[ CAS No. 1121057-75-7 ] {[proInfo.proName]}

Name: 1121057-75-7|4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride|95%
Brand: Ambeed
SKU: A219175
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Quality Control of [ 1121057-75-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1121057-75-7 ]

Product Details of [ 1121057-75-7 ]

CAS No. :	1121057-75-7	MDL No. :	MFCD11506076
Formula :	C₁₁H₂₁BClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WNMYCAJTXUCHBQ-UHFFFAOYSA-N
M.W :	245.55	Pubchem ID :	49761084
Synonyms :

Calculated chemistry of [ 1121057-75-7 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.82
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	73.03
TPSA :	30.49 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) :	-6.5 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.83
Log Po/w (WLOGP) :	1.96
Log Po/w (MLOGP) :	1.07
Log Po/w (SILICOS-IT) :	1.01
Consensus Log Po/w :	1.17

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.45
Solubility :	0.873 mg/ml ; 0.00355 mol/l
Class :	Soluble
Log S (Ali) :	-2.09
Solubility :	1.99 mg/ml ; 0.00812 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.68
Solubility :	0.518 mg/ml ; 0.00211 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.57

Safety of [ 1121057-75-7 ]

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 [ 1121057-75-7 ]

* 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 [ 1121057-75-7 ]
Downstream synthetic route of [ 1121057-75-7 ]

[ 1121057-75-7 ] Synthesis Path-Upstream 1~4

1
[ 1121057-75-7 ]
[ 501-53-1 ]
[ 286961-15-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In dichloromethane at 20℃; for 2 h;	Example 2: Tetrahydropyridine 2 was prepared in 3 steps starting with the deprotection of 1 using Method 3. The resulting HCl amine salt was dissolved in dichloromethane (0.2 M). Benzyl chloroformate (1.2 equiv) was added followed by triethylamine (3.0 equiv). The reaction was allowed to stir at room temperature for 2h after which point it was diluted with IN HCl and extracted with excess dichloromethane. The organic layer was dried over MgSψ4 and concentrated to provide the desired carbamate in quantitative yield, which was converted directly to boronic acid 2 using Method 2. [M-H]- = 260.1 m/z. Activity: B

Reference： [1] Patent: WO2010/118159, 2010, A1, . Location in patent: Page/Page column 65-66

2
[ 1121057-75-7 ]
[ 75-36-5 ]
[ 1227068-67-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine In dichloromethane at 0 - 20℃; for 0.5 h;	4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2,3,6-tetrahydropyridine hydrochloride (Intermediate G3, 1.4 g, 5.70 mmol) was suspended in DCM (15 mL) at 0°C, then TEA (2.384 ml, 17.10 mmol) and AcC1 (0.405 ml, 5.70 mmol) were added The reaction was allowed to warm up to rt and stirred for further 30 mm, then the reaction volume was reduced to 1/3 of the initial volume and the residue diluted with AcOEt (150ml). Organic phase was washed twice with water, once with 0,2 M HClaqueous and once with saturated NaChqueous, dried over Na2SO4 and solvent removed under reduced pressure to give the title compound (1.24 g, 87 percent yield) as yellowish solid.UPLC-MS: 0.83 mm, 252.3 [M+H]+, method 9.
87%	With triethylamine In dichloromethane at 0 - 20℃; for 0.5 h;	4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (Intermediate G3, 1.4 g, 5.70 mmol) was suspended in DCM (15 mL) at 0° C., then TEA (2.384 ml, 17.10 mmol) and AcCl (0.405 ml, 5.70 mmol) were added The reaction was allowed to warm up to rt and stirred for further 30 min, then the reaction volume was reduced to 1/3 of the initial volume and the residue diluted with AcOEt (150 ml). Organic phase was washed twice with water, once with 0.2 M HCl_aqueousand once with saturated NaCl_aqueous, anhydrified over Na₂SO₄and solvent removed under reduced pressure to give the title compound (1.24 g, 87percent yield) as yellowish solid.UPLC-MS: 0.83 min, 252.3 [M+H]+, method 9

Reference： [1] Patent: WO2015/91685, 2015, A1, . Location in patent: Page/Page column 139
[2] Patent: US2015/166549, 2015, A1, . Location in patent: Paragraph 0861; 0862; 0863
[3] Patent: WO2011/143495, 2011, A1, . Location in patent: Page/Page column 86

3
[ 375853-82-0 ]
[ 1121057-75-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride In tert-butyl methyl ether at 20℃;	Method 3: General conditions for the deprotection of a 7V-Boc carbamate in the presence of a boronate ester: The boronate ester is dissolved in te/t-butylmethylether (0.4 M final ester concentration) after which point HCl (g) is bubbled in over the course of 15 min. The reaction is allowed to stir at room temperature for an additional hour after which point the solvent is removed under a stream of nitrogen to provide the desired HCl amine salt as a white solid in quantitative yield.; Example 2: Tetrahydropyridine 2 was prepared in 3 steps starting with the deprotection of 1 using Method 3. The resulting HCl amine salt was dissolved in dichloromethane (0.2 M). Benzyl chloroformate (1.2 equiv) was added followed by triethylamine (3.0 equiv). The reaction was allowed to stir at room temperature for 2h after which point it was diluted with IN HCl and extracted with excess dichloromethane. The organic layer was dried over MgSψ4 and concentrated to provide the desired carbamate in quantitative yield, which was converted directly to boronic acid 2 using Method 2. [M-H]- = 260.1 m/z. Activity: B
96%	With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃;	To tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- 1 -carboxylate 51 (3 g, 9.7 mmol) in dichloromethane (5 mL) was added hydrochloric acid in 1,4-dioxane (4 N, 5 mL). The reaction was stirred at room temperature overnight, then concentrated twice from toluene. The residue was washed with ethyl acetate and dried under vacuum to produce compound 52 as an HC1 salt (2.3 g, 96percent). The data from the ^lH NMR spectrum were consistent with the structure of the compound.
90%	With hydrogenchloride In diethyl ether; tert-butyl methyl ether at 20℃;	tert-butyl 4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-5 ,6-dihydropyridine- 1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HC1 in Et20 (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et20 to give the title compound (1.434 g, 90 percent).UPLC-MS: 0.51 mm, 210.3 [M+H]+, method 9.

90%	With hydrogenchloride In diethyl ether; tert-butyl methyl ether at 20℃;	tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HCl in Et₂O (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et₂O to give the title compound (1.434 g, 90percent).UPLC-MS: 0.51 min, 210.3 [M+H]+, method 9.
8 g	With hydrogenchloride In dichloromethane; isopropyl alcohol for 12 h;	Step 1: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinium chloride Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCl in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the solvent is again evaporated to give the title compound. Yield: 8 g; LC (method 11): t_R=0.68 min; Mass spectrum (ESI⁺): m/z=210 [M+H]⁺.
8 g	With hydrogenchloride In dichloromethane; isopropyl alcohol for 12 h;	Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (1 0 g) is d issolved in d ichloromethane (1 00 m L) and 5 M HCI in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the sollvent is again evaporated to give the title compound. Yield: 8 g; LC (method 1 1 ): t_R = 0.68 min; Mass spectrum (EST): m/z = 210 [M+H]⁺.
8 g	With hydrogenchloride In dichloromethane; isopropyl alcohol for 12 h;	Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCI in isopropanol (120 mL) and stirred for 1 2 hours. The solvents are evaporated, the residue is redissolved in toluene and the sollvent is again evaporated to give the title compound. Yield: 8 g; LC (method 1 1 ): t_R = 0.68 min; Mass spectrum (EST): m/z = 210 [M+H]⁺.

Reference： [1] Patent: WO2010/118159, 2010, A1, . Location in patent: Page/Page column 64; 65-66
[2] Patent: WO2014/100620, 2014, A2, . Location in patent: Paragraph 0318
[3] Patent: WO2015/91685, 2015, A1, . Location in patent: Page/Page column 138; 139
[4] Patent: US2015/166549, 2015, A1, . Location in patent: Paragraph 0858; 0859; 0860
[5] Patent: WO2011/143495, 2011, A1, . Location in patent: Page/Page column 85
[6] Patent: US2013/252937, 2013, A1, . Location in patent: Paragraph 0512
[7] Patent: WO2013/144097, 2013, A1, . Location in patent: Page/Page column 96
[8] Patent: WO2013/144098, 2013, A1, . Location in patent: Page/Page column 149

4
[ 1121057-75-7 ]
[ 4023-34-1 ]
[ 1616388-38-5 ]

Reference： [1] Patent: WO2014/100620, 2014, A2, . Location in patent: Paragraph 0319

[ 1121057-75-7 ] Synthesis Path-Downstream 1~38

1
[ 32315-10-9 ]
[ 1121057-75-7 ]
[ 100-46-9 ]
C₁₉H₂₇BN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 20℃; for 2h;	Example 7: Tetrahydropyridine 7 was prepared in 3 steps starting with the deprotection of 1 using Method 3. The resulting HCl amine salt was suspended in dichloro methane (0.2 M). Triphosgene (0.67 equiv) was added followed by benzylamine (2.67 equiv) and triethylamine (5.0 equiv) after which point the reaction became homogeneous. The reaction was allowed to stir at room temperature for 2h after which point it was diluted with IN HCl and extracted with excess dichloromethane. The organic layer was dried over MgSpsi4, and concentrated to provide the desired urea which was converted directly to boronic acid 7 using Method 2 and isolated using semi-preparatory reverse phase liquid chromatography. [M-H]- = 259.1 m/z. Activity: B

Reference： [1]Patent: WO2010/118159,2010,A1 .Location in patent: Page/Page column 67

2
[ 1121057-75-7 ]
[ 501-53-1 ]
[ 286961-15-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 20℃; for 2h;	Example 2: Tetrahydropyridine 2 was prepared in 3 steps starting with the deprotection of 1 using Method 3. The resulting HCl amine salt was dissolved in dichloromethane (0.2 M). Benzyl chloroformate (1.2 equiv) was added followed by triethylamine (3.0 equiv). The reaction was allowed to stir at room temperature for 2h after which point it was diluted with IN HCl and extracted with excess dichloromethane. The organic layer was dried over MgSpsi4 and concentrated to provide the desired carbamate in quantitative yield, which was converted directly to boronic acid 2 using Method 2. [M-H]- = 260.1 m/z. Activity: B

Reference： [1]Patent: WO2010/118159,2010,A1 .Location in patent: Page/Page column 65-66

3
[ 375853-82-0 ]
[ 1121057-75-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; In tert-butyl methyl ether; at 20℃;	Method 3: General conditions for the deprotection of a 7V-Boc carbamate in the presence of a boronate ester: The boronate ester is dissolved in te/t-butylmethylether (0.4 M final ester concentration) after which point HCl (g) is bubbled in over the course of 15 min. The reaction is allowed to stir at room temperature for an additional hour after which point the solvent is removed under a stream of nitrogen to provide the desired HCl amine salt as a white solid in quantitative yield.; Example 2: Tetrahydropyridine 2 was prepared in 3 steps starting with the deprotection of 1 using Method 3. The resulting HCl amine salt was dissolved in dichloromethane (0.2 M). Benzyl chloroformate (1.2 equiv) was added followed by triethylamine (3.0 equiv). The reaction was allowed to stir at room temperature for 2h after which point it was diluted with IN HCl and extracted with excess dichloromethane. The organic layer was dried over MgSpsi4 and concentrated to provide the desired carbamate in quantitative yield, which was converted directly to boronic acid 2 using Method 2. [M-H]- = 260.1 m/z. Activity: B
100%	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 4h;	To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-5,6-dihydropyridine-1(2H)-carboxylate (5g, 16 mmol) in dioxane (10 mL) was added 4N HCl dioxane solution (24.2 mL, 97 mmol) at RT, and the reaction was stirred at RT for 4 h. The mixture was concentrated under reduced pressure to afford the title compound (4 g, yield 100percent) as a white solid.MS (ES+) C11H21BCINO2 requires: 209, found 210 [M+H]+.
100%	With hydrogenchloride; In ethyl acetate; at 0 - 26℃; for 3h;	Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (ARK PHARMA, 25 g, 80.851 mmol) was dissolved in 250 mL of EtOAc and HCI 4N in EtOAc (SYMAX FINE CHEMICALS, 250 mL) was added at 0 °C. The mixture was allowed to 26 °C and stirred for 3 h. The reaction mixture was evaporated under reduced pressure. The crude was washed with diethyl ether and filtered to give title compound (20 g, quantitative). NMR (400 MHz, DMSO-d6) delta ppm: 9.30 (br s, 2H), 6.40-6.30 (m, 1 H), 3.64- 3.52 (m, 2H), 3.15-3.00 (m, 2H), 2.34-2.22 (m, 2H), 1.21 (s, 12H).

96%	With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃;	To tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- 1 -carboxylate 51 (3 g, 9.7 mmol) in dichloromethane (5 mL) was added hydrochloric acid in 1,4-dioxane (4 N, 5 mL). The reaction was stirred at room temperature overnight, then concentrated twice from toluene. The residue was washed with ethyl acetate and dried under vacuum to produce compound 52 as an HC1 salt (2.3 g, 96percent). The data from the lH NMR spectrum were consistent with the structure of the compound.
90%	With hydrogenchloride; In diethyl ether; tert-butyl methyl ether; at 20℃;	tert-butyl 4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-5 ,6-dihydropyridine- 1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HC1 in Et20 (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et20 to give the title compound (1.434 g, 90 percent).UPLC-MS: 0.51 mm, 210.3 [M+H]+, method 9.
90%	With hydrogenchloride; In diethyl ether; tert-butyl methyl ether; at 20℃;	tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HCl in Et2O (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et2O to give the title compound (1.434 g, 90percent).UPLC-MS: 0.51 min, 210.3 [M+H]+, method 9.
	With hydrogenchloride; In methanol; at 20℃; for 1h;	The mixture of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (4.0 g, 12.9 mmol) in HCl/MeOH (20 mL) was stirred at room temperature for lhour. Then it was concentrated to give 4-(4,4,5,5-Tetramethyl- [l,3,2]dioxaborolan-2-yl)-l,2,3,6-tetrahydro-pyridine hydyochloride (2.9 g, 11.8mmol, yield:91.4percent)which was used in the next step without further purification. ESI-MS (M+1): 210 calc. for CnH2oBN02 209
8 g	With hydrogenchloride; In dichloromethane; isopropyl alcohol; for 12h;	Step 1: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinium chloride Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCl in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the solvent is again evaporated to give the title compound. Yield: 8 g; LC (method 11): tR=0.68 min; Mass spectrum (ESI+): m/z=210 [M+H]+.
8 g	With hydrogenchloride; In dichloromethane; isopropyl alcohol; for 12h;	Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (1 0 g) is d issolved in d ichloromethane (1 00 m L) and 5 M HCI in isopropanol (120 mL) and stirred for 12 hours. The solvents are evaporated, the residue is redissolved in toluene and the sollvent is again evaporated to give the title compound. Yield: 8 g; LC (method 1 1 ): tR = 0.68 min; Mass spectrum (EST): m/z = 210 [M+H]+.
8 g	With hydrogenchloride; In dichloromethane; isopropyl alcohol; for 12h;	Tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (10 g) is dissolved in dichloromethane (100 mL) and 5 M HCI in isopropanol (120 mL) and stirred for 1 2 hours. The solvents are evaporated, the residue is redissolved in toluene and the sollvent is again evaporated to give the title compound. Yield: 8 g; LC (method 1 1 ): tR = 0.68 min; Mass spectrum (EST): m/z = 210 [M+H]+.

Reference： [1]Patent: WO2010/118159,2010,A1 .Location in patent: Page/Page column 64; 65-66
[2]Patent: WO2018/218197,2018,A2 .Location in patent: Paragraph 0364; 0365
[3]Patent: WO2019/34701,2019,A1 .Location in patent: Page/Page column 37; 38
[4]Patent: WO2014/100620,2014,A2 .Location in patent: Paragraph 0318
[5]Patent: WO2015/91685,2015,A1 .Location in patent: Page/Page column 138; 139
[6]Patent: US2015/166549,2015,A1 .Location in patent: Paragraph 0858; 0859; 0860
[7]Patent: WO2011/143495,2011,A1 .Location in patent: Page/Page column 85
[8]Patent: US2013/252937,2013,A1 .Location in patent: Paragraph 0512
[9]Patent: WO2013/144097,2013,A1 .Location in patent: Page/Page column 96
[10]Patent: WO2013/144098,2013,A1 .Location in patent: Page/Page column 149

4
[ 3133-78-6 ]
[ 1121057-75-7 ]
[ 1251537-36-6 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃;	Example 5: Tetrahydropyridine 5 was prepared in 2 steps starting with the deprotection of 1 usingMethod 3. The resulting HCl amine salt was dissolved in 7V,7V-dimethylformamide (0.2 M). 3- Methyl-l-benzothiophene-2-carboxylic acid (1.0 equiv) and PyBOP (1.0 equiv) were added followed by the dropwise addition of triethylamine (3.0 equiv). After stirring at room temperature for 30 min, the reaction was diluted with water and filtered. The isolated material was then purified using semi -preparatory liquid chromatography to isolate the fraction of desired boronic acid 5 that resulted from pinacol ester deprotection during the course of the acid coupling. [M-H]- = 300.1 m/z. Activity: B

Reference： [1]Patent: WO2010/118159,2010,A1 .Location in patent: Page/Page column 66-67

5
[ 1121057-75-7 ]
[ 75-36-5 ]
[ 1227068-67-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h;	4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2,3,6-tetrahydropyridine hydrochloride (Intermediate G3, 1.4 g, 5.70 mmol) was suspended in DCM (15 mL) at 0C, then TEA (2.384 ml, 17.10 mmol) and AcC1 (0.405 ml, 5.70 mmol) were added The reaction was allowed to warm up to rt and stirred for further 30 mm, then the reaction volume was reduced to 1/3 of the initial volume and the residue diluted with AcOEt (150ml). Organic phase was washed twice with water, once with 0,2 M HClaqueous and once with saturated NaChqueous, dried over Na2SO4 and solvent removed under reduced pressure to give the title compound (1.24 g, 87 % yield) as yellowish solid.UPLC-MS: 0.83 mm, 252.3 [M+H]+, method 9.
87%	With triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h;	4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (Intermediate G3, 1.4 g, 5.70 mmol) was suspended in DCM (15 mL) at 0 C., then TEA (2.384 ml, 17.10 mmol) and AcCl (0.405 ml, 5.70 mmol) were added The reaction was allowed to warm up to rt and stirred for further 30 min, then the reaction volume was reduced to 1/3 of the initial volume and the residue diluted with AcOEt (150 ml). Organic phase was washed twice with water, once with 0.2 M HClaqueous and once with saturated NaClaqueous, anhydrified over Na2SO4 and solvent removed under reduced pressure to give the title compound (1.24 g, 87% yield) as yellowish solid.UPLC-MS: 0.83 min, 252.3 [M+H]+, method 9
	With hydrogenchloride; triethylamine; In dichloromethane; at 20℃; for 1.0h;	To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6- tetrahydropyridine hydrochloride (2.9 g, 11.8mmol)in DCM (30 mL) were added Et3N (3.6 g, 35.4 mmol) and acetyl chloride (AcCl) (932 mg, 1 1.8 mmol). The reaction mixture was stirred at room temperature for 1 hour, then diluted with DCM (20 mL), washed with H20 (2 0 mL). The organic layer was washed with brine (20 mL), dried over Na2S04, and filtered, evaporated to give the crude product (3.2 g, crude). ESI-MS (M+l): 252 calc. for C13H22BNO3 251.

Reference： [1]Patent: WO2015/91685,2015,A1 .Location in patent: Page/Page column 139
[2]Patent: US2015/166549,2015,A1 .Location in patent: Paragraph 0861; 0862; 0863
[3]Patent: WO2011/143495,2011,A1 .Location in patent: Page/Page column 86

6
[ 1121057-75-7 ]
[ 124-63-0 ]
[ 1382137-67-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine; In dichloromethane; at 20℃;	To a mixture of the product from the previous step (4.0 g, 16 mmol) and TEA (6.3 mL, 48 mmol) in CH2Cl2 (60 mL) at RT was added methanesulfonyl chloride (1.5 mL, 20 mmol) dropwise and the reaction was stirred at RT overnight. The reaction mixture was diluted with CH2Cl2 (60 mL), washed with IN HCl to pH = 5, then with brine (50 mL), and then dried over Na2S04, filtered and concentrated under reduced pressure. The residue was washed with petroleum ether (100 mL) to afford the title compound (3.5 g, 75percent yield) as a white solid.MS (ES+) C12H22BNO4S, requires: 287, found 288 [M+H]+.
7.4 g	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 12h;	Step 2: 1-(Methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine To a cooled (0° C.) solution of <strong>[1121057-75-7]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinium chloride</strong> (8 g) and N-ethyldiisopropylamine (12 mL) in dichloromethane (100 mL) is added dropwise methanesulfonyl chloride (3 mL). The mixture is stirred for 12 hours at room temperature. The mixture is partitioned between dichloromethane and 0.1 M hydrochloric acid. The organic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is crystallized from diethylether to give the title compound. Yield: 7.4 g; LC (method 15): tR=0.98 min; Mass spectrum (ESI+): m/z=288 [M+H]+.
7.4 g	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 12h;	To a cooled (0°C) solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2,3,6- tetrahydropyridinium chloride (8 g) and N-ethyldiisopropylamine (12 mL) in dichloromethane (100 mL) is added dropwise methanesulfonyl chloride (3 mL). The mixture is stirred for 1 2 hours at room temperature. The mixture is partitioned between dichloromethane and 0.1 M hydrochloric acid. The organic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is crystallized from diethylether to give the title compound. Yield: 7.4 g; LC (method 15): tR = 0.98 min; Mass spectrum (ESI+): m/z = 288 [M+H]+.

With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 12h;

To a cooled (0°C) solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2,3,6- tetrahydropyridinium chloride (8 g) and N-ethyldiisopropylamine (12 mL) in dichloromethane (100 mL) is added dropwise methanesulfonyl chloride (3 mL). The mixture is stirred for 12 hours at room temperature. The mixture is partitioned between dichloromethane and 0.1 M hydrochloric acid. The organ ic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is crystallized from diethylether to give the title compound. Yield: 7.4 g; LC (method 15): tR = 0.98 min; Mass spectrum (ESI+): m/z = 288 [M+H]+.

Reference： [1]Patent: WO2018/218197,2018,A2 .Location in patent: Paragraph 0364; 0367; 0368
[2]Patent: US2013/252937,2013,A1 .Location in patent: Paragraph 0513
[3]Patent: WO2013/144097,2013,A1 .Location in patent: Page/Page column 96
[4]Patent: WO2013/144098,2013,A1 .Location in patent: Page/Page column 149; 150

7
[ 1121057-75-7 ]
[ 1616388-07-8 ]

Reference： [1]Patent: WO2014/100620,2014,A2

8
[ 1121057-75-7 ]
[ 1616388-08-9 ]

Reference： [1]Patent: WO2014/100620,2014,A2

9
[ 1121057-75-7 ]
[ 1616385-59-1 ]

Reference： [1]Patent: WO2014/100620,2014,A2

10
[ 1121057-75-7 ]
[ 4023-34-1 ]
[ 1616388-38-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 3h;	To 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,2,3,6- tetrahydropyridine hydrochloride 52 (0.7 g, 2.85 mmol) in acetonitrile (15 mL) was added cyclopropanecarbonyl chloride 53 (0.3 g, 2.87 mmol), followed by N,N-diisopropylethylamine (0.8 mL). The reaction mixture was stirred at room temperature for 3 hours, then passed through a silica gel column (eluting with ethyl acetate and hexanes) to provide crude product in light-colored fractions. The fractions were combined and concentrated. The residue was triturated with a mixture of ethyl acetate and hexanes. The mother liquid was collected and concentrated to provide compound 54 as an orange gel. The compound 54 was used for the subsequent reactions without further purification.

Reference： [1]Patent: WO2014/100620,2014,A2 .Location in patent: Paragraph 0319

11
[ 1121057-75-7 ]
[ 1616387-37-1 ]
[ 1616388-12-5 ]

Yield	Reaction Conditions	Operation in experiment
55%	With dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) acetone adduct; potassium carbonate; In 1,4-dioxane; water; at 130℃; for 0.333333h;Microwave irradiation;	To N-(2-iodo-lH-pyrrolo[2,3-Z?]pyridin-5-yl)-3,4- dimethyl-lH-pyrazole-5-carboxamide 59 (0.15 g, 0.39 mmol) in 1,4-dioxane (3 ml) was added 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine hydrochloride 52 (0.19 g, 0.79 mmol), dichloro(l, l-bis(diphenylphosphino)ferrocene)palladium(ii) acetone adduct (0.02 g, 0.03 mmol) and aqueous potassium carbonate (1.2 mL, 1 M). The reaction mixture was heated in a microwave reactor at 130 °C for 20 minutes. The reaction mixture was poured into iced water and the precipitate was collected by filtration, and then triturated with ethyl acetate to provide compound 60 (73 mg, 55percent). The compound was used for subsequent reaction without further purification.

Reference： [1]Patent: WO2014/100620,2014,A2 .Location in patent: Paragraph 0326

12
[ 1121057-75-7 ]
[ 1616387-37-1 ]
[ 1616385-60-4 ]

Reference： [1]Patent: WO2014/100620,2014,A2

13
[ 1121057-75-7 ]
tert-butyl 4-(4-(4-(benzyloxy)-2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-4-oxobutanoate [ No CAS ]

Reference： [1]Patent: US2015/225354,2015,A1

14
[ 1121057-75-7 ]
tert-butyl 4-(4-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)piperidin-1-yl)-4-oxobutanoate [ No CAS ]

Reference： [1]Patent: US2015/225354,2015,A1

15
[ 1121057-75-7 ]
tert-butyl 3-(4-(4-(benzyloxy)-2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)propanoate [ No CAS ]

Reference： [1]Patent: US2015/225354,2015,A1

16
[ 1121057-75-7 ]
tert-butyl 3-(4-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)piperidin-1-yl)propanoate [ No CAS ]

Reference： [1]Patent: US2015/225354,2015,A1

17
[ 15026-17-2 ]
[ 1121057-75-7 ]
tert-butyl 4-oxo-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.84 g	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 35℃; for 72h;	G) tert-Butyl 4-oxo-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)butanoate HATU (3.68 g) was added to a mixture of <strong>[1121057-75-7]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride</strong> (1.98 g), 4-tert-butoxy-4-oxobutanoic acid (1.686 g), N,N-diisopropylethylamine (3.38 mL), and DMF (20 mL) at 0 C, and the obtained mixture was stirred at room temperature for 3 days. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to obtain the title compound (1.84 g). MS: [M+H]+ 366.3.

Reference： [1]Patent: US2015/225354,2015,A1 .Location in patent: Paragraph 0609; 0610

18
[ 1663-39-4 ]
[ 1121057-75-7 ]
tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.11 g	With potassium carbonate; In acetonitrile; at 70℃;	A) tert-Butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)propanoate A mixture of <strong>[1121057-75-7]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride</strong> (100 mg), tert-butyl acrylate (0.089 mL), potassium carbonate (169 mg), and acetonitrile (2 mL) was stirred overnight at 70 C. In another reaction vessel, a mixture of <strong>[1121057-75-7]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride</strong> (1.00 g), tert-butyl acrylate (0.895 mL), potassium carbonate (1.688 g), and acetonitrile (10 mL) was stirred overnight at 70 C. These two reaction mixtures were combined, and water was added thereto, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to obtain the title compound (1.11 g). MS: [M+H]+ 338.2.

Reference： [1]Patent: US2015/225354,2015,A1 .Location in patent: Paragraph 0667; 0668

19
[ 1121057-75-7 ]
3-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-(1-(4-tert-butoxy-4-oxobutanoyl)piperidin-4-yl)phenyl 4-carbamimidamidobenzoate [ No CAS ]

Reference： [1]Patent: US2015/225354,2015,A1

20
[ 1121057-75-7 ]
4-(4-(2-(5,5-bis(carboxymethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-((4-carbamimidamidobenzoyl)oxy)phenyl)piperidin-1-yl)-4-oxobutanoic acid trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2015/225354,2015,A1

21
[ 1121057-75-7 ]
3-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-(1-(3-tert-butoxy-3-oxopropyl)piperidin-4-yl)phenyl 4-carbamimidamidobenzoate [ No CAS ]

Reference： [1]Patent: US2015/225354,2015,A1

22
[ 1121057-75-7 ]
3-(4-(2-(5,5-bis(carboxymethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-((4-carbamimidamidobenzoyl)oxy)phenyl)piperidin-1-yl)propanoic acid ditrifluoroacetate [ No CAS ]

Reference： [1]Patent: US2015/225354,2015,A1

23
[ 625-08-1 ]
[ 1121057-75-7 ]
3-hydroxy-3-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)butan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17.8%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 4h;	To a solution of 3-hydroxy-3-methylbutanoic acid (7.94 g, 67.2 mmol), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (14.05 g, 73.3 mmol) and N,N-dimethylpyridin-4- amine (26.1 g, 214 mmol) in DCM (700 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,2,3,6-tetrahydropyridine, HQ (15 g, 61.1 mmol). The reaction was stirred at 25 °C for 4 h. The reaction was diluted with DCM (500 mL), washed with IN HC1 (400 mL) and brine (400 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (0-100percent EtOAc/hexane) to give the title compound (4 g, 17.8 percent); 1H NMR (400 MHz, CDCl3-d): delta 1.16 - 1.35 (m, 18 H), 2.20 - 2.30 (m, 2 H), 2.42 (d, J=15.44 Hz, 2 H), 3.46 (t, J=5.73 Hz, 1 H), 3.63 (t, J=5.51 Hz, 1 H), 3.97 (q, J=2.65 Hz, 1 H), 4.12 (q, J=2.65 Hz, 1 H), 5.27 (d, J=12.35 Hz, 1 H), 6.35 - 6.54 (m, 1 H).

Reference： [1]Patent: WO2016/168641,2016,A1 .Location in patent: Page/Page column 206

24
[ 625-08-1 ]
[ 1121057-75-7 ]
3-methoxy-3-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)butan-1-one [ No CAS ]

Reference： [1]Patent: WO2016/168641,2016,A1

25
[ 6226-25-1 ]
[ 1121057-75-7 ]
[ 1219931-41-5 ]

Yield	Reaction Conditions	Operation in experiment
51%	Stage #1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloric acid With triethylamine In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: 2,2,2-trifluoroethyl trifluoromethanesulphonate In tetrahydrofuran at 20℃; for 16h;	12 Step 2: 4-(4,4,5,5-Tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-(2,2,2- trifluoroethyl)-1,2,3,6-tetrahydropyridine (12-2): To a stirred solution of 12-1 (500 mg,2.040 mmol) in THF (5 mL) was added TEA (1.4 mL, 10.2 mmol). After being stirred at rt for 10 mi 2,2,2-trifluoroethyl trifluoromethane sulfonate (473 mg, 2.040 mmol) was added and stirred at ft for 16h. The mixture was poured into a sat’d NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 12-2 (300 mg, 51%) which was used in the next step without further purification. GCMS: 291.1 [M]

Reference： [1]Current Patent Assignee: RECURIUM IP HOLDINGS LLC - WO2018/67512, 2018, A1 Location in patent: Paragraph 0286

26
[ 1121057-75-7 ]
1-(5-{3-[1-(1,4-dioxane-2-ylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-5-methylphenoxy}-4-methyl-2,3-dihydro-1H-indole-1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone [ No CAS ]

Reference： [1]Patent: JP2016/128387,2016,A

27
[ 1121057-75-7 ]
1-(5-{3-[1-(1,4-dioxane-2-ylcarbonyl)piperidine-4-yl]-5-methylphenoxy}-4-methyl-2,3-dihydro-1H-indole-1-yl)-2-[2-(methylsulfonyl)phenyl]ethanone [ No CAS ]

Reference： [1]Patent: JP2016/128387,2016,A

28
[ 89364-41-0 ]
[ 1121057-75-7 ]
1,4-dioxane-2-yl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl]methanone [ No CAS ]