Name: 4-(Hydroxymethyl)phenylboronic acid pinacol ester
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Quality Control of 4-(Hydroxymethyl)phenylboronic acid pinacol ester Purity: 98% SDS Specification

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Product Details of 4-(Hydroxymethyl)phenylboronic acid pinacol ester

CAS No. :	302348-51-2
Formula :	C₁₃H₁₉BO₃
M.W :	234.10
SMILES Code :	CC1(C)OB(OC1(C)C)C1=CC=C(CO)C=C1
MDL No. :	MFCD09837617
InChI Key :	GZZBZWITJNATOD-UHFFFAOYSA-N
Pubchem ID :	11402050

Safety of 4-(Hydroxymethyl)phenylboronic acid pinacol ester

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

Application In Synthesis of 4-(Hydroxymethyl)phenylboronic acid pinacol ester

* 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.

Downstream synthetic route of [ 302348-51-2 ]

[ 302348-51-2 ] Synthesis Path-Downstream 1~55

1
[ 128376-64-7 ]
[ 302348-51-2 ]

Yield	Reaction Conditions	Operation in experiment
513 mg	With sodium tetrahydroborate; at 20℃; for 5h;	To a mixture of a4-formylbenzenboronic acid (1a, 375 mg, 2.50 mmol), pinacol (355 mg, 3.00 mmol) and anhydrous magnesium sulfate (625 mg, 5.00 mmol), methanol was added (12.50 mL). The mixture was stirred at room temperature for 6 h. After the reaction was completed, the crude solution was filtered, and then sodium borohydride (47 mg, 1.25 mmol) was added to the filtrate. Afterwards, the reaction mixture was stirred for an additional 5 h. Once the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the desired product 2a as a white solid (m.p. 75?77 °C) in88percent yield (513 mg). 1H-NMR (CD3OD-d4) delta ppm 7.71 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H),4.62 (s, 2H), 1.34 (s, 12H); 13C-NMR (CD3OD-d4) delta ppm 146.23, 135.93, 127.26, 85.19, 65.24, 25.34;11B-NMR (CDCl3) delta ppm 34.82.

References: [1]Synthetic Communications,2002,vol. 32,p. 2669 - 2676.
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2487 - 2491.
[3]Israel Journal of Chemistry,2009,vol. 49,p. 1 - 8.
[4]Molecules,2013,vol. 18,p. 12346 - 12367.

2
[ 302348-51-2 ]
[ 138500-85-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 18h;Inert atmosphere;	2-(4-(Bromomethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3) The compound 2(1 eq, 5.72 mmol) was dissolved in THF (25 mL) followed by the addition of triphenylphosphine (2 eq, 11.4 mmol). The mixture was cooled to 0C with an ice bath then tetrabromomethane (2 eq, 11.4 mmol) was carefully added portion wise. The reaction was stirred at rt for 18h. The solution was poured into water (30 mL) and extracted 3 times (3 x 25 mL) with EtOAc. The combined organic extracts were dried, filtered and evaporated under vacuum. The compound was purified using column chromatography (silica gel, 99/1Hex/EtOAc) to afford the desired compound (Rf = 0.2) as a colourless solid (1.6 g, 94%). 1H-NMR (CDCI3, 600 MHz) delta 7.78 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 4.49 (s, 2H), 1.34 (s, 12H); 13C-NMR (CDC13, 150 MHz) delta 140.8, 135.3, 128.4, 84.0, 33.4, 25.0.
92%	With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 20℃; for 4h;Cooling with ice;	4-hydroxymethylphenylboronic acid, pinacol ester (1.08 g, 4.61 mmol) was dissolved in THF (20 ml) together with triphenylphosphine (2.42 g, 9.23mmol). The reaction mixture was cooled in an ice-water bath, and carbon tetrabromide (3.06 g, 9.23 mmol) was added portion wise. After stirring for 4 hours at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was combined and dried by sodium sulfate. After filtration, the solvent was evaporated, and the residue was purified by flash chromatography to give the product as a white solid (1.72 g, 92%). 1H NMR (300 MHz, CD2C12, delta): 7.62 (d, J = 6.0 Hz, 2H), 7.32 (d, J = 6.0 Hz, 2H), 4.58 (d, 2H), 1.34 (s, 9H); MS (ESI) m/z 297.0.

References: [1]Patent: WO2019/63634,2019,A1 .Location in patent: Page/Page column 28-29.
[2]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 743 - 748.
[3]Patent: WO2013/25885,2013,A1 .Location in patent: Paragraph 0086.
[4]Synthetic Communications,2002,vol. 32,p. 2669 - 2676.
[5]Chemical Communications (Cambridge, United Kingdom),2019,vol. 55,p. 3343 - 3346.
[6]Patent: EP2450354,2012,A1 .

3
[ 545-06-2 ]
[ 302348-51-2 ]
[ 911707-70-5 ]

References: [1]Synlett,2006,p. 1729 - 1733.

4
[ 302348-51-2 ]
C₂₁H₂₇BO₄ [ No CAS ]

References: [1]Synlett,2006,p. 1729 - 1733.

5
[ 302348-51-2 ]
2-(4-benzylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ No CAS ]

References: [1]Synlett,2006,p. 1729 - 1733.

6
[ 76-09-5 ]
sodium-compound of pinacol [ No CAS ]
[ 302348-51-2 ]

References: [1]Synthetic Communications,2002,vol. 32,p. 2669 - 2676.

7
[ 87199-17-5 ]
[ 302348-51-2 ]

References: [1]Synthetic Communications,2002,vol. 32,p. 2669 - 2676.
[2]Molecules,2013,vol. 18,p. 12346 - 12367.

8
C₁₉H₁₆N₂O₆ [ No CAS ]
[ 302348-51-2 ]
[ 1018786-02-1 ]

References: [1]Journal of the American Chemical Society,2008,vol. 130,p. 4596 - 4597.

9
[ 1018781-12-8 ]
[ 302348-51-2 ]
Peroxy Lucifer 1 [ No CAS ]

References: [1]Journal of the American Chemical Society,2008,vol. 130,p. 4596 - 4597.

10
C₂₈H₅₃NO₄Si₃ [ No CAS ]
[ 302348-51-2 ]
C₄₁H₇₂BNO₇Si₃ [ No CAS ]

References: [1]Chemical Communications,2008,p. 5701 - 5703.

11
C₂₁H₂₅NO₅ [ No CAS ]
[ 302348-51-2 ]
C₃₄H₄₄BNO₈ [ No CAS ]

References: [1]Chemical Communications,2008,p. 5701 - 5703.

12
[ 57876-69-4 ]
[ 302348-51-2 ]
[ 1160829-14-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2487 - 2491.

13
[ 52334-81-3 ]
[ 302348-51-2 ]
[ 1160829-13-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2487 - 2491.

14
[ 302348-51-2 ]
[ 1169945-44-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With chloro-trimethyl-silane; sodium iodide; In acetonitrile; at 0 - 20℃; for 1h;	To a stirred solution of <strong>[302348-51-2](4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol</strong> (1) (0.55 g, 2.35 mmol) in acetonitrile (20 mL), sodium iodide (1.1 g, 7.05 mmol) and Trimethylsilyl chloride (0.65 mL, 7.05 mmol) are added at about 0°C. The reaction mixture is allowed to stir at room temperature for about 1 hour. After completion of the reaction, solvent is evaporated under vacuum. The crude product is dissolved in saturated solution of Na2S203 to quench the unreacted iodide and the product is extracted with dichloromethane. The crude product is purified by column chromatography on silica gel using ethyl acetate\hexane (5:95) as an eluent to give product 2-(4-(iodomethyl)phenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (2) in excellent yield (90percent). 1H NMR (400 MHz, ( 7X 7 ,· ) dppm 7.73 (d, J = 8 Hz, 21 1 ). 7.37 (d, J = 8 Hz, 2H), 4.45 (s, 2H), 1.34 (s, 12H) 1 C NMR (100 MHz, ( 7 ,·) 5ppm 142.3, 135.3, 128.0, 24.9, 5.4

References: [1]Patent: WO2017/33163,2017,A1 .Location in patent: Page/Page column 33; 34; 35.
[2]Macromolecules,2013,vol. 46,p. 8416 - 8425.
[3]Journal of the American Chemical Society,2009,vol. 131,p. 9934 - 9936.

15
[ 124-63-0 ]
[ 302348-51-2 ]
4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl methanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0℃; for 2h;Inert atmosphere;	(ii) Synthesis of Compound (15); (4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl methanesulfonate) (see Non-patent Literature 14); Under argon atmosphere, triethylamine (3.15 mL, 22.6 mmol) and methanesulfonyl chloride (1.40 mL, 18.1 mmol) were sequentially added to a CH2Cl2 (60 mL) solution of Compound (14) (3.48 g, 14.9 mmol), and the mixture was stirred at 0 °C for 2 hours. Water (150 mL) was added to the mixture, and the mixture was extracted with CH2Cl2 (100 mL .x. 3). All the organic phases were mixed, sequentially rinsed with water (70 mL .x. 3) and a saline solution (70 mL .x. 3), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (110 g of silica gel, n-hexane/EtOAc = 3/1) to obtain Compound (15) as a colorless solid. The Compound (15) was not purified furthermore and used in the next step. TLC 0.41 (n-hexane/EtOAc = 2/1).
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 3h;Inert atmosphere;	2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]isoindoline-1,3-dione (3a). Compound 2a (585 mg, 2.50 mmol), and dichloromethane (25.00 mL) were added to a dry flask containing a magnetic stir bar under a nitrogen atmosphere. The flask was cooled to 0 °C, then methanesulfonyl chloroide (0.29 mL, 3.75 mmol) and N,N-diisopropylethylamine (DIPEA, 0.87 mL, 5.00 mmol) were slowly added to the flask. The reaction mixture was stirred at 0 °C for 3 h. After the reaction was completed, the reaction mixture was diluted with dichloromethane (25.00 mL) before H2O (25.00 mL)was added. The organic layer was then washed with brine and dried with MgSO4. The resulting organic layer was then filtered and the filtrate was concentrated in vacuo. The resulting crude material was re-dissolved in DMF (4.68 mL) after which both potassium phthalimide salt (695 mg, 3.75 mmol), and K2CO3 (1,036 mg, 7.50 mmol) were added to the solution. The reaction was then allowed to stir at room temperature for 3 days. After the reaction was completed, the distilled H2O (20.00 mL) was slowly added to the reaction mixture to afford the formation of a solid precipitate. The reaction mixture was then filtered and the filtered cake was collected. The filtered cake was re-dissolved in tertbutanol/H2O (4:1, v/v) (10.00 mL) before a freeze-drying process was applied to remove the remaining DMF. The desired product 3a was obtained as a white solid (m.p. 166?169 °C) in 96percent yield (872 mg);1H-NMR (CDCl3) delta ppm 7.84?7.82 (m, 2 H), 7.74 (d, J = 7.85 Hz, 2 H), 7.71?7.68 (m, 2H), 7.42 (d,J = 7.85 Hz, 2H), 4.85 (s, 2H), 1.34 (s, 12H); 13C-NMR (CDCl3) delta ppm 167.90, 139.26, 135.12,133.93, 132.04, 127.76, 123.29, 83.73, 41.60, 24.77; 11B-NMR (CDCl3) delta ppm 30.94.

References: [1]Israel Journal of Chemistry,2009,vol. 49,p. 1 - 8.
[2]Tetrahedron,2010,vol. 66,p. 2384 - 2389.
[3]Patent: EP2450354,2012,A1 .Location in patent: Page/Page column 20.
[4]Molecules,2013,vol. 18,p. 12346 - 12367.

16
allyl 5-amino-2-nitrobenzoate [ No CAS ]
[ 32315-10-9 ]
[ 302348-51-2 ]
[ 1219600-17-5 ]

References: [1]Journal of the American Chemical Society,2010,vol. 132,p. 3945 - 3952.

17
[ 1225050-00-9 ]
[ 302348-51-2 ]

References: [1]Tetrahedron,2010,vol. 66,p. 2384 - 2389.

18
[ 70-34-8 ]
[ 302348-51-2 ]
[ 1225050-01-0 ]

References: [1]Tetrahedron,2010,vol. 66,p. 2384 - 2389.

19
[ 1055310-43-4 ]
[ 302348-51-2 ]
[ 1219600-17-5 ]

References: [1]Journal of the American Chemical Society,2010,vol. 132,p. 3945 - 3952.

20
[ 74124-79-1 ]
[ 302348-51-2 ]
[ 1255209-41-6 ]

References: [1]Chemical Communications,2010,vol. 46,p. 7510 - 7512.
[2]Angewandte Chemie - International Edition,2019,vol. 58,p. 561 - 565.
Angew. Chem.,2019,vol. 131,p. 571 - 575,5.

21
[ 7693-46-1 ]
[ 302348-51-2 ]
[ 1254765-89-3 ]

Yield	Reaction Conditions	Operation in experiment
80%		To a solution of 4-nitrophenyl chloroformate (264 mg, 1.26 mmol) in 3 mL of DCM at 0 C was added dropwise Et3N (177 muL, 1.26 mmol). The mixture was stirred during 20 min under argon then a solution of 6a (100 mg, 0.42 mmol) in 4 mL of DCM was added dropwise to the first solution and the mixture was stirred during 3 h at r.t. The reaction was quenched with brine, extracted with DCM (3×20 mL), the organic layers were combined, dried with MgSO4 and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography over silica gel with cyclohexane-EtOAc: 90- 10 to 60-40 to give the expected product (135 mg, yield: 80%). 1H NMR (300 MHz, CDCl3) delta 7.88-7.82 (m, 2H), 7.46-7.41 (m, 2H), 7.40-7.35 (m, 2H), 5.31 (m, 2H), 1.35 (s, 12H). 13C NMR (75 MHz, CDCl3) delta 155.47, 152.38, 145.36, 137.02, 135.15, 127.58, 127.23, 125.25, 121.74, 83.95, 70.75, 24.82. HRMS (ESI): m/z Calcd for C20H22BNO7Na, [M+Na]+:422.1387, found: 422.1367.
60%	With triethylamine; In tetrahydrofuran; at 20℃; for 1h;Product distribution / selectivity;	4-(Hydroxymethyl)phenylboronic acid pinacol ester (0.5 g, 2.1 mmol) was dissolved in 20 mL of dry THF. Triethylamine (0.6 mL, 4.3 mmol) was added followed by 4-nitrophenyl chloroformate (0.47 g, 2.3 mmol) and the reaction was allowed to stir at room temperature for 1 h. The reaction was diluted with EtOAc and washed with 1.0 M HCl followed by saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Compound B2a was purified on a silica gel column eluting with 5% EtOAc in hexanes to give 0.51 g (1.3 mmol, 60% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta=8.25 (d, J=9.2 Hz, 2H), 7.85 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.36 (d, J=9.2 Hz, 2H), 5.31 (s, 2H), 1.35 (s, 12H). 13C NMR (100 MHz, CDCl3) delta=155.7, 152.7, 145.6, 137.2, 135.4, 127.9, 125.5, 122.0, 84.2, 71.0, 25.1. ESI-MS(+): m/z 417.19 [M+NH4]+, 422.20 [M+Na]+.
	In dichloromethane; at 0℃;	1) Preparation of active small molecules:Mixing 4-(hydroxymethyl)phenylboronic acid pinacol ester and p-nitrophenoxycarbonyl chloride as a molar ratio of 1:1The solution was dissolved in dichloromethane in that order, and the reaction was stirred well at 0 C.Synthesizing a small molecule capable of reversibly binding to methotrexate;

References: [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 5435 - 5441.
[2]Bioorganic Chemistry,2019,vol. 91.
[3]Journal of the American Chemical Society,2018,vol. 140,p. 6109 - 6121.
[4]Angewandte Chemie - International Edition,2010,vol. 49,p. 6795 - 6797.
[5]Chemical Communications,2011,vol. 47,p. 7968 - 7970.
[6]Patent: US2011/312905,2011,A1 .Location in patent: Page/Page column 39.
[7]Journal of the American Chemical Society,2019,vol. 141,p. 4073 - 4079.
[8]Patent: CN110156823,2019,A .Location in patent: Paragraph 0023-0025; 0027-0029.

22
[ 76-09-5 ]
[ 59016-93-2 ]
[ 302348-51-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	In tetrahydrofuran; for 22h;Reflux;	A suspension of 4-(hydroxymethyl)phenylboronic acid (1.00 g, 6.6. mmol) and pinacol (0.79 g, 6.7 mmol) in tetrahydrofurane (40 mL) was refluxed over 22 h. During this time the starting materials were completely dissolved. The solvent was removed in vacuum (10 mbar), the residue redissolved in CH2Cl2 / EtOAc and purified by column chromatography on silica gel using the mixture of CH2Cl2 / EtOAc (9/1, v/v) as eluent. Yield 1.4 g (92%). Rf= 0.3 (silica, eluent - CH2Cl2 / EtOAc, 9/1, v/v). 1H NMR (200 MHz, CDCl3), delta in ppm: 1.35 (s, 12H), 4.71 (s, 2H), 7.37 (d, 2H, 3J = 8.2 Hz), 7.81 (d, 2H, 3J = 8.2 Hz).
92%	In tetrahydrofuran; for 22h;Reflux;	Synthesis4-(Hvdroxymethyl)phenylboronic acid pinacol ester:A suspension of 4-(hydroxymethyl)phenylboronic acid (1.00 g, 6.6 mmol) and pinacol (0.79 g, 6.7 mmol) in tetrahydrofurane (40 ml_) was refluxed over 22 h. During this time the starting materials were completely dissolved. The solvent was removed in vacuum (10 mbar), the residue redissolved in CH2CI2 / EtOAc and purified by column chromatography on silica gel using the mixture of CH2CI2 / EtOAc (9/1 , v/v) as eluent. Yield 1.4 g (92%). Rf= 0.3 (silica, eluent - CH2CI2 / EtOAc, 9/1 , v/v). H NMR (200 MHz, CDCI3), delta in ppm: 1.35 (s, 12H), 4.71 (s, 2H), 7.37 (d, 2H, 3J = 8.2 Hz), 7.81 (d, 2H, 3J = 8.2 Hz).
	With magnesium sulfate; In acetonitrile; for 24h;Reflux;	To a stirred solution of 4-(hydroxymethyl) phenylboronic acid (0.4 g, 2.63 mmol) in acetonitrile (15 mL), MgS04 (3 g) and pinacol (0.37 g, 3.15 mmol) are added. The reaction mixture is heated up to about 80C and allowed to reflux for about 24 hours. After completion of the reaction, solvent is evaporated under vacuum. The crude mixture is dissolved in dichloromethane and filtered. The obtained product (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methanol (i.e. compound 1) is used for further reaction without purification.

References: [1]Journal of the American Chemical Society,2011,vol. 133,p. 756 - 758.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 924 - 934.
[3]Patent: EP2497775,2012,A1 .Location in patent: Page/Page column 11.
[4]Patent: WO2012/123076,2012,A1 .Location in patent: Page/Page column 21-22.
[5]Angewandte Chemie - International Edition,2017,vol. 56,p. 14025 - 14030.
    Angew. Chem.,2017,vol. 129,p. 14213 - 14218,6.
[6]Angewandte Chemie - International Edition,2019,vol. 58,p. 561 - 565.
    Angew. Chem.,2019,vol. 131,p. 571 - 575,5.
[7]Organic Letters,2013,vol. 15,p. 4850 - 4853.
[8]Angewandte Chemie - International Edition,2017,vol. 56,p. 3206 - 3210.
    Angew. Chem.,2017,vol. 129,p. 3254 - 3258,5.
[9]Chemical Communications (Cambridge, United Kingdom),2019,vol. 55,p. 3343 - 3346.
[10]Angewandte Chemie - International Edition,2017,vol. 56,p. 9155 - 9159.
    Angew. Chem.,2017,vol. 129,p. 9283 - 9287,5.
[11]Organic and Biomolecular Chemistry,2017,vol. 15,p. 2459 - 2466.
[12]Analytical Chemistry,2016,vol. 88,p. 10728 - 10735.
[13]Patent: WO2017/33163,2017,A1 .Location in patent: Page/Page column 33; 34.

23
[ 530-62-1 ]
[ 302348-51-2 ]
[ 1262015-14-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	In dichloromethane; at 20℃;Inert atmosphere;	Compound 2 (660 mg, 2.82 mmol) was dissolved in 10 mL of dry CH2Cl2.Then, N,N'-carbonyldiimidazole (915 mg, 5.64 mmol) was added, and the mixture was stirred at room temperature for 1-2 h under N2. After the reaction was completed, 40 ml of CH 2 Cl 2 was added, and the mixture was washed three times with an equal amount of 1 M HCl solution, and the organic phase was dried over anhydrous sodium sulfate.Concentrated under reduced pressure to give a white solid 787mg, yield 85%.
	In dichloromethane; at 20℃; for 2h;	2.07 g of 1,1'-carbonyldiimidazole and 2.07 g of 4- (hydroxymethyl) phenylboronic pinicole ester(4- (hydroxymethyl) phenylboronic acid pinacol ester) was dissolved in 20 mL of dichloromethane (DCM)And allowed to react at room temperature for 2 hours. The product was named 1 and 1 was obtained by silica gel chromatography using an eluent of 1: 1 mixture of ethyl acetate and hexane.

References: [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 561 - 565.
Angew. Chem.,2019,vol. 131,p. 571 - 575,5.
[2]Patent: CN108148098,2018,A .Location in patent: Paragraph 0058; 0061; 0062.
[3]Journal of the American Chemical Society,2014,vol. 136,p. 14742 - 14745.
[4]Journal of the American Chemical Society,2011,vol. 133,p. 756 - 758.
[5]Journal of the American Chemical Society,2018,vol. 140,p. 1235 - 1238.
[6]Patent: KR101963327,2019,B1 .Location in patent: Paragraph 0099; 0100; 0102-0104.

24
[ 1276130-32-5 ]
[ 302348-51-2 ]
[ 1312816-01-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 3h;	To a slurry of methyl 5-bromo-3-(4-methyl-benzylamino)-thiophene-2-carboxylate (154 mg, 0.45 mmol) and <strong>[302348-51-2][4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanol</strong> (158 mg, 0.68 mmol) in DMF (4.5 mL) and sat'd. aq. Na2CO3 (1.9 mL) was added Pd(PPh3)4 (73 mg). The reaction mixture was heated to 100° C. for 3 h then cooled to RT. The solvent was removed and the crude product purified by SiO2 chromatography (Isco) eluting with an EtOAc/hexane gradient (0percent to 30percent EtOAc) to afford 255 mg of methyl 5-(4-hydroxymethyl-phenyl)-3-(4-methyl-benzylamino)-thiophene-2-carboxylate (72): MS calcd for C21H21NO3S [M+H]+ 368. Found, 368.

References: [1]Patent: US2011/70190,2011,A1 .Location in patent: Page/Page column 35.

25
[ 1021913-05-2 ]
[ 302348-51-2 ]
C₂₈H₃₂BrClN₂O₄ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2351 - 2358.

26
[ 1314568-35-8 ]
[ 302348-51-2 ]
C₂₆H₁₆ClF₃N₂O₂ [ No CAS ]

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

27
[ 302348-51-2 ]
[ 1325206-81-2 ]

References: [1]Chemical Communications,2011,vol. 47,p. 7968 - 7970.
[2]Patent: US2011/312905,2011,A1 .

28
[ 302348-51-2 ]
[ 1325206-82-3 ]

References: [1]Chemical Communications,2011,vol. 47,p. 7968 - 7970.
[2]Patent: US2011/312905,2011,A1 .

29
[ 302348-51-2 ]
[ 1325206-76-5 ]

References: [1]Chemical Communications,2011,vol. 47,p. 7968 - 7970.
[2]Patent: US2011/312905,2011,A1 .

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Yield	Reaction Conditions	Operation in experiment
		Add anhydrous sodium carbonate (1.59 g, 10 mmol) to a three-necked flask. After removing the water at high temperature, it is cooled to room temperature, and after three times of gas exchange, Anhydrous toluene (5 mL) was added thereto under argon gas, Ice bath to around 0 C, A solution of triphosgene (592 mg, 2 mmol) in toluene (10 mL) was added dropwise. After stirring at 0 C for 30 min, A solution of 4-(hydroxymethyl)phenylboronic acid pinacol ester (234 mg, 1 mmol) in toluene (10 mL) was added dropwise. After the addition was completed, the mixture was slowly warmed to room temperature for 5 hours. Use argon to drive away the remaining phosgene for 1 h. After filtration, the solvent was evaporated under reduced pressure to give Intermediate 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxycarbonyl chloride. After drying in vacuo, it was dissolved in anhydrous dichloromethane (10 mL). Temperature-controlled 0 C slowly added dropwise to 2-[2-[2-benzylamino-3-[(1,3-dihydro-1,3,3-trimethyl-2H-indole-2-ylidene) Ethylene]-1-cyclohexen-1-yl]vinyl]-1,3,3-trimethylphosphonium iodide (68 mg, 0.1 mmol) And N,N-diisopropylethylamine (132 muL, 0.8 mmol) In dichloromethane solution (20 mL), After the addition is completed, the reaction is slowly raised to room temperature for 12 to 18 hours.After the reaction was completed, it was washed twice with 0.1 N hydrochloric acid (20 mL). Wash once with saturated sodium carbonate solution (20 mL). Wash once with saturated sodium chloride solution (20 mL). The organic phase is dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give a crude material. Subsequent purification on a silica gel column (dichloromethane / 0-5% methanol). The green solid product is 2-[2-[2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-) Benzyloxycarbonyl]benzylamino]-3-[(1,3-dihydro-1,3,3-trimethyl-2H-indol-2-ylidene)ethylene]-1-cyclo Hexen-1-yl]vinyl]-1,3,3-trimethylphosphonium iodide, 10% yield.

References: [1]Journal of the American Chemical Society,2016,vol. 138,p. 13353 - 13360.
[2]Chemical Communications,2011,vol. 47,p. 9618 - 9620.
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 4498 - 4510.
[4]Chemical Science,2018,vol. 9,p. 5999 - 6005.
[5]ChemMedChem,2018,vol. 13,p. 2073 - 2079.
[6]Patent: CN109096319,2018,A .Location in patent: Paragraph 0052; 0082-0088.
[7]ChemMedChem,2019,vol. 14,p. 1384 - 1391.

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[ 1011734-80-7 ]

References: [1]Chemical Communications,2011,vol. 47,p. 9618 - 9620.

Yield	Reaction Conditions	Operation in experiment
96%	With potassium phosphate tribasic heptahydrate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; XPhos; In ethanol; at 20℃; for 0.5h;	General procedure: Method (1): Synthesis from 4-tert-butylchlorobenzene as a raw material: K3P04 · 7H20 (3.0 g, 8.85 mmol) and bis-pinacol borate (749 mg, 2.95 mmol) were sequentially added to the reaction flask.The catalyst-chloro (2-dicyclohexyl phosphino-2 ', 4', 6'-tri - triisopropyl-1,1'-biphenyl) (1,1'-biphenyl -2-amino-2'_ -yl)palladium(II) (12 mg, 0.015 mmol) and ligand 2-dicyclohexylphosphine-2',4',6/-triisopropylbiphenyl (4 mg, 0.008 mmol), followed by EtOH (6 mL) The mixture was stirred, and p-tert-butylchlorobenzene (0.5 mL, 2.95 mmol) was added and the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (2 mL) After washing with ethyl acetate (6 mL) in three portions, the filtrate was combined, and the solvent was evaporated to dryness, and the solvent was separated by silica gel (200 to 300 mesh). The eluent was petroleum ether and ethyl acetate. 10~80:1), obtained as a white solid, identified by NMR spectrum as 4-tert-butylphenylboronic acid pinacol ester, yield 98%
94%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;	General procedure: Step 34b: N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (Compound 0602-107)[0334]To a solution of compound 0601-107 (2.5 g, 11.6 mmol) and bis(pinacolato)diboron (4.4 g, 17.5 mmol) in dioxane (100 mL) was added potassium acetate (3.4 g, 35 mmol) and PdCl2(dppf)2 (0.95 g, 1.1 mmol). The mixture was degassed with nitrogen and heated at 85 C. for overnight. The reaction mixture was concentrated under reduced pressure to afford the crude product, which purified by column chromatography (ethyl acetate in petroleum ether, 15% v/v) to give the compound 0602-107 (1.55 g, 51%) as a pink solid. LCMS: 262 [M+1]+. 1H NMR (400 MHz, DMSO-d6) delta 1.29 (s, 12H), 2.03 (s, 3H), 7.30 (s, 1H), 7.31 (d, J=2.0 Hz 1H), 7.73 (d, J=2.0 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 9.93 (s, 1H).
94%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;	General procedure: Compound in dioxane (100mL) 0601-107 (2.5g, 11.6mmol) and a solution of bis (pinacolato) diboron (4.4 g, 17.5 mmol), potassium acetate (3.4 g, 35 mmol) and and PdCl2 (dppf) 2 ( 0.95g, 1.1mmol) was added. The mixture was degassed with nitrogen and heated overnight at 85 C.. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether in ethyl acetate, 15% v / v) to give the compound 0602-107 as a pink solid obtained (1.55 g, 51%).

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References: [1]Patent: US2011/312905,2011,A1 .

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[ 1349832-91-2 ]