[ CAS No. 180516-87-4 ] {[proInfo.proName]}

Name: 180516-87-4|4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid|98%
Brand: Ambeed
SKU: A132897
Price: 8.0 USD
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Quality Control of [ 180516-87-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 180516-87-4 ]

SDS Specification

Alternatived Products of [ 180516-87-4 ]

Product Details of [ 180516-87-4 ]

CAS No. :	180516-87-4	MDL No. :	MFCD01863710
Formula :	C₁₃H₁₇BO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IYDKBQIEOBXLTP-UHFFFAOYSA-N
M.W :	248.08	Pubchem ID :	2734621
Synonyms :

Calculated chemistry of [ 180516-87-4 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.46
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	69.88
TPSA :	55.76 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.09 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.43
Log Po/w (WLOGP) :	1.68
Log Po/w (MLOGP) :	1.27
Log Po/w (SILICOS-IT) :	1.25
Consensus Log Po/w :	1.33

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.02
Solubility :	0.235 mg/ml ; 0.000947 mol/l
Class :	Soluble
Log S (Ali) :	-3.24
Solubility :	0.142 mg/ml ; 0.00057 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.38
Solubility :	0.104 mg/ml ; 0.000421 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.76

Safety of [ 180516-87-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 180516-87-4 ]

* 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 [ 180516-87-4 ]
Downstream synthetic route of [ 180516-87-4 ]

[ 180516-87-4 ] Synthesis Path-Upstream 1~21

1
[ 19524-06-2 ]
[ 180516-87-4 ]
[ 4385-76-6 ]

Reference： [1] Patent: US6399656, 2002, B1,

2
[ 106-40-1 ]
[ 180516-87-4 ]
[ 5730-78-9 ]

Reference： [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 20, p. 3144 - 3150

3
[ 150-13-0 ]
[ 73183-34-3 ]
[ 180516-87-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	With tert.-butylnitrite; eosin In acetonitrile at 20℃; for 2 h; Irradiation	General procedure: tert-Butyl nitrite (155 mg, 1.1 mmol) wasadded drop wise to a mixture of bis(pinacolato)diborane (127 mg, 0.5 mmol),4-anisidine (61 mg, 0.5 mmol) and eosin Y (0.01 mmol) in acetonitrile (3 mL).The resulting mixture was stirred at room temperature under irradiation withblue LED for 2 h (TLC). This mixture after being diluted with ethyl acetate(5 mL) was ltered through celite and the ltrate was extracted with ethylacetate (3 10 mL). The extract was washed with brine, dried over anhydrousNa 2 SO 4 , and evaporated to leave the crude product which was puried bycolumn chromatography over silica gel with hexane–ethyl acetate (98:2) aseluent to furnish pure 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a light yellow viscous liquid (3d, 208 mg, 88percent); IR (neat)2978, 2933, 2839, 2526, 2050, 1950, 1911, 1724, 1605, 1570 cm1;1H NMR(500 MHz, CDCl 3 ) d 1.33 (s, 12H), 7.82 (s, 3H), 6.89 (d, J = 8.0 Hz, 2H), 7.75 (d,J = 8.0 Hz, 2H);13C NMR (125 MHz, CDCl 3 ) d 24.9 (4C), 55.2, 83.6 (2C), 113.4(2C), 136.6 (2C), 162.3. The spectroscopic data is in full agreement with thosereported for an authentic sample.14This procedure was followed for all thereactions listed in Table 2. All of these products (3a,143b,143c,16a3d,143e,143f,8a3g,143h,143i,143j,8a3k,8a3l,8a3m,143n,8c3o,16b) are known compounds,and their spectroscopic data are in agreement with those previously reported.

Reference： [1] Synlett, 2012, vol. 23, # 9, p. 1394 - 1396
[2] Tetrahedron Letters, 2016, vol. 57, # 14, p. 1551 - 1554
[3] Journal of Organic Chemistry, 2013, vol. 78, # 5, p. 1923 - 1933

4
[ 76-09-5 ]
[ 14047-29-1 ]
[ 180516-87-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	for 2 h; Heating / reflux	4-Carboxyphenylboronic acid (10.0 g, 60.3 mmol) was suspended in 100 mL of toluene and pinnacol added (7.1 g, 60.3 mmol). The reaction was heated to reflux with a Dean-Stark trap attached. The reaction became homogenous upon heating. After 2 h reflux the reaction was allowed to stand overnight and white needles were collected by filtration, rinsed with toluene, and vacuum dried to 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid 12.2 g (81percent). MS (FD MS): M=248. Analysis calculated for C13H17BO4: C, 62.94; H, 6.91 Found: C, 62.71; H, 6.91.
81%	for 2 h; Heating / reflux	4-Carboxyphenylboronic acid (10.0 g, 60.3 mmol) was suspended in 100 mL of toluene and pinnacol added (7.1 g, 60.3 mmol). The reaction was heated to reflux with a Dean-Stark trap attached. The reaction became homogenous upon heating. After 2 h reflux the reaction was allowed to stand overnight and white needles were collected by filtration and rinsed with toluene. The title compound was vacuum dried to 12.2 g (81percent).[0153] Mass Spectrum (FD MS): M=248. Analysis calculated for C13H17BO4: percent C, 62.94; percent H, 6.91; Found: percent C, 62.71; percent H, 6.91.

Reference： [1] Synthetic Communications, 2002, vol. 32, # 17, p. 2669 - 2676
[2] Journal of Organic Chemistry, 2006, vol. 71, # 20, p. 7915 - 7918
[3] Patent: US2004/6114, 2004, A1, . Location in patent: Page 64
[4] Patent: US6639107, 2003, B1, . Location in patent: Page/Page column 31
[5] Organic letters, 2001, vol. 3, # 6, p. 917 - 920
[6] Patent: US2002/55631, 2002, A1,
[7] Patent: US2002/86887, 2002, A1,
[8] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 16, p. 5012 - 5016
[9] Patent: WO2015/106292, 2015, A1, . Location in patent: Paragraph 00323; 00330; 00331
[10] Chemistry - An Asian Journal, 2017, vol. 12, # 10, p. 1087 - 1094
[11] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 1842 - 1851

5
[ 619-58-9 ]
[ 25015-63-8 ]
[ 180516-87-4 ]

Reference： [1] Patent: US6680401, 2004, B1, . Location in patent: Page column 21

6
[ 124-38-9 ]
[ 195062-61-4 ]
[ 180516-87-4 ]

Reference： [1] Journal of the American Chemical Society, 2012, vol. 134, # 22, p. 9106 - 9109

7
[ 73183-34-3 ]
[ 74-11-3 ]
[ 180516-87-4 ]

Reference： [1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 22, p. 3604 - 3610

8
[ 76-09-5 ]
[ 494225-46-6 ]
[ 180516-87-4 ]

Reference： [1] Tetrahedron Letters, 2013, vol. 54, # 2, p. 166 - 169

9
[ 7647-01-0 ]
[ 124-38-9 ]
[ 195062-61-4 ]
[ 180516-87-4 ]

Reference： [1] Journal of the American Chemical Society, 2012, vol. 134, # 22, p. 9106 - 9109

10
[ 586-76-5 ]
[ 73183-34-3 ]
[ 180516-87-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 13, p. 4036 - 4040

11
[ 87199-17-5 ]
[ 180516-87-4 ]

Reference： [1] Synthetic Communications, 2002, vol. 32, # 17, p. 2669 - 2676

12
[ 586-76-5 ]
[ 180516-87-4 ]

Reference： [1] Tetrahedron Letters, 2013, vol. 54, # 2, p. 166 - 169

13
[ 619-58-9 ]
[ 180516-87-4 ]

Reference： [1] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 1842 - 1851

14
[ 74-11-3 ]
[ 180516-87-4 ]

Reference： [1] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 1842 - 1851

15
[ 180516-87-4 ]
[ 179117-44-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 3 h;	Step 1 4-(4,4,5,5-Metramethyl-1,3,2-dioxaborolan-2-yl)benzamide Procedure To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (200 mg, 0.746 mmol), EDCI (214 mg, 1.12 mmol), HOBt (151 mg, 1.12 mmol) and Et3N (151 mg, 1.49 mmol) in DCM (20 mL) was bubbled ammonia until saturation. The mixture was stirred at room temperature for 3 h, then was filtered and the filtrate was concentrated to give residue which was purified by column chromatography (DCM:MeOH=50:1) to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (90 mg, 45percent) as a yellow solid. LC-MS: 248 [M+H]⁺, t_R=1.421 min.

Reference： [1] Patent: US2012/252777, 2012, A1, . Location in patent: Page/Page column 96
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 13, p. 4036 - 4040

16
[ 124-40-3 ]
[ 180516-87-4 ]
[ 214360-57-3 ]

Reference： [1] Patent: WO2006/4703, 2006, A2, . Location in patent: Page/Page column 50

17
[ 180516-87-4 ]
[ 214360-57-3 ]

Reference： [1] Patent: US6639107, 2003, B1,

18
[ 74-89-5 ]
[ 180516-87-4 ]
[ 214360-57-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 13, p. 4036 - 4040

19
[ 124-40-3 ]
[ 180516-87-4 ]
[ 400727-57-3 ]

Yield	Reaction Conditions	Operation in experiment
62%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃;	To a solution of 4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl) benzoic acid (500mg, 2.024 mmol) in anhydrous dichloromethane /DMF (9:1) (4.5 mL:0.5 mL) was addedN,N-dimethylamine (264 mg, 3.036 mmol), EDCI.hydrochloride (582 mg, 3.036 mmol), 1-hydroxybenzotriazol (410 mg, 3.036 mmol) and triethylamine (0.54 mL, 4.048 mmol). The reaction mixture was stirred at room temperature for overnight. The reaction mixture was diluted with dichloromethane and then washed with water, brine solution, dried overanhydrous sodium sulfate and concentrated under vacuum to get the product (400 mg,62percentyield) as an off-white solid. MS (E+) m/z: 276 (M+H); LCMS retention time: 1.49 mm (Method 7).

Reference： [1] Patent: WO2015/27021, 2015, A1, . Location in patent: Page/Page column 89

20
[ 506-59-2 ]
[ 180516-87-4 ]
[ 400727-57-3 ]

Yield	Reaction Conditions	Operation in experiment
38%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 80℃; for 5 h; Inert atmosphere	Weigh 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)Benzoic acid (1.0 g, 4.0 mmol),Dimethylamine hydrochloride (650 mg, 8 mmol),2-(7-Azobenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate (HATU) (2.2 g, 6 mmol), DIPEA (1.5 g, 12 mmol), dry DMF (15 mL) were placed in a 25 mL round bottom flask,Warm up to 80°C for 5 hours under nitrogen protection.After stopping the reaction, add water and extract with ethyl acetate (40mL*3).Reuse saturationAfter washing with NaCl (10 mL), the final ester layer was dried over anhydrous Na2SO4 and purified by column chromatography (410 mg, 38percent)

Reference： [1] Patent: CN104211703, 2018, B, . Location in patent: Paragraph 0163; 0164; 0165; 0168; 0169

21
[ 180516-87-4 ]
[ 1420477-60-6 ]

Reference： [1] Patent: CN108250186, 2018, A,
[2] Patent: CN108250186, 2018, A,

[ 180516-87-4 ] Synthesis Path-Downstream 1~62

1
[ 18282-59-2 ]
[ 180516-87-4 ]
[ 7111-64-0 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; trifluoroacetic acid; Wang resin Multistep reaction;

Reference： [1]Hajduk, Philip J.; Dinges, Jürgen; Miknis, Gregory F.; Merlock, Megan; Middleton, Tim; Kempf, Dale J.; Egan, David A.; Walter, Karl A.; Robins, Terry S.; Shuker, Suzy B.; Holzman, Thomas F.; Fesik, Stephen W. [Journal of Medicinal Chemistry, 1997, vol. 40, # 20, p. 3144 - 3150]

2
[ 578-57-4 ]
[ 180516-87-4 ]
[ 5728-32-5 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; trifluoroacetic acid; Wang resin Multistep reaction;

3
[ 591-17-3 ]
[ 180516-87-4 ]
[ 5728-33-6 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; trifluoroacetic acid; Wang resin Multistep reaction;

4
[ 623-00-7 ]
[ 180516-87-4 ]
[ 5728-46-1 ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 3144 - 3150

5
[ 89465-97-4 ]
[ 180516-87-4 ]
3'-Chloro-4'-nitro-biphenyl-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; trifluoroacetic acid; Wang resin Multistep reaction;

6
[ 76-09-5 ]
[ 14047-29-1 ]
[ 180516-87-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	In tetrahydrofuran; toluene
100%	In tetrahydrofuran; toluene at 45℃;
99%	In tetrahydrofuran; toluene at 45℃; for 2h; Inert atmosphere;

98%	In toluene Dean-Stark; Reflux;	4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2) A mixture of 4-carboxybenzeneboronic acid (0.5g; 3.0mmol) and 2,3-dimethyl-2,3-butanediol (0.36g; 3.0mmol) was suspended in toluene (100mL) and refluxed in a Dean-Stark apparatus until the theoretical amount of water was removed. The solution was then evaporated to yield on recrystallisatiion from CH3CN a colourless solid. Yield 0.78g (98%); m.p. 230°C-232°C (lit.45 228°C-231°C); 1H NMR (270MHz, CDCl3): δ 1.5 (s, 12H), 7.9 (d, 2H, J=8.1), 8.15 (d, 2H, J=8.1); 13 C NMR (67.8MHz, CDCl3): δ 25.1, 85.5, 129.4, 131.7, 135.0; LRMS (CIMS (NH3)) m/z (%): 266 ((M+NH4)+, 77), 162 (22), 144 (27), 136 (100), 126 (16); calcd for C13H17O4 B: C, 62.87; H, 6.91; found: C, 63.06; H, 7.15.
93.7%	In hexane at 70℃; for 3h;	1 To a 500 mL reaction flask was added p-carboxyphenylboronic acid (50 g, 0.3 mol), pinacol (39 g, 0.33 mol), n-hexane 100 g, and the temperature was raised to 70 ° C, and the reaction was carried out for 3 hours, and concentrated under reduced pressure. Drying in vacuo gave 73 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid as a white solid. Yield: 98%.
90%	In dichloromethane Molecular sieve;
81%	In toluene for 2h; Heating / reflux;	21 Preparation 21; N-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide 4-Carboxyphenylboronic acid (10.0 g, 60.3 mmol) was suspended in 100 mL of toluene and pinnacol added (7.1 g, 60.3 mmol). The reaction was heated to reflux with a Dean-Stark trap attached. The reaction became homogenous upon heating. After 2 h reflux the reaction was allowed to stand overnight and white needles were collected by filtration, rinsed with toluene, and vacuum dried to 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid 12.2 g (81%). MS (FD MS): M=248. Analysis calculated for C13H17BO4: C, 62.94; H, 6.91 Found: C, 62.71; H, 6.91.
81%	In toluene for 2h; Heating / reflux;	16 4-Carboxyphenylboronic acid (10.0 g, 60.3 mmol) was suspended in 100 mL of toluene and pinnacol added (7.1 g, 60.3 mmol). The reaction was heated to reflux with a Dean-Stark trap attached. The reaction became homogenous upon heating. After 2 h reflux the reaction was allowed to stand overnight and white needles were collected by filtration and rinsed with toluene. The title compound was vacuum dried to 12.2 g (81%).[0153] Mass Spectrum (FD MS): M=248. Analysis calculated for C13H17BO4: % C, 62.94; % H, 6.91; Found: % C, 62.71; % H, 6.91.
78%	In toluene for 4h; Heating;
	In toluene	3.B 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid EXAMPLE 3B 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid A solution of 4-(dihydroxyboryl)benzoic acid (1.66 g, 10 mmol) and pinacol (12 mmol) in toluene (70 m) was refluxed in a Dean-Stark apparatus for 16 hours and concentrated. The concentrate was triturated with diethyl ether and filtered to provide the desired product of sufficient purity for subsequent use.
	In toluene	3.B 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid Example 3B 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid A solution of 4-(dihydroxyboryl)benzoic acid (1.66 g, 10 mmol) and pinacol (12 mmol) in toluene (70 mL) was refluxed in a Dean-Stark apparatus for 16 hours and concentrated. The concentrate was triturated with diethyl ether and filtered to provide the desired product of sufficient purity for subsequent use.
	In ethyl acetate for 4h; Inert atmosphere;	3.1.3. Esterification of boronic acids 4 and 5 General procedure: The boronic acids 4 and 5 (0.667 mmol) were dissolved in 6 mL of ethyl acetate and, stirring the solution, pinacol (0.667 mmol) was added. After 4 h the reaction was stopped by adding anhydrous Na2SO4 (1 g) and CaCl2 (1 g). The mixture was filtered and concentrated in vacuo (Yield: 91% of 6 and 90% of 7).
	In tetrahydrofuran; toluene at 20℃; for 1h;	4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2): 1003311 A solution of 4-boronobenzoic acid (5.0 g, 30.1 mmol) in 1:1 THF:toluene (200 mL) was charged with pinacol (4.0 g, 30.1 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo at 40-45 °C resulting in solid residue which wasdissolved in 1:1 THF: Toluene (100 mL) and concentrated in vacuo resulting in 7.50 g of crude compound as white solid. The crude compound was used in the next step without further purification. ‘H NMR (400 MHz, DMSO-d6): ö = 9.59 (br. s, 1H), 8.40 (d, J= 4.02 Hz, 1H), 7.67 - 7.86 (m, 2H), 7.30 (d, J= 8.25 Hz, 1H), 2.42 - 2.52 (m, 12H).
7.84 g	In tetrahydrofuran at 20℃; for 3.5h;
	In ethyl acetate at 40℃;
	In diethyl ether at 20℃; for 18h; Inert atmosphere;
	In tetrahydrofuran at 20℃; for 3h;

Reference： [1]De Filippis, Arnault; Morin, Christophe; Thimon, Christian [Synthetic Communications, 2002, vol. 32, # 17, p. 2669 - 2676]
[2]Kumar, Anil; Ye, Guofeng; Ahmadibeni, Yousef; Parang, Keykavous [Journal of Organic Chemistry, 2006, vol. 71, # 20, p. 7915 - 7918]
[3]Arthur, Michel; Atze, Heiner; Bouchet, Flavie; Ethève-Quelquejeu, Mélanie; Iannazzo, Laura [Organic Letters, 2021, vol. 23, # 20, p. 7755 - 7758]
[4]D’Silva, Claudius [Journal of Chemical Research, 2021, vol. 45, # 7-8, p. 655 - 659]
[5]Current Patent Assignee: ZHEJIANG CHEMTRUE BIOMEDICINE - CN109053780, 2018, A Location in patent: Paragraph 0021; 0038; 0041; 0047; 0053; 0059; 0065; 0071
[6]Gong, Shuai; Liu, Bin; Thayumanavan, S.; Wu, Ruiling; Xiao, Hang [Angewandte Chemie - International Edition, 2020, vol. 59, # 35, p. 15135 - 15140][Angew. Chem., 2020, vol. 132, # 35, p. 15247 - 15252,6]
[7]Current Patent Assignee: ELI LILLY & CO - US2004/6114, 2004, A1 Location in patent: Page 64
[8]Current Patent Assignee: ELI LILLY & CO - US6639107, 2003, B1 Location in patent: Page/Page column 31
[9]Draffin; Duggan; Duggan [Organic letters, 2001, vol. 3, # 6, p. 917 - 920]
[10]Current Patent Assignee: ABBVIE INC - US2002/55631, 2002, A1
[11]Current Patent Assignee: ABBVIE INC - US2002/86887, 2002, A1
[12]Location in patent: experimental part De Simone, Rosa; Bruno, Ines; Riccio, Raffaele; Stadler, Katharina; Bauer, Julia; Schaible, Anja M.; Laufer, Stefan; Werz, Oliver [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 16, p. 5012 - 5016]
[13]Current Patent Assignee: COFERON, INC. - WO2015/106292, 2015, A1 Location in patent: Paragraph 00323; 00330; 00331
[14]Tashiro, Shohei; Chiba, Masayuki; Shionoya, Mitsuhiko [Chemistry - An Asian Journal, 2017, vol. 12, # 10, p. 1087 - 1094]
[15]Zernickel, Anna; Du, Weiyuan; Ghorpade, Seema A.; Sawant, Dinesh N.; Makki, Arwa A.; Sekar, Nagaiyan; Eppinger, Jörg [Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 1842 - 1851]
[16]Ling, Liang; He, Yuan; Zhang, Xue; Luo, Meiming; Zeng, Xiaoming [Angewandte Chemie - International Edition, 2019, vol. 58, # 20, p. 6554 - 6558][Angew. Chem., 2019, vol. 131, # 20, p. 6626 - 6630,5]
[17]Xu, Yanyun; Huang, Yushu; Lu, Wei; Liu, Shiyuan; Xiao, Yi; Yu, Jiahui [European Journal of Pharmaceutics and Biopharmaceutics, 2019, vol. 144, p. 193 - 206]

7
[ 585-79-5 ]
[ 180516-87-4 ]
[ 5737-85-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate In tetrahydrofuran at 80℃; for 6h;	1; 4 4- (4, 4,5, 5-Tetramethyl- [1, 3,2] dioxaborolan-2-yl)-benzoic acid (0.004 mol, 1 eq) and KOAc (0.012 mol, 3 eq) are placed in THF (25 ml) creating a slurry. PdCl2 (dppf) (0.00012 mol, 3 mol %) and p-bromo- nitrobenzene (0.005 mol, 1. 2 eq) are then added to the solution with stirring and the solution is heated gently to 80°C. After 6 hrs the reaction is complete by TLC (20: 1 CH2CIz/CH30H). The reaction mixture is evaporated to dryness, dissolved in CH2Cl2 (30 ml) and washed with distilled water and saturated NaHCO3. The resultant biphenyl compound is taken directly to the next step.

Reference： [1]Current Patent Assignee: GLYCOMIMETICS, INC. - WO2005/51920, 2005, A2 Location in patent: Page/Page column 14; 4/22

8
[ 19524-06-2 ]
[ 180516-87-4 ]
[ 4385-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine)palladium (0); In N-methyl-acetamide;	a 4-(4-pyridinyl)benzoic acid 4-Bromopyridine hydrochloride (0.4 g, 2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.5 g, 2 mmol), and tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.04 mmol) in dimethylformamide (15 mL) was treated with 2M potassium carbonate (2 mL) and the mixture was heated to 80° C. for 16 h. The mixture was concentrated in vacuo and the residue was diluted with water to afford a solid which was filtered to afford the title compound (0.26 g).

Reference： [1]Patent: US6399656,2002,B1

9
[ 754230-78-9 ]
[ 180516-87-4 ]
[ 877619-67-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water;Heating / reflux;	A mixture of 5-bromo-3-(substituted-benzyloxy)-pyridin-2-ylamine or 5-bromo-3-(substituted-benzyloxy)-pyrazin-2-ylamine (1 molar equivalent), aryl boronic acid or ester (1.2 molar equivalent), bis(triphenylphosphine) palladium II chloride (0.03 molar equivalent) and sodium carbonate (3.0 molar equivalent.) in ethylene glycol dimethyl ether and water (10:0.5, 0.03 M) is de-gassed and charged with nitrogen for three times, and then heated to reflux under nitrogen for overnight. The reaction is cooled to ambient temperature and diluted with ethyl acetate. The mixture is washed with water, brine, dried over Na2S04, and purified on a silica gel column to afford 5-aryl-3-(substituted-benzyloxy)-pyridin-2-ylamine, or 5-aryl-3-(substituted-benzyloxy)-pyrazin-2-ylamine; 6-Amino-5-benzyloxy-nicotinic acid was prepared according to procedure 3 from <strong>[754230-78-9]3-benzyloxy-5-bromo-pyridin-2-ylamine</strong> and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid. MS m/z 321(M+1).

Reference： [1]Patent: WO2006/21886,2006,A1 .Location in patent: Page/Page column 54; 57

10
[ 1003-03-8 ]
[ 180516-87-4 ]
[ 933987-10-1 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	58 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaboro.an-2yl)benzoic acid (514 mg ) and 0.23 ml of cyclopentylamin are dissolved in dichloromethane. After addition of 1-(3- Dimethylaminopropyl)-3-ethycarbodiimide hydrochlorid (463 mg) and 1- Hydroxybenzotriazole (326 mg ), The reaction is stirred at room temperature . The reaction mixture is diluted with ethyl acetate washed with 1 N hydrochloric acid / brine and dried over sodium sulfate. After evaporation of the solvent the residual yellow solid 800 mg is purified by flash chromatography (ethyl acetate / hexane :1/9)..160 mg of N-Cyclopentyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-benzamide and 50 mg of 6-(2-Chloro-pyridin-4-yl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one are dissolved in 2 ml dimethylformamide . The solution is degassed by introduction of a stream of argon, Pd(PPh2J2CI2 (14 mg, ) and 0.5 ml of sodium carbonate 2N are added. The mixture is heated for 15 min in a microwave oven at 160 0C . The reaction mixture is diluted with ethyl acetate washed with water / brine . After being dried over sodium sulfate, the residue is purified by HPLC (acetonitrile / water, RP-18). EPO MS (ESI ) m/z: 398 [M-H]"

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2007/39285, 2007, A1 Location in patent: Page/Page column 66-67

11
[ 261951-70-6 ]
[ 180516-87-4 ]
[ 1029438-21-8 ]

Yield	Reaction Conditions	Operation in experiment
43%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;	16 Boronate ester 32 (500 mg, 1.0 eq), benzyl bromide 33 (450 mg, 1.1 eq) and cesium carbonate(920 mg, 1.4 eq) were dissolved in anhydrous DMF and stirred for 3 h at rt. The reaction was diluted with EtOAc (25 mL). The solution was then washed with water, 5% NaHCO3, water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to a white solid which was purified via column chromatography (hexanes) to give 34 (320 mg, 43% yield) as a white solid.

Reference： [1]Current Patent Assignee: INFINITY PHARMACEUTICALS INC - WO2008/63300, 2008, A2 Location in patent: Page/Page column 178

12
[ 180516-87-4 ]
[ 1171044-16-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; Inert atmosphere of argon;	A solution of 3-Formylphenylboronic acid (1 eq, 2 mmol, 0.3 g) in dry DCM (7 ml) under an inert atmosphere of argon is treated with 1-methyl-piperazine (1.2 eq, 2.4 mmol, 0.266 ml) followed by acetic acid (1.2 eq, 2.4 mmol, 0.14 ml) and NaBH(OAc)3 (1.6 eq, 3.2 mmol, 0.678 mg) and the resulting mixture is stirred at room temperature for 3 hours. The reaction is quenched by addition of water and is then extracted with DCM. The organic extracts are concentrated in vacuo and the crude residue is purified by flash chromatography on silica eluting with MeOH/DCM (0 to 100% MeOH in DCM) followed by 2M NH3 in MeOH. The appropriate fractions are combined and concentrated in vacuo to afford the title compound; [M+H]+ =235.

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2009/87212, 2009, A2 Location in patent: Page/Page column 143

13
[ 2038-03-1 ]
[ 180516-87-4 ]
[ 787591-39-3 ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: 4-carboxyphenylboronic acid pinacol ester With triethylamine; isobutyl chloroformate In dichloromethane at -15℃; for 0.0833333h; Stage #2: 4-(2-AMINOETHYL)MORPHOLINE In dichloromethane at -15 - 20℃; for 0.166667h;	90.1 Example 90; 4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-N-(2-morpholin-4-yl-ethyl)-benzamide In a 2 dram vial under nitrogen, 500 mg (2.0 mmol) of E was added and dissolved in dichloromethane (DCM) (5 mL). 606 mg (6.0 mmol) of triethyl amine (TEA) was then added via syringe and the stirring mixture cooled to -15° C. 272 mg (2.0 mmol) of isobutyl chloroformate (IBC) was then added dropwise and the reaction mixture stirred for 5 minutes. After 5 minutes the formation of a white precipitate was observed, at which point the amine F was added and the solution allowed to warm to room temperature. Upon warming, the reaction was stirred for an additional 10 minutes. The reaction mixture was then diluted with dichloromethane (100 mL) and extracted with a saturated solution of sodium bicarbonate (2*25 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated under vacuum. The colorless oil was then triturated using hexanes (50 mL) to provide G as a white solid. Yield: 53%. 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J=8.2, 2H), 7.75 (d, J=8.2, 2H), 6.75 (br. s, 1H), 3.72 (t, J=4.6, 4H), 3.15 (q, J=5.7, 2H) 2.61 (t, J=6.0, 2H) 2.51 (t, J=4.5, 4H), 1.35 (s, 12H).
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;

Reference： [1]Current Patent Assignee: PFIZER INC - US2004/220189, 2004, A1 Location in patent: Page 45-46
[2]Location in patent: scheme or table Trujillo, John I.; Kiefer, James R.; Huang, Wei; Day, Jacqueline E.; Moon, Joseph; Jerome, Gina M.; Bono, Christine P.; Kornmeier, Christine M.; Williams, Melanie L.; Kuhn, Cyrille; Rennie, Glen R.; Wynn, Thomas A.; Carron, Christopher P.; Thorarensen, Atli [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 11, p. 3795 - 3799]

14
[ 180516-87-4 ]
[ 32664-13-4 ]
[ 158144-50-4 ]

Yield	Reaction Conditions	Operation in experiment
5%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In tetrahydrofuran; water at 60℃; for 24h; Inert atmosphere;

Reference： [1]Location in patent: experimental part Kumar, A. Sanjeev; Ghosh, Samir; Soundararajan; Mehta [Synthetic Communications, 2010, vol. 40, # 13, p. 1907 - 1914]

15
[ 6638-79-5 ]
[ 180516-87-4 ]
[ 1073353-58-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃;	5.A A suspension of 4- (4, 4, 5, 5-tetraitiethyl-l, 3, 2- dioxaborolan-2-yl) benzoic acid (10.05 g) , N,0- dimethylhydroxylamine hydrochloride (4.35 g) , WSC (9.32 g) , HOBt (6.57 g) , and TEA (6.21 mL) in DMF (80 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgS04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) and crystallized from hexane to give the title compound (7.60 g) .MS (ESI+) : [M+H]+ 292.2.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2012/18909, 2012, A1 Location in patent: Page/Page column 140-141

16
[ 765-30-0 ]
[ 180516-87-4 ]
[ 827614-68-6 ]

Yield	Reaction Conditions	Operation in experiment
62%	With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h;	1-97.1-1 To a DMF (96 mL) solution of 4-carboxyphenylboronic acid pinacol ester (19.2 g, 77 mmol), cyclopropaneamine (8.84 g, 10.7 mL, 155 mmol) and triethylamine (11.8 g, 116 mmol), HATU (32.4 g, 85 mmol) was added and stirred at room temperature for one hour. To the reaction solution under ice cooling, water (96 mL) was added dropwise and the resultant solid substance was obtained by filtration and washed with water to obtain the titled compound (13.7 g, 47.6 mmol, 62%) as a white solid substance.1H-NMR (300 MHz, DMSO-d6) δ 0.54-0.60 (m, 2H), 0.63-0.71 (m, 2H), 1.29 (s, 12H), 2.80-2.88 (m, 1H), 7.71 (d, J=7.7 Hz, 2H), 7.81 (d, J=7.7 Hz, 2H), 8.48 (d, J=4.2 Hz, 1H).MS (ESI) m/z=288 (M+H)+.

Reference： [1]Current Patent Assignee: ONCOTHERAPY SCIENCE INC - US2012/59162, 2012, A1 Location in patent: Page/Page column 52-53

17
[ 100-46-9 ]
[ 180516-87-4 ]
[ 1073353-57-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With benzotriazol-1-ol; triethylamine In N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere;	3.1.4. Synthesis of amides 9a-f and 10a-e General procedure: The pinacol ester 6 or 7 (1 equiv) and the appropriate amine a-f (2 equiv) were dissolved in N,N-dimethylformamide (DMF). Triethylamine (TEA), N-hydroxybenzotriazole (HOBt) and N,N-dicyclohexylcarbodiimide (DIC) (2 equiv of each) were added. The mixture was left at room temperature for 48 h under stirring. When TLC showed the consumption of the pinacol ester 6 or 7, the reaction was stopped by adding HCl 1 N (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 10 mL) and the organic phase was washed firstly with a saturated solution of NaHCO3 and then with brine. Afterward, the organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by flash chromatography (10% diethyl ether/n-hexane to 70% diethyl ether/n-hexane).
	Stage #1: 4-carboxyphenylboronic acid pinacol ester With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1.25h; Stage #2: benzylamine In N,N-dimethyl-formamide at 20℃; for 16h;	General procedure for the synthesis of arylboronic acids 2 and 4 General procedure: To a stirred solution of the carboxylic acid 10 (1.0mmol) in DMF (1mL) were added at 0°C HOBt (1.0mmol) and EDC (1.0mmol). The mixture was stirred for 15min at 0°C and for 1h at room temperature. Then the appropriate amine (1.0mmol) was added and the mixture was stirred overnight at room temperature. The mixture was diluted with brine and extracted with AcOEt. The organic phase was washed with 2N HCl solution, saturated NaHCO3, and brine, dried (Na2SO4), and evaporated under vacuum. The residue was purified by column chromatography (silica gel, hexane/AcOEt mixtures). Sodium periodate (3mmol) was added at room-temperature to a solution of the purified pinacol boronate ester 11 (1.0mmol) in THF/H2O (15/5mL) and then 2N HCl (0.40mL) was added. The solution was stirred at room temperature for 3-5h, concentrated under vacuum, diluted with water, and extracted with AcOEt. The organic phase was separated, washed twice with water, dried (Na2SO4), and evaporated under vacuum. The residue was crystallized from THF/H2O to afford pure title compound.

Reference： [1]De Simone, Rosa; Bruno, Ines; Riccio, Raffaele; Stadler, Katharina; Bauer, Julia; Schaible, Anja M.; Laufer, Stefan; Werz, Oliver [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 16, p. 5012 - 5016]
[2]Morera, Enrico; Di Marzo, Vincenzo; Monti, Ludovica; Allarà, Marco; Schiano Moriello, Aniello; Nalli, Marianna; Ortar, Giorgio; De Petrocellis, Luciano [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 5, p. 1401 - 1405]

18
[ 180516-87-4 ]
[ 57260-71-6 ]
[ 864754-13-2 ]

Yield	Reaction Conditions	Operation in experiment
95.4%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; water; N,N-dimethyl-formamide at 20℃;	5.1 At room temperature will carboxyphenyl boronic acid pinacol ester (0.894g, 4.8mmol) was dissolved in dichloromethane (10ml, 0.156mol) And N, N- dimethylformamide (1ml, 17.78mmol) was added N-Boc piperazine (1g, 4.03mmol), and washed sequentially Was added 1-ethyl - (3-dimethylaminopropyl) carbodiimide hydrochloride (0.93g, 4.8mmol), N-hydroxybenzotriazole (0.66g, 4.8mmol), triethylamine (0.84ml, 6.04mmol), the reaction mixture was stirred at room temperature until the starting material the reaction monitored by TLC Complete, the reaction mixture was added to 30ml of water, stirred for 30 minutes, (100ml * 3) and extracted with methylene chloride, then with saturated chlorine Sodium hydroxide solution (100ml * 2) washing the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, to give: 4- [4- (4,4,5,5- Tetramethyl - [1,3,2] bis boryl 2-yl) benzoyl -] - piperazine-1-tert-butyl ester (1.6 g of, white solid), yield 95.4%.
80%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	3.1 Step 1. tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoyl)piperazine-l-carboxylate A mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (15 g, 60.5 mmol), tert-butyl piperazine-l-carboxylate (11.26 g, 60.5 mmol), 1H- benzo[d][l,2,3]triazol-l-ol hydrate (4.63 g, 30.2 mmol), Nl-((ethylimino)methylene)- N3,N3-dimethylpropane-l,3-diamine hydrochloride (12.75 g, 66.5 mmol), and triethylamine (33.7 mL, 242 mmol) in dichloromethane (180 mL) was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution (75 mL), 0.5 M HC1 solution (75 mL), and again with saturated aqueous sodium bicarbonate solution (75 mL). The combined organic phases were concentrated and the resulting solid was slurried in a solution of 1: 1 methyl tert-butyl ether/hexane (200 mL). The material was filtered and dried to afford tert-butyl 4- (4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoyl)piperazine-l-carboxylate (20.03 g, 48.1 mmol, 80%). MS (ESI, pos. ion) m/z: 417 (M + 1).
72%	With benzotriazol-1-ol; triethylamine In N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere;	3.1.4. Synthesis of amides 9a-f and 10a-e General procedure: The pinacol ester 6 or 7 (1 equiv) and the appropriate amine a-f (2 equiv) were dissolved in N,N-dimethylformamide (DMF). Triethylamine (TEA), N-hydroxybenzotriazole (HOBt) and N,N-dicyclohexylcarbodiimide (DIC) (2 equiv of each) were added. The mixture was left at room temperature for 48 h under stirring. When TLC showed the consumption of the pinacol ester 6 or 7, the reaction was stopped by adding HCl 1 N (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 10 mL) and the organic phase was washed firstly with a saturated solution of NaHCO3 and then with brine. Afterward, the organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by flash chromatography (10% diethyl ether/n-hexane to 70% diethyl ether/n-hexane).

Reference： [1]Current Patent Assignee: SHANGHAI XIMAI MEDICAL TECHNOLOGY; SHANGHAI CDYMAX PHARMACEUTICALS - CN103087077, 2016, B Location in patent: Paragraph 0107-0109
[2]Current Patent Assignee: FORMA THERAPEUTICS, INC. - WO2014/164749, 2014, A1 Location in patent: Page/Page column 239; 240
[3]De Simone, Rosa; Bruno, Ines; Riccio, Raffaele; Stadler, Katharina; Bauer, Julia; Schaible, Anja M.; Laufer, Stefan; Werz, Oliver [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 16, p. 5012 - 5016]

19
[ 1258457-59-8 ]
[ 180516-87-4 ]
[ 1411773-94-8 ]

Reference： [1]Patent: US2012/294885,2012,A1

20
[ 1258457-59-8 ]
[ 180516-87-4 ]
C₃₅H₄₀BN₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine;dmap; In N,N-dimethyl-formamide; for 1h;	Synthesis of compound 23: (4-((4-((4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzyl)carbamoyl)phenyl)boronic acid To a solution of 22 (63 mg, 0.26 mmol) in anhydrous DMF, were added triethylamine (58 mg, 0.58 mmol), HBTU (97 mg, 0.26 mmol), a catalytic amount of DMAP and 7d (100 mg, 0.23 mol). The reaction mixture was stirred for 1 hour, followed by removal of the solvent under vacuum. The residue was then dissolved in ethylacetate and washed with water, brine, dried using sodium sulfate and concentrated under vacuum to obtain the crude boronic acid pinacolester derivative. This was then dissolved in a solution of 9:1 acetonitrile:1N HCl and polymer-bound boronic acid (767 mg, 1.15 mmol) was added to the solution. The reaction was stirred for 12 hours. The beads were then filtered and the filtrate was concentrated under reduced pressure to obtain the residue which was purified using C18 reverse-phase column chromatography (60% MeOH/H2O) to obtain compound 23 (83 mg, 71%). 1H NMR (500 MHz, DMSO) δ 9.00 (t, J=6.0 Hz, 1H), 8.19 (s, 1H), 7.98 (dd, J=13.6, 5.5 Hz, 1H), 7.87-7.77 (m, 4H), 7.63 (d, J=8.8 Hz, 2H), 7.44-7.36 (m, 2H), 7.33-7.20 (m, 3H), 7.13 (d, J=7.6 Hz, 1H), 7.01 (t, J=6.3 Hz, 2H), 5.87 (d, J=5.6 Hz, 2H), 4.42 (d, J=5.9 Hz, 2H), 2.91 (dd, J=14.4, 6.8 Hz, 2H), 1.70 (dd, J=15.3, 7.8 Hz, 2H), 1.42-1.32 (m, 2H), 0.86 (t, J=7.4 Hz, 3H). 13C NMR (126 MHz, DMSO) δ 166.28, 150.81, 150.78, 150.60, 138.98, 135.47, 134.71, 133.90, 127.79, 127.72, 126.06, 125.47, 120.48, 114.73, 113.91, 113.77, 47.89, 42.12, 40.12, 40.06, 39.97, 39.89, 39.80, 39.73, 39.64, 39.56, 39.47, 39.30, 39.14, 38.97, 29.46, 26.18, 21.79, 13.66.

Reference： [1]Patent: US2012/294885,2012,A1 .Location in patent: Page/Page column 28

21
[ 108-00-9 ]
[ 180516-87-4 ]
[ 832114-11-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-methyl-1H-imidazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	16.1 Step 1N-(2-(Dimethylamino)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide ProcedureA mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (300 mg, 1.2 mmol), N,N-dimethylethane-1,2-diamine (128 mg, 1.45 mmol), EDCI (690 mg, 3.6 mmol) and 1-methyl-1H-imidazole (393 mg, 4.8 mmol) in dichloromethane (50 mL) were stirred at room temperature overnight. The solvent was washed with saturated NaHCO3 (aq., 30 mL), H2O (30 mL) and brine (30 mL), then dried over Na2SO4. The organic phase was concentrated under reduced pressure to give N-(2-(dimethylamino)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (250 mg) as crude product which was used directly in the next step without further purification. LC/MS: 319 [M+H]+.
	With 1-methyl-1H-imidazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	16.1 A mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (300 mg, 1.2 mmol), N,N-dimethylethane-l,2-diamine (128 mg, 1.45 mmol), EDCI (690 mg, 3.6 mmol) and 1 -methyl- IH-imidazole (393 mg, 4.8 mmol) in dichloromethane (50 mL) were stirred at room temperature overnight. The solvent was washed with saturated NaHC03 (aq., 30 mL), H20 (30 mL) and brine (30 mL), then dried over Na2S04. The organic phase was concentrated under reduced pressure to give N-(2-(dimethylamino)ethyl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (250 mg) as crude product which was used directly in the next step without further purification. LC/MS: 319 [M + H]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2012/309746, 2012, A1 Location in patent: Page/Page column 45-46
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2012/163724, 2012, A1 Location in patent: Page/Page column 71

22
[ 908269-97-6 ]
[ 180516-87-4 ]
[ 1419221-44-5 ]

Yield	Reaction Conditions	Operation in experiment
61.2%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h;	T.b (b) N-(4-cyclopropylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide 4-cyclopropylpyridin-2-amine (28.0 g, 0.209 mol), DIPEA (92.6 mL, 0.52 mol), O-Benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium tetrafluoroborate (TBTU) (67.1 g, 0.209 mol) dissolved in 500 mL DCM was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (51.8 g, 0.209 mmol). The reactionmixture was stirred 18h at rt. The reactionmixture was washed with 2x250 mL Na2CO3 solution and 2x250 mL citric acid solution. The organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified using gel chromatography (Petroleumether: EtAOc 5:1) to give N-(4-cyclopropylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (46.5 g, 61.2%).

Reference： [1]Current Patent Assignee: MERCK & CO INC - EP2548877, 2013, A1 Location in patent: Paragraph 0208

23
[ 7496-50-6 ]
[ 180516-87-4 ]
[ 1419221-46-7 ]

Yield	Reaction Conditions	Operation in experiment
55.5%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	V N-(6-methyl-4,5,6,7-tetrahydrobenzofdlthiazol-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1460 mg, 5.88 mmol), 6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (990 mg, 5.88 mmol) and O-Benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium tetrafluoroborate (TBTU) (2267 mg, 7.06 mmol) in dichloromethane (100mL) was added N,N-Diisopropylethylamine (1.233 ml, 7.06 mmol) at rt. The reactionmixture was stirred overnight at rt. The reaction was washed with 20 mL sat. Na2CO3 solution, 20 mL water, 20 mL brine, dried (Na2SO4), filtered and concentrated. The residue was purified using gel chromatography (EtOAc:Heptane 10:90 to 30-70) to give N-(6-methyl-4,5,6,7-tetrahydrobenzo[dJthiazol-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.50 g, 55.5%).

Reference： [1]Current Patent Assignee: MERCK & CO INC - EP2548877, 2013, A1 Location in patent: Paragraph 0212

24
[ 288315-03-7 ]
[ 180516-87-4 ]
[ 1542254-39-6 ]

Yield	Reaction Conditions	Operation in experiment
57%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 72h;	B166 Compound B166a. (3,3-Difluoroazetidin-1-yl)( 4-( 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)methanone General procedure: A mixture of 4-( 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid ( 490mg, 2.0 mmol), 3,3-difluoroazetidine hydrochloride (260 mg, 2.00 mmol), DIPEA (0.6865 mL, 3.93 mmol) and HATU (900 mg, 2.4 mmol) in DMF (4 mL) was stirred at roomtemperature for 3 days. The reaction mixture was diluted with EtOAc, the organic portionwashed successively with water and brine, dried over sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The residue was purified by silica gelchromatography (eluting with 0-100% EtOAc/hexane) to give Compound B 166a (36010 mg, 57% yield) as a white solid. HPLC: RT = 1.9 min (LCMS Method Q). MS (ES):m/z = 324.0 [M+H( 1H NMR (400MHz, CHLOROFORM-d) 8 7.87 (s, 2H), 7.62 (d,J=8.1 Hz, 2H), 4.53 (t, J=12.0 Hz, 4H), 1.36 (s, 12H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2014/15088, 2014, A1 Location in patent: Paragraph 00226

25
[ 29022-11-5 ]
[ 64709-55-3 ]
[ 180516-87-4 ]
[ 147290-11-7 ]
[ 1609670-33-8 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 5854 - 5857

26
[ 64709-55-3 ]
[ 143824-78-6 ]
[ 180516-87-4 ]
[ 147290-11-7 ]
[ 1609670-32-7 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 5854 - 5857
[2]New Journal of Chemistry,2017,vol. 41,p. 2593 - 2603

27
[ 57260-73-8 ]
[ 180516-87-4 ]
[ 1312069-26-3 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 16h;	104.1 To a solution mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid (1 .0 g, 4.03 mmol), HOBT (925.3 mg, 6.85 mmol) and EDC.HCI (1.15 g, 5.98 mmol) in dichloromethane (20 mL) was stirred at room temperature for 5 mm and were added tertbutyl (2-aminoethyl)carbamate (645 mg, 4.03 mmol) and TEA (1 .15 mL, 8.19 mmol). The resulting reaction mixture was stirred at temperature for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous Na2504 and the solvent was distilled off under reduced pressure to afford 1 .0 g (crude) of tert-Butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzamido) ethyl) carbamate 104-1 as white solid. The crude product was used as such for the next step without further purification.

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2014/78802, 2014, A1 Location in patent: Page/Page column 171

28
[ 149978-42-7 ]
[ 180516-87-4 ]
[ 1620678-56-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	With HATU In N,N-dimethyl-formamide at 20℃; for 15h;	183.1 Step 1 : (4-(( 1 -methyl-5 -(trifluoromethyl)- 1 H-pyrazol-3 - vDcarbamovDphenvDboronic acid 1 -methyl-5 -(trifluoromethyl)- 1 H-pyrazol-3 -amine (66.6 mg, 0.403 mmol), N- ethyl-N-isopropylpropan-2-amine (0.141 ml, 0.806 mmol), 2-(3H-[l ,2,3]triazolo[4,5- b]pyridin-3-yl)-l , l ,3,3-tetramethylisouronium hexafluorophosphate(V) (153 mg, 0.403 mmol) were added to the reaction vial with 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)benzoic acid (100 mg, 0.403 mmol) and stirred at room temperature in DMF (2 ml) for 15 hours. Reaction mixture was separated on flash LC on 12 g column (Hexane/EtOAc) to give (4-((l -methyl-5 -(trifluoromethyl)- 1 H-pyrazol-3 - yl)carbamoyl)phenyl)boronic acid (1 12 mg, 0.358 mmol, 89 % yield). LC-MS: LC-MS method A, RET. TIME = 2.72 min., MS found M+m/z = 341.13.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/114185, 2014, A1 Location in patent: Page/Page column 285

29
[ 149978-42-7 ]
[ 180516-87-4 ]
4-(8-amino-5-chloro-3-((6R,8aS)-3-oxooctahydroindolizin-6-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)benzamide tritrifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: HATU / N,N-dimethyl-formamide / 15 h / 20 °C 2: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / water; 1,4-dioxane / 2 h / 90 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/114185, 2014, A1

30
[ 53484-15-4 ]
[ 180516-87-4 ]
4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In toluene; acetonitrile; at 90℃; for 18.0h;Inert atmosphere;	Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(tetramethyl-l ,3,2-dioxaborolan-2-yl)benzoic acid (2.35 g, 9.47 mmol, 1.00 equiv) in CH3CN/toluene (70/12 mL), 5-bromo- l-methyl- lH- benzo[d] imidazole (2 g, 9.48 mmol, 1.00 equiv), Pd(PPh3)4 (548 mg, 0.47 mmol, 0.05 equiv), sodium carbonate (0.4M, 50 mL, 2.00 equiv). The resulting solution was stirred for 18 h at 90C. After cooled to room temperature, the reaction mixture was poured into 50 ml of water. The mixture was washed with 2x100 mL of ethyl acetate and the aqueous layer was collected. The pH value of the solution was adjusted to 4 with hydrochloric acid (IN). The solids were collected by filtration and dried under vacuum. This resulted in 2 g (84%) of the title compound as a white solid, which was dried under vacuum. LC- MS (ES, m/z): 253 [M+H]+

Reference： [1]Patent: WO2014/164749,2014,A1 .Location in patent: Page/Page column 279

31
[ 2812-46-6 ]
[ 180516-87-4 ]
(S)-tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)pyrrolidine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃;	17.A A. (S)-tert-Butyl1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yI)benzoyl)pyrrolidine-2-carboxylate, 17a [0559] To a solution of4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid (2.00 g, 8.06 mmol) in DMF (20 mL) wasadded HATU (6.20 g, 16.3 mmol), (S)-tert-butyl pyrrolidine-2-carboxylate (2.00 g, 11.7 mmol) and DIPEA (4.20 g, 32.5mmol). The reaction mixture was stirred at rt overnight, andwas quenched with H2 0 (20 mL). The resulting solution wasextracted with DCM (3x100 mL). The combined organiclayers were washed with brine, dried over Na2 S04 and concentrated underreducedpressure. The residue was purified byflash column chromatography on silica gel, eluting withEtOAc/petroleum ether (1:20-1:10 v/v) to obtain compound17a as a yellow solid (1.40 g, 37% yield). Mass Spectrum(LCMS, ESI pos.): Calcd. for C22H32BN05 : 402.2 (M+H).Found 402.1.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2014/364414, 2014, A1 Location in patent: Paragraph 0557-0559

32
[ 589-87-7 ]
[ 180516-87-4 ]
[ 5731-11-3 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In water; N,N-dimethyl-formamide at 90℃; for 4h; Microwave irradiation;	A Step A 4-(4-bromophenyl)benzoic acid Step A 4-(4-bromophenyl)benzoic acid10541] Palladium tetrakis (0.500 g, 0.433 mmol), 4-(4,4,5, 5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzoic acid (2 g,8.06 mmol), and 1 -bromo-4-iodo-benzene (2.4 g, 8.48 mmol) were dissolved in DMF (40 ml). 1.0 M aqueous potassium carbonate (20 ml, 20.00 ml) was added to the reaction mixture, which was microwaved at 90° C. for 4 hours. The reaction mixture was evaporated under reduced pressure and the resulting residue was used in the next step without further purification or characterization.
	With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 4h;	A Step A 4-(4-bromophenyl)benzoic acid Palladium tetrakis (0.500 g, 0.433 mmol), 4-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzoic acid (2 g, 8.06 mmol), and i-bromo-4-iodo-benzene (2.4 g, 8.48 mmol) were dissolved in DMF (40 ml). 1.0 M aqueous potassium carbonate (20 ml, 20.00 ml) was added to the reactionmixture, which was microwaved at 90° C. for 4 hours. The reaction mixture was evaporated under reduced pressure and the resulting residue was used in the next step without further purification or characterization.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2015/203487, 2015, A1 Location in patent: Paragraph 0540; 0541
[2]Current Patent Assignee: MERCK & CO INC - US9868733, 2018, B2 Location in patent: Page/Page column 74

33
[ 171268-71-6 ]
[ 180516-87-4 ]
N-(3-methoxy-2,2-dimethylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h;	559 Compound 5 59a. N-(3 -Methoxy-2,2-dimethylpropyl)-4-(4,4,5 ,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)benzamide EDC (0.85 g, 4.4 mmol) was added to DMF (6 mL) solution of 4-(4,4,5,5- tetramethyl- 1,3 ,2-dioxaborolan-2-yl)benzoic acid (0.55 g, 2.2 mmol), 3 -methoxy-2,2- dimethylpropan-1-amine hydrochloride (0.51 g, 3.3 mmol), HOBT hydrate (0.68 g, 4.4 mmol) and TEA (0.80 mL, 4.4 mmol) at room temperature. After 16 h, the reactionmixture was diluted with water (50 mL), extracted with DCM (2 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using silica gel chromatography (50% ethyl acetate/hexanes) to isolate Compound 559a (730 mg, 95% yield) as a clear oil. HPLC RT = 1.11 mm (LCMS Method M). MS(ES):m/z = 347.9 [M+H]. ‘H NMR (500MHz, chloroform-d) ö 7.87 (d, J=8.0 Hz, 2H), 7.80 -7.69 (m, 2H), 7.36 - 7.29 (m, 1H), 3.45 - 3.37 (m, 5H), 3.28 (s, 2H), 1.36 (s, 12H), 1.00(s, 6H).
95%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h;	559 Compound 559a. N-(3-Methoxy-2,2-dimethylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide EDC (0.85 g, 4.4 mmol) was added to DMF (6 mL) solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.55 g, 2.2 mmol), 3-methoxy-2,2-dimethylpropan-1-amine hydrochloride (0.51 g, 3.3 mmol), HOBT hydrate (0.68 g, 4.4 mmol) and TEA (0.80 mL, 4.4 mmol) at room temperature. After 16 h, the reaction mixture was diluted with water (50 mL), extracted with DCM (2*50 mL), dried over -Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using silica gel chromatography (50% ethyl acetate/hexanes) to isolate Compound 559a (730 mg, 95% yield) as a clear oil. HPLC RT=1.11 min (LCMS Method M). -MS(ES): m/z=347.9 [M+H]+. -1H NMR (500 MHz, chloroform-d) δ 7.87 (d, J=8.0 Hz, 2H), 7.80-7.69 (m, 2H), 7.36-7.29 (m, 1H), 3.45-3.37 (m, 5H), 3.28 (s, 2H), 1.36 (s, 12H), 1.00 (s, 6H)

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2015/105749, 2015, A1 Location in patent: Paragraph 00242
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2016/326125, 2016, A1 Location in patent: Paragraph 0453-0454

34
[ 712-76-5 ]
[ 180516-87-4 ]
C₂₆H₂₈BNO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-carboxyphenylboronic acid pinacol ester With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1.25h; Stage #2: N-(4-phenyl)benzylamine In N,N-dimethyl-formamide at 20℃; for 16h;	General procedure for the synthesis of arylboronic acids 2 and 4 General procedure: To a stirred solution of the carboxylic acid 10 (1.0mmol) in DMF (1mL) were added at 0°C HOBt (1.0mmol) and EDC (1.0mmol). The mixture was stirred for 15min at 0°C and for 1h at room temperature. Then the appropriate amine (1.0mmol) was added and the mixture was stirred overnight at room temperature. The mixture was diluted with brine and extracted with AcOEt. The organic phase was washed with 2N HCl solution, saturated NaHCO3, and brine, dried (Na2SO4), and evaporated under vacuum. The residue was purified by column chromatography (silica gel, hexane/AcOEt mixtures). Sodium periodate (3mmol) was added at room-temperature to a solution of the purified pinacol boronate ester 11 (1.0mmol) in THF/H2O (15/5mL) and then 2N HCl (0.40mL) was added. The solution was stirred at room temperature for 3-5h, concentrated under vacuum, diluted with water, and extracted with AcOEt. The organic phase was separated, washed twice with water, dried (Na2SO4), and evaporated under vacuum. The residue was crystallized from THF/H2O to afford pure title compound.

Reference： [1]Morera, Enrico; Di Marzo, Vincenzo; Monti, Ludovica; Allarà, Marco; Schiano Moriello, Aniello; Nalli, Marianna; Ortar, Giorgio; De Petrocellis, Luciano [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 5, p. 1401 - 1405]

35
[ 2450-71-7 ]
[ 180516-87-4 ]
[ 1218790-49-8 ]

Yield	Reaction Conditions	Operation in experiment
61%	With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In methanol at 20℃; for 20h; Inert atmosphere;
52%	With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In methanol at 20℃; for 20h; Inert atmosphere;

Reference： [1]Okuro, Kou; Sasaki, Mizuki; Aida, Takuzo [Journal of the American Chemical Society, 2016, vol. 138, # 17, p. 5527 - 5530]
[2]Ju, Enguo; Wang, Faming; Wang, Zhenzhen; Liu, Chaoying; Dong, Kai; Pu, Fang; Ren, Jinsong; Qu, Xiaogang [Chemistry - A European Journal, 2020, vol. 26, # 34, p. 7573 - 7577]

36
[ 19472-74-3 ]
[ 180516-87-4 ]
[ 917373-75-2 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 16h;	2-(2-Bromophenyl)acetonitrile (500 mg, 2.55 mmol), 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)ben- zoic acid (633 mg, 2.55 mmol), tetrakis[triphenylphosphine] palladium(0) (147 mg, 0.13 mmol), tribasic potassium phosphate (1.62 g, 7.64 mmol), 1 ,4-dioxane (30 mE) and water (3 mE) were added to a 100-mE round-bottom flask fitted with a nitrogen inlet, magnetic stir bar and condenser. The resulting solution was stirred for 16 h at 1000 C. The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC with ethyl acetate/petroleum ether (1:5 v/v) to provide 2?-(cya- nomethyl)-[ 1, 1?-biphenyl]-4-carboxylic acid (Intermediate 2-5, 500 mg, 83%). LCMS: (ESI) m/z 236 [M-H].

Reference： [1]Patent: US2016/185785,2016,A1 .Location in patent: Paragraph 1984; 1985

37
[ 180516-87-4 ]
[ 59878-57-8 ]
(4-cyclopropylcarbonylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61.4%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; water; N,N-dimethyl-formamide; at 20℃;	At room temperature will 4-carboxyphenyl boronic acid pinacol ester (3g, 12.10mmol) was dissolved in dichloromethane (27ml, 0.422mol) And N,N-dimethylformamide (9ml, 0.116mol) was added 1-cyclopropyl-methylpiperazine (2.3g, 14.9mmol), And successively added 1-ethyl - (3-dimethylaminopropyl)carbodiimide hydrochloride (2.79g, 14.4mmol), N- hydroxybenzotriazole (1.98g, 12.9mmol), triethylamine (2.5ml, 17.99mmol), The reaction was stirred at room temperature until TLC monitoring Completion of the reaction starting material, the reaction solution was added 30ml of water, stirred for 30 minutes, (100ml * 3) and extracted with dichloromethane, and then With a saturated sodium chloride solution (100ml * 2) washing the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, to give: (4- Cyclopropylcarbonyl - piperazin-1-yl) - [4- (4,4,5,5-tetramethyl - [1,3,2] dioxaborolan-2-yl) - phenyl ] - methanone (3.5g, White solid), 61.4% yield, used in the next reaction.

Reference： [1]Patent: CN103087077,2016,B .Location in patent: Paragraph 0083-0085

38
[ 103-76-4 ]
[ 180516-87-4 ]
[ 1432742-20-5 ]

Yield	Reaction Conditions	Operation in experiment
68.8%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; water; N,N-dimethyl-formamide at 20℃;	4.1 At room temperature will 4-carboxyphenyl boronic acid pinacol ester (3g, 12.10mmol) was dissolved in dichloromethane (27ml, 0.422mol) And N, N- dimethylformamide (9ml, 0.116mol) was added N- hydroxyethyl piperazine (2g, 15.36mmol), and by Was added 1-ethyl - (3-dimethylaminopropyl) carbodiimide hydrochloride (2.79g, 14.4mmol), N- hydroxybenzotriazole (1.98g, 12.9mmol), triethylamine (2.5ml, 17.99mmol), The reaction was stirred at room temperature until the starting material was monitored by TLC Completion of the reaction, the reaction solution was added 30ml of water, stirred for 30 minutes, (100ml * 3) and extracted with methylene chloride, then saturated And sodium chloride solution (100ml * 2) washing the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, to give: (4- Hydroxyethyl - piperazin-1-yl) - [4- (4,4,5,5-tetramethyl - [1,3,2] dioxaborolan-2-yl) - phenyl] - methanone (3.0g, White solid), 68.8% yield, used in the next reaction.

Reference： [1]Current Patent Assignee: SHANGHAI XIMAI MEDICAL TECHNOLOGY; SHANGHAI CDYMAX PHARMACEUTICALS - CN103087077, 2016, B Location in patent: Paragraph 0095-0097

39
[ 64709-55-3 ]
[ 96402-49-2 ]
[ 180516-87-4 ]
[ 147290-11-7 ]
C₄₃H₃₉BN₄O₆ [ No CAS ]

Reference： [1]New Journal of Chemistry,2017,vol. 41,p. 2593 - 2603

40
[ 64709-55-3 ]
[ 35661-40-6 ]
[ 180516-87-4 ]
[ 147290-11-7 ]
C₃₉H₃₇BN₄O₆ [ No CAS ]

Reference： [1]New Journal of Chemistry,2017,vol. 41,p. 2593 - 2603

41
[ 64709-55-3 ]
[ 109425-51-6 ]
[ 180516-87-4 ]
[ 147290-11-7 ]
C₃₆H₃₅BN₆O₆ [ No CAS ]

Reference： [1]New Journal of Chemistry,2017,vol. 41,p. 2593 - 2603

42
[ 504-29-0 ]
[ 180516-87-4 ]
[ 1383385-64-5 ]

Yield	Reaction Conditions	Operation in experiment
93.7%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30℃; for 4h;	1 To a 500 mL reaction flask was added p-carboxyphenylboronic acid (50 g, 0.3 mol), pinacol (39 g, 0.33 mol), n-hexane 100 g, and the temperature was raised to 70 ° C, and the reaction was carried out for 3 hours, and concentrated under reduced pressure. Drying in vacuo gave 73 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid as a white solid. Yield: 98%; MS m / z: 249 [M + H] +. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (50 g, 0.2 mol) was added to the reaction flask, 2-amino Pyridine (20.7 g, 0.22 mol), EDC hydrochloride (77.3 g, 0.4 mol), DMAP (2 g, 0.016 mol), and dichloromethane (200 mL), and warmed to 30 ° C for 4 hours. The reaction was quenched with 10% aqueous citric acid solution, and the organic phase was washed with saturated brine, dried, and then distilled under reduced pressure. 60.5 g of the target product N-2-pyridyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was obtained. Yield: 93.7%.
85%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25 - 30℃;	9 Example 9 7 (24.81 g, 100 mmol) and N,N-dimethylformamide (124 mL) were added to a three-neck flask.Stir well and cool to 0~5 °C.Add EDCI (23.00g, 120mmol),2-Aminopyridine (11.29 g, 110 mmol) was added.Diisopropylethylamine (25.85 g, 200 mmol) was added dropwise.After the addition, the reaction is carried out at 25 to 30 ° C for 6 to 8 hours.At the end of the reaction, water (248 mL) was added.Extracted 3 times with ethyl acetate (124 mL).The combined organic phase 10% sodium bicarbonate solution (124 mL) was washed once.Washed twice with saturated saline (124 mL),Dry over anhydrous sodium sulfate,After concentration, it is beaten with ethyl acetate petroleum ether mixed solvent.filter,Drying gave compound 8 (27.56 g, 85%).
13.1 g	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;	1.8 Under nitrogen protection,To a solution of 2-aminopyridine (5 g, 53.19 mmol)4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid (13.20 g, 53.19 mmol)DIPEA (13.72 g, 106.38 mmol)In 50mL DMF (0 ) solution,HBTU (26.21 g, 69.15 mmol) was added portionwise,The reaction mixture was stirred at room temperature overnight,TLC shows the raw material reaction is complete,The reaction solution was quenched by the addition of water,Extracted with EA (30 mL x 3)Organic phase with saturated salt water backwash,Anhydrous Na2SO4 dried,After vacuum evaporation, the residue was purified by column chromatography (PE / EA = 20/1)To give 13.1 g of the title compound

1.1 g

Stage #1: 4-carboxyphenylboronic acid pinacol ester In N,N-dimethyl-formamide for 1h; Stage #2: 2-aminopyridine In N,N-dimethyl-formamide

Preparation of Intermediate 33b A solution of compound 33b-1 (1 g, 4 mmol), DIPEA (1 g, 8 mmol), HATU (2.45 g, 6.45 mmol) in DMF (25 mL) was stirred for 1 hour, then 2-aminopyridine (450 mg, 4.8 mmol) was added and stirred overnight. LC-MS was used to trace the reaction until the reaction was complete. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 1.1 g of compound 33b. MS m/z (ESI): 325 [M+H]+.

Reference： [1]Current Patent Assignee: ZHEJIANG CHEMTRUE BIOMEDICINE - CN109053780, 2018, A Location in patent: Paragraph 0021; 0038; 0042; 0048; 0054; 0060; 0066; 0072
[2]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN108250186, 2018, A Location in patent: Paragraph 0069; 0070; 0071
[3]Current Patent Assignee: CHENGDU BRILLIANT PHARMACEUTICAL CO LTD - CN106831787, 2017, A Location in patent: Paragraph 0145; 0168; 0169
[4]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - US2020/262813, 2020, A1 Location in patent: Paragraph 0255-0256

43
[ 887338-51-4 ]
[ 180516-87-4 ]
4-[6-fluoro-1-(p-tolylsulfonyl)indol-3-yl]benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium carbonate In 1,4-dioxane; water at 70℃; for 20h; Inert atmosphere;	3.a (a) 4-[6-Fluoro-1-(p-tolylsulfonyl)indol-3-yl]benzoic acid 3-bromo-6-fluoro-1-(p-tolylsulfonyl)indole (3.9 g, 10.59 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (3.94 g, 15.88 mmol) were dissolved in dioxane (60 mL) and a solution of 2N K2CO3 in water (26.5 ml) was added. The reaction mixture was purged with nitrogen for 5 min after which PdCl2(dppf) (424 mg, 0.52 mmol) was added. The reaction mixture was stirred for 20 h at 70 °C under nitrogen atmosphere. The mixture was diluted with ethyl acetate and filtered over Decalite. The filtrate was collected and the pH was adjusted to pH 3 by addition of 2N aq. HCl-solution. The organic layer was separated and washed with water and brine, dried over sodium sulfate, filtered and evaporated to dryness to give crude product. The crude product was triturated with acetonitrile at 50 °C for 15 min. After cooling, the precipitate was filtered and washed with acetonitrile, dried under vacuum to give 3.7 g of the title compound (91%) as a light brown solid.

Reference： [1]Current Patent Assignee: NETHERLANDS TRANSLATIONAL RESEARCH CENTER - EP3269714, 2018, A1 Location in patent: Paragraph 0088

44
[ 70261-82-4 ]
[ 180516-87-4 ]
N-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20℃;	A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (154 mg, 0.605 mmol), TBTU (232 mg, 0.725 mmol), 4-[(4-methylpiperazin-1-yl)methyl]aniline (150 mg, 0.725 mmol) and DIPEA (0.155 mL, 0.907 mmol) inDMA (7 mL) was let under stirring at rt overnight. The mixture was diluted with EtOAc, washed with a saturated solution of NaHCO3, water and brine, dried over Na2SO4, filtered and taken to dryness under reduced pressure. After treatment with Et20, the solid was filtered and used without any further purification.HRMS (ESI+): calcd. for 025H35BN303 [M + H] 436.2766; found 436.2762.

Reference： [1]Patent: WO2018/19681,2018,A1 .Location in patent: Page/Page column 118

45
[ 763111-47-3 ]
[ 180516-87-4 ]
4-(4-fluoro-3-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37 mg	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	A reaction mixture of amine precursor (51 mg, 0.139 mmol), 4-carboxylphenylboronic acid pinacol ester (38 mg, 0.153 mmol), HATU (60 mg, 0.158 mmol) and DIPEA (50 muL) in DMF (1 mL) was stirred at room temperature overnight. Water (10 mL) was added, and precipitate was filtered and rinsed with water, and then dissolved in ethyl acetate. After drying by magnesium sulfate, the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford final product (37 mg) as white solid. M.P.: 288-291 C; 1H NMR (400MHz, CDCl3) delta 10.66 (s, 1H), 8.47 (s, 1H), 7.85-7.72 (m, 5H), 7.38-7.33 (m, 4H), 7.04 (m, 1H), 4.29 (s, 2H), 3.73 (m, 4H), 3.37 (m, 4H), 1.35 (s, 9H), 1.27 (s, 3H). 13C NMR (100MHz, CDCl3) delta 160.4, 145.5, 142.2, 135.0, 134.4, 133.7, 131.6, 129.5, 129.2, 128.3, 127.2, 126.1, 125.0, 121.5, 84.1, 37.7, 29.7, 24.8; HRMS m/z: calcd for C33H34BFN4O5+H, 597.2679; found 579.2661.

Reference： [1]Organic Letters,2018,vol. 20,p. 1752 - 1755
[2]Tetrahedron Letters,2018,vol. 59,p. 1963 - 1967

46
[ 180516-87-4 ]
[ 1420477-60-6 ]

Reference： [1]Patent: CN108250186,2018,A
[2]Patent: CN108250186,2018,A

47
[ 5004-07-9 ]
[ 180516-87-4 ]
[ 957198-27-5 ]

Yield	Reaction Conditions	Operation in experiment
42%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 60℃;	Asolution of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid (9.80 mmol, 2.43 g), <strong>[5004-07-9]4-(1-pyrrolidinyl)piperidine</strong>(10.77 mol, 1.66 g), 1-hydroxybenzotriazole (16.67 mmol, 2.25 g), and N-(3-dimethylaminopropyl)-N?-ethylcarbodiimidehydrochloride (19.57 mmol, 3.75 g) in DMF (30 mL) was stirred overnight at 60C. Upon removal of DMF on rotavap,the residue was taken into mixture of EtOAc and H2O. The combined organic layers from extraction were stirred withaq. 2N HCl for 20 min and the aqueous layer was purified by reverse phase prep-HPLC to furnish the desired boronicacid (1.24g. 42%).

Reference： [1]Patent: EP2365809,2018,B1 .Location in patent: Paragraph 0313

48
[ 7188-38-7 ]
[ 180516-87-4 ]
[ 214360-73-3 ]
[ 443776-94-1 ]
N-(2-(tert-butylamino)-1-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	Stage #1: 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)aniline; 2-fluoro-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzaldehyde In methanol at 60℃; for 1h; Microwave irradiation; Stage #2: tert-butylisonitrile; 4-carboxyphenylboronic acid pinacol ester In methanol at 60℃; for 2h; Microwave irradiation;	General procedure for synthesis of multiple boron-containing Ugi analogs General procedure: N-(2-(tert-Butylamino)-2-oxo-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide (1) A 10-mL glass tube containing 4-aminophenylboronic acid pinacol ester (300 mg, 1.37 mmol), 4-formylphenylboronic acid pinacol ester (256 mg, 1.09 mmol), and 2.7 mL methanol was first stirred for 60 min under microwave irradiation (50 °C, 150 W). Then, 4-carboxyphenylboronic acid pinacol ester (374 mg, 1.51 mmol) and tert-butyl isocyanide (0.2 mL, 1.37 mmol) were added to the reaction mixture. Microwave irradiation was applied again for an additional 120 min (50 °C, 150 W) under medium-speed magnetic stirring, and the reaction mixture was concentrated and redissolved in ethylacetate. The crude solution was then washed with 1 M HCl(aq) and NaHCO3(aq), respectively. The organic solution was collected and dried over MgSO4 and concentratedin vacuo. The resulting crude material was purified by flash chromatography with ethyl acetate:n-hexane = 3:7 to afford the desired product in 85 %yield (708.19 mg).

Reference： [1]Chen, Yi-Wei; Liao, Pei-Chun; Zhang, Yu-Xuan; Yeh, Shang-Yi; Wu, Yu-Hsuan; Qiu, Shuo-Bei; Tsai, Pei-Ni; Xin, Zhuo; Ting, Yen-Yu; Chen, Hsien-Chi; Cheung, Siu-Fung; Hsu, Chen-Yun; Lien, Wan-Hsing; Pan, Po-Shen [Research on Chemical Intermediates, 2019, vol. 45, # 1, p. 103 - 118]

49
[ 7188-38-7 ]
[ 1112208-82-8 ]
[ 180516-87-4 ]
[ 214360-73-3 ]
N-(2-(tert-butylamino)-1-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: 2-fluoro-5-formylphenylboronic acid pinacol ester; 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)aniline In methanol at 60℃; for 1h; Microwave irradiation; Stage #2: tert-butylisonitrile; 4-carboxyphenylboronic acid pinacol ester In methanol at 60℃; for 2h; Microwave irradiation;	General procedure for synthesis of multiple boron-containing Ugi analogs General procedure: N-(2-(tert-Butylamino)-2-oxo-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide (1) A 10-mL glass tube containing 4-aminophenylboronic acid pinacol ester (300 mg, 1.37 mmol), 4-formylphenylboronic acid pinacol ester (256 mg, 1.09 mmol), and 2.7 mL methanol was first stirred for 60 min under microwave irradiation (50 °C, 150 W). Then, 4-carboxyphenylboronic acid pinacol ester (374 mg, 1.51 mmol) and tert-butyl isocyanide (0.2 mL, 1.37 mmol) were added to the reaction mixture. Microwave irradiation was applied again for an additional 120 min (50 °C, 150 W) under medium-speed magnetic stirring, and the reaction mixture was concentrated and redissolved in ethylacetate. The crude solution was then washed with 1 M HCl(aq) and NaHCO3(aq), respectively. The organic solution was collected and dried over MgSO4 and concentratedin vacuo. The resulting crude material was purified by flash chromatography with ethyl acetate:n-hexane = 3:7 to afford the desired product in 85 %yield (708.19 mg).

50
[ 854601-60-8 ]
[ 180516-87-4 ]
1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,8,11,14,17,20,23,26,29,32,35-undecaoxaazahexatriacontan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	4-(4,4,5,5-Tetramethyl-l ,3,2-dioxaborolan-2-yl)benzoic acid (100 mg) and2,5,8,1 l,14,17,20,23,26,29,32-undecaoxatetratriacontan-34-amine (229 mg) were dissolved in dichloromethane (2 mL). N1-((Ethylimino)methylene)-N3^V3-dimethylpropane-l,3-diaminehydrochloride (162 mg) and NN-dimethylpyridin-4-amine (73.9 mg) were added. The solution was mixed at room temperature overnight. The solution was concentrated under vacuum and purified by flash column chromatography using a gradient of 0-20% methanol in dichloromethane. The solvent was removed under vacuum to yield the title compound. 'H NMR (500 MHz, dimethylsulfoxide-cfe) δ ppm 8.56 (t, IH), 7.85 (d, 2H), 7.74 (d, 2H), 3.56-3.46 (m, 44H), 3.24 (s, 3H), 1.31 (s, 12H). MS (ESI) m/z 763.0 (M+NH4)+.

Reference： [1]Patent: WO2019/35927,2019,A1 .Location in patent: Paragraph 00457

51
[ 4597-87-9 ]
[ 180516-87-4 ]
N-methyl-N-(2-pyridyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
367 mg	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 21℃;	N-methyl-N-(2-pyridyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoic acid (650 mg, 2.62 mmol), EDCI (553 mg, 2.88 mmol) and DMAP (38.4 mg, 0.31 mmol) were dissolved in DCM (10 mL). N-methylpyridin-2-amine (297 uL, 2.88 mmol) was added. The reaction mixture was stirred overnight at 21 ºC. The organic layer was washed twice with water (10 mL), dried using a PE-filter and concentrated in vacuo. The crude product was purified using flash chromatogaphy (0-10% methanol in DCM) to give 367 mg of N-methyl-N-(2-pyridyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide as a white solid.

Reference： [1]Barf, Tjeerd; Covey, Todd; Izumi, Raquel; Van De Kar, Bas; Gulrajani, Michael; Van Lith, Bart; Van Hoek, Maaike; De Zwart, Edwin; Mittag, Diana; Demont, Dennis; Verkaik, Saskia; Krantz, Fanny; Pearson, Paul G.; Ulrich, Roger; Kaptein, Allard [Journal of Pharmacology and Experimental Therapeutics, 2017, vol. 363, # 2, p. 240 - 252]

52
[ 180516-87-4 ]
[ 73852-88-7 ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 10514 - 10520
Angew. Chem.,2019,vol. 131,p. 10624 - 10630,7

53
[ 138529-46-1 ]
[ 180516-87-4 ]
5‐[(3aS,4S,6aR)‐2‐oxo‐hexahydro‐1H‐thieno[3,4‐d]imidazolidin‐4‐yl]‐N‐{2‐[2‐(2‐[4‐(tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)phenyl]formamido}ethoxy)ethoxy]ethyl}pentanamide [ No CAS ]

Reference： [1]Chemical Communications,2019,vol. 55,p. 15121 - 15124

54
[ 180516-87-4 ]
[ 568577-88-8 ]

Reference： [1]Journal of the American Chemical Society,2020,vol. 142,p. 5918 - 5923

55
H₂O*CHLiO₂ [ No CAS ]
[ 73852-88-7 ]
[ 180516-87-4 ]

Reference： [1]Chemical Communications,2020,vol. 56,p. 4067 - 4069

56
[ 1142943-96-1 ]
[ 180516-87-4 ]
[ 1142936-98-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 70 - 100℃; Inert atmosphere;	1.4 Step 4 Synthesis of 4- (2- (cyclopropylcarboxamido)-[1,2,4] triazolo [1,5-a] pyridin-5-yl) benzoic acid (VI) Under the protection of nitrogen at room temperature, 1.0g (3.5mmol) of intermediate V, 1.2g (5.3mmol) of 4-carboxyphenylboronic acid pinacol ester, 1.0g (7mmol) of potassium carbonate and 0.14g (0.35mmol) of Pd (dppf) Cl2 was added to a mixed solvent of 10 mL dioxane / water (8: 1), and the temperature was slowly raised to 70-100 ° C with stirring, and the reaction was performed for 5-14 h. After the reaction was completed, part of the solvent was distilled off, 15 mL of water was added to the residue, and the aqueous layer was washed with DCM. The aqueous layer was adjusted to pH 2-3 with 4N HCl, suction filtered, and purified by column chromatography to obtain 0.86 g of white solid in 75% yield;
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃;

Reference： [1]Current Patent Assignee: SHENZHEN KUNJIAN INNOVATION PHARMACEUTICAL RES INS - CN111072655, 2020, A Location in patent: Paragraph 0059; 0066-0067
[2]Chen, Dawei; Jiang, Yuyang; Li, Anqi; Liu, Zijian; Lu, Kuan; Wu, Weibin; Xiao, Boren; Yuan, Zigao; Zhai, Xin; Zhang, Cunlong [Bioorganic and medicinal chemistry letters, 2020, vol. 30, # 14]

57
[ 626-89-1 ]
[ 180516-87-4 ]
4-methylpentyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 16h;

Reference： [1]Fawcett, Alexander; Keller, M. Josephine; Herrera, Zachary; Hartwig, John F. [Angewandte Chemie - International Edition, 2021, vol. 60, # 15, p. 8276 - 8283][Angew. Chem., 2021, vol. 133, # 15, p. 8357 - 8364,8]

58
[ 629-41-4 ]
[ 180516-87-4 ]
C₃₄H₄₈B₂O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 5h;	3.1 (1) Synthesis of compound E In a 100 mL eggplant flask, 0.532 g (3.64 mmol) of octane-1,8-diol, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid 2 Add .128 g (8.58 mmol), 1.044 g (8.55 mmol) of 4-dimethylaminopyridine and 28.0 mL of dry DMF, stir at 0 ° C., and stir 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. 1.630 g (8.50 mmol) was added, the temperature was returned to room temperature, and the mixture was stirred for 5 hours. The reaction was stopped with water, extracted with methylene chloride, and washed once with 1 mol / L hydrochloric acid and three times with saturated aqueous sodium chloride solution. Anhydrous sodium sulfate was added, dried, and then filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from methanol to obtain 1.368 g (62%) of white powdery crystals

Reference： [1]Current Patent Assignee: NISSAN CHEMICAL CORPORATION; KANAGAWA UNIVERSITY - JP2021/119120, 2021, A Location in patent: Paragraph 0050-0051

59
[ 74-85-1 ]
[ 180516-87-4 ]
[ 1256359-22-4 ]

Reference： [1]Chemical Communications,2021,vol. 57,p. 9064 - 9067

60
[ 60254-10-6 ]
[ 180516-87-4 ]
C₃₁H₃₀BO₄P [ No CAS ]

Reference： [1]Organic Letters,2021,vol. 23,p. 7755 - 7758

61
[ 866546-13-6 ]
2-(3-(isocyanomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ No CAS ]
[ 180516-87-4 ]
[ 214360-73-3 ]
N-(1-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxo-2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl)amino)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde; 2-(4-Aminophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In 2,2,2-trifluoroethanol at 65℃; for 0.25h; Microwave irradiation; Stage #2: 2-(3-(isocyanomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid In 2,2,2-trifluoroethanol at 65℃; for 2h; Microwave irradiation;

Reference： [1]Ai, Guan-Lin; Chen, Jen-Kun; Chen, Pin-Rui; Chen, Yi-Wei; Pan, Kuan-Lin; Pan, Po-Shen; Qiu, Shuo-Bei; Xiao, Jing-Han [European Journal of Organic Chemistry, 2022]

62
[ 1112208-82-8 ]
2-(3-(isocyanomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ No CAS ]
[ 180516-87-4 ]
[ 214360-73-3 ]
N-(1-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxo-2-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amino)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: 2-fluoro-5-formylphenylboronic acid pinacol ester; 2-(4-Aminophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In 2,2,2-trifluoroethanol at 65℃; for 0.25h; Microwave irradiation; Stage #2: 2-(3-(isocyanomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid In 2,2,2-trifluoroethanol at 65℃; for 2h; Microwave irradiation;

Reference： [1]Ai, Guan-Lin; Chen, Jen-Kun; Chen, Pin-Rui; Chen, Yi-Wei; Pan, Kuan-Lin; Pan, Po-Shen; Qiu, Shuo-Bei; Xiao, Jing-Han [European Journal of Organic Chemistry, 2022]

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P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
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.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
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:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
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.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
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
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
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. 180516-87-4 ] {[proInfo.proName]}

Quality Control of [ 180516-87-4 ]

Related Doc. of [ 180516-87-4 ]

Product Details of [ 180516-87-4 ]

Calculated chemistry of [ 180516-87-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 180516-87-4 ]

Application In Synthesis of [ 180516-87-4 ]

[ 180516-87-4 ] Synthesis Path-Upstream 1~21

[ 180516-87-4 ] Synthesis Path-Downstream 1~62

Related Functional Groups of [ 180516-87-4 ]

Organoboron

Aryls

Carboxylic Acids

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 180516-87-4 ]