[ CAS No. 1003845-06-4 ] {[proInfo.proName]}

Name: 1003845-06-4|2-Chloro-5-pyrimidineboronic acid|98%
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SKU: A110557
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Quality Control of [ 1003845-06-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1003845-06-4 ]

Product Details of [ 1003845-06-4 ]

CAS No. :	1003845-06-4	MDL No. :	MFCD08063113
Formula :	C₄H₄BClN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YTCIHPTZKKWKKC-UHFFFAOYSA-N
M.W :	158.35	Pubchem ID :	21747362
Synonyms :

Calculated chemistry of [ 1003845-06-4 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	36.87
TPSA :	66.24 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.22 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.07
Log Po/w (WLOGP) :	-1.19
Log Po/w (MLOGP) :	-1.57
Log Po/w (SILICOS-IT) :	-0.83
Consensus Log Po/w :	-0.7

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.24
Solubility :	9.03 mg/ml ; 0.057 mol/l
Class :	Very soluble
Log S (Ali) :	-1.01
Solubility :	15.3 mg/ml ; 0.0966 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.15
Solubility :	11.3 mg/ml ; 0.0713 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.08

Safety of [ 1003845-06-4 ]

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 [ 1003845-06-4 ]

* 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 [ 1003845-06-4 ]
Downstream synthetic route of [ 1003845-06-4 ]

[ 1003845-06-4 ] Synthesis Path-Upstream 1~6

1
[ 1003845-06-4 ]
[ 22536-67-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-chloro-succinimide; copper(l) chloride In acetonitrile at 80℃; for 16 h;	Step 2: Synthesis of 2,5-dichloropyrimidine To a stirred solution of 2-chloropyrimidin-5-yl-5-boronic acid (0.5 g, 3.164 mmol) and CuCl (0.569 g, 6.329 mmol) in MeCN (20 mL) was added N-Chloro succinimide (0.084 g, 6.329 mmol) and heated at 80° C. for 16 h. Completion of reaction was monitored by TLC. Reaction was quenched with sat. Soln. Of NaHCO₃ up to pH-8 and extracted with Diethyl ether. The organic layer was washed with water, brine, dried over Na₂SO₄, evaporated under reduced pressure to give 2,5-dichloropyrimidine (0.2 g, 75percent) as light yellow solid. MS: 148.9 [M⁺+1]

Reference： [1] Patent: US2017/291910, 2017, A1, . Location in patent: Paragraph 0511-0513

2
[ 1003845-06-4 ]
[ 4983-28-2 ]

Reference： [1] Patent: WO2011/84402, 2011, A1, . Location in patent: Page/Page column 153-154

3
[ 110-91-8 ]
[ 1003845-06-4 ]
[ 870521-33-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine In ethanol at 20℃; for 1 h;	2-Chloropyrimidin-5-ylboronic acid (1 g, 6.32 mmol), morpholine (2.19 mL,25.26 mmol) and triethylamine (0.88 mL, 6.32 mmol) were stirred in ethanol (25 mL) at20°C for 1 h. Water (50 mL) was slowly added to the reaction mixture. The resultingprecipitate was filtered and washed with water to afford the title compound (950 mg,70percent) as a cream solid. H (250 MHz, DMSO-d6) 8.63 (s, 2H), 8.05 (s, 2H), 3.68 (ddd, J23.4, 5.7, 3.9 Hz, 8H).
70%	With triethylamine In ethanol at 20℃; for 1 h;	A solution of (2-chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol), morpholine (2.19 mL, 25.26 mmol) and triethylamine (0.9 mL, 6.32 mmol) in ethanol (25 mL) was stirred at 20°C for 1 h. Water (50 mL) was slowly added to the reaction mixture to form a precipitate that was collected by filtration, to afford the title compound (950 mg, 70percent) ascream solid. H (250 MHz, DMSO-d6) 8.63 (s, 2H), 8.05 (s, 2H), 3.68 (ddd, J23.4, 5.7,3.9 Hz, 8H). LCMS m/z 210 [M+H].
70%	With triethylamine In ethanol at 20℃; for 1 h; Inert atmosphere	A solution of (2-chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol), morpholine (2.19 mL, 25.26 mmol) and triethylamine (0.9 mL, 6.32 mmol) in ethanol (25 mL) was stirred at 20°C for 1 h. Water (50 mL) was slowly added to the reaction mixture to form a precipitate that was collected by filtration, to afford the title compound as a cream solid (950 mg, 70percent). δΗ (250 MHz, DMSO-d₆) 8.63 (s, 2H), 8.05 (s, 2H), 3.68 (ddd, J23.4, 5.7, 3.9 Hz, 8H). LCMS(ES⁺) 210 (M+H)⁺.

70%	With triethylamine In ethanol at 20℃; for 1 h;	A solution of (2-chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol), morpholine (2.19 mL, 25.26 mmol) and triethylamine (0.9 mL, 6.32 mmol) in ethanol (25 mL) was stirred at 20°C for 1 h. Water (50 mL) was slowly added to the reaction mixture to form a precipitate that was collected by filtration, to afford the title compound as a cream solid (950 mg, 70percent). δΗ (250 MHz, DMSO-d₆) 8.63 (s, 2H), 8.05 (s, 2H), 3.68 (ddd, J23.4, 5.7, 3.9 Hz, 8H). LCMS(ES⁺) 210.0 (M+H)⁺.
70%	With triethylamine In ethanol at 20℃; for 1 h;	A solution of(2-chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol), morpholine (2.19 mL, 25.26 mmol) and triethylamine (0.9 mL, 6.32 mmol) in ethanol (25 mL) was stirred at 20°C for 1 h. Water (50 mL) was slowly added to the reaction mixture to form a precipitate that was collected by filtration, to afford the title compound as a cream solid(950 mg, 70percent). oH (250 MHz, DMSO-d6) 8.63 (s, 2H), 8.05 (s, 2H), 3.68 (ddd, J23.4, 5.7, 3.9 Hz, 8H). LCMS(ES) 210 (M+H).
68%	With triethylamine In ethanol at 80℃; for 5 h;	A mixture of 2-chloropyrimidin-5-ylboronic acid (3 g, 19.0 mmol), morpholine (1.66 mL, 19 mmol) and triethylamine (1.67 mL, 19.19 mmol) in EtOH (20 mL) was stirred at 80°C for 5 h. LCMS indicated completion of the reaction. The reaction mixturewas concentrated in vacuo and the residue was taken up in ethanol (approximately 5 mL). Diethyl ether was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off, washed with the minimum amount of water and dried bysuction, to give the title compound (2.7 g, 68percent) as an off-white solid. oH (DMSO-d6)8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ES+) 210 (M+H), RT0.15 minutes.
68%	With triethylamine In ethanol at 80℃; for 5 h;	A mixture of 2-chloropyrimidin-5-ylboronic acid (3 g, 19.0 mmol), morpholine (1.66 mL, 19.0 mmol) and triethylamine (1.67 mL, 19.2 mmol) in EtOH (20 mL) wasstirred at 80°C for 5 h. The reaction mixture was concentrated in vacuo and the residue was taken up in Et20 (approximately 5 mL). Et20 was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off, washed with the minimum amount of water and dried by suction, to give the title compound (2.7 g, 68percent) as an off-white solid. oH (DMSO-d6) 8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ESj 210 (M+H), RT 0.15 minutes.
68%	With triethylamine In ethanol at 80℃; for 5 h;	INTERMEDIATE 4 2-(Morpholin-4-yl)pyrimidin-5 -ylboronic acidA mixture of 2-chloropyrimidin-5-ylboronic acid (3.0 g, 19.0 mmol), morpholine (1.66 mL, 19.0 mmol) and triethylamine (1.67 mL, 19.2 mmol) in EtOH (20 mL) was stirred at 80°C for 5 h. The reaction mixture was concentrated in vacuo and the residue was taken up in Et20 (approximately 5 mL). Et20 was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off,washed with the minimum amount of water and dried by suction, to give the title compound (2.7 g, 68percent) as an off-white solid. H (400 MHz, DMSO-d6) 8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ESj 210 (M+H), RT 0.15 minutes.
68%	With triethylamine In ethanol at 80℃; for 5 h;	INTERMEDIATE 5 2- (Morpholin-4- yl)p yrimidin- 5 - ylboronic acid A mixture of 2-chloropyrimidin-5-ylboronic acid (3 g, 19.0 mmol), morpholine (1.66 mL, 19.0 mmol) and triethylamine (1.67 mL, 19.2 mmol) in EtOH (20 mL) was stirred at 80°C for 5 h. The reaction mixture was concentrated in vacuo and the residue was taken up in Et₂0 (approximately 5 mL). Et₂0 was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off, washed with the minimum amount of water and dried by suction, to give the title compound (2.7 g, 68percent) as an off-white solid. δ_Η (DMSO-d₆) 8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ES⁺) 210 (M+H)⁺, RT 0.15 minutes.
68%	With triethylamine In ethanol at 80℃; for 5 h;	INTERMEDIATE 3 2-(Morpholin-4-yl)pyrimidin-5 -ylboronic acid A mixture of 2-chloropyrimidin-5 -ylboronic acid (3.0 g, 19.0 mmol), morpholine (1.66 mL, 19.0 mmol) and triethylamine (1.67 mL, 19.2 mmol) in EtOH (20 mL) was stirred at 80°C for 5 h. The reaction mixture was concentrated in vacuo and the residue was taken up in Et₂0 (approximately 5 mL). Et₂0 was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off, washed with the minimum amount of water and dried by suction, to give the title compound (2.7 g, 68percent) as an off-white solid. δ_Η (400 MHz, DMSO-dg) 8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ES⁺) 210 (M+H)⁺, RT 0.15 minutes.

Reference： [1] Patent: WO2015/86506, 2015, A1, . Location in patent: Page/Page column 131
[2] Patent: WO2015/86512, 2015, A1, . Location in patent: Page/Page column 102
[3] Patent: WO2015/86527, 2015, A1, . Location in patent: Page/Page column 114; 115
[4] Patent: WO2015/86526, 2015, A1, . Location in patent: Page/Page column 147
[5] Patent: WO2015/86525, 2015, A1, . Location in patent: Page/Page column 121; 122
[6] Patent: WO2014/9295, 2014, A1, . Location in patent: Page/Page column 128; 129
[7] Patent: WO2015/86502, 2015, A1, . Location in patent: Page/Page column 82; 83
[8] Patent: WO2015/86511, 2015, A1, . Location in patent: Page/Page column 74; 75
[9] Patent: WO2015/86501, 2015, A1, . Location in patent: Page/Page column 89
[10] Patent: WO2015/86496, 2015, A1, . Location in patent: Page/Page column 74

4
[ 5419-55-6 ]
[ 32779-36-5 ]
[ 1003845-06-4 ]

Yield	Reaction Conditions	Operation in experiment
73.3%	With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 4 h;	Step 1: Synthesis of 2-chloropyrimidin-5-yl-5-boronic acid To a stirred solution of 5-bromo-2-chloropyrimidine (1.0 g, 5.170 mmol) in mixture of THF:Toluene (25 mL, 4:1) was added n-BuLi (1.6M in Hexane) (3.87 mL, 5.61 mmol) dropwise at -78° C. And allowed to stir at -78° C. for 4 h. On completion, Reaction mass diluted with water and stirred at RT for 1 h, extracted with Diethyl ether. Then acidify using 1N HCl up to pH 2-3and extracted with EtOAc. Organic portions were combined, dried over Na₂SO₄, evaporated under reduced pressure to give 2-chloropyrimidin-5-yl-5-boronic acid (0.6 g, 73.3percent) as white solid. MS: 159.3[M⁺+1]
51%	With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1.75 h;	34). Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine; To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 ml.) in toluene (16 ml) and THF (4 mi_) is added n-buty. lithium \\r, hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78 ⁰C over 45 min and stirred at -78 ⁰C for 1 hour. The mixture is warmed to -20 ⁰C, then added aq. hydrogen chloride (1M, 20 mL). The mixture is warmed to room temperature. The precipitate is collected and washed with hexane to give a colorless powder (808 mg, 51percent). A mixture of the powder (3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO₄ (18.15 mmol, 2.2 g) in toluene (10 mL) is <n="192"/>stirred at room temperature for 15 hour. The mixture is filtrated and the solution is concentrated under reduced pressure. The resultant solid is washed with water to give 2- chloro-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrimidine (875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol]\\ Retention time 1.75 min (condition A).

Reference： [1] Patent: US2017/291910, 2017, A1, . Location in patent: Paragraph 0508-0510
[2] Patent: WO2008/9435, 2008, A1, . Location in patent: Page/Page column 189-190
[3] Patent: WO2011/84402, 2011, A1, . Location in patent: Page/Page column 153

5
[ 32779-36-5 ]
[ 1003845-06-4 ]

Yield	Reaction Conditions	Operation in experiment
51%	Stage #1: With n-butyllithium; Triisopropyl borate In tetrahydrofuran; hexane; toluene at -78 - -20℃; for 1.75 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran; hexane; toluene at -20℃;	Example 14; 1) Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 mL) in toluene (16 mL) and THF (4 mL) is added n-butyl lithium in hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78° C. over 45 min and stirred at -78° C. for 1 hour. The mixture is warmed to -20° C., then added aqueous 1 M HCl (20 mL). The mixture is warmed to room temperature. The precipitate is collected and washed with hexane to give a colorless powder (808 mg, 51percent). A mixture of the powder (3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO4 (18.15 mmol, 2.2 g) in toluene (10 mL) is stirred at room temperature for 15 hour. The mixture is filtrated and the solution is concentrated under reduced pressure. The resultant solid is washed with water to give 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol]+, Retention time 1.75 min (condition A).

Reference： [1] Applied Organometallic Chemistry, 2012, vol. 26, # 7, p. 330 - 334
[2] Patent: US2009/118287, 2009, A1, . Location in patent: Page/Page column 67-68
[3] Patent: US2009/136473, 2009, A1, . Location in patent: Page/Page column 37

6
[ 76-09-5 ]
[ 1003845-06-4 ]
[ 1003845-08-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With magnesium sulfate In toluene at 20℃; for 15 h;	34). Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine; To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 ml.) in toluene (16 ml) and THF (4 mi_) is added n-buty. lithium \\r, hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78 ⁰C over 45 min and stirred at -78 ⁰C for 1 hour. The mixture is warmed to -20 ⁰C, then added aq. hydrogen chloride (1M, 20 mL). The mixture is warmed to room temperature. The precipitate is collected and washed with hexane to give a colorless powder (808 mg, 51percent). A mixture of the powder (3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO₄ (18.15 mmol, 2.2 g) in toluene (10 mL) is <n="192"/>stirred at room temperature for 15 hour. The mixture is filtrated and the solution is concentrated under reduced pressure. The resultant solid is washed with water to give 2- chloro-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrimidine (875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol]\\ Retention time 1.75 min (condition A).
100%	With magnesium sulfate In toluene at 20℃; for 15 h;	Example 14; 1) Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 mL) in toluene (16 mL) and THF (4 mL) is added n-butyl lithium in hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78° C. over 45 min and stirred at -78° C. for 1 hour. The mixture is warmed to -20° C., then added aqueous 1 M HCl (20 mL). The mixture is warmed to room temperature. The precipitate is collected and washed with hexane to give a colorless powder (808 mg, 51percent). A mixture of the powder (3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO4 (18.15 mmol, 2.2 g) in toluene (10 mL) is stirred at room temperature for 15 hour. The mixture is filtrated and the solution is concentrated under reduced pressure. The resultant solid is washed with water to give 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol]+, Retention time 1.75 min (condition A).

Reference： [1] Patent: WO2008/9435, 2008, A1, . Location in patent: Page/Page column 189-190
[2] Patent: US2009/118287, 2009, A1, . Location in patent: Page/Page column 67-68

[ 1003845-06-4 ] Synthesis Path-Downstream 1~88

1
[ 5419-55-6 ]
[ 32779-36-5 ]
[ 1003845-06-4 ]

Yield	Reaction Conditions	Operation in experiment
73.3%	With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane; toluene; at -78℃; for 4h;	Step 1: Synthesis of 2-chloropyrimidin-5-yl-5-boronic acid To a stirred solution of 5-bromo-2-chloropyrimidine (1.0 g, 5.170 mmol) in mixture of THF:Toluene (25 mL, 4:1) was added n-BuLi (1.6M in Hexane) (3.87 mL, 5.61 mmol) dropwise at -78 C. And allowed to stir at -78 C. for 4 h. On completion, Reaction mass diluted with water and stirred at RT for 1 h, extracted with Diethyl ether. Then acidify using 1N HCl up to pH 2-3and extracted with EtOAc. Organic portions were combined, dried over Na2SO4, evaporated under reduced pressure to give 2-chloropyrimidin-5-yl-5-boronic acid (0.6 g, 73.3%) as white solid. MS: 159.3[M++1]
51%	With n-butyllithium; In tetrahydrofuran; hexane; toluene; at -78℃; for 1.75h;	34). Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine; To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 ml.) in toluene (16 ml) and THF (4 mi_) is added n-buty. lithium r, hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78 0C over 45 min and stirred at -78 0C for 1 hour. The mixture is warmed to -20 0C, then added aq. hydrogen chloride (1M, 20 mL). The mixture is warmed to room temperature. The precipitate is collected and washed with hexane to give a colorless powder (808 mg, 51%). A mixture of the powder (3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO4 (18.15 mmol, 2.2 g) in toluene (10 mL) is <n="192"/>stirred at room temperature for 15 hour. The mixture is filtrated and the solution is concentrated under reduced pressure. The resultant solid is washed with water to give 2- chloro-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrimidine (875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol] Retention time 1.75 min (condition A).
		chloropyrimidine (200 g, 1034 mmol). THF (900 mL) and toluene (900 mL) were added, followed by triisopropyl borate (294 mL, 1241 mmol). The solution was cooled using a dry ice/acetone bath to -70C. n-Butyl lithium (496 mL, 1241 mmol) was added dropwise via addition funnel over 1.5 hrs, maintaining the internal temperature at -69C to -71C, forming- a clear yellow solution. The reaction mixture was warmed slowly to -45 C for lh-2h, giving a red solution. The reaction was quenched slowly with saturated NH4CI (700 mL) at -5C or below, resulting in significant precipitate formation. Water (500 mL) was added to dissolve the white solid. The aqueous phase was separated and acidified with 2 N HCl (~ 700 mL) to pH' ~1.EtOAc (1.5 L) was added and the biphasic mixture was stirred at r.t. to dissolve all the solid. The aqueous phase was extracted with further portions of EtOAc (2x500 mL). NaCl was added to the aqueous phase until no more would dissolve, then extracted with THF (2 x 500 mL). All the organic phases were combined and dried over MgS0 , filtered and concentrated to obtain (2- chloropyrimidin-5-yl)boronic acid as an orange solid

Reference： [1]Patent: US2017/291910,2017,A1 .Location in patent: Paragraph 0508-0510
[2]Patent: WO2008/9435,2008,A1 .Location in patent: Page/Page column 189-190
[3]Patent: WO2011/84402,2011,A1 .Location in patent: Page/Page column 153

2
[ 76-09-5 ]
[ 1003845-06-4 ]
[ 1003845-08-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With magnesium sulfate; In toluene; at 20℃; for 15h;	34). Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine; To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 ml.) in toluene (16 ml) and THF (4 mi_) is added n-buty. lithium r, hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78 0C over 45 min and stirred at -78 0C for 1 hour. The mixture is warmed to -20 0C, then added aq. hydrogen chloride (1M, 20 mL). The mixture is warmed to room temperature. The precipitate is collected and washed with hexane to give a colorless powder (808 mg, 51%). A mixture of the powder (3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO4 (18.15 mmol, 2.2 g) in toluene (10 mL) is <n="192"/>stirred at room temperature for 15 hour. The mixture is filtrated and the solution is concentrated under reduced pressure. The resultant solid is washed with water to give 2- chloro-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrimidine (875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol] Retention time 1.75 min (condition A).
100%	With magnesium sulfate; In toluene; at 20℃; for 15h;	Example 14; 1) Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 mL) in toluene (16 mL) and THF (4 mL) is added n-butyl lithium in hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78 C. over 45 min and stirred at -78 C. for 1 hour. The mixture is warmed to -20 C., then added aqueous 1 M HCl (20 mL). The mixture is warmed to room temperature. The precipitate is collected and washed with hexane to give a colorless powder (808 mg, 51%). A mixture of the powder (3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO4 (18.15 mmol, 2.2 g) in toluene (10 mL) is stirred at room temperature for 15 hour. The mixture is filtrated and the solution is concentrated under reduced pressure. The resultant solid is washed with water to give 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol]+, Retention time 1.75 min (condition A).

Reference： [1]Patent: WO2008/9435,2008,A1 .Location in patent: Page/Page column 189-190
[2]Patent: US2009/118287,2009,A1 .Location in patent: Page/Page column 67-68

3
[ 7752-82-1 ]
[ 1003845-06-4 ]
[ 1004972-12-6 ]

Reference： [1]European Journal of Organic Chemistry,2007,p. 5712 - 5716

4
[ 5332-24-1 ]
[ 1003845-06-4 ]
[ 1004972-10-4 ]

Reference： [1]European Journal of Organic Chemistry,2007,p. 5712 - 5716

5
C₁₀H₁₆BClN₂O₂ [ No CAS ]
[ 1003845-06-4 ]

Reference： [1]European Journal of Organic Chemistry,2007,p. 5712 - 5716
[2]Organic Process Research and Development,2007,vol. 11,p. 237 - 240

6
[ 32779-36-5 ]
[ 1003845-06-4 ]

Yield	Reaction Conditions	Operation in experiment
51%		Example 14; 1) Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 mL) in toluene (16 mL) and THF (4 mL) is added n-butyl lithium in hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78 C. over 45 min and stirred at -78 C. for 1 hour. The mixture is warmed to -20 C., then added aqueous 1 M HCl (20 mL). The mixture is warmed to room temperature. The precipitate is collected and washed with hexane to give a colorless powder (808 mg, 51%). A mixture of the powder (3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO4 (18.15 mmol, 2.2 g) in toluene (10 mL) is stirred at room temperature for 15 hour. The mixture is filtrated and the solution is concentrated under reduced pressure. The resultant solid is washed with water to give 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol]+, Retention time 1.75 min (condition A).
		Synthesis of 2-chloro-pyrimidine-5-boronic acid A 200 mL round bottom was charged under nitrogen with 5-bromo-2-chloro pyrimidine (30 mmol, 5.79 g), toluene (48 mL), THF (12 mL) and triisopropyl borate (36 mmol, 8.4 mL). The mixture was stirred at -70 C. and n-butyl lithium (2.5M in hexane, 36 mmol, 14.4 mL) was added slowly (1.5 h period). After 2 h of stirring at -70 C., the reaction was warmed to -20 C. before 2N HCl (30 mL) was added. Upon the HCl addition the reaction mixture turned from a pale homogeneous solution to a white bi-phasic solution. When the mixture reached rt, it was transferred to a reparatory funnel and the layers were separated. The aqueous layer was neutralized to PH=7 with 1N NaOH followed by extractions with THF (3*150 mL). The combined organic layers were dried over NA2SO4 and concentrated. The crude was dissolved in THF (5 mL) and ether (100 mL) was added. A yellow solid precipitated out. The solid was collected and dried to give Int-28 (3.79 g) as a pale yellow solid.

Reference： [1]Applied Organometallic Chemistry,2012,vol. 26,p. 330 - 334
[2]Patent: US2009/118287,2009,A1 .Location in patent: Page/Page column 67-68
[3]Patent: US2009/136473,2009,A1 .Location in patent: Page/Page column 37

7
[ 1003845-06-4 ]
[ 1155877-85-2 ]
[ 1155877-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 85℃;	Int-20 (2.5 mmol, 824 mg) and Int-28 (2.5 mmol, 400 mg) were dissolved in toluene (10 mL) and ethanol (2.5 mL). Pd (PPh3)4 (144 mg, 0.125 mmol) was added followed by Na2CO3 in water (2M, 5 mL, 2.5 mmol). The reaction mixture was heated overnight at 85 C. The resultant mixture was diluted with EtOAc (25 mL), washed with water and brine, and then dried over Na2SO4. The organic solution was filtered and concentrated under reduced pressure. The crude was purified by silica gel (40 g) column (½ inch diameter) chromatography, eluted with Hexane/EtOAc (9:1) gave the title compound (297.4 mg) as a pale yellow solid.

Reference： [1]Patent: US2009/136473,2009,A1 .Location in patent: Page/Page column 37

8
[ 1003845-06-4 ]
[ 1200400-56-1 ]
[ 1202190-99-5 ]

Yield	Reaction Conditions	Operation in experiment
2%	With pyridine;copper diacetate; In dichloromethane; at 20℃; for 24h;	0.515 g (3 mmol) of copper(II) acetate and 0.306 ml (4 mmol) of pyridine were added to 0.5 g (2 mmol) of methyl[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]acetate in 10 ml of dichloromethane. 0.598 g (4 mmol) of <strong>[1003845-06-4]2-chloropyrimidine-5-boronic acid</strong> was then added, and the mixture was stirred at 20 C. for 24 h. The mixture was then added to 1 M HCl and extracted with dichloromethane. The combined organic phases were dried with magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC. This gave 0.015 g of product (2% of theory).NMR (CDCl3, 400 MHz): 2.34 (s, 3H); 3.39 (s, 2H); 3.71 (s, 3H); 7.2 (d, 2H); 7.45 (d, 2H); 8.52 (s, 2H).

Reference： [1]Patent: US2010/160164,2010,A1 .Location in patent: Page/Page column 33; 34

9
1,3-dibromo-5-butoxylbenzene [ No CAS ]
[ 1003845-06-4 ]
5,5'-(5-butoxy-1,3-phenylene)bis(2-chloropyrimidine) [ No CAS ]

Reference： [1]Applied Organometallic Chemistry,2012,vol. 26,p. 330 - 334

10
1,3-dibromo-5-butoxylbenzene [ No CAS ]
[ 1003845-06-4 ]
C₁₄H₁₄BrClN₂O [ No CAS ]
5,5'-(5-butoxy-1,3-phenylene)bis(2-chloropyrimidine) [ No CAS ]

Reference： [1]Applied Organometallic Chemistry,2012,vol. 26,p. 330 - 334
[2]Applied Organometallic Chemistry,2012,vol. 26,p. 330 - 334

11
[ 1003845-06-4 ]
[ 4983-28-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium perborate tetrahydrate; In tetrahydrofuran; water; at 20℃; for 18h;	A 2.0 L round bottom flask was charged with <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (40.0 g, 253 mmol), THF (440 mL) and water (440 mL). Solid sodium perborate tetrahydrate (1 17 g, 758 mmol) was added in one portion and the resulting suspension stirred at r.t. for 18 hours. Note: after 10 minutes of solid sodium perborate tetrahydrate addition a small exotherm occurred, from 28°C to 34°C over 30min. The reaction was quenched with saturated NH4CI (250 mL) and EtOAc (250 mL) was added. A 10percent solution of sodium bisulfite (1 L) was added to the mixture portionwise at 0°C until no more peroxide was detected by I-starch paper. (Note: Exotherm occurred during sodium bisulfite addition). The aqueous phase was separated and extracted-with further portions of EtOAc (2 x250 mL). Solid NaCl was added to the aqueous phase until no-more dissolved then extracted with THF (2 x 250 mL). All the organic phases were combined and dried-over MgS04, filtered and concentrated to obtain a yellow solid. The product-solid was suspended in toluene heptane (1 :1 ratio^ 800 mL) and the mixture heated to 50°C The mixture was cooled to r.t. and the solid collected by filtration and washed with toluene/heptane (1 : 1 ratio, 250 mL) followed by heptane (150 mL). The product solid was suspended in 15percent toluene/DCM (100 mL) at r.t., filtered and washed twice with toluene/DCM (1 : 1 ratio, x50 mL) then with 100percent DCM (100 mL) to give 2-chloropyrimidin-5-ol.

Reference： [1]Patent: WO2011/84402,2011,A1 .Location in patent: Page/Page column 153-154

12
[ 1003845-06-4 ]
[ 1722-12-9 ]

Reference： [1]Organic Process Research and Development,2007,vol. 11,p. 237 - 240

13
[ 5625-67-2 ]
[ 1003845-06-4 ]
[ 1536391-89-5 ]

Yield	Reaction Conditions	Operation in experiment
30%	In 1,4-dioxane; at 100℃; for 0.75h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (1.0 g, 6.32 mmol) and piperazin-2-one (1.6mmol) were suspended in 1,4-dioxane (10 mL) and the mixture was heated atunder microwave irradiation for 45 minutes. The supernatant liquid was decantedthe suspension and the residue was triturated with methanol and diethyl ether. The resultant solids were filtered off and dried under vacuum to afford the title compoundmg, 30%) as a pale pink solid. Method B HPLC-MS: MH+ m/z 223, RT 0.25
30%	In 1,4-dioxane; at 100℃; for 0.75h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (1.0 g, 6.32 mmol) and piperazin-2-one (1.6 g, 16.0 mmol) were suspended in 1,4-dioxane (10 mL) and the mixture was heated at 100C under microwave irradiation for 45 minutes. The supernatant liquid was decanted from the suspension and the residue was triturated with methanol and diethyl ether. The resultant solids were filtered off and dried under vacuum to afford the title compound (706 mg, 30%) as a pale pink solid. LCMS: MH+ 223
30%	In 1,4-dioxane; at 100℃; for 0.75h;Microwave irradiation;	2-Chloropyrimidin-5-ylboronic acid (1.0 g, 6.32 mmol) and piperazin-2-one (1.6 g, 16.0 mmol) were suspended in 1,4-dioxane (10 mL) and the mixture was heated at 100C under microwave irradiation for 45 minutes. The supernatant liquid was decantedfrom the suspension and the residue was triturated with MeOH and Et20. The resultant solids were filtered off and dried under vacuum to afford the title compound (706 mg, 30%) as a pale pink solid. LCMS: MH+ 223.

30%	In 1,4-dioxane; at 100℃; for 0.75h;Microwave irradiation;	2-Chloropyrimidin-5-ylboronic acid (1.0 g, 6.32 mmol) and piperazin-2-one (1.6 g, 16.0 mmol) were suspended in 1,4-dioxane (10 mL) and the mixture was heated at100C under microwave irradiation for 45 minutes. The supernatant liquid was decanted from the suspension and the residue was triturated with MeOH and Et20. The resultant solids were filtered off and dried under vacuum to afford the title compound (706 mg, 30%) as a pale pink solid. LCMS: MH+ 223.
30%	In 1,4-dioxane; at 100℃; for 0.75h;Microwave irradiation;	INTERMEDIATE 7 r2-(3-Oxopiperazin-l-yl)pyrimidin-5-yllboronic acid 2-Chloropyrimidin-5-ylboronic acid (1.0 g, 6.32 mmol) and piperazin-2-one (1.6 g, 16.0 mmol) were suspended in 1,4-dioxane (10 mL) and the mixture was heated at 100C under microwave irradiation for 45 minutes. The supernatant liquid was decanted from the suspension and the residue was triturated with MeOH and Et20. The resultant solids were filtered off and dried under vacuum to afford the title compound (706 mg, 30%) as a pale pink solid. LCMS (ES+) 223 (M+H)+.
30%	In 1,4-dioxane; at 100℃; for 0.75h;Microwave irradiation;	INTERMEDIATE 5[2-(3 -Oxopiperazin- 1 -yl)pyrimidin-5 -yllboronic acid2-Chloropyrimidin-5-ylboronic acid (1.0 g, 6.32 mmol) and piperazin-2-one (1.6 g, 16.0 mmol) were suspended in 1,4-dioxane (10 mL) and the mixture was heated at 100C under microwave irradiation for 45 minutes. The supernatant liquid was decanted from the suspension and the residue was triturated with MeOH and Et20. The resultant solids were filtered off and dried under vacuum to afford the title compound (706 mg, 30%) as a pale pink solid. LCMS: (M+H)+ 223.
30%	In 1,4-dioxane; at 100℃; for 0.75h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (1.0 g, 6.32 mmol) and piperazin-2-one (1.6 g, 16.0 mmol) were suspended in 1,4-dioxane (10 mL) and the mixture was heated at 100 C. under microwave irradiation for 45 minutes. The supernatant liquid was decanted from the suspension and the residue was triturated with methanol and diethyl ether. The resultant solids were filtered off and dried under vacuum to afford the title compound (706 mg, 30%) as a pale pink solid. LCMS: MH+223.
	In 1,4-dioxane; at 100℃; for 0.75h;Microwave irradiation;	To the <strong>[1003845-06-4]2-chloropyrimidine-5-boronic acid</strong> (2.00 g, 12.6 mmol) in 1,4-dioxane ( 15 mL) was added piperazin-2-one (1.26 g, 12.6 mmol). The mixture was heated in a microwave for about 45 min at about 100 C. The mixture was evaporated to dryness to give the crude title compound (2.8 g, 100%); LC/MS (Table 1, Method d) R, = 0.1 1 min; MS m/z: 223 (M+ H)+

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 142
[2]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 91; 128
[3]Patent: WO2015/86508,2015,A1 .Location in patent: Page/Page column 75
[4]Patent: WO2015/86502,2015,A1 .Location in patent: Page/Page column 83
[5]Patent: WO2015/86501,2015,A1 .Location in patent: Page/Page column 90
[6]Patent: WO2015/86496,2015,A1 .Location in patent: Page/Page column 75
[7]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0472
[8]Patent: WO2016/168641,2016,A1 .Location in patent: Page/Page column 143

14
[ 34376-54-0 ]
[ 1003845-06-4 ]
[ 1536391-92-0 ]

Yield	Reaction Conditions	Operation in experiment
145 mg	In 1,4-dioxane; at 100℃; for 0.75h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (200 mg, 1.26 mmol) and 1 ,4-diazepan-5-(288.34 mg, 2.53 mmol) were suspended in 1,4-dioxane (3 mL) and the mixtureat 100C under microwave irradiation for 45 minutes. The resulting slurryconcentrated under vacuum and triturated with MeOH to afford the title compound30%) as a cream precipitate, which was used without further purification. MethodHPLC-MS: MH+ m/z 237, RT 0.40 minutes.
	In 1,4-dioxane; at 100℃; for 0.75h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (200 mg, 1.26 mmol) and l,4-diazepan-5- one (288 mg, 2.53 mmol) were suspended in 1,4-dioxane (3 mL) and the mixture was heated at 100C under microwave irradiation for 45 minutes. The resulting slurry was concentrated under vacuum and triturated with MeOH to afford the title compound as a cream precipitate, which was used without further purification. LCMS: MH+ 237
	In 1,4-dioxane; at 100℃; for 0.75h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (200 mg, 1.26 mmol) and 1,4-diazepan-5-one (288 mg, 2.53 mmol) were suspended in 1,4-dioxane (3 mL) and the mixture was heated at 100 C. under microwave irradiation for 45 minutes. The resulting slurry was concentrated under vacuum and triturated with MeOH to afford the title compound as a cream precipitate, which was used without further purification. LCMS: MH+237.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 142
[2]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 91
[3]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0473

15
[ 1003845-06-4 ]
[ 176523-95-8 ]
[ 1536390-34-7 ]
[ 1536380-19-4 ]

Yield	Reaction Conditions	Operation in experiment
38%		(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol), ethyl 3-methyl- piperidine-3 -carboxylate hydrochloride (131 mg, 0.63 mmol) and triethylamine (0.18 mL, 1.26 mmol) were dissolved in ethanol (3 mL) and the mixture was heated at 90C in a sealed tube for 2 h. The mixture was cooled to room temperature and diluted with 1,4- dioxane (3 mL), then Intermediate 7 (232 mg, 0.63 mmol) and 2M aqueous potassium carbonate solution (0.93 mL) were added. The mixture was degassed with nitrogen, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-l-yl]iron-dichloropalladium-dichloro- methane complex (26 mg, 0.03 mmol) was added and the mixture was heated at 90C for 4 h. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method C) to afford the title compound (130 mg, 38%) as a sticky brown oil. deltaEta (500 MHz, CDC13) 8.36 (s, 2H), 7.73 (s, IH), 7.61 (d, J 9.2 Hz, IH), 7.26- 7.20 (m, 2H), 7.15 (d, J 8.1 Hz, IH), 7.06 (t, J 7.5 Hz, IH), 6.83 (d, J7.6 Hz, IH), 6.63 (t, J 73.7 Hz, IH), 4.54 (d, J 13.2 Hz, IH), 4.28 (s, 2H), 4.16-3.99 (m, 3H), 3.45 (ddd, J 12.9, 8.9, 3.7 Hz, IH), 3.35 (d, J 13.2 Hz, IH), 2.50 (s, 3H), 2.18 (dt, J 11.5, 4.8 Hz, IH), 1.67 (ddtt, J26.8, 13.3, 8.6, 4.2 Hz, 2H), 1.51 (ddd, J 13.5, 9.4, 4.3 Hz, IH), 1.21 (s, 3H), 1.15 (t, J7.1 Hz, 3H). Method D HPLC-MS: MH+ mlz 536, RT 2.78 minutes (100%).

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 282

16
[ 1003845-06-4 ]
[ 1536390-34-7 ]
[ 950725-13-0 ]
[ 1536381-65-3 ]

Yield	Reaction Conditions	Operation in experiment
2%		(2-Chloropyrimidin-5-yl)boronic acid (0.78 g, 4.93 mmol) and 5-(azetidin-3-yl)-2H-1,2,3,4-tetrazole (0.8 g, 4.93 mmol) were dissolved in DMF (12 mL) and K2C03 (4.08 g, 29.55 mmol) was added. The mixture was heated at 80C in a sealed tube for 2 h, after which time the reaction mixture was cooled to room temperature. To the mixture were added Intermediate 7 (0.3 g, 0.82 mmol), 2M aqueous K2C03 solution (2.5 mL) and 1,4-dioxane (9 mL). The mixture was degassed with nitrogen for 15 minutes, then tetrakis(triphenylphosphine) palladium(0) (0.14 g, 0.12 mmol) was added. The mixture was heated at 80C in a sealed tube for 16 h. Upon cooling to room temperature, the mixture was evaporated to dryness and the residue was purified by FCC, eluting with 0-100% MeOH in DCM. The material was further purified by preparative HPLC (Method D) toafford the title compound (7.7 mg, 2%) as a white solid. OH (500 MHz, CD3OD) 10.12 (s,2H), 9.97 (s, 1H), 9.33 (dd, J9.3, 1.5 Hz, 1H), 9.27 (d, J9.3 Hz, 1H), 8.93-8.85 (m, 1H),8.81-8.70 (m, 3H), 8.49 (t,J74.0 Hz, 1H), 6.19 (t,J8.7 Hz, 2H), 6.02 (s, 2H), 5.96 (dd,J8.4, 6.3 Hz, 2H), 5.93-5.85 (m, 1H), 4.04 (s, 3H). Method E HPLC-MS: MH+ m/z 490,RT 1.75 minutes.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 308

17
[ 1003845-06-4 ]
[ 1536390-34-7 ]
[ 1389264-36-1 ]
3-[5-(3-[2-(difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidin-2-yl]-3-azabicyclo[3.1.1]heptane-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol), methyl 3-azabicyclo- [3.1.1]heptane-6-carboxylate hydrochloride (100 mg, 0.52 mmol) and triethylamine (0.25 mL, 1.79 mmol) were dissolved in ethanol (5 mL) and stirred for 2 hat 80C in a sealedtube. To the mixture were added Intermediate 7 (170 mg, 0.46 mmol), 2M aqueous potassium carbonate solution (0.7 mL) and 1 ,4-dioxane (3 mL). The mixture was degassed with nitrogen, then bis [3 -(diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yl]iron dichloropalladium dichloromethane complex (40 mg, 0.05 mmol) was added. Themixture was heated at 80C in a sealed tube for 4 h. The mixture was diluted with ethyl acetate (20 mL), then washed with water (2 x 10 mL), followed by brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 0-10% methanol in DCM. The resulting material (250mg) was dissolved in 1:1 THF/water (4 mL), then 2M aqueous NaOH solution (0.5 mL) was added and the mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM (20 mL), then extracted with water (10 mL), followed by 2M aqueous potassium carbonate solution (10 mL). The combined aqueous layers were extracted with 1:1 isopropanol/chloroform (20 mL), then the organic layer was separated andconcentrated under vacuum. The residue was purified by chiral preparative SFC (Method A), eluting with methanol (+ 0.2% diethylamine) in carbon dioxide to afford the two stereoisomers of the title compound.Isomer A (12.8 mg, 5%) was obtained as a light brown solid. oH (500 MHz, DMSO-d6) 8.76 (s, 2H), 8.63 (s, 1H), 7.82 (d,J9.3 Hz, 1H), 7.75 (d,J9.3 Hz, 1H), 7.44-7.14 (m, 5H), 4.45 (s, 2H), 3.83 (q, J 11.7 Hz, 4H), 2.77 (d, J6.2 Hz, 2H), 2.55 (d, J5.7 Hz, 1H), 2.45 (d, J8.9 Hz, 1H), 2.37 (s, 3H), 1.39 (dd, J9.4, 5.9 Hz, 1H). SFC-MS:MH+ m/z 506, RT 16.42 minutes.Isomer B (44.8 mg, 18%) was obtained as a light brown solid. OH (500 MHz, DMSO-d6) 8.68 (s, 2H), 8.44 (s, 1H), 7.71 (d, J3.6 Hz, 1H), 7.68 (s, 1H), 7.45-7.12 (m,4H), 7.08 (d,J7.5 Hz, 1H), 4.38 (s, 2H), 4.22-4.18 (m, 1H), 4.10 (d,J11.8 Hz, 2H), 3.55 (d, J 11.9 Hz, 2H), 3.12 (t, J6.0 Hz, 1H), 2.74 (t, J5.8 Hz, 2H), 2.33 (s, 3H), 2.12-2.04

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 319; 320

18
[ 1003845-06-4 ]
[ 1111943-58-8 ]
[ 1536390-34-7 ]
[ 1536392-28-5 ]

Yield	Reaction Conditions	Operation in experiment
61%		(2-Chloropyrimidin-5-yl)boronic acid (194 mg, 1.23 mmol), methyl 3-methyl- pyrrolidine-3-carboxylate (234 mg, 1.63 mmol) and K2C03 (226 mg, 1.63 mmol) were stirred in N,N-dimethylformamide (4 mL) in a sealed tube at 80C for 1 h. Intermediate(300 mg, 0.82 mmol) in 1,4-dioxane (6 mL) was added and the mixture was degassed30 with nitrogen for 5 minutes. Degassed 2M aqueous potassium carbonate solution (1.3 mL) and bis [3 -(diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yl]iron dichloropalladium dichloromethane complex (34 mg, 0.04 mmol) were added and the mixture was heated at 80C for 3 h in a sealed tube under nitrogen. The mixture was diluted with water (10mL), extracted with EtOAc (3 x 20 mL), washed with brine (10 mL), dried over magnesium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with 0-2% ammonia/methanol in DCM, to afford the title compound (296 mg, 61%). oH (500 MHz, CDC13) 8.41 (s, 2H), 7.78 (s, 1H), 7.69 (d, J9.2 Hz, 1H), 7.32-5 7.29 (m, 1H), 7.28-7.25 (m, 1H), 7.19 (d,J8.1 Hz, 1H), 7.10 (t,J7.5 Hz, 1H), 6.88 (d,J6.9 Hz, 1H), 6.65 (t, J73.7 Hz, 1H), 4.32 (s, 2H), 4.10 (d, J 11.4 Hz, 1H), 3.73 (d, J9.7Hz, 5H), 3.51 (d, J 11.4 Hz, 1H), 2.55 (s, 3H), 2.52 (dd, J 13.1, 6.5 Hz, 1H), 2.00-1.94(m, 1H), 1.44 (s, 3H). Method C HPLC-MS: MH+ m/z 508, RT 1.12 minutes.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 149; 150

19
[ 1003845-06-4 ]
[ 1536390-34-7 ]
[ 746577-57-1 ]
[ 1536381-72-2 ]

Yield	Reaction Conditions	Operation in experiment
5%		(2-Chloropyrimidin-5 -yl)boronic acid (135 mg, 0.85 mmo 1), 5 -azaspiro [2.4]-heptane-1-carboxylic acid (100 mg, 0.71 mmol) and triethylamine (0.2 mL, 1.43 mmol)were dissolved in ethanol (5 mL), and the mixture was stirred for 2 h at 80C in a sealed tube. To the mixture were added Intermediate 7 (200 mg, 0.54 mmol), 2M aqueous K2C03 solution (0.8 mL) and 1,4-dioxane (3 mL). The mixture was degassed with nitrogen, then bis[3 -(diphenylphosphanyl)cyclopenta-2,4-dien- l-yl] iron dichloro5 palladium dichloromethane complex (40 mg, 0.05 mmol) was added. The mixture washeated at 80C in a sealed tube and allowed to stir for 18 h. Further Intermediate 7 (50 mg, 0.135 mmol) was added and the mixture was stirred for a further 16 h at 80C. The mixture was diluted with DCM (20 mL) and extracted with water (10 mL), followed by 2M aqueous potassium carbonate solution (10 mL). The combined aqueous layers wereextracted with 1:1 isopropanollchloroform (20 mL). The crude material was twice purified by preparative HPLC (Method D) to afford the title compound (12.8 mg, 5%). oH (500 MHz, CD3OD) 8.45 (s, 2H), 8.13 (s, 1H), 7.54 (d,J9.2 Hz, 1H), 7.46 (d,J9.1 Hz, 1H), 7.29 (t, J7.4 Hz, 1H), 7.20 (d, J8.1 Hz, 1H), 7.14 (t, J7.4 Hz, 1H), 7.09-6.76 (m, 2H), 4.39 (s, 2H), 3.81-3.67 (m, 4H), 2.44 (s, 3H), 2.08 (dt, J 13.5, 7.1 Hz, 1H), 1.95 (dd,J 12.8, 6.0 Hz, 1H), 1.76 (d, J6.3 Hz, 1H), 1.31-1.26 (m, 1H), 1.05 (s, 1H). Method D HPLC-MS: MH+ m/z 506, RT 2.08 minutes.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 309

20
[ 1003845-06-4 ]
[ 1536390-34-7 ]
[ 1536398-58-9 ]
[ 1536382-00-9 ]

Yield	Reaction Conditions	Operation in experiment
11%		(2-Chloropyrimidin-5-yl)boronic acid (0.22 g, 1.39 mmol) and 3-azabicyclo-[4.1 .0]heptane-6-carboxylic acid hydrochloride (0.25 g, 1.39 mmol) were dissolved inDMF (5 mL) and K2C03 (1.15 g, 8.34 mmol) was added. The mixture was heated at80C in a sealed tube for 2 h, then cooled to room temperature. To the mixture were added Intermediate 7 (0.5 g, 1.36 mmol), 2M aqueous K2C03 solution (2.04 mL) and 1,4- dioxane (6 mL). The mixture was degassed with nitrogen for 15 minutes, then tetrakis(triphenylphosphine)palladium(0) (236 mg, 0.2 mmol) was added. The mixture washeated at 80C in a sealed tube for 16 h. Upon cooling to room temperature, the mixture was diluted with EtOAc (40 mL) and extracted with water (20 mL), followed by 2Maqueous potassium carbonate solution (20 mL). The combined aqueous layers wereacidified to pH 4 by the addition of 6M hydrochloric acid. The aqueous layer wasextracted into 1:1 isopropanol/chloroform (6 x 25 mL), then the combined organic layers were dried over magnesium sulfate and concentrated. The residue was purified by FCC, eluting with 0-100% MeOH in DCM, to afford the title compound (81.7 mg, 11%) as an off-white solid. oH (500 MHz, DMSO-d6) 8.63 (s, 2H), 8.38 (s, 1H), 7.53 (d, J9.3 Hz,1H), 7.46 (dd,J9.3, 1.6 Hz, 1H), 7.44-7.09 (m, 4H), 7.03 (d,J6.6 Hz, 1H), 4.35 (s, 2H),4.22 (d, J 12.5 Hz, 1H), 4.15-3.99 (m, 1H), 3.88 (dd, J 13.7, 4.7 Hz, 1H), 3.75 (dt, J 12.6,5.9 Hz, 1H), 3.17 (d, J3.9 Hz, 2H), 2.31 (s, 3H), 1.87-1.74 (m, 1H), 1.75-1.67 (m, 1H),1.34-1.16 (m, 1H). Method A HPLC-MS: MH+ m/z 506, RT 3.13 minutes.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 314; 315

21
[ 1003845-06-4 ]
[ 1536390-34-7 ]
[ 1536392-01-4 ]
[ 1536381-69-7 ]

Yield	Reaction Conditions	Operation in experiment
11%		(2-Chloropyrimidin-5-yl)boronic acid (147 mg, 0.93 mmol), Intermediate 76 (165mg, 0.93 mmol) and K2C03 (193 mg, 1.397 mmol) were combined in DMF (2 mL) and the mixture was heated at 80C for a total of 5 h in a sealed tube. Further K2C03 was added and the mixture was heated for 10 minutes at 80C. To the mixture were added Intermediate 7 (228 mg, 0.62 1 mmol), 2M aqueous K2C03 solution (0.3 mL, 0.6 mmol)and 1,4-dioxane (3 mL). The mixture was degassed with nitrogen, the bis[3-(diphenyl- phosphanyl)cyclopenta-2,4-dien- l-yl] iron dichloropalladium dichloromethane complex (25 mg, 0.31 mmol) was added and the mixture was heated at 80C overnight. EtOAc (20 mL) was added, then the mixture was washed with water (2 x 20 mL) and brine. The mixture was extracted with further EtOAc (2 x 20 mL) and washed with brine (10 mL).The organic layers were combined and dried over sodium sulfate. The crude product waspurified using an SCX cartridge. The resulting material was dissolved in THF (2 mL),1M aqueous NaOH solution (0.73 mL) was added and the mixture was stirred at 80C for1.5 h. The mixture was concentrated to dryness and water was added. The mixture wasacidified to pH 5 using 1M HC1, then extracted with 1:1 isopropanollchloroform (3 x 20mL), dried over sodium sulfate and concentrated under vacuum. The residue was purifiedby preparative HPLC (Method D) to afford the title compound (50.5 mg, 11%) as an off- white solid. oH (500 MHz, DMSO-d6) 8.64 (s, 2H), 8.37 (s, 1H), 7.53 (d, J9.3 Hz, 1H), 7.47-7.09 (m, 5H), 7.06-7.01 (m, 1H), 4.35 (s, 2H), 3.91-3.85 (m, 1H), 3.85-3.80 (m, 1H),3.59 (dd,J 11.1, 4.3 Hz, 1H), 2.54 (s, 1H), 2.31 (s, 3H), 2.13 (dt,J8.9, 4.8 Hz, 1H), 1.50(dd, J8.2, 4.1 Hz, 1H), 0.82 (t, J4.7 Hz, 1H). Method D HPLC-MS: MH+ m/z 492, RT2.02 minutes.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 309

22
[ 1003845-06-4 ]
[ 1536390-34-7 ]
[ 1375303-88-0 ]
[ 1536392-07-0 ]

Yield	Reaction Conditions	Operation in experiment
13%		A mixture of<strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (261 mg, 1.65 mmol), 10 Intermediate 79 (351 mg, 1.98 mmol) and triethylamine (0.83 mL, 5.93 mmol) in EtOH(2 mL) were heated under microwave irradiation at 80C for 1 h. Intermediate 7 (403 mg,1.1 mmol), 1,2-dimethoxyethane (18 mL) and 2M aqueous sodium carbonate solution (4mL) were added and the reaction mixture was thoroughly degassed. Tetrakis(triphenylphosphine)palladium(0) (190 mg, 0.16 mmol) was added and the mixture was heated in15 sealed tube at 80C under nitrogen overnight. The mixture was allowed to cool to room temperature, then water (10 mL) and EtOAc (15 mL) were added. The organic phase was separated and the aqueous phase was extracted with EtOAc (15 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with 0-10% MeOH in DCM, to20 afford the title compound (160 mg, 13%) as a light brown gummy solid. Method B HPLC-MS: MH+ m/z 506, RT 1.52 minutes (80%).

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 146

23
[ 1003845-06-4 ]
[ 1536390-34-7 ]
[ 1536390-97-2 ]

Yield	Reaction Conditions	Operation in experiment
12%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; at 90℃; for 42h;Inert atmosphere;	Intermediate 7(1.0 g, 2.72 mmol) and <strong>[1003845-06-4]2-chloropyrimidin-5-ylboronic acid</strong> (517mg, 3.3 mmol) were dissolved in 1,4-dioxane (10 mL) and a 2M aqueous solution ofpotassium carbonate (4.9 mL) was added. The reaction mixture was degassed with nitrogen for 5 minutes, then bis [3 -(diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yl]irondichloropalladium-dichloromethane complex (111.2 mg, 0.14 mmol) was added. The reaction mixture was heated at 90C under nitrogen for 18 h. The reaction mixture wasre-treated with additional <strong>[1003845-06-4]2-chloropyrimidin-5-ylboronic acid</strong> (517.5 mg, 3.27 mmol) and heated at 90C under nitrogen for a further 24 h. The reaction mixture was diluted with EtOAc, washed with water (x 2) and brine, filtered to remove a black solid, then dried over sodium sulfate and dried under vacuum. The residue obtained was purified bycolumn chromatography, eluting with 0-90% EtOAc in heptanes, to yield the title compound (130 mg, 12%). 5H (500 MHz, DMSO-d6) 9.14 (s, 2H), 8.73 (s, 1H), 7.64 (s, 2H), 7.46-7.09 (m, 5H), 4.40 (s, 2H), 2.30 (s, 3H). Method B HPLC-MS: MH+ m/z401/403, RT 1.47 minutes (88%).

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 124; 125

24
[ 1003845-06-4 ]
[ 933743-15-8 ]
[ 1536395-25-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol;	To a suspension of <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (1.0 eq) in ethanol isadded the appropriate amine (0.95 eq). Triethylamine (2.5 eq) is added and the mixture stirred at either ambient temperature or 80C until the reaction is complete by TLC or LCMS. If the product precipitates the desired compound is isolated by filtration. For soluble products the reaction mixture is concentrated in vacuo and the crude productmixture is partitioned between aqueous medium and ethyl acetate. The aqueous layer is separated and re-extracted with ethyl acetate. The organic layers are combined and washed with brine, then dried (Na2SO4), filtered and concentrated in vacuo. The product can be further purified if required by column chromatography on silica gel or preparative5 mass-directed HPLC.The title compound was prepared from 1 ,4-oxazepane-7-carboxylic acid and (2- chloropyrimidin-5-yl)boronic acid in accordance with General Method C.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 216; 217

25
[ 1003845-06-4 ]
[ 1536390-56-3 ]
[ 1536391-38-4 ]

Yield	Reaction Conditions	Operation in experiment
56%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tri-tert-butyl phosphine; sodium carbonate; In 1,4-dioxane; water; at 120℃; for 8h;Inert atmosphere;	A mixture of Intermediate 16 (1 g, 2.3 mmol), <strong>[1003845-06-4]2-chloropyrimidin-5-ylboronic acid</strong> (1.09 g, 6.89 mmol) and 2M aqueous sodium carbonate solution (4.6 mL) in 1,4-dioxane(50 mL) was degassed with nitrogen for 5 minutes. Tri-tert-butylphosphine (23 mg, 0.11 mmol) and bis(triphenylphosphine)palladium(II) dichloride (81 mg, 0.11 mmol) were added and the reaction mixture was heated at 120C for 8 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting dark brown gum was purified by column chromatography, eluting with 30-80% ethyl acetate inheptanes, to afford the title compound (604 mg, 56%). OH (500 MHz, CDC13) 8.58 (s,2H), 8.18 (d,J18.6 Hz, 1H), 7.85 (s, 1H), 7.31 (t,J7.1 Hz, 1H), 7.20-7.05 (m, 2H), 6.97 (d, J7.4 Hz, 1H), 6.57 (t, J73.5 Hz, 1H), 4.31 (s, 2H), 2.61 (s, 3H). MH+ 469/471.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 133

26
[ 1003845-06-4 ]
[ 1536390-70-1 ]
[ 1536391-31-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tri-tert-butyl phosphine; sodium carbonate; In 1,4-dioxane; water; at 110 - 120℃; for 1h;Inert atmosphere;	Intermediate 20 (371 mg, 0.97 mmol) and <strong>[1003845-06-4]2-chloropyrimidin-5-ylboronic acid</strong> (462 mg, 2.92 mmol) were dissolved in 1 ,4-dioxane (3 mL) and a 2M aqueous sodium carbonate solution (1.5 mL) was added. The resulting mixture was degassed withnitrogen for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (34 mg, 0.05 mmol) and tri-tert-butylphosphine (10 mg, 0.05 mmol) were added and the reaction mixture was heated at 110C under microwave irradiation for 30 minutes. Additional 2- chloropyrimidin-5-ylboronic acid (462 mg, 2.92 mmol) was added and the reaction mixture was heated at 120C under microwave irradiation for 30 minutes. The reactionmixture was diluted with EtOAc, and washed with water and brine, then dried (Na2SO4), filtered and concentrated to dryness. The residue obtained was purified by column chromatography to yield the title compound (280 mg, 52%). OH NMR (500 MHz, CDC13) 8.55 (s, 2H), 7.61 (s, 1H), 7.45 (s, 1H), 7.26 (m, 1H), 7.13 (d, J8.0 Hz, 1H), 7.08 (t, J7.6 Hz, 1H), 6.87 (d, J7.7 Hz, 1H), 6.60 (t, J73.7 Hz, 1H), 4.26 (s, 2H), 2.50 (d, J4.3 Hz,3H), 2.28 (s, 3H). MH+ 415.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 132

27
[ 1003845-06-4 ]
(1R,5S,6r)-ethyl 3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloric acid [ No CAS ]
{2-[(1R,5S,6r)-6-(ethoxycarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]pyrimidin-5-yl}boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With triethylamine; In ethanol; at 80℃;	(2-Chloropyrimidin-5-yl)boronic acid (250 mg, 1.6 mmol), ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (303 mg, 1.6 mmol) and triethylamine (0.22 mL, 1.6 mmol) were dissolved in ethanol (8 mL) and stirred at 80C overnight. The reaction mixture was cooled and concentrated under vacuum. Water (30 mL) was added and the resulting material was filtered and dried to afford the titlecompound (253 mg, 58%) as a pale brown solid. Method B HPLC-MS: MH+ m/z 278, RT 1.35 minutes (100%).
58%	With triethylamine; In ethanol; at 80℃;	(2-Chloropyrimidin-5-yl)boronic acid (250 mg, 1.58 mmol), ethyl (lR,5S,6r)-3- azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (303 mg, 1.58 mmol) and triethyl- amine (0.22 mL, 1.58 mmol) were dissolved in ethanol (8 mL) and stirred at 80C overnight. The reaction mixture was cooled and concentrated under vacuum. Water (30 mL) was added, and the solid was filtered and dried, to afford the title compound (253 mg, 58%) as a pale brown solid. Method B HPLC-MS: MH+ m/z 278, RT 1.35 minutes
58%	With triethylamine; In ethanol; at 80℃;	(2-Chloropyrimidin-5-yl)boronic acid (250 mg, 1.58 mmol), ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (303 mg, 1.58 mmol) and triethylamine (0.22 mL, 1.58 mmol) were dissolved in ethanol (8 mL) and stirred at 80 C. overnight. The reaction mixture was cooled and concentrated under vacuum. Water (30 mL) was added, and the solid was filtered and dried, to afford the title compound (253 mg, 58%) as a pale brown solid. Method B HPLC-MS: MH+ m/z 278, RT 1.35 minutes.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 138
[2]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 95
[3]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0480

28
[ 1126-09-6 ]
[ 1003845-06-4 ]
[ 1536391-58-8 ]

Yield	Reaction Conditions	Operation in experiment
51%	In 1,4-dioxane; at 60℃; for 1h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (2 g, 13 mmol) and ethyl piperidine-4-carboxylate (1.94 mL, 13 mmol) were dissolved in 1 ,4-dioxane (20 mL) and heated to 60C under microwave irradiation for 1 h. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The organic layer was separated,washed with brine, dried over Na2SO4 and concentrated to dryness, to afford the title compound (1.79 g, 51%) as a yellow gum. Method C HPLC-MS: MH+ m/z 280, RT 0.94 minutes (89%).
51%	In 1,4-dioxane; at 60℃; for 1h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (2 g, 12.63 mmol) and ethyl piperidine-4- carboxylate (1.94 mL, 12.63 mmol) were dissolved in 1,4-dioxane (20 mL) and heated at 60C under microwave irradiation for 1 h. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to dryness, to afford the title compound (1.79 g, 51%) as a yellow gum. Method C HPLC-MS: MH+ mlz 280, RT 0.94 minutes
51%	In 1,4-dioxane; at 60℃; for 1h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (2 g, 12.63 mmol) and ethyl piperidine-4-carboxylate (1.94 mL, 12.63 mmol) were dissolved in 1,4-dioxane (20 mL) and heated at 60 C. under microwave irradiation for 1 h. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to dryness, to afford the title compound (1.79 g, 51%) as a yellow gum. Method C HPLC-MS: MH+ m/z 280, RT 0.94 minutes.

29
[ 1003845-06-4 ]
[ 225240-71-1 ]
[ 1515922-46-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In ethanol; at 70℃; for 5h;Inert atmosphere;	A mixture of <strong>[1003845-06-4]2-chloropyrimidine-5-boronic acid</strong> (3.95 g, 24.2 mmol),Intermediate 26 (5.03 g, 24.2 mmol) and TEA (60.6 mmol, 8.50 mL) in EtOH (50 mL) was heated at 70C for 5h. The reaction was cooled and partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was separated and re-extracted with further ethyl acetate (2 x 100 mL). The organic layers were combined and washed with brine (100 mL) before separating, drying over MgS04, filtering under reduced pressure and concentrating in vacuo, yieling the title compound as a brown foam (quantitive yield). LCMS (ES+) RT 1.228 min, 294.0 (M+H)+.
100%	With triethylamine; In ethanol; at 70℃; for 5h;	A mixture of <strong>[1003845-06-4]2-chloropyrimidine-5-boronic acid</strong> (3.95 g, 24.2 mmol), Intermediate 38 (5.03 g, 24.2 mmol) and triethylamine (60.6 mmol, 8.50 mL) in EtOH(50 mL) was heated at 70C for 5h. The reaction was cooled and partitioned between water (100 mL) and EtOAc (100 mL). The aq. layer was separated and re-extracted with further EtOAc (2 x 100 mL). The organic layers were combined and washed with brine (100 mL) before separating, drying (MgSO4), filtering under reduced pressure and concentrating in vacuo, yielding the title compound as a brown foam (quantitive yield).LCMS (ESj RT 1.23 mm 294.0 (M+H).
74%	With triethylamine; In ethanol; at 80℃; for 3h;	To <strong>[1003845-06-4]2-chloropyrimidine-5-boronic acid</strong> (4.00 g, 25.3 mmol) were added ethyl 4-methylpiperidine-4-carboxylate hydrochloride (4.09 g, 23.9 mmol), ethanol (40 mL) and triethylamine (9.0 mL, 64.0 mmol). The mixture was heated at 80C for 3 h before being concentrated in vacuo. The reaction mixture was partitioned between water (100 mL) andethyl acetate (100 mL), then the aqueous layer was separated and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined and washed with brine (100 mL), then dried (Na2SO4). The solvent was then removed under reduced pressure and the crude reaction mixture was purified by flash column chromatography on silica (Biotage SNAP 100 g, Isolera). Gradient elution, with 100% dichloromethane to 30% methanoldichloromethane, afforded the title compound (4.27 g, 43% yield, 74% purity) as a brown oil. LCMS (pH 10): MH+ m/z 294.1, RT 0.652 minutes.

Reference： [1]Patent: WO2015/86527,2015,A1 .Location in patent: Page/Page column 114
[2]Patent: WO2015/86525,2015,A1 .Location in patent: Page/Page column 118
[3]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 137

30
[ 1003845-06-4 ]
[ 1536392-78-5 ]
[ 1536392-81-0 ]

Yield	Reaction Conditions	Operation in experiment
57%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tri-tert-butyl phosphine; sodium carbonate; In 1,4-dioxane; water; at 120℃; for 1.16667h;Microwave irradiation;	Intermediate 105 (477 mg, 1.16 mmol) and <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (552 mg, 3.48 mmol) were dissolved in 1,4-dioxane (7 mL) and 2M sodium carbonate inwater (1.74 mL) was added. The resulting mixture was degassed with nitrogen for 5 minutes, then dichlorobis(triphenylphosphine)palladium(II) (41 mg, 0.058 mmol) and tntert-butylphosphine (12 mg, 0.058 mmol) were added. The reaction mixture was heated at 120C under microwave irradiation for a total of 70 minutes. The reaction was repeated on the same scale and the two reaction mixtures were combined, diluted withEtOAc (25 mL), washed with water (20 mL) and brine (20 mL), then dried over sodiumsulfate and concentrated to dryness. The residue was purified by FCC, eluting with 50-100% EtOAc in heptane followed by 0-5% MeOH in EtOAc, to afford the title compound(585 mg, 57%) as a yellow gum. oH (500 MHz, CDC13) 8.40 (s, 2H), 8.11 (s, 1H), 7.66(d,J7.4 Hz, 1H), 7.40 (s, 1H), 7.38-7.34(m, 1H), 7.26 (t,J7.6 Hz, 1H), 7.08 (d,J8.0Hz, 1H), 6.19 (t, J73.5 Hz, 1H), 2.45 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H). Method CHPLC-MS: MH+ m/z 445, RT 0.97 minutes.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 160; 161

31
[ 498-94-2 ]
[ 1003845-06-4 ]
[ 1515925-20-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	With triethylamine; In ethanol; at 80℃; for 16h;	2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in ethanol (25 mL). Triethylamine (1.78 mL, 12.6mmol) was added and the mixture was heated at 80C for 16 h. The reaction mixture was cooled and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 7.6 mmol, 60%) as a white solid. OH (d6- DMSO) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ESj 252 (M+H).
60%	With triethylamine; In ethanol; at 80℃; for 16h;	2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in EtOH (25 mL). Triethylamine (1.78 mL, 12.65 mmol) was added and the mixture was heated at 80C for 16 h. The reaction mixture wascooled to room temperature and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 60%) as a white solid. H(400 MHz, DMSO-d6) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m,2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ESj 252 (M+H).
60%	With triethylamine; In ethanol; at 80℃; for 16h;	2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid(1.63 g, 12.6 mmol) were suspended in EtOH (25 mL). Triethylamine (1.78 mL, 12.65 mmol) was added and the mixture was heated at 80C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes,then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 60%) as a white solid. 0H (DMSO-d6) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ESj 252 (M+H).

60%	With triethylamine; In ethanol; at 80℃; for 16h;	INTERMEDIATE 5 1 -(5 -Boronopyrimidin-2-yl)piperidine-4-carboxylic acid2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in EtOH (25 mL). Triethylamine (1.78 mL, 12.65 mmol) was added and the mixture was heated at 80C for 16 h. The reaction mixture wascooled to room temperature and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 60%) as a white solid. H(400 MHz, DMSO-d6) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m,2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ESj 252 (M+H).
60%	With triethylamine; In ethanol; at 80℃; for 16h;	INTERMEDIATE 6 l-(5-Boronopyrimidin-2-yl)piperidine-4-carboxylic acid 2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in EtOH (25 mL). Triethylamine (1.78 mL, 12.65 mmol) was added and the mixture was heated at 80C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 60%) as a white solid, deltapi (DMSO-d6) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ES+) 252 (M+H)+.
60%	With triethylamine; In ethanol; at 80℃; for 16h;	INTERMEDIATE 41 -(5 -Boronopyrimidin-2-yl)piperidine-4-carboxylic acid2-Chloropyrimidin-5 -ylboronic acid (2.00 g, 12.6 mmol) and isonipecotic acid (1.63 g, 12.6 mmol) were suspended in EtOH (25 mL). Triethylamine (1.78 mL, 12.65 mmol) was added and the mixture was heated at 80C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to dryness. Water (30 mL) was added and the reaction mixture was swirled until the product completely dissolved. On standing, crystallisation occurred. The mixture was cooled in an ice bath for 30 minutes, then filtered. The resultant solid was washed sparingly with water and dried under suction, then freeze-dried, to give the title compound (1.90 g, 60%) as a white solid. deltaEta (400 MHz, DMSO-d6) 8.60 (s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H), 2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ES+) 252 (M+H)+.
	With triethylamine; In ethanol; at 80℃; for 4h;	(2-Chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol) was dissolved in EtOH (15 mL) and piperidine-4-carboxylic acid (816 mg, 6.32 mmol) was added, followed by triethylamine (881 mu, 6.32 mmol). The reaction mixture was heated at 80C for a total of 4 h. The reaction mixture was concentrated to dryness and 10 mL of water was added. The resulting suspension was cooled to 0C for 30 minutes, then filtered, and the solid was washed with minimal water. Only a trace amount of precipitate was isolated so this was recombined with the filtrate and concentrated to dryness to afford the title compound. The crude product was used without purification. Method C HPLC-MS: MH+ mlz 252, RT 0.70 minutes
	With triethylamine; In ethanol; at 80℃; for 4h;	(2-Chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol) was dissolved in EtOH (15 mL) and piperidine-4-carboxylic acid (816 mg, 6.32 mmol) was added, followed by triethylamine (881 muL, 6.32 mmol). The reaction mixture was heated at 80 C. for a total of 4 h. The reaction mixture was concentrated to dryness and 10 mL of water was added. The resulting suspension was cooled to 0 C. for 30 minutes, then filtered, and the solid was washed with minimal water. Only a trace amount of precipitate was isolated so this was recombined with the filtrate and concentrated to dryness to afford the title compound. The crude product was used without purification. Method C HPLC-MS: MH+ m/z 252, RT 0.70 minutes.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 128
[2]Patent: WO2015/86508,2015,A1 .Location in patent: Page/Page column 75
[3]Patent: WO2015/86502,2015,A1 .Location in patent: Page/Page column 83
[4]Patent: WO2015/86511,2015,A1 .Location in patent: Page/Page column 75
[5]Patent: WO2015/86501,2015,A1 .Location in patent: Page/Page column 89-90
[6]Patent: WO2015/86496,2015,A1 .Location in patent: Page/Page column 74; 75
[7]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 94
[8]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0479

32
[ 110-91-8 ]
[ 1003845-06-4 ]
[ 870521-33-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine; In ethanol; at 20℃; for 1h;	2-Chloropyrimidin-5-ylboronic acid (1 g, 6.32 mmol), morpholine (2.19 mL,25.26 mmol) and triethylamine (0.88 mL, 6.32 mmol) were stirred in ethanol (25 mL) at20°C for 1 h. Water (50 mL) was slowly added to the reaction mixture. The resultingprecipitate was filtered and washed with water to afford the title compound (950 mg,70percent) as a cream solid. H (250 MHz, DMSO-d6) 8.63 (s, 2H), 8.05 (s, 2H), 3.68 (ddd, J23.4, 5.7, 3.9 Hz, 8H).
70%	With triethylamine; In ethanol; at 20℃; for 1h;	A solution of <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (1 g, 6.32 mmol), morpholine (2.19 mL, 25.26 mmol) and triethylamine (0.9 mL, 6.32 mmol) in ethanol (25 mL) was stirred at 20°C for 1 h. Water (50 mL) was slowly added to the reaction mixture to form a precipitate that was collected by filtration, to afford the title compound (950 mg, 70percent) ascream solid. H (250 MHz, DMSO-d6) 8.63 (s, 2H), 8.05 (s, 2H), 3.68 (ddd, J23.4, 5.7,3.9 Hz, 8H). LCMS m/z 210 [M+H].
70%	With triethylamine; In ethanol; at 20℃; for 1h;Inert atmosphere;	A solution of <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (1 g, 6.32 mmol), morpholine (2.19 mL, 25.26 mmol) and triethylamine (0.9 mL, 6.32 mmol) in ethanol (25 mL) was stirred at 20°C for 1 h. Water (50 mL) was slowly added to the reaction mixture to form a precipitate that was collected by filtration, to afford the title compound as a cream solid (950 mg, 70percent). deltaEta (250 MHz, DMSO-d6) 8.63 (s, 2H), 8.05 (s, 2H), 3.68 (ddd, J23.4, 5.7, 3.9 Hz, 8H). LCMS(ES+) 210 (M+H)+.

70%	With triethylamine; In ethanol; at 20℃; for 1h;	A solution of <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (1 g, 6.32 mmol), morpholine (2.19 mL, 25.26 mmol) and triethylamine (0.9 mL, 6.32 mmol) in ethanol (25 mL) was stirred at 20°C for 1 h. Water (50 mL) was slowly added to the reaction mixture to form a precipitate that was collected by filtration, to afford the title compound as a cream solid (950 mg, 70percent). deltaEta (250 MHz, DMSO-d6) 8.63 (s, 2H), 8.05 (s, 2H), 3.68 (ddd, J23.4, 5.7, 3.9 Hz, 8H). LCMS(ES+) 210.0 (M+H)+.
70%	With triethylamine; In ethanol; at 20℃; for 1h;	A solution of<strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (1 g, 6.32 mmol), morpholine (2.19 mL, 25.26 mmol) and triethylamine (0.9 mL, 6.32 mmol) in ethanol (25 mL) was stirred at 20°C for 1 h. Water (50 mL) was slowly added to the reaction mixture to form a precipitate that was collected by filtration, to afford the title compound as a cream solid(950 mg, 70percent). oH (250 MHz, DMSO-d6) 8.63 (s, 2H), 8.05 (s, 2H), 3.68 (ddd, J23.4, 5.7, 3.9 Hz, 8H). LCMS(ES) 210 (M+H).
68%	With triethylamine; In ethanol; at 80℃; for 5h;	A mixture of <strong>[1003845-06-4]2-chloropyrimidin-5-ylboronic acid</strong> (3 g, 19.0 mmol), morpholine (1.66 mL, 19 mmol) and triethylamine (1.67 mL, 19.19 mmol) in EtOH (20 mL) was stirred at 80°C for 5 h. LCMS indicated completion of the reaction. The reaction mixturewas concentrated in vacuo and the residue was taken up in ethanol (approximately 5 mL). Diethyl ether was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off, washed with the minimum amount of water and dried bysuction, to give the title compound (2.7 g, 68percent) as an off-white solid. oH (DMSO-d6)8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ES+) 210 (M+H), RT0.15 minutes.
68%	With triethylamine; In ethanol; at 80℃; for 5h;	A mixture of <strong>[1003845-06-4]2-chloropyrimidin-5-ylboronic acid</strong> (3 g, 19.0 mmol), morpholine (1.66 mL, 19.0 mmol) and triethylamine (1.67 mL, 19.2 mmol) in EtOH (20 mL) wasstirred at 80°C for 5 h. The reaction mixture was concentrated in vacuo and the residue was taken up in Et20 (approximately 5 mL). Et20 was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off, washed with the minimum amount of water and dried by suction, to give the title compound (2.7 g, 68percent) as an off-white solid. oH (DMSO-d6) 8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ESj 210 (M+H), RT 0.15 minutes.
68%	With triethylamine; In ethanol; at 80℃; for 5h;	INTERMEDIATE 4 2-(Morpholin-4-yl)pyrimidin-5 -ylboronic acidA mixture of <strong>[1003845-06-4]2-chloropyrimidin-5-ylboronic acid</strong> (3.0 g, 19.0 mmol), morpholine (1.66 mL, 19.0 mmol) and triethylamine (1.67 mL, 19.2 mmol) in EtOH (20 mL) was stirred at 80°C for 5 h. The reaction mixture was concentrated in vacuo and the residue was taken up in Et20 (approximately 5 mL). Et20 was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off,washed with the minimum amount of water and dried by suction, to give the title compound (2.7 g, 68percent) as an off-white solid. H (400 MHz, DMSO-d6) 8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ESj 210 (M+H), RT 0.15 minutes.
68%	With triethylamine; In ethanol; at 80℃; for 5h;	INTERMEDIATE 5 2- (Morpholin-4- yl)p yrimidin- 5 - ylboronic acid A mixture of <strong>[1003845-06-4]2-chloropyrimidin-5-ylboronic acid</strong> (3 g, 19.0 mmol), morpholine (1.66 mL, 19.0 mmol) and triethylamine (1.67 mL, 19.2 mmol) in EtOH (20 mL) was stirred at 80°C for 5 h. The reaction mixture was concentrated in vacuo and the residue was taken up in Et20 (approximately 5 mL). Et20 was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off, washed with the minimum amount of water and dried by suction, to give the title compound (2.7 g, 68percent) as an off-white solid. deltaEta (DMSO-d6) 8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ES+) 210 (M+H)+, RT 0.15 minutes.
68%	With triethylamine; In ethanol; at 80℃; for 5h;	INTERMEDIATE 32-(Morpholin-4-yl)pyrimidin-5 -ylboronic acidA mixture of 2-chloropyrimidin-5 -ylboronic acid (3.0 g, 19.0 mmol), morpholine (1.66 mL, 19.0 mmol) and triethylamine (1.67 mL, 19.2 mmol) in EtOH (20 mL) was stirred at 80°C for 5 h. The reaction mixture was concentrated in vacuo and the residue was taken up in Et20 (approximately 5 mL). Et20 was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off, washed with the minimum amount of water and dried by suction, to give the title compound (2.7 g, 68percent) as an off-white solid. deltaEta (400 MHz, DMSO-dg) 8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ES+) 210 (M+H)+, RT 0.15 minutes.

Reference： [1]Patent: WO2015/86506,2015,A1 .Location in patent: Page/Page column 131
[2]Patent: WO2015/86512,2015,A1 .Location in patent: Page/Page column 102
[3]Patent: WO2015/86527,2015,A1 .Location in patent: Page/Page column 114; 115
[4]Patent: WO2015/86526,2015,A1 .Location in patent: Page/Page column 147
[5]Patent: WO2015/86525,2015,A1 .Location in patent: Page/Page column 121; 122
[6]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 128; 129
[7]Patent: WO2015/86502,2015,A1 .Location in patent: Page/Page column 82; 83
[8]Patent: WO2015/86511,2015,A1 .Location in patent: Page/Page column 74; 75
[9]Patent: WO2015/86501,2015,A1 .Location in patent: Page/Page column 89
[10]Patent: WO2015/86496,2015,A1 .Location in patent: Page/Page column 74

33
[ 410545-38-9 ]
[ 1003845-06-4 ]
[ 1536391-25-9 ]

Yield	Reaction Conditions	Operation in experiment
1.40 g	In ethanol;Reflux;	2-Chloropyrimidin-5-ylboronic acid (1.00 g, 6.32 mmol) and Intermediate 44 (1.75 g, 6.96 mmol) were dissolved in ethanol (25 mL) and heated at reflux overnight. Analysis by LCMS showed the major UV visible component to have the desired mass. The mixture was concentrated in vacuo, re-dissolved in water (20 mL) and acidified with acetic acid (1 mL). The mixture was concentrated in vacuo again and purified by chromatography (silica, 50 g, eluted with 82% DCM, 15% MeOH, 2% AcOH, 1% water)to give the title compound (1.40 g). The product was used in the next step without further purification.

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 113

34
[ 1003845-06-4 ]
[ 1423070-45-4 ]
C₁₃H₁₈BN₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3.5h;Sealed tube;	(2-Chloropyrimidin-5-yl)boronic acid (231 mg, 1.46 mmol) and Intermediate 42 (300 mg, 1.46 mmol) were dissolved in DMF (5 mL) and potassium carbonate (302 mg, 2.19 mmol) was added. The mixture was heated at 80C in a sealed tube for 3.5 h. The reaction mixture was cooled down to r.t., then Intermediate 6 (347 mg, 0.94 mmol), a 2M solution of potassium carbonate in water (1.39 mL) and 1,4-dioxane (6 mL) were added. The mixture was degassed with nitrogen, then Pd(dppf)Cl2.DCM (39 mg, 0.048 mmol) was added. The mixture was heated at 80C in a sealed tube for 3 h. The reaction mixture was cooled down to r.t. and concentrated under vacuum. The resulting brown residue was partitioned between EtOAc (5 mL) and water (3 mL). The organic phase was washed with water (3 x 3 mL), then the aqueous washes were combined and extracted with EtOAc (3 x 3 mL). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated. The resulting crude brown oil was purified by FCC (Si02, heptanes:EtOAc 7.5:2.5 to 2:8) to afford a solid which was further purified by trituration in diethyl ether, then dissolved in a mixture of DMSO and water. The solid which precipitated out of solution was filtered and washed with diethyl ether, to afford the title compound (55 mg, 11%). Method C HPLC-MS: MH+ mlz 535, RT 1.46 minutes

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 104; 105

35
tetrahydrofuran-3-amine monohydrochloride [ No CAS ]
[ 1003845-06-4 ]
C₈H₁₂BN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In 1,4-dioxane; at 100℃; for 1h;	(2-Chloropyrimidin-5-yl)boronic acid (50 mg, 0.32 mmol) was dissolved in 1,4- dioxane (1 mL) and tetrahydrofuran-3-amine hydrochloride (117 mg, 0.95 mmol) was added, followed by sodium carbonate (117.13 mg, 1.11 mmol). The reaction mixture was heated at 100C under microwave irradiation for 1 h. The reaction mixture was transferred to a pressure tube and diluted with 1 ,2-dimethoxyethane (2 mL). Intermediate 6 (58 mg, 0.16 mmol) was added, followed by 2M aqueous sodium carbonate solution (0.76 mL), and the reaction mixture was degassed with nitrogen for 5 minutes. Pd(PPh3)4 (36 mg, 0.03 mmol) was added, and the mixture was heated at 90C for 2 h. The reaction mixture was diluted with EtOAc (15 mL), washed with water (10 mL) and brine (10 mL), then dried over sodium sulfate and concentrated to dryness. The residue was purified by preparative HPLC, to afford the title compound (22 mg, 15%>) as a white solid. 5H (500 MHz, CD3OD) 8.91 (s, 1H), 8.80 (d, J4.1 Hz, 2H), 8.50 (s, 1H), 7.32 (t, J 7.7 Hz, 1H), 7.24-7.14 (m, 3H), 6.91 (t, J 73.9 Hz, 1H), 4.60-4.52 (m, 1H), 4.45 (s, 2H), 4.03-3.94 (m, 2H), 3.90-3.82 (m, 1H), 3.72 (dd, J9.1, 3.7 Hz, 1H), 2.45 (s, 3H), 2.35-2.27 (m, 1H), 1.98 (m, J4.9 Hz, 1H). Method D HPLC-MS: MH+ mlz 453, RT 2.51 minutes

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 115

36
[ 1003845-06-4 ]
4,4-difluoropiperidine hydrochloride [ No CAS ]
(2-(4,4-difluoropiperidin-1-yl)pyrimidin-5-yl)boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; at 100℃; for 1h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (200 mg, 1.26 mmol) and 4,4-difluoro- piperidine hydrochloride (239 mg, 1.52 mmol) were suspended in 1,4-dioxane (3 mL) and heated for 1 h at 100C under microwave irradiation. The mixture was filtered and concentrated under vacuum. Intermediate 6 (200 mg, 0.54 mmol) and 1,4-dioxane (4 mL) were added, and the mixture was degassed for 5 minutes. Degassed 2M aqueous potassium carbonate solution (0.81 mL) and bis[3-(diphenylphosphanyl)cyclopenta-2,4- dien-l-yl]iron dichloropalladium dichloromethane complex (31 mg, 0.04 mmol) were added and the mixture was heated at 100C for 16 h. The mixture was partitioned between EtOAc (30 mL) and water (20 mL) and the aqueous phase was extracted with further EtOAc (20 mL). The organic layers were combined and washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of 0-5% ammonia/MeOH in DCM. The material was then triturated in hot MeOH, and the solids were filtered, to afford the title compound (124 mg, 47%) as a pale peach solid. deltaEta (250 MHz, CDCl3) 9.16 (s, 1H), 8.78 (s, 2H), 8.00 (s, 1H), 7.30 (d, J 8.4 Hz, 1H), 7.16 (dd, J 12.3, 7.4 Hz, 2H), 7.01-6.34 (m, 2H), 4.34 (s, 2H), 4.10-3.99 (m, 4H), 2.62 (s, 3H), 2.03 (tt, J 13.6, 5.8 Hz, 4H). Method A HPLC-MS: MH+ mlz 487, RT 4.55 minutes.

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 116

37
[ 1003845-06-4 ]
[ 1159599-99-1 ]
C₉H₁₂BN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1,4-dioxane; at 100℃; for 1h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (150 mg, 0.95 mmol) and 2-oxa-6-azaspiro- [3.3]heptane oxalate (239 mg, 1.26 mmol) were suspended in 1,4-dioxane (6 mL) and triethylamine (0.18 mL, 1.26 mmol) was added. The mixture was heated at 100C under microwave irradiation for 1 h. The mixture was diluted with MeOH (20 mL), then concentrated. To the resulting orange oil were added Intermediate 6 (228 mg, 0.62 mmol), 2M aqueous potassium carbonate solution (1.4 mL) and 1,4-dioxane (5 mL). The mixture was thoroughly degassed before the addition of bis[3-(diphenylphosphanyl)- cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (36 mg, 0.04 mmol), then the mixture was heated at 100C for 15 h. EtOAc (10 mL) was added, then the mixture was washed with water (2 x 10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with a gradient of 0-7% MeOH in DCM. The resulting material was further purified by preparative HPLC, to afford the title compound (21.2 mg, 5%) as a white solid. deltaEta (500 MHz, CDC13) 9.04 (d, J 4.5 Hz, IH), 8.74 (s, 2H), 7.93 (s, IH), 7.28 (t, J 7.9 Hz, IH), 7.17 (d, J 8.2 Hz, IH), 7.12 (t, J 7.5 Hz, IH), 6.94 (d, J 7.6 Hz, IH), 6.63 (t, J 73.5 Hz, IH), 4.87 (s, 4H), 4.35 (s, 4H), 4.32 (s, 2H), 2.57 (s, 3H). Method A HPLC-MS: MH+ mlz 465, RT 3.59 minutes

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 116; 117

38
[ 141-91-3 ]
[ 1003845-06-4 ]
[2-(2,6-DIMETHYLMORPHOLIN-4-YL)PYRIMIDIN-5-YL]BORONIC ACID [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; at 100℃; for 1h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (50 mg, 0.32 mmol) was dissolved in 1,4- dioxane (1 mL) and 2,6-dimethylmorpholine (117 mu, 0.95 mmol) was added. The reaction mixture was heated at 100C under microwave irradiation for 1 h. The reaction mixture was transferred to a pressure tube and diluted with 1 ,2-dimethoxyethane (2 mL). Intermediate 6 (77 mg, 0.21 mmol) was added, followed by 2M aqueous sodium carbonate solution (0.76 mL), and the reaction was degassed with nitrogen for 5 minutes. Pd(PPh3)4 (36 mg, 0.03 mmol) was added and the mixture was heated at 90C for 100 minutes. The reaction mixture was diluted with EtOAc (15 mL) and washed with water (10 mL), followed by brine (10 mL), then dried over sodium sulfate and concentrated to dryness. The residue was purified by preparative HPLC to afford the title compound (17.6 mg, 12%) as a white solid. deltaEta (500 MHz, CD3OD) 8.90 (d, J 1.3 Hz, IH), 8.83 (s, 2H), 8.50 (d, J 1.3 Hz, IH), 7.36-7.28 (m, IH), 7.24-7.14 (m, 3H), 6.91 (t, J 74.0 Hz, IH), 4.64 (d, J 11.8 Hz, 2H), 4.45 (s, 2H), 3.71-3.58 (m, 2H), 2.62 (dd, J 13.3, 10.6 Hz, 2H), 2.45 (s, 3H), 1.24 (d, J 6.1 Hz, 6H). Method D HPLC-MS: MH+ mlz 481, RT 3.42 minutes

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 117

39
[ 62848-20-8 ]
[ 1003845-06-4 ]
C₉H₁₄BN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1,4-dioxane; at 60℃; for 0.75h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.632 mmol) and 3-methoxy- pyrrolidine (64 mg, 0.63 mmol) were suspended in 1,4-dioxane (3 mL), triethylamine (0.09 mL, 0.632mmol) was added and the mixture was heated at 60C under microwave irradiation for 45 minutes. The reaction mixture was concentrated under vacuum, dissolved in DCM (20 mL) and washed with water (2 x 10 mL). The aqueous layer was concentrated under vacuum. To the resulting off-white solid were added Intermediate 6 (173 mg, 0.47 mmol), 2M aqueous potassium carbonate solution (1.09 mL) and 1,4- dioxane (5 mL). The mixture was thoroughly degassed before the addition of bis [3- (diphenylphosphanyl)cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (27 mg, 0.034 mmol). The mixture was heated at 100C overnight. Rho(RhoRho1)4 (0.034 mmol) was added and the mixture was heated at 100C overnight. EtOAc (10 mL) was added and the mixture was washed with water (2 x 10 mL) and brine (10 mL). The organic fraction was dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with 0-7% MeOH in DCM. The material was then further purified by preparative HPLC to afford the title compound (7.3 mg, 2%) as a yellow solid. deltaEta (500 MHz, CDC13) 9.06 (s, 1H), 8.76 (s, 2H), 7.91 (s, 1H), 7.29 (t, J 7.8 Hz, 1H), 7.17 (d, J 8.1 Hz, 1H), 7.12 (t, J 7.5 Hz, 1H), 6.93 (d, J 7.7 Hz, 1H), 6.81-6.45 (m, 1H), 4.32 (s, 2H), 4.16-4.05 (m, 1H), 3.85-3.74 (m, 2H), 3.74-3.62 (m, 2H), 3.38 (s, 3H), 2.58 (s, 3H), 2.25-2.16 (m, 1H), 2.10 (m, 1H). Method D HPLC-MS: MH+ mlz 466, RT 2.77 minutes

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 120

40
[ 1003845-06-4 ]
[ 1172252-57-1 ]
C₁₁H₁₄BN₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;Sealed tube;	(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol) and 2-azaspiro[3.3]- heptane-6-carboxylic acid hydrochloride (113 mg, 0.64 mmol) were dissolved in DMF (2 mL), then potassium carbonate (131 mg, 0.95 mmol) was added. The mixture was heated at 80C in a sealed tube for 2 h. To the mixture were added Intermediate 6 (150 mg, 0.41 mmol), 2M aqueous potassium carbonate solution (0.6 mL) and 1,4-dioxane (3 mL). The mixture was degassed with nitrogen, then bis[3-(diphenylphosphanyl)cyclopenta-2,4- dien-l-yl]iron dichloropalladium dichloromethane complex (17 mg, 0.02 mmol) was added. The mixture was heated at 80C in a sealed tube for 4 h. The mixture was diluted with DCM (20 mL) and extracted with water (10 mL), followed by 2M aqueous potassium carbonate solution (10 mL). The combined aqueous layers were acidified to pH 4 by the addition of 6M hydrochloric acid. The mixture was left to stand for 10 minutes and the resultant precipitate was collected by filtration. The solids were washed with water (5 mL) and DCM (5 mL), and dried under vacuum, to afford the title compound (50.9 mg, 25%) as a pale pink solid. deltaEta (500 MHz, CD3OD) 8.92 (s, 1H), 8.83 (s, 2H), 8.54 (s, 1H), 7.32 (t, J 7.0 Hz, 1H), 7.23-7.15 (m, 3H), 6.90 (t, J 73.9 Hz, 1H), 4.61 (s, 1H), 4.46 (s, 2H), 4.20 (s, 2H), 4.13 (s, 2H), 3.06-3.01 (m, 1H), 2.56-2.47 (m, 4H), 2.45 (s, 3H). Method D HPLC-MS: MH+ mlz 507, RT 2.51 minutes.

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 121

41
[ 1003845-06-4 ]
[ 498-95-3 ]
[ 1536396-93-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h;Sealed tube; Inert atmosphere;	(2-Chloropyrimidin-5-yl)boronic acid (65 mg, 0.41 mmol), (35)-piperidine-3- carboxylic acid (56 mg, 0.431 mmol) and potassium carbonate (57 mg, 0.41 mmol) were charged to a sealed tube with DMF (2 mL) under nitrogen. The reaction mixture was stirred at 80C for 60 minutes. To the mixture were added Intermediate 6 (100 mg, 0.271 mmol), 1,4-dioxane (2 mL) and 2M aqueous sodium carbonate solution (0.16 mL, 1.231 mmol). The mixture was degassed, bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-l- yljiron dichloropalladium dichloromethane complex (17 mg, 0.021 mmol) was added and the mixture was stirred at 80C under nitrogen for 6 h. The mixture was partitioned between DCM (20 mL) and water (10 mL), and the aqueous fraction was washed with DCM (10 mL). The aqueous layer was acidified to pH 1, then extracted with DCM (3 x 15 mL). The combined extracts were washed with brine (10 mL), dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to afford the title compound (30 mg, 15%) as a light brown solid. deltaEta (500 MHz, DMSO-d6) 8.98 (s, 1H), 8.94 (s, 2H), 8.78 (s, 1H), 7.44-7.10 (m, 5H), 4.78-4.70 (m, 1H), 4.52 (d, J 13.0 Hz, 1H), 4.42 (s, 2H), 3.18-3.10 (m, 1H), 3.05 (t, J 11.0 Hz, 1H), 2.44-2.35 (m, 1H), 2.34 (s, 3H), 2.01 (d, J 9.4 Hz, 1H), 1.79-1.59 (m, 2H), 1.44 (q, J 11.9 Hz, 1H). Method D HPLC-MS: MH+ mlz 495, RT 2.84 minutes.

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 122

42
[ 1003845-06-4 ]
[ 1216735-73-7 ]
C₉H₁₂BN₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 100℃; for 1h;Microwave irradiation;	A mixture of <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (100 mg, 0.63 mmol) and 3- carboxypyrrolidin-l-ium trifluoroacetate (200 mg, 0.87 mmol) was heated under microwave irradiation at 100C for 1 h. Intermediate 6 (150 mg, 0.41 mmol), 2M aqueous sodium carbonate solution (0.65 mL) and 1 ,2-dimethoxyethane (4 mL) were added. The mixture was thoroughly degassed, then Pd(PPh3)4 (50 mg, 0.04 mmol) was added. The mixture was heated at 90C in a sealed tube under nitrogen for 2 h. The mixture was cooled to r.t., then diluted with DCM (20 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC to afford the title compound (8.9 mg, 5%) as a tan solid. 5H (250 MHz, DMSO-dg) 8.93 (d, J 1.2 Hz, 1H), 8.90 (s, 2H), 8.73 (s, 1H), 7.53-6.93 (m, 5H), 4.38 (s, 2H), 3.73-3.65 (m, 2H), 3.55 (q, J6.9 Hz, 2H), 3.19-3.12 (m, 1H), 2.29 (s, 3H), 2.21-2.09 (m, 2H). Method D HPLC-MS: MH+ mlz 481, RT 2.44 minutes.

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 127

43
2-(piperazin-1-yl)propanoic acid [ No CAS ]
[ 1003845-06-4 ]
C₁₁H₁₇BN₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 6h;Sealed tube;	(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol) and 2-(piperazin-l- yl)propanoic acid (100 mg, 0.63 mmol) were dissolved in DMF (2 mL) and potassium carbonate (131 mg, 0.95 mmol) was added. The mixture was heated at 80C in a sealed tube for 6 h. To the mixture were added Intermediate 6 (150 mg, 0.41 mmol), 2M aqueous potassium carbonate solution (0.6 mL) and 1,4-dioxane (3 mL). The mixture was degassed with nitrogen, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-l-yl]- iron dichloropalladium dichloromethane complex (25 mg, 0.03 mmol) was added. The mixture was heated at 80C in a sealed tube for 4 h. The mixture was diluted with DCM (20 mL) and extracted with water (10 mL), followed by 2M aqueous potassium carbonate solution (10 mL). The combined aqueous layers were extracted with 1 : 1 isopropanol/ chloroform (20 mL), then the organic layer was separated and concentrated under vacuum. The residue was purified by preparative HPLC to afford the title compound (43.8 mg, 21%). deltaEta (500 MHz, DMSO-d6) 8.97 (d, J 1.1 Hz, 1H), 8.94 (s, 2H), 8.78 (s, 1H), 7.33-7.29 (m, 1H), 7.26 (t, J 15 Hz, 1H), 7.18 (d, J 8.1 Hz, 1H), 7.16 (d, J 6.2 Hz, 2H), 4.41 (s, 2H), 3.79 (dt, J 14.1, 6.9 Hz, 4H), 3.24 (q, J 7.0 Hz, 1H), 2.65 (dt, J 16.1, 4.3 Hz, 4H), 2.32 (s, 3H), 1.19 (d, J 7.0 Hz, 3H). Method A HPLC-MS: MH+ mlz 524, RT 3.15 minutes

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 127

44
[ 1003845-06-4 ]
[ 1537169-53-1 ]
[ 121-44-8 ]
(2-{7-oxo-3,6-diazabicyclo[3.2.2]nonan-3-yl}pyrimidin-5-yl)boronic acid triethylazanium chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 80℃; for 72h;	(2-Chloropyrimidin-5-yl)boronic acid (1.13 g, 7.14 mmol) and (15',5i?)-3,6-diaza- bicyclo[3.2.2]nonan-7-one (1.00 g, 7.13 mmol) were mixed together in ethanol (15 mL) and triethylamine (1.00 mL, 7.10 mmol) was added. The mixture was heated to 80C for 3 days. The mixture was concentrated in vacuo to afford the title compound (2.70 g, UV purity 94.7%) as an off-white solid, which was used in subsequent coupling reactions without any further purification. deltaEta (300 MHz, DMSO-d6) 10.54-9.53 (br s, 2H), 8.08 (s, 2H), 4.88-4.74 (m, 2H), 3.65-3.53 (m, 1H), 3.48-3.39 (m, 1H), 3.24-3.11 (m, 2H), 3.03 (q, J 7.3 Hz, 6H), 2.59-2.52 (m, 1H), 1.78-1.53 (m, 4H), 1.19 (t, J 7.3 Hz, 9H)
	In ethanol; at 80℃; for 72h;	(2-Chloropyrimidin-5-yl)boronic acid (1.13 g, 7.14 mmol) and (1S,5R)-3,6-diazabicyclo[3.2.2]nonan-7-one (1.00 g, 7.13 mmol) were mixed together in ethanol (15 mL) and triethylamine (1.00 mL, 7.10 mmol) was added. The mixture was heated to 80 C. for 3 days. The mixture was concentrated in vacuo to afford the title compound (2.70 g, UV purity 94.7%) as an off-white solid, which was used in subsequent coupling reactions without any further purification. deltaH (300 MHz, DMSO-d6) 10.54-9.53 (br s, 2H), 8.08 (s, 2H), 4.88-4.74 (m, 2H), 3.65-3.53 (m, 1H), 3.48-3.39 (m, 1H), 3.24-3.11 (m, 2H), 3.03 (q, J7.3 Hz, 6H), 2.59-2.52 (m, 1H), 1.78-1.53 (m, 4H), 1.19 (t, J7.3 Hz, 9H).

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 99
[2]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0490

45
[ 103039-88-9 ]
[ 1003845-06-4 ]
[ 1515922-46-9 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; at 65℃; for 1h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (321 mg, 2.03 mmol) and ethyl 4-methyl- piperidine-4-carboxylate (347 mg, 2.03 mmol) were stirred in 1,4-dioxane (6 mL) and the mixture was degassed with nitrogen for 5 minutes. The tube was sealed and heated under microwave irradiation for 30 minutes at 65C. Further <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (36 mg, 0.23 mmol) was added and the mixture was heated under microwave irradiation for 30 minutes at 65C. The mixture was concentrated to afford the title compound, which was used without further purification. Method C HPLC-MS: MH+ mlz 294, RT 1.09 minutes
	With triethylamine; In ethanol; at 80℃; for 3h;	[2-(4-Ethoxycarbonyl-4-methylpiperidin-1-yl)pyrimidin-5-yl]boronic acid To <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (4.00 g, 25.3 mmol) were added Intermediate 88 (4.09 g, 23.9 mmol) and ethanol (40 mL). Triethylamine (9.0 mL, 64 mmol) was added and the mixture was heated at 80 C. for 3 h before concentrating in vacuo. The mixture was partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer was separated and re-extracted with EtOAc (2*100 mL). The organic layers were combined and washed with brine (100 mL) before separating, drying (Na2SO4), filtering under reduced pressure and removing the solvent in vacuo. The resulting brown foam was purified by column chromatography on silica, using 100% DCM to 30% MeOH/DCM, to afford the title compound (4.00 g, 74% purity) as a brown oil. LCMS (pH 10): MH+ m/z 294, RT 0.65 minutes (74%).
	In 1,4-dioxane; at 65℃; for 1h;Inert atmosphere; Sealed tube; Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (321 mg, 2.03 mmol) and ethyl 4-methylpiperidine-4-carboxylate (347 mg, 2.03 mmol) were stirred in 1,4-dioxane (6 mL) and the mixture was degassed with nitrogen for 5 minutes. The tube was sealed and heated under microwave irradiation for 30 minutes at 65 C. Further <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (36 mg, 0.23 mmol) was added and the mixture was heated under microwave irradiation for 30 minutes at 65 C. The mixture was concentrated to afford the title compound, which was used without further purification. Method C HPLC-MS: MH+ m/z 294, RT 1.09 minutes.

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 96
[2]Patent: US2015/152065,2015,A1 .Location in patent: Paragraph 0583
[3]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0483

46
methyl 4-hydroxy-4-piperidinecarboxylate [ No CAS ]
[ 1003845-06-4 ]
[ 1536396-19-6 ]

Yield	Reaction Conditions	Operation in experiment
48%	In dimethyl sulfoxide; at 70℃; for 0.833333h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (0.25 g, 1.579 mmol) and methyl 4- hydro xypiperidine-4-carboxylate (0.528 g, 3.315 mmol) were dissolved in DMSO (5 mL) and heated at 70C under microwave irradiation for 50 minutes. The mixture was diluted with EtOAc (45 mL) and washed with saturated aqueous ammonium chloride solution (3 x 6 mL), water (6 mL) and brine (10 mL), then dried over sodium sulfate and concentrated, to afford the title compound (230 mg, 48%) as a brown gum. Method C HPLC-MS: MH+ mlz 282, RT 0.70 minutes
48%	In dimethyl sulfoxide; at 70℃; for 0.833333h;Microwave irradiation;	(2-Chloropyrimidin-5-yl)boronic acid (0.25 g, 1.579 mmol) and methyl 4-hydroxypiperidine-4-carboxylate (0.528 g, 3.315 mmol) were dissolved in DMSO (5 mL) and heated at 70 C. under microwave irradiation for 50 minutes. The mixture was diluted with EtOAc (45 mL) and washed with saturated aqueous ammonium chloride solution (3×6 mL), water (6 mL) and brine (10 mL), then dried over sodium sulfate and concentrated, to afford the title compound (230 mg, 48%) as a brown gum. Method C HPLC-MS: MH+ m/z 282, RT 0.70 minutes.

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 96
[2]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0484

47
[ 1003845-06-4 ]
[ 1609169-25-6 ]
[ 1533399-25-5 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 828 - 835

48
[ 1003845-06-4 ]
[ 1580440-73-8 ]
[ 1580440-74-9 ]

Yield	Reaction Conditions	Operation in experiment
0.7 g	With potassium carbonate; In 1,4-dioxane; at 90℃; for 3h;	To a stirred solution of 4-hydroxybenzaldehyde (6.00 g, 49.1 mmol) in acetonitrile (200 mL) was added cesium carbonate (40.0 g, 123 mmol) and l-chloro-2-methoxyethane (6.90 g, 73.7 mmol). The solution was heated at reflux overnight and then diluted with water (100 mL). The mixture was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried (Na2S04) and concentrated. The residue was purified by flash chromatography over silica gel using a hexane/ethyl acetate eluant to afford 4-(2-methoxyethoxy)benzaldehyde as a light yellow oil (6.00 g, 67%). To a stirred solution of this compound (2.70 g, 15.0 mmol) in 1,4-dioxane (50 mL) was added 4-methylbenzenesulfonohydrazide (2.79 g, 15.0 mmol). The solution was heated at 90 C for 1 hour and then concentrated to afford crude N'-(4-(2-methoxyethoxy)benzylidene)-4- methylbenzenesulfonohydrazide as a yellow solid (5.22 g, 99%>). This material was used without purification in the next step. To a stirred solution of the hydrazone (5.22 g, 15.0 mmol) in 1,4-dioxane (50 mL) was added potassium carbonate (6.20 g, 44.9 mmol) and <strong>[1003845-06-4]2-chloropyrimidin-5-ylboronic acid</strong> (2.37 g, 15.0 mmol). Mixture was heated at 90 C for 3 hours, diluted with water (100 mL) and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2S04) and concentrated. The residue was purified by flash chromatography over silica gel using a hexane/ethyl acetate eluant to afford 2-chloro-5-(4-(2-methoxyethoxy)benzyl)pyrimidine as a light yellow oil (0.700 g , 17%)). To a stirred solution of this intermediate (0.700 g, 2.52 mmol) in acetonitrile (15 mL) was added ethyl 4-fiuoropiperidine-4-carboxylate hydrochloride (0.453 g, 2.59 mmol) and cesium carbonate (2.46 g, 7.55 mmol). The mixture was heated at 80 C overnight, diluted with water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2S04) and concentrated. The residue purified by flash chromatography over silica gel using a dichloromethane/methanol eluant to afford ethyl 4-fluoro-l-(5-(4-(2- methoxyethoxy)benzyl)pyrimidin-2-yl)piperidine-4-carboxylate as a light yellow solid (0.667 g, 74%). Exchanging ethyl l-(4-(4-fluorophenyl)pyrimidin-2-yl)piperidine-4- carboxylate for the present intermediate, the final two steps of Example 41 were used to prepare the title compound. 1H NMR (400 MHz, CDC13) delta 8.16 (s, 2H), 7.08 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.37 (d, J= 7.2 Hz, 1H), 4.70-4.66 (m, 2H), 4.11 (t, J = 4.4 Hz, 2H), 3.76-3.74 (m, 4H), 3.46 (s, 3H), 3.26-3.19 (m, 2H), 2.96-2.79 (m, 6H), 2.28- 2.15 (m, 3H), 1.87-1.77 (m, 4H), 1.58-1.50 (m, 5H) ppm. 13C NMR (100 MHz, CDC13) delta 171.3, 171.1, 160.5, 157.9, 157.4, 132.4, 129.5, 122.4, 114.8, 97.0, 95.1, 71.0, 67.3, 63.0, 59.2, 52.8, 46.5, 46.3, 39.3, 34.7, 31.9, 31.8, 31.7, 31.6, 30.1, 24.2, 22.9, 22.3 ppm. Purity: > 93% LCMS (214 nm & 254 nm); retention time 1.36 min; (M+H+) 512.3.

Reference： [1]Patent: WO2014/43068,2014,A1 .Location in patent: Page/Page column 225

49
[ 1003845-06-4 ]
5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine [ No CAS ]
2-chloro-5-[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium hydrogencarbonate; In acetonitrile; at 120℃; for 0.2h;Microwave irradiation;	Example 2 2-Chloro-5-[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine (Intermediate 2, 100 mg, 0.321 mmol), <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (76 mg, 0.481 mmol) in ACN (3.2 mL) was added NaHCO3 (417 mg, 1.282 mmol) and PdCl2(dppf)-DCM (23 mg, 0.032 mmol). The reaction was heated under microwave conditions, at 120 C. for 12 minutes. Water was removed from the reaction with a pipette, and the crude reaction mix was filtered thru CELITE, and washed with EtOAc. The combined organics were dried (Na2SO4), filtered and concentrated onto silica. Purification (FCC, SiO2, 30-70% EtOAc/hexanes) afforded the title compound (61 mg, 55%). 1H NMR (400 MHz, DMSO-d6) delta 8.34 (s, 2H), 8.11 (d, J=2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.53-7.36 (m, 3H), 3.83 (s 2H), 3.73 (s, 3H). [M+H]=346.11.

Reference： [1]Patent: US2014/275531,2014,A1 .Location in patent: Paragraph 0392; 0393

50
[ 1003845-06-4 ]
[ 100-39-0 ]
[ 859209-15-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 22h;Inert atmosphere;	To a nitrogen-degassed mixture of <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (1.61 g, 10.2 mmol), bis(triphenylphosphine)palladium(II)dichloride (0.36 g, 0.51 mmol), sodium carbonate (3.24 g, 30.6 mmol), water (6.5 mL), and dioxane (16 mL) was added benzyl bromide (1.92 g, 11.2 mmol). The mixture was stirred about 22 hours at 100C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (80 mL), and washed with water (60 mL) and then brine (50 mL), then dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude amber oil was purified by silica gel chromatography with hexanes to 30% ethyl acetate / hexanes gradient to yield the product 5-benzyl-2-chloropyrimidine as an orange oil which solidified upon standing (1.21 g, 58% yield).

Reference： [1]Patent: WO2014/160521,2014,A1 .Location in patent: Page/Page column 26-27

51
[ 1003845-06-4 ]
N-{4-[(3-iodo-5-methoxybenzene)amido]phenyl}pyridine-2-carboxamide [ No CAS ]
N-(4-[3-(2-chloropyrimidin-5-yl)-5-methoxybenzene]amido}phenyl)pyridine-2-carboxamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 6256 - 6269

52
[ 1003845-06-4 ]
6-bromo-1-(2-difluoromethoxybenzyl)-2-methyl-1H-benzimidazole [ No CAS ]
6-(2-chloropyrimidin-5-yl)-1-[2-difluoromethoxybenzyl]-2-methyl-1H-benzimidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%		6-(2-Chlororimidin-5yl)-1-[2-difluoron(benzyl]-2-methyl-1H-benzimidazole To Intermediate 47 (1.0 g, 2.72 mmol) under a nitrogen atmosphere were added <strong>[1003845-06-4]2-chloropyrimidin-5-ylboronic acid</strong> (533 mg, 3.27 mmol), Pd(PPh3)4 (158 mg, 0.136 mmol), 2M aqueous sodium carbonate solution (13 mL) and 1,4-dioxan (60 mL). The reaction was stirred at 105 C. under nitrogen for 18 h. After this time, PdCl2(dppf) (100 mg, 5 mol %) and a further quantity of <strong>[1003845-06-4]2-chloropyrimidin-5-ylboronic acid</strong> (266 mg, 0.5 equiv.) were added. Heating was continued at 105 C. for 5 h. The reaction was worked up by the addition of water (50 mL). The aqueous phase was extracted with ethyl acetate (2*100 mL) and the combined organic layers were concentrated in vacuo to a black oil. The crude residue was purified by silica flash column chromatography (10-50% ethyl acetate/DCM) to give the title compound (460 mg, 42%) as a pink solid. deltaH (d6-DMSO, 400 MHz) 9.12 (2H, s), 8.01 (1H, d, J 1.3 Hz), 7.72 (1H, d, J 8.4 Hz), 7.66-7.53 (2H, m), 7.40-7.35 (1H, m), 7.27 (1H, d, J 7.5 Hz), 7.19-7.13 (1H, m), 6.73-6.71 (1H, m), 5.58 (2H, s), 3H not observed (CH3) under d6-DMSO peak at 2.50 ppm. LCMS (pH 3) 401.6, MH+, RT 1.67 minutes, 100% UV. LCMS (pH 10) 401.6, MH+, RT 2.09 minutes, 94.9% UV.

Reference： [1]Patent: US2015/152065,2015,A1 .Location in patent: Paragraph 0554

53
[ 1003845-06-4 ]
C₉H₁₅NO₂ [ No CAS ]
{2-[(1R,5S,8R)-8-Methoxycarbonyl-3-azabicyclo[3.2.1]octan-3-yl]pyrimidin-5-yl}boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.9 g	With triethylamine; In ethanol; at 80℃; for 5h;	{2-[(1R,5S,8r)-8-Methoxycarbonyl-3-azabicyclo[3.2.1]octan-3-yl]pyrimidin-5-yl}boronic acid Methyl (1R,5S,8r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylate (9.0 g, 35.3 mmol) was suspended in HCl solution (2.25M in MeOH) and the reaction mixture was heated to reflux for 4 h. The reaction mixture was allowed to cool to r.t. and then concentrated in vacuo to give a white solid. (2-Chloropyrimidin-5-yl)boronic acid (5.58 g, 35.2 mmol) was added and the mixture was suspended in EtOH (130 mL). Triethylamine (9.90 mL, 70.5 mmol) was added and the reaction mixture was heated at 80 C. for 5 h. The reaction mixture was allowed to cool to r.t. and then water was added (30 mL). The reaction mixture was concentrated to around one third volume, then more water (100 mL) was added. An off-white solid precipitated out, which was filtered and washed with water (2*30 mL), to afford the title compound (8.9 g, 86%) as an off-white powder. deltaH (300 MHz, d6-DMSO) 8.59 (2H, s), 8.02 (2H, s), 4.45 (2H, dd, J 13.1, 3.4 Hz), 3.62 (3H, s), 2.98 (2H, br d, J 12.4 Hz), 2.77 (1H, s), 2.59 (2H, br s), 1.66-1.63 (2H, m), 1.38-1.33 (2H, m). HPLC-MS (pH10): MH+ m/z 292, RT 0.97 minutes.

Reference： [1]Patent: US2015/152065,2015,A1 .Location in patent: Paragraph 0579

54
[ 1003845-06-4 ]
6-bromo-1-[2-(difluoromethoxy)benzyl]-5-fluoro-2-methyl-1H-benzimidazole [ No CAS ]
6-(2-chloropyrimidin-5-yl)-1-[2-(difluoromethoxy)phenyl]methyl}-5-fluoro-2-methylbenzimidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 10h;	6-(2-Chloropyrimidin-5-yl)-1-[2-(difluoromethoxy)phenyl]methyl}-5-fluoro-2-methylbenzimidazole A mixture of Intermediate 50 (0.5 g, 1 mmol), <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (0.3 g, 2 mmol), Pd(dppf)Cl2 (0.03 g, 0.04 mmol) and 2M aqueous sodium carbonate solution (2 mL) in 1,4-dioxane (8 mL) was degassed and stirred at 110 C. After 6 h, further <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (60 mg) and Pd(dppf)Cl2 (10 mg) were added, and the reaction mixture was degassed and stirred at the same temperature for 4 h. The cooled reaction mixture was partitioned between EtOAc and brine, then the organic layer was dried (MgSO4) and concentrated. The crude residue was purified by column chromatography (hexanes:EtOAc, 3:2 to 1:1) to afford the title compound (200 mg, 40%) as a white crystalline solid. deltaH (400 MHz, DMSO-d6) 8.98 (d, J 1.5 Hz, 2H), 7.86 (d, J 6.8 Hz, 1H), 7.61 (m, 1H), 7.39 (m, 1H), 7.34 (t, J 72, 76 Hz, 1H), 7.26 (d, J 7.7 Hz, 1H), 7.16 (m, 1H), 6.76 (dd, J 7.7, 1.3 Hz, 1H), 5.56 (s, 1H), 2.50 (s, 3H). LCMS (pH 10) MH+ 419, RT 1.53 minutes.

Reference： [1]Patent: US2015/152065,2015,A1 .Location in patent: Paragraph 0561

55
[ 1003845-06-4 ]
[ 162648-32-0 ]
1-(5-boronopyrimidin-2-yl)-4-methylpiperidine-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine; In ethanol; at 80℃; for 12h;	To a solution of Intermediate 10 (434 mg, 3.03 mmol) in EtOH (8 mL) was added triethylamine (0.76 mL, 7.59 mmol), followed by <strong>[1003845-06-4]2-chloropyrimidin-5-ylboronic acid</strong> (400 mg, 2.51 mmol). The reaction mixture was heated at 80C for 12 h, then concentrated in vacuo. The crude solid obtained was washed with water, then dried, to give the title compound (500 mg, 74%). LCMS (ES+) 265 (M+H), RT 0.36 minutes.

Reference： [1]Patent: WO2015/86502,2015,A1 .Location in patent: Page/Page column 85

56
[ 67-56-1 ]
[ 1003845-06-4 ]
(1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid [ No CAS ]
{2-[(1R,5S)-8-(methoxycarbonyl)-3-azabicyclo[3.2.1]octan-3-yl]pyrimidin-5-yl}boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%		INTERMEDIATE 8 {2-r(lR,5tS')-8-Methoxycarbonyl-3-azabicvclor3.2.11octan-3-yllpyrimidin-5-yl\|boronic acid (lR,5S)-3-(ie/t-Butoxycarbonyl)-3-azabicyclo[3.2. l]octane-8-carboxylic acid (9.0 g, 35.3 mmol) was suspended in HC1 solution (2.25M in MeOH). The reaction mixture was heated under reflux for 4 h, then allowed to cool to room temperature and concentrated in vacuo. To the resulting white solid was added 2-chloropyrimidin-5- ylboronic acid (5.58 g, 35.2 mmol) and the mixture was suspended in EtOH (130 mL). Triethylamine (9.90 mL, 70.5 mmol) was added and the reaction mixture was heated at 80C for 5 h. The reaction mixture was allowed to cool to room temperature, then water (30 mL) was added. The reaction mixture was concentrated to around one-third volume, then more water (100 mL) was added. An off-white solid precipitated out, which was filtered and washed with water (2 x 30 mL) to afford the title compound (8.9 g, 86%) as an off-white powder. deltaEta (300 MHz, DMSO-d6) 8.59 (s, 2H), 8.02 (s, 2H), 4.45 (dd, 2H, / 13.1, 3.4 Hz), 3.62 (s, 3H), 2.98 (br d, 2H, / 12.4 Hz), 2.77 (s, 1H), 2.59 (br s, 2H), 1.66- 1.63 (m, 2H), 1.38-1.33 (m, 2H). LCMS (pH 10) (ES+) 292 (M+H)+, RT 0.97 minutes.

Reference： [1]Patent: WO2015/86501,2015,A1 .Location in patent: Page/Page column 90

57
[ 1003845-06-4 ]
[ 64-17-5 ]
(1R,5S)-3-(tert-Butoxycarbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid [ No CAS ]
2-[(1R,5S)-8-methoxycarbonyl-3-azabicyclo[3.2.1]octan-3-yl]pyrimidin-5-ylboronicacid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%		(1R,5S)-3 -(tert-Butoxycarbonyl)-3 -azabicyclo [3.2.1 ]octane-8-carboxylic acid (9.0g, 35.3 mmol) was suspended in HC1 solution (2.25M in MeOH) and the reaction mixture was heated at reflux for 4 h. The reaction mixture was allowed to cool to room temperature, then concentrated in vacuo. To the resulting white solid was added 2- chloropyrimidin-5-ylboronic acid (5.58 g, 35.2 mmol) and the mixture was suspended in EtOH (130 mL). Triethylamine (9.90 mL, 70.5 mmol) was added and the reactionmixture was heated at 80C for 5 h. The reaction mixture was allowed to cool to room temperature, then water (30 mL) was added. The reaction mixture was concentrated to around one-third volume, then more water (100 mL) was added. The off-white solid precipitate was filtered and washed with water (2 x 30 mL) to afford the title compound (8.9 g, 86%) as an off-white powder. H (300 MHz, DMSO-d6) 8.59 (2H, s), 8.02 (2H, s),4.45 (2H, dd, J 13.1, 3.4 Hz), 3.62 (3H, s), 2.98 (2H, br d, J 12.4 Hz), 2.77 (1H, s), 2.59 (2H, br s), 1.66-1.63 (2H, m), 1.38-1.33 (2H, m). LCMS m/z 292.

Reference： [1]Patent: WO2015/86506,2015,A1 .Location in patent: Page/Page column 149

58
[ 1003845-06-4 ]
(1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid [ No CAS ]
{2-[(1R,5S)-8-(methoxycarbonyl)-3-azabicyclo[3.2.1]octan-3-yl]pyrimidin-5-yl}boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%		(1R,5S)-3 -tert-Butoxycarbonyl-3 -azabicyclo [3.2.1 ]octane-8-carboxylic acid (9.0 g, 35.3 mmol) was suspended in HC1 solution (2.25M in MeOH) and the reaction mixture was heated at reflux for 4 h. The reaction mixture was allowed to cool to room temperature, then concentrated in vacuo. To the resulting white solid was added <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (5.58 g, 35.2 mmol) and the mixture was suspended in EtOH (130 mL). Triethylamine (9.90 mL, 70.5 mmol) was added and the reaction mixture was heated at 80C for 5 h. The reaction mixture was allowed to cool to room temperature, then water (30 mL) was added. The reaction mixture was concentrated to around one-third volume, then more water (100 mL) was added. The resulting off-white solid precipitate was filtered and washed with water (2 x 30 mL), to afford the title compound (8.9 g, 86%) as an off-white powder. H (300 MHz, DMSO-d6) 8.59 (2H, s), 8.02 (2H, s), 4.45 (2H, dd, J 13.1, 3.4 Hz), 3.62 (3H, s), 2.98 (2H, br d, J 12.4 Hz), 2.77(1H, s), 2.59 (2H, br s), 1.66-1.63 (2H, m), 1.38-1.33 (2H, m). LCMS m/z 292 [M+H].
86%		(lR,5S)-3-tert-butoxycarbonyl-3-azabicyclo[3.2.1]octane-8-carboxylic acid (9.0 g, 35.3 mmol) was suspended in HC1 solution (2.25 M in MeOH) and the reaction heated to reflux for 4 h. The reaction was allowed to cool to r.t. and then concentrated in vacuo to give a white solid. <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (5.58 g, 35.2 mmol) was added and the mixture suspended in EtOH (130 mL). TEA (9.90 mL, 70.5 mmol) was added and the reaction heated at 80 C for 5 h. The reaction was allowed to cool to r.t. and then water was added (30 mL). The reaction mixture was concentrated to around 1/3 volume and then more water added (100 mL). An off-white solid precipitated out, which was filtered and washed with water (2 x 30 mL) to afford the title compound (8.9 g, 86%> yield) as an off-white powder. 1H NMR (300 MHz, DMSO-d6) delta ppm 8.59 (s, 2H), 8.02 (s, 2H), 4.45 (dd, J 13.1, 3.4 H, 2H), 3.62 (s, 3H), 2.98 (br d, J 12.4 Hz, 2H), 2.77 (s, - -1H), 2.59 (br s, 2H), 1.66-1.63 (m, 2H), 1.38-1.33 (m, 2H). LCMS (ES+) RT 0.97 min, 292.0 (M+H)+.
86%		(1 R,5 S)-3-tert-butoxycarbonyl-3 -azabicyclo [3.2.1 ]octane-8-carboxylic acid (9.0 g,35.3 mmol) was suspended in HC1 solution (2.25 M in MeOH) and the reaction heated to reflux for 4 h. The reaction was allowed to cool to r.t. and then concentrated in vacuo to give a white solid. <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (5.58 g, 35.2 mmol) was added and the mixture suspended in EtOH (130 mL). Triethylamine (9.90 mL, 70.5 mmol) wasadded and the reaction heated at 80 C for 5 h. The reaction was allowed to cool to r.t.and then water was added (30 mL). The reaction mixture was concentrated to around 1/3volume and then more water added (100 mL). An off-white solid precipitated out , whichwas filtered and washed with water (2 x 30 mL) to afford the title compound (8.9 g, 86%yield) as an off-white powder. 1H NMR (300 MHz, DMSO- d6) oe ppm 8.59 (2H, s), 8.02(2H, s), 4.45 (2H, dd, J 13.1, 3.4 Hz), 3.62 (3H, s), 2.98 (2H, br d, J 12.4 Hz), 2.77 (1H,s), 2.59 (2H, br s), 1.66-1.63 (2H, m), 1.38-1.33 (2H, m). LCMS (ESj RT 0.97 mill 292.0 (M+H).

Reference： [1]Patent: WO2015/86512,2015,A1 .Location in patent: Page/Page column 102; 013
[2]Patent: WO2015/86526,2015,A1 .Location in patent: Page/Page column 117; 118
[3]Patent: WO2015/86525,2015,A1 .Location in patent: Page/Page column 118; 119

59
[ 5625-67-2 ]
[ 1003845-06-4 ]
[ 1537169-20-2 ]
[ 1537168-91-4 ]

Yield	Reaction Conditions	Operation in experiment
3%		A mixture of <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (100 mg, 0.63 mmol) and piperazin-2-one (63 mg, 0.632 mmol) was heated in 1,4-dioxane (2 mL) under microwave irradiation at 100 C. for 1 h. Intermediate 5 (160 mg, 0.417 mmol), 2M aqueous sodium carbonate solution (1.516 mL, 3.03 mmol) and 1,2-dimethoxyethane (1 mL) were added. The mixture was thoroughly degassed, then Pd(PPh3)4 (73 mg, 0.06 mmol) was added. The mixture was heated at 90 C. in a sealed tube under nitrogen for 8 h. The mixture was diluted with EtOAc (20 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was separated and washed with brine (10 mL), then dried over sodium sulfate and concentrated under vacuum. The residue was suspended in hot DMSO (2 mL), allowed to cool and filtered. The solids were washed with MeOH (2×2 mL), and the combined filtrates were purified preparative HPLC, to afford the title compound (10 mg, 3%) as a white solid. deltaH (500 MHz, DMSO-d6) 8.98 (m, 3H), 8.91-8.85 (m, 1H), 8.15 (s, 1H), 8.04 (dd, J5.7, 3.7 Hz, 1H), 7.38 (dt, J7.4, 3.7 Hz, 2H), 7.23-6.88 (m, 2H), 6.55 (d, J4.1 Hz, 1H), 6.34 (d, J 4.2 Hz, 1H), 4.25 (s, 2H), 4.05-3.90 (m, 2H), 3.31 (t, J 6.5 Hz, 2H), 2.19 (s, 3H). Method D HPLC-MS: MH+ m/z 482, RT 2.05 minutes.

Reference： [1]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0542

60
[ 1003845-06-4 ]
[ 1537169-11-1 ]
ethyl 3-azabicyclo[4.1.0]heptane-6-carboxylate hydrochloride [ No CAS ]
[ 1537169-44-0 ]

Yield	Reaction Conditions	Operation in experiment
11%		(2-Chloropyrimidin-5-yl)boronic acid (231 mg, 1.46 mmol) and Intermediate 42 (300 mg, 1.46 mmol) were dissolved in DMF (5 mL) and potassium carbonate (302 mg, 2.19 mmol) was added. The mixture was heated at 80 C. in a sealed tube for 3.5 h. The reaction mixture was cooled down to r.t., then Intermediate 6 (347 mg, 0.94 mmol), a 2M solution of potassium carbonate in water (1.39 mL) and 1,4-dioxane (6 mL) were added. The mixture was degassed with nitrogen, then Pd(dppf)Cl2.DCM (39 mg, 0.048 mmol) was added. The mixture was heated at 80 C. in a sealed tube for 3 h. The reaction mixture was cooled down to r.t. and concentrated under vacuum. The resulting brown residue was partitioned between EtOAc (5 mL) and water (3 mL). The organic phase was washed with water (3×3 mL), then the aqueous washes were combined and extracted with EtOAc (3×3 mL). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated. The resulting crude brown oil was purified by FCC (SiO2, heptanes:EtOAc 7.5:2.5 to 2:8) to afford a solid which was further purified by trituration in diethyl ether, then dissolved in a mixture of DMSO and water. The solid which precipitated out of solution was filtered and washed with diethyl ether, to afford the title compound (55 mg, 11%). Method C HPLC-MS: MH+ m/z 535, RT 1.46 minutes.

Reference： [1]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0500

61
[ 1003845-06-4 ]
[ 1537169-11-1 ]
tetrahydrofuran-3-amine hydrochloride [ No CAS ]
[ 1537168-66-3 ]

Yield	Reaction Conditions	Operation in experiment
15%		(2-Chloropyrimidin-5-yl)boronic acid (50 mg, 0.32 mmol) was dissolved in 1,4-dioxane (1 mL) and tetrahydrofuran-3-amine hydrochloride (117 mg, 0.95 mmol) was added, followed by sodium carbonate (117.13 mg, 1.11 mmol). The reaction mixture was heated at 100 C. under microwave irradiation for 1 h. The reaction mixture was transferred to a pressure tube and diluted with 1,2-dimethoxyethane (2 mL). Intermediate 6 (58 mg, 0.16 mmol) was added, followed by 2M aqueous sodium carbonate solution (0.76 mL), and the reaction mixture was degassed with nitrogen for 5 minutes. Pd(PPh3)4 (36 mg, 0.03 mmol) was added, and the mixture was heated at 90 C. for 2 h. The reaction mixture was diluted with EtOAc (15 mL), washed with water (10 mL) and brine (10 mL), then dried over sodium sulfate and concentrated to dryness. The residue was purified by preparative HPLC, to afford the title compound (22 mg, 15%) as a white solid. deltaH (500 MHz, CD3OD) 8.91 (s, 1H), 8.80 (d, J4.1 Hz, 2H), 8.50 (s, 1H), 7.32 (t, J 7.7 Hz, 1H), 7.24-7.14 (m, 3H), 6.91 (t, J73.9 Hz, 1H), 4.60-4.52 (m, 1H), 4.45 (s, 2H), 4.03-3.94 (m, 2H), 3.90-3.82 (m, 1H), 3.72 (dd, J9.1, 3.7 Hz, 1H), 2.45 (s, 3H), 2.35-2.27 (m, 1H), 1.98 (m, J4.9 Hz, 1H). Method D HPLC-MS: MH+ m/z 453, RT 2.51 minutes.

Reference： [1]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0521

62
[ 1003845-06-4 ]
4,4-difluoro-piperidine hydrochloride [ No CAS ]
[ 1537169-11-1 ]
[ 1537168-67-4 ]

Yield	Reaction Conditions	Operation in experiment
47%		(2-Chloropyrimidin-5-yl)boronic acid (200 mg, 1.26 mmol) and 4,4-difluoro-piperidine hydrochloride (239 mg, 1.52 mmol) were suspended in 1,4-dioxane (3 mL) and heated for 1 h at 100 C. under microwave irradiation. The mixture was filtered and concentrated under vacuum. Intermediate 6 (200 mg, 0.54 mmol) and 1,4-dioxane (4 mL) were added, and the mixture was degassed for 5 minutes. Degassed 2M aqueous potassium carbonate solution (0.81 mL) and bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (31 mg, 0.04 mmol) were added and the mixture was heated at 100 C. for 16 h. The mixture was partitioned between EtOAc (30 mL) and water (20 mL) and the aqueous phase was extracted with further EtOAc (20 mL). The organic layers were combined and washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of 0-5% ammonia/ MeOH in DCM. The material was then triturated in hot MeOH, and the solids were filtered, to afford the title compound (124 mg, 47%) as a pale peach solid. deltaH (250 MHz, CDCl3) 9.16 (s, 1H), 8.78 (s, 2H), 8.00 (s, 1H), 7.30 (d, J8.4 Hz, 1H), 7.16 (dd, J 12.3, 7.4 Hz, 2H), 7.01-6.34 (m, 2H), 4.34 (s, 2H), 4.10-3.99 (m, 4H), 2.62 (s, 3H), 2.03 (tt, J 13.6, 5.8 Hz, 4H). Method A HPLC-MS: MH+ m/z 487, RT 4.55 minutes.

Reference： [1]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0522

63
[ 1003845-06-4 ]
2-oxa-6-aza-spiro[3.3]heptane oxalate [ No CAS ]
[ 1537169-11-1 ]
[ 1537168-68-5 ]

Yield	Reaction Conditions	Operation in experiment
5%		(2-Chloropyrimidin-5-yl)boronic acid (150 mg, 0.95 mmol) and 2-oxa-6-azaspiro-[3.3]heptane oxalate (239 mg, 1.26 mmol) were suspended in 1,4-dioxane (6 mL) and triethylamine (0.18 mL, 1.26 mmol) was added. The mixture was heated at 100 C. under microwave irradiation for 1 h. The mixture was diluted with MeOH (20 mL), then concentrated. To the resulting orange oil were added Intermediate 6 (228 mg, 0.62 mmol), 2M aqueous potassium carbonate solution (1.4 mL) and 1,4-dioxane (5 mL). The mixture was thoroughly degassed before the addition of bis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (36 mg, 0.04 mmol), then the mixture was heated at 100 C. for 15 h. EtOAc (10 mL) was added, then the mixture was washed with water (2×10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with a gradient of 0-7% MeOH in DCM. The resulting material was further purified by preparative HPLC, to afford the title compound (21.2 mg, 5%) as a white solid. deltaH (500 MHz, CDCl3) 9.04 (d, J4.5 Hz, 1H), 8.74 (s, 2H), 7.93 (s, 1H), 7.28 (t, J7.9 Hz, 1H), 7.17 (d, J8.2 Hz, 1H), 7.12 (t, J 7.5 Hz, 1H), 6.94 (d, J7.6 Hz, 1H), 6.63 (t, J73.5 Hz, 1H), 4.87 (s, 4H), 4.35 (s, 4H), 4.32 (s, 2H), 2.57 (s, 3H). Method A HPLC-MS: MH+ m/z 465, RT 3.59 minutes.

Reference： [1]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0523

64
[ 141-91-3 ]
[ 1003845-06-4 ]
[ 1537169-11-1 ]
[ 1537168-70-9 ]

Yield	Reaction Conditions	Operation in experiment
12%		(2-Chloropyrimidin-5-yl)boronic acid (50 mg, 0.32 mmol) was dissolved in 1,4-dioxane (1 mL) and 2,6-dimethylmorpholine (117 muL, 0.95 mmol) was added. The reaction mixture was heated at 100 C. under microwave irradiation for 1 h. The reaction mixture was transferred to a pressure tube and diluted with 1,2-dimethoxyethane (2 mL). Intermediate 6 (77 mg, 0.21 mmol) was added, followed by 2M aqueous sodium carbonate solution (0.76 mL), and the reaction was degassed with nitrogen for 5 minutes. Pd(PPh3)4 (36 mg, 0.03 mmol) was added and the mixture was heated at 90 C. for 100 minutes. The reaction mixture was diluted with EtOAc (15 mL) and washed with water (10 mL), followed by brine (10 mL), then dried over sodium sulfate and concentrated to dryness. The residue was purified by preparative HPLC to afford the title compound (17.6 mg, 12%) as a white solid. deltaH (500 MHz, CD3OD) 8.90 (d, J 1.3 Hz, 1H), 8.83 (s, 2H), 8.50 (d, J 1.3 Hz, 1H), 7.36-7.28 (m, 1H), 7.24-7.14 (m, 3H), 6.91 (t, J 74.0 Hz, 1H), 4.64 (d, J 11.8 Hz, 2H), 4.45 (s, 2H), 3.71-3.58 (m, 2H), 2.62 (dd, J 13.3, 10.6 Hz, 2H), 2.45 (s, 3H), 1.24 (d, J6.1 Hz, 6H). Method D HPLC-MS: MH+ m/z 481, RT 3.42 minutes.

Reference： [1]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0524

65
[ 62848-20-8 ]
[ 1003845-06-4 ]
[ 1537169-11-1 ]
[ 1537168-77-6 ]

Yield	Reaction Conditions	Operation in experiment
2%		(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.632 mmol) and 3-methoxy-pyrrolidine (64 mg, 0.63 mmol) were suspended in 1,4-dioxane (3 mL), triethylamine (0.09 mL, 0.632 mmol) was added and the mixture was heated at 60 C. under microwave irradiation for 45 minutes. The reaction mixture was concentrated under vacuum, dissolved in DCM (20 mL) and washed with water (2×10 mL). The aqueous layer was concentrated under vacuum. To the resulting off-white solid were added Intermediate 6 (173 mg, 0.47 mmol), 2M aqueous potassium carbonate solution (1.09 mL) and 1,4-dioxane (5 mL). The mixture was thoroughly degassed before the addition of bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (27 mg, 0.034 mmol). The mixture was heated at 100 C. overnight. Pd(PPh3)4 (0.034 mmol) was added and the mixture was heated at 100 C. overnight. EtOAc (10 mL) was added and the mixture was washed with water (2×10 mL) and brine (10 mL). The organic fraction was dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with 0-7% MeOH in DCM. The material was then further purified by preparative HPLC to afford the title compound (7.3 mg, 2%) as a yellow solid. deltaH (500 MHz, CDCl3) 9.06 (s, 1H), 8.76 (s, 2H), 7.91 (s, 1H), 7.29 (t, J7.8 Hz, 1H), 7.17 (d, J 8.1 Hz, 1H), 7.12 (t, J 7.5 Hz, 1H), 6.93 (d, J 7.7 Hz, 1H), 6.81-6.45 (m, 1H), 4.32 (s, 2H), 4.16-4.05 (m, 1H), 3.85-3.74 (m, 2H), 3.74-3.62 (m, 2H), 3.38 (s, 3H), 2.58 (s, 3H), 2.25-2.16 (m, 1H), 2.10 (m, 1H). Method D HPLC-MS: MH+ m/z 466, RT 2.77 minutes.

Reference： [1]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0529

66
[ 1003845-06-4 ]
[ 1537169-11-1 ]
2-azaspiro[3.3]heptane-6-carboxylic acid hydrochloride [ No CAS ]
[ 1537168-78-7 ]

Yield	Reaction Conditions	Operation in experiment
25%		(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol) and 2-azaspiro[3.3]-heptane-6-carboxylic acid hydrochloride (113 mg, 0.64 mmol) were dissolved in DMF (2 mL), then potassium carbonate (131 mg, 0.95 mmol) was added. The mixture was heated at 80 C. in a sealed tube for 2 h. To the mixture were added Intermediate 6 (150 mg, 0.41 mmol), 2M aqueous potassium carbonate solution (0.6 mL) and 1,4-dioxane (3 mL). The mixture was degassed with nitrogen, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (17 mg, 0.02 mmol) was added. The mixture was heated at 80 C. in a sealed tube for 4 h. The mixture was diluted with DCM (20 mL) and extracted with water (10 mL), followed by 2M aqueous potassium carbonate solution (10 mL). The combined aqueous layers were acidified to pH 4 by the addition of 6M hydrochloric acid. The mixture was left to stand for 10 minutes and the resultant precipitate was collected by filtration. The solids were washed with water (5 mL) and DCM (5 mL), and dried under vacuum, to afford the title compound (50.9 mg, 25%) as a pale pink solid. deltaH (500 MHz, CD3OD) 8.92 (s, 1H), 8.83 (s, 2H), 8.54 (s, 1H), 7.32 (t, J 7.0 Hz, 1H), 7.23-7.15 (m, 3H), 6.90 (t, J 73.9 Hz, 1H), 4.61 (s, 1H), 4.46 (s, 2H), 4.20 (s, 2H), 4.13 (s, 2H), 3.06-3.01 (m, 1H), 2.56-2.47 (m, 4H), 2.45 (s, 3H). Method D HPLC-MS: MH+ m/z 507, RT 2.51 minutes.

Reference： [1]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0530

67
[ 1003845-06-4 ]
[ 1537169-11-1 ]
[ 498-95-3 ]
[ 1537168-80-1 ]

Yield	Reaction Conditions	Operation in experiment
15%		(2-Chloropyrimidin-5-yl)boronic acid (65 mg, 0.41 mmol), (3S)-piperidine-3-carboxylic acid (56 mg, 0.431 mmol) and potassium carbonate (57 mg, 0.41 mmol) were charged to a sealed tube with DMF (2 mL) under nitrogen. The reaction mixture was stirred at 80 C. for 60 minutes. To the mixture were added Intermediate 6 (100 mg, 0.271 mmol), 1,4-dioxane (2 mL) and 2M aqueous sodium carbonate solution (0.16 mL, 1.231 mmol). The mixture was degassed, bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (17 mg, 0.021 mmol) was added and the mixture was stirred at 80 C. under nitrogen for 6 h. The mixture was partitioned between DCM (20 mL) and water (10 mL), and the aqueous fraction was washed with DCM (10 mL). The aqueous layer was acidified to pH 1, then extracted with DCM (3×15 mL). The combined extracts were washed with brine (10 mL), dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to afford the title compound (30 mg, 15%) as a light brown solid. deltaH (500 MHz, DMSO-d6) 8.98 (s, 1H), 8.94 (s, 2H), 8.78 (s, 1H), 7.44-7.10 (m, 5H), 4.78-4.70 (m, 1H), 4.52 (d, J 13.0 Hz, 1H), 4.42 (s, 2H), 3.18-3.10 (m, 1H), 3.05 (t, J 11.0 Hz, 1H), 2.44-2.35 (m, 1H), 2.34 (s, 3H), 2.01 (d, J9.4 Hz, 1H), 1.79-1.59 (m, 2H), 1.44 (q, J 11.9 Hz, 1H). Method D HPLC-MS: MH+ m/z 495, RT 2.84 minutes.

Reference： [1]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0532

68
[ 1003845-06-4 ]
[ 1537169-11-1 ]
3-carboxypyrrolidin-1-ium trifluoroacetate [ No CAS ]
[ 1537168-89-0 ]

Yield	Reaction Conditions	Operation in experiment
5%		A mixture of <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (100 mg, 0.63 mmol) and 3-carboxypyrrolidin-1-ium trifluoroacetate (200 mg, 0.87 mmol) was heated under microwave irradiation at 100 C. for 1 h. Intermediate 6 (150 mg, 0.41 mmol), 2M aqueous sodium carbonate solution (0.65 mL) and 1,2-dimethoxyethane (4 mL) were added. The mixture was thoroughly degassed, then Pd(PPh3)4 (50 mg, 0.04 mmol) was added. The mixture was heated at 90 C. in a sealed tube under nitrogen for 2 h. The mixture was cooled to r.t., then diluted with DCM (20 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC to afford the title compound (8.9 mg, 5%) as a tan solid. deltaH (250 MHz, DMSO-d6) 8.93 (d, J 1.2 Hz, 1H), 8.90 (s, 2H), 8.73 (s, 1H), 7.53-6.93 (m, 5H), 4.38 (s, 2H), 3.73-3.65 (m, 2H), 3.55 (q, J6.9 Hz, 2H), 3.19-3.12 (m, 1H), 2.29 (s, 3H), 2.21-2.09 (m, 2H). Method D HPLC-MS: MH+ m/z 481, RT 2.44 minutes.

Reference： [1]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0540

69
2-(piperazin-1-yl)propanoic acid [ No CAS ]
[ 1003845-06-4 ]
[ 1537169-11-1 ]
[ 1537168-90-3 ]

Yield	Reaction Conditions	Operation in experiment
21%		(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol) and 2-(piperazin-1-yl)propanoic acid (100 mg, 0.63 mmol) were dissolved in DMF (2 mL) and potassium carbonate (131 mg, 0.95 mmol) was added. The mixture was heated at 80 C. in a sealed tube for 6 h. To the mixture were added Intermediate 6 (150 mg, 0.41 mmol), 2M aqueous potassium carbonate solution (0.6 mL) and 1,4-dioxane (3 mL). The mixture was degassed with nitrogen, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]-iron dichloropalladium dichloromethane complex (25 mg, 0.03 mmol) was added. The mixture was heated at 80 C. in a sealed tube for 4 h. The mixture was diluted with DCM (20 mL) and extracted with water (10 mL), followed by 2M aqueous potassium carbonate solution (10 mL). The combined aqueous layers were extracted with 1:1 isopropanol/chloroform (20 mL), then the organic layer was separated and concentrated under vacuum. The residue was purified by preparative HPLC to afford the title compound (43.8 mg, 21%). deltaH (500 MHz, DMSO-d6) 8.97 (d, J 1.1 Hz, 1H), 8.94 (s, 2H), 8.78 (s, 1H), 7.33-7.29 (m, 1H), 7.26 (t, J 15 Hz, 1H), 7.18 (d, J 8.1 Hz, 1H), 7.16 (d, J6.2 Hz, 2H), 4.41 (s, 2H), 3.79 (dt, J 14.1, 6.9 Hz, 4H), 3.24 (q, J7.0 Hz, 1H), 2.65 (dt, J 16.1, 4.3 Hz, 4H), 2.32 (s, 3H), 1.19 (d, J 7.0 Hz, 3H). Method A HPLC-MS: MH+ m/z 524, RT 3.15 minutes.

Reference： [1]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0541

70
[ 1003845-06-4 ]
(1S,5R)-3,6-diazabicyclo[3.2.2]nonan-7-one [ No CAS ]
[ 121-44-8 ]
[2-[(1R,5S)-7-oxo-3,6-diazabicyclo[3.2.2]nonan-3-yl]pyrimidin-5-yl]boronic acid triethylammonium chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.7%	In ethanol; at 80℃; for 4h;	General procedure: <strong>[1003845-06-4]2-chloropyrimidine-5-boronic acid</strong> (52.3 mmol, 8.53 g), thiomorpholine (52.3 mmol, 5.3 ml) and TEA (52.3 mmol, 7.3 ml) were dissolved in EtOH (100 ml) and heated at 80C for 4h. The solvent was removed in vacuo and the resulting solid triturated with Et20 yielding the title compound (8.64 g, 74%). deltaEta(300MHz, DMSO-d6) 8.63 (s, 2H); 8.06 (s, 2H); 4.08 (m, 4H); 2.59 (m, 4H). LCMS (ES+) RT 0.21 min 226.8 (M+H)+. -

Reference： [1]Patent: WO2015/86526,2015,A1 .Location in patent: Page/Page column 128; 129

71
[ 123-90-0 ]
[ 1003845-06-4 ]
(2-thiomorpholinopyrimidin-5-yl)boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine; In ethanol; at 80℃; for 4h;	<strong>[1003845-06-4]2-chloropyrimidine-5-boronic acid</strong> (52.3 mmol, 8.53 g), thiomorpholine (52.3 mmol, 5.3 ml) and TEA (52.3 mmol, 7.3 ml) were dissolved in EtOH (100 ml) and heated at 80C for 4h. The solvent was removed in vacuo and the resulting solid triturated with Et20 yielding the title compound (8.64 g, 74%). deltaEta(300MHz, DMSO-d6) 8.63 (s, 2H); 8.06 (s, 2H); 4.08 (m, 4H); 2.59 (m, 4H). LCMS (ES+) RT 0.21 min 226.8 (M+H)+. -

Reference： [1]Patent: WO2015/86526,2015,A1 .Location in patent: Page/Page column 128
[2]Patent: WO2015/86526,2015,A1 .Location in patent: Page/Page column 128

72
[ 3934-20-1 ]
[ 1003845-06-4 ]
C₈H₄Cl₂N₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With palladium diacetate; potassium carbonate; triphenylphosphine; In tetrahydrofuran; water; for 4h;Inert atmosphere; Reflux;	Pd(OAc)2 (3.52 g) and PPh3 (3.93 g) were added to a mixture of (2-chloropyrimidin-5- yl)boronic acid (47.5 g; 300 mmol), 2,4-dichloropyrimidine (49.16 g; 330 mmol), K2C03 (124.2 g), THF (720 mL) and H20 (750 mL) under N2-gas atmosphere. The mixture was heated to reflux for 4 h. The reaction mixture was cooled to 50 C. The organic layer was separated at 50 C. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Yield: 30 g of Int. 186 (44 %).

Reference： [1]Patent: WO2015/150555,2015,A1 .Location in patent: Page/Page column 153

73
[ 73583-37-6 ]
[ 1003845-06-4 ]
C₉H₅Cl₂N₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26.7%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane;Reflux; Inert atmosphere;	a) Preparation of Int. 120 A solution of <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (31.6 g; 200 mmol), 2-chloro 4- bromo pyridine (40.4 g; 209 mmol) and Na2C03(42.4 g) in dioxane(1000 ml) was degassed with N2 for 30 min. Pd(PPh3)4 was added and the mixture was refluxed overnight. The mixture was filtered over Celite and poured into water. The precipitate was filtered and washed with tert-butyl methyl ether. The residue was purified by column chromatography (eluent: PE / EtOAc 2/1). The desired fractions were collected and the solvent was evaporated. Yield: 12 g of Int. 120 (26.7 %).

Reference： [1]Patent: WO2015/150557,2015,A1 .Location in patent: Page/Page column 133

74
[ 1003845-06-4 ]
C₁₈H₂₅BrN₂OSi [ No CAS ]
C₂₂H₂₇ClN₄OSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With bis(tri-t-butylphosphine)palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;	b) Preparation of Int. 257 A flask was charged with Int. 256 (32.0 g; 81 mmol), <strong>[1003845-06-4]2-chloropyrimidine-5-boronic acid</strong> (15.4 g; 97 mmol), Na2C03 (2M aqueous) and dioxane (q.s.). Bis[tris(l,l- dimethylethyl)phosphine] -palladium (2.1 g; 4.1 mmol) was added to the reaction mixture and the mixture was heated at 100 C for 2 h. The mixture was extracted with EtOAc. The organic phase was evaporated in vacuo to give the crude intermediate which was purified by column chromatography over silica gel (eluent: DCM/MeOH 20/1). The desired fractions were collected and the solvent was evaporated. Yield: 32 g of Int. 257 (92 %).

Reference： [1]Patent: WO2015/150557,2015,A1 .Location in patent: Page/Page column 173

75
[ 446-48-0 ]
[ 1003845-06-4 ]
2-chloro-5-(2-fluorobenzyl)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 85℃; for 16h;	(2-Chloropyrimidin-5-yl)boronic acid (586 mg, 3.70 mmol) and 1 -(bromomethyl)-2-fluorobenzene (700 mg, 3.70 mmol) were dissolved in Tol (10 mL) and EtOH (2.5 mL). Pd(PPh3)4 (214 mg, 0.19 mmol) was added followed by Na2CO3 (392 mg, 3.70 mmol) in H20 (5 mL). The reaction mixture was heated at 85C for 16 h. The resultant mixture was diluted with EtOAc (25 mL), washed with water and brine, dried over Na2SO4and evaporated. Purification by column chromatography (silica, 0% -> 50% EtOAc in heptane) gave INT7-5 (591 mg, 2.65 mmol, 72%) as white crystals. LCMS: calculated for [M+H]: 223, found: 223.

Reference： [1]Patent: WO2016/8593,2016,A1 .Location in patent: Page/Page column 101

76
[ 1003845-06-4 ]
4-[(2-ethylbutyl)amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-quinolinecarboxamide [ No CAS ]
6-(2-chloropyrimidin-5-yl)-4-(2-ethylbutylamino)quinoline-3-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 6281 - 6292

77
[ 1003845-06-4 ]
[ 109-85-3 ]
2-(2-methoxyethylamino)pyrimidin-5-ylboronic acid [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 831 - 834

78
[ 1003845-06-4 ]
[ 1234813-62-7 ]
(R)-(2-(2-(hydroxymethyl)morpholino)pyrimidin-5-yl)boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With triethylamine; In ethanol; at 80℃; for 1h;	Step 2: (i?)-(2-(2-(Hydroxymethyl)morpholino)pyrimidin-5-yl)boronic aeid (2-Chloropyrimidin-5-yl)boronic acid (0.122 g, 0.768 mmol), EtOIT (2 mL), TEA (0.13 mL, 0.92 mmol) and (i?)-moipholin-2-ylmethanol TFA salt (0.108 g, 0.922 mmol) were heated to about 80 C for about 1 h. The reaction mixture was cooled to rt and then concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel (50 - 100% EtOAc/DCM then 0 - 6% MeOH/DCM). The appropriate fractions were concentrated to give the title compound (0.139 g, 76%); LC/MS (Table A, Method b) K, = 0.91 mi ; MS m/z: 240 (M i n' .

Reference： [1]Patent: WO2016/168638,2016,A1 .Location in patent: Page/Page column 44

79
[ 1003845-06-4 ]
hexahydroimidazo[1,5-a]pyrazin-3(2H)-one hydrochloride [ No CAS ]
(S)-7-bromo-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine [ No CAS ]
7-(5-((S)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		To a vial was added <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (0.096 g, 0.608 mmol), EtOH (2 mL), and hexahydroimidazo[l,5- ]pyrazin-3(2H)-one hydrochloride (0.086 g, 0.608 mmol) followed by the addition of TEA (0.109 mL, 0.790 mmol). The contents were heated at about 95 C for about 2 h. The mixture was then added to a second vial preloaded with (<S)-7-bromo-4-phenyl-3,4-dihydro-lH- benzo[4,5]imidazo[2, l-c7[l,4]oxazine (0.100 g, 0.304 mmol, Preparation 24), 2M Cs2C03 (0.304 mL, 0.608 mmol), and SiliaCirf DPP-Pd (0.122 g, 0.030 mmol, 0.25 mmol/g load, SiliCycle Cat R390-100). The contents were heated at about 95 C for about 4 h, the mixture was cooled to rt, concentrated onto silica gel and purified by flash-column chromatography on silica gel (1-10% DCM/MeOH) to give the title compound (0.085 g, 60%); LC/MS (Table 1, Method n) Rt = 1.01 min; MS m/z: 468 (M+H)+ . (TNF ICso=A).

Reference： [1]Patent: WO2016/168641,2016,A1 .Location in patent: Page/Page column 243

80
[ 1003845-06-4 ]
hexahydroimidazo[1,5-a]pyrazin-3(2H)-one hydrochloride [ No CAS ]
7-bromo-4-(2-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine [ No CAS ]
7-(5-(4-(2-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		To a vial was added <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (0.041 g, 0.262 mmol), EtOH (2 mL), and hexahydroimidazo[l,5-a]pyrazin-3(2H)-one hydrochloride (0.046 g, 0.262 mmol) followed by the addition of TEA (0.42 mL, 0.300 mmol). The contents were heated at about 95 C for about 2 h. The mixture was then added to a second vial preloaded with 7-bromo-4-(2-(trifluoromethyl)phenyl)-3,4- dihydro-lH-benzo[4,5]imidazo[2, l-c][l,4]oxazine (0.040 g, 0.101 mmol, Preparation 71), 2M Cs2C03 (0.101 mL, 0.201 mmol), and SiliaCirf DPP-Pd (0.041 g, 0.010 mmol, 0.25 mmol/g load, SiliCycle Cat R390-100). The contents were heated at about 95 C for about 4 h, the mixture was cooled to rt, concentrated onto silica gel and purified by flash-column chromatography on silica gel (1-10% DCM/MeOH). The fractions were dried and then dissolved in 1 mL DCM. 1 mL of 4N hydrochloric acid in 1,4-dioxane was added and after stirring for 30 min the contents were dried under vacuum to give the title compound (0.037 g, 61%) as an HC1 salt; LC/MS (Table 1, Method f) P = 0.83 min; MS m/z: 536 (M+H)+ . (TNF IC50=A).

Reference： [1]Patent: WO2016/168641,2016,A1 .Location in patent: Page/Page column 273; 274

81
[ 1003845-06-4 ]
(R)-7-bromo-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [ No CAS ]
hexahydroimidazo[1,5-a]pyrazin-3(2H)-one hydrochloride [ No CAS ]
7-(5-((R)-1-phenyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		To a vial was added <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (0.030 g, 0.192 mmol), EtOH (1 mL), hexahydroimidazo[l,5-a]pyrazin-3(2H)-one hydrochloride (0.034 g, 0.192 mmol) and TEA (0.027 mL, 0.192 mmol). The mixture was heated at about 95 C for about 1 h then (i?)-7-bromo-l-phenyl-2,3- dihydro-lH-benzo[<f]pyrrolo[l,2-a]imidazole (0.030 g, 0.096 mmol, Preparation 4), CS2CO3 (0.062 g, 0.192 mmol), and SiliaCirf DPP-Pd (0.038 g, 9.58 muiotaetaomicron) were added. The contents were heated to about 95 C for about 2 h. The reaction was cooled to rt, filtered, the filtercake washed with MeOH, and the filtrate concentrated to dryness. The crude product was purified by preparative HPLC (Table 1, Method 1) to give the title compound (0.021 g, 49%); LC/MS (Table 1, Method f) Rt = 0.68 min; MS m/z: 452 (M+ H)+. (TNF IC50 = A).

Reference： [1]Patent: WO2016/168641,2016,A1 .Location in patent: Page/Page column 218

82
[ 5382-16-1 ]
[ 1003845-06-4 ]
2'-bromo-2,3,6',8'-tetrahydrospiro[indene-1,9'-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine] [ No CAS ]
1-(5-(1,2',3,3'-tetrahydrospiro[benzo[4,5]imidazo[2,1-c][1,4]oxazine-4,1'-inden]-7-yl)pyrimidin-2-yl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%		To a vial was added <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (0.200 g, 1.263 mmol), EtOH (3 mL), and piperidin-4-ol (128 mg, 1.263 mmol) followed by the addition of TEA (196 mu, 1.404 mmol). The contents were heated at about 80 C for about 0.5 h. The mixture was then added to 2-5 mL microwave vial preloaded with 2'-bromo-2,3,6',8'-tetrahydrospiro[indene-l,9'-pyrido[3',2':4,5]imidazo[2, l- c][l,4]oxazine] (0.100 g, 0.281 mmol, Preparation 92) and SiliaCirf DPP-Pd (0.112 g, 0.028 mmol, 0.25 mmol/g load, SiliCycle Cat R390-100). The final volume of EtOH was brought to 4 mL and 1M Cs2C03 (0.101 mL, 0.201 mmol) was added. The vial was capped and the contents were heated via microwave irradiation (Biotage Initiator) at 130 C for 20 min. The contents were cooled and concentrated directly onto silica gel and purified by flash chromatography (1-10% DCM/MeOH, 40 g Redisep Gold). Fractions were concentrated to yield title compound (0.085 g, 66%) as a white solid; LC/MS (Table 1, Method f) R, = 0.87 min; MS m/z: 455 (M+H)+ . (TNF IC50=A).

Reference： [1]Patent: WO2016/168641,2016,A1 .Location in patent: Page/Page column 297

83
[ 1003845-06-4 ]
2-iodo-9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine [ No CAS ]
2-(2-chloropyrimidin-5-yl)-9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,1-c][1,4]oxazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane; In tetrahydrofuran; at 60℃; for 1h;Inert atmosphere;	To a solution of 2-iodo-9-phenyl-8,9-dihydro-6H-pyrido[3',2':4,5]imidazo[2,l-c][l,4]oxazine (0.380 g, 1.007 mmol) and <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (0.160 g, 1.007 mmol) in THF (4 mL) at rt was added Cs2C03 (1.007 mL, 2.015 mmol), Pd2(dba)3 (0.090 g, 0.098 mmol) and l,3,5,7-tetramethyl-6- phenyl-2,4,8-trioxa-6-phosphaadamantane (0.058 g, 0.198 mmol). The mixture was degassed (3 x vacuum/purge with N2) and heated to 60 C. After 1 h, the reaction was cooled to rt and concentrated. The residue taken up in CH2CI2 and washed with water and brine; then dried (NaaSOzi), filtered and concentrated. The residue was purified by chromatography on silica gel (100% DCM; then 10 to 50% THF/DCM) to give the title compound (0.296 g; 81%); lH NMR (400 MHz, THF-d8) delta 9.05 (s, 2H), 8.05 (d, J= 8.3 Hz, 1H), 7.82 (d, J= 8.3 Hz, 1H), 7.40 - 7.18 (m, 5H), 5.69 (t, J= 4.3 Hz, 1H), 5.24 - 4.97 (m, 2H), 4.29 (ddd, J= 80.1, 12.0, 4.3 Hz, 2H); MS (DCI) m/z: 364 (M+H)+.

Reference： [1]Patent: WO2016/168641,2016,A1 .Location in patent: Page/Page column 194

84
[ 5382-16-1 ]
[ 1003845-06-4 ]
2-bromo-8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine [ No CAS ]
1-(5-(8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-2-yl)pyrimidin-2-yl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%		To a vial was added <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (48.2 mg, 0.305 mmol) , EtOH (1 mL) and piperidin-4-ol (30.8 mg, 0.305 mmol) followed by the addition of TEA (0.042 mL, 0.305 mmol). The mixture was heated at about 95 C for about 2 h. The reaction was cooled to rt and to the solution was added 2-bromo-8-methyl-8-phenyl-7,8-dihydro-6H-pyrrolo[2', l':2,3]imidazo[4,5-6]pyridine (50 mg, 0.152 mmol, Preparation 16), Cs2C03 (99 mg, 0.305 mmol), and Siliacat Pd-DPP (60.9 mg, 0.015 mmol). The mixture was heated to about 95 C for about 2. The reaction was cooled to rt, filtered, the filter cake wash with MeOH, and the filtate concentrated under reduced pressure. The crude product was purified by preparative HPLC (Table 1, Method ap) to afford the title compound (56 mg, 86 %); LC/MS (Table 1, method e) Rt = 0.75 min; MS m/z: 427 (M+H)+. (TNF IC50= A).

Reference： [1]Patent: WO2016/168641,2016,A1 .Location in patent: Page/Page column 329; 330

85
[ 1003845-06-4 ]
8-bromo-1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine [ No CAS ]
8-(2-chloropyrimidin-5-yl)-1-phenyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 120℃; for 0.75h;Inert atmosphere; Microwave irradiation;	A mixture of 8-bromo-l-phenyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- ]pyridine (0.25 g, 0.76 mmol), <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (0.133 g, 0.840 mmol), PdCl2(dppf) (0.056 g, 0.076 mmol), Na2C03 (0.162 g, 1.53 mmol), 1,4-dioxane (2 mL) and water (2 mL) was heated in a microwave at about 120 C for about 45 min under a N2 atmosphere. The reaction was cooled to rt, diluted with EtO Ac, and the organics collected. The combined organic layer was washed with brine, dried by Na2SOzi, filtered and concentrated under reduced pressure. The residue was purified by flash-column chromatography on silica gel (50-100% EtO Ac/heptane) to give the title compound (0.110 g, 40%); LC/MS (Table 1, Method e) Rt = 1.35 min; MS m/z: 361(M+ H)+

Reference： [1]Patent: WO2016/168641,2016,A1 .Location in patent: Page/Page column 137

86
[ 15862-37-0 ]
[ 1003845-06-4 ]
5-(5-bromo-3-nitropyridin-2-yl)-2-chloropyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 65℃;Inert atmosphere; Sealed tube;	In a 250 mL thick-walled flask was added <strong>[1003845-06-4](2-chloropyrimidin-5-yl)boronic acid</strong> (1 g, 6.32 mmol),2,5-dibromo-3-nitropyridine (1.780 g, 6.32 mmol) in 90 mL of THF. Added tripotassium phosphate (2.68 g, 12.6 mmol)and PdChidppO-CLhChAdduct (0.103 g, 0.126 mmol) . Bubbled in argon through the mixture while sonicating for 1 min. Capped flask and heated in an oil bath at 65 C overnight. Concentrated to afford a brown solid. The crude material was purified on a 120 g ISCO column, eluting with 20% EtOAc/hexanes to 50% EtOAc/hexanes over 20 column volumes. The fractions containing the title compound were concentrated to afford 0.72 g (36% yield) of a yellow solid. NMR (400MHz, CDCh) delta 9.04 (d, J=2.0 Hz, 1H), 8.83 (s, 2H), 8.58 (d, J=2.0 Hz, 1H).

Reference： [1]Patent: WO2016/183118,2016,A1 .Location in patent: Page/Page column 235

87
[ 1003845-06-4 ]
[ 1292324-44-7 ]
(S)-(2-(methyl(tetrahydrofuran-3-yl)amino)pyrimidin-5-yl)boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; at 75℃; for 5h;	To a mixture of <strong>[1003845-06-4]2-chloropyrimidine-5-boronic acid</strong> (32 mg, 0.2 mmol) and (S)-methyl-(tetrahydro-furan-3-yl)-amine hydrochloride (29 mg, 0.21 mmol) in EtOH (2 mL) was added triethylamine (0.070 mL, 0.5 mmol). The resulting mixture was stirred at 75 C for 5 h. Solvents were removed to give crude (S)-(2- (methyl(tetrahydromran-3-yl)amino)pyrirnidin-5-yl)boronic acid as a light yellow semisolid. LCMS [M + H]+ 224.2. The title compound (light beige solid, 8.3 mg, 14%) was prepared by a procedure similar to that of the last step of Example 273 using crude (S)- (2-(methyl(tetrahydrofuran-3-yl)amino)pyrimidin-5-yl)boronic acid (0.2 mmol) and (S)- N-(5 -bromo-2-(3 ,4-dimethylpiperazin- 1 -yl)-4-fluorophenyl)-6-oxo-4-(trifluoromethyl)- l,6-dihydropyridine-3-carboxamide (49.1 mg, 0.1 mmol). 1H NMR (500MHz, CHLOROFORM-d) delta = 8.72 (br s, 1H), 8.57 (s, 2H), 8.47 (br d, J=8.1 Hz, 1H), 7.88 (s, 1H), 7.05 (br d, J=11.0 Hz, 1H), 7.02 (s, 1H), 5.69 - 5.63 (m, 1H), 4.13 (dt, J=4.7, 8.5 Hz, 1H), 3.94 - 3.87 (m, 2H), 3.79 (q, J=8.1 Hz, 1H), 3.16 (s, 3H), 3.03 - 2.88 (m, 3H), 2.83 (br d, J=10.9 Hz, 1H), 2.61 (br t, J=10.3 Hz, 1H), 2.43 - 2.29 (m, 5H), 2.23 (br s, 1H), 2.06 - 1.97 (m, 1H), 1.12 (br d, J=5.9 Hz, 3H); LCMS [M+ H]+ 590.6.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00706

88
[ 3970-68-1 ]
[ 1003845-06-4 ]
(2-(4-hydroxy-4-methylpiperidin-1-yl)pyrimidin-5-yl)boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; at 80℃; for 1h;	To a mixture of <strong>[1003845-06-4]2-chloropyrimidine-5-boronic acid</strong> (48 mg, 0.3 mmol) and 4-methylpiperidin-4-ol (36 mg, 0.315 mmol) in EtOH (2 mL) was added triethylamine (0.070 mL, 0.5 mmol). The resulting mixture was stirred at 80 C for 1 h and solvents were removed to give crude (2-(4-hydroxy-4-methylpiperidin-l- yl)pyrimidin-5-yl)boronic acid as a yellow solid. LCMS [M + H]+ 238.4. The title compound (light beige solid, 34.7 mg, 57%) was prepared according to a method similar to Example 40 using crude (2-(4-hydroxy-4-methylpiperidin-l-yl)pyrimidin-5- yl)boronic acid (0.3 mmol) and (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-l-yl)-4- fluorophenyl)-6-oxo-4-(trifluoromethyl)-l ,6-dihydropyridine-3-carboxamide (49 mg, 0.1 mmol). 11H NMR (500MHz, METHANOL-d4) delta = 8.51 (s, 2H), 7.99 (s, IH), 7.91 (br d, J=8.2 Hz, IH), 7.10 (d, J=12.1 Hz, IH), 6.93 (s, IH), 4.29 (td, J=4.0, 13.2 Hz, 2H), 3.63 - 3.53 (m, 2H), 3.14 - 3.03 (m, 2H), 2.99 - 2.91 (m, 2H), 2.61 - 2.52 (m, 2H), 2.47 - 2.42 (m, IH), 2.39 (s, 3H), 1.71 - 1.58 (m, 4H), 1.28 (s, 3H), 1.14 (d, J=6.2 Hz, 3H); LCMS [M + H]+ 604.5.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00784

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Precautionary Statements-General
Code	Phrase
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Prevention
Code	Phrase
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P270	Do not eat, drink or smoke when using this product.
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P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
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P285	In case of inadequate ventilation wear respiratory protection.
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Response
Code	Phrase
P301	IF SWALLOWED:
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P320
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P321
P322
P330	Rinse mouth.
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P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
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P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
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P361	Remove/Take off immediately all contaminated clothing.
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P370	In case of fire:
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P378
P380	Evacuate area.
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P391	Collect spillage. Hazardous to the aquatic environment
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P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
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P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
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P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
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P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
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Storage
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P401
P402	Store in a dry place.
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P411 + P235	Keep cool.
Disposal
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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
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H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
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H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
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H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1003845-06-4 ] {[proInfo.proName]}

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[ 1003845-06-4 ] Synthesis Path-Upstream 1~6

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Organoboron

Chlorides

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Pyrimidines

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