Name: 2051-76-5|Acrylic anhydride|98% (stabilized with MEHQ)
Brand: Ambeed
SKU: A457066
Rating: 96 (25 reviews)

1
[ 2051-76-5 ]
[ 100-52-7 ]
phenylmethylene diacrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With toluene-4-sulfonic acid at 20℃; for 12h;	20 General procedure B: synthesis of acylals General procedure: para-Toluenesulfonic acid (mono hydrate) (0.18g, 0.94mmol) was added to a mixture of benzaldehyde (1.0g, 9.4mmol) and anhydride (18.8mmol) at rt. The reaction was stirred for 12h and then diluted with Et2O (50mL) and washed with saturated Na2CO3 (3×20mL). The organics were dried (MgSO4) and concentrated in vacuo to give the title compound which was used without further purification unless stated otherwise.
97%	With toluene-4-sulfonic acid at 20℃; for 12h;	34 General procedure C: synthesis of 1,1-diacylals General procedure: para-Toluenesulphonic acid (mono hydrate) (0.18 g, 0.94 mmol) was added to a mixture of benzaldehyde (1.0 g, 9.4 mmol) and anhydride (18.8 mmol) at rt. The reaction was stirred for 12 h and then diluted with Et2O (50 mL) and washed with saturated Na2CO3 (3×20mL). The organics were dried (MgSO4) and concentrated in vacuo to give the title compound which was used in subsequent steps without further purification unless otherwise stated.
	With sulfuric acid; copper

Reference： [1]Chapman, Robert. S.L.; Tibbetts, Joshua. D.; Bull, Steven. D. [Tetrahedron, 2018, vol. 74, # 38, p. 5330 - 5339]
[2]Chapman, Robert S.L.; Francis, Molly; Lawrence, Ruth; Tibbetts, Joshua D.; Bull, Steven D. [Tetrahedron, 2018, vol. 74, # 44, p. 6442 - 6452]
[3]Arbusowa et al. [Zhurnal Obshchei Khimii, 1956, vol. 26, p. 1127; engl. Ausg. S. 1279]

2
[ 79-10-7 ]
[ 2051-76-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With trifluorormethanesulfonic acid; acetic anhydride at 100℃;	3 Example 3 Acrylic anhydride CH2═CH-C(═O)-O-(O═)C═CH═CH was prepared according to the process of the invention by reaction between acrylic acid and acetic anhydride. The sequence of appliances is represented in FIG. 3. (0114) In the reaction region, the reaction temperature was set at 100° C. and the pressure was set at atmospheric pressure. (0115) In the distillation (extraction) region, the pressure was set at 20 mbar absolute and a temperature gradient (between 90° C. at the column bottom and 25° C. at the column top) was observed. (0116) As indicated in FIG. 3, the reaction region was fed with the stream 1, with an overall flow rate of 2 kg/h and composed of the recycling stream 5 and of a continuous feed of a fresh mixture of acetic anhydride, acrylic acid and triflic acid. (0117) The adjustments of the stream 1, composed of the stream of fresh mixture and of the stream 5, were such that, in the reaction region, there was continuously: (0118) acetic anhydride: incoming flow rate of 795 g/h (7.794 mol/h), (0119) acrylic acid: incoming flow rate of 1004 g/h (13.95 mol/h), and (0120) triflic acid at 50 ppm by weight, with respect to the combination {acetic anhydride+acrylic acid}. (0121) At the outlet of this reaction region, the stream 2 essentially conveyed acrylic anhydride, acetic acid, triflic acid and mixed acrylic/acetic anhydride towards the distillation column. (0122) Under the conditions described above, the acrylic anhydride, with a purity of greater than 95%, was recovered in the stream 3 with a flow rate of approximately 840 g/h (6.66 mol/h). At the column top, the stream 4 (950 g/h, 14.8 mol/h) was very predominantly (>95% by weight) composed of acetic acid. The recycling stream 5 essentially transported triflic acid and mixed acrylic/acetic anhydride in order to reinject them into the reaction region.
91%	With triethylamine; benzenesulfonyl chloride In dichloromethane at 5 - 30℃; for 3h;	2 Example 2 Example 2 In a 3-liter, four-necked glass reactor provided with a thermometer and a stirrer were placed, in a dry air atmosphere, 1,240 g of methylene chloride, 1.08 g (0.5% by mass) of Sumilizer GM, 0.65 g (0.3% by mass) of Sumilizer TP-D, 0.65 g (0.3% by mass) of Sumilizer WX-R (each Sumilizer is a trade name and a polymerization inhibitor produced by Sumitomo Chemical Co., Ltd.), 216 g (3.0 mol) of acrylic acid and 264 g (1.5 mol) of benzenesulfonyl chloride.. The mixture was cooled to 5°C. Then, 304 g (3.0 mol, 1 equivalent relative to the acids generated from benzenesulfonyl chloride) of triethylamine was dropwise added in 2 hours with the temperature of the reaction mixture being controlled at 30°C or lower.. After the completion of the dropwise addition, stirring was made for 1 hour with the same temperature being kept.. The reaction mixture was analyzed by GC, which indicated that the conversion of acrylic acid was 99%. After the completion of the reaction, 375 g of water was added to the reaction mixture to wash the reaction mixture.. The reaction mixture was further washed twice each time with 563 g of water, after which distillation was conducted to remove methylene chloride.. The yield of the acrylic acid anhydride obtained was 172 g and 91% and its purity by GC analysis was 99%, and no high-molecular by-product was detected.
79%	With methanesulfonyl chloride; triethylamine In dichloromethane at 5 - 30℃; for 3h;	1 Example 1 Example 1 In a 3-liter, four-necked glass reactor provided with a thermometer and a stirrer were placed, in a nitrogen atmosphere, 1,240 g of methylene chloride, 1.08 g (0.5% by mass) of Sumilizer GM, 0.65 g (0.3% by mass) of Sumilizer TP-D, 0.65 g (0.3% by mass) of Sumilizer WX-R (each Sumilizer is a trade name and a polymerization inhibitor produced by Sumitomo Chemical Co., Ltd.), 216 g (3.0 mol) of acrylic acid and 172 g (1.5 mol) of methanesulfonyl chloride.. The mixture was cooled to 5°C. Then, 304 g (3.0 mol, 1 equivalent relative to the acids generated from methanesulfonyl chloride) of triethylamine was dropwise added in 2 hours with the temperature of the reaction mixture being controlled at 30°C or lower.. After the completion of the dropwise addition, stirring was made for 1 hour with the same temperature being kept.. The reaction mixture was analyzed by a gas chromatograph (GC), which indicated that the conversion of acrylic acid was 99%. After the completion of the reaction, 375 g of water was added to the reaction mixture to wash the reaction mixture.. The reaction mixture was further washed twice each time with 563 g of water, after which distillation was conducted to remove methylene chloride.. The yield of the acrylic acid anhydride obtained was 172 g and 91% and its purity by GC analysis was 98%, and no high-molecular by-product was detected.. The identification of acrylic acid anhydride was conducted by analyses of nuclear magnetic resonance spectrum, elemental analysis data, and mass spectrum.. The same analytical techniques were used also in later Examples and Comparative Examples to determine various values. Comparative Example 1 A reaction was conducted in accordance with Example 1 except that the amount of triethylamine used in Example 1 was changed to 455 g (4.5 mol, 1.5 equivalents relative to the acids generated from methanesulfonyl chloride). _ ;Acrylic acid anhydride could be produced at an acrylic acid conversion of 99%, at a yield of 150 g and 79%, and at a purity (determined by GC analysis) of 74%. The amount of high-molecular by-products formed was 20%

56%	Stage #1: acrylic acid With triethylamine; benzenesulfonyl chloride In dichloromethane at 5 - 30℃; for 0.5h; Stage #2: With sodium carbonate In dichloromethane at 30℃; for 10h;	4; 5; 6; 18; 24; 25; 26 Example 18 Example 18 In a 3-liter, four-necked glass reactor provided with a thermometer and a stirrer were placed, in a nitrogen atmosphere, 1,240 g of methylene chloride, 1.08 g (0.5% by mass) of Sumilizer GM, 0.65 g (0.3% by mass) of Sumilizer TP-D, 0.65 g (0.3% by mass) of Sumilizer WX-R (each Sumilizer is a trade name and a polymerization inhibitor produced by Sumitomo Chemical Co., Ltd.), 216 g (3.0 mol) of acrylic acid and 265 g (1.5 mol) of benzenesulfonyl chloride.. The mixture was cooled to 5°C. Then, 30 g (0.3 mol, 0.1 equivalent relative to the acids generated from methanesulfonyl chloride) of triethylamine was dropwise added in 30 minutes with the temperature of the reaction mixture being controlled at 30°C or lower.. Further, 148 g (1.4 mol, 0.93 equivalent relative to the acids generated from benzenesulfonyl chloride) of sodium carbonate was added.. Then, stirring was made for 10 hours with the same temperature being kept.. The reaction mixture was analyzed by GC, which indicated that the conversion of acrylic acid was 99%. After the completion of the reaction, 500 g of water was added to the reaction mixture to wash the reaction mixture.. The reaction mixture was further washed twice each time with 563 g of water, after which distillation was conducted to remove methylene chloride.. The yield of the acrylic acid anhydride obtained was 180 g and 95% and its purity by GC analysis was 98%, and no high-molecular by-product was detected.
55.6%	With thionyl chloride In dichloromethane at 0℃; for 2h;
	With 4-methyleneoxetan-2-one; copper (I) acetate
	With methanesulfonyl chloride; triethylamine In toluene at 0 - 7℃; for 1h;
	With 2,6-di-tert-butyl-4-methyl-phenol; triethylamine; p-toluenesulfonyl chloride In ethyl acetate at -5 - 0℃; for 1h;	2 Synthesis of the monomer MONC; [0206]MONC EPO [0207] Ethyiacetate (480 mL) was cooled to 00C. Acrylic acid (19.0 g, 0.264 mol) and 2,6-di-tert-butyl-4- methylphenol (0.2 g, 0.00088 mol) were added. Triethylamine (26.7 g, 0.264 mol) was added drop-wise while the temperature was maintained between -50C and O0C. Finally benzene sulfonyl chloride (22.3 g, 0.126 mol) was added drop-wise. Triethylamine hydrochloride precipitated. The reaction mixture was allowed to stir for 1 hour at 00C resulting in the formation of the symmetric anhydride. To this mixture N-hydroxysuccinimide (0.7 g, 0.006 mol) and MC-2 (22.3 g, 0.06 mol) were added at 5°C. The reaction mixture was refluxed (78°C) for about 17 hours. The reaction mixture was diluted with EtOAc (100 mL) and extracted with distilled water (400 mL). The organic layer was separated and again extracted with a mixture of an aqueous solution of hydrochloric acid and distilled water (1/5). Finally the organic layer was washed with water and dried over MgSO4. After evaporation of the solvent, the residue was suspended into distilled water and stirred for 45 minutes. Filtration provided a yellow solid.
	With 2,6-di-tert-butyl-4-methyl-phenol; triethylamine; p-toluenesulfonyl chloride In ethyl acetate at -5 - 0℃; for 1h;	1 Synthesis of the monomer MONC EPO [0172][0173] Ethylacetate (480 ml) was cooled to 00C. Acrylic acid (19.0 g, 0.264 mol) and 2,6-di-tert-butyl-4- methylphenol (0.2 g, 0.00088 mol) were added. Triethylamine (26.7 g, 0.264 mol) was added drop-wise while the temperature was maintained between -5°C and 00C. Finally benzene sulfonyl chloride (22.3 g, 0.126 mol) was added drop-wise. Triethylamine hydrochloride precipitated. The reaction mixture was allowed to stir for 1 hour at 00C resulting in the formation of the symmetric anhydride. To this mixture N-hydroxysuccinimide (0.7 g, 0.006 mol) and MC-2 (22.3 g, 0.06 mol) were added at 5°C. The reaction mixture was refluxed (78°C) for about 17 hours. The reaction mixture was diluted with EtOAc (100 ml) and extracted with distilled water (400 ml). The organic layer was separated and again extracted with a mixture of an aqueous solution of hydrochloric acid and distilled water (1/5). Finally the organic layer was washed with water and dried over MgSO4. After evaporation of the solvent, the residue was suspended into distilled water and stirred for 45 minutes. Filtration provided a yellow solid. EPO [0174] Synthesis scheme of MONC:
	With 2,6-di-tert-butyl-4-methyl-phenol; triethylamine; p-toluenesulfonyl chloride In ethyl acetate at -5 - 0℃; for 1h;	Synthesis of the monomer MONC Ethylacetate (480 ml) was cooled to O0C. Acrylic acid (19.0 g, 0.264 mol) and 2,6-di-tert-butyl-4- methylphenol (0.2 g, 0.00088 mol) were added. Triethylamine (26.7 g, 0.264 mol) was added drop-wise while the temperature was maintained between -5°C and 00C. Finally benzene sulfonyl chloride (22.3 g, 0.126 mol) was added drop-wise. Triethylamine hydrochloride precipitated. The reaction mixture was allowed to stir for 1 EPO hour at 00C resulting in the formation of the symmetric anhydride. To this mixture N-hydroxysuccinimide (0.7 g, 0.006 mol) and MC-2 (22.3 g, 0.06 mol) were added at 50C. The reaction mixture was refluxed (78°C) for about 17 hours. The reaction mixture was diluted with EtOAc (100 ml) and extracted with distilled water (400 ml). The organic layer was separated and again extracted with a mixture of an aqueous solution of hydrochloric acid and distilled water (1/5). Finally the organic layer was washed with water and dried over MgSO4. After evaporation of the solvent, the residue was suspended into distilled water and stirred for 45 minutes. Filtration provided a yellow solid. [0204] Synthesis scheme of MONC:
	With 2,6-di-tert-butyl-4-methyl-phenol; triethylamine; p-toluenesulfonyl chloride In ethyl acetate at 0℃; for 1h;	2 Synthesis of the monomer MONC EPO [0165][0166] Ethylacetate (480 ml) was cooled to 00C. Acrylic acid (19.0 g, 0.264 mol) and 2,6-di-tert-butyl-4- methylphenol (0.2 g, 0.00088 mol) were added. Triethylamine (26.7 g, 0.264 mol) was added drop-wise while the temperature was maintained between -5°C and 00C. Finally benzene sulfonyl chloride (22.3 g, 0.126 mol) was added drop-wise. Triethylamine hydrochloride precipitated. The reaction mixture was allowed to stir for 1 hour at 00C resulting in the formation of the symmetric anhydride. To this mixture N-hydroxysuccinimide (0.7 g, 0.006 mol) and MC-2 (22.3 g, 0.06 mol) were added at 5°C. The reaction mixture was refluxed (78°C) for about 17 hours. The reaction mixture was diluted with EtOAc (100 ml) and extracted with distilled water (400 ml). The organic layer was separated and again extracted with a mixture of an aqueous solution of hydrochloric acid and distilled water (1/5). Finally the organic layer was washed with water and dried over MgSO4. After evaporation of the solvent, the residue was suspended into distilled water and stirred for 45 minutes. Filtration provided a yellow solid. EPO [0167] Synthesis scheme of MONC:
	Stage #1: acrylic acid With 2,6-di-tert-butyl-4-methyl-phenol; triethylamine In ethyl acetate at -5 - 0℃; Stage #2: With benzenesulfonyl chloride In ethyl acetate at 0℃; for 1h;	1 Synthesis of the monomer MONC; [0169][0170] Ethylacetate (480 ml_) was cooled to O0C. Acrylic acid (19.0 g, 0.264 mol) and 2,6-di-tert-butyl-4- methylphenol (0.2 g, 0.00088 mol) were added. Triethylamine (26.7 g, 0.264 mol) was added drop-wise while the temperature was maintained between -5°C and 00C. Finally benzene sulfonyl chloride (22.3 g, 0.126 mol) was added drop-wise. Triethylamine hydrochloride precipitated. The reaction mixture was allowed to stir for 1 hour at O0C resulting in the formation of the symmetric anhydride. To this mixture N-hydroxysuccinimide (0.7 g, 0.006 mol) and MC-2 (22.3 g, 0.06 mol) were added at 5°C. The reaction mixture was refluxed (78°C) for about 17 hours. The reaction mixture was diluted with EtOAc (100 ml_) and extracted with distilled water (400 mL). The organic layer was separated and again extracted with a mixture of an aqueous solution of hydrochloric acid and distilled water (1/5). Finally the organic layer was washed with water and dried over MgSO4. After evaporation of the solvent, the residue was suspended into distilled water and stirred for 45 minutes. Filtration provided a yellow solid.
	Stage #1: acrylic acid With triethylamine In benzene at 0 - 10℃; Inert atmosphere; Stage #2: With hydroquinone In benzene Inert atmosphere; Stage #3: With thionyl chloride In benzene Inert atmosphere;
	With trifluorormethanesulfonic acid; acetic anhydride at 100℃; Flow reactor;	3 Example 3 Example 3 Acrylic anhydride CH2═CH-C(═O)-O-(O═)C═CH═CH was prepared according to the process of the invention by reaction between acrylic acid and acetic anhydride. The sequence of appliances is represented in FIG. 3. In the reaction region, the reaction temperature was set at 100° C. and the pressure was set at atmospheric pressure. In the distillation (extraction) region, the pressure was set at 20 mbar absolute and a temperature gradient (between 90° C. at the column bottom and 25° C. at the column top) was observed. As indicated in FIG. 3, the reaction region was fed with the stream 1, with an overall flow rate of 2 kg/h and composed of the recycling stream 5 and of a continuous feed of a fresh mixture of acetic anhydride, acrylic acid and triflic acid. The adjustments of the stream 1, composed of the stream of fresh mixture and of the stream 5, were such that, in the reaction region, there was continuously: The adjustments of the stream 1, composed of the stream of fresh mixture and of the stream 5, were such that, in the reaction region, there was continuously: acetic anhydride: incoming flow rate of 795 g/h (7.794 mol/h), acrylic acid: incoming flow rate of 1004 g/h (13.95 mol/h), and triflic acid at 50 ppm by weight, with respect to the combination {acetic anhydride+acrylic acid}. At the outlet of this reaction region, the stream 2 essentially conveyed acrylic anhydride, acetic acid, triflic acid and mixed acrylic/acetic anhydride towards the distillation column. Under the conditions described above, the acrylic anhydride, with a purity of greater than 95%, was recovered in the stream 3 with a flow rate of approximately 840 g/h (6.66 mol/h). At the column top, the stream 4 (950 g/h, 14.8 mol/h) was very predominantly (>95% by weight) composed of acetic acid. The recycling stream 5 essentially transported triflic acid and mixed acrylic/acetic anhydride in order to reinject them into the reaction region.
	With dicyclohexyl-carbodiimide In toluene at -5 - 5℃; for 0.5h; Inert atmosphere;	1.1; 3 Step 1: Synthesizing Diacrylic Anhydride N,N′-dicyclohexylcarbodiimide (hereinafter, sometimes referred to as “DCC”) (20.5 g, 0.10 moles) serving as the condensation agent and toluene (64.8 g, 75 mL) serving as the solvent were charged in a 100-mL reaction container equipped with a nitrogen gas supplying pipe, a thermometer, and a stirrer in a nitrogen atmosphere, and the reacting solution was cooled such that the inner temperature was in a temperature range of -5° C. to 5° C., being stirred at 500 rpm. After the cooling, acrylic acid (15.1 g, 0.21 moles) serving as the material was dropped into the toluene solution of DCC, being stirred, while the inner temperature was being controlled in the above range. After the completion of the dropping, the reaction solution was further stirred for 30 minutes under a condition of the inner temperature of 0° C. to proceed the reaction. After the completion of the stirring, the white solid of deposited dicyclohexylurea was filtered through suction filtration and the dicyclohexylurea was washed with toluene (25.9 g, 30 mL) to obtain the washing solution. Then, the filtrate and the washing solution were mixed and thereby a toluene solution of diacrylic anhydride was obtained.
	With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 6h; Cooling with ice;
	With di-<i>tert</i>-butyl dicarbonate; magnesium chloride In acetonitrile at 30℃; for 0.33h; Inert atmosphere;

Reference： [1]Current Patent Assignee: SOLVAY - US9266811, 2016, B2 Location in patent: Paragraph 0113-0122
[2]Current Patent Assignee: TOKUYAMA CORPORATION - EP1413572, 2004, A1 Location in patent: Page 9-10
[3]Current Patent Assignee: TOKUYAMA CORPORATION - EP1413572, 2004, A1 Location in patent: Page 9
[4]Current Patent Assignee: TOKUYAMA CORPORATION - EP1413572, 2004, A1 Location in patent: Page 12
[5]Fife, Wilmer K.; Zhang, Zhi-dong [Tetrahedron Letters, 1986, vol. 27, # 41, p. 4937 - 4940]
[6]Current Patent Assignee: EASTMAN KODAK CO - US2476859, 1948, A
[7]Current Patent Assignee: TAKASAGO INTERNATIONAL CORPORATION - JP2005/200406, 2005, A Location in patent: Page/Page column 16
[8]Current Patent Assignee: AGFA-GEVAERT - WO2007/6634, 2007, A2 Location in patent: Page/Page column 57-58
[9]Current Patent Assignee: AGFA-GEVAERT - WO2007/6635, 2007, A2 Location in patent: Page/Page column 48-50
[10]Current Patent Assignee: AGFA-GEVAERT - WO2007/6636, 2007, A2 Location in patent: Page/Page column 62-63
[11]Current Patent Assignee: AGFA-GEVAERT - WO2007/6637, 2007, A2 Location in patent: Page/Page column 45-47
[12]Current Patent Assignee: AGFA-GEVAERT - WO2007/6639, 2007, A2 Location in patent: Page/Page column 41-42
[13]Scoccia, Jimena; Gerbino, Dario C.; Terraza, Victor F.; Zuniga, Adriana E.; Podesta, Julio C. [European Journal of Organic Chemistry, 2013, # 20, p. 4418 - 4426]
[14]Current Patent Assignee: SOLVAY - US2015/203433, 2015, A1 Location in patent: Paragraph 0112-0121
[15]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - US2020/115322, 2020, A1 Location in patent: Paragraph 0107-0109; 0136
[16]Delbianco, Martina; Seeberger, Peter H.; Zhu, Yuntao [Journal of the American Chemical Society, 2021, vol. 143, # 26, p. 9758 - 9768]
[17]Fouilloux, Hugo; Placet, Vincent; Qiang, Wei; Robert, Carine; Thomas, Christophe M. [Angewandte Chemie - International Edition, 2021, vol. 60, # 35, p. 19374 - 19382][Angew. Chem., 2021, vol. 133, # 35, p. 19523 - 19531]

3
[ 35320-23-1 ]
[ 2051-76-5 ]
[ 50715-50-9 ]
[ 61366-16-3 ]

Reference： [1]Patent: US3971822,1976,A

4
[ 2051-76-5 ]
[ 59410-82-1 ]
(S)-N-Acryloyl-phenylglycin-ethylester [ No CAS ]

Reference： [1]Chemische Berichte,1976,vol. 109,p. 1967 - 1975

5
[ 2051-76-5 ]
[ 4089-07-0 ]
(S)-N-Acryloyl-tyrosin-ethylester [ No CAS ]

Reference： [1]Chemische Berichte,1976,vol. 109,p. 1967 - 1975

6
[ 7446-81-3 ]
[ 814-68-6 ]
[ 2051-76-5 ]

Reference： [1]Australian Journal of Chemistry,1978,vol. 31,p. 209 - 213
[2]Journal of the American Chemical Society,1998,vol. 120,p. 2493 - 2500

7
[ 2051-76-5 ]
[ 707-37-9 ]
[ 23743-72-8 ]

Reference： [1]Chemistry Letters,1991,p. 1145 - 1148

8
[ 79-10-7 ]
[ 814-68-6 ]
[ 2051-76-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine In tetrahydrofuran at 20℃; for 16.0833h; Inert atmosphere; Cooling with ice;
80%	With triethylamine In tetrahydrofuran at 20℃; for 16h; Cooling with ice; Inert atmosphere;	Synthesis of Acrylic Anhydride Synthesis of Acrylic Anhydride Acrylic anhydride was synthesized in 70-80% yield as in the following example. Acryloyl chloride (2.7 g, 30 mmol) was added dropwise over 5 min to an ice-cooled solution of acrylic acid (2.0 g, 30 mmol) and triethylamine (2.8 g, 30 mmol) in THF (50 mL), and the solution was stirred at room temperature for 16 h. The NH4+Cl- precipitate was collected in a fritted glass filter, and the solvent was then removed from the filtrate by rotary evaporation. The residue was dissolved in CH2Cl2 (25 mL), washed twice with dilute aq. NaHCO3 (50 mL each) and once with satd. NaCl aq. soln. (50 mL), and dried over anhy. Na2SO4. After filtration and removing the solvent by rotary evaporation, 2.8 g (80%) of acrylic anhydride was obtained as a light yellow liquid. It was used without further purification. 1H NMR (CDCl3, 77.23 ppm): 6.04 (m, ═CH trans to CO2), 6.14 (m, ═CH gem to CO2), 6.50 (d, ═CH cis to CO2). 13C NMR (CDCl3/DMSO-d6): 127.4 (═CH), 134.7 (′CH2), 161.2 (C═O).
75%	With triethylamine In tetrahydrofuran at 20℃; for 16h;

	With sodium hydride 1) THF, room temperature, 1 h, 2) room temperature, 1 h; Multistep reaction;
	With sodium hydride 1.) -78 deg C to room temp., 2.) room temp., 1 h;
	With triethylamine In tetrahydrofuran at -20℃; for 1h;
	With triethylamine In ethyl acetate at 0 - 20℃;
	With triethylamine In tetrahydrofuran at -25℃; for 1h;
	With triethylamine at -25℃; for 1h;
	With triethylamine In ethyl acetate at 0 - 20℃; for 0.5h;
	With triethylamine In ethyl acetate at 0 - 20℃;
	With triethylamine; hydroquinone In tetrahydrofuran	3 Acrylic Anhydride PREPARATION 3 Acrylic Anhydride Two hundred fifty ml of tetrahydrofuran was added to a 1 liter jacketed flask with stir bar and nitrogen purge, and 250 mg of butylated hydroxytoluene, 250 mg of hydroquinone and 25.3 g of triethylamine were added. The solution was cooled to 0°, and to it was added 18.0 g of acrylic acid over a 2 minute period. The solution was cooled again to 0°, and 22.6 g of acryloyl chloride was added over a 10 minute period. It is important to maintain the addition rate constant during the acryloyl chloride addition. Maintaining the jacket temperature at 0° and continuing the nitrogen purge, the solution was stirred for 1 hour, and then it was filtered in a vacuum filter and the cake was washed with 50 ml of additional tetrahydrofuran.
	With triethylamine; hydroquinone In tetrahydrofuran	2 Preparation 2 Preparation 2 Acrylic Anhydride Two hundred fifty ml of tetrahydrofuran was added to a 1 liter jacketed flask with stir bar and nitrogen purge, and 250 mg of butylated hydroxytoluene, 250 mg of hydroquinone and 25.3 g of triethylamine were added. The solution was cooled to 0°, and to it was added 18.0 g of acrylic acid over a 2 minute period. The solution was cooled again to 0°, and 22.6 g of acryloyl chloride was added over a 10 minute period. It is important to maintain the addition rate constant during the acryloyl chloride addition. Maintaining the jacket temperature at 0° and continuing the nitrogen purge, the solution was stirred for 1 hour, and then it was filtered in a vacuum filter and the cake was washed with 50 ml of additional tetrahydrofuran.
	With triethylamine; hydroquinone In tetrahydrofuran	3 Acrylic Anhydride Preparation 3 Acrylic Anhydride Two hundred fifty ml of tetrahydrofuran was added to a 1 liter jacketed flask with stir bar and nitrogen purge, and 250 mg of butylated hydroxytoluene, 250 mg of hydroquinone and 25.3 g of triethylamine were added. The solution was cooled to 0° and to it was added 18.0 g of acrylic acid over a 2 minute period. The solution was cooled again to 0°, and 22.6 g of acryloyl chloride was added over a 10 minute period. It is important to maintain the addition rate constant during the acryloyl chloride addition. Maintaining the jacket temperature at 0° and continuing the nitrogen purge, the solution was stirred for 1 hour, and then it was filtered in a vacuum filter and the cake was washed with 50 ml of additional tetrahydrofuran.
	With triethylamine; hydroquinone In tetrahydrofuran	3 acrylic anhydride Preparation 3 acrylic anhydride Two hundred fifty ml of tetrahydrofuran was added to a 1 liter jacketed flask with stir bar and nitrogen purge, and 250 mg of butylated hydroxytoluene, 250 mg of hydroquinone and 25.3 g of triethylamine were added. The solution was cooled to 0°, and to it was added 18.0 g of acrylic acid over a 2 minute period. The solution was cooled again to 0°, and 22.6 g of acryloyl chloride was added over a 10 minute period. It is important to maintain the addition rate constant during the acryloyl chloride addition. Maintaining the jacket temperature at 0° and continuing the nitrogen purge, the solution was stirred for 1 hour, and then it was filtered in a vacuum filter and the cake was washed with 50 ml of additional tetrahydrofuran.
	With triethylamine In tetrahydrofuran at -20℃; for 1h;
	With triethylamine In ethyl acetate at 0 - 20℃; for 1.5h;
	With triethylamine In tetrahydrofuran at -20℃; for 1h;
	With triethylamine In tetrahydrofuran at -20℃; for 1h;	4.9. Preparation of N-acryloyl-4-benzyloxazolidin-2-one 2⁹ An oven-dried three necked round-bottom flask containing a stir bar was charged with solution of acrylic acid (1.88 g, 26 mmol), triethylamine (5.06 g, 50 mmol), and THF (100 mL) and to this solution was added acryloyl chloride (2.17 g, 24 mmol) at -20 °C. A white solid was formed instantaneously. The mixture was stirred at -20 °C for 1 h.
	With sodium hydride
	With triethylamine In tetrahydrofuran at -20℃; for 1h;
	With triethylamine In tetrahydrofuran at -20℃; for 1h;
	With triethylamine In tetrahydrofuran for 16h;	Acrylic anhydride (13) Acryloyl chloride (2.7 g, 30 mmol) was added dropwise over 5 min to an ice-cooled solution of acrylic acid (2.0 g, 28 mmol) and Et3N (2.8 g, 28 mmol) in THF (50 mL), and the solution was stirred at room temperature for 16 h. The ammonium chloride precipitate was collected in a fritted glass filter, and the solvent was removed from the filtrate by rotary evaporation. The residue was dissolved in CH2Cl2(25 mL), washed twice with dilute aqueous NaHCO3(50 mL each) and once with saturated aqueous NaCl (50 mL), and dried over Na2SO4. After filtration and removing the solvent by rotary evaporation, the product was used without further purification.

Reference： [1]Pugh, Coleen; Raveendra, Bindu; Singh, Anirudha; Samuel, Reichel; Garcia, Guillermina [Synlett, 2010, # 13, p. 1947 - 1950]
[2]Current Patent Assignee: UNIVERSITY SYSTEM OF OHIO - US8524942, 2013, B2 Location in patent: Page/Page column 18-19
[3]Jian, Zhongbao; Baier, Moritz C.; Mecking, Stefan [Journal of the American Chemical Society, 2015, vol. 137, # 8, p. 2836 - 2839]
[4]Paulvannan, K.; Stille, John R. [Journal of Organic Chemistry, 1992, vol. 57, # 20, p. 5319 - 5328]
[5]Cook, Gregory R.; Beholz, Lars G.; Stille, John R. [Journal of Organic Chemistry, 1994, vol. 59, # 13, p. 3575 - 3584]
[6]Ho, Guo-Jie; Mathre, David J. [Journal of Organic Chemistry, 1995, vol. 60, # 7, p. 2271 - 2273]
[7]Suga, Hiroyuki; Kakehi, Akikazu; Mitsuda, Masashi [Bulletin of the Chemical Society of Japan, 2004, vol. 77, # 3, p. 561 - 568]
[8]Nakano, Hiroto; Tsugawa, Natsumi; Takahashi, Kouichi; Okuyama, Yuko; Fujita, Reiko [Tetrahedron, 2006, vol. 62, # 47, p. 10879 - 10887]
[9]Cannizzaro, Carina E.; Ashley, Jon A.; Janda; Houk [Journal of the American Chemical Society, 2003, vol. 125, # 9, p. 2489 - 2506]
[10]Bull, Steven D.; Davies, Stephen G.; Garner, A. Christopher; Kruchinin, Dennis; Key, Min-Suk; Roberts, Paul M.; Savory, Edward D.; Smith, Andrew D.; Thomson, James E. [Organic and Biomolecular Chemistry, 2006, vol. 4, # 15, p. 2945 - 2964]
[11]Beddow, James E.; Davies, Stephen G.; Ling, Kenneth B.; Roberts, Paul M.; Russell, Angela J.; Smith, Andrew D.; Thomson, James E. [Organic and Biomolecular Chemistry, 2007, vol. 5, # 17, p. 2812 - 2825]
[12]Current Patent Assignee: ELI LILLY & CO - US5550134, 1996, A
[13]Current Patent Assignee: ELI LILLY & CO - US5574160, 1996, A
[14]Current Patent Assignee: ELI LILLY & CO - US5578724, 1996, A
[15]Current Patent Assignee: ELI LILLY & CO - US5629007, 1997, A
[16]Sibi, Mukund P.; Kawashima, Keisuke; Stanley, Levi M. [Organic Letters, 2009, vol. 11, # 17, p. 3894 - 3897]
[17]Mukund P, Sibi; Soeta, Takahlro; Jasperse, Craig P. [Organic Letters, 2009, vol. 11, # 23, p. 5366 - 5369]
[18]Location in patent: experimental part Hirama, Masafumi; Kato, Yuji; Seki, Chigusa; Nakano, Hiroto; Takeshita, Mitsuhiro; Oshikiri, Noriko; Iyoda, Masahiko; Matsuyama, Haruo [Tetrahedron, 2010, vol. 66, # 38, p. 7618 - 7624]
[19]Location in patent: experimental part Seki, Chigusa; Hirama, Masafumi; Hutabarat, N.D.M. Romauli; Takada, Junko; Suttibut, Chonticha; Takahashi, Hideto; Takaguchi, Takuya; Kohari, Yoshihito; Nakano, Hiroto; Uwai, Koji; Takano, Nobuhiro; Yasui, Mitsukuni; Okuyama, Yuko; Takeshita, Mitsuhiro; Matsuyama, Haruo [Tetrahedron, 2012, vol. 68, # 6, p. 1774 - 1781]
[20]Location in patent: body text Janoschka, Tobias; Teichler, Anke; Krieg, Andreas; Hager, Martin D.; Schubert, Ulrich S. [Journal of Polymer Science, Part A: Polymer Chemistry, 2012, vol. 50, # 7, p. 1394 - 1407]
[21]Hutabarat, N.D.M. Romauli; Seki, Chigusa; Shimizu, Takashi; Hirama, Masafumi; Kohari, Yoshihito; Nakano, Hiroto; Uwai, Koji; Takano, Nobuhiro; Kwon, Eunsang; Matsuyama, Haruo [Heterocycles, 2012, vol. 86, # 1, p. 203 - 217]
[22]Maynard, Andrew; Crosby, Renae M.; Ellis, Byron; Hamatake, Robert; Hong, Zhi; Johns, Brian A.; Kahler, Kirsten M.; Koble, Cecilia; Leivers, Anna; Leivers, Martin R.; Mathis, Amanda; Peat, Andrew J.; Pouliot, Jeffrey J.; Roberts, Christopher D.; Samano, Vicente; Schmidt, Rachel M.; Smith, Gary K.; Spaltenstein, Andrew; Stewart, Eugene L.; Thommes, Pia; Turner, Elizabeth M.; Voitenleitner, Christian; Walker, Jill T.; Waitt, Greg; Weatherhead, Jason; Weaver, Kurt; Williams, Shawn; Wright, Lois; Xiong, Zhiping Z.; Haigh, David; Shotwell, J. Brad [Journal of Medicinal Chemistry, 2014, vol. 57, # 5, p. 1902 - 1913]
[23]Xiao, Tao; Sun, Luxin; Zhang, Min; Li, Zilu; Haura, Eric B.; Schonbrunn, Ernst; Ji, Haitao [Bioorganic and Medicinal Chemistry Letters, 2021, vol. 51]

10
[ 54705-42-9 ]
[ 2051-76-5 ]
[ 506444-76-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine; lithium chloride In tetrahydrofuran at 20℃; for 12h;	(S)-3-Acryloyl-4-(tert-butyl)oxazolidin-2-one (15) Acrylic anhydride obtained from the previous step was dissolved in THF and immediately used. Compound14was then prepared by following the literature method2.1H NMR (500 MHz, CDCl3) δ 6.02 (s, 1H), 4.37 (t,J= 9.0 Hz, 1H), 4.19 (dd,J= 9.0, 5.8 Hz, 1H), 3.59 (ddd,J= 9.0, 5.8, 1.1 Hz, 1H), 0.91 (s, 9H).To a suspension of14(0.43 g, 3 mmol) and lithium chloride (0.16g, 3.75 mmol) in 30 mL THF was added Et3N (0.38 g, 3.75 mmol), followed by adding the acrylic anhydride solution. The resulting mixture was stirred for 12 h, and the solvent was removed in vacuo. 1 M HCl (100 mL) was added, and the mixture was extracted with dichloromethane. Combined organic layers were washed with saturated NaHCO3aqueous solution, brine, and dried over Na2SO4. Concentrationin vacuoand purified by silica gel column chromatography (hexanes/ethyl acetate = 4/1) gave acrylamide15as white solid (0.50 g, yield85%).1H NMR (500 MHz, CDCl3) δ 7.52 (dd,J= 17.0, 10.4 Hz, 1H), 6.53 (dd,J= 17.0, 1.7 Hz, 1H), 5.90 (dd,J= 10.4, 1.8 Hz, 1H), 4.51 (dd,J= 7.9, 1.3 Hz, 1H), 4.35 - 4.22 (m, 2H), 0.95 (s, 9H).
271 mg	With triethylamine; lithium chloride In tetrahydrofuran at 20℃; for 4h;

Reference： [1]Xiao, Tao; Sun, Luxin; Zhang, Min; Li, Zilu; Haura, Eric B.; Schonbrunn, Ernst; Ji, Haitao [Bioorganic and Medicinal Chemistry Letters, 2021, vol. 51]
[2]Bull, Steven D.; Davies, Stephen G.; Garner, A. Christopher; Kruchinin, Dennis; Key, Min-Suk; Roberts, Paul M.; Savory, Edward D.; Smith, Andrew D.; Thomson, James E. [Organic and Biomolecular Chemistry, 2006, vol. 4, # 15, p. 2945 - 2964]

11
[ 7446-81-3 ]
[ 98-88-4 ]
[ 2051-76-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 3 Synthesis of Acrylic Anhydride from Benzoyl Chloride A 60.09 g (0.4277 mol) sample of benzoyl chloride was added to a 500-ml round-bottomed flask equipped with a magnetic stirring bar. 30.02 g (0.3194 mol) of <strong>[7446-81-3]sodium acrylate</strong> were then added and stirred for 30 minutes, after which another 15.21 g (0.1618 mol) portion of <strong>[7446-81-3]sodium acrylate</strong> was added in one portion, and stirring was continued for additional 30 minutes under the same conditions. The mixture was vacuum filtered neat to obtain 56.41 g of crude product. It should be noted that a more efficient vacuum filtration system would increase the percent recovery of the crude products. Acrylic anhydride was distilled at 65°-67° C. and about 5-10 mm Hg pressure to afford 20.84 g (77.3percent yield). MS data: m/z 98 (<2,M-CO), 55 (100, CH2 =CH-CO+). IR data: 1794.5 and 1730.2 cm-1 C=O,16.28.9 cm-1 C=C. P-NMR data: vinyl protons all giving doublets of doublets at 6,587, 6,591 and 6.531, 6.535 ppm; 6.227, 6.193 and 6.171, 6.137 ppm; and 6.092, 6,087 and 6.057, 6.053 ppm respectively. C-13 NMR data: 162 ppm (C=O), 135 ppm and 128 ppm (C=C). The residual material in the distillation flask was found to be 31.68 g benzoic anhydride (65.6percent yield).

Reference： [1]Patent: US5491244,1996,A

12
[ 2051-76-5 ]
[ 1201-91-8 ]
[ 136775-80-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap In pyridine	I.B B. B. 4-(N-2-acryloyloxyethyl-N-methylamino)benzaldehyde (compound A) A solution of 161.3 g (0.9 mole) of 4-(N-2-hydroxyethyl-N-methylamino)benzaldehyde, 227.0 g (1.8 moles) of acrylic anhydride, and 1.1 g (1 mole%) of 4-N,N-dimethylaminopyridine in pyridine is heated at 80° C. until the reaction is complete. After cooling to room temperature, the solution is poured into water, and compound A is collected by filtration, and purified by recrystallization from ethanol.

Reference： [1]Current Patent Assignee: CELANESE CORP - US4978476, 1990, A

13
[ 2051-76-5 ]
[ 7691-28-3 ]
[ 1020105-72-9 ]

Yield	Reaction Conditions	Operation in experiment
68%	With triethylamine In tetrahydrofuran at 20℃; for 21.1667h;
68%	With triethylamine In tetrahydrofuran at 20℃; for 21h; Inert atmosphere;	Synthesis of (2-Bromo-2-methoxycarbonyl)ethyl propenoate General procedure: Synthesis of (2-Bromo-2-methoxycarbonyl)ethyl propenoate (2-Bromo-2-methoxycarbonyl)ethyl propenoate was synthesized in 55-68% (68%) yield as in the following example. A solution of acrylic anhydride (0.80 g, 6.3 mmol) in THF (5 mL) was added dropwise over 10 min to a solution of methyl 2-bromo-3-hydroxypropionate (0.50 g, 2.7 mmol) and triethylamine (0.55 g, 5.4 mmol) in THF (25 mL) at room temperature. After stifling at RT for 21 h, the solution was poured into ice-cooled water (25 mL) and stirred for 3 h. THF was removed by rotary evaporation and CH2Cl2 was added. After separating the two layers, the organic phase was washed twice with dil. aq. NaHCO3 (25 mL each) and once with satd. NaCl aq. soln. (25 mL), and dried over Na2SO4. After filtration and removing the solvent by rotary evaporation (2-bromo-2-methoxycarbonyl)ethyl propenoate was obtained as a yellow liquid. Pure product as a clear liquid (0.44 g, 68%) was obtained by vacuum distillation at full vacuum at 92-94° C. 1H NMR (CDCl3, 7.27 ppm): 3.83 (s, CH3), 4.58 (m, CO2CH2 & CHBr), 5.92 (dd, ═CH trans to CO2), 6.14 (dd, ═CHCO2), 6.43 (dd, ═CH cis to CO2). 13C NMR (CDCl3, 77.23 ppm): 40.4 (CBr), 53.5 (CH3), 64.31 (CH2O2C), 127.6 (═CH), 132.4 (═CH2), 165.3 (CO2CH3), 168.3 (CO2CH2). Anal. C, H: calcd. 35.47, 3.83; found 35.24, 3.75.

Reference： [1]Location in patent: experimental part Pugh, Coleen; Raveendra, Bindu; Singh, Anirudha; Samuel, Reichel; Garcia, Guillermina [Synlett, 2010, # 13, p. 1947 - 1950]
[2]Current Patent Assignee: UNIVERSITY SYSTEM OF OHIO - US8524942, 2013, B2 Location in patent: Page/Page column 19

14
[ 2051-76-5 ]
[ 1334724-09-2 ]
[ 1334724-10-5 ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1.5h;	P7 Example P7: 1 -(6-(4-(2-(difluoromethvn-1 H-benzordlimidazol-1-vn-6 morpholino-1 ,3,5- triazin-2-yl)-2,6-diazaspiror3.3lheptan-2-yl)prop-2-en-1 -one (317)Compound 303 (20 mg, 46.7 μηιοΙ, 1 .0 eq.) was dissolvedin DCM (2 ml_). Diisopropylethylamine (8.7 μΙ_, 51 .3 μηιοΙ,1 .1 eq.) and acrylic anhydride (5.4 μΙ_, 46.7 μηιοΙ, 1 .0 eq.)were added and the reaction mixture was stirred for 1 .5 hat RT. The solvent was removed under reduced pressureand the residue was purified by flash column chromatography (Si02, gradient 0% to 2% MeOH in DCM) toprovide the title compound as a colorless solid (15.3 mg, 68%). RF: 0.60 (DCM/MeOH 95:5 v/v); 1H NMR (CDCI3, 400 MHz): δ 8.41 (dd, J = 7.2, 1.6 Hz, 1 H), 7.88 (dd, J = 7.2, 1 .6 Hz, 1 H), 7.63 (t, J = 53.6 Hz, 1 H), 7.41 -7.37 (m, 2H), 6.37 (dd, J = 17.0, 1 .6 Hz, 1 H), 6.18 (dd, J = 17.0, 10.4 Hz, 1 H ), 5.72 (dd, J = 10.4, 1 .6 Hz, 1 H), 4.42 (d, J = 12.8 Hz, 4H), 4.29 (sbr, 4H); 3.87 (sbr, 4H), 3.78 (sbr, 4H); 19F-NMR (CDCI3, 376 MHz): δ -1 16.7 (d, J = 53.0 Hz, 2F); ESI-MS (C23H24F2N802): Calc'd. 505.19 [M+H]+, Found 505.40.
68%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1.5h; Inert atmosphere;	P7 Example P71-(6-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6 morpholino-1,3,5-triazin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one (317) Example P7 1-(6-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6 morpholino-1,3,5-triazin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one (317) Compound 303 (20 mg, 46.7 μmol, 1.0 eq.) was dissolved in DCM (2 mL). Diisopropylethylamine (8.7 μL, 51.3 μmol, 1.1 eq.) and acrylic anhydride (5.4 μL, 46.7 μmol, 1.0 eq.) were added and the reaction mixture was stirred for 1.5 h at RT. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (SiO2, gradient 0% to 2% MeOH in DCM) to provide the title compound as a colorless solid (15.3 mg, 68%). RF: 0.60 (DCM/MeOH 95:5 v/v); 1H NMR (CDCl3, 400 MHz): δ 8.41 (dd, J=7.2, 1.6 Hz, 1H), 7.88 (dd, J=7.2, 1.6 Hz, 1H), 7.63 (t, J=53.6 Hz, 1H), 7.41-7.37 (m, 2H), 6.37 (dd, J=17.0, 1.6 Hz, 1H), 6.18 (dd, J=17.0, 10.4 Hz, 1H), 5.72 (dd, J=10.4, 1.6 Hz, 1H), 4.42 (d, J=12.8 Hz, 4H), 4.29 (sbr, 4H); 3.87 (sbr, 4H), 3.78 (sbr, 4H); 19F-NMR (CDCl3, 376 MHz): δ -116.7 (d, J=53.0 Hz, 2F); ESI-MS (C23H24F2N8O2): Calc'd. 505.19 [M+H]+. Found 505.40.

Reference： [1]Current Patent Assignee: UNIVERSITY OF BASEL - WO2011/114275, 2011, A1 Location in patent: Page/Page column 78-79
[2]Current Patent Assignee: UNIVERSITY OF BASEL - US2013/40934, 2013, A1 Location in patent: Paragraph 0251-0252

15
[ 2051-76-5 ]
[ 1345988-63-7 ]
[ 1345988-64-8 ]

Yield	Reaction Conditions	Operation in experiment
47%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h;	N-(2-(4-(4-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)ethyl)acrylamide (10) To a solution of compound 9 (100 mg, 218 μmol, 1.0 eq.) in methylene chloride (4.0 ml) are added N,N-diisopropylethylamine (46.0 μl, 264 μmol, 1.1 eq.) and acrylic anhydride (38.0 μl, 218 μmol, 1.0 eq.). The reaction mixture is stirred for 2 h at room temperature. Solvent evaporation and further purification via preparative thin layer chromatography (10% methanol/ethyl acetate) yields the title compound as colourless solid (53 mg, 47%). RF: 0.40 (ethyl acetate/methanol, 9:1 v/v); 1H NMR (CDCl3, 500 MHz) δ 8.32 (d, J=8.2 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.66-7.36 (m, 3H), 6.31-6.28 (m, 2H), 6.17-6.11 (m, 1H), 5.65 (d, J=10.4 Hz, 1H), 3.89-3.86 (m, 8H), 3.77 (br. s, 4H), 3.52-3.49 (m, 2H), 2.62-2.57 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 165.62, 165.05, 164.77, 162.02, 146.17, 145.96, 145.75, 141.94, 133.58, 130.80, 128.20, 126.54, 125.81, 124.42, 121.31, 115.88, 110.36, 108.45, 106.54, 66.66, 56.65, 52.68, 52.52, 44.07, 43.95, 43.47, 43.26, 35.90; 19F (CDCl3, 400 MHz) δ -117.49 (d, J=53.9 Hz, 2 F); ESI-MS (C24H29F2N9O2): Calc'd. 514.25 (M+). Found 514.30 and 536.24 (M+Na)+. Found 536.20.

Reference： [1]Current Patent Assignee: UNIVERSITY OF BASEL - US2013/40912, 2013, A1 Location in patent: Paragraph 0097

16
4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)morpholine [ No CAS ]
[ 2051-76-5 ]
[ 1345988-62-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h;	1-(4-(4-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)prop-2-en-1-one (8) To a solution of 4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)morpholine (15) (100 mg, 240 μmol, 1.0 eq., obtained from intermediate 3 and BOC-protected piperazine according to the general procedure followed by deprotection) in methylene chloride (4.0 ml) are added N,N-diisopropylethylamine (46.0 μl, 264 μmol, 1.1 eq.) and acrylic anhydride (27.7 μl, 240 μmol, 1.0 eq.). The reaction mixture is stirred for 2 h at room temperature. Solvent evaporation and purification via silica gel flash column chromatography (2% methanol/methylene chloride) yields the title compound as a colourless solid (100 mg, 88%). RF: 0.20 (methylene chloride/methanol, 97:3 v/v); 1H NMR (CDCl3, 400 MHz) δ 8.30 (d, J=7.58 Hz, 1H), 7.87-7.85 (m, 1H), 7.66-7.35 (m, 3H), 6.63-6.56 (m, 1H), 6.34 (dd, J=1.8, 16.7 Hz, 1H), 5.75 (dd, J=1.8, 10.6 Hz, 1H), 3.90-3.86 (m, 8H), 3.79-3.67 (m, 8H); 19F (CDCl3, 400 MHz) δ; ESI-MS (C22H24F2N8O2): Calc'd. 493.20 (M+Na)+.

Reference： [1]Current Patent Assignee: UNIVERSITY OF BASEL - US2013/40912, 2013, A1 Location in patent: Paragraph 0094

17
[ 2051-76-5 ]
hexakis-(2,3,6-tri-O-benzyl)-α-cyclodextrin [ No CAS ]
hexias(6-O-acryl-2,3-di-O-benzyl)-α-cyclodextrin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.5%	With boron trifluoride dimethyl etherate In dichloromethane at 0 - 20℃; for 8h; Inert atmosphere; regioselective reaction;	Hexias(6-O-acryl-2,3-di-O-benzyl)-a-cyclodextrin2a To a stirred solution of per-O-benzyl-a-cyclodextrin(228 mg, 0.0879 mmol) in dry CH2Cl2 (2.0 mL) cooled to0 C, acrylic anhydride (365lL, 3.16 mmol) was added.Then BF3Me2O (48lL, 0.527 mmol) was slowly droppedinto the solution in N2 atmosphere. The mixture stirred for8 h at room temperature and poured into a mixture ofsaturate NaHCO3 solution (4 mL) and CH2Cl2 (2 mL), andstirred for 0.5 h. The organic layer was separated, driedwith MgSO4, and solvent was evaporated. The mixture waspurified by column chromatography on silica gel withPetroleum-EtOAc (4:1) to afford desired product.
76.5%	With trimethylsilyl trifluoromethanesulfonate In dichloromethane at -15℃; Inert atmosphere;	2 Example 2 Hexa (6-0-acryloyl-2,3-a-dibenzyl)-α-cyclodextrin Perbenzyl a-cyclodextrin (228 mg, 0.0879 mmol) was dissolved in dichloromethane(2.0 mL), under nitrogen atmosphere, acrylic anhydride (0.365 mL, 3.16 mmol) was added, and placed at -15°C, TMS (68 uL, 0.537 mmol) was slowly added and the reaction was allowed to proceed at -15°C overnight. After the reaction is completed, the mixture was quenched with saturated sodium bicarbonate, extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride, dried over anhydrous MgS04, and subjected to rotary evaporation and column chromatography to obtain hexa (6-0-acryloyl-2,3). -dibenzyl)-a-cyclodextrin (160 mg, 76.5%)

Reference： [1]Cui, Yanli; Xu, Shanshan; Mao, Jianwei [Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2015, vol. 83, # 1-2, p. 187 - 191]
[2]Current Patent Assignee: ZHEJIANG UNIVERSITY - CN104387426, 2018, B Location in patent: Paragraph 0030-0032

18
[ 2051-76-5 ]
[ 89615-40-7 ]
C₃₄H₃₆O₈ [ No CAS ]
benzyl 6-O-acryl-2,3,4-tri-O-benzyl-β-D-mannopyranoside [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45.5%	With boron trifluoride dimethyl etherate In dichloromethane at 20℃; Inert atmosphere; regioselective reaction;	Benzyl 6-O-acryl-2,3,4-tri-O-benzyl-bmannopyranoside3a Yield:45.5 %; yellow oil; Rf 5 0.43 (cyclohexane-EtOAc,5:1)1H NMR (400 MHz, CDCl3) d 7.47-7.19 (m, 20H, Ar),6.43 (dd, J = 18.7 Hz, 7.5 Hz, 1H, CH=CH2), 6.17 (dd,J = 17.4 Hz, 10.4 Hz, 1H, CH=CH2), 5.86-5.73 (m, 1H,CH=CH2), 5.04-4.84 (m, 3H), 4.64- 4.34 (m, 7H), 3.94 (m,3H), 3.58-3.42 (m, 2H).13C NMR (101 MHz, CDCl3) d 166.06 (C=O), 138.64,138.02, 137.96, 137.14 (C-1, Ar), 131.04, 129.05(CH=CH2), 128.43-127.43 (C, Ar), 100.07 (C-1), 82.28(C-3), 75.23, 74.62, 73.73, 73.66, 71.43, 70.76 (C-5), 63.83(C-6).ESI-MS. Anal. Calcd for C37H38O7Na: 617.25 Found:m/z 617.597 for [M ? Na]?.

Reference： [1]Cui, Yanli; Xu, Shanshan; Mao, Jianwei [Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2015, vol. 83, # 1-2, p. 187 - 191]

19
[ 2051-76-5 ]
N₁-(2-(dimethylamino)ethyl)-N₁-methyl-N₄-(4-(1-methyl-1H-indol-3-yl)-5-trifluoromethylpyrimidin-2-yl)-5-methoxybenzene-1,2,4-triamine [ No CAS ]
N-(2-[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-[4-(1-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.9%	With triethylamine In dichloromethane at 20℃; for 1h;	23.b b. synthesis of: N- (2 - ((2- (dimethylamino) ethyl) (methyl) amino-4-methoxy-5- (4- (1-methyl -1H- indol-3-yl) - 5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) (compound 23) Take N1- (2- (dimethylamino) ethyl) -5-methoxy -N1- methyl -N4- (4- (1- methyl -1H- indol-3Yl) -5- (trifluoromethyl) pyrimidin-2-yl) -2-nitrophenyl-1,4-diamine (350 mg of) were added to 100mlOne-port flask, absolute ethanol (15ml) and water (5ml) mixed solvent was added under stirring at room temperatureIron powder (200mg, 5.0eq) and ammonium chloride (178mg), 65 reaction was stirred, TLC detection reactionAfter the water was added 100ml, equal amounts of ethyl acetate and extracted three times, the organic layers combined, dried over anhydrous sodium sulfateDry, solvent was distilled off under reduced pressure to give the amine (307mg). The resulting amine was dissolved in 15ml of dichloromethane, theretoAdded triethylamine (526mg), cooled to below 0 , slowly added dropwise thereto acrylic anhydride (262mg), and warm naturally to room temperature after completion of dropwise 1h, TLC the reaction was complete, 80ml of water, etc.Extracted three times the amount of dichloromethane, organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure flash chromatographyThe target compound N- (2 - ((2- (dimethylamino) ethyl) (methyl) amino-4-methoxy-5- (4- (1-methyl -1H-Indol-3-yl) -5- (trifluoromethyl) pyrimidin-2-ylamino) phenyl) acrylamide (193mg, yield 56.9%).

Reference： [1]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN105461695, 2016, A Location in patent: Paragraph 0293; 0294; 0295; 0296; 0297; 0298

20
[ 2051-76-5 ]
[ 1221291-25-3 ]
(Z)-(5-(bromomethylene)-2-oxo-2,5-dihydrothiophen-3-yl)methyl acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.5h;	(Z)-(5-(Bromomethylene)-2-oxo-2,5-dihydrothiophen-3-yl)methyl acrylate 4c Hünig’s base (0.83 mL, 4.7 mmol) was added drop wiseto a solution of acrylic anhydride (1.14 g, 9 mmol) and compound1a (1.00 g, 4.5 mmol) in DCM (15 mL) at 0 oC. Thereaction mixture was stirred for 30 min, diluted with Et2O(50 mL) and washed with H2O (3 x 25 mL). The combinedaqueous phases were extracted with Et2O (25 mL), dried(MgSO4), filtered, and the solvents removed in vacuo. Thereaction mixture was purified by flash column chromatographyusing 0-10% EtOAc in hexanes for elution; yield: 0.97g(78%); yellow solid; mp. 85-87 oC; νmax/cm -1 (film): 3061,1720, 1674; δH(300 MHz, CDCl3): 7.43 (1H, s), 7.11 (1H,s), 6.43 (1H, dd, J 17.3, 1.4), 6.24 (1H, dd, J 17.3, 10.4),5.87 (1H, dd, J 10.4, 1.4), 4.92 (2H, d, J 1.2, 0.9); δC(75MHz, CDCl3): 191.3, 165.4, 144.1, 142.6, 140.2, 132.0,127.5, 113.2, 58.0; m/z (EI+): 276 (M++2, 5%), 274 (M+, 5),55 (100). HRMS (EI+): Exact mass calculated forC9H7BrO3S+ 273.9299. Found 273.9291.

Reference： [1]Benneche, Tore; Chamgordani, Elahe Jafari; Herstad, Gunnar; Tannæs, Bjørg Siw Møller; Scheie, Anne Aamdal [Letters in Organic Chemistry, 2016, vol. 13, # 6, p. 428 - 436]

21
[ 2051-76-5 ]
[ 1022150-12-4 ]
ibrutinib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10℃;Inert atmosphere; Large scale;	Under the protection of nitrogen, for 50L in the reactor are sequentially added 13.30 kg methylene chloride, in the middle of the-1(1k g1eq)(0.40kg1.2eq)NN--10Next, the start of the dropping of the dichloromethane solution acrylic anhydride (will be 0.39 kg, 1 . 2eq acrylic anhydride dissolved in0.40kg)90Thermal insulation -10 C, fully stirring until the raw material the reaction is complete (TLC detection, methanol: ethyl acetate: three150.05)40kg 520Minutes, standing liquid, removing the aqueous phase, concentrated evaporate dichloromethane to the condenser in the liquid-dropped. 5.13kg620.005kgActive carbon, thermal insulation 60 C, stirring 20 minutes, is still hot filtration. The filtrate under stirring the temperature to 35 C,9.75kg60304 hours, filtering, cake 1.5 kg ethanol and pure water (1: 1.5) system leaching a, the resulting40120.68kg80
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10℃; for 0.5h;Inert atmosphere;	Under nitrogen, 50 mL of dichloromethane, intermediate-1 (5 g, 1 eq), N, N-diisopropylethylamine (2 g, 1.2 eq) was added sequentially to a 100 mL three-necked flask. -10 temperature conditions, dropwise addition of acrylic anhydride (1.96g, 1.2eq) in dichloromethane was added dropwise for 30 minutes, after the addition was complete, the turbid solution became clear, -10 insulation, sufficiently stirred The reaction was complete (TLC detection, methanol: ethyl acetate: triethylamine = 1: 5: 0.05). The reaction solution was washed with 200 mL of 5% aqueous citric acid solution, the aqueous phase was removed, and the dichloromethane was concentrated and distilled off. Ibrutinib crude: 3.63g.

Reference： [1]Patent: CN106146512,2016,A .Location in patent: Paragraph 0078; 0079
[2]Patent: CN106146516,2016,A .Location in patent: Paragraph 0068; 0069

22
[ 2051-76-5 ]
C₂₅H₂₉ClN₆O₄ [ No CAS ]
C₂₈H₃₁ClN₆O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -78 - 20℃; for 0.333333h; Inert atmosphere;	32.III Step III: To a solution of compound 56 (51 mg, 0.1 mmol) in DCM (2 mL) at-78 °C was added acrylic anhydride (25 mg, 0.2 mmol), followed by addition of DIPEA (52 mg, 0.4 mmol). After the reaction was slowly warmed up to room temperature, LC/MS showed completion of reaction. The reaction mixture was diluted with DCM (35 mL) and IPA (15 mL). The mixture was washed with water, brine, and sodium bicarbonate solution, dried over Na2SO4, and concentration. The residue obtained was purified by silica gel chromatography (MeOHIDCM, 5%) to afford compound 55 in 45% yield (25.7 mg). MS observed for C28H32C1N605: 567.2 (M+H); HPLC retention time: 1.67 mm.

Reference： [1]Current Patent Assignee: CAPELLA THERAPEUTICS - WO2017/53537, 2017, A1 Location in patent: Paragraph 00489; 00492

23
[ 2051-76-5 ]
N-((1R,2R)-2-aminocyclopentyl)-5-(2-isopropylpyridin-4-yl)-4-oxo-4,5-dihydro- 3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide [ No CAS ]
N-((1R,2R)-2-acrylamidocyclopentyl)-5-(2-isopropylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.0833333h; Inert atmosphere;	337 Compound 337: N-(( 1R,2R)-2-Acrylamidocyclopentyl)-5 -(2-isopropylpyridin-4-yl)-4-oxo-4,5 - dihydro-3H- 1 -thia-3 ,5, 8-triazaacenaphthylene-2-carboxamide. To a cooled (0 °C) solution of N-(( 1R,2R)-2-aminocyclopentyl)-5 -(2-isopropylpyridin-4-yl)-4- oxo-4,5 -dihydro-3H- 1 -thia-3 ,5, 8-triazaacenaphthylene-2-carboxamide (Compound 336, 270 mg, 0.62 mmol) and DIPEA (0.08 mL, 0.74 mmol) in DCM (5 mL) was added prop-2-enoyl prop-2-enoate (0.08 mL, 0.74 mmol). The reaction mix was stirred for 5 mm. The solvent was removedunder reduced pressure and the crude mix was purified (FCC, Si02, MeOH/H20) to afford thetitle Compound (160 mg, 52%). MS (ESI): mass calcd. for C25H26N603S, 490.6; m/z found,491.2 [M+Hf’. ‘H NMR (400 MHz, CD3OD): ö 8.73-8.64 (m, 1H), 8.36-8.25 (m, 1H), 7.54-7.44 (m, 1H), 7.40-7.35 (m, 1H), 6.25-6.15 (m, 3H), 5.67-5.59 (m, 1H), 4.33-4.16 (m, 2H), 3.21-3.10 (m, 1H), 2.23-2.08 (m, 2H), 1.87-1.77 (m, 2H), 1.72-1.51 (m, 2H), 1.34 (d, J= 6.9 Hz, 6H).
52%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.0833333h;	337 Example 337: N-(( 1R,2R)-2-Acrylamidocyclopentyl)-5 -(2-i sopropylpyridin-4-yl)-4-oxo-4, 5- dihydro-3H- 1 -thia-3 .5, 8-triazaacenaphthylene-2-carboxamide. To a cooled (0 °C) solution of N-(( 1R,2R)-2-aminocyclopentyl)-5 -(2-i sopropylpyridin-4-yl)-4- oxo-4, 5 -dihydro-3H-i -thia-3 ,5, 8-triazaacenaphthylene-2-carboxamide (Example 336, 270 mg, 0.62 mmol) and DIPEA (0.08 mL, 0.74 mmol) in DCM (5 mL) was added prop-2-enoyl prop-2-enoate (0.08 mL, 0.74 mmol). The reaction mix was stirred for 5 mm. The solvent was removedunder reduced pressure and the crude mix was purified (FCC, Si02, MeOHIH2O) to afford thetitle compound (160 mg, 52%). MS (ESI): mass calcd. for C25H26N6035, 490.6; m/z found,491.2 [M+H]. ‘HNMR(400 MHz, CD3OD): ö 8.73-8.64 (m, 1H), 8.36-8.25 (m, 1H), 7.54-7.44 (m, 1H), 7.40-7.35 (m, 1H), 6.25-6.15 (m, 3H), 5.67-5.59 (m, 1H), 4.33-4.16 (m, 2H), 3.21-3.10 (m, 1H), 2.23-2.08 (m, 2H), 1.87-1.77 (m, 2H), 1.72-1.51 (m, 2H), 1.34 (d, J= 6.9 Hz, 6H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/100662, 2017, A1 Location in patent: Page/Page column 103; 321; 322
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2018/103060, 2018, A1 Location in patent: Page/Page column 320; 321

24
[ 2051-76-5 ]
[ 364385-54-6 ]
tert-butyl ((1R,2S)-2-acrylamidocyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with ice; Inert atmosphere;	To a solution of tert-butyl((1R,25)-2-aminocyclohexyl)carbamate (1.0 g, 5.0 mmol) and triethylamine (0.606 g, 5.99mmol) in DCM (10 mL) was added acrylic anhydride (824 mg, 6.53 mmol) dropwise in an icebath and was stirred at room temperature for 1 h. The reaction was diluted with DCM, washedwith HC1 (1.0 M), saturated aqueous NaHCO3, and aqueous NaC1 successively. The organic phase was collected, dried over anhydrous Na2504, and concentrated to dryness to give the title Compound (1.1 g, 87% yield) as a white solid, which was used without further purification in next reaction. MS (ESI): mass calcd. for C,3H22N203, 254.32; m/z found, 255.0 [M+Hf’.
74%	With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with ice; Inert atmosphere;	To a solution of tert-butyl((1R,2S)-2-aminocyclohexyl)carbamate (1.4 g, 6.5 mmol) and triethylamine (1.32 g, 13.1 mmol)in DCM (15 mL) was added acrylic anhydride (824 mg, 6.53 mmol) dropwise in an ice bath and was stirred at room temperature for 1 h. The reaction was washed with HC1 (0.5 M), aqueous NaHCO3, and aqueous NaC1. The organic phase was collected, dried over anhydrous Na2504, and concentrated to dryness to give the title compound (1.3 g, 74% yield) as a yellow solid,which was used without further purification in next reaction.
		To a solution of <strong>[364385-54-6]tert-butyl ((1R,2S)-2-aminocyclohexyl)carbamate</strong> (411.5 mg, 1.92 mmol) and triethylamine (291, 2.88 mmol) in DCM (5 mL) was added acrylic anhydride (208.5 mg, 2.304 mmol) dropwise in an ice bath and was stirred at room temperature for 30 minutes. The reaction was diluted with DCM, washed with HC1 (1 M), saturated aqueous NaHCO3, and brinesuccessively. The organic phase was collected and concentrated to dryness. The residue was dissolved in DCM (2 mL) and methanesulfonic acid (369 mg, 3.84 mmol) was added and was stirred at room temperature for 5 h. The reaction was concentrated to dryness to give the title compound (611 mg, 189% yield), which was used without further purification in next reaction.

Reference： [1]Patent: WO2017/100662,2017,A1 .Location in patent: Page/Page column 103; 124; 125; 126
[2]Patent: WO2018/103060,2018,A1 .Location in patent: Page/Page column 102; 125
[3]Patent: WO2018/103060,2018,A1 .Location in patent: Page/Page column 124; 125

25
[ 2051-76-5 ]
(S)-3′-aminoblebbistatin [ No CAS ]
(S)-N-(3-(3a-hydroxy-6-methyl-4-oxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-b]quinolin-1-yl)phenyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With guanidine hydrochloride In ethanol at 40℃; for 0.5h; Inert atmosphere;	4.2.3. General procedure for the amidation of anilines using acidanhydrides General procedure: The selective mono-amidation of anilines was adopted from apublication of Jahani et al. [23].In a bulb of 10 mL containing 3 mL of absolute ethanol, 0.0028 gof guanidine hydrochloride (0.0293 mmol, 0.15 equiv), acid anhydride(0.197 mmol, 1.01 equiv) and aniline (0.195 mmol, 1 equiv)were brought together under a nitrogen atmosphere. The reactionmixture was heated to 40 °C and stirred for 30 min. Next, themixture was diluted with 75 mL of ethyl acetate and washed withsaturated aqueous NaHCO3 (2 x 40 mL) and brine (30 mL). Theorganic layer was dried over magnesium sulfate and evaporated invacuo.

Reference： [1]Verhasselt, Sigrid; Roman, Bart I.; Bracke, Marc E.; Stevens, Christian V. [European Journal of Medicinal Chemistry, 2017, vol. 136, p. 85 - 103]

26
[ 2051-76-5 ]
(R)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide dihydrochloride [ No CAS ]
(R)-N-(1-acryloylpiperidin-3-yl)-5-(R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.0833333h;	661.F (R)-N-(l-Acryloylpiperidin-3-yl)-5-(R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4.5- dihvdro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide. To a round bottom flask were added (R)-5-(*S)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1- thia-3,5,8-triazaacenaphthylene-2-carboxamide-2 Hci (4.18 g, 7.29 mol), DIEPA (5.0 mL, 29 mmol), and DCM (70 mL). The reaction mixture was cooled at 0 °C, and acrylic anhydride (0.936 mL, 8.12 mmol) was added in three portions. The reaction mixture was stirred at 0 °C for 5 min, then saturated aqueous sodium bicarbonate (100 mL) was added followed by DCM (100 mL). The mixture was stirred vigorously for 10 min, then the DCM layer was separated. The aqueous layer was extracted again with DCM (50 mL). The organic layers were dried (Na2SC>4) and purified (FCC, S1O2, isocratic EtOAc). The fractions containing product were combined and concentrated to give the title compound (2.14 g, 53%) as a white solid. Absolute stereochemical configuration of the title compound was confirmed via X-ray analysis after cocrystallization with BTK protein. MS (ESI): mass calcd. for C29H26N604S, 554.17; m/z found, 555.0 [M+H]+.1H NMR (600 MHz, MeOD) δ 8.34 (d, J = 5.5 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.28 - 7.23 (m, 1H), 7.21 - 7.16 (m, 2H), 6.90 (d, J = 8.6 Hz, 1H), 6.83 - 6.74 (m, 1H), 6.23 - 6.17 (m, 1H), 6.13 (d, J = 5.5 Hz, 1H), 5.77 - 5.69 (m, 1H), 4.58 - 4.27 (m, 1H), 4.22 - 3.97 (m, 1H), 3.95 - 3.86 (m, 1H), 3.20 - 3.12 (m, 1H), 2.96 - 2.80 (m, 1H), 2.24 (s, 3H), 2.10 - 2.02 (m, 1H), 1.92 - 1.84 (m, 1H), 1.80 - 1.66 (m, 1H), 1.63 - 1.52 (m, 1H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/100668, 2017, A1 Location in patent: Page/Page column 630; 631

27
[ 2051-76-5 ]
C₃₀H₃₈FN₇O₃ [ No CAS ]
tert-butyl N-{2-[(4-[4-(5-fluoro-1-methyl-1H-indol-3-yl)-5-methylpyrimidin-2-yl]amino}-5-methoxy-2-(acrylamido)phenyl)(methyl)amino]ethyl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With triethylamine In dichloromethane at 0 - 20℃; for 1h;	1.c C. 2 - (2-acrylamido-4- (4- (5-fluoro-1-methyl-1H-indol-3-yl) -5-methylpyrimidin-2-ylamino) (Phenyl) (meth) amino) ethyl (methyl) carbamate (Compound 1) A solution of 2 - ((4- (4- (5-fluoro-1-methyl-1H-indol-3-yl) -5-methylpyrimidin-2-ylamino) Nitro-phenyl) (methyl) amino) ethyl (methyl) carbamate (5.46 g) Was added to a 500 ml single-necked flask, anhydrous methanol (300 ml) was added, Nitrogen, 10% Pd / C (400 mg) was added and the hydrogen was replaced several times at room temperature Stirring reaction 8h, After the TLC monitoring reaction was complete, the filtrate was concentrated under reduced pressure to remove the solvent to give the intermediate amine. The resulting intermediate amine was dissolved in 50 ml of dichloromethane, triethylamine (3.6 g) was added thereto, cooled to below 0 ° C, acrylic anhydride (3.7 g) was slowly added dropwise thereto, Dripping naturally rise to room temperature reaction for about 1h, TLC monitoring reaction is complete, add 100ml of water, the same amount of dichloromethane extraction 3 times, combined organic phase, anhydrous sodium sulfate drying, concentrated under reduced pressure column chromatography, dichloromethane / methanol 50/1 get the target product 2 - (2-acrylamido-4- (4- (5-fluoro-1-methyl-1H-indol-3-yl) -5-methylpyrimidin-2-ylamino) (Methyl) amino) methyl (meth) carbamate (Compound 1) (2.39 g, yield 42%).

Reference： [1]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN106995437, 2017, A Location in patent: Paragraph 0085; 0086; 0095-0097

28
[ 2051-76-5 ]
[ 1022150-12-4 ]
(R)-8-(1-acryloylpiperidin-3-yl)-10-(4-phenoxyphenyl)-3,4-dihydropyrazolo[4,3-e]pyrimido[1,2-c]pyrimidin-2(8H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
531 mg	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -20 - 10℃;Inert atmosphere;	Nitrogen, 100ml of methylene chloride was added to a 250mL three-necked flask, were added with stirring Intermediate-1:(4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine (YLTN-1)(2.00 g, 1 eq), N, N-diisopropylethylamine (1.30 g, 2.0 eq) was cooled to -20 C to 10 C. Beginning dropwise addition of acrylic anhydride (1.33g, 2eq), the temperature during the addition -10 deg.] C; dropwise, stirring continued for 20 to 30 minutes, LC-MS detection, target product formation, temperature 30 ~ 40 ,Vacuum: -0.08MPa, vacuum distillation, distillation of dichloromethane to no distillate distillation; get crude by column chromatography method, the elution ratio: methanol: ethyl acetate = 1: 5, the eluent , Temperature control 30 ~ 40 , vacuum: -0.08MPa, vacuum distillation, evaporation of solvent to no distillate distillation. A white powder of 531 mg was obtained (R)-8-(1-acryloylpiperidin-3-yl)-10-(4-phenoxyphenyl)-3,4-dihydropyrazolo[4,3-e]pyrimido[1,2-c]pyrimidin-2(8H)-one.

Reference： [1]Patent: CN106146516,2016,A .Location in patent: Paragraph 0072; 0073

29
[ 2051-76-5 ]
C₁₀H₁₁NO₅ [ No CAS ]
C₁₆H₁₅NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With dmap In methanol; chloroform at 50℃; for 1h; Inert atmosphere;	3.2 Preparation of difunctional acrylate crosslinking agents 22.1 g of the dihydroxy Diels-Alder adduct obtained in the above step (1), 23.18 g (0.19 mol) of 4-dimethylaminopyridine (DMAP) and 150 ml of trichloromethane were added successively under nitrogen atmosphere To a 250 ml three-necked flask, 35.28 g (0.28 mol) of acrylic anhydride was added thereto, and the reaction was stirred at 50 ° C for 30 minutes. To this was added 30 ml of anhydrous methanol, the reaction was continued for 30 minutes. After completion of the reaction, the resulting solution was distilled off under reduced pressure to distill off the solvent. The residue was dissolved in 250 ml of methylene chloride and washed three times with 0.1 M aqueous hydrochloric acid (100 ml). The organic phase was collected, dried over anhydrous magnesium sulfate, filtered Magnesium sulfate was removed and the dichloromethane was removed by distillation under reduced pressure to give the product as a white viscous material in 89% yield. The structure of the product was confirmed by nuclear magnetic resonance spectroscopy, and the NMR spectrum was omitted.

Reference： [1]Current Patent Assignee: HANGZHOU LONGQIN ADVANCED MATERIALS SCI TECH - CN105294936, 2017, B Location in patent: Paragraph 0052; 0055; 0056

30
[ 2051-76-5 ]
2-(2-hydroxyethyl)-4-(hydroxymethyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione [ No CAS ]
C₁₇H₁₇NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With pyridine In methanol; dichloromethane at 30℃; for 2.5h; Inert atmosphere;	2.2 Preparation of difunctional acrylate crosslinking agents 23.9 g (0.1 mol) of the dihydroxy Diels-Alder adduct obtained in the above step (1), 15.8 g (0.2 mol) of pyridine and 120 ml of dichloromethane were successively added under a nitrogen atmosphere to a 250 ml three-necked flask, After stirring and stirring, 37.8 g (0.3 mol) of acrylic anhydride was added thereto, and the reaction was stirred at 30 ° C for 2 hours. To this was added 25 ml of anhydrous methanol, the reaction was continued for 30 minutes. After completion of the reaction, the resulting solution was distilled off under reduced pressure to distill off the solvent. The residue was dissolved in 250 ml of methylene chloride and washed three times with 0.1 M aqueous hydrochloric acid (100 ml). The organic phase was collected, dried over anhydrous magnesium sulfate, filtered Magnesium sulfate was removed and the dichloromethane was removed by distillation under reduced pressure to give the product as a white viscous material in 87% yield. The structure of the product was confirmed by nuclear magnetic resonance spectroscopy, and the NMR spectrum was omitted.

Reference： [1]Current Patent Assignee: HANGZHOU LONGQIN ADVANCED MATERIALS SCI TECH - CN105294936, 2017, B Location in patent: Paragraph 0047; 0050-0051

31
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4-[3-[[7-(3-methoxy-6-methyl-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine [ No CAS ]
1-[4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.7%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -40℃; for 1h; Inert atmosphere;	43.C Step C: 1-[4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one: To a mixture of prop- 2-enoyl prop-2-enoate (56.8 mg, 450 μιηο, 0.80 eq) and DIEA (727 mg, 5.63 mmol, 983 μ,, 10.0 eq) in DCM (2.00 mL) was added a solution of 4-[3-[[7-(3-methoxy-6-methyl-l-naphthyl)- 4-piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine (300 mg, 563 μπιο, 1.00 eq) DCM (1.00 mL) at - 40°C under a nitrogen atmosphere. The mixture was stirred for 1 hour. The reaction mixture was quenched by addition of MeOH (50 iL) at -40°C, diluted with water (10.0 mL), extracted with DCM(10.0 mL), dried over Na2S04, filtered and concentrated under reduced pressure to provide l-[4-[7-(3-methoxy-6-methyl-l-naphthyl)-2-(3- morpholinopropoxy) -6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-1- one (270 mg, 460 μιηο, 81.7 % yield) ESI MS m/z 587.6 [M+H]+.
270 mg	With N-ethyl-N,N-diisopropylamine In dichloromethane at -40℃; for 1h; Inert atmosphere;	43.C Step C: 1-[4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihyd- ro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one To a mixture of prop-2-enoyl prop-2-enoate (56.8 mg, 450 μmol, 0.80 eq) and DIEA (727 mg, 5.63 mmol, 983 μL, 10.0 eq) in DCM (2.00 mL) was added a solution of 4-[3-[[7-(3-methoxy-6-methyl-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-- pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine (300 mg, 563 μmol, 1.00 eq) DCM (1.00 mL) at -40° C. under a nitrogen atmosphere. The mixture was stirred for 1 hour. The reaction mixture was quenched by addition of MeOH (50 μL) at -40° C., diluted with water (10.0 mL), extracted with DCM (10.0 mL), dried over Na 2SO 4, filtered and concentrated under reduced pressure to provide 1-[4-[7-(3-methoxy-6-methyl-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihyd- ro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one (270 mg, 460 μmol, 81.7% yield) ESI MS m/z 587.6 [M+H] +.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/201161, 2017, A1 Location in patent: Paragraph 0347
[2]Current Patent Assignee: PFIZER INC; MIRATI THERAPEUTICS, INC. - US2019/144444, 2019, A1 Location in patent: Paragraph 0619

32
[ 2051-76-5 ]
7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine bis-trifluoroacetate [ No CAS ]
1-[4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.5%	With triethylamine In dichloromethane at -78 - 0℃; for 0.5h;	52.E Step E: 1-[4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one: To a solution of 7-(3 -methoxy- 1- naphthyl)-4-piperazin-l-yl-2-[2- (l-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine bis-trifluoroacetate (145 mg, crude) and Et3N (221 mg, 2.18 mmol, 303 μ.) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (25.0 mg, 198 μιηο) at -78 °C. After stirring at 0 °C for 0.5 h, the mixture quenched with MeOH and concentrated under vacuum. The mixture was purified by column chromatography (Si02, DCM/MeOH = 10: 1) to give l-[4-[7-(3-methoxy-l- naphthyl)-2-[2-(l-piperidyl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l- yl]prop-2-en-l-one (90.0 mg, 162 μιηο, two steps 81.5 % yield) a yellow solid. ESI MS m/z 557.3 [M+H]+.
90 mg	With triethylamine In dichloromethane at -78 - 0℃; for 0.5h;	52.E Step E: 1-[4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl) ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-- en-1-one To a solution of 7-(3-methoxy-1-naphthyl)-4-piperazin-1-yl-2-[2-(1-piperidyl)ethoxy]-6,8-d- ihydro-5H-pyrido[3,4-d]pyrimidine bis-trifluoroacetate (145 mg, crude) and Et 3N (221 mg, 2.18 mmol, 303 μL) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (25.0 mg, 198 μmol) at -78° C. After stirring at 0° C. for 0.5 h, the mixture quenched with MeOH and concentrated under vacuum. The mixture was purified by column chromatography (SiO 2, DCM/MeOH=10:1) to give 1-[4-[7-(3-methoxy-1-naphthyl)-2-[2-(1-piperidyl)ethoxy]-6,8-dihydro-5H-p- yrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one (90.0 mg, 162 μmol, two steps 81.5% yield) a yellow solid. ESI MS m/z 557.3 [M+H] +.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/201161, 2017, A1 Location in patent: Paragraph 0405
[2]Current Patent Assignee: PFIZER INC; MIRATI THERAPEUTICS, INC. - US2019/144444, 2019, A1 Location in patent: Paragraph 0689

33
[ 2051-76-5 ]
2-[4-[2-[(1R)-2-(dimethylamino)-1-methylethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile [ No CAS ]
2-[4-[2-[(1R)-2-(dimethylamino)-1-methylethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36.6%	With triethylamine In dichloromethane at 0℃; for 0.5h;	152.C Step C: 2-[4-[2-[(1R)-2-(dimethylamino)-1-methylethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile: To a solution of 2-[4-[2-[(lR)-2-(dimethylamino)-l-methyl- ethoxy]-7- (5-methyl-l-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile (0.20 g, crude) and TEA (176mg, 1.74 mmol, 243 uL) in dichloromethane (1.00 mL) was added prop-2-enoyl prop-2-enoate (44.0 mg, 349 umol) at 0 °C. and the reaction stirred at 0 °C for 0.5 h. The mixture was quenched by addition of methanol (0.10 mL) and concentrated under vacuum. The residue was purified by reversed phase flash [water (Formic Acid, 0.1 %)/acetonitrile]. The collected fractions were combined and the pH adjusted to pH > 7 by addition of saturated sodium bicarbonate solution and the aqueous layer extracted with dichloromethane/methanol (10/1) (3 χ 5.00 mL). The extracts were washed with saturated sodium chloride solution (1 x 10 mL), dried over Na2S04, filtered and concentrated under vacuum to give 2-[4-[2-[(lR)-2-(dimethylamino)-l- methyl-ethoxy]-7-(5- methyl-l-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l- prop-2-enoyl-piperazin-2-yl]acetonitrile (0.10 g, 127 umol, two steps 36.6 % yield) as a yellow solid. ES+APCI MS m/z 628.6 [M+H]+.
0.1 g	With triethylamine In dichloromethane at 0℃; for 0.5h;	152.C Step C: 2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydro- pyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido [3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile To a solution of 2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydro- pyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido [3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile (0.20 g, crude) and TEA (176 mg, 1.74 mmol, 243 uL) in dichloromethane (1.00 mL) was added prop-2-enoyl prop-2-enoate (44.0 mg, 349 umol) at 0° C. and the reaction stirred at 0° C. for 0.5 h. The mixture was quenched by addition of methanol (0.10 mL) and concentrated under vacuum. The residue was purified by reversed phase flash [water (Formic Acid, 0.1%)/acetonitrile]. The collected fractions were combined and the pH adjusted to pH >7 by addition of saturated sodium bicarbonate solution and the aqueous layer extracted with dichloromethane/methanol (10/1) (3 5.00 mL). The extracts were washed with saturated sodium chloride solution (1 10 mL), dried over Na 2SO 4, filtered and concentrated under vacuum to give 2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1-tetrahydro- pyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido [3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile (0.10 g, 127 umol, two steps 36.6% yield) as a yellow solid. ES+APCI MS m/z 628.6 [M+H] +.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/201161, 2017, A1 Location in patent: Paragraph 0610
[2]Current Patent Assignee: PFIZER INC; MIRATI THERAPEUTICS, INC. - US2019/144444, 2019, A1 Location in patent: Paragraph 1001

34
[ 2051-76-5 ]
[4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl] 2,2-dimethylpropanoate trifluoroacetic acid [ No CAS ]
[4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl] 2,2-dimethylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.6%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 18℃; for 1h;	153.C Step C: [4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl] 2,2-dimethylpropanoate: To a solution of [4-[4-[3-(cyanomethyl)piperazin-l-yl]-2- ^-[(l^^^^-oxa-S-azabicycloP^. lJheptan-S-ylJpropoxyJ-e^-dihydro-SH-pyridofS^- d]pyrimidin-7-yl]-2-naphthyl] 2,2-dimethylpropanoate (140 mg, 161 umol) and DIEA (167 mg, 1.29 mmol, 225 uL) in DCM (2 mL) was added prop-2-enoyl prop-2-enoate (30.5 mg, 242 umol) at 0°C. The reaction mixture was stirred at 18 °C for 1 hour. Upon completion,the reaction mixture was quenched by addition of water (5 mL) and the aqueous layer extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by reversed flash (Base condition, MeCN/NH3*H20 in water: 50 % to 80%) to give [4-[4-[3-(cyanomethyl)-4-prop-2-enoyl- piperazin-l-yl]-2-[3-[(l,S',4)S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-7-yl]-2-naphthyl] 2,2-dimethylpropanoate (60 mg, 86.5 umol, 53.6% yield). NMR (400MHz, CHLOROFORM-d) δ = 8.22 - 8.13 (m, 1H), 7.84 - 7.78 (m, 1H), 7.56 - 7.45 (m, 2H), 7.31 (d, J=2.0 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 6.62 (br s, 1H), 6.47 - 6.37 (m, 1H), 5.92 - 5.79 (m, 1H), 5.24 - 4.88 (m, 1H), 4.75 (br s, 1H), 4.45 - 4.36 (m, 3H), 4.31 - 4.20 (m, 2H), 4.15 (br d, J=13.6 Hz, 1H), 4.10 - 4.01 (m, 2H), 3.64 (dd, J=1.6, 7.6 Hz, 2H), 3.51 (br s, 2H), 3.38 (br s, 2H), 3.14 (br s, 1H), 3.08 - 2.73 (m, 7H), 2.56 (br d, J=10.0 Hz, 1H), 2.03 - 1.93 (m, 2H), 1.88 (br d, J=9.6 Hz, 1H), 1.78 - 1.70 (m, 1H), 1.61 (s, 9H), 1.43 (s, 9H).
53.6%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 18℃; for 1h;	153.C Step C: [4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa- -5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrim- idin-7-yl]-2-naphthyl] 2,2-dimethylpropanoate To a solution of [4-[4-[3-(cyanomethyl)piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa-5-azabicyclo[2.- 2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-2-nap- hthyl] 2,2-dimethylpropanoate (140 mg, 161 umol) and DIEA (167 mg, 1.29 mmol, 225 uL) in DCM (2 mL) was added (30.5 mg, 242 umol) at 0° C. The reaction mixture was stirred at 18° C. for 1 hour. Upon completion, the reaction mixture was quenched by addition of water (5 mL) and the aqueous layer extracted with DCM (3 10 mL). The combined organic layers were dried over Na 2SO 4, filtered and concentrated under vacuum. The residue was purified by reversed flash (Base condition, MeCN/NH 3.H 2O in water: 50% to 80%) to give [4-[4-[3-(cyanomethyl)-4-prop-2-enoyl-piperazin-1-yl]-2-[3-[(1S,4S)-2-oxa- -5-azabicyclo[2.2.1]heptan-5-yl]propoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrim- idin-7-yl]-2-naphthyl] 2,2-dimethylpropanoate (60 mg, 86.5 umol, 53.6% yield). 1H NMR (400 MHz, CHLOROFORMprop-2-enoyl prop-2-enoate -d) δ=8.22-8.13 (m, 1H), 7.84-7.78 (m, 1H), 7.56-7.45 (m, 2H), 7.31 (d, J=2.0 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 6.62 (br s, 1H), 6.47-6.37 (m, 1H), 5.92-5.79 (m, 1H), 5.24-4.88 (m, 1H), 4.75 (br s, 1H), 4.45-4.36 (m, 3H), 4.31-4.20 (m, 2H), 4.15 (br d, J=13.6 Hz, 1H), 4.10-4.01 (m, 2H), 3.64 (dd, J=1.6, 7.6 Hz, 2H), 3.51 (br s, 2H), 3.38 (br s, 2H), 3.14 (br s, 1H), 3.08-2.73 (m, 7H), 2.56 (br d, J=10.0 Hz, 1H), 2.03-1.93 (m, 2H), 1.88 (br d, J=9.6 Hz, 1H), 1.78-1.70 (m, 1H), 1.61 (s, 9H), 1.43 (s, 9H).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/201161, 2017, A1 Location in patent: Paragraph 0614
[2]Current Patent Assignee: PFIZER INC; MIRATI THERAPEUTICS, INC. - US2019/144444, 2019, A1 Location in patent: Paragraph 1006

35
[ 2051-76-5 ]
7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine trifluoroacetic acid [ No CAS ]
(S)-1-(4-(7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25.7%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -50℃; for 0.5h;	155.E Step E: 1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one: To a mixture of 7- (5-methyl-lH-indazol-4-yl)-2-[[(2,S)-l-methylpyrrolidin-2-yl]methoxy]-4-piperazin-l-yl-6,8- dihydro-5H-pyrido[3,4-d]pyrimidine (250 mg, 362 umol, 2 TFA) in DCM (2 mL) was added DIEA (702 mg, 5.43 mmol, 946 uL) and the mixture cooled to -50 °C. Prop-2-enoyl prop-2- enoate (36.5 mg, 289 umol) was added in portions to the reaction at -50 °C and the mixture stirred at -50 °C for 30 minutes. After completion, the reaction mixture was quenched by addition of MeOH (1 mL) and the mixture concentrated. The residue was taken up in DCM (10 mL) and the organics washed with H2O (2 x 8 mL). The organics were dried over Na2S04, filtered and concentrated. The residue was purified by prep-HPLC ((Instrument: gx-1; Column: Phenomenex Gemini C18 25050mm 10 um; Condition: water (0.05% ammonia hydroxide v/v)-ACN; Begin B: 32; End B: 62; Gradient Time (min): 12; 100%B Hold Time (min): 2; FlowRate (ml/min): 25) to give l-[4-[7-(5-methyl-lH-indazol-4-yl)-2-[[(25)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l- yl]prop-2-en-l-one (48.6 mg, 92.9 umol, 25.7% yield, 98.7% purity) as yellow solid. ES+APCI MS m/z 517.5 [M+H]+.
48.6 mg	With N-ethyl-N,N-diisopropylamine In dichloromethane at -50℃; for 0.5h;	155.E Step E: 1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]metho- xy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-- one To a mixture of 7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-4-- piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (250 mg, 362 umol, 2TFA) in DCM (2 mL) was added DIEA (702 mg, 5.43 mmol, 946 uL) and the mixture cooled to -50° C. Prop-2-enoyl prop-2-enoate (36.5 mg, 289 umol) was added in portions to the reaction at -50° C. and the mixture stirred at -50° C. for 30 minutes. After completion, the reaction mixture was quenched by addition of MeOH (1 mL) and the mixture concentrated. The residue was taken up in DCM (10 mL) and the organics washed with H 2O (2 8 mL). The organics were dried over Na 2SO 4, filtered and concentrated. The residue was purified by prep-HPLC ((Instrument: gx-1; Column: Phenomenex Gemini C18 25050 mm10 um; Condition: water (0.05% ammonia hydroxide v/v)-ACN; Begin B: 32; End B: 62; Gradient Time (min): 12; 100% B Hold Time (min): 2; FlowRate (ml/min): 25) to give 1-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]metho- xy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-- one (48.6 mg, 92.9 umol, 25.7% yield, 98.7% purity) as yellow solid. ES+APCI MS m/z 517.5 [M+H] +.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/201161, 2017, A1 Location in patent: Paragraph 0625
[2]Current Patent Assignee: PFIZER INC; MIRATI THERAPEUTICS, INC. - US2019/144444, 2019, A1 Location in patent: Paragraph 1019

36
[ 2051-76-5 ]
N,N-diethyl-2-[[7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]ethanamine dihydrochloride [ No CAS ]
1-[4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -40℃; for 1h; Inert atmosphere;	163.C Step C: 1-[4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one: To a mixture of N,N-diethyl-2-[[7-[5-methyl-l-(2- trimethylsilyl ethoxymethyl)indazol-4-yl]-4-piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-2-yl]oxy]ethanamine (105 mg, 158 umol, 2 HC1) and DIEA (204 mg, 1.58 mmol, 276 uL) in DCM (8 mL) at - 40°C was added a solution of prop-2-enoyl prop-2-enoate (15.9 mg, 126.4 umol) in DCM (2 mL) under nitrogen atmosphere and the reaction stirred for 1 hour. The reaction mixture was quenched by addition NaHCCb (500 uL) at - 40°C, and then diluted with water (10 mL). The aqueous layer was extracted with DCM (10 ml), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 0- 20% MeOH/DCM as eluent to give l-[4-[2-[2- (diethylamino)ethoxy]- 7-[5-methyl-l-(2-trimethylsilylethoxymethyl)indazol-4-yl]-6,8-dihydro- 5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one (60.0 mg, 71.2 umol, 45.0 % yield). ES+APCI MS m/z 649.3 [M+H]+.
45%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -40℃; for 1h; Inert atmosphere;	163.C Step C: 1-[4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymet- hyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-y- l]prop-2-en-1-one To a mixture of N,N-diethyl-2-[[7-[5-methyl-1-(2-trimethylsilyl ethoxymethyl)indazol-4-yl]-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]p- yrimidin-2-yl]oxy]ethanamine (105 mg, 158 umol, 2 HCl) and DIEA (204 mg, 1.58 mmol, 276 uL) in DCM (8 mL) at -40° C. was added a solution of prop-2-enoyl prop-2-enoate (15.9 mg, 126.4 umol) in DCM (2 mL) under nitrogen atmosphere and the reaction stirred for 1 hour. The reaction mixture was quenched by addition NaHCO 3 (500 uL) at -40° C., and then diluted with water (10 mL). The aqueous layer was extracted with DCM (10 ml), dried over Na 2SO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 0 20% MeOH/DCM as eluent to give 1-[4-[2-[2-(diethylamino)ethoxy]-7-[5-methyl-1-(2-trimethylsilylethoxymet- hyl)indazol-4-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-y- l]prop-2-en-1-one (60.0 mg, 71.2 umol, 45.0% yield). ES+APCI MS m/z 649.3 [M+H] +.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/201161, 2017, A1 Location in patent: Paragraph 0644
[2]Current Patent Assignee: PFIZER INC; MIRATI THERAPEUTICS, INC. - US2019/144444, 2019, A1 Location in patent: Paragraph 1046

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[ 2051-76-5 ]
4-[3-[[7-(2-fluoro-3-methoxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine trifluoroacetic acid [ No CAS ]
1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65.5%	With triethylamine In dichloromethane at -40℃; for 0.5h;	165.H Step H: 1-[4-[7-(2-fluoro-3-methoxy-1-naphthyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one: To a solution of 4-[3-[[7-(2- fluoro-3-methoxy-l-naphthyl)-4- piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2- yl]°xy]ProPyl]m^h°lme (0.41 g, crude, TFA salt) and TEA (635 mg, 6.27 mmol, 873 uL) in dichloromethane (5.0 mL) was added prop-2-enoyl prop-2-enoate (79.1 mg, 627 umol) at - 40 °C. After stirring at - 40 °C for 0.5 h, the mixture was quenched with methanol (0.10 mL) and concentrated under vacuum. The residue was purified by column chromatography (AI2O3, dichloromethane/methanol = 10/1) to give l-[4-[7-(2-fluoro-3-methoxy-l-naphthyl)-2-(3- mo holinopropoxy)-6,8- dihydro-5H-pyrido[3,4-+.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/201161, 2017, A1 Location in patent: Paragraph 0656

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[ 2051-76-5 ]
2-methyl-4-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1,3-benzothiazol-6-ol dihydrochloride [ No CAS ]
1-[4-[7-(6-hydroxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30.2%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -50 - -20℃; for 0.5h;	166.I Step I: 1-[4-[7-(6-hydroxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-one: To a solution of 2-methyl-4-[2-(3-morpholinopropoxy)-4-piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-7-yl]-l,3-benzothiazol-6-ol (110 mg, 184 umol, 2 HCl) and DIEA (143 mg, 1.10 mmol, 193 uL) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (18.5 mg, 147 umol) dropwise at - 50 °C. The mixture was stirred at -40 - -20 °C for 30 minutes. Upon completion, the mixture was quenched by MeOH (0.5 mL) and concentrated under vacuum. The residue was diluted with water (2 mL) and extracted with DCM (3 x 6 mL). The organic layers were dried over Na2S04 and concentrated under vacuum. The residue was purified by column chromatography over AI2O3 (DCM/MeOH 20/1 to 10/1), prep-HPLC (column: Gemini 150*25 5u;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 21%-51%,12min) to give l-[4-[7-(6-hydroxy-2-methyl-l,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one (32.4 mg, 55.4 umol, 30.2 % yield, 99.1 % purity) as a yellow solid. ES+APCI MS m/z 580.4[M+H]+.
32.4 mg	With N-ethyl-N,N-diisopropylamine In dichloromethane at -50 - -20℃; for 0.5h;	166.I Step I: 1-[4-[7-(6-hydroxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy- )-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-on- e To a solution of 2-methyl-4-[2-(3-morpholinopropoxy)-4-piperazin-1-yl-6,8-dihydro-5H-pyrid- o[3,4-d]pyrimidin-7-yl]-1,3-benzothiazol-6-ol (110 mg, 184 umol, 2 HCl) and DIEA (143 mg, 1.10 mmol, 193 uL) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (18.5 mg, 147 umol) dropwise at -50° C. The mixture was stirred at -40--20° C. for 30 minutes. Upon completion, the mixture was quenched by MeOH (0.5 mL) and concentrated under vacuum. The residue was diluted with water (2 mL) and extracted with DCM (3 6 mL). The organic layers were dried over Na 2SO 4 and concentrated under vacuum. The residue was purified by column chromatography over Al 2O 3(DCM/MeOH 20/1 to 10/1), prep-HPLC (column: Gemini 150*25 5 u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 21%-51%,12 min) to give 1-[4-[7-(6-hydroxy-2-methyl-1,3-benzothiazol-4-yl)-2-(3-morpholinopropoxy- )-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl]prop-2-en-1-on- e (32.4 mg, 55.4 umol, 30.2% yield, 99.1% purity) as a yellow solid. ES+APCI MS m/z 580.4[M+H] +.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/201161, 2017, A1 Location in patent: Paragraph 0669
[2]Current Patent Assignee: PFIZER INC; MIRATI THERAPEUTICS, INC. - US2019/144444, 2019, A1 Location in patent: Paragraph 1074

39
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2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile [ No CAS ]
2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 10℃; for 4h;	170.G Step G: 2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile: To a solution of 2-[4-[7-(3-benzyloxy-l-naphthyl)-2-[2- (dimethylamino)ethoxy]- 6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile (60 mg, 104 umol) and DIEA (67.1 mg, 519 umol, 90.7 uL) in DCM (2 mL) was added prop-2-enoyl prop-2-enoate (13.1 mg, 104 umol) at 0 °C. After stirred at 10 °C for 4 hours, the mixture was quenched with MeOH (0.1 mL), then concentrated under vacuum. The residue was purified by column chromatography (S1O2, DCM/MeOH 10/1) to give 2-[4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)ethoxy] - 6,8-dihydro-5H-pyrido [3,4-d]pyrimidin-4-yl]-l-prop-2-enoyl-piperazin-2-yl]acetonitrile (40.0 mg, 63.3 umol, 61.0 % yield) as a yellow oil. ES+APCI MS m/z 632.3[M+H]+.
61%	In dichloromethane Alkaline conditions; Cooling;	170.G Step G: 2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-- 5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile To a solution of 2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-- 5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile (60 mg, 104 umol) and DIEA (67.1 mg, 519 umol, 90.7 uL) in DCM (2 mL) was added prop-2-enoyl prop-2-enoate (13.1 mg, 104 umol) at 0° C. After stirred at 10° C. for 4 hours, the mixture was quenched with MeOH (0.1 mL), then concentrated under vacuum. The residue was purified by column chromatography (SiO 2, DCM/MeOH 10/1) to give 2-[4-[7-(3-benzyloxy-1-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-- 5H-pyrido [3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitril- e (40.0 mg, 63.3 umol, 61.0% yield) as a yellow oil. ES+APCI MS m/z 632.3[M+H] +.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/201161, 2017, A1 Location in patent: Paragraph 0697
[2]Current Patent Assignee: PFIZER INC; MIRATI THERAPEUTICS, INC. - US2019/144444, 2019, A1 Location in patent: Paragraph 1106

40
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tert-butyl (5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethylpyrrolidine-1-carboxylate [ No CAS ]
tert-butyl (5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.6%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -40℃; for 1h; Inert atmosphere;	174.D Step D: tert-Butyl (5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate: To a mixture of tert-butyl (5R)-5-[[7-(3-hydroxy-l-naphthyl)-4- piperazin-l-yl- 6,8-dihydro-5H-pyrido[3,4-
98.6%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -40℃; for 1h; Inert atmosphere;	174.D Step D: tert-Butyl (5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-di- hydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1- -carboxylate To a mixture of tert-butyl (5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-piperazin-1-yl-6,8-dihydro-5H-pyrido[- 3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (130 mg, 221 umol) and DIEA (285 mg, 2.21 mmol, 385 uL) in dichloromethane (3 mL) was added a solution of prop-2-enoyl prop-2-enoate (22.3 mg, 176 umol) in dichloromethane (1 mL) at -40° C. under nitrogen atmosphere. The mixture was stirred at -40° C. for 1 hour. The reaction was quenched by addition of saturated NaHCO 3 (2 mL) aqueous solution. Then the mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL 2). The combined organics was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO 2, dichloromethane/methanol=1/0 to 10/1). tert-Butyl (5R)-5-[[7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)-6,8-di- hydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]-2,2-dimethyl-pyrrolidine-1- -carboxylate (140 mg, 217 umol, 98.6% yield) was obtained as a brown oil. ES+APCI MS m/z 643.6 [M+H] +.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/201161, 2017, A1 Location in patent: Paragraph 0726
[2]Current Patent Assignee: PFIZER INC; MIRATI THERAPEUTICS, INC. - US2019/144444, 2019, A1 Location in patent: Paragraph 1139

41
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(1S,4S)-5-(3-((7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)propyl)-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]
1-(4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28.3%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -40 - -20℃; for 0.5h;	181.D Step D: 1-(4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one: To a solution of (IS, 4,S)-5-(3-((7-(5-methyl-lH-indazol-4-yl)-4-(piperazin-l-yl)-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)propyl)-2-oxa-5-azabicyclo[2.2. l]heptane (20 mg, 39.6 umol, 1 eq) and DIEA (30.7 mg, 238 umol, 41.4 uL, 6 eq) in DCM (2 mL) was added prop-2-enoyl prop-2-enoate (4.00 mg, 31.7 umol, 0.8 eq) at -50 °C. The mixture was stirred at - 40 - -20 °C for 0.5 hour. The mixture was concentrated under vacuum. The obtained product was purified by prep-HPLC (column: Phenomenex Gemini 15025mm 10um;mobile phase: [water (0.05% ammonia hydroxide v/v)-AC ];B%: 35%-65%,12min). The product l-(4-(2-(3- ((l,S',4)S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-methyl-lH-indazol-4-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l-yl)prop-2-en-l-one (6.48 mg, 11.2 umol, two steps 28.3 % yield, 96.8 % purity) was obtained as white solid. ES+APCI MS m/z 559.5[M+H]+.
6.48 mg	With N-ethyl-N,N-diisopropylamine In dichloromethane for 0.5h; Cooling;	181.D Step D. 1-(4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-me- thyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pipera- zin-1-yl)prop-2-en-1-one To a solution of (1S,4S)-5-(3-((7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)-5,6,7,8-te- trahydropyrido[3,4-d]pyrimidin-2-yl)oxy)propyl)-2-oxa-5-azabicyclo[2.2.1]h- eptane (20 mg, 39.6 umol, 1 eq) and DIEA (30.7 mg, 238 umol, 41.4 uL, 6 eq) in DCM (2 mL) was added prop-2-enoyl prop-2-enoate (4.00 mg, 31.7 umol, 0.8 eq) at -50° C. The mixture was stirred at -40--20° C. for 0.5 hour. The mixture was concentrated under vacuum. The obtained product was purified by prep-HPLC (column: Phenomenex Gemini 15025 mm10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 35%-65%,12 min). The product 1-(4-(2-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy)-7-(5-me- thyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pipera- zin-1-yl)prop-2-en-1-one (6.48 mg, 11.2 umol, two steps 28.3% yield, 96.8% purity) was obtained as white solid. ES+APCI MS m/z 559.5[M+H] +.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2017/201161, 2017, A1 Location in patent: Paragraph 0767
[2]Current Patent Assignee: PFIZER INC; MIRATI THERAPEUTICS, INC. - US2019/144444, 2019, A1 Location in patent: Paragraph 1187

42
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[ 141-43-5 ]
[ 7646-67-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: ethanolamine With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; 10H-phenothiazine In acetonitrile Electric arc; Stage #2: acrylic acid anhydride In acetone at 25 - 50℃; for 2h;	2 Example 2 Preparation of N-hydroxyethyl acrylamide The reaction flask was added ethanolamine 45.8g (0.75mol), acetonitrile 100mL,Phenothiazine 0.3g and TEMPO 0.15g, open electric stirring,Cool the cold water and control the dropping speed. Slowly add 94.5g (0.75mol) of acrylic anhydride to keep the temperature of the reaction solution at 25-35 . The addition was completed, heated to 50 heat continued reaction 2h. The mixture was distilled under reduced pressure to remove the solvent acetonitrile. Then, the mixture was distilled under reduced pressure to obtain 65.5 g of N-hydroxyethylacrylamide. The yield was 76% and the purity was 97% (GC test value).

Reference： [1]Current Patent Assignee: SHANDONG RBL CHEMICALS CO LTD - CN107245039, 2017, A Location in patent: Paragraph 0017; 0018; 0019; 0020; 0021; 0022

43
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C₂₁H₂₁F₂N₅O₂ [ No CAS ]
1-(1-(prop-2-enoyl)piperidin-3-yl)-5-amino-3-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51.8%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -20℃; for 2.5h;	6 Example 6: Preparation of 1-(1-(prop-2-enoyl)piperidin-3-yl)-5-amino-3-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazole-4-carboxamide (compound 6b) Synthesis of Compound 5b Referring to the above Examples 1 to 3, the synthesis of compound 6b was as follows:In a dry 10 L three-necked flask were sequentially added Compound 5b (413 g, 1.0 mol)4 L of dichloromethane and diisopropylethylamine (DIEA) (323 g, 2.5 mol),To be dissolved after cooling to an internal temperature of -20 .Acrylic anhydride (126 g, 1.0 mol) was slowly added dropwise with a constant pressure funnelAnd methylene chloride (1 L) for 1.5 hours. After the reaction was continued for 1 hour.Sent to HPLC monitoring reaction, the reaction was completed, the reaction flask was added 2L of water, stirred for 1 hour,The organic phase was taken out, washed once with saturated citric acid solution (2L), twice with water (2L / time), stirred with anhydrous sodium sulfate, filtered and the filtrate was concentrated. The crude product was beaten with ethyl acetate,Compound 6b (242 g, 51.8%) was obtained with a HPLC purity of 98.5%.

Reference： [1]Current Patent Assignee: SHOUYAO HOLDINGS BEIJING CO LTD - CN105884747, 2016, A Location in patent: Paragraph 0106-0109

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1,2,3,4,6-pentabenzyl-D-galactose [ No CAS ]
6-O-acryloyl-1,2,3,4-O-tetrabenzyl-D-galactose [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54.5%	With boron trifluoride In dichloromethane at -15℃; for 10h; Inert atmosphere;	1 Example 1 6-0-acryloyl-1,2,3,4-O-tetrabenzyl-D-galactose 1,2,3,4,6-pentabenzyl-D-galactose (117 mg, 0.185 mmol) was dissolved in dichloromethane (1.5 mL), under nitrogen protection, acrylic anhydride (0.127 mL, 1.112 mmol) was added, placed at -15°C, BF3 (23 μL, 0.185 mmol) was slowly added, and reacted at -15°C for 10 h. After the reaction was completed, the mixture is quenched with saturated sodium bicarbonate, extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride, dried over anhydrous MgSCU, and subjected to rotary evaporation and column chromatography to obtain 6-0-acryloyl-1,2,3. 4-0-tetrabenzyl-D-galactose (60 mg, 54.5%)

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY - CN104387426, 2018, B Location in patent: Paragraph 0024-0026

45
[ 2051-76-5 ]
[ 4081-00-9 ]
spiro[9H-fluorene-9,9'-xanthene]-3',6'-diacrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.7%	Stage #1: spiro[fuoroline-9,9'-(2',7'-dihydroxyxanthone)] With dmap; triethylamine In dichloromethane at 0℃; for 0.5h; Stage #2: acrylic acid anhydride In dichloromethane at 0℃; for 5h;	6 example 6 Into a 250 ml three-necked flask, add 100 ml of dichloromethane solvent, add spiro [9H-fluorene-9,9'-[9H] xanthene]-3',6'-diphenol 3.64g (O.O1mol) and triethylamine 4.0g (0.04mol) respectively, stir until dissolved, after that add catalyst 4-dimethylaminopyridine 0.12g (0.001mol), stir and dissolve at 0°C for 30 minutes, after that slowly added the drops of Acrylic anhydride 3.78g (0.03mol) of dichloromethane solution, carry on reaction at 0 °C for 5h, add 100ml water to wash for 30min, separate the organic phase, dry over anhydrous sodium sulfate, remove the solvent, and re-crystallize the crude product, obtained white solid 4.47g, yield is 94.7%. Melting point: 169.6-172.5 °C, refractive index nD = 1.626 (25 °C).

Reference： [1]Current Patent Assignee: CHANGZHOU HIGH TECH RESEARCH INSTITUTE OF NANJING - CN108033941, 2018, A Location in patent: Paragraph 0044; 0045

46
[ 2051-76-5 ]
C₁₂H₂₅N₃O₂ [ No CAS ]
[ 5117-12-4 ]
[ 3845-76-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,6-di-tert-butyl-4-methyl-phenol; In 5,5-dimethyl-1,3-cyclohexadiene; at 140 - 145℃; for 1.0h;	Under argon protection,2.77 g of morpholinylpropionylpropanediamine,25 ml of xylene,1.72 grams of acrylic anhydride,And 0.05 g of polymerization inhibitor BHT mixed,The reaction was heated at 140-145 C for about 1 hour.Recovery of xylene under reduced pressure,The crude product obtained was washed with a 1/1-3/1 volume ratio of ethyl acetate/hexanes to afford 1.39 g of acryl dimethyl propyldiamine and 1.17 g of acryloyl morpholine.

Reference： [1]Patent: CN108164477,2018,A .Location in patent: Paragraph 0021

47
[ 2051-76-5 ]
[ 721395-15-9 ]
tert-butyl ((1R,2S)-2-acrylamidocyclopentyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with ice; Inert atmosphere;	To a solution of tert-butyl((1R,2g)-2-aminocyclohexyl)carbamate (1.0 g, 5.0 mmol) and triethylamine (0.606 g, 5.99 mmol)in DCM (10 mL) was added acrylic anhydride (824 mg, 6.53 mmol) dropwise in an ice bath andwas stirred at room temperature for 1 h. The reaction was diluted with DCM, washed with HC1(1.0 M), saturated aqueous NaHCO3, and aqueous NaC1 successively. The organic phase wascollected, dried over anhydrous Na2504, and concentrated to dryness to give the title compound(1.1 g, 87% yield) as a white solid, which was used without further purification in next reaction.MS (ESI): mass calcd. for C13H22N203, 254.32; m/z found, 255.0 [M+H].

Reference： [1]Patent: WO2018/103060,2018,A1 .Location in patent: Page/Page column 102; 123

48
[ 2051-76-5 ]
4-(6-chloro-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-8-fluoro-2-(2-morpholinoethoxy)quinazolin-7-yl)-5-methylbenzo[d]isoxazol-3-amine [ No CAS ]
1-((2R,5S)-4-(7-(3-amino-5-methylbenzo[d]isoxazol-4-yl)-6-chloro-8-fluoro-2-(2-morpholinoethoxy)quinazolin-4-yl)-2,5-dimethylpiperazin-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With triethylamine In dichloromethane at 0℃; for 0.25h;	4 1-((2R,5S)-4-(7-(3-amino-5-methylbenzo[d]isoxazol-4-yl)-6-chloro-8-fluoro-2-(2-morpholinoethoxy)quinazolin-4-yl)-2,5-dimethylpiperazin-1-yl)prop-2-en-1-one (4E) To a stirred solution of compound 4D (90 mg, 0.16 mmol) in DCM (30 mL) at 0 °C were added Et3N (80 mg, 0.79 mmol) and acrylic anhydride (20 mg, 0.16 mmol). The mixture was stirred at 0 °C for 15 min. The mixture was extracted with DCM and NaHCO3. The solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product (50 mg, 51%). ESI-MS m/z: 624.2 [M+H]+; 1H NMR (400 MHz, DMSO-i) δ: 7.95 (s, 1H), 7.55 (dd, J= 8.4, 16.2 Hz, 2H), 6.8 (m, 1H) 6.2 (m, 1H), 5.75 (m, 1H), 5.2-5.1 (m, 2H), 4.8-4.7 (m, 2H), 4.6-4.4 (m, 3H), 4.2-4.05 (m, 2H), 4.0-3.75 (m, 3H), 3.7-3.5 (m, 6H), 2.8-2.65 (m, 2H), 2.2-2.1 (m, 3H), 1.3-1.2 (m, 6H).

Reference： [1]Current Patent Assignee: ARAXES PHARMA LLC - WO2018/218070, 2018, A2 Location in patent: Page/Page column 179; 180

49
[ 2051-76-5 ]
6-chloro-7-(3-cyclopropyl-5-methyl-1H-indazol-4-yl)-N-(1-cyclopropylpiperidin-4-yl)-8-fluoro-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)quinazolin-2-amine [ No CAS ]
1-((2R,5S)-4-(2-(1-cyclopropylpiperidin-4-ylamino)-6-chloro-7-(3-cyclopropyl-5-methyl-1H-indazol-4-yl)-8-fluoroquinazolin-4-yl)-2,5-dimethylpiperazin-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With triethylamine In dichloromethane at 0℃; for 0.5h;	6 1-((2R,5S)-4-(2-(1-cyclopropylpiperidin-4-ylamino)-6-chloro-7-(3-cyclopropyl-5-methyl-1H-indazol-4-yl)-8-fluoroquinazolin-4-yl)-2,5-dimethylpiperazin-1-yl)prop-2-en-1-one (6G) To a solution of 6-chloro-7-(3-cyclopropyl-5-methyl-1H-indazol-4-yl)-N-(1-cyclopropylpiperidin-4-yl)-8-fluoro-4-((2S,5R)-2,5-dimethylpiperazin-l-yl)quinazolin- 2-amine(l . lg, 1.83 mmol) in DCM (10 mL) at 0 °C, acrylic anhydride (242.13 mg, 1.92 mmol) and Et3N (554.49 mg, 5.49 mmol) were added. The mixture was stirred for 0.5 h. The mixture was extracted with EA, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desire product (480 mg, 62% yield). ESI-MS m/z: 658.2 [M+H]+.

Reference： [1]Current Patent Assignee: ARAXES PHARMA LLC - WO2018/218070, 2018, A2 Location in patent: Page/Page column 185; 187

50
[ 2051-76-5 ]
C₈H₁₅O^(1-)*Cl^(1-)*Mg⁽²⁺⁾ [ No CAS ]
[ 251909-25-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	With 10H-phenothiazine In tetrahydrofuran at 15 - 20℃; for 7h; Inert atmosphere;	2 The specific experimental procedures of this example are as follows. To a 2 L four-neck reaction flask, tetrahydrofuran THF (1000 g) was added, and the internal temperature was lowered to 0 ± 5 ° C by an ethanol dry ice bath, controlled at 0 ± 5 ° C by chloroethane (329g, and cooled to -30 ± 5 °C, After 1.5 hours of ventilation, the solution was ready for use. Magnesium (or Magnesium powsder) (59.4g) and THF (80g) were added to a 2L four-neck reaction flask, protected by nitrogen, then dropwise addition of 1,2-dibromoethane for initiation. A large number of bubbles appeared in the reaction flask, and a sharp exotherm occurred, and the reaction liquid was black. was cooled to 35 ± 5 ° C, the temperature of the system was stabilized at 35 ± 5 ° C, and the THF solution of methyl chloride was added dropwise, and the mixture was dropped in about 2 hours. Then the system was cooled to -10 ± 5 ° C, and cyclohexanone (200 g) was added dropwise. The dropping temperature was controlled at-10 ± 5 ° C. The reaction liquid was black at the beginning, and then slowly became gray and sticky. After 60 minutes of dropwise addition, maintain a reaction at -10 ± 5 °C for 2 hours (central control 1, raw material control was qualified, the temperature was raised to 15 ± 5 ° C, phenothiazine was added, and acrylic anhydride was added dropwise. When adding dropwise, the reaction liquid gradually changed from black to black green, and the addition was completed in about 1 hour, and the reaction was carried out at room temperature for 6 hours. At the time of dropwise addition, the reaction liquid gradually changed from black to black-green, and the addition was completed in about 1 hour, and the reaction was carried out at room temperature for 6 hours (central control 2, intermediate ≤ 5%). After the completion of the reaction, a 5% hydrochloric acid solution (80 g of 36% hydrochloric acid, 496 g of water) was added dropwise while maintaining the temperature at 20 ° C, stirred for 15 min, and the layers were separated, and the lower aqueous layer was retained as a waste acid. The upper organic layer was added with 5% sodium hydroxide solution (22.5 g NaOH 422.5 g water), Adjusted ΡΗ=8~9, control the temperature below 20 °C, the layers were separated, the lower aqueous layer was retained as a waste alkali. The upper organic phase was dried by adding 50 g of anhydrous sodium sulfate, and the water was taken for sampling (central control 3, moisture ≤ 5%). The aqueous layers were combined, 200 g of ethyl acetate was added, and the mixture was stirred for 15 minutes, and the layers were separated. The upper organic phase was dried by adding 30 g of anhydrous sodium sulfate, and the sample was measured for moisture (central control 4, moisture ≤ 5%). [0048] The organic phase (THF) was transferred to a 2L single-mouth bottle, and 3 g of phenothiazine was added thereto. The temperature of the water bath was controlled at 30 to 40 ° C, and concentrated to obtain a brownish yellow liquid(central control 5, Solvent residues ≤ 6%). The organic phase (ethyl actetate) was transferred to a 500 mL single-mouth bottle, and 1 g of phenothiazine was added thereto. The temperature of the water bath was controlled at 30 to 40 ° C,and concentrated to obtain a brownish yellow liquid (central control 6, Solvent residues ≤ 6%). The organic phases were combined for crude product. The crude product was transferred to a 500 mL single-mouth bottle and supplemented with 1g phenothiazine, and subjected to vacuum distillation using a 20 cm glass spring packed column. When the oil bath was at 50 ° C and the top temperature is at 24 to 26 ° C, the fraction was taken out. The oil bath was heated to 60 ° C. After the top temperature was stabilized at 34 ° C for 5 minutes, the main fraction was taken to obtain a colorless transparent liquid of 237 g. (central control 7, GC ≤ 6%). Yield 69%.

Reference： [1]Current Patent Assignee: XUZHOU B&C CHEMICAL CO LTD - CN109232243, 2019, A Location in patent: Paragraph 0051-0062

51
[ 2051-76-5 ]
C₇H₁₃O^(1-)*Cl^(1-)*Mg⁽²⁺⁾ [ No CAS ]
Propenoic acid methyl cyclohexyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With 10H-phenothiazine In tetrahydrofuran at 15 - 20℃; for 7h; Inert atmosphere;	1 The specific experimental procedures of this example are as follows. To a 2 L four-neck reaction flask, tetrahydrofuran THF (1000 g) was added, and the internal temperature was lowered to 0 ± 5 ° C by an ethanol dry ice bath, controlled at 0 ± 5 ° C by Chloromethane (257.3g), and cooled to -30 ± 5 °C, After 1.5 hours of ventilation, the solution was ready for use. [0044] Magnesium (or Magnesium powsder) (59.4g) and THF (80g) were added to a 2L four-neck reaction flask, protected by nitrogen, then dropwise addition of 1,2-dibromoethane for initiation. A large number of bubbles appeared in the reaction flask, and a sharp exotherm occurred, and the reaction liquid was black. was cooled to 35 ± 5 ° C, the temperature of the system was stabilized at 35 ± 5 ° C, and the THF solution of methyl chloride was added dropwise, and the mixture was dropped in about 2 hours. [0045] Then the system was cooled to -10 ± 5 ° C, and cyclohexanone (200 g) was added dropwise. The dropping temperature was controlled at-10 ± 5 ° C. The reaction liquid was black at the beginning, and then slowly became gray and sticky. After 60 minutes of dropwise addition, maintain a reaction at -10 ± 5 °C for 2 hours (central control 1, raw material control was qualified, the temperature was raised to 15 ± 5 ° C, phenothiazine was added, and acrylic anhydride was added dropwise. When adding dropwise, the reaction liquid gradually changed from black to black green, and the addition was completed in about 1 hour, and the reaction was carried out at room temperature for 6 hours. At the time of dropwise addition, the reaction liquid gradually changed from black to black-green, and the addition was completed in about 1 hour, and the reaction was carried out at room temperature for 6 hours (central control 2, intermediate ≤ 5%). , [0046] After the completion of the reaction, a 5% hydrochloric acid solution (80 g of 36% hydrochloric acid, 496 g of water) was added dropwise while maintaining the temperature at 20 ° C, stirred for 15 min, and the layers were separated, and the lower aqueous layer was retained as a waste acid. The upper organic layer was added with 5% sodium hydroxide solution (22.5 g NaOH 422.5 g water), Adjusted ΡΗ=8~9, control the temperature below 20 °C, the layers were separated, the lower aqueous layer was retained as a waste alkali. The upper organic phase was dried by adding 50 g of anhydrous sodium sulfate, and the water was taken for sampling (central control 3, moisture ≤ 5%). [0047] The aqueous layers were combined, 200 g of ethyl acetate was added, and the mixture was stirred for 15 minutes, and the layers were separated. The upper organic phase was dried by adding 30 g of anhydrous sodium sulfate, and the sample was measured for moisture (central control 4, moisture ≤ 5%). [0048] The organic phase (THF) was transferred to a 2L single-mouth bottle, and 3 g of phenothiazine was added thereto. The temperature of the water bath was controlled at 30 to 40 ° C, and concentrated to obtain a brownish yellow liquid(central control 5, Solvent residues ≤ 6%). [0049] The organic phase (ethyl actetate) was transferred to a 500 mL single-mouth bottle, and 1 g of phenothiazine was added thereto. The temperature of the water bath was controlled at 30 to 40 ° C,and concentrated to obtain a brownish yellow liquid (central control 6, Solvent residues ≤ 6%). The organic phases were combined for crude product. [0050] The crude product was transferred to a 500 mL single-mouth bottle and supplemented with 1g phenothiazine, and subjected to vacuum distillation using a 20 cm glass spring packed column. When the oil bath was at 50 ° C and the top temperature is at 24 to 26 ° C, the fraction was taken out. The oil bath was heated to 60 ° C. After the top temperature was stabilized at 34 ° C for 5 minutes, the main fraction was taken to obtain a colorless transparent liquid of 237 g. (central control 7, GC ≤ 6%). Yield 69%.

Reference： [1]Current Patent Assignee: XUZHOU B&C CHEMICAL CO LTD - CN109232243, 2019, A Location in patent: Paragraph 0039-0050

52
[ 2051-76-5 ]
N,N-bis(2-hydroxyethyl)octadeca-9,11,13-trienamide [ No CAS ]
C₂₈H₄₃NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With dmap In dichloromethane at 0 - 30℃; for 19h;	1.2 (2) In a 500 mL three-necked flask, 0.4 mol of the first step product EDEA obtained in the step (1) and 45 mmol of dimethylaminopyridine were dissolved in 250 mL of dichloromethane, and 0.1 mol of acrylic anhydride was slowly added in an ice water bath, and stirred. Slowly heating to 30 ° C, the reaction is continued for 19 h, the reaction solution after the end of the reaction is added to an aqueous solution of sodium hydrogencarbonate, and then stirred vigorously for 30 min, and then the organic layer is repeatedly washed with sodium hydrogen carbonate solution and NaCl solution to extract the organic phase. The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed by rotary evaporation.Get a light yellow liquid MEAM,Its yield was 99%.

Reference： [1]Current Patent Assignee: SOUTH CHINA AGRICULTURAL UNIVERSITY - CN109776347, 2019, A Location in patent: Paragraph 0024; 0027; 0029

53
[ 2051-76-5 ]
[ 132834-58-3 ]
1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.79%	With triethylamine; In dichloromethane; at 20 - 30℃; for 1h;	A solution of Int-A18 (1 g, 4.32 mmol, 1 equiv), prop-2-enoyl prop-2-enoate (600 mg, 4.76 mmol, 1.10 equiv) and TEA (1.3 g, 12.85 mmol, 2.97 equiv) in DCM (50 mL) was stirred for 1 h at room temperature. The resulting solution was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc/petroleum ether (1:1) to afford 750 mg (60.79%) of the title compound as a white solid. LCMS (ESI, m/z): 286.11 [M+H]+

Reference： [1]Patent: US2019/330194,2019,A1 .Location in patent: Paragraph 1884

54
[ 745066-18-6 ]
[ 2051-76-5 ]
1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.6%	With triethylamine In dichloromethane at -40℃; for 0.5h;	561.1 Step 1: 1-(4-(5-Trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-en-1-one A solution of Int-A2 (300 g, 1.1 mol, 1 equiv), prop-2-enoyl prop-2-enoate (156 g, 1.24 mol, 1.1 equiv) and TEA (375 g, 3.71 mol, 3.3 equiv) in DCM (2.5 L) was stirred for 30 min at -40° C. 2 L of DCM was added to the resulting solution after the reaction completed and the resulting solution was extracted with 2*1 L of water. The organic layer was concentrated and the residue was applied onto a silica gel column eluting with EtOAc/petroleum ether (1/4). The collected fractions were combined and concentrated to afford 200 g (62.6%) of title compound as a white solid. LCMS: [M+H]+ 287.23.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC; RIBON THERAPEUTICS INC - US2019/330194, 2019, A1 Location in patent: Paragraph 1730

55
[ 2051-76-5 ]
5-chloro-2-(piperazin-1-yl)pyrimidine dihydrochloride [ No CAS ]
1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With triethylamine In dichloromethane at 20 - 30℃; for 1h;	Int-A23: 1-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one A solution of Int-A3 (1 g, 3.70 mmol, 1.00 equiv), TEA (1.5 g, 14.82 mmol, 4.00 equiv), and prop-2-enoyl prop-2-enoate (700 mg, 5.55 mmol, 1.50 equiv) in DCM (20 mL) was stirred for 1 h at RT. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc/petroleum ether (2:3) to afford 720 mg (77%) of title compound as a white solid. LCMS [M+H]+ 253.07.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC; RIBON THERAPEUTICS INC - US2019/330194, 2019, A1 Location in patent: Paragraph 0638; 0640

56
[ 2051-76-5 ]
6-(piperazin-1-yl)pyridine-3-carbonitrile dihydrochloride [ No CAS ]
6-[4-(prop-2-enoyl)piperazin-1-yl]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With triethylamine In dichloromethane at -40℃; for 1h;	Int-A25: 6-[4-(Prop-2-enoyl)piperazin-1-yl]pyridine-3-carbonitrile Prop-2-enoyl prop-2-enoate (17.42 g, 138.132 mmol, 1.30 equiv) was added to a solution of Int-A4 (20 g, 106.251 mmol, 1 equiv), and TEA (32.25 g, 318.752 mmol, 3 equiv) in DCM (500 mL) at -40° C. The resulting solution was stirred for another 1 h at -40° C. The reaction was quenched by 500 mL of water and extracted with 2*500 mL of DCM. After concentration, the residue was applied onto a silica gel column eluting with EtOAc/petroleum ether (70:30) to afford 16.4 g (64%) of title compound as a yellow solid. LCMS [M+H]+ 243.13.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC; RIBON THERAPEUTICS INC - US2019/330194, 2019, A1 Location in patent: Paragraph 0642; 0643

57
[ 2051-76-5 ]
1-(5-chloropyridin-2-yl)piperazine dihydrochloride [ No CAS ]
1-[4-(5-chloropyridin-2-yl)piperazin-1-yl]prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine In dichloromethane at 20 - 30℃; for 1.5h;	Int-A22: 1-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]prop-2-en-1-one A solution of Int-A5 (2.4 g, 8.92 mmol, 1.00 equiv), TEA (4 g, 39.5 mmol, 4.00 equiv), and prop-2-enoyl prop-2-enoate (3.64 g, 28.9 mmol, 3.00 equiv) in DCM (20 mL) was stirred for 1.5 h at RT. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc/petroleum ether (1:1) to afford 1280 mg (57%) of title compound as a yellow oil. LCMS [M+H]+ 252.09.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC; RIBON THERAPEUTICS INC - US2019/330194, 2019, A1 Location in patent: Paragraph 0636; 0637

58
[ 2051-76-5 ]
[ 100-46-9 ]
[ 13304-62-6 ]

Yield	Reaction Conditions	Operation in experiment
5.65 g	With sodium hydrogencarbonate; sodium hydroxide; In water; toluene; at 0 - 25℃; for 0.5h;Inert atmosphere;	General procedure: Benzylamine (11.7 g, 0.11 moles) serving as the material, toluene (25.9 g, 30 mL) serving as the solvent and 9% sodium hydroxide aqueous solution (87.9 g, 0.20 moles) serving as the base were charged in a 500-mL reaction container equipped with a nitrogen gas supplying pipe, a thermometer, and a stirrer in a nitrogen atmosphere, and the reacting solution was cooled such that the inner temperature came to be 0 C., being stirred at 300 rpm. After the cooling, the reacting solution was regarded as a base solution and the toluene solution of diacrylic anhydride obtained in Step 1 was dropped into the base solution, being stirred, such that the inner temperature did not exceed 5 C., i.e., being controlled in the temperature range of 0 C. to 5 C. After the completion of the dropping, the jacket temperature was raised to 25 C. and the reaction solution was stirred for 30 minutes. After the completion of the stirring, the reaction solution was stood still for 5 minutes and the aqueous phase was removed by separation to obtain a toluene solution of NBA.

Reference： [1]Patent: US2020/115322,2020,A1 .Location in patent: Paragraph 0107; 0110-0112; 0136-0149

59
[ 2051-76-5 ]
(S)-N₄-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((1-methylpyrrolidin-2-yl)methoxy)quinazoline-4,6-diamine [ No CAS ]
C₃₀H₃₁ClN₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With triethylamine In N,N-dimethyl-formamide at 25℃; for 0.5h;	1 To a solution of (S)-N4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-((l-methylpyrrolidin-2- yl)methoxy) quinazoline-4, 6-diamine (170 mg, 346 umol, 1.00 eq) and triethylamine (70.1 mg, 692 umol, 96.4 uL, 2.00 eq) in dimethyl form amide (4.00 rnL) was added acrylic anhydride (56.8 mg, 450 umol, 1.30 eq) dropwise at 25 °C. The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered. The filtrate was purified by prep-HPLC (column: X innate C 18 15025mm5um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 37%-67%, lOmin) to give (S)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy) phenyl)amino)-7-((I- methylpyrrolidin-2-yl)methoxy)quinazolin-6-yl)acrylamide 96 (124.49 mg, 228 umol, 65% yield, 100% purity, 99% ee) as a yellow solid. 1H NMR (400 MHz, CDC13) 5 = 9.11 (s, 1 H), 8.86 (br s, 1 H), 8.65 (s, 1 H), 8.62 (d, J = 5.0 Hz, 1 H), 7.90 (d, J = 2.8 Hz, 1 H), 7.82 - 7.74 (m, 1 H), 7.71 - 7 65 (m, 1 H), 7 58 (s, 1 H), 7.52 (dd, J = 8.8, 2.6 Hz, 1 H), 7.31 (s, 1 H), 7.26 (br d, J = 6.8 Hz, 1 H), 7.02 (d, J = 9.0 Hz, 1 H), 6.56 - 6.45 (m, 1 H), 6.44 - 6.31 (m, 1 H), 5.86 (d, J = 11.2 Hz, 1 H), 5.32 (s, 2 H), 4.50 - 4 39 (m, 2 H), 3 19 (br d, I = 7.4 Hz, 1 H), 2.79 (br s, 1 H), 2.51 (s, 3 H), 2.46 - 2.36 (m, 1 H), 2.16 - 2.02 (m, 1 H), 1.98 - 1.92 (m, 3 H). MS (ESI) m/z 545.4 [M+H]+

Reference： [1]Current Patent Assignee: BLACK DIAMOND THERAPEUTICS INC - WO2020/68867, 2020, A1 Location in patent: Page/Page column 386-387

60
[ 2051-76-5 ]
[ 35453-19-1 ]
[ 783279-02-7 ]

Reference： [1]Chemical Communications,2020,vol. 56,p. 5885 - 5888

61
[ 2051-76-5 ]
5,7,12,16-tetraisopropyl-4,13-dihydroxy[2,2]-paracyclophane [ No CAS ]
C₃₁H₄₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydride In chloroform at 0 - 40℃; for 1.5h; Inert atmosphere;	1 In a dry 500ml three-necked flask equipped with a thermometer and electromagnetic stirring, nitrogen was introduced to continuously replace the system. Transfer the entire device to a low temperature constant temperature bath, and set the bath temperature to 0°C. Add 41.0g of 5,7,12,16-tetraisopropyl-4,13-dihydroxy[2,2] p-cycloarane into the flask,(0.1mol, M=410g/mol) and 150ml of anhydrous trichloromethane. Start the low-temperature constant-temperature bath and stir. When the thermometer shows the value between 0 and 2°C, slowly add 3.6g of sodium hydride (0.15mol, M=24.0g/mol). After the addition of sodium hydride, after no bubbles are generated in the reaction system,Slowly drip 40ml of a chloroform solution containing 12.61g (0.1mol, M=126.1g/mol) of acrylic anhydride, and raise the temperature of the constant temperature bath to 40°C after the addition is complete.React for 1.5 hours.After the reaction is complete, slowly add 5% dilute sulfuric acid to treat the remaining sodium hydride, control the pH value of the reaction system at 4-5, and stop the nitrogen flow. Finally, add 60ml of water and stir for 5min. After the system was filtered, the organic layer was separated, washed twice with water, dried with anhydrous sodium sulfate and then spin-dried the organic solvent with a rotary evaporator to obtain a crude product. The crude product was chromatographed on a silica gel column and eluted with petroleum ether: dichloromethane=1:3 to obtain a white solid with a yield of 81%.

Reference： [1]Current Patent Assignee: WANHUA CHEMICAL GROUP CO LTD - CN111689853, 2020, A Location in patent: Paragraph 0045-0047

62
[ 2051-76-5 ]
5,12-di-tertpentyl-7,16-diisopropyl-4,13-dihydroxy[2,2]paracyclophane [ No CAS ]
C₃₅H₅₀O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With lithium diisopropyl amide In N,N-dimethyl-formamide at 10 - 55℃; for 1h; Inert atmosphere;	3 In a dry 500ml three-necked flask equipped with a thermometer and electromagnetic stirring, nitrogen was introduced to continuously replace the system.Transfer the entire device to a low temperature constant temperature bath, and set the bath temperature to 10°C.Add 46.4g (0.1mol, M=464g/mol) of 5,12-di-tertpentyl-7,16-diisopropyl-4,13-dihydroxy[2,2] p-cycloarane into the flask and 150ml of anhydrous N,N-dimethylformamide.Start the low-temperature constant-temperature bath and stir. When the thermometer shows the value between 10-11, slowly add 24.6g (0.23mol, M=107.1g/mol) of lithium diisopropylamide. After no bubbles are generated in the reaction system, Slowly drip 40 ml of N,N-dimethyl sulfoxide solution containing 18.9 g (0.15 mol, M=126.1 g/mol) of acrylic anhydride. After the dripping is completed, the temperature of the constant temperature bath is increased to 55° C. and reacted for 1 hour. After the reaction is complete, slowly add 5% dilute sulfuric acid to treat the remaining lithium diisopropylamide, control the pH value of the reaction system at 4-5, and stop the nitrogen flow. Finally, add 60ml of water and stir for 5min. After the system was filtered, the organic layer was separated, washed twice with water, dried with anhydrous sodium sulfate and then spin-dried the organic solvent with a rotary evaporator to obtain a crude product. The crude product was chromatographed on a silica gel column and eluted with petroleum ether: dichloromethane=1:3 to obtain a white solid with a yield of 82%.

Reference： [1]Current Patent Assignee: WANHUA CHEMICAL GROUP CO LTD - CN111689853, 2020, A Location in patent: Paragraph 0051-0053

63
[ 2051-76-5 ]
5,12-di-tert-pentyl-7,16-di-tert-butyl-8,15-diisopropyl-4,13-dihydroxy[2,2]paracyclophane [ No CAS ]
C₄₃H₆₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With n-butyllithium In acetone at 15 - 60℃; for 2h; Inert atmosphere;	4 In a dry 500ml three-necked flask equipped with a thermometer and electromagnetic stirring, nitrogen was introduced to continuously replace the system. Transfer the entire device to a low temperature constant temperature bath, and set the bath temperature to 15°C. Add 5,12-di-tert-pentyl-7,16-di-tert-butyl-8,15-diisopropyl-4,13-dihydroxy[2,2] p-cycloarane 57.6g (0.1 mol, M=576g/mol) and 180ml of anhydrous acetone. Start the low-temperature constant-temperature bath and stir. When the thermometer shows that the value is stable at 15°C, slowly add 16.7g of n-butyl lithium (0.26mol, M=64.05g/mol). After adding the n-butyllithium, there will be no bubbles in the reaction system. , Slowly drip 40ml of anhydrous acetone solution containing 22.7g (0.18mol, M=126.1g/mol) of acrylic anhydride. After the dripping is completed, the temperature of the constant temperature bath is increased to 60°C and reacted for 2 hours. After the reaction is completed, the temperature is lowered to 0°C, 5% dilute sulfuric acid is slowly added to treat the remaining butyl lithium, the pH value of the reaction system is controlled at 4-5, and the nitrogen gas is stopped. Finally, add 60ml of water and stir for 5min. After the system was filtered, the organic layer was separated, washed twice with water, dried with anhydrous sodium sulfate and then spin-dried the organic solvent with a rotary evaporator to obtain a crude product. The crude product was chromatographed on a silica gel column and eluted with petroleum ether: dichloromethane=1:3 to obtain a white solid with a yield of 91%.

Reference： [1]Current Patent Assignee: WANHUA CHEMICAL GROUP CO LTD - CN111689853, 2020, A Location in patent: Paragraph 0054-0056

64
[ 2051-76-5 ]
5,12-dineohexyl-7,8,15,16-tetra-tert-butyl-4,13-dihydroxy[2,2]paracyclophane [ No CAS ]
C₄₇H₇₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: acrylic acid anhydride; 5,12-dineohexyl-7,8,15,16-tetra-tert-butyl-4,13-dihydroxy[2,2]paracyclophane In dimethyl sulfoxide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: With anion exchange resin D₃₀₁ In dimethyl sulfoxide at 90℃; for 2h; Inert atmosphere;	5 In a dry and clean 500ml three-necked flask equipped with a thermometer, add 63.2g (0.1mol, M=632g/mol) 5,12-dioxinhexyl-7,8,15,16-tetra-tert-butyl-4, 13-dihydroxy[2,2] p-cycloarane, 150ml anhydrous N,N-dimethyl sulfoxide, 25.2g (0.2mol, M=126.1g/mol) acrylic anhydride. Transfer the entire device to an oil bath at room temperature, turn on electromagnetic stirring, stop stirring after 10 minutes, and add pretreated 63g macroporous strong basic anion exchange resin D301 (0.3mol, total exchange capacity 4.8mmol/g) . Increase the temperature of the oil bath to 90°C and react for 2 hours. TLC monitors the progress of the reaction. After the reaction is completed, the oil bath is turned off and the temperature of the reaction system drops to close to room temperature, and then all the materials in the three-neck flask are filtered. After the filtrate is dried over anhydrous sodium sulfate, the organic solvent is spin-dried with a rotary evaporator to obtain a crude product. The crude product was chromatographed on a silica gel column and eluted with petroleum ether: dichloromethane=1:3 to obtain a white solid with a yield of 79%.

Reference： [1]Current Patent Assignee: WANHUA CHEMICAL GROUP CO LTD - CN111689853, 2020, A Location in patent: Paragraph 0057-0059

65
[ 2051-76-5 ]
5,15-di-tert-pentyl-8,12-di-tert-butyl-4,7,13,16-tetrahydroxy[2.2]paracyclophane [ No CAS ]
C₄₀H₅₆O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: acrylic acid anhydride; 5,15-di-tert-pentyl-8,12-di-tert-butyl-4,7,13,16-tetrahydroxy[2.2]paracyclophane In cyclohexanone at 20℃; for 0.166667h; Inert atmosphere; Stage #2: With anion exchange resin D₂₉₆R In cyclohexanone at 80℃; for 2h; Inert atmosphere;	6 In a dry and clean 500ml three-necked flask equipped with a thermometer, add 52.4g (0.1mol, M=524g/mol) 5,15-di-tert-pentyl-8,12-di-tert-butyl-4,7,13 ,16-Tetrahydroxy[2,2]paracycloalkane, 150ml anhydrous cyclohexanone, 22.7g (0.18mol, M=126.1g/mol) acrylic anhydride. Transfer the entire device to an oil bath at room temperature, and turn on electromagnetic stirring. Stirring was stopped after 10 minutes, and 70 g of pretreated macroporous strongly basic anion exchange resin D296R (0.26 mol, exchange capacity 3.7 mmol/g) was added. Increase the temperature of the oil bath to 80°C and react for 2 hours. TLC monitors the progress of the reaction. After the reaction is completed, the oil bath is turned off and the temperature of the reaction system drops to close to room temperature, and then all the materials in the three-neck flask are filtered. After the filtrate is dried over anhydrous sodium sulfate, the organic solvent is spin-dried with a rotary evaporator to obtain a crude product. The crude product was chromatographed on a silica gel column and eluted with petroleum ether: dichloromethane=1:3 to obtain a white solid with a yield of 71%.

Reference： [1]Current Patent Assignee: WANHUA CHEMICAL GROUP CO LTD - CN111689853, 2020, A Location in patent: Paragraph 0060-0062

66
[ 2051-76-5 ]
5,15-di-neohexyl-8,12-di-tert-butyl-4,7,13,16-tetrahydroxy[2.2]paracyclophane [ No CAS ]
C₄₂H₆₀O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium fluoride on basic alumina In toluene at 110℃; for 2h; Inert atmosphere;	7 In a dry 500ml three-necked flask equipped with a thermometer and electromagnetic stirring, nitrogen was introduced to continuously replace the system. Transfer the whole set of equipment to a constant temperature bath at 25°C,Add 55.2g (0.1mol, M=552g/mol) into the flask5,15-Di-neohexyl-8,12-di-tert-butyl-4,7,13,16-tetrahydroxy[2,2]p-cycloarane, 180ml anhydrous toluene and pretreated 50ggKF/γ- Al2O3 solid base catalyst (0.27mol, exchange capacity 5.4mmol/g). Start the constant temperature bath and stir, slowly add 22.7 g of acrylic anhydride, 0.18 mol (M=126.1 g/mol) dropwise, raise the temperature of the constant temperature bath to 110° C. after the dropwise addition is completed, separate the produced water with an oil-water separator and react for 2 hours. TLC monitors the progress of the reaction. After the reaction is completed, the oil bath is turned off and the temperature of the reaction system drops to close to room temperature, and then all the materials in the three-neck flask are filtered. After the filtrate is dried over anhydrous sodium sulfate, the organic solvent is spin-dried with a rotary evaporator to obtain a crude product. The crude product was chromatographed on a silica gel column and eluted with petroleum ether: dichloromethane=1:3 to obtain a white solid with a yield of 82%.

Reference： [1]Current Patent Assignee: WANHUA CHEMICAL GROUP CO LTD - CN111689853, 2020, A Location in patent: Paragraph 0063-0065

67
[ 2051-76-5 ]
5,7,12,16-tetra-tert-butyl-4,13-dihydroxy[2,2]paracyclophane [ No CAS ]
C₃₅H₅₀O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium hydride In tetrahydrofuran at 5 - 50℃; for 2h; Inert atmosphere;	2 In a dry 500ml three-necked flask equipped with a thermometer and electromagnetic stirring, nitrogen was introduced to continuously replace the system. Transfer the entire device to a low-temperature thermostatic bath,The bath temperature is set to 5°C. 46.4g (0.1mol, M=464g/mol) of 5,7,12,16-tetra-tert-butyl-4,13-dihydroxy[2,2]p-cycloarane and 150ml of anhydrous tetrahydrofuran were added to the flask. Start the low temperature constant temperature bath for stirring,When the thermometer shows that the value is between 5-6°C, slowly add 8.22g of potassium hydride (0.2mol, M=41.1g/mol). After the addition of potassium hydride, when there are no bubbles in the reaction system, slowly add dropwise containing acrylic anhydride 16.39g (0.13mol, M=126.1g/mol) of 40ml tetrahydrofuran solution, after the dropwise addition is completed, the temperature of the constant temperature bath is raised to 50°C, and the reaction is carried out for 2 hours. After the reaction is complete, slowly add 5% dilute sulfuric acid to treat the remaining potassium hydride, control the pH value of the reaction system at 4-5, and stop the nitrogen flow. Finally, add 60ml of water and stir for 5min. After the system was filtered, the organic layer was separated, washed twice with water, dried with anhydrous sodium sulfate and then spin-dried the organic solvent with a rotary evaporator to obtain a crude product. The crude product was chromatographed on a silica gel column and eluted with petroleum ether:dichloromethane=1:3 to obtain a white solid with a yield of 84%

Reference： [1]Current Patent Assignee: WANHUA CHEMICAL GROUP CO LTD - CN111689853, 2020, A Location in patent: Paragraph 0048-0050

68
[ 2051-76-5 ]
2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine dihydrochloride [ No CAS ]
1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.6%	With triethylamine In dichloromethane at -40℃; for 0.5h;	1.3 Step 3: l-(4-(5-Trifluoromethyl)pyrimidin-2-yl)piperazin-l-yl)prop-2-en-1-one A solution of 2-(piperazin-l -yl)-5-(trifluoromethyl)pyrimidine dihydrochloride (300 g, 1.1 mol, 1 equiv), prop-2-enoyl prop-2-enoate (156 g, 1.24 mol, 1.1 equiv) and TEA (375 g, 3.71 mol, 3.3 equiv) in DCM (2.5 L) was stirred for 30 min at -40 °C. 2 L of DCM was added to the resulting solution after the reaction completed and the resulting solution was extracted with 2 x 1 L of water. The organic layer was concentrated and the residue was applied onto a silica gel column eluting with EtOAc/petroleum ether (1/4). The collected fractions were combined and concentrated to afford 200 g (62.6%) of title compound as a white solid. LCMS: [M+H]+ 287.23.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - WO2020/223229, 2020, A1 Location in patent: Page/Page column 29; 30

69
[ 2051-76-5 ]
[ 1421372-66-8 ]
[ 1421373-65-0 ]

Yield	Reaction Conditions	Operation in experiment
62%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 5℃; for 2h;	1.2-9.2 Step (2) Synthesis of Intermediate 3 Add 5.9g of Intermediate 2 (13.3mmol), 90mL of dichloromethane and 2.0g of N,N-diisopropylethylamine (DIEA, 15.5mmol) into the reaction flask, stir and cool to 5°C, slowly add 1.95g dropwise Acrylic anhydride (15.5 mmol), then continue to stir and react at 5°C for 2 hours. Use TLC (thin layer chromatography) to check the progress of the reaction. The developing solvent is dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 10: 1. After the reaction is completed, add 60 mL of saturated sodium bicarbonate aqueous solution to the system to neutralize the unreacted acrylic anhydride and acrylic acid in the system, stir and stand for separation to obtain an organic layer 1 and an aqueous layer. The aqueous layer uses 50 mL of dichloride Methane was extracted once to obtain organic layer 2. Combine organic layer 1 and organic layer 2. The combined organic layer was concentrated to dryness at 40°C under reduced pressure, and then 50 mL of ethanol was added to the resulting residue, and stirred at room temperature until solution After clarification, add 10mL of water, continue to stir at room temperature for 2 hours, precipitate crystals, filter with suction, and then vacuum dry the obtained solid at a drying temperature of 45°C and a drying time of 8h to obtain 4.1g of a yellow solid with a yield of 62 %

Reference： [1]Current Patent Assignee: BEIJING XINKAIYUAN PHARMACEUTICALS; GANSU HAIPU NUORUICHUANG PHARMACEUTICAL - CN112028880, 2020, A Location in patent: Paragraph 0007; 0029; 0055; 0057; 0063-0070

70
[ 107-41-5 ]
[ 2051-76-5 ]
[ 188837-17-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	With N,N,N,N,-tetramethylethylenediamine at 60℃;	4 Example 4 (0065) (0066) 2-methylpentane-2,4-diol (20.0 g, 169 mmol), N,N,N′,N′-tetramethylethylenediamine (5.9 g, 50.8 mmol, 0.30 eq.), and acrylic anhydride (64.03 g, 508 mmol, 3.0 eq.) were placed in a 250 mL round-bottom flask, and reacted at 60° C. for 12 hours or more. Thereafter, it was filtered using a celite pad with 200 mL of n-hexane, and concentrated to obtain a product DA 4 (31.8 g, yield 83%). (0067) 1H NMR (500 MHz, CDCl3): δ 6.38 (1H, dd), 6.31 (1H, dd), 6.08 (1H, dd), 6.01 (1H, dd), 5.25 (1H, m), 1.57 (3H, s), 1.51 (6H, s), 1.28 (2H, d).
52%	With dmap; triethylamine In toluene at 50℃; for 13h; Cooling with ice;	2 Comparative Preparation Example 2 2-methylpentane-2,4-diol (3.5 g, 30 mmol), toluene (50 mL), 4-dimethylaminopyridine (0.4 g, 3 mmol), and Triethylamine (9.1 g, 90 mmol) were added to a 100 mL flask and ice bath It was stirred slowly at. Acrylic anhydride (12 g, 90 mmol) was added dropwise to this reaction vessel over 1 hour. After further stirring at 50° C. for 12 hours, the reaction was terminated after checking the conversion rate (80% conversion rate) of the reaction using TLC and GC. Toluene, a reaction solvent, was distilled under reduced pressure, and extracted three times with water and n-hexane. Residual moisture in the collected hexane layer was removed with MgSO4, filtered and distilled under reduced pressure to obtain compound 2 (2-methylpentane-2,4-diyl diacrylate, yield: 52%).

Reference： [1]Current Patent Assignee: LG CHEM CO.,LTD. - US2020/407308, 2020, A1 Location in patent: Paragraph 0065-0067
[2]Current Patent Assignee: LG CHEM CO.,LTD. - KR2021/38095, 2021, A Location in patent: Paragraph 0157-0159

71
[ 107-41-5 ]
[ 2051-76-5 ]
[ 188837-17-4 ]
Acrylsaeure-(3-hydroxy-1,3-dimethylbutylester) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With dmap; triethylamine In toluene at 110℃; for 14h;	C.2 Comparative Example 2 (0073) (0074) 2-methylpentane-2,4-diol (20.0 g, 169 mmol), toluene (170 mL), triethylamine (51.38 g, 508 mmol, 3.0 eq.), and 4-dimethylaminopyridine (2.07 g, 16.92 mmol, 0.1 eq.) were placed in a 250 mL round-bottom flask, and acrylic anhydride (64.03 g, 507.7 mmol, 3.0 eq.) was slowly added thereto at 110° C. for 2 hours. Thereafter, they reacted at 110° C. for 12 hours. Then, toluene, which is a solvent, was removed under reduced pressure, diluted with 200 mL of n-hexane, and washed twice with 200 mL of water. Magnesium sulfate was added to the n-hexane solution to remove water, and the mixture was filtered using a celite pad and then concentrated to obtain a mixture of DA 4 and A 1.

Reference： [1]Current Patent Assignee: LG CHEM CO.,LTD. - US2020/407308, 2020, A1 Location in patent: Paragraph 0073-0075

72
[ 2051-76-5 ]
(1R,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]hexane-2-ol [ No CAS ]
isobornyl acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.9%	With sulfuric acid In toluene at 60 - 80℃; for 4.5h;	2 Add 250g of toluene, 50g (0.32mol) of isobornyl alcohol and 0.1g of concentrated sulfuric acid into a four-necked flask equipped with condensed reflux. After it is completely dissolved, the temperature is increased to 60-80 °C and 52.4g (0.42mol) of acrylic anhydride is added dropwise under stirring. The addition is completed within 30 minutes. After keeping this temperature and reacting for 4 hours, IBOA is produced, and its chemical reaction formula is shown in the above reaction formula (2). The conversion rate of isobornyl alcohol detected by GC was 99.3%. After stopping the reaction, it was washed twice with 50g of 10% NaOH aqueous solution, twice with pure water, and dried. The 110°C-130°C fractions were collected under a vacuum of 1.0 kpa to obtain 65.8 g of a colorless transparent liquid with a purity of 99.3%. The calculated IBOA yield was 98.9%.

Reference： [1]Current Patent Assignee: JIANGSU NATA OPTO-ELECTRONIC MATERIAL CO., LTD. - CN112094188, 2020, A Location in patent: Paragraph 0049-0056

73
[ 2051-76-5 ]
(S)-12-cyclopropyl-2-(2-fluoro-6-hydroxyphenyl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one [ No CAS ]
(S)-7-acryloyl-12-cyclopropyl-2-(2-fluoro-6-hydroxyphenyl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With triethylamine In dichloromethane at 0℃; for 0.25h;	18.7 Step 7: (S)-12-Cyclopropyl-2-(2-fluoro-6-hydroxyphenyl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a, 10,12-Pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one (0.430g, 1.051mmol) dissolved in dichloromethane (30mL), Add triethylamine (1.06 g, 10.51 mmol). Cool the reaction to 0°C, Acrylic anhydride (112.6 mg, 0.8936 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0°C for 15 minutes. Add 80 mL of dichloromethane to the reaction solution, Wash with 100mL saturated NaHCO3 aqueous solution, 80mL saturated brine, dry and concentrate, The crude product is purified by a flash silica gel column (methanol/dichloromethane: 0-20%) to obtain the target product Z18 (S)-7-acryloyl-12-cyclopropyl-2-(2-fluoro-6-hydroxyphenyl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one (209mg, yield: 56%).

Reference： [1]Current Patent Assignee: ZHEJIANG GENFLEET PHARMACEUTICAL; GENFLEET THERAPEUTICS SHANGHAI - CN112390818, 2021, A Location in patent: Paragraph 0234-0235; 0242

74
[ 2051-76-5 ]
(R)-2-(2-fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester [ No CAS ]
(R)-7-acryloyl-2-(2-fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: (R)-2-(2-fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester With trifluoroacetic acid In dichloromethane at 20 - 25℃; for 2h; Stage #2: acrylic acid anhydride With triethylamine In dichloromethane at 0℃; for 0.25h;	27.2 Step 2: (R)-2-(2-Fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester (80mg, 0.13mmol) dissolved in dichloromethane (8mL), Add trifluoroacetic acid (2 mL). After stirring for 2h at room temperature, the reaction solution was concentrated to obtain the target intermediate. The intermediate was dissolved in dichloromethane (15 mL), and triethylamine (1 g, 10 mmol) was added. The reaction was cooled to 0°C, and acrylic anhydride (30 mg, 0.24 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0°C for 15 minutes. 40mL of dichloromethane was added to the reaction solution, Wash with 50mL saturated NaHCO3 aqueous solution, 40mL saturated brine, dry and concentrate, The crude product was purified with a fast silica gel column to obtain the target product Z27 (R)-7-acryloyl-2-(2-fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one( 43mg, yield: 58%).

Reference： [1]Current Patent Assignee: ZHEJIANG GENFLEET PHARMACEUTICAL; GENFLEET THERAPEUTICS SHANGHAI - CN112390818, 2021, A Location in patent: Paragraph 0170; 0291-0292; 0294

75
[ 2051-76-5 ]
(S)-2-(2,5-difluoro-3-methoxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cycloheptano[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester [ No CAS ]
(S)-7-acryloyl-2-(2,5-difluoro-3-methoxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cycloheptano[1,2,3-de]naphthalene-11(12H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: (S)-2-(2,5-difluoro-3-methoxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cycloheptano[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester With trifluoroacetic acid In dichloromethane at 20 - 25℃; for 2h; Stage #2: acrylic acid anhydride With triethylamine In dichloromethane at 0℃; for 0.25h;	31.1 Step 1: (S)-2-(2,5-difluoro-3-methoxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cycloheptano[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester (860mg, 1.35mmol) dissolved in dichloromethane (8mL), Add trifluoroacetic acid (2 mL). After stirring for 2h at room temperature, the reaction solution was concentrated to obtain the target intermediate. The intermediate was dissolved in dichloromethane (15 mL), and triethylamine (2 g, 20 mmol) was added. The reaction was cooled to 0°C, and acrylic anhydride (170 mg, 1.35 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0°C for 15 minutes. 40mL of dichloromethane was added to the reaction solution, Wash with 50mL saturated NaHCO3 aqueous solution, 40mL saturated brine, dry and concentrate, The crude product is purified by a fast silica gel column to obtain the target product (S)-7-acryloyl-2-(2,5-difluoro-3-methoxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cycloheptano[1,2,3-de]naphthalene-11(12H)-one (470mg, yield: 58%).

Reference： [1]Current Patent Assignee: ZHEJIANG GENFLEET PHARMACEUTICAL; GENFLEET THERAPEUTICS SHANGHAI - CN112390818, 2021, A Location in patent: Paragraph 0170; 0312-0314

76
[ 2051-76-5 ]
(S)-2-(2,5-difluoro-6-methoxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cycloheptano[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester [ No CAS ]
(S)-7-acryloyl-2-(2,5-difluoro-6-methoxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cycloheptano[1,2,3-de]naphthalene-11(12H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: (S)-2-(2,5-difluoro-6-methoxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cycloheptano[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester With trifluoroacetic acid In dichloromethane at 20 - 25℃; for 2h; Stage #2: acrylic acid anhydride With triethylamine In dichloromethane at 0℃; for 0.25h;	33.1 Step 1: (S)-2-(2,5-Difluoro-6-methoxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a, 6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cycloheptano[1,2,3-de] Naphthalene 7(5H)-carboxylic acid tert-Butyl ester (860mg, 1.35mmol) dissolved in dichloromethane (8mL), Add trifluoroacetic acid (2 mL). After stirring for 2h at room temperature, the reaction solution was concentrated to obtain the target intermediate. The intermediate was dissolved in dichloromethane (15 mL), and triethylamine (2 g, 20 mmol) was added. The reaction was cooled to 0°C, and acrylic anhydride (170 mg, 1.35 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0°C for 15 minutes. 40mL of dichloromethane was added to the reaction solution, Wash with 50mL saturated NaHCO3 aqueous solution, 40mL saturated brine, dry and concentrate, The crude product is purified by a fast silica gel column to obtain the target product (S)-7-acryloyl-2-(2,5-difluoro-6-methoxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cycloheptano[1,2,3-de]naphthalene-11(12H)-one (470mg, yield: 58%).

Reference： [1]Current Patent Assignee: ZHEJIANG GENFLEET PHARMACEUTICAL; GENFLEET THERAPEUTICS SHANGHAI - CN112390818, 2021, A Location in patent: Paragraph 0170; 0322-0324

77
[ 2051-76-5 ]
(S)-2-(2-amino-6-fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester [ No CAS ]
(S)-7-acryloyl-2-(2-amino-6-fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: (S)-2-(2-amino-6-fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester With trifluoroacetic acid In dichloromethane at 20 - 25℃; for 2h; Stage #2: acrylic acid anhydride With triethylamine In dichloromethane at 0℃; for 0.25h;	13.4; 14.4; 25.2 Step 4: (S)-2-(2-Amino-6-fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9 ,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester (400mg, 0.66mmol) dissolved in dichloromethane (8mL), Add trifluoroacetic acid (2 mL). After stirring for 2h at room temperature, the reaction solution was concentrated to obtain the target intermediate. The intermediate was dissolved in dichloromethane (15 mL), and triethylamine (400 mg, 4.0 mmol) was added. The reaction was cooled to 0°C, and acrylic anhydride (80 mg, 0.63 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0°C for 15 minutes. 40mL of dichloromethane was added to the reaction solution, Wash with 50mL saturated NaHCO3 aqueous solution, 40mL saturated brine, dry and concentrate, The crude product is purified by a fast silica gel column to obtain the target product (S)-7-acryloyl-2-(2-amino-6-fluorophenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-5,5a,6,7 ,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one (250mg, yield: 68%).

Reference： [1]Current Patent Assignee: ZHEJIANG GENFLEET PHARMACEUTICAL; GENFLEET THERAPEUTICS SHANGHAI - CN112390818, 2021, A Location in patent: Paragraph 0170; 0208-0209; 0213; 0215-0216; 0220; 0280-0281

78
[ 10192-85-5 ]
[ 2051-76-5 ]

Yield	Reaction Conditions	Operation in experiment
93.3%	With 10H-phenothiazine; methanesulfonyl chloride; 4-methoxy-phenol In acetone for 0.5h; Cooling with ice;	1-4 <Synthesis of acrylate anhydride; potassium acrylate, MsCl type> Acetone 151.5 mL, potassium acrylate 50.5 g (0.46 mol), 4-methoxyphenol 50.5 mg, and phenothiazine 50.5 mg under an ice bath while passing pure air through a 300 ml four-necked flask equipped with a stirrer and a thermometer. Was charged, stirred and dispersed. 25.0 g (0.22 mol) of MsCl was added dropwise thereto over 30 minutes. Then, the mixture was stirred under an ice bath, and when it was confirmed that the exotherm had subsided, the outside temperature was set to 25 ° C., and the reaction was followed by GC while aging for 1 hour. As a result, it was confirmed that MsCl had disappeared. The conversion rate of the crude body was 99.1%. After completion of the reaction, the mixture was filtered using a filter paper, washed with 100 mL of acetone three times, and then acetone was distilled off under reduced pressure to obtain 28.5 g of crude acrylic anhydride (crude yield 103.5% with respect to MsCl, GC). Purity 95.3%) was obtained. The crude product was distilled under reduced pressure under pure air to obtain 25.7 g of acrylic anhydride (b.p. 40 ° C. (O.4 kPa), yield 93.3% with respect to MsCl, GC purity 99.3%).

Reference： [1]Current Patent Assignee: KIKUKAWA HIDEAKI - JP2021/80211, 2021, A Location in patent: Paragraph 0024-0031; 0040

79
[ 2051-76-5 ]
(3S)-10-(2,4-difluorophenyl)-7-((3S,SR)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one [ No CAS ]
(3S)-7-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-10-(5-chloro-2,4-difluorophenyl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With triethylamine In dichloromethane at 0℃; for 1h;	HH.546; HH.547 (3S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-l-yl)-10-(2,4-difluorophenyl)- 3-(methoxymethyl)-9-(trifluoromethyl)-2H-[l,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one To a mixture of (3S)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin- l-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[l,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one (120 mg, 0.22 mmol) and triethyl amine (44 mg, 0.44 mmol) in dichloromethane (5 ml) was added acrylic anhydride (42 mg, 0.33 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. After completion, the mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was dried over Na2SC>4 and filtered. After concentration, the residue was purified by preparative High Performance Liquid Chromatography (20% to 95% acetonitrile in water) to afford (3S)-7-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin-l-yl)-10-(2,4-difluorophenyl)-3-(methoxymethyl)-9- (trifluoromethyl)-2H-[l,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (100 mg, 76% yield) as a white solid. NMR (400 MHz, CDCb) d 8.07 (s, 1H), 7.17 (q, J = 8.0 Hz, 1H), 7.06- 6.93 (m, 2H), 6.62 (dd, J = 10.4 Hz, 16.8 Hz, 1H), 6.40 (dd, J = 2.0 Hz, 16.8 Hz, 1H), 5.77 (dd, J = 2.0 Hz, 10.4 Hz, 1H), 5.48-5.41 (m, 1H), 4.79-4.53 (m, 2H), 4.21-4.16 (m, 2H), 3.69-3.59 (m, 2H), 3.37-3.30 (m, 6H), 3.05-2.99 (m, 1H), 1.62 (d, J = 6.8 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H). MS (ESI) m/z 595.6 [M+H]+. [1582] The above racemate (72 mg) was dissolved in EtOH (5 mL) and separated by chiral supercritical fluid chromatography (separation condition: Column: Chiralpak AD-H 5 pm 20 x 250 mm; Mobile Phase: CO2 : EtOH = 70 : 30 at 25 mL/min; Temp: 25 °C; Wavelength: 254 nm) to afford two atropisomers of the title compounds PI (30.0 mg, 41 % yield, 100 % de), and P2 (35.0 mg, 48 % yield, 100 % de); Chiral HPLC Analytical: on CHIRALPAK AD-H was using 5 pm 4.6 x 250 mm column, Mobile Phase: CO2 : EtOH = 70 : 30 at 2.5 mL/min; Temp: 25 °C; Wavelength: 254 nm). [1583] PI: NMR (400 MHz, CDCb) d 8.07 (s, 1H), 7.18 (q, J= 8.0 Hz, 1H), 7.05- 6.93 (m, 2H), 6.62 (dd, ./= 6.0 Hz, 16.4 Hz, 1H), 6.40 (dd, .7= 1.6 Hz, 16.4 Hz, 1H), 5.77 (dd, J= 1.6 Hz, 10.4 Hz, 1H), 5.48-5.45 (m, 1H), 4.70-4.60 (m, 1H), 4.22-4.17 (m, 2H), 3.74-3.60 (m, 3H), 3.39-3.31 (m, 6H), 3.03-2.99 (m, 1H), 1.63-1.61 (m, 3H), 1.47 (d, J = 7.2 Hz, 3H); Chiral SFC fraction 1: d.e. = 100%, Rt = 4.14 min. [1584] P2: 'HNMR (400 MHz, CDCb) d 8.07 (s, 1H), 7.18 (q, J= 7.6 Hz, 1H), 7.04- 6.94 (m, 2H), 6.62 (dd, J= 10.0 Hz, 16.8 Hz, 1H), 6.40 (dd, ./= 2.0 Hz, 16.8 Hz, 1H), 5.77 (dd, J= 2.0 Hz, 10.8 Hz, 1H), 5.46-5.42 (m, 1H), 4.73-4.61 (m, 1H), 4.21-4.16 (m, 2H), 3.74-3.64 (m, 3H), 3.40-3.30 (m, 6H), 3.03 (dd, J= 2.4 Hz, 13.2 Hz, 1H), 1.63-1.61 (m, 3H), 1.47 (d, J= 7.2 Hz, 3H); Chiral SFC fraction 1: d.e. = 100%, Rt = 4.29 min. II.

Reference： [1]Current Patent Assignee: ERASCA, INC - WO2021/127404, 2021, A1 Location in patent: Paragraph 1566; 1581-1584

80
[ 2051-76-5 ]
(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one [ No CAS ]
(3S)-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With triethylamine In dichloromethane at 0℃; for 1h;	II.560 3S)-3-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-7-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin-l-yl)-10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2H- [l,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (9) To a mixture of (3S)-3-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)- 10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-l-yl)-9-(trifluoromethyl)-2H- [l,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (160 mg, 0.26 mmol) and triethyl amine (40 mg, 0.39 mmol) in dichloromethane (5 mL) was added acrylic anhydride (40 mg, 0.31 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. After completion, the mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (3 x 20 mL). The mixture was concentrated and the residue was purified by preparative high performance liquid chromatography (20% to 95% acetonitrile in water) to afford (3S)-3-((lS,4S)-2-oxa- 5-azabicyclo[2.2.1]heptan-5-ylmethyl)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-l-yl)- 10-(2,4-difluorophenyl)-9-(trifluoromethyl)-2H-[l,4]thiazino[2,3,4-ij]quinazolin-5(3H)- one (103 mg, 59% yield) as a white solid. [1602] NMR (400 MHz, CDCb) d 8.07 (s, 1H), 7.21-7.14 (m, 1H), 7.06-6.93 (m, 2H), 6.66-6.59 (m, 1H), 6.43-6.38 (m, 1H), 5.77 (d, J= 12.0 Hz, 1H), 5.28-5.24 (m, 1H), 4.74-4.60 (m, 2H), 4.43-4.37 (m, 1H), 4.19 (d, J= 13.6 Hz, 2H), 3.91-3.84 (m, 1H), 3.69- 3.31 (m, 5.5H), 2.99-2.85 (m, 4.5H), 1.75-1.66 (m, 2H), 1.60-1.58 (m, 3H), 1.49-1.41 (m, 3H). MS (ESI) m/z: 662.1 [M+H]+.

Reference： [1]Current Patent Assignee: ERASCA, INC - WO2021/127404, 2021, A1 Location in patent: Paragraph 1585; 1599-1600

81
[ 2051-76-5 ]
(3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-10-(2,4-difluorophenyl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one [ No CAS ]
(3S,10S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(2,4-difluorophenyl)9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With triethylamine In dichloromethane at 0℃; for 2h;	JJ.576; JJ.577 3S)-3-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-7-((3S',5i?)-4-acryloyl-3,5- dimethylpiperazin- 1 -yl)- 10-(2.4-di fluorophenyl )-9-(trifl uoromethyl)-2//- [l,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (9) To a mixture of (3

Reference： [1]Current Patent Assignee: ERASCA, INC - WO2021/127404, 2021, A1 Location in patent: Paragraph 1603

82
[ 2051-76-5 ]
9-(3-aminophenyl)-3-(2-chloro-4-hydroxybenzyl)-1,7-dimethyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione [ No CAS ]
N-(3-(3-(2-chloro-4-hydroxybenzyl)-1,7-dimethyl-2,4-dioxo-1,2,3,4,7,8-hexahydropyrimido[1,2-f]purin-9(6H)-yl)phenyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.7%	With triethylamine In dichloromethane at -60℃;	22 Example 22: Preparation of N-(3-(3-(2-chloro-4-hydroxybenzyl)-l,7-dimethyl-2,4-dioxo-l,2,3,4,7,8- hexahydropyrimido[l,2-f]purin-9(6H)-yl)phenyl)acrylamide (Compound 31) To the mixture of 9-(3-aminophenyl)-3-(2-chloro-4-hydroxybenzyl)-l,7-dimethyl-6, 7,8,9- tetrahydro pyrimido[l,2-f]purine-2,4(lH,3H)-dione (42 mg, 0.14 mmol) and TEA (23 mg, 0.42 mmol) in DCM (5 mL) was added slowly a solution of acrylic anhydride (12 uL, 0.11 mmol) in DCM (3 mL) at -60 °C. After the reaction completed as monitored by TLC, the reaction solution was quenched with ice water and extracted with DCM (20 mL x 3). The organic layer was washed with water and brine, dried over Na2SC>4, filtered and the solvent was removed by evaporation. The crude product was purified by Prep- TLC plate to obtain N-(3-(3-(2-chloro-4-hydroxybenzyl)-l,7-dimethyl-2,4-dioxo-l,2,3,4,7,8- hexahydropyrimido[l,2-f]purin-9(6H)-yl)phenyl)acrylamide (11.3 mg, 78.7%) as a white solid (Compound 31). LCMS: (ES+): m/z 521.1 [M]+. (0279) NMR (400 MHz, CDC1 ) d 8.08 (s, 1H), 7.35-7.31 (m, 3H), 7.09 (m, 1H), 6.89 (d, 7= 8.4 Hz, 1H), 6.80 (s, 1H), 6.58 (d, 7 = 8.0 Hz, 1H), 6.46 (J = 16.4 Hz, 1H), 6.30-6.27 (m, 1H), 5.80 (d, 7 = 10.4 Hz, 1H), 5.23 (s, 2H), 4.58-4.53 (m, 1H), 3.84-3.81 (m, 2H), 3.55 (m, 1H), 3.50 (s, 3H), 2,51 (br, 1H), 1.18 (d, 7 = 6.8 Hz, 3H).
78.7%	With triethylamine In dichloromethane at -60℃;	22 Example 22: Preparation of N-(3-(3-(2-chloro-4-hydroxybenzyl)-l,7-dimethyl-2,4-dioxo-l,2,3,4,7,8- hexahydropyrimido[l,2-f]purin-9(6H)-yl)phenyl)acrylamide (Compound 31) To the mixture of 9-(3-aminophenyl)-3-(2-chloro-4-hydroxybenzyl)-l,7-dimethyl-6, 7,8,9- tetrahydro pyrimido[l,2-f]purine-2,4(lH,3H)-dione (42 mg, 0.14 mmol) and TEA (23 mg, 0.42 mmol) in DCM (5 mL) was added slowly a solution of acrylic anhydride (12 uL, 0.11 mmol) in DCM (3 mL) at -60 °C. After the reaction completed as monitored by TLC, the reaction solution was quenched with ice water and extracted with DCM (20 mL x 3). The organic layer was washed with water and brine, dried over Na2SC>4, filtered and the solvent was removed by evaporation. The crude product was purified by Prep- TLC plate to obtain N-(3-(3-(2-chloro-4-hydroxybenzyl)-l,7-dimethyl-2,4-dioxo-l,2,3,4,7,8- hexahydropyrimido[l,2-f]purin-9(6H)-yl)phenyl)acrylamide (11.3 mg, 78.7%) as a white solid (Compound 31). LCMS: (ES+): m/z 521.1 [M]+. (0279) NMR (400 MHz, CDC1 ) d 8.08 (s, 1H), 7.35-7.31 (m, 3H), 7.09 (m, 1H), 6.89 (d, 7= 8.4 Hz, 1H), 6.80 (s, 1H), 6.58 (d, 7 = 8.0 Hz, 1H), 6.46 (J = 16.4 Hz, 1H), 6.30-6.27 (m, 1H), 5.80 (d, 7 = 10.4 Hz, 1H), 5.23 (s, 2H), 4.58-4.53 (m, 1H), 3.84-3.81 (m, 2H), 3.55 (m, 1H), 3.50 (s, 3H), 2,51 (br, 1H), 1.18 (d, 7 = 6.8 Hz, 3H).

Reference： [1]Current Patent Assignee: ACCUTAR BIOTECHNOLOGY INC - WO2021/252339, 2021, A1 Location in patent: Paragraph 185
[2]Current Patent Assignee: ACCUTAR BIOTECHNOLOGY INC - WO2021/252339, 2021, A1 Location in patent: Paragraph 185

83
[ 2051-76-5 ]
[ 3119-15-1 ]
[ 98085-79-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In methanol; at 100℃; for 4.0h;	10 g of <strong>[3119-15-1]3-amino-2,4,6-triiodobenzoic acid</strong> and 0.2 mL of concentrated sulfuric acid were added to 100 mL of methanol, and after stirring uniformly, the system was controlled at 20 C., and 30 mL of acrylic anhydride was slowly added dropwise.After the dropwise addition, the reaction was carried out at 100 C. for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, washed with acetonitrile, and dried to obtain 3-acrylamido-2,4,6-triiodobenzoic acid.

Reference： [1]Patent: CN114057600,2022,A .Location in patent: Paragraph 0067-0069; 0093-0095

84
[ 2051-76-5 ]
tert-butyl (S)-3-((7-chloro-1-(4-isopropyl-2-methylpyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)oxy)methylpiperazin-1-formate [ No CAS ]
tert-butyl (R)-2-chloro-12-(4-isopropyl-2-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hex ahydro-4-oxo-1,7,9a,10,12-pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-7(5H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With 1-propanephosphonic acid cyclic anhydride; N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate at 20℃; for 0.5h;	92.4 Step 4: tert-butyl (S)-3-(((7-chloro-1-(4-isopropyl-2-methylpyridin-3-yl)-2,4-dioxo-1 ,2,3,4-tetrah ydropyrido[2,3-d]pyrimidin-5-yl)oxy)methylpiperazin-1-formate (1.34 g,2.45 mmol), diisopropylethylamine(20 mL), dichloromethane(30 mL) were added to a round bottom flask. propylphosphonic anhydride solution (20 mL, 50%w/wethyl acetate solution was dropped thereto. The reaction was stirred at room temperature for 30 minutes. The completion of the reaction was detected by LC-MS. 50 mL of dichloromethane was added to the reaction, and the organic phase was washed with 30 mL of hydrochloric acid (1M) and 100 mL of the saturated sodium bicarbonate aqueous solution. The organic phase was dried and concentrated. The crude product was purified by a fast silica gel column (methanol /dichloromethane:0-3%) to obtain tert-butyl (R)-2-chloro-12-(4-isopropyl-2-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hex ahydro-4-oxo-1,7,9a,10,12-pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-7 (5H)-carboxylate (903mg, 70%). ES-API: [M+H]+=527.3.
70%	With 1-propanephosphonic acid cyclic anhydride; N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate at 20℃; for 0.5h;	92.4 Step 4: tert-butyl (S)-3-(((7-chloro-1-(4-isopropyl-2-methylpyridin-3-yl)-2,4-dioxo-1 ,2,3,4-tetrah ydropyrido[2,3-d]pyrimidin-5-yl)oxy)methylpiperazin-1-formate (1.34 g,2.45 mmol), diisopropylethylamine(20 mL), dichloromethane(30 mL) were added to a round bottom flask. propylphosphonic anhydride solution (20 mL, 50%w/wethyl acetate solution was dropped thereto. The reaction was stirred at room temperature for 30 minutes. The completion of the reaction was detected by LC-MS. 50 mL of dichloromethane was added to the reaction, and the organic phase was washed with 30 mL of hydrochloric acid (1M) and 100 mL of the saturated sodium bicarbonate aqueous solution. The organic phase was dried and concentrated. The crude product was purified by a fast silica gel column (methanol /dichloromethane:0-3%) to obtain tert-butyl (R)-2-chloro-12-(4-isopropyl-2-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hex ahydro-4-oxo-1,7,9a,10,12-pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-7 (5H)-carboxylate (903mg, 70%). ES-API: [M+H]+=527.3.

Reference： [1]Current Patent Assignee: GENFLEET THERAPEUTICS SHANGHAI; ZHEJIANG GENFLEET THERAPEUTICS; ZHEJIANG GENFLEET PHARMACEUTICAL - EP3964516, 2022, A1 Location in patent: Paragraph 0511; 0515
[2]Current Patent Assignee: GENFLEET THERAPEUTICS SHANGHAI; ZHEJIANG GENFLEET THERAPEUTICS; ZHEJIANG GENFLEET PHARMACEUTICAL - EP3964516, 2022, A1 Location in patent: Paragraph 0511; 0515

85
[ 2051-76-5 ]
C₂₈H₂₅⁽²⁾H₃F₂N₆O₃ [ No CAS ]
C₃₁H₂₇⁽²⁾H₃F₂N₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With triethylamine In dichloromethane at 0℃; for 0.25h;	100.4 Step 4: the intermediate was dissolved in dichloromethane (15 mL), and triethylamine (1g,10mmol) was added. The reaction was cooled to 0°C, and acrylic anhydride (120 mg, 0.95mmol) was dropped to the reaction solution. The reaction was stirred at 0°C for 15 minutes. 40 mL of dichloromethane was added to the reaction solution, the reaction solution was washed with 50mL of the saturated NaHCO3 aqueous solution, 40mL of the saturated brine, dried and concentrated, the crude product was purified by preparative liquid chromatography to obtain the target product: Z100(55mg,yield: 48%). ES-API: [M+H]+=592.2.
48%	With triethylamine In dichloromethane at 0℃; for 0.25h;	100.4 Step 4: the intermediate was dissolved in dichloromethane (15 mL), and triethylamine (1g,10mmol) was added. The reaction was cooled to 0°C, and acrylic anhydride (120 mg, 0.95mmol) was dropped to the reaction solution. The reaction was stirred at 0°C for 15 minutes. 40 mL of dichloromethane was added to the reaction solution, the reaction solution was washed with 50mL of the saturated NaHCO3 aqueous solution, 40mL of the saturated brine, dried and concentrated, the crude product was purified by preparative liquid chromatography to obtain the target product: Z100(55mg,yield: 48%). ES-API: [M+H]+=592.2.

Reference： [1]Current Patent Assignee: GENFLEET THERAPEUTICS SHANGHAI; ZHEJIANG GENFLEET THERAPEUTICS; ZHEJIANG GENFLEET PHARMACEUTICAL - EP3964516, 2022, A1 Location in patent: Paragraph 0549; 0553
[2]Current Patent Assignee: GENFLEET THERAPEUTICS SHANGHAI; ZHEJIANG GENFLEET THERAPEUTICS; ZHEJIANG GENFLEET PHARMACEUTICAL - EP3964516, 2022, A1 Location in patent: Paragraph 0549; 0553

86
[ 2051-76-5 ]
C₂₆H₂₄ClFN₈O₃ [ No CAS ]
C₂₉H₂₆ClFN₈O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With triethylamine In dichloromethane at 0℃; for 0.25h;	120.3 Step 3: the intermediate was dissolved in dichloromethane (15 mL), and triethylamine (1g, 9.9mmol) was added. The reaction was cooled to 0°C, and acrylic anhydride (14 mg, 0.11mmol) was dropped to the reaction solution. The reaction was stirred at 0°C for 15 minutes. 40 mL of dichloromethane was added to the reaction solution, the reaction solution was washed with 50mL of the saturated NaHCO3 aqueous solution, 40mL of the saturated brine, dried and concentrated. The crude product was purified by preparative liquid chromatography to obtain Compound Z120 (64mg,yield:44%). ES-API: [M+H]+=605.1. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s,1H),8.16-8.09 (m,1H), 7.26 (d, J = 7.2 Hz,1H),6.90-6.66 (m, 3H),6.20 (dd, J = 16.7,2.2 Hz,1H), 5.77 (dd, J = 10.4,2.2 Hz,1H), 4.91 (s,2H), 4.63-4.27 (m, 4H), 3.86 (d, J = 102.5 Hz, 3H), 3.55-3.37 (m,1H),1.40 (dd, J = 5.0, 3.2 Hz, 9H).
44%	With triethylamine In dichloromethane at 0℃; for 0.25h;	120.3 Step 3: the intermediate was dissolved in dichloromethane (15 mL), and triethylamine (1g, 9.9mmol) was added. The reaction was cooled to 0°C, and acrylic anhydride (14 mg, 0.11mmol) was dropped to the reaction solution. The reaction was stirred at 0°C for 15 minutes. 40 mL of dichloromethane was added to the reaction solution, the reaction solution was washed with 50mL of the saturated NaHCO3 aqueous solution, 40mL of the saturated brine, dried and concentrated. The crude product was purified by preparative liquid chromatography to obtain Compound Z120 (64mg,yield:44%). ES-API: [M+H]+=605.1. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s,1H),8.16-8.09 (m,1H), 7.26 (d, J = 7.2 Hz,1H),6.90-6.66 (m, 3H),6.20 (dd, J = 16.7,2.2 Hz,1H), 5.77 (dd, J = 10.4,2.2 Hz,1H), 4.91 (s,2H), 4.63-4.27 (m, 4H), 3.86 (d, J = 102.5 Hz, 3H), 3.55-3.37 (m,1H),1.40 (dd, J = 5.0, 3.2 Hz, 9H).

Reference： [1]Current Patent Assignee: GENFLEET THERAPEUTICS SHANGHAI; ZHEJIANG GENFLEET THERAPEUTICS; ZHEJIANG GENFLEET PHARMACEUTICAL - EP3964516, 2022, A1 Location in patent: Paragraph 0598; 0601
[2]Current Patent Assignee: GENFLEET THERAPEUTICS SHANGHAI; ZHEJIANG GENFLEET THERAPEUTICS; ZHEJIANG GENFLEET PHARMACEUTICAL - EP3964516, 2022, A1 Location in patent: Paragraph 0598; 0601

87
[ 2051-76-5 ]
2-{3-[(3S)-3-aminobut-1-yn-1-yl]pyridin-4-yl}-3-[(3-chloro-2-methoxyphenyl)amino]-1H,5H,6H,7H-pyrrolo[3,2-c]pyridin-4-one [ No CAS ]
N-[(2S)-4-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-1H,5H,6H,7H-pyrrolo[3,2-c]pyridin-2-yl}pyridin-3-yl)but-3-yn-2-yl]prop-2-enamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39.27%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -40℃; for 0.5h; Inert atmosphere;	116.3 116.3. Synthesis of N-[(2S)-4-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 1H,5H,6H,7H-pyrrolo[3,2-c]pyridin-2-yl}pyridin-3-yl)but-3-yn-2-yl]prop-2-enamide in-4-yl}-3-[(3-chloro-2- methoxyphenyl)amino]-1H,5H,6H,7H-pyrrolo[3,2-c]pyridin-4-one (80 mg, 0.18 mmol, 1.00 equiv) in DCM (2.00 mL) was added DIEA (119 mg, 0.92 mmol, 5.00 equiv) at room temperature. Prop-2-enoyl prop-2-enoate (46 mg, 0.37 mmol, 2.00 equiv) was added dropwise at -40°C. The mixture was stirred for 0.5 h at -40°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with CH2Cl2:MeOH (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (90 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 42% B in 10 min, 42% B; Wave Length: 254/220 nm; RT1(min): 9; Number Of Runs: 0) to afford N-[(2S)-4-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 1H,5H,6H,7H-pyrrolo[3,2-c]pyridin-2-yl}pyridin-3-yl)but-3-yn-2-yl]prop-2-enamide (35.6 mg, 39.27%) as a light yellow solid. LC-MS: (M+H)+ found:490.05. 1H NMR (400 MHz, Chloroform-d): δ 10.94 (s, 1H), 8.52 (s, 1H), 8.12 (d, 1H), 7.81 (s, 1H), 7.38 (d, 1H), 6.72 (d, 1H), 6.61 (t, 1H), 6.37 - 6.14 (m, 4H), 5.76 (d, 1H), 5.25 (s, 1H), 4.82 - 4.76 (m, 1H), 4.07 (s, 3H), 3.65 - 3.59 (m, 2H), 3.30 - 3.23 (m, 2H), 1.66 (d, 3H).
39.27%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -40℃; for 0.5h; Inert atmosphere;	116.3 116.3. Synthesis of N-[(2S)-4-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 1H,5H,6H,7H-pyrrolo[3,2-c]pyridin-2-yl}pyridin-3-yl)but-3-yn-2-yl]prop-2-enamide in-4-yl}-3-[(3-chloro-2- methoxyphenyl)amino]-1H,5H,6H,7H-pyrrolo[3,2-c]pyridin-4-one (80 mg, 0.18 mmol, 1.00 equiv) in DCM (2.00 mL) was added DIEA (119 mg, 0.92 mmol, 5.00 equiv) at room temperature. Prop-2-enoyl prop-2-enoate (46 mg, 0.37 mmol, 2.00 equiv) was added dropwise at -40°C. The mixture was stirred for 0.5 h at -40°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with CH2Cl2:MeOH (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (90 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 42% B in 10 min, 42% B; Wave Length: 254/220 nm; RT1(min): 9; Number Of Runs: 0) to afford N-[(2S)-4-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 1H,5H,6H,7H-pyrrolo[3,2-c]pyridin-2-yl}pyridin-3-yl)but-3-yn-2-yl]prop-2-enamide (35.6 mg, 39.27%) as a light yellow solid. LC-MS: (M+H)+ found:490.05. 1H NMR (400 MHz, Chloroform-d): δ 10.94 (s, 1H), 8.52 (s, 1H), 8.12 (d, 1H), 7.81 (s, 1H), 7.38 (d, 1H), 6.72 (d, 1H), 6.61 (t, 1H), 6.37 - 6.14 (m, 4H), 5.76 (d, 1H), 5.25 (s, 1H), 4.82 - 4.76 (m, 1H), 4.07 (s, 3H), 3.65 - 3.59 (m, 2H), 3.30 - 3.23 (m, 2H), 1.66 (d, 3H).

Reference： [1]Current Patent Assignee: SCORPION THERAPEUTICS - WO2022/66734, 2022, A1 Location in patent: Page/Page column 587-588
[2]Current Patent Assignee: SCORPION THERAPEUTICS - WO2022/66734, 2022, A1 Location in patent: Page/Page column 587-588

88
[ 2051-76-5 ]
C₄₂H₄₆ClF₄N₇O₃ [ No CAS ]
C₄₅H₄₈ClF₄N₇O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.7%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -25℃; for 2.5h; Large scale;	17 Example 17 To the solution of Compound 1e (3.02 kg, 5.32 mol, 1.0 equiv) in DCM (in 100 L reactor) was charged DIPEA (2.05 kg, 15.86 mol, 2.98 equiv). The mixture was cooled to ^25 °C, and a solution of acrylic anhydride (0.87 kg, 6.90 mol, 1.30 equiv) in DCM (28.30 kg, 7V) was slowly added over 140 min while maintaining the temperature below -20 °C. The reaction mixture was agitated for a minimum of 10 min, warmed to 5 °C and quenched with 10 wt% aqueous potassium bicarbonate solution (12.1 kg, 4V). The organic layer was washed with 20 wt% aqueous ammonium chloride solution (12.2 kg, 4V), followed by 10 wt% aqueous solution of monobasic potassium phosphosphate and dried with magnesium sulfate (1.50 kg, 50 wt%). The slurry was filtered and rinsed with DCM (8.05 kg, 2V) before passed through CUNO filter housing containing E-Pak Graver C-941 (850 g). The filtrate was then concentrated to 19 L (6V) and diluted with acetonitrile (9.60 kg, 4V). The solution was transferred to a 25 L reactor through in-line polish filter. Distillation was continued to remove DCM while replacing with acetonitrile (8.80 kg, 4V) to reach a final volume of 18 L before cooling the thick slurry to 0 °C. After holding at 0 °C for a minimum of 3 h, the slurry was filtered, rinsed with pre- cooled (temperature = 0 °C) acetonitrile (4.65 kg, 2V) and dried at 20 °C to give Compound A (2.32 kg) in 69.7% yield.1H NMR (400 MHz, DMSO-d6) 7.84 (d, J = 1.6 Hz, 1H), 6.87 (s, 2H), 6.83 (m, 1H), 6.52 (m, 1H), 6.20 (dd, J = 16.8, 6.8 Hz, 1H), 5.75 (dd, J = 10.4, 2.4 Hz, 1H), 4.76 (m, 1H), 4.41 (dd, J = 10.8, 4.7 Hz, 1H), 4.24 (m, 1H), 4.18 (dd, J = 10.8, 6.5 Hz, 1H), 4.13 (m, 2H), 3.67 (m, 1H), 3.47 (m, 1H), 3.25 (m, 1H), 2.95 (m, 1H), 2.58 (m, 1H), 2.39 (m, 3H), 2.37 (s, 3H), 2.17 (m, 1H), 1.94 (m, 1H), 1.68 (m, 3H), 1.29 (t, J = 6.6 Hz, 3H); 13C NMR (101 MHz, DMSO-d6): 165.4, 164.8, 164.7, 162.2, 161.3, 154.4, 151.8, 148.7, 148.7, 147.6, 143.0, 142.8, 131.1, 130.9, 129.6, 128.4, 128.4, 128.3, 128.2, 128.1, 126.9, 125.2, 125.2, 124.2, 121.5, 120.9, 120.9, 114.6, 114.6, 112.5, 112.2, 111.9, 111.7, 110.5, 69.8, 63.8, 57.4, 52.4, 52.3, 49.3, 45.8, 45.1, 44.8, 44.2, 42.0, 41.6, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.4, 29.0, 23.1, 20.3, 20.2, 15.8, 15.2; 19F NMR (376 MHz, DMSO-d6): ^53.7, ^125.9.
69.7%	With N-ethyl-N,N-diisopropylamine In dichloromethane at -25℃; for 2.5h; Large scale;	17 Example 17 To the solution of Compound 1e (3.02 kg, 5.32 mol, 1.0 equiv) in DCM (in 100 L reactor) was charged DIPEA (2.05 kg, 15.86 mol, 2.98 equiv). The mixture was cooled to ^25 °C, and a solution of acrylic anhydride (0.87 kg, 6.90 mol, 1.30 equiv) in DCM (28.30 kg, 7V) was slowly added over 140 min while maintaining the temperature below -20 °C. The reaction mixture was agitated for a minimum of 10 min, warmed to 5 °C and quenched with 10 wt% aqueous potassium bicarbonate solution (12.1 kg, 4V). The organic layer was washed with 20 wt% aqueous ammonium chloride solution (12.2 kg, 4V), followed by 10 wt% aqueous solution of monobasic potassium phosphosphate and dried with magnesium sulfate (1.50 kg, 50 wt%). The slurry was filtered and rinsed with DCM (8.05 kg, 2V) before passed through CUNO filter housing containing E-Pak Graver C-941 (850 g). The filtrate was then concentrated to 19 L (6V) and diluted with acetonitrile (9.60 kg, 4V). The solution was transferred to a 25 L reactor through in-line polish filter. Distillation was continued to remove DCM while replacing with acetonitrile (8.80 kg, 4V) to reach a final volume of 18 L before cooling the thick slurry to 0 °C. After holding at 0 °C for a minimum of 3 h, the slurry was filtered, rinsed with pre- cooled (temperature = 0 °C) acetonitrile (4.65 kg, 2V) and dried at 20 °C to give Compound A (2.32 kg) in 69.7% yield.1H NMR (400 MHz, DMSO-d6) 7.84 (d, J = 1.6 Hz, 1H), 6.87 (s, 2H), 6.83 (m, 1H), 6.52 (m, 1H), 6.20 (dd, J = 16.8, 6.8 Hz, 1H), 5.75 (dd, J = 10.4, 2.4 Hz, 1H), 4.76 (m, 1H), 4.41 (dd, J = 10.8, 4.7 Hz, 1H), 4.24 (m, 1H), 4.18 (dd, J = 10.8, 6.5 Hz, 1H), 4.13 (m, 2H), 3.67 (m, 1H), 3.47 (m, 1H), 3.25 (m, 1H), 2.95 (m, 1H), 2.58 (m, 1H), 2.39 (m, 3H), 2.37 (s, 3H), 2.17 (m, 1H), 1.94 (m, 1H), 1.68 (m, 3H), 1.29 (t, J = 6.6 Hz, 3H); 13C NMR (101 MHz, DMSO-d6): 165.4, 164.8, 164.7, 162.2, 161.3, 154.4, 151.8, 148.7, 148.7, 147.6, 143.0, 142.8, 131.1, 130.9, 129.6, 128.4, 128.4, 128.3, 128.2, 128.1, 126.9, 125.2, 125.2, 124.2, 121.5, 120.9, 120.9, 114.6, 114.6, 112.5, 112.2, 111.9, 111.7, 110.5, 69.8, 63.8, 57.4, 52.4, 52.3, 49.3, 45.8, 45.1, 44.8, 44.2, 42.0, 41.6, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.4, 29.0, 23.1, 20.3, 20.2, 15.8, 15.2; 19F NMR (376 MHz, DMSO-d6): ^53.7, ^125.9.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2022/35790, 2022, A1 Location in patent: Paragraph 0518-0520
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2022/35790, 2022, A1 Location in patent: Paragraph 0518-0520

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

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CAS No. :	2051-76-5	MDL No. :	MFCD00048146
Formula :	C₆H₆O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ARJOQCYCJMAIFR-UHFFFAOYSA-N
M.W :	126.11	Pubchem ID :	74919
Synonyms :

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	3265
Hazard Statements:	H314	Packing Group:	Ⅱ
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
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P103	Read label before use
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Code	Phrase
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P211	Do not spray on an open flame or other ignition source.
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
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P285	In case of inadequate ventilation wear respiratory protection.
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Response
Code	Phrase
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P322
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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

[ CAS No. 2051-76-5 ] {[proInfo.proName]}

Quality Control of [ 2051-76-5 ]

Related Doc. of [ 2051-76-5 ]

Product Details of [ 2051-76-5 ]

Safety of [ 2051-76-5 ]

Application In Synthesis of [ 2051-76-5 ]

[ 2051-76-5 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 2051-76-5 ]

Alkenes

Aliphatic Chain Hydrocarbons

Acid Anhydrides

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

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