[ CAS No. 885693-20-9 ] {[proInfo.proName]}

Name: 885693-20-9|tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate|97%
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SKU: A119303
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Quality Control of [ 885693-20-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 885693-20-9 ]

SDS Specification

Alternatived Products of [ 885693-20-9 ]

Product Details of [ 885693-20-9 ]

CAS No. :	885693-20-9	MDL No. :	MFCD10697911
Formula :	C₁₆H₂₈BNO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KEEIJBAOTMNSEN-UHFFFAOYSA-N
M.W :	309.21	Pubchem ID :	49835909
Synonyms :

Calculated chemistry of [ 885693-20-9 ]

Physicochemical Properties

Num. heavy atoms :	22
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.81
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	91.9
TPSA :	48.0 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.52 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.34
Log Po/w (WLOGP) :	2.8
Log Po/w (MLOGP) :	1.54
Log Po/w (SILICOS-IT) :	1.18
Consensus Log Po/w :	1.57

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.97
Solubility :	0.333 mg/ml ; 0.00108 mol/l
Class :	Soluble
Log S (Ali) :	-2.99
Solubility :	0.318 mg/ml ; 0.00103 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.84
Solubility :	0.448 mg/ml ; 0.00145 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	4.13

Safety of [ 885693-20-9 ]

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 [ 885693-20-9 ]

* 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 [ 885693-20-9 ]
Downstream synthetic route of [ 885693-20-9 ]

[ 885693-20-9 ] Synthesis Path-Upstream 1~6

1
[ 180691-65-0 ]
[ 73183-34-3 ]
[ 885693-20-9 ]

Yield	Reaction Conditions	Operation in experiment
71%	With 1,1'-bis-(diphenylphosphino)ferrocene; potassium acetate In 1,4-dioxane at 80℃; for 16 h;	PdCl₂dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol), 4,4,5,5,4',4',5',5'- octamethyl-[2,2']bi[[l,3,2]dioxaborolanyl] (2.07 g, 8.13 mmol), and dppf (0.12 g, 0.22 mmol) were placed in a round-bottomed flask, and the flask was flushed with Ar. A degassed solution of 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated to 80 ⁰C for 16 h. The mixture was filtered through a glass-fritted funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Silica gel chromatography (5 percent EtOAc in hexanes) afforded the title compound (1.62 g, 71 percent) as a colorless oil. ¹H-NMR (CDCl₃; 400 MHz): δ 6.69-6.60 (m, IH), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s, 9H), 1.27 (s, 12H). LC-MS (ESI, m/z): Calcd. for Ci₈H₂₈BNO₄ 310.2 (M+H), found 311.0.
71%	With potassium acetate In 1,4-dioxane at 80℃; for 16 h;	PdCl₂dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol), 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (2.07 g, 8.13 mmol), and dppf(0.12 g, 0.22 mmol) were placed in a round-bottomed flask, and the flask was flushed with Ar. A degassed solution of 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated to 80° C. for 16 h. The mixture was filtered through a glass-fritted funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Silica gel chromatography (5percent EtOAc in hexanes) afforded the title compound (1.62 g, 71percent) as a colorless oil. ¹H-NMR (CDCl₃; 400 MHz): δ 6.69-6.60 (m, 1H), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s, 12H). LC-MS (ESI, m/z): Calcd. for C₁₈H₂₈BNO₄310.2 (M+H), found 311.0.
71%	With potassium acetate In 1,4-dioxane at 80℃; for 16 h;	b) 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester PdCl₂dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol), 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (2.07 g, 8.13 mmol), and dppf (0.12 g, 0.22 mmol) were placed in a round-bottomed flask, and the flask was flushed with Ar. A degassed solution of 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated to 80° C. for 16 h. The mixture was filtered through a glass-fritted funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Silica gel chromatography (5percent EtOAc in hexanes) afforded the title compound (1.62 g, 71percent) as a colorless oil. ¹H-NMR (CDCl₃; 400 MHz): δ 6.69-6.60 (m, 1H), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s, 9H), 1.27 (s, 12H). LC-MS (ESI, m/z): Calcd. for C₁₈H₂₈BNO₄ 310.2 (M+H). found 311.0.

71%	With 1,1'-bis(diphenylphosphino)ferrocene; potassium acetate In 1,4-dioxane at 80℃; for 16 h;	PdCl₂dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol), 4,4,5,5,4',4',5',5'- octamethyl-[2,2']bi[[l,3,2]dioxaborolanyl] (2.07 g, 8.13 mmol), and dppf (0.12 g, 0.22 mmol) were placed in a round-bottomed flask, and the flask was flushed with Ar. A degassed solution of 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-l- carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated to 80 ⁰C for 16 h. The mixture was filtered through a glass-fritted funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Silica gel chromatography (5 percent EtOAc in hexanes) afforded the title compound (1.62 g, 71 percent) as a colorless oil. ¹H-NMR (CDCl₃; 400 MHz): δ 6.69-6.60 (m, IH), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s, 9H), 1.27 (s, 12H). LC-MS (ESI, m/z): Calcd. for C₁₈H₂₈BNO₄ 310.2 (M+H), found 311.0.
70%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 18 h; Inert atmosphere	Step 2 To a degassed solution of 5-trifluoromethanesulfonyloxy-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (340 mg, 1.0 mmol, 1 eq) in dioxane (10 mL) was added bis-(pinacolato)-diboron (287 mg, 1.1 mmol, 1.1 eq), potassium acetate (302 mg, 3.0 mmol, 3 eq), 1,1'-bis(diphenylphosphino)ferrocene (17 mg, 0.03 mmol, 0.03 eq) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium) (23 mg, 0.03 mmol, 0.03 eq) were added. The mixture was stirred at 80° C. for 18 h. After cooling down, the mixture was filtered and the filtrate was concentrated and purified by flash chromatography using cyclohexane and ethyl acetate (100/0 to 96/4) to afford the corresponding boronic ester (225 mg, 70percent yield).
64%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere	To a solution of tert-butyl 3-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine- l(2H)- carboxylate (503-2) (1.4 g, 4.3 mmol), BPin ( 1.3 g, 5.1 mmol) and KOAc (1.26 g, 12.9 mmol) in dioxane (10 mL) was added Pd(dppf)Cl₂.DCM (351 mg, 0.43 mmol). The resulting mixture was purged with N₂ X 3 and heated to 80 °C overnight. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, 0 to 10percent EA in PE) to give tert-butyl 3-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (503-3) (850 mg, 64percent) as a yellow oil.
42%	With potassium acetate In 1,4-dioxane at 80℃; for 12 h;	To a high pressure vessel was added 5-trifluoromethanesulfonyloxy-3,6- dihydro-2H-pyridine- l-carboxylic acid tert-butyl ester (1.0 g, 3.0 mmol), dichloro[l ,l '- bis(diphenylphosphino)ferrocene]palladium (II) acetone adduct (0.2 g, 0.3 mmol), Ι , - bis(diphenylphosphino)ferrocene (0.2 g, 0.3 mmol), bis(pinacolato)diboron (0.84 g, 3.3 mmol) and K₂OAc (0.89 g, 9.0 mmol) in 1 ,4-dioxane (7 mL, 90 mmol). The reaction was heated for 12 h at 80 °C. After cooling to RT, the mixture was diluted with EtOAc, the organic phase was concentrated in vacuo, and the residue purified by column chromatography to afford the named compound (42percent). ^.H NMR (CDC1₃, 400 MHz): δ 6.57 (br. s., 1H), 3.91 (br. s., 2H), 3.39 (t, J = 5.81 Hz, 2H), 2.13 (br. s., 2H), 1.39-1.41 (m, 9H), 1.19 (s, 12H).
41%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In N,N-dimethyl-formamide at 85℃; for 4 h; Inert atmosphere	A mixture of tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (3.5 g, 14.5 mmol), Pd(dppf)Cl₂ (0.38 g, 0.53 mmol), bis(pinacolato)diboron (3.9 g, 15.8 mmol), and KOAc (3.1 g, 31.5 mmol) in anhydrous DMF was degassed and purged with nitrogen three times. The mixture was heated at 85° C. for 4 h. After cooling down to room temperature, the reaction was diluted with ethyl acetate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to afford tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.4 g, 41percent) as a colorless oil.

Reference： [1] Patent: WO2006/47277, 2006, A2, . Location in patent: Page/Page column 97
[2] Patent: US2006/281788, 2006, A1, . Location in patent: Page/Page column 73
[3] Patent: US2008/51402, 2008, A1, . Location in patent: Page/Page column 60
[4] Patent: WO2007/48088, 2007, A2, . Location in patent: Page/Page column 115
[5] Patent: US2013/102601, 2013, A1, . Location in patent: Paragraph 184
[6] Patent: WO2016/4272, 2016, A1, . Location in patent: Paragraph 00654
[7] Patent: WO2011/29046, 2011, A1, . Location in patent: Page/Page column 122; 123
[8] Patent: US2018/72743, 2018, A1, . Location in patent: Paragraph 1625-1626
[9] Patent: US2007/105864, 2007, A1, . Location in patent: Page/Page column 180
[10] Patent: WO2012/127506, 2012, A1, . Location in patent: Page/Page column 68-69
[11] Patent: WO2010/59771, 2010, A1, . Location in patent: Page/Page column 47

2
[ 98977-36-7 ]
[ 885693-20-9 ]
[ 1121057-77-9 ]

Reference： [1] Patent: WO2011/143495, 2011, A1, . Location in patent: Page/Page column 85

3
[ 98977-36-7 ]
[ 885693-20-9 ]

Reference： [1] Patent: WO2011/29046, 2011, A1,
[2] Patent: WO2012/127506, 2012, A1,
[3] Patent: WO2016/4272, 2016, A1,
[4] Patent: US2017/174641, 2017, A1,
[5] Patent: US2018/72743, 2018, A1,
[6] Patent: US2013/102601, 2013, A1,
[7] Patent: WO2010/59771, 2010, A1,

4
[ 180691-65-0 ]
[ 885693-20-9 ]

Reference： [1] Patent: US2017/174641, 2017, A1,

5
[ 86447-11-2 ]
[ 885693-20-9 ]

Reference： [1] Patent: CN105503924, 2016, A,

6
[ 98977-36-7 ]
[ 885693-20-9 ]
[ 1121057-77-9 ]

Reference： [1] Patent: WO2011/143495, 2011, A1, . Location in patent: Page/Page column 85

[ 885693-20-9 ] Synthesis Path-Downstream 1~88

1
[ 180691-65-0 ]
[ 73183-34-3 ]
[ 885693-20-9 ]

Yield	Reaction Conditions	Operation in experiment
71%	With 1,1'-bis-(diphenylphosphino)ferrocene; potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 16h;	PdCl2dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol), 4,4,5,5,4',4',5',5'- octamethyl-[2,2']bi[[l,3,2]dioxaborolanyl] (2.07 g, 8.13 mmol), and dppf (0.12 g, 0.22 mmol) were placed in a round-bottomed flask, and the flask was flushed with Ar. A degassed solution of 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated to 80 0C for 16 h. The mixture was filtered through a glass-fritted funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Silica gel chromatography (5 percent EtOAc in hexanes) afforded the title compound (1.62 g, 71 percent) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): delta 6.69-6.60 (m, IH), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s, 9H), 1.27 (s, 12H). LC-MS (ESI, m/z): Calcd. for Ci8H28BNO4 310.2 (M+H), found 311.0.
71%	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 16h;	PdCl2dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol), 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (2.07 g, 8.13 mmol), and dppf(0.12 g, 0.22 mmol) were placed in a round-bottomed flask, and the flask was flushed with Ar. A degassed solution of 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated to 80° C. for 16 h. The mixture was filtered through a glass-fritted funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Silica gel chromatography (5percent EtOAc in hexanes) afforded the title compound (1.62 g, 71percent) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): delta 6.69-6.60 (m, 1H), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s, 12H). LC-MS (ESI, m/z): Calcd. for C18H28BNO4 310.2 (M+H), found 311.0.
71%	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 16h;	b) 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester PdCl2dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol), 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (2.07 g, 8.13 mmol), and dppf (0.12 g, 0.22 mmol) were placed in a round-bottomed flask, and the flask was flushed with Ar. A degassed solution of 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated to 80° C. for 16 h. The mixture was filtered through a glass-fritted funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Silica gel chromatography (5percent EtOAc in hexanes) afforded the title compound (1.62 g, 71percent) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): delta 6.69-6.60 (m, 1H), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s, 9H), 1.27 (s, 12H). LC-MS (ESI, m/z): Calcd. for C18H28BNO4 310.2 (M+H). found 311.0.

71%	With 1,1'-bis(diphenylphosphino)ferrocene; potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 16h;	PdCl2dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol), 4,4,5,5,4',4',5',5'- octamethyl-[2,2']bi[[l,3,2]dioxaborolanyl] (2.07 g, 8.13 mmol), and dppf (0.12 g, 0.22 mmol) were placed in a round-bottomed flask, and the flask was flushed with Ar. A degassed solution of 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-l- carboxylic acid tert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol) in dioxane (70 mL) was added to the flask and heated to 80 0C for 16 h. The mixture was filtered through a glass-fritted funnel to remove the solid KOAc, and the filtrate was concentrated in vacuo. Silica gel chromatography (5 percent EtOAc in hexanes) afforded the title compound (1.62 g, 71 percent) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): delta 6.69-6.60 (m, IH), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s, 9H), 1.27 (s, 12H). LC-MS (ESI, m/z): Calcd. for C18H28BNO4 310.2 (M+H), found 311.0.
70%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 18h;Inert atmosphere;	Step 2 To a degassed solution of 5-trifluoromethanesulfonyloxy-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (340 mg, 1.0 mmol, 1 eq) in dioxane (10 mL) was added bis-(pinacolato)-diboron (287 mg, 1.1 mmol, 1.1 eq), potassium acetate (302 mg, 3.0 mmol, 3 eq), 1,1'-bis(diphenylphosphino)ferrocene (17 mg, 0.03 mmol, 0.03 eq) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium) (23 mg, 0.03 mmol, 0.03 eq) were added. The mixture was stirred at 80° C. for 18 h. After cooling down, the mixture was filtered and the filtrate was concentrated and purified by flash chromatography using cyclohexane and ethyl acetate (100/0 to 96/4) to afford the corresponding boronic ester (225 mg, 70percent yield).
64%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃;Inert atmosphere;	To a solution of tert-butyl 3-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine- l(2H)- carboxylate (503-2) (1.4 g, 4.3 mmol), BPin ( 1.3 g, 5.1 mmol) and KOAc (1.26 g, 12.9 mmol) in dioxane (10 mL) was added Pd(dppf)Cl2.DCM (351 mg, 0.43 mmol). The resulting mixture was purged with N2 X 3 and heated to 80 °C overnight. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, 0 to 10percent EA in PE) to give tert-butyl 3-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (503-3) (850 mg, 64percent) as a yellow oil.
42%	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-acetone complex; In 1,4-dioxane; at 80℃; for 12h;	To a high pressure vessel was added 5-trifluoromethanesulfonyloxy-3,6- dihydro-2H-pyridine- l-carboxylic acid tert-butyl ester (1.0 g, 3.0 mmol), dichloro[l ,l '- bis(diphenylphosphino)ferrocene]palladium (II) acetone adduct (0.2 g, 0.3 mmol), Iota , - bis(diphenylphosphino)ferrocene (0.2 g, 0.3 mmol), bis(pinacolato)diboron (0.84 g, 3.3 mmol) and K2OAc (0.89 g, 9.0 mmol) in 1 ,4-dioxane (7 mL, 90 mmol). The reaction was heated for 12 h at 80 °C. After cooling to RT, the mixture was diluted with EtOAc, the organic phase was concentrated in vacuo, and the residue purified by column chromatography to afford the named compound (42percent). .H NMR (CDC13, 400 MHz): delta 6.57 (br. s., 1H), 3.91 (br. s., 2H), 3.39 (t, J = 5.81 Hz, 2H), 2.13 (br. s., 2H), 1.39-1.41 (m, 9H), 1.19 (s, 12H).
41%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 85℃; for 4h;Inert atmosphere;	A mixture of tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (3.5 g, 14.5 mmol), Pd(dppf)Cl2 (0.38 g, 0.53 mmol), bis(pinacolato)diboron (3.9 g, 15.8 mmol), and KOAc (3.1 g, 31.5 mmol) in anhydrous DMF was degassed and purged with nitrogen three times. The mixture was heated at 85° C. for 4 h. After cooling down to room temperature, the reaction was diluted with ethyl acetate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography to afford tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.4 g, 41percent) as a colorless oil.
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃;	To a 25 mL round bottom flask charged with bis(pinacolato)diboron (1.50 g, 6 mmol), potassium acetate (1.5 g, 15 mmol), Pd(dppf)Cl2 (408 mg, 0.5 mmol) and DPPF (277 mg, 0.5 mmol). Compound 195 (1.55 g, 5.0 mmol) in dioxane 20 mL) was added to the above mixture. The mixture was degassed thoroughly and placed under argon. This resulting mixture was then heated at 80° C. for overnight, diluted with EtOAc (40 mL) and filtered through celite. After concentration, the residue was purified with column chromatography (silica gel, Hexane/EtOAc=60/40) to give the product (832 mg) as an oil. HPLC-MS tR=2.41 min (UV254 nm), mass calculated for formula C16H28BNO4, 309.2; observed MH+-t-Bu (LCMS) 254.2(m/z).
	With potassium acetate; In 1,4-dioxane;	Preparation 5: tert-butyl 5-(3H-pyrroIo[3,2-fJ[l,7]naphthyridin-9-yl)-3,6-dihydro-2H- pyridine-l-carboxylate (36) The compound 36 is prepared according to the procedure described in patent applications WO 2007/146838 and WO 2010/059771
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃;Inert atmosphere;	5-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester[370] A mixture of Bis(pinacolato)diboron (0.864 g, 3.40 mmol), (1 ,1'-bis-(diphenyl- phosphino)ferrocene)palladium (0.29 g, 0.39 mmol), potassium acetate (0.642 g, 6.54 mmol) and 5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester(0.600 g, 1.81 mmol) in 1 ,4-dioxane (20 ml.) was degassed and refilled with N2 three times.The resulting material was stirred at 80 °C for overnight. The reaction mixture was filtrated through a celite pad, concentrated in vacuo and purified by silica gel (Hexanes: EtOAc = 9:1 , v:v) to afford the desired product. 1H NMR (400 MHz, CDCI3): delta = 1.38 (s, 9 H), 2.01-2.19 (m,2 H), 3.28-3.41 (m, 2 H), 3.89 (d, J = 2.23 Hz, 2 H), 6.55 (br. s., 1 H).

Reference： [1]Patent: WO2006/47277,2006,A2 .Location in patent: Page/Page column 97
[2]Patent: US2006/281788,2006,A1 .Location in patent: Page/Page column 73
[3]Patent: US2008/51402,2008,A1 .Location in patent: Page/Page column 60
[4]Patent: WO2007/48088,2007,A2 .Location in patent: Page/Page column 115
[5]Patent: US2013/102601,2013,A1 .Location in patent: Paragraph 184
[6]Patent: WO2016/4272,2016,A1 .Location in patent: Paragraph 00654
[7]Patent: WO2011/29046,2011,A1 .Location in patent: Page/Page column 122; 123
[8]Patent: US2018/72743,2018,A1 .Location in patent: Paragraph 1625-1626
[9]Patent: US2007/105864,2007,A1 .Location in patent: Page/Page column 180
[10]Patent: WO2012/127506,2012,A1 .Location in patent: Page/Page column 68-69
[11]Patent: WO2010/59771,2010,A1 .Location in patent: Page/Page column 47

2
[ 885693-24-3 ]
[ 885693-20-9 ]
5-[5-(1-acetyl-piperidin-4-yl)-2-amino-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%		A solution of 5-(4,4,5,5-tetramethyl-[ 1,3, 2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (as prepared in Example 46, step (b), 0.62 g, 2.02 mmol) and l-[4-(4-amino-3-bromo-phenyl)-piperidin-l-yl]-ethanone (as prepared in the previous step, 0.20 g, 0.67 mmol) in toluene:EtOEta (2:1, 9 mL) was treated with 2.0 M aqueous Na2CO3 (2.7 mL, 5.38 mmol) and was degassed with sonication under Ar. The mixture was heated to 80 0C, treated with Pd(PPh3)4 (54 mg, 0.05 mmol), and stirred at 80 °C for 4.5 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and EPO <DP n="101"/>concentrated in vacuo to afford the title compound (0.25 g, 93 percent) as an off-white solid. LC-MS (ESI, m/z): Calcd. for C23H33N3O3 422.2 (M+Na), found 422.0.
93%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 4.5h;	A solution of <strong>[885693-20-9]5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester</strong> (as prepared in Example 46, step (b), 0.62 g, 2.02 mmol) and 1-[4-(4-amino-3-bromo-phenyl)-piperidin-1-yl]-ethanone (as prepared in the previous step, 0.20 g, 0.67 mmol) in toluene:EtOH (2:1, 9 mL) was treated with 2.0 M aqueous Na2CO3 (2.7 mL, 5.38 mmol) and was degassed with sonication under Ar. The mixture was heated to 80° C., treated with Pd(PPh3)4 (54 mg, 0.05 mmol), and stirred at 80° C. for 4.5 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.25 g, 93percent) as an off-white solid. LC-MS (ESI, m/z): Calcd. for C23H33N3O3 422.2 (M+Na), found 422.0.
93%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 4.5h;	f) 5-[5-(1-Acetyl-piperidin-4-yl)-2-amino-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester A solution of <strong>[885693-20-9]5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester</strong> (as prepared in Example 46, step (b), 0.62 g, 2.02 mmol) and 1-[4-(4-amino-3-bromo-phenyl)-piperidin-1-yl]-ethanone (as prepared in the previous step, 0.20 g, 0.67 mmol) in toluene:EtOH (2:1, 9 mL) was treated with 2.0 M aqueous Na2CO3 (2.7 mL, 5.38 mmol) and was degassed with sonication under Ar. The mixture was heated to 80° C., treated with Pd(PPh3)4 (54 mg, 0.05 mmol), and stirred at 80° C. for 4.5 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.25 g, 93percent) as an off-white solid. LC-MS (ESI, m/z): Calcd. for C23H33N3O3 422.2 (M+Na). found 422.0.

93%

With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 4.5h;

A solution of 5-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester (as prepared in Example 46, step (b), 0.62 g, 2.02 mmol) and l-[4-(4-amino-3-bromo-phenyl)-piperidin-l-yl]-ethanone (as prepared in the previous step, 0.20 g, 0.67 mmol) in toluene:EtOH (2:1, 9 mL) was treated with 2.0 M aqueous Na2COs (2.7 mL, 5.38 mmol) and was degassed with sonication under Ar. The mixture was heated to 80 0C, treated with Pd(PPh3)4 (54 mg, 0.05 mmol), and stirred at 80 °C for 4.5 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.25 g, 93 percent) as an off-white solid. LC-MS (EST, m/z): Calcd. for C23H33N3O3 422.2 (M+Na), found 422.0.

Reference： [1]Patent: WO2006/47277,2006,A2 .Location in patent: Page/Page column 99-100
[2]Patent: US2006/281788,2006,A1 .Location in patent: Page/Page column 74-75
[3]Patent: US2008/51402,2008,A1 .Location in patent: Page/Page column 61
[4]Patent: WO2007/48088,2007,A2 .Location in patent: Page/Page column 117

3
[ 885693-20-9 ]
[ 887475-71-0 ]
[ 887475-83-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃;	To a 25 mL round bottom flask charged with boronate 197 (456 mg, 1.5 mmol), K2CO3 (800 mg, 6 mmol), and Pd(dppf)Cl2 (160 mg, 0.2 mmol) was added a solution of product from example 177(360 mg, 1.5 mmol) in DMF (10 mL). The mixture was degassed thoroughly and placed under argon. This resulting mixture was then heated at 80° C. overnight. The reaction mixture was diluted with EtOAc (40 mL) and filtered through Celite. After concentration, the residue was purified by column chromatography (silica gel, Hexane/EtOAc=60/40) to give the product 198 (258 mg) as an oil. HPLC-MS tR=1.91 min (UV254 nm); mass calculated for formula C17H22N4O2S, 346.1; observed MH+ (LCMS) 347.2 (m/z).

Reference： [1]Patent: US2007/105864,2007,A1 .Location in patent: Page/Page column 180

4
[ 98977-36-7 ]
[ 885693-20-9 ]

Reference： [1]Patent: WO2011/29046,2011,A1
[2]Patent: WO2012/127506,2012,A1
[3]Patent: WO2016/4272,2016,A1
[4]Patent: US2017/174641,2017,A1
[5]Patent: US2018/72743,2018,A1
[6]Patent: US2013/102601,2013,A1
[7]Patent: WO2010/59771,2010,A1

5
[ 885693-20-9 ]
[ 1227611-86-0 ]
[ 1227611-56-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 66: 3-[(S)-1-(2,6-Dichloro-3-fluorophenyl)ethyl]-5-(1 ,2,5,6-tetrahydropyridin- 3-yl)-1H-pyrrolo[2,3-b]pyridine[368] A mixture of 5-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2/-/-pyridine-1- carboxylic acid tert-butyl ester (0.0154 g, 0.0498 mmol), ((S)-I -{5-Bromo-3-[(S)-1 -(2,6- dichloro-3-fluorophenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carbonyl}-3-methyl-butyl)-carbamic acid 9/-/-fluoren-9-ylmethyl ester (0.020 g, 0.028 mmol), Pd(PPh3)4 (0.0048 g, 0.0041 mmol) and K2CO3 (0.0172 g, 0.124 mol) in DME (1.2 mL) and H2O (0.3 mL) was stirred at 100 °C under microwave condition for 30 min. The reaction mixture was directly loaded onto Prep TLC (5percent MeOH in DCM) to afford 10 mg crude product. The crude product was dissolved in DCM (2 mL) and treated with 4 M HCl in dioxane for 2 h at rt. The resulting solution was loaded onto a Prep TLC (20x20 cm plate, silica gel 500 muM, 5percent 7 N NH3 in MeOH in DCM) to afford the desired product. 1H-NMR (CD3OD, 400 MHz): delta = 1.86 (d, J = 7.1 Hz, 3 H), 2.30 (m, 2 H), 2.99 (t, J = 5.9 Hz, 2 H), 3.58 (m, 2 H), 5.26 (m, 1 H), 5.97-6.07 (m, 1 H), 7.15-7.24 (m, 2 H), 7.37 (d, J = 1.3 Hz, 1 H), 8.15 (d, J = 2.0 Hz, 1 H). MS (ES+): m/z 390.07 (MH+, 35CI), 392.02(MH+, 37CI), HPLC: tR = 2.50 min (ZQ3, polar_5min).

Reference： [1]Patent: WO2010/59771,2010,A1 .Location in patent: Page/Page column 46-47

6
[ 26218-75-7 ]
[ 885693-20-9 ]
[ 1271809-16-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 12h;	To a high pressure vessel was added 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-bu yX ester (1.0 g, 3.2 mmol), methyl 6- bromopicolinate (0.77 g, 3.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.3 mmol), 1 M of sodium carbonate in water (9.7 mL, 9.7 mmol) and DME (10.1 mL, 97.0 mmol). The reaction was heated for 12 h at 80 °C,then cooled to RT and diluted with water and EtOAc. The organic phase was separated, dried (Na2SC>4), filtered and concentrated in vacuo. The crude material was purified by column chromatography (gradient hexane-EtOAc) to afford the named compound (0.71 g, 70percent yield). .H NMR (CDC13, 300 MHz): delta 7.79 (d, J = 7.55 Hz, 1H), 7.72 (t, J = 7.93 Hz, 1H), 7.44 (d, J = 8.31 Hz, 1H), 4.32-4.41 (m, 1H), 3.90-3.96 (s, 3H), 3.55-3.64 (m, 2H), 2.50 (br. s., 2H), 1.84-1.95 (m, 2H), 1.48 (s, 12H). EIMS (m/z): calcd. for Ci7H2204N2 (M-C4H9, +1H) 263, found 263.

Reference： [1]Patent: WO2011/29046,2011,A1 .Location in patent: Page/Page column 122; 123

7
[ 885693-20-9 ]
[ 1271802-77-7 ]

Reference： [1]Patent: WO2011/29046,2011,A1

8
[ 885693-20-9 ]
[ 1271809-18-7 ]

Reference： [1]Patent: WO2011/29046,2011,A1

9
4,4,4',4',5,5,5'-heptamethyl-2,2'-bi(1,3,2-dioxaborolane) [ No CAS ]
[ 98977-36-7 ]
[ 885693-20-9 ]
[ 1121057-77-9 ]

Yield	Reaction Conditions	Operation in experiment
		A flask with 4.4.4',4',5,5,5'-heptamethyl-2,2'-bi(l,3.2-dioxaborolane) (10.48 g, 43.7 mmol), (dppf)PdCl2 (0.930 g, 1.139 mmol), and potassium acetate (11.18 g, 114 mmol) was flushed with N2 (3 X), then 1,4-dioxane (100 mL) was added followed by a solution of tert-butyl 5-(trifluoromethylsulfonyloxy)-3,4-dihydropyridine-l(2H)-carboxylate and tert-butyl 3- (trifluoromethylsulfonyloxy)-5,6-dihydropyridine-l(2H)-carboxylate (1 : 1 ratio, 12.58 g, 38.0 mmol) in 1,4-dioxane (100 mL). The solution was heated in an 80 °C oil bath for 20 hours. The reaction was quenched with water (100 mL) and the aqueous layer extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaCl (100 mL), dried with magnesium sulfate (MgS04), and concentrated. The residue was purified by silica gel chromatography using ISCO.(TM). (330 g Si02, 0-20percent EtOAc/hexane) to give tert-butyl 3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate and tert-butyl 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-l(2H)-carboxylate (7.29 g, 23.58 mmol, 62.1 percent yield) (inseperable 2: 1 mixture of olefin regioisomers) as a white solid.

Reference： [1]Patent: WO2011/143495,2011,A1 .Location in patent: Page/Page column 85

10
[ 885693-20-9 ]
[ 1401442-67-8 ]