[ CAS No. 20876-99-7 ]

Name: 20876-99-7|4-Hydroxy-N,N-dimethylbenzamide|98%
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Product Details of [ 20876-99-7 ]

CAS No. :	20876-99-7	MDL No. :	MFCD01168919
Formula :	C₉H₁₁NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	165.19 g/mol	Pubchem ID :	-
Synonyms :

Safety of [ 20876-99-7 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P264-P270-P280-P301+P312+P330-P305+P351+P338-P337+P313-P501	UN#:
Hazard Statements:	H302-H319	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 20876-99-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 20876-99-7 ]

[ 20876-99-7 ] Synthesis Path-Downstream 1~31

1
[ 33513-42-7 ]
[ 99-96-7 ]
[ 20876-99-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	With dipotassium peroxodisulfate; (p-cymene)ruthenium(II) chloride; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene at 160℃; for 12h;	3 General procedure for the synthesis of 3 and 4 General procedure: Carboxylic acids (0.3 mmol), catalyst (5 mol %), Xantphos (10 mol %), K2S2O8 (2 equiv) and N-substituted formamides (2 mL) were mixed in a 20 mL tube. Tighten the cap and the mixture was stirred at 160°C for 12 h or more until the reaction was finished. The mixture was filtered and the solution was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, n-hexane-EtOAc,1:1).
83%	With potassium thiosulfate; [RhCl₂(p-cymene)]2; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene at 160℃; for 12h; Inert atmosphere; Sealed tube;	3 Example 3 Synthesis of 4-hydroxybenzamide (3c) with 4-hydroxybenzoic acid (1c) and DMF (2a) as raw materials: In a 20 mL reaction flask equipped with a magnet, 4-hydroxybenzoic acid (0.041 g, 0.3 mmol), Xantphos (0.017 g, 0.03 mmol), K2S2O8 (0.162 g, 0.6 mmol), Ru(p-cymene)Cl2 (0.0092g, 0.015mmol) and DMF (2mL) were added and charged with argon, tightened cap and sealed at ambient temperature of 160 °C for 12h. The reaction solution was filtered and the reaction solution was filtered. The solvent was removed by rotary evaporation and separated by column chromatography (ethyl acetate: n-hexane = 1: 1) to give 3c as a white solid in 83% yield.
55%	With trichlorophosphate at 120℃; for 1h; Sealed tube;	3 Example 3To 4 - hydroxy benzoic acid and DMF as raw material synthetic N, N - dimethyl 4 - hydroxy benzamide In the of the magneton with 20 ml reaction flask add 4 - hydroxy benzoic acid (0.041g, 0 . 3mmol), POCl3(Lequiv), DMF (2 ml), tighten the bottle cap, of outer 120 °C airtight reaction 1h; gas chromatographic monitoring the reaction is complete; after cooling to be reacted, adding 10 ml saturated Na2CO3Aqueous solution, extracted with ethyl acetate (3 × 10 ml), the combined organic phase, anhydrous magnesium sulfate drying, rotary evaporation in addition to the solvent, by column chromatography (ethyl acetate: hexane=1:1) after separation to obtain colorless transparent liquid, yield 55%.

55%	With trichlorophosphate at 120℃; for 1h;	General procedure General procedure: Carboxylic acids (0.3 mmol), POCl3(1equiv.) and N-substituted formamides (2 mL) were mixed in a 20 mL tube. Tighten the cap and the mixture was stirred at 120 °C for 1h. The mixture was cooled to room temperature, and Na2CO3 saturated solution (10 mL) was added. Then the solution was extracted with ethyl acetate (3×10 mL), combined the organic layers and dried with anhydrous MgSO4 over night. The solution was evaporated under reduced pressure and the crude product was purified by column chromatography (silica gel, n-hexane-EtOAc, 1:1).
	With phosphorus pentoxide

Reference： [1]Bi, Xiaojing; Li, Junchen; Shi, Enxue; Wang, Hongmei; Gao, Runli; Xiao, Junhua [Tetrahedron, 2016, vol. 72, # 50, p. 8210 - 8214]
[2]Current Patent Assignee: 63975 PLA TROOPS - CN106496056, 2017, A Location in patent: Paragraph 0035; 0036; 0037; 0038; 0039
[3]Current Patent Assignee: 63975 PLA TROOPS - CN106187803, 2016, A Location in patent: Paragraph 0040; 0041; 0042; 0043; 0044
[4]Bi, Xiaojing; Li, Junchen; Shi, Enxue; Li, Yu; Liu, Ying; Wang, Hongmei; Xiao, Junhua [Phosphorus, Sulfur and Silicon and the Related Elements, 2019, vol. 194, # 3, p. 236 - 240]
[5]Schindlbauer,H. [Monatshefte fur Chemie, 1968, vol. 99, p. 1799 - 1807] Schiemenz,G.P.; Stein,G. [Tetrahedron, 1970, vol. 26, p. 2007 - 2026]

2
[ 20876-99-7 ]
[ 109-70-6 ]
[ 117022-51-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate In acetone for 24h; Heating;

Reference： [1]Walsh, David A.; Franzyshen, Stephen K.; Yanni, John M. [Journal of Medicinal Chemistry, 1989, vol. 32, # 1, p. 105 - 118]

3
[ 20876-99-7 ]
[ 117023-73-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 78 percent / K₂CO₃ / acetone / 24 h / Heating 2: 65 percent / 1) Na₂CO₃, KI / 1) n-butanol, reflux

Reference： [1]Walsh, David A.; Franzyshen, Stephen K.; Yanni, John M. [Journal of Medicinal Chemistry, 1989, vol. 32, # 1, p. 105 - 118]

4
[ 845654-95-7 ]
[ 20876-99-7 ]
[ 1190090-01-7 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In acetone at 20℃; for 24h;

Reference： [1]Location in patent: scheme or table Williams, David H.; Adam, Fiona; Fenwick, David R.; Fok-Seang, Juin; Gardner, Iain; Hay, Duncan; Jaiessh, Rawal; Middleton, Donald S.; Mowbray, Charles E.; Parkinson, Tanya; Perros, Manos; Pickford, Christopher; Platts, Michelle; Randall, Amy; Siddle, Daniel; Stephenson, Peter T.; Tran, Thien-Duc; Vuong, Hannah [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 17, p. 5246 - 5249]

5
[ 1245216-73-2 ]
[ 20876-99-7 ]
[ 1245216-54-9 ]

Yield	Reaction Conditions	Operation in experiment
12%	With potassium phosphate In toluene at 110℃; for 18h; Inert atmosphere;	Preparation of ethyl 4-(4-(dimethylcarbamoyl)phenoxy)-2-methyl-2H- indazole-6-carboxylate (l-1f-22):(l-1f-22)To a solution of ethyl 2-methyl-4-(trifluoromethylsulfonyloxy)-2H-indazole-6- carboxylate (l-1f-33: 220mg, 0.624mmol) and 4-hydroxy-N,N- dimethylbenzannide (113mg, 0.686mnnol) in toluene (7.3mL) was added potassium phosphate (265mg, 1.25mnnol). After stirring under nitrogen for 5 minutes, a solution of palladium (II) acetate (21.1 mg, 0.094mmol) and 2-di-t- butylphosphino-2',4',6'-tri-isopropyl-1 ,1 '-biphenyl (79.4 mg, 0.187 mmol) in toluene (1.OmL) was added to the mixture. The reaction was heated to 110 0C for 18 hours. The reaction was then concentrated, the crude dissolved in dichloromethane and washed with water. The organics were dried over magnesium sulfate, filtered, and concentrated. Purification by column chromatography, eluting with methanol in dichloromethane, gave the desired ethyl 4-(4-(dimethylcarbamoyl)phenoxy)-2-methyl-2H-indazole-6-carboxylate (l-1f-22: 27mg, 12%) as a yellow solid. MS (IVM ): 367.9 RT 2.22 min.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2010/103438, 2010, A1 Location in patent: Page/Page column 63-64

6
[ 106-41-2 ]
[ 33513-42-7 ]
[ 20876-99-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; trichlorophosphate at 165℃; for 24h; Inert atmosphere;

Reference： [1]Sawant, Dinesh N.; Wagh, Yogesh S.; Bhatte, Kushal D.; Bhanage, Bhalchandra M. [Journal of Organic Chemistry, 2011, vol. 76, # 13, p. 5489 - 5494]

7
[ 540-38-5 ]
[ 33513-42-7 ]
[ 20876-99-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; trichlorophosphate at 135℃; for 6h; Inert atmosphere;
62%	Stage #1: p-Iodophenol; N,N-dimethyl-formamide With palladium diacetate at 20℃; for 0.166667h; Inert atmosphere; Stage #2: With trichlorophosphate at 140℃; for 24h; Inert atmosphere;

Reference： [1]Sawant, Dinesh N.; Wagh, Yogesh S.; Bhatte, Kushal D.; Bhanage, Bhalchandra M. [Journal of Organic Chemistry, 2011, vol. 76, # 13, p. 5489 - 5494]
[2]Location in patent: experimental part Iranpoor, Nasser; Firouzabadi, Habib; Motevalli, Somayeh [Journal of Molecular Catalysis A: Chemical, 2012, vol. 355, p. 69 - 74]

8
[ 20876-99-7 ]
[ 24167-56-4 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 544 - 547
[2]Journal of the American Chemical Society,2011,vol. 133,p. 11482 - 11484
[3]Journal of the American Chemical Society,2017,vol. 139,p. 1452 - 1455

9
[ 405520-68-5 ]
[ 20876-99-7 ]

Reference： [1]Chemical Communications,2012,vol. 48,p. 7203 - 7205

10
[ 108-77-0 ]
[ 20876-99-7 ]
[ 100-53-8 ]
[ 1391926-37-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: 1,3,5-trichloro-2,4,6-triazine; phenylmethanethiol With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 4℃; for 1h; Inert atmosphere; Stage #2: 4-hydroxy-N,N-dimethyl-benzamide In tetrahydrofuran at 20℃; for 3h; Inert atmosphere;	1 Step 1Cyanuric chloride [2] (1.0 g, 5.4 mmol) was suspended in anhydrous THF (20 ml) in a three neck RB flask under inert atmosphere and cooled using ice-bath, followed by addition of DIPEA (5.16 mmol) and benzyl mercaptan (5.08 mmol). The reaction mixture was allowed to stir at 0-4 °C for 1 h and monitored by TLC examination (5% EtOAc/Hexane). A mixture of DIPEA (5.40 mmol) and 4-hydroxy-N,N-dimethylbenzamide [ 116] (5.40 mmol) was added to reaction mixture followed by an addition stirring for 3 h at RT. The excess solvent was evaporated under reduced pressure to obtained crude product which was purified using silica gel column chromatography (eluent, 25% EtOAc/Hexane) to obtain product [33] in 87% yield.
87%	Stage #1: 1,3,5-trichloro-2,4,6-triazine; phenylmethanethiol With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 4℃; for 1h; Inert atmosphere; Stage #2: 4-hydroxy-N,N-dimethyl-benzamide In tetrahydrofuran at 20℃; for 3h; Inert atmosphere;	1 Stepl Cyanuric chloride [21 (1.0 g, 5.4 mmol) was suspended in anhydrous THF (20 ml) in a three neck RB flask under inert atmosphere and cooled using ice-bath, followed by addition of DIPEA (5.16 mmol) and benzyl mercaptan (5.08 mmol). The reaction mixture was allowed to stir at 0-4 "C for I h and monitored by TLC examination (5% EtOAc/Hexane). A mixture nf TMPC A f< Λ( η A ,Λ,- ν >, M M I ; ,->ioth ΙΚοη-,., mi rlo Π11 AC ,-nmr>l ^ΛΛαΛ to reaction mixture followed by an addition stirring for 3 h at RT. The excess solvent was evaporated under reduced pressure to obtained crude product which was purified using silica gel column chromatography (eluent, 25% EtOAc/ Hexane) to obtain product [13] in 87% yield. ESIMS: 401 (M+ + l ).

Reference： [1]Current Patent Assignee: SPHAERA PHARMA - WO2012/101654, 2012, A2 Location in patent: Page/Page column 47-48
[2]Current Patent Assignee: SPHAERA PHARMA - WO2014/16849, 2014, A2 Location in patent: Page/Page column 97; 98

11
[ 20876-99-7 ]
[ 1391926-60-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 0 - 4 °C / Inert atmosphere 1.2: 3 h / 20 °C / Inert atmosphere 2.1: sodium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,2-dimethoxyethane / 16 h / Inert atmosphere; Reflux 3.1: Oxone / water; tetrahydrofuran / 0 - 20 °C

Reference： [1]Current Patent Assignee: SPHAERA PHARMA - WO2012/101654, 2012, A2

12
[ 20876-99-7 ]
[ 1391926-38-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 0 - 4 °C / Inert atmosphere 1.2: 3 h / 20 °C / Inert atmosphere 2.1: sodium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,2-dimethoxyethane / 16 h / Inert atmosphere; Reflux

Reference： [1]Current Patent Assignee: SPHAERA PHARMA - WO2012/101654, 2012, A2

13
[ 1391926-35-4 ]
[ 20876-99-7 ]
[ 1391926-36-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 0.5h; Sealed tube; Microwave irradiation;
44%	With potassium carbonate In acetonitrile at 100℃; for 0.5h; Microwave irradiation; sealed vial;	4 Step 4To a solution of compound [29] (0.25 g, 0.48 mmol, 1 eq) in acetonitrile (2 ml) in a microwave vial, were added successively compound [30] (0.053 g, 0.38 mmol, 0.8 eq) and potassium carbonate (0.132 g, 0.96 mmol, 2 eq). The sealed vial was then heated for 30 mins at 100°C in MW, and after cooling, the solvent was evaporated under vacuum. The resulting crude solid was dissolved in water (10ml) and was washed with ether (10ml) followed by ethyl acetate (10 mL). The aqueous layer was acidified up to pH = 4 to 5 using dilute HC1, and the off-white ppt. so obtained was filtered and dried at 50°C to yield compound [31] as an off-white solid (0.105 g, 44%).ESIMS: 503 (M+ + 1)

Reference： [1]Dugar, Sundeep; Hollinger, Frank P.; Mahajan, Dinesh; Sen, Somdutta; Kuila, Bilash; Arora, Reena; Pawar, Yogesh; Shinde, Vaibhav; Rahinj, Mahesh; Kapoor, Kamal K.; Bhumkar, Rahul; Rai, Santosh; Kulkarni, Rakesh [ACS Medicinal Chemistry Letters, 2015, vol. 6, # 12, p. 1190 - 1194]
[2]Current Patent Assignee: SPHAERA PHARMA - WO2012/101654, 2012, A2 Location in patent: Page/Page column 45-46

14
[ 591-87-7 ]
[ 20876-99-7 ]
[ 1446279-71-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer In 1,2-dichloro-ethane at 110℃; for 16h;

Reference： [1]Feng, Chao; Feng, Daming; Loh, Teck-Peng [Organic Letters, 2013, vol. 15, # 14, p. 3670 - 3673]

15
(Z)-(2-(bromomethyl)-3-fluoroallyl)carbamic acid tert-butyl ester [ No CAS ]
[ 20876-99-7 ]
(Z)-tert-butyl 2-((4-(dimethylcarbamoyl)phenoxy)-methyl)-3-fluoroallylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	2.A Procedure A: Preparation of (Z)-tert-butyl 2-((4-(dimethylcarbamoyl)phenoxy)-methyl)-3-fluoroallylcarbamate To a vigorously stirring suspension of (Z)-tert-butyl 2-(bromomethyl)-3-fluoroallylcarbamate (430.0 mg, 1.60 mmol) and potassium carbonate (332.5 mg, 2.41 mmol) in dry DMF (2.0 mL) at room temperature under N2 was added 4-hydroxy-N,N- dimethylbenzarnide (291.4 mg, 1.76 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water (40 mL) and ethyl acetate (20 mL) and the aqueous layer was extracted with further ethyl acetate (2 x 20 ml). The combined organics were washed with saturated aqueous NH4Cl (40 mL),brine (40 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude material over silica gel eluting with 60% ethyl acetate in n-hexane followed by 75% ethyl acetate in n-hexane gave (Z)-tert-butyl 2-((4-(dimethylcarbamoyl)phenoxy)rnethyl)-3-fluoroallylcarbarnate (520.0 mg, 92 %) as a colourless oil. 1H-NMR (300 MHz; CDCl3) 6ppm: 1.44 (9 H, s), 3.07 (6 K, br s), 3.78 (2 H, br s), 4.74(2K, dd,J2.7, 0.8 Hz), 4.80(1 H, br s), 6.75(1 H, d,J82.7 Hz), 6.95(2 H, d, J 8.9 Hz), 7.42 (2 H, d, J8.8 Hz).

Reference： [1]Current Patent Assignee: PHARMAXIS LTD - WO2013/163675, 2013, A1 Location in patent: Paragraph 00189

16
[ 20877-09-2 ]
[ 20876-99-7 ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium carbonate In methanol at 20℃; for 5h;
0.8 g	With potassium carbonate In methanol at 20℃; for 5h;	3 Step 3 Compound [100] ( 1.5 g, 7.2 mmol) was dissolved in MeOH (20 ml) to which K2C03 (3.0 g, 21.7 mmol) was added. The resulting suspension was stirred at RT for 5 hrs. The progress of the reaction was monitored by TLC. After complete conversion, the solvent was removed under reduced pressure and purification was done by silica gel chromatography 2% MeOH/ DCM to obtain compound [12] as a white solid (0.80 g, 68% yield). ESIMS: 165 (M+ + 1 )

Reference： [1]Dugar, Sundeep; Hollinger, Frank P.; Mahajan, Dinesh; Sen, Somdutta; Kuila, Bilash; Arora, Reena; Pawar, Yogesh; Shinde, Vaibhav; Rahinj, Mahesh; Kapoor, Kamal K.; Bhumkar, Rahul; Rai, Santosh; Kulkarni, Rakesh [ACS Medicinal Chemistry Letters, 2015, vol. 6, # 12, p. 1190 - 1194]
[2]Current Patent Assignee: SPHAERA PHARMA - WO2014/16849, 2014, A2 Location in patent: Page/Page column 122; 123

17
[ 6601-22-5 ]
[ 20876-99-7 ]
[ 1391926-57-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With 18-crown-6 ether; potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4h;
76%	With sodium hydrogencarbonate In water; acetone at 20℃; for 2h;	2 Step 2 Compound [20] (3.2 g, 13.6 mmol) was taken in a solution of acetone:NaHC( s( aq.) [ 1 : 1 ] (30 ml). The reaction mass turned hazy and was stirred at RT until effervescence ceased. Compound [12] was added ( 1.49 g. 10.8 mmol) and the reaction mass was further stirred at RT for 2hrs. The excess of acetone from the reaction, mixture was evaporated to dryness. More water (20 ml) was added and the mixture was filtered through Buchner funnel. The filtrate was washed with DCM; the DCM layer was discarded and the water layer was acidified to pH = 4. A precipitate formed, was filtered, washed with water and dried to give compound [21] (3.5 g, 76%) as white solid. ESIMS: 364 (M+ + 1 ).

Reference： [1]Mahajan, Dinesh; Sen, Somdutta; Kuila, Bilash; Sharma, Amit; Arora, Reena; Sagar, Milind; Mahapatra, Amal Ray; Gawade, Lalita Babasaheb; Dugar, Sundeep [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 11121 - 11130]
[2]Current Patent Assignee: SPHAERA PHARMA - WO2014/16849, 2014, A2 Location in patent: Page/Page column 99; 100

18
[ 108-77-0 ]
[ 20876-99-7 ]
[ 1542268-09-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 4h;	1 Step l To a solution of compound [2] (5.00 g, 27.17 mmol) in THF at 0 °C was added DIPEA (4.89 ml, 27. 17 mmol) and compound [12] (4.45 g, 27. 17 mmol). The mixture was stirred at 0 °C for 4 hrs. TLC was used to monitor for consumption of starting material [2]. Once the starting material was consumed, solvent was removed under reduced pressure. Purification was done by silica gel column chromatography with 20% EtOAc/ cyclohexane to give compound [32] as a white solid (6.0 g, 71 %). ESIMS: 3 13 (M+ + 1 )

Reference： [1]Current Patent Assignee: SPHAERA PHARMA - WO2014/16849, 2014, A2 Location in patent: Page/Page column 104

19
[ 20876-99-7 ]
4-(dimethylcarbamoyl)phenyl sulfofluoridate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With fluorosulfonyl fluoride; triethylamine In 1,4-dioxane at 20℃; for 24h;

Reference： [1]Schimler, Sydonie D.; Cismesia, Megan A.; Hanley, Patrick S.; Froese, Robert D.J.; Jansma, Matthew J.; Bland, Douglas C.; Sanford, Melanie S. [Journal of the American Chemical Society, 2017, vol. 139, # 4, p. 1452 - 1455]

20
[ 20876-99-7 ]
methanesulfonic acid 5-(3,3-dimethyl-2-oxa-spiro[4.5]dec-8-yl)-pentyl ester [ No CAS ]
4-[5-(3,3-dimethyl-2-oxaspiro[4.5] dec-8-yl)-pentyloxy]-N,N-dimethylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 3h;	Synthesis of 4-[5-(3,3-dimethyl-2-oxa-spiro[4.5] dec-8-yl)-pentyloxy]-N,N-dimethyl-benzamide (17). To a solution of 38 (4.19 g, 16.5 mmol) in EtOAc (22 ml) were added triethylamine (2.60 ml, 18.7 mmol) and methanesulfonyl chloride (1.40 ml, 18.1 mmol) at 0 °C. After stirring at room temperature for 1 h, the reaction mixture was diluted with EtOAc (20 ml). The reaction mixture was washed with H2O (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The precipitate was washed with n-hexane-EtOAc to give methanesulfonic acid 5-(3,3-dimethyl-2-oxa-spiro[4.5]dec-8-yl)-pentyl ester (3.17 g, 58%) as a white solid.A suspension of methanesulfonic acid 5-(3,3-dimethyl-2-oxa-spiro[4.5]dec-8-yl)-pentyl ester (100 mg, 0.30 mmol), 4-hydroxy-N,N-dimethylbenzamide (55 mg, 0.33 mmol), and cesium carbonate (117 mg, 0.36 mmol) in DMF (0.3 ml) was stirred at 80 °C for 3 h. After cooling to room temperature, the reaction mixture was quenched with H2O (1 ml). The precipitate was filtered off and recrystallized from n-hexane-EtOAc to give compound 17 (78 mg, 65%) as a white solid.1H NMR (DMSO-d6) δ: 7.37-7.33 (m, 2H), 6.96-6.92 (m, 2H), 3.98 (t, 2H, J = 6.4 Hz), 3.52 (s, 2H), 2.94 (s, 6H), 1.74-1.54 (m, 6H), 1.50 (s, 2H), 1.42-1.24 (m, 6H), 1.20-1.12 (m, 9H), 0.93-0.82 (m, 2H).

Reference： [1]Harada, Kazuhito; Mizukami, Jun; Kadowaki, Sho; Matsuda, Isamu; Watanabe, Takashi; Oe, Yasuhiro; Kodama, Yoshitoshi; Aoki, Kenta; Suwa, Katsunori; Fukuda, Sumiaki; Yata, Shinji; Inaba, Takashi [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 7, p. 1228 - 1233]

21
[ 20876-99-7 ]
N-[5-[5-bromo-2-(difluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide [ No CAS ]
N-[5-[2-(difluoromethoxy)-5-[4-(dimethylcarbamoyl)phenoxy]phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With bis(η3-allyl-μ-chloropalladium(II)); t-BuBrettPhos; caesium carbonate In toluene at 90℃; Inert atmosphere;	1 Step 1: Synthesis of N-[5-[2-(difluoromethoxy)-5-[4-(dimethylcarbamoyl)phenoxy]phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide To a solution of N-5-[5-bromo-2-(difluoromethoxy)phenyl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazol-4-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate 1, 1.17 g, 2.02 mmol) in toluene (10 mL) was added 4-hydroxy-N,N-dimethylbenzamide (0.400 g, 2.42 mmol), Cs2CO3 (0.790 g, 2.43 mmol), [PdCl(allyl)]2 (37.0 mg, 0.101 mmol) and t-BuBrettPhos (98.0 mg, 0.202 mmol) under nitrogen. The reaction mixture was stirred overnight at 90° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (95/5) to give 1.3 g (81%) of N-[5-[2-(difluoromethoxy)-5-[4-(dimethylcarbamoyl)phenoxy]phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow oil. LC/MS (Method H, ESI): [M+H]+=664.4, RT=1.36 min.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2018/333416, 2018, A1 Location in patent: Paragraph 0321-0322

22
[ 13154-24-0 ]
[ 20876-99-7 ]
[ 1345732-61-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With 1H-imidazole In N,N-dimethyl-formamide at 24℃; for 5h;

Reference： [1]Ong, Derek Yiren; Yen, Zhihao; Yoshii, Asami; Revillo Imbernon, Julia; Takita, Ryo; Chiba, Shunsuke [Angewandte Chemie - International Edition, 2019, vol. 58, # 15, p. 4992 - 4997][Angew. Chem., 2019, vol. 131, p. 5046 - 5051,6]

23
[ 454-73-9 ]
[ 20876-99-7 ]
N,N-dimethyl-4-(3-nitro-5-(trifluoromethyl)phenoxy)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium phosphate; In N,N-dimethyl acetamide; at 100℃; for 12h;	General procedure: To a round-bottomed flask equipped with a magnetic stir bar wasadded <strong>[454-73-9]1-fluoro-3-nitro-5-(trifluoromethyl)benzene</strong> (18) (1.0 eq), 4-substituted phenol (1.0 eq), potassium phosphate (2 eq), and DMA(2.0 M). The reaction vessel was immersed in a 100 C preheated oilbath for 12 h until the reaction was completed as determined by TLC.After cooling, the reaction was diluted with water and extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous MgSO4. After filtration and concentration, thecrude product was purified on a silica gel column, eluted with hexane/ethyl acetate to afford 19a-f.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 3619 - 3631

24
[ 20876-99-7 ]
3-methyl-1-(methyldithiocarbonyl)imidazolium iodide [ No CAS ]
C₁₁H₁₃NO₂S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine In acetonitrile at 0℃; for 1h; Inert atmosphere;

Reference： [1]Yoritate, Makoto; Londregan, Allyn T.; Lian, Yajing; Hartwig, John F. [Journal of Organic Chemistry, 2019, vol. 84, # 24, p. 15767 - 15776]

25
[ 777-52-6 ]
[ 20876-99-7 ]
alanine isopropyl ester hydrochloride [ No CAS ]
isopropyl ((4-(dimethylcarbamoyl)phenoxy)(4-nitrophenoxy)phosphoryl)-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-dichlorophosphoryloxy-4-nitro-benzene; alanine isopropyl ester hydrochloride With triethylamine In tetrahydrofuran; dichloromethane at -78℃; for 0.5h; Stage #2: 4-hydroxy-N,N-dimethyl-benzamide With triethylamine In dichloromethane at -78℃; for 1.5h;	Intermediate 43. Isopropyl ((4-(dimethylcarbamoyl)phenoxy)(4- nitrophenoxy)phosphoryl)-L-alaninate To a solution of 4-nitrophenyl phosphorodichloridate (620 mg, 2.422 mmol) and isopropyl L-alanine-HCl (406 mg, 2.422 mmol) in DCM-THF (10:3 mL) was added TEA (0.68 mL, 4.844 mmol) in DCM (3.32 mL) over 30 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and cooled to -78 °C and N,N-dimethyl-4- hydroxybenzamide (400 mg, 2.422 mmol) was added in one portion and TEA (0.34 mL, 2.422 mmol) in DCM (3.66 mL) added over 30 min at -78 °C. The resulting mixture was stirred for 1 h after removal of dry ice bath, then diluted with EtOAc, washed with brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (EtOAc 0 to 100% in hexanes) to afford the product.1H NMR (400 MHz, Chloroform-d) δ 8.26 - 8.18 (m, 2H), 7.45 - 7.35 (m, 3H), 7.27 (m, 2H), 6.76 (m, 1H), 5.01 (m, 1H), 4.17 - 3.94 (m, 2H), 3.19 - 2.84 (m, 6H), 1.39 (m, 3H), 1.27 - 1.16 (m, 6H).31P NMR (162 MHz, Chloroform-d) δ -3.13, - 3.21. MS m/z = 480 (M+H). LCMS: MS m/z = 480.26 [M+1]; tR = 1.00 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 µL/min.
	Stage #1: 1-dichlorophosphoryloxy-4-nitro-benzene; alanine isopropyl ester hydrochloride With triethylamine In tetrahydrofuran; dichloromethane at -78 - 20℃; for 1h; Stage #2: 4-hydroxy-N,N-dimethyl-benzamide With triethylamine In tetrahydrofuran; dichloromethane at -78 - 20℃; for 1.5h;	Intermediate 43. Isopropyl ((4-(dimethylcarbamoyl)phenoxy)(4- nitrophenoxy)phosphoryl)-L-alaninate To a solution of 4-nitrophenyl phosphorodichloridate (620 mg, 2.422 mmol) and isopropyl L-alanine-HCl (406 mg, 2.422 mmol) in DCM-THF (10:3 mL) was added TEA (0.68 mL, 4.844 mmol) in DCM (3.32 mL) over 30 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and cooled to -78 °C and N,N-dimethyl-4- hydroxybenzamide (400 mg, 2.422 mmol) was added in one portion and TEA (0.34 mL, 2.422 mmol) in DCM (3.66 mL) added over 30 min at -78 °C. The resulting mixture was stirred for 1 h after removal of dry ice bath, then diluted with EtOAc, washed with brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (EtOAc 0 to 100% in hexanes) to afford the product. 1H NMR (400 MHz, Chloroform-d) δ 8.26 - 8.18 (m, 2H), 7.45 - 7.35 (m, 3H), 7.27 (m, 2H), 6.76 (m, 1H), 5.01 (m, 1H), 4.17 - 3.94 (m, 2H), 3.19 - 2.84 (m, 6H), 1.39 (m, 3H), 1.27 - 1.16 (m, 6H). 31P NMR (162 MHz, Chloroform-d) δ -3.13, - 3.21. MS m/z = 480 (M+H). LCMS: MS m/z = 480.26 [M+1]; tR = 1.00 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL/min.
	Stage #1: 1-dichlorophosphoryloxy-4-nitro-benzene; alanine isopropyl ester hydrochloride With triethylamine In tetrahydrofuran; dichloromethane at -78 - 20℃; for 1h; Stage #2: 4-hydroxy-N,N-dimethyl-benzamide With triethylamine In tetrahydrofuran; dichloromethane at -78 - 20℃; for 1.5h;	Intermediate 43. Isopropyl ((4-(dimethylcarbamoyl)phenoxy)(4- nitrophenoxy)phosphoryl)-L-alaninate To a solution of 4-nitrophenyl phosphorodichloridate (620 mg, 2.422 mmol) and isopropyl L-alanine-HCl (406 mg, 2.422 mmol) in DCM-THF (10:3 mL) was added TEA (0.68 mL, 4.844 mmol) in DCM (3.32 mL) over 30 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and cooled to -78 °C and N,N-dimethyl-4- hydroxybenzamide (400 mg, 2.422 mmol) was added in one portion and TEA (0.34 mL, 2.422 mmol) in DCM (3.66 mL) added over 30 min at -78 °C. The resulting mixture was stirred for 1 h after removal of dry ice bath, then diluted with EtOAc, washed with brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (EtOAc 0 to 100% in hexanes) to afford the product. 1H NMR (400 MHz, Chloroform-d) δ 8.26 - 8.18 (m, 2H), 7.45 - 7.35 (m, 3H), 7.27 (m, 2H), 6.76 (m, 1H), 5.01 (m, 1H), 4.17 - 3.94 (m, 2H), 3.19 - 2.84 (m, 6H), 1.39 (m, 3H), 1.27 - 1.16 (m, 6H). 31P NMR (162 MHz, Chloroform-d) δ -3.13, - 3.21. MS m/z = 480 (M+H). LCMS: MS m/z = 480.26 [M+1]; tR = 1.00 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL/min.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/168038, 2021, A1 Location in patent: Paragraph 0304
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/167882, 2021, A1 Location in patent: Paragraph 0304
[3]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/167882, 2021, A1 Location in patent: Paragraph 0304

26
[ 20876-99-7 ]
[ 100-39-0 ]
[ 84403-55-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In acetone at 70℃; for 12h; Sealed tube;