1121057-75-7|4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride| Ambeed

Structure of 1121057-75-7

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Quality Control of [ 1121057-75-7 ] Purity: 95% SDS Specification

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Product Details of [ 1121057-75-7 ]

CAS No. :	1121057-75-7
Formula :	C₁₁H₂₁BClNO₂
M.W :	245.55
SMILES Code :	CC1(C)C(C)(C)OB(C2=CCNCC2)O1.[H]Cl
MDL No. :	MFCD11506076
InChI Key :	WNMYCAJTXUCHBQ-UHFFFAOYSA-N
Pubchem ID :	49761084

Safety of [ 1121057-75-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 1121057-75-7 ] Show Less

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 ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	30.49 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.83
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.96
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.07
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.01
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.17

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.45
Solubility	0.873 mg/ml ; 0.00355 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.09
Solubility	1.99 mg/ml ; 0.00812 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.68
Solubility	0.518 mg/ml ; 0.00211 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	Yes
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.5 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.57

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 1~2

1
[ 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
100%	With hydrogenchloride In 1,4-dioxane at 20℃; for 4 h;	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 3 h;	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) δ 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.
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]⁺.

References: [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.

2
[ 1121057-75-7 ]
[ 4023-34-1 ]
[ 1616388-38-5 ]

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

[ 1121057-75-7 ] Synthesis Path-Downstream 1~35

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

References: [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

References: [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]+.

References: [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

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

5
[ 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]+.

References: [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.

6
[ 1121057-75-7 ]
[ 1616388-07-8 ]

References: [1]Patent: WO2014/100620,2014,A2 .

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

References: [1]Patent: WO2014/100620,2014,A2 .

8
[ 1121057-75-7 ]
[ 1616385-59-1 ]

References: [1]Patent: WO2014/100620,2014,A2 .

9
[ 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.

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

10
[ 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.

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

11
[ 1121057-75-7 ]
[ 1616387-37-1 ]
[ 1616385-60-4 ]

References: [1]Patent: WO2014/100620,2014,A2 .

12
[ 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 ]

References: [1]Patent: US2015/225354,2015,A1 .

13
[ 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 ]

References: [1]Patent: US2015/225354,2015,A1 .

14
[ 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 ]

References: [1]Patent: US2015/225354,2015,A1 .

15
[ 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 ]

References: [1]Patent: US2015/225354,2015,A1 .

16
[ 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.

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

17
[ 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.

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

18
[ 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 ]

References: [1]Patent: US2015/225354,2015,A1 .

19
[ 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 ]

References: [1]Patent: US2015/225354,2015,A1 .

20
[ 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 ]

References: [1]Patent: US2015/225354,2015,A1 .

21
[ 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 ]

References: [1]Patent: US2015/225354,2015,A1 .

22
[ 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).

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

23
[ 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 ]

References: [1]Patent: WO2016/168641,2016,A1 .

24
[ 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 ]

References: [1]Patent: JP2016/128387,2016,A .

25
[ 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 ]

References: [1]Patent: JP2016/128387,2016,A .

26
[ 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 ]