Step-2 [0066] A mixture of 2 (50 mg), A (60 mg), Pd(OAc)2 (19.7 mg), P(o-tol)3 (53.6 mg), DIPEA (142 mg) in EtCN (0.8 mL) and DMF (0.2 mL) was refluxed for 16 h, the reaction cooled to room temperature. The solution was concentrated to dryness. The residue was purified by prepared HPLC to obtain the desired VT-02-00002 (10 mg) as solid. MS (ESI): m/z 362 (M+H)+.

Reference： [1]Patent: WO2013/42035,2013,A1 .Location in patent: Page/Page column 16-17
[2]Patent: US2014/249170,2014,A1 .Location in patent: Paragraph 0064; 0066

38
[ 148038-83-9 ]
[ 138500-88-6 ]
6-(4-(aminomethyl)phenyl)-1H-imidazo[4,5-b]pyridine-2(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With palladium(0)bis(tricyclohexylphosphine); sodium carbonate; In 1,4-dioxane; water; at 100℃;	6- (4- (aminomethyl) phenyl) lH-imidazo [4,5-b] pyridine -2 (3H) --one: 2.65 g of 6-bromo-1,3-dihydro - imidazo [4,5-b] pyridin-2-one (12.4 mmol) and 3.00 g 4- (N-Boc- aminoethyl) phenylboronic acid (11.9 mmol) in 60.0 ml 1,4 oxygen six ring (769 mmol) and 26.0 ml containing 1.04M saturated sodium bicarbonate (26.9 mmol) in aqueous solution was stirred, the mixture was degassed for 10 minutes and then added to 558.1 mg of bis (tricyclohexylphosphine) palladium (0.8364 mm mole), was heated to 100 deg.] C overnight, the reaction with 200 ml of ethyl acetate, 100 ml of water and 100 ml of saturated sodium bicarbonate solution, and the resulting emulsion / solution precipitate was filtered, washed twice with water, washing with ethyl acetate twice under high vacuum overnight, collected the white powder 1.967 gm (48%).

Reference： [1]Patent: TWI525093,2016,B .Location in patent: Page/Page column 332; 333

39
[ 148038-83-9 ]
[ 138500-88-6 ]
[ 1289182-62-2 ]

Reference： [1]Patent: TWI525093,2016,B

40
[ 148038-83-9 ]
ethyl 2-(2-oxo-6-(5-(trifluoromethyl)thiophen-2-yl)-3-trityl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)acetate [ No CAS ]