Name: 917389-32-3|(S)-2-(8-Fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetic acid|98%
Brand: Ambeed
SKU: A236700
Price: 17.0 USD
Availability: InStock
Rating: 92 (32 reviews)

1
[ 917389-30-1 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
96.4%	With water; sodium hydrogencarbonate; sodium hydroxide In tert-butyl methyl ether Reflux; Large scale;	3b A mixture of (2S 3^-2,3-bis [(4-methylbenzoyl)oxy]succininc acid -{(45 8-fluoro-2-[4-(3- methoxyphenyl)piperazin- 1 -yl] -3 -[2-methoxy-5-(trifluoromethyl)phenyl] -3 ,4-dihydro- quinazolin-4-yl} acetic acid methyl ester (l :l-salt) (30,8 kg), sodium hydrogen carbonate (16.4 kg) and water (315 L) is stirred with MTBE (160 L). The phases obtained are separated and the organic phase is treated with 35 L of a 7% sodium hydrogen carbonate solution. The phases obtained are separated again and the organic phase is treated with 125 L of a 4% sodium hydroxide solution. The mixture is heated under reflux conditions. The solvent is distilled to run dry. The residual content of the reactor is stirred for further 5 h at 55 - 60°C. To the mixture MTBE (160 L) and water (65 L) is added under stirring at 22°C. The phases obtained are separated again and the organic phase is extracted with the aid of a 6% aqueous sodium chloride solution (30 L). The aqueous phases are reunited and stirred with water (25 L) and MTBE (160 L). The pH is adjusted to 6.5 with the aid of IN muriatic acid. The organic phase is separated, the solvent is gently distilled to run dry and the residue is dissolved in acetone (approximately 75 L). A change of the solvent is conducted towards acetone by means of 6 distillation steps of 130 L each. The product is subsequently precipitated by adding the residual solvent (approximately 60 L) under stirring conditions (61 rpm) in an excess of water (492 L) at room temperature. Followed by centrifugation, the isolated product is dried in a vacuum dryer equipped with a spiral crumbling roller at 40 to 80°C. By this procedure a yield of 16,5 kg of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin- l-yl]-3-(2-memoxy-5-trifluormethylphenyl)-3,4-dihydroquina2olin-4-yl}acetic acid is obtained as amorphous compound corresponding to 96.4% in theory.1H NMR (300 MHz, d6-DMSO): δ = 7,53 (d,2J - 8,4, 1H), 7,41 (brs, 1H), 7,22 (d,2J = 8,5, 1H), 7,09-7,01 (m, 2H), 6,86 (m, 2H)56,45 (dd,2J = 8,2,3J = 1,8, 1H), 6,39-6,34 (m, 2H), 4,87 (t,2J= 7,3, 1H), 3,79 (brs, 3H), 3,68 (s, 3H), 3,50-3,38 (m, 4H), 2,96-2,75 (m, 5H), 2,45- 2,40 (m, 1H) ppm; MS (API-ES-neg.): m/z = 571 [(M-H), 100 %];
96.4%	With water; sodium hydrogencarbonate; sodium hydroxide In tert-butyl methyl ether at 22℃; Reflux; Large scale;	6A Example 6A (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazoline-4-yl}acetic acid A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid methyl ester (1:1 salt) (30.8 kg), sodium bicarbonate (16.4 kg), and water (315 l) is mixed with MTBE (160 l). The phases are separated and the organic phase is treated with 35 l of an approximately seven-percent aqueous solution of sodium bicarbonate. The phases are separated and the organic phase is added to 125 l of an approximately four-percent aqueous solution of sodium hydroxide. The reaction mixture is heated to reflux, the solution is evaporated to dryness, and the reactor contents are then agitated for an additional 5 h at 55-60° C. The reaction mixture is then added at approx. 22° C. to MTBE (160 l) and water (65 l) and agitated. The phases are separated and the organic phase is extracted with an approximately six-percent aqueous solution of sodium chloride (30 l). The combined aqueous phases are mixed with water (25 l) and MTBE (160 l) and the pH value is adjusted to approx. 6.5 with approx. 1 N of hydrochloric acid. The organic phase is separated, the solvent is evaporated to dryness, and the residue is dissolved in acetone (approx. 75 l). The solvent is changed to acetone (6 distillations with approx. 130 l each). The final product is then precipitated by adding water, isolated through centrifugation, and dried in a vacuum dryer. A total of 16.5 kg of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazoline-4-yl}acetic acid is thus obtained as an amorphous solid, corresponding to 96.4% of theory. 1H NMR (300 MHz, d6-DMSO): δ=7.53 (d, 2J=8.4, 1H), 7.41 (brs, 1H), 7.22 (d, 2J=8.5, 1H), 7.09-7.01 (m, 2H), 6.86 (m, 2H), 6.45 (dd, 2J=8.2, 3J=1.8, 1H), 6.39-6.34 (m, 2H), 4.87 (t, 2J=7.3, 1H), 3.79 (brs, 3H), 3.68 (s, 3H), 3.50-3.38 (m, 4H), 2.96-2.75 (m, 5H), 2.45-2.40 (m, 1H) ppm; MS (API-ES-neg.): m/z=571 [(M+H), 100%];HPLC (Method 1): RT=15.1 min; HPLC (Method 2): 99.8% e.e.; Pd (ICP): <1 ppm.
96.4%	With water; sodium hydrogencarbonate In tert-butyl methyl ether Large scale;	6A (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazoline-4-yl}acetic acid A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid methyl ester (1:1 salt) (30.8 kg), sodium bicarbonate (16.4 kg), and water (315 l) is mixed with MTBE (160 l). The phases are separated and the organic phase is treated with 35 l of an approximately seven-percent aqueous solution of sodium bicarbonate. The phases are separated and the organic phase is added to 125 l of an approximately four-percent aqueous solution of sodium hydroxide. The reaction mixture is heated to reflux, the solution is evaporated to dryness, and the reactor contents are then agitated for an additional 5 h at 55-60° C. The reaction mixture is then added at approx. 22° C. to MTBE (160 l) and water (65 l) and agitated. The phases are separated and the organic phase is extracted with an approximately six-percent aqueous solution of sodium chloride (30 l). The combined aqueous phases are mixed with water (25 l) and MTBE (160 l) and the pH value is adjusted to approx. 6.5 with approx. 1 N of hydrochloric acid. The organic phase is separated out, the solvent is evaporated to dryness, and the residue is dissolved in acetone (approx. 75 l). The solvent is changed to acetone (6 distillations with approx. 130 l each). The final product is then precipitated by adding water, isolated through centrifugation, and dried in a vacuum dryer. A total of 16.5 kg of (S)-[8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazoline-4-yl]acetic acid is thus obtained as an amorphous solid, corresponding to 96.4% of theory. 1H NMR (300 MHz, d6-DMSO): δ=7.53 (d, 2J=8.4, 1H), 7.41 (brs, 1H), 7.22 (d, 2J=8.5, 1H), 7.09-7.01 (m, 2H), 6.86 (m, 2H), 6.45 (dd, 2J=8.2, 3J=1.8, 1H), 6.39-6.34 (m, 2H), 4.87 (t, 2J=7.3, 1H), 3.79 (brs, 3H), 3.68 (s, 3H), 3.50-3.38 (m, 4H), 2.96-2.75 (m, 5H), 2.45-2.40 (m, 1H) ppm; MS (API-ES-neg.): m/z=571 [(M+H), 100%];

92%	Stage #1: (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid {(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-(trifluormethyl)phenyl)-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester With sodium phosphate dibasic dihydrate In tert-butyl methyl ether; water at 20℃; for 0.666667h; Stage #2: With potassium hydroxide In methanol; tert-butyl methyl ether; water at 50℃; for 6h; Stage #3: With hydrogenchloride In tert-butyl methyl ether; water	6 Preparation of Compound A To a slurry of compound 7 (20g, 18.9 mmol) in MTBE (40.0 mL) at room temperature was added a solution of sodium phosphate dibasic dihydrate (8.42 g, 47.3 mmol) in water (80 mL) and the resulting slurry was allowed to stir at room temperature for 40 minutes. The reaction mixture was transferred to a separatory funnel and the organic phase was collected and washed with a solution of sodium phosphate dibasic dihydrate (3.37 g, 18.91 mmol) in water (40.0 mL). A solution of KOH (4.99 g, 76 mmol) in water (80 mL) and methanol (10.00 mL) was then added to the organic phase and the resulting mixture was heated to 50 °C and allowed to stir at this temperature for 6 hours. MTBE (20 mL) and water (40 mL) were then added to the reaction mixture and the resulting solution was transferred to a separatory funnel and the aqueous layer was collected and washed with MTBE (20 mL). Additional MTBE (40 mL) was added to the aqueous layer and the resulting solution was adjusted to pH 4-5 via slow addition of concentrated HCl. The resulting acidified solution was transferred to a separatory funnel and the organic phase was collected, concentrated in vacuo and solvent switched with acetone, maintaining a 30 mL volume. The resulting acetone solution was added dropwise to water and the precipitate formed was filtered to provide compound A as a white solid (10 g, 92%). 1H NMR (500 MHz, d6-DMSO): δΗ 12.6 (1H, s), 7.52 (1H, dd, J= 8.6, 1.3 Hz), 7.41 (1H, brs), 7.22 (1H, d, J= 7.2 Hz), 7.08-7.02 (2H, m), 6.87-6.84 (2H, m), 6.44 (1H, dd, J= 8.3, 1.8 Hz), 6.39 (1H, t, J= 2.1 Hz), 6.35 (1H, dd, J= 8.1, 2.0 Hz), 4.89 (1H, t, J= 7.3 Hz), 3.79 (3H, br s), 3.68 (3H, s), 3.47 (2H, br s), 3.39 (2H, br s), 2.96-2.93 (2H, m), 2.82-2.77 (3H, m), 2.44 (1H, dd, J = 14.8, 7.4 Hz).
81.2%	Stage #1: (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid {(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-(trifluormethyl)phenyl)-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester With water; sodium hydrogencarbonate In ethyl acetate Stage #2: With sodium hydroxide; water In 1,4-dioxane at 20℃; for 3 - 18h; Stage #3: With hydrogenchloride; water In 1,4-dioxane; isobutyl methyl ether

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2014/202737, 2014, A1 Location in patent: Page/Page column 53
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1 Location in patent: Paragraph 0134-0139
[3]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/133461, 2015, A1 Location in patent: Paragraph 0142; 0143
[4]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2015/88931, 2015, A1 Location in patent: Page/Page column 21-22
[5]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1 Location in patent: Page/Page column 3; 30; 31-32; 36-37

2
[ 917389-37-8 ]
[ 917389-32-3 ]
[ 791116-51-3 ]

Yield	Reaction Conditions	Operation in experiment
98.7%	Stage #1: (R)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetic acid; (S)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)-phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetic acid With methanol; sodium methylate In acetonitrile for 77h; Heating / reflux; Stage #2: With hydrogenchloride; water In 4-methyl-2-pentanone; acetonitrile

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1 Location in patent: Page/Page column 38

3
[ 917389-34-5 ]
[ 917389-37-8 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
14.6 % ee	Stage #1: (R)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetate With water; sodium hydrogencarbonate In ethyl acetate Stage #2: With sodium hydroxide; water In 1,4-dioxane at 20℃; for 18h; Stage #3: With hydrogenchloride; water In isobutyl methyl ether

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1 Location in patent: Page/Page column 37

4
C₁₉H₁₆F₄N₂O₄ [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / Reflux 2: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / Reflux 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / Reflux 4: ethyl acetate / 20 °C 5: sodium hydrogencarbonate; sodium hydroxide; water / tert-butyl methyl ether / Reflux; Large scale
	Multi-step reaction with 4 steps 1.1: phosphorus pentachloride; α-picoline / toluene / 4 h / 40 °C 2.1: sodium dihydrogenphosphate / toluene; water / 1 h / 20 °C 2.2: 1 h / 0 - 20 °C 3.1: potassium phosphate / toluene; water / 1 h / 20 °C 3.2: 0 °C 3.3: 12 h / 20 °C 4.1: sodium phosphate dibasic dihydrate / water; tert-butyl methyl ether / 0.67 h / 20 °C 4.2: 6 h / 50 °C 4.3: pH 4 - 5

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2014/202737, 2014, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2015/88931, 2015, A1

5
[ 917389-21-0 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / Reflux 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / Reflux 3: ethyl acetate / 20 °C 4: sodium hydrogencarbonate; sodium hydroxide; water / tert-butyl methyl ether / Reflux; Large scale
	Multi-step reaction with 3 steps 1.1: trichlorophosphate / chlorobenzene / 3 h / Reflux; Large scale 1.2: 9 h / Reflux; Large scale 2.1: ethyl acetate / 1 h / 20 °C / Large scale 2.2: 72 h / 20 °C / Large scale 3.1: sodium hydrogencarbonate / water; tert-butyl methyl ether / Large scale 3.2: Reflux; Large scale
	Multi-step reaction with 4 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 12 h / Reflux; Large scale 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / 4 h / Reflux; Large scale 3: ethyl acetate / 76 h / 0 - 20 °C / Large scale 4: sodium hydrogencarbonate; water; sodium hydroxide / tert-butyl methyl ether / 22 °C / Reflux; Large scale

	Multi-step reaction with 2 steps 1.1: trichlorophosphate / chlorobenzene / 3 h / Reflux; Large scale 1.2: 9 h / Reflux; Large scale 1.3: Large scale 2.1: sodium hydrogencarbonate; water / tert-butyl methyl ether / Large scale
	Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 3.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 4.1: water; sodium hydrogencarbonate / ethyl acetate 4.2: 3 - 18 h / 20 °C 4.3: pH 7.0 - 7.5
	Multi-step reaction with 5 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 3.1: sodium hydroxide; water / 1,4-dioxane / 2 h / 20 °C 4.1: sulfuric acid / 26 h / Heating / reflux 5.1: water; sodium hydrogencarbonate / ethyl acetate 5.2: 18 h / 20 °C 5.3: pH 7 - 14

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2014/202737, 2014, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/38514, 2015, A1
[3]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1
[4]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/133461, 2015, A1
[5]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[6]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

6
methyl 2-[2-chloro-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl]acetate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / Reflux 2: ethyl acetate / 20 °C 3: sodium hydrogencarbonate; sodium hydroxide; water / tert-butyl methyl ether / Reflux; Large scale
	Multi-step reaction with 3 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / 4 h / Reflux; Large scale 2: ethyl acetate / 76 h / 0 - 20 °C / Large scale 3: sodium hydrogencarbonate; water; sodium hydroxide / tert-butyl methyl ether / 22 °C / Reflux; Large scale
	Multi-step reaction with 3 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 2.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 3.1: water; sodium hydrogencarbonate / ethyl acetate 3.2: 3 - 18 h / 20 °C 3.3: pH 7.0 - 7.5

Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 2.1: sodium hydroxide; water / 1,4-dioxane / 2 h / 20 °C 3.1: sulfuric acid / 26 h / Heating / reflux 4.1: water; sodium hydrogencarbonate / ethyl acetate 4.2: 18 h / 20 °C 4.3: pH 7 - 14

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2014/202737, 2014, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1
[3]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[4]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

7
[ 348-54-9 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: acetonitrile / Reflux 2: acetic acid; palladium diacetate 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / Reflux 4: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / Reflux 5: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / Reflux 6: ethyl acetate / 20 °C 7: sodium hydrogencarbonate; sodium hydroxide; water / tert-butyl methyl ether / Reflux; Large scale
	Multi-step reaction with 6 steps 1.1: acetonitrile / 4 h / Reflux; Large scale 2.1: acetic acid; sulfuric acid; sulfur trioxide; palladium diacetate; oxygen / 20 h / 20 °C / Inert atmosphere; Large scale 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / Reflux; Large scale 4.1: trichlorophosphate / chlorobenzene / 3 h / Reflux; Large scale 4.2: 9 h / Reflux; Large scale 5.1: ethyl acetate / 1 h / 20 °C / Large scale 5.2: 72 h / 20 °C / Large scale 6.1: sodium hydrogencarbonate / water; tert-butyl methyl ether / Large scale 6.2: Reflux; Large scale
	Multi-step reaction with 7 steps 1.1: acetonitrile / 7.25 h / 0 °C / Reflux; Large scale 2.1: acetic acid / Inert atmosphere; Large scale 2.2: 20 h / 20 °C / Inert atmosphere; Large scale 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 55 °C / Reflux; Large scale 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 12 h / Reflux; Large scale 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / 4 h / Reflux; Large scale 6.1: ethyl acetate / 76 h / 0 - 20 °C / Large scale 7.1: sodium hydrogencarbonate; water; sodium hydroxide / tert-butyl methyl ether / 22 °C / Reflux; Large scale

	Multi-step reaction with 5 steps 1.1: acetonitrile / 4 h / Reflux; Large scale 2.1: palladium diacetate; fuming sulphuric acid; acetic acid / 20 h / 20 °C / Inert atmosphere; Large scale 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / Reflux; Large scale 4.1: trichlorophosphate / chlorobenzene / 3 h / Reflux; Large scale 4.2: 9 h / Reflux; Large scale 4.3: Large scale 5.1: sodium hydrogencarbonate; water / tert-butyl methyl ether / Large scale
	Multi-step reaction with 7 steps 1.1: acetonitrile / 4 h / 82 °C 2.1: sulfuric acid; acetic acid / palladium diacetate / 20 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 56 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 6.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 7.1: water; sodium hydrogencarbonate / ethyl acetate 7.2: 3 - 18 h / 20 °C 7.3: pH 7.0 - 7.5
	Multi-step reaction with 8 steps 1.1: acetonitrile / 4 h / 82 °C 2.1: sulfuric acid; acetic acid / palladium diacetate / 20 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 56 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 6.1: sodium hydroxide; water / 1,4-dioxane / 2 h / 20 °C 7.1: sulfuric acid / 26 h / Heating / reflux 8.1: water; sodium hydrogencarbonate / ethyl acetate 8.2: 18 h / 20 °C 8.3: pH 7 - 14

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2014/202737, 2014, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/38514, 2015, A1
[3]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1
[4]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/133461, 2015, A1
[5]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[6]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

8
[ 16588-75-3 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: acetonitrile / Reflux 2: acetic acid; palladium diacetate 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / Reflux 4: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / Reflux 5: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / Reflux 6: ethyl acetate / 20 °C 7: sodium hydrogencarbonate; sodium hydroxide; water / tert-butyl methyl ether / Reflux; Large scale
	Multi-step reaction with 6 steps 1.1: acetonitrile / 4 h / Reflux; Large scale 2.1: acetic acid; sulfuric acid; sulfur trioxide; palladium diacetate; oxygen / 20 h / 20 °C / Inert atmosphere; Large scale 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / Reflux; Large scale 4.1: trichlorophosphate / chlorobenzene / 3 h / Reflux; Large scale 4.2: 9 h / Reflux; Large scale 5.1: ethyl acetate / 1 h / 20 °C / Large scale 5.2: 72 h / 20 °C / Large scale 6.1: sodium hydrogencarbonate / water; tert-butyl methyl ether / Large scale 6.2: Reflux; Large scale
	Multi-step reaction with 7 steps 1.1: acetonitrile / 7.25 h / 0 °C / Reflux; Large scale 2.1: acetic acid / Inert atmosphere; Large scale 2.2: 20 h / 20 °C / Inert atmosphere; Large scale 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 55 °C / Reflux; Large scale 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 12 h / Reflux; Large scale 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / 4 h / Reflux; Large scale 6.1: ethyl acetate / 76 h / 0 - 20 °C / Large scale 7.1: sodium hydrogencarbonate; water; sodium hydroxide / tert-butyl methyl ether / 22 °C / Reflux; Large scale

	Multi-step reaction with 5 steps 1.1: acetonitrile / 4 h / Reflux; Large scale 2.1: palladium diacetate; fuming sulphuric acid; acetic acid / 20 h / 20 °C / Inert atmosphere; Large scale 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / Reflux; Large scale 4.1: trichlorophosphate / chlorobenzene / 3 h / Reflux; Large scale 4.2: 9 h / Reflux; Large scale 4.3: Large scale 5.1: sodium hydrogencarbonate; water / tert-butyl methyl ether / Large scale
	Multi-step reaction with 6 steps 1.1: acetonitrile / 38 - 45 h / 35 - 88 °C 2.1: triethylamine / dichloro bis(acetonitrile) palladium(II); tris-(o-tolyl)phosphine / Isobutyronitrile / 16 - 22 h / 90 - 102 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 5.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 6.1: water; sodium hydrogencarbonate / ethyl acetate 6.2: 3 - 18 h / 20 °C 6.3: pH 7.0 - 7.5
	Multi-step reaction with 7 steps 1.1: acetonitrile / 4 h / 82 °C 2.1: sulfuric acid; acetic acid / palladium diacetate / 20 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 56 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 6.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 7.1: water; sodium hydrogencarbonate / ethyl acetate 7.2: 3 - 18 h / 20 °C 7.3: pH 7.0 - 7.5
	Multi-step reaction with 7 steps 1.1: acetonitrile / 38 - 45 h / 35 - 88 °C 2.1: triethylamine / dichloro bis(acetonitrile) palladium(II); tris-(o-tolyl)phosphine / Isobutyronitrile / 16 - 22 h / 90 - 102 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 5.1: sodium hydroxide; water / 1,4-dioxane / 2 h / 20 °C 6.1: sulfuric acid / 26 h / Heating / reflux 7.1: water; sodium hydrogencarbonate / ethyl acetate 7.2: 18 h / 20 °C 7.3: pH 7 - 14
	Multi-step reaction with 8 steps 1.1: acetonitrile / 4 h / 82 °C 2.1: sulfuric acid; acetic acid / palladium diacetate / 20 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 56 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 6.1: sodium hydroxide; water / 1,4-dioxane / 2 h / 20 °C 7.1: sulfuric acid / 26 h / Heating / reflux 8.1: water; sodium hydrogencarbonate / ethyl acetate 8.2: 18 h / 20 °C 8.3: pH 7 - 14

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2014/202737, 2014, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/38514, 2015, A1
[3]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1
[4]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/133461, 2015, A1
[5]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[6]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[7]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[8]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

9
[ 917389-24-3 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: acetic acid; palladium diacetate 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / Reflux 3: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / Reflux 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / Reflux 5: ethyl acetate / 20 °C 6: sodium hydrogencarbonate; sodium hydroxide; water / tert-butyl methyl ether / Reflux; Large scale
	Multi-step reaction with 5 steps 1.1: acetic acid; sulfuric acid; sulfur trioxide; palladium diacetate; oxygen / 20 h / 20 °C / Inert atmosphere; Large scale 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / Reflux; Large scale 3.1: trichlorophosphate / chlorobenzene / 3 h / Reflux; Large scale 3.2: 9 h / Reflux; Large scale 4.1: ethyl acetate / 1 h / 20 °C / Large scale 4.2: 72 h / 20 °C / Large scale 5.1: sodium hydrogencarbonate / water; tert-butyl methyl ether / Large scale 5.2: Reflux; Large scale
	Multi-step reaction with 6 steps 1.1: acetic acid / Inert atmosphere; Large scale 1.2: 20 h / 20 °C / Inert atmosphere; Large scale 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 55 °C / Reflux; Large scale 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 12 h / Reflux; Large scale 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / 4 h / Reflux; Large scale 5.1: ethyl acetate / 76 h / 0 - 20 °C / Large scale 6.1: sodium hydrogencarbonate; water; sodium hydroxide / tert-butyl methyl ether / 22 °C / Reflux; Large scale

	Multi-step reaction with 4 steps 1.1: palladium diacetate; fuming sulphuric acid; acetic acid / 20 h / 20 °C / Inert atmosphere; Large scale 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / Reflux; Large scale 3.1: trichlorophosphate / chlorobenzene / 3 h / Reflux; Large scale 3.2: 9 h / Reflux; Large scale 3.3: Large scale 4.1: sodium hydrogencarbonate; water / tert-butyl methyl ether / Large scale
	Multi-step reaction with 6 steps 1.1: sulfuric acid; acetic acid / palladium diacetate / 20 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 56 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 5.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 6.1: water; sodium hydrogencarbonate / ethyl acetate 6.2: 3 - 18 h / 20 °C 6.3: pH 7.0 - 7.5
	Multi-step reaction with 7 steps 1.1: sulfuric acid; acetic acid / palladium diacetate / 20 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 56 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 5.1: sodium hydroxide; water / 1,4-dioxane / 2 h / 20 °C 6.1: sulfuric acid / 26 h / Heating / reflux 7.1: water; sodium hydrogencarbonate / ethyl acetate 7.2: 18 h / 20 °C 7.3: pH 7 - 14

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2014/202737, 2014, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/38514, 2015, A1
[3]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1
[4]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/133461, 2015, A1
[5]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[6]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

10
[ 917389-32-3 ]
monosodium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium hydroxide In ethanol; di-isopropyl ether at 50℃; for 3.41667h;	B.1 Monosodium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid Example 1 Monosodium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid 333.1 g of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid (Example 6A) are dissolved in 1300 ml of a mixture of ethanol and diisopropyl ether (1:1) in a 2000 ml three-neck flask. 21.9 g (546.84 mmol) of NaOH are added as a solid to the solution. The mixture is heated for 25 min. to an inner temperature of 50° C., and this yields a clear orange-coloured solution. The solution thus obtained is stirred for 3 hours at this temperature, and a thin suspension is formed already after 1 hour. The reaction mixture is then cooled down for 10 hours at a cooling rate of 3° C./hour to an inner temperature of 20° C. and then stirred for a further 5 hours at this temperature. The total volume of the reaction mixture is reduced under vacuum to approximately 750 ml and the suspension obtained in this way is stirred at 20° C. for 2 hours. Next, 250 ml diisopropyl ether is added over a period of 10 min. to the reaction mixture obtained and the mixture is stirred for further 2 hours. The crystalline product which is obtained is vacuumed off by a suction device, washed 2* with in each case 250 ml diisopropyl ether, and dried in a vacuum drying cabinet for 20 hours at 20° C. and 160 mbar. The crystalline solid obtained in this way is then dried for 10 min. at 90° C. in an IR dryer and then again for further 16 hours at 60° C. in the vacuum drying cabinet. In this way a total of 274.4 g (86% of the theoretical yield) of the desired crystalline sodium salt is obtained.

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/38514, 2015, A1 Location in patent: Paragraph 0146

11
methyl-(2Z)-3-[3-fluoro-2-([2-methoxy-5-(trifluoromethyl)phenyl]carbamoyl}amino)-phenyl]acrylate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / Reflux; Large scale 2.1: trichlorophosphate / chlorobenzene / 3 h / Reflux; Large scale 2.2: 9 h / Reflux; Large scale 3.1: ethyl acetate / 1 h / 20 °C / Large scale 3.2: 72 h / 20 °C / Large scale 4.1: sodium hydrogencarbonate / water; tert-butyl methyl ether / Large scale 4.2: Reflux; Large scale
	Multi-step reaction with 5 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 55 °C / Reflux; Large scale 2: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 12 h / Reflux; Large scale 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / 4 h / Reflux; Large scale 4: ethyl acetate / 76 h / 0 - 20 °C / Large scale 5: sodium hydrogencarbonate; water; sodium hydroxide / tert-butyl methyl ether / 22 °C / Reflux; Large scale
	Multi-step reaction with 3 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / Reflux; Large scale 2.1: trichlorophosphate / chlorobenzene / 3 h / Reflux; Large scale 2.2: 9 h / Reflux; Large scale 2.3: Large scale 3.1: sodium hydrogencarbonate; water / tert-butyl methyl ether / Large scale

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/38514, 2015, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1
[3]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/133461, 2015, A1

12
(2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}methyl acetate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
96.4%	Stage #1: (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}methyl acetate With sodium hydrogencarbonate In tert-butyl methyl ether; water Large scale; Stage #2: With water; sodium hydroxide In tert-butyl methyl ether Reflux; Large scale;	A.6A Example 6A (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethyl-phenyl)-3,4-dihydroquinazoline-4-yl}acetic acid Example 6A (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethyl-phenyl)-3,4-dihydroquinazoline-4-yl}acetic acid A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid methyl ester (1:1 salt) (30.8 kg), sodium bicarbonate (16.4 kg), and water (315 l) is mixed with MTBE (160 l). The phases are separated and the organic phase is treated with 35 l of an approximately seven-percent aqueous solution of sodium bicarbonate. The phases are separated and the organic phase is added to 125 l of an approximately four-percent aqueous solution of sodium hydroxide. The reaction mixture is heated to reflux, the solution is evaporated to dryness, and the reactor contents are then agitated for an additional 5 h at 55-60° C. The reaction mixture is then added at approx. 22° C. to MTBE (160 l) and water (65 l) and agitated. The phases are separated and the organic phase is extracted with an approximately six-percent aqueous solution of sodium chloride (30 l). The combined aqueous phases are mixed with water (25 l) and MTBE (160 l) and the pH value is adjusted to approx. 6.5 with approx. 1 N of hydrochloric acid. The organic phase is separated, the solvent is evaporated to dryness, and the residue is dissolved in acetone (approx. 75 l). The solvent is changed to acetone (6 distillations with approx. 130 l each). The final product is then precipitated by adding water, isolated through centrifugation, and dried in a vacuum dryer. A total of 16.5 kg of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazoline-4-yl}acetic acid is thus obtained as an amorphous solid, corresponding to 96.4% of theory. 1H NMR (300 MHz, d6-DMSO): δ=7.53 (d, 2J=8.4, 1H), 7.41 (brs, 1H), 7.22 (d, 2J=8.5, 1H), 7.09-7.01 (m, 2H), 6.86 (m, 2H), 6.45 (dd, 2J=8.2, 3J=1.8, 1H), 6.39-6.34 (m, 2H), 4.87 (t, 2J=7.3, 1H), 3.79 (brs, 3H), 3.68 (s, 3H), 3.50-3.38 (m, 4H), 2.96-2.75 (m, 5H), 2.45-2.40 (m, 1H) ppm; MS (API-ES-neg.): m/z=571 [(M+H), 100%]; HPLC (Method 1): RT=15.1 min; [0139] HPLC (Method 2): 99.8% e.e.; Pd (ICP): <1 ppm.

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/38514, 2015, A1 Location in patent: Paragraph 0134-0139

13
[ 917389-32-3 ]
calcium saltof {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.5%	With calcium hydroxide In ethanol at 50℃; for 3.41667h;	3 Example 3 Production of the 2,5 hydrate of the calcium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid Example 3 Production of the 2,5 hydrate of the calcium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid [0151] 10 g of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid (Example 6A) are dissolved in 45 ml of ethanol in a 50 ml three-neck flask and 1.294 g Ca(OH2) are added as a solid in the form of a powder to the solution obtained. The resulting suspension is heated for 25 min. to 50° C. and then stirred for 3 hours at this temperature. 62.6 g of water are added to the suspension obtained in this way and the resulting solution is cooled to 0° C. Previously produced seed crystals are added to the solution thus obtained and the suspension, which contains a partially oily product, is heated to room temperature and allowed to remain at room temperature for 72 hours. The suspension thus obtained is again cooled to 0° C. and then stirred for 2 h at this temperature. The crystalline product that is obtained is filtered off and washed 2× with in each case 15 ml of a 1:1 mixture of ethanol and water and then dried at 50° C. and 160 mbar in the vacuum drying cabinet. Altogether 7.4 g (68.5% of the theoretical yield) of the salt is obtained as a crystalline solid. [0152] Using the crystalline solid obtained in Example 3 an X-ray powder diffractogram (XRD), which is shown in FIG. 2, was recorded under the same conditions as those mentioned in Example 2.

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/38514, 2015, A1 Location in patent: Paragraph 0151-0152

14
[ 917389-32-3 ]
[ 98-11-3 ]
(S)-(+)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid besylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.4%	In water; acetone at 0 - 40℃;	1 Example 1 Besylate salt of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trif- luoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid 235.00 g (0.41 mol) of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy- -5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid (Example 6A) are dissolved in 1645 ml of acetone and 16.45 ml of water is added to the resulting mixture. The resulting yellowish solution is filtered and 64.92 g (0.41 mol) of benzenesulfonic acid as a solid is added portion by portion. The resulting solution is heated to about 40° C. and suitable seed crystals are added at this temperature. The resulting solution is cooled down to room temperature under stirring and the resulting suspension is cooled to 0-5° C. and stirred for an additional 2 hours at that temperature. The resulting solid is filtered, washed 2 with acetone (100 ml, 0° C.) and dried at 60° C. to constant weight. This process yields a total of 243.87 g (81.4% of the theoretic quantity) of the target compound.[0145] From the crystalline solid obtained in Example 1, an X-ray powder diffractogram (XRD) was recorded with a Siemens Powder Diffractometer D5000 that is shown in FIG. 1, under the following conditions.[0146] The peak lists for the salt obtained in Example 1 as well as for the salt obtained in Example 2 are shown in Table 2.[0147] Measuring Conditions[0148] Copper anode (wavelength 1.5418 Å)[0149] Voltage: 4000 V, Current: 30 mA[0150] Secondary graphite monochromator,[0151] variable (theta-dependent) divergence and anti-diffusion shield[0152] Detector aperture: 0.2 mm[0153] 6 10 mm effective sample surface[0154] Scanning 0.02° (2 theta), 2 sec.

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1 Location in patent: Paragraph 0144-0154

15
[ 917389-32-3 ]
(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazoline-4-yl}acetic acid monosulfate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid In water at 20℃; for 168h;	Crystallization Experiments General procedure: Crystallization experiments to find a suitable crystalline salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluor- omethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid were conducted. The crystallization experiments were based on (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trif- luoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid and the respective acid either by slurrification in the individually specified solvent for one week at 20° C. or by crystallization through cooling/evaporation of a solution that was kept at 50° C. for 4 hours, followed by slow cooling to 20° C. at a ratio of 3° C./hour.[0141] The results of the crystallization experiments are given in Table 1 below where the abbreviation API denotes (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trif- luoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid. "API" is the acronym for "active pharmaceutical ingredient".

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1 Location in patent: Paragraph 0140-0142

16
[ 917389-32-3 ]
(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazoline-4-yl}acetic acid dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In water at 20℃; for 168h;	Crystallization Experiments General procedure: Crystallization experiments to find a suitable crystalline salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluor- omethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid were conducted. The crystallization experiments were based on (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trif- luoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid and the respective acid either by slurrification in the individually specified solvent for one week at 20° C. or by crystallization through cooling/evaporation of a solution that was kept at 50° C. for 4 hours, followed by slow cooling to 20° C. at a ratio of 3° C./hour.[0141] The results of the crystallization experiments are given in Table 1 below where the abbreviation API denotes (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trif- luoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid. "API" is the acronym for "active pharmaceutical ingredient".

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1 Location in patent: Paragraph 0140-0142

17
[ 917389-32-3 ]
(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazoline-4-yl}acetic acid monophosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With phosphoric acid In water at 20℃; for 168h;	Crystallization Experiments General procedure: Crystallization experiments to find a suitable crystalline salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluor- omethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid were conducted. The crystallization experiments were based on (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trif- luoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid and the respective acid either by slurrification in the individually specified solvent for one week at 20° C. or by crystallization through cooling/evaporation of a solution that was kept at 50° C. for 4 hours, followed by slow cooling to 20° C. at a ratio of 3° C./hour.[0141] The results of the crystallization experiments are given in Table 1 below where the abbreviation API denotes (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trif- luoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid. "API" is the acronym for "active pharmaceutical ingredient".

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1 Location in patent: Paragraph 0140-0142

18
[ 917389-32-3 ]
[ 104-15-4 ]
(S)-(+)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid tosylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.3%	In water; acetone at 0 - 36℃;	2 Example 2 Tosylate salt of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trif- luoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid 235.00 g (0.41 mol) of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trif- luoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid (Example 6A) are dissolved in 1645 ml of acetone and 16.45 ml of water is added to the solution. The resulting yellowish solution is filtered and 78.07 g (0.41 mol) of solid p-toluenesulfonic acid monohydrate are added portion by portion at about 36° C. The solution is cooled down to room temperature under stirring and the resulting suspension is then cooled to 0-5° C. and stirred for an additional 2 hours at that temperature. The solid material is separated, washed 2 with acetone (100 ml, 0° C.) and dried at 60° C. to constant weight. This process yielded a total of 248.11 g (79.3% of the theoretic quantity) of the desired final product.[0156] From the crystalline solid material obtained in Example 2 an X-ray powder diffractogram (XRD), shown in FIG. 2, was recorded under the same conditions as for Example 1.

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1 Location in patent: Paragraph 0155; 0156

19
[ 917389-32-3 ]
[ 77-92-9 ]
(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazoline-4-yl}acetic acid monocitrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water at 20℃; for 168h;	Crystallization Experiments General procedure: Crystallization experiments to find a suitable crystalline salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluor- omethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid were conducted. The crystallization experiments were based on (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trif- luoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid and the respective acid either by slurrification in the individually specified solvent for one week at 20° C. or by crystallization through cooling/evaporation of a solution that was kept at 50° C. for 4 hours, followed by slow cooling to 20° C. at a ratio of 3° C./hour.[0141] The results of the crystallization experiments are given in Table 1 below where the abbreviation API denotes (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trif- luoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid. "API" is the acronym for "active pharmaceutical ingredient".

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - US2015/45371, 2015, A1 Location in patent: Paragraph 0140-0142

20
C₁₉H₁₄F₄N₂O₃ [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium dihydrogenphosphate / toluene; water / 1 h / 20 °C 1.2: 1 h / 0 - 20 °C 2.1: potassium phosphate / toluene; water / 1 h / 20 °C 2.2: 0 °C 2.3: 12 h / 20 °C 3.1: sodium phosphate dibasic dihydrate / water; tert-butyl methyl ether / 0.67 h / 20 °C 3.2: 6 h / 50 °C 3.3: pH 4 - 5

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2015/88931, 2015, A1

21
[ 65896-11-9 ]
[ 917389-32-3 ]

Reference： [1]Patent: WO2015/88931,2015,A1
[2]Organic Process Research and Development,2016,vol. 20,p. 1097 - 1103
[3]Organic Process Research and Development,2016,vol. 20,p. 1097 - 1103
[4]Organic Process Research and Development,2016,vol. 20,p. 1097 - 1103
[5]Angewandte Chemie - International Edition,2017,vol. 56,p. 16032 - 16036
Angew. Chem.,2017,vol. 129,p. 16248 - 16252,5
[6]Patent: WO2006/133822,2006,A1
[7]Patent: WO2006/133822,2006,A1

22
C₁₇H₁₄FNO₄ [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: dmap / Isopropyl acetate / 5 h / Reflux 2.1: phosphorus pentachloride; α-picoline / toluene / 4 h / 40 °C 3.1: sodium dihydrogenphosphate / toluene; water / 1 h / 20 °C 3.2: 1 h / 0 - 20 °C 4.1: potassium phosphate / toluene; water / 1 h / 20 °C 4.2: 0 °C 4.3: 12 h / 20 °C 5.1: sodium phosphate dibasic dihydrate / water; tert-butyl methyl ether / 0.67 h / 20 °C 5.2: 6 h / 50 °C 5.3: pH 4 - 5

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2015/88931, 2015, A1

23
[ 917389-32-3 ]
C₂₉H₂₆⁽²⁾H₂F₄N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,6-(2,6-<SUP>i</SUP>Pr<SUB>2</SUB>-C<SUB>6</SUB>H<SUB>3</SUB>-4,5-H<SUB>2</SUB>-imidazol-2-ylidene)<SUB>2</SUB>C<SUB>5</SUB>H<SUB>3</SUB>NFe(N<SUB>2</SUB>)<SUB>2</SUB>; deuterium In tetrahydrofuran at 45℃; for 24h;

Reference： [1]Pony Yu, Renyuan; Hesk, David; Rivera, Nelo; Pelczer, Istvan; Chirik, Paul J. [Nature, 2016, vol. 529, # 7585, p. 195 - 199]

24
[ 917389-21-0 ]
[ 917389-37-8 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trichlorophosphate; N-ethyl-N,N-diisopropylamine / 16 h / 120 °C / Inert atmosphere 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / 3 h / 130 °C / Microwave irradiation 3: sodium hydroxide; water / 1,4-dioxane / 20 °C
	Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 3.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 4.1: water; sodium hydrogencarbonate / ethyl acetate 4.2: 18 h / 20 °C 4.3: pH 7 - 14

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2016/109360, 2016, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

25
methyl 2-[2-chloro-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl]acetate [ No CAS ]
[ 917389-37-8 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / 3 h / 130 °C / Microwave irradiation 2: sodium hydroxide; water / 1,4-dioxane / 20 °C
	Multi-step reaction with 3 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 2.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 3.1: water; sodium hydrogencarbonate / ethyl acetate 3.2: 18 h / 20 °C 3.3: pH 7 - 14

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2016/109360, 2016, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

26
[ 791117-40-3 ]
[ 917389-37-8 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
62.2 mg	With water; sodium hydroxide In 1,4-dioxane at 20℃;	1.5 (S)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3- methoxyphenyl)piperazin-l-yl)-3,4-dihydroquinazolin-4-yl)acetic acid [00190] To a solution of methyl 2-[8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2- [4-(3-methoxyphenyl)piperazin-l-yl]-3,4-dihydroquinazolin-4-yl]acetate (5, 600 mg) in dioxane (5 mL ) was added 1 mol/L NaOH (2.5 mL) and the mixture was stirred for 1 overnight at room-temperature and was monitored by LCMS. The reaction mixture was adjusted pH to 3 with 1 mol/L HC1 and extracted with 3 x 5 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium, filtered and concentrated under vacuum. The crude product was purified by Prep-SFC with the following conditions: Column, Chiralpak OD-H, 20*250mm, 20um; mobile phase, CO2(70%), methanol(30%); Detector, UV 254 nm to afford 62.2 mg of the product as a light yellow solid. NMR (300 MHz, CDCh) δ: 7.69 - 6.31 (m , 10 H), 4.93 - 4.88 (m, 1 H), 3.74 (s, 6 H), 3.66 - 2.62 (m, 10 H). LC-MS: m/z = 573.15 [M+l]+.
	Multi-step reaction with 2 steps 1.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 2.1: water; sodium hydrogencarbonate / ethyl acetate 2.2: 18 h / 20 °C 2.3: pH 7 - 14

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2016/109360, 2016, A1 Location in patent: Paragraph 00189-00190
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

27
[ 65896-11-9 ]
[ 917389-37-8 ]
[ 917389-32-3 ]

Reference： [1]Patent: WO2016/109360,2016,A1
[2]Patent: WO2006/133822,2006,A1

28
[ 349-65-5 ]
[ 917389-37-8 ]
[ 917389-32-3 ]

Reference： [1]Patent: WO2016/109360,2016,A1

29
[ 917389-23-2 ]
[ 917389-37-8 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine; dichloro bis(acetonitrile) palladium(II); tris-(o-tolyl)phosphine / acetonitrile / 2 h / 110 °C / Microwave irradiation 2: trichlorophosphate; N-ethyl-N,N-diisopropylamine / 16 h / 120 °C / Inert atmosphere 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane / 3 h / 130 °C / Microwave irradiation 4: sodium hydroxide; water / 1,4-dioxane / 20 °C
	Multi-step reaction with 5 steps 1.1: triethylamine / dichloro bis(acetonitrile) palladium(II); tris-(o-tolyl)phosphine / Isobutyronitrile / 16 - 22 h / 90 - 102 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 4.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 5.1: water; sodium hydrogencarbonate / ethyl acetate 5.2: 18 h / 20 °C 5.3: pH 7 - 14

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2016/109360, 2016, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

30
C₃₀H₂₉BrF₄N₄O₄ [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: C₁₄H₁₈N₂O₆Pd₂S₂; (1R)-1-[(1R)-1-[bis[3,5-bis(trifluoromethyl)-phenyl]phosphino]ethyl]-2-[2-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-phenyl]ferrocene; cesium formate / N,N-dimethyl-formamide / 12 h / 60 °C / Inert atmosphere 2.1: toluene / 45 °C / Inert atmosphere 3.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 3.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

31
methyl-(2E)-3-(3-fluoro-2-((((2-methoxy-5-(trifluoromethyl)phenyl)amino)(4-(3-methoxyphenyl)-piperazin-1-yl)methylene)amino)phenyl)acrylate 2-hydrobenzoate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium phosphate / toluene; water / 1 h / 45 °C 1.2: 5 h / 0 °C 2.1: toluene / 45 °C / Inert atmosphere 3.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 3.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

32
C₃₀H₃₀F₄N₄O₄ [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: C₁₄H₁₈N₂O₆Pd₂S₂; (1R)-1-[(1R)-1-[bis[3,5-bis(trifluoromethyl)-phenyl]phosphino]ethyl]-2-[2-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-phenyl]ferrocene; cesium formate / N,N-dimethyl-formamide / 12 h / 60 °C / Inert atmosphere 2.1: toluene / 45 °C / Inert atmosphere 3.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 3.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

33
[ 690664-20-1 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: disodium hydrogenphosphate / water; Isopropyl acetate / 14 h / 20 - 60 °C / Inert atmosphere; Large scale 2.1: dmap / Isopropyl acetate / 5 h / Inert atmosphere; Reflux; Large scale 3.1: potassium phosphate; C₂₉H₃₄N₃O₆⁽¹⁺⁾*Br^(1-) / toluene; water / Inert atmosphere 4.1: phosphorus pentachloride / 2,2,2-trifluoroethanol / Inert atmosphere 5.1: toluene / 45 °C / Inert atmosphere 6.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 6.2: 5 h / 60 °C / Inert atmosphere
	Multi-step reaction with 7 steps 1.1: disodium hydrogenphosphate / water; Isopropyl acetate / 14 h / 20 - 60 °C / Inert atmosphere; Large scale 2.1: dmap / Isopropyl acetate / 5 h / Inert atmosphere; Reflux; Large scale 3.1: phosphorus pentachloride; α-picoline / toluene / 5 h / 20 - 40 °C / Inert atmosphere; Large scale 4.1: triethylamine / toluene; water / 1.5 h / 20 - 40 °C / Inert atmosphere; Large scale 4.2: 3 h / 0 °C / Large scale 5.1: potassium phosphate / toluene; water / 1 h / 45 °C 5.2: 5 h / 0 °C 6.1: toluene / 45 °C / Inert atmosphere 7.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 7.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]
[2]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

34
methyl (2E)-3-(3-fluoro-2-((phenoxycarbonyl)amino)-phenyl)acrylate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: dmap / Isopropyl acetate / 5 h / Inert atmosphere; Reflux; Large scale 2.1: potassium phosphate; C₂₉H₃₄N₃O₆⁽¹⁺⁾*Br^(1-) / toluene; water / Inert atmosphere 3.1: phosphorus pentachloride / 2,2,2-trifluoroethanol / Inert atmosphere 4.1: toluene / 45 °C / Inert atmosphere 5.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 5.2: 5 h / 60 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: dmap / Isopropyl acetate / 5 h / Inert atmosphere; Reflux; Large scale 2.1: phosphorus pentachloride; α-picoline / toluene / 5 h / 20 - 40 °C / Inert atmosphere; Large scale 3.1: triethylamine / toluene; water / 1.5 h / 20 - 40 °C / Inert atmosphere; Large scale 3.2: 3 h / 0 °C / Large scale 4.1: potassium phosphate / toluene; water / 1 h / 45 °C 4.2: 5 h / 0 °C 5.1: toluene / 45 °C / Inert atmosphere 6.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 6.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]
[2]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

35
methyl (2E)-3-(3-fluoro-2-((((2-methoxy-5-(trifluoromethyl)phenyl)imino)methylene)amino)phenyl)acrylate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: triethylamine / toluene; water / 1.5 h / 20 - 40 °C / Inert atmosphere; Large scale 1.2: 3 h / 0 °C / Large scale 2.1: potassium phosphate / toluene; water / 1 h / 45 °C 2.2: 5 h / 0 °C 3.1: toluene / 45 °C / Inert atmosphere 4.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 4.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

36
1-(3-methoxyphenyl)piperazine dihydrochloride [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: disodium hydrogenphosphate / water; Isopropyl acetate / Inert atmosphere 1.2: Inert atmosphere 2.1: phosphorus pentachloride / acetonitrile 3.1: potassium hexamethylsilazane / N,N-dimethyl acetamide / 60 °C / Inert atmosphere 4.1: C₁₄H₁₈N₂O₆Pd₂S₂; (1R)-1-[(1R)-1-[bis[3,5-bis(trifluoromethyl)-phenyl]phosphino]ethyl]-2-[2-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-phenyl]ferrocene; cesium formate / N,N-dimethyl-formamide / 12 h / 60 °C / Inert atmosphere 5.1: toluene / 45 °C / Inert atmosphere 6.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 6.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

37
C₃₀H₂₈F₄N₄O₄ [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: hydrogen; titanium(IV) isopropylate; bis(norbornadiene)rhodium(l)tetrafluoroborate; (S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a']-dinaphthalen-4-yl)piperidine / 2-methyltetrahydrofuran / 40 °C / 25858.1 Torr 2.1: toluene / 45 °C / Inert atmosphere 3.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 3.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

38
methyl (S)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: phosphorus pentachloride / 2,2,2-trifluoroethanol / Inert atmosphere 2.1: toluene / 45 °C / Inert atmosphere 3.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 3.2: 5 h / 60 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: trichlorophosphate; dmap / toluene / 100 °C / Reflux 1.2: 24 h / 100 °C 2.1: sodium hydroxide; water / tetrahydrofuran / 10 h / 60 °C

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]
[2]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1

39
(S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetate (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate ethyl acetate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetate (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate ethyl acetate With disodium hydrogenphosphate; tert-butyl methyl ether In water for 2h; Stage #2: With sodium hydroxide In water at 60℃; for 5h; Inert atmosphere;
92%	Stage #1: (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetate (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate ethyl acetate With sodium phosphate dibasic dihydrate; water In tert-butyl methyl ether at 20℃; for 0.666667h; Stage #2: With water; potassium hydroxide In methanol; tert-butyl methyl ether at 50℃; for 6h;	Preparation of Compound A To a slurry of compound 7 (20g, 18.9 mmol) in MTBE (40 mL) at room temperature was added a solution of sodium phosphate dibasic dihydrate (8.42 g, 47.3 mmol) in water (80 mL) and the resulting slurry was allowed to stir at room temperature for 40 minutes. The reaction mixture was transferred to a separatory funnel and the organic phase was collected and washed with a solution of sodium phosphate dibasic dihydrate (3.37 g, 18.91 mmol) in water (40 mL). A solution of KOH (4.99 g, 76 mmol) in water (80 mL) and methanol (10 mL) was then added to the organic phase and the resulting mixture was heated to 50°C and allowed to stir at this temperature for 6 hours. MTBE (20 mL) and water (40 mL) were then added to the reaction mixture and the resulting solution was transferred to a separatory funnel and the aqueous layer was collected and washed with MTBE (20 mL). Additional MTBE (40 mL) was added to the aqueous layer and the resulting solution was adjusted to pH 4-5 via slow addition of concentrated HCl. The resulting acidified solution was transferred to a separatory funnel and the organic phase was collected, concentrated in vacuo and solvent switched with acetone, maintaining a 30 mL volume. The resultingacetone solution was added dropwise to water and the precipitate formed was filtered toprovide compound A as a white solid (10 g, 92%). 1H NMR (500 MHz, d6-DMSO): δH 12.6(1H, s), 7.52 (1H, dd, J= 8.6, 1.3 Hz), 7.41 (1H, brs), 7.22 (1H, d, J 7.2 Hz), 7.08-7.02 (2H,m), 6.87-6. 84 (2H, m), 6.44 (1H, dd, J 8.3, 1.8 Hz), 6.39 (1H, t, J 2.1 Hz), 6.35 (1H, dd, J= 8.1, 2.0 Hz), 4.89 (1H, t, J= 7.3 Hz), 3.79 (3H, br s), 3.68 (3H, s), 3.47 (2H, br s), 3.39(2H, br s), 2.96-2.93 (2H, m), 2. 82-2.77 (3H, m), 2.44 (1H, dd, J= 14.8, 7.4 Hz).

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]
[2]Current Patent Assignee: MERCK & CO INC - WO2017/91453, 2017, A1 Location in patent: Page/Page column 25; 26

40
[ 917389-26-5 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium phosphate; C₂₉H₃₄N₃O₆⁽¹⁺⁾*Br^(1-) / toluene; water / Inert atmosphere 2.1: phosphorus pentachloride / 2,2,2-trifluoroethanol / Inert atmosphere 3.1: toluene / 45 °C / Inert atmosphere 4.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 4.2: 5 h / 60 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: phosphorus pentachloride; α-picoline / toluene / 5 h / 20 - 40 °C / Inert atmosphere; Large scale 2.1: triethylamine / toluene; water / 1.5 h / 20 - 40 °C / Inert atmosphere; Large scale 2.2: 3 h / 0 °C / Large scale 3.1: potassium phosphate / toluene; water / 1 h / 45 °C 3.2: 5 h / 0 °C 4.1: toluene / 45 °C / Inert atmosphere 5.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 5.2: 5 h / 60 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 56 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 4.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 5.1: water; sodium hydrogencarbonate / ethyl acetate 5.2: 3 - 18 h / 20 °C 5.3: pH 7.0 - 7.5

Multi-step reaction with 6 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 56 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 4.1: sodium hydroxide; water / 1,4-dioxane / 2 h / 20 °C 5.1: sulfuric acid / 26 h / Heating / reflux 6.1: water; sodium hydrogencarbonate / ethyl acetate 6.2: 18 h / 20 °C 6.3: pH 7 - 14

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]
[2]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]
[3]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[4]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

41
2-fluoro-6-vinylaniline [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: disodium hydrogenphosphate / water; Isopropyl acetate / Inert atmosphere 2.1: dmap / Isopropyl acetate / 80 °C / Inert atmosphere 3.1: phosphorus pentachloride; α-picoline / toluene / 40 °C / Inert atmosphere 4.1: triethylamine / toluene; water / Inert atmosphere 5.1: palladium diacetate; (S)-(6,6'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(bis(3,5-dimethylphanyl))phosphine; potassium acetate; copper(II) bis(tetrafluoroborate); carbon monoxide / methanol; tetrahydrofuran / 18 h / 70 °C / 1810.07 Torr 6.1: toluene / 45 °C / Inert atmosphere 7.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 7.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

42
C₁₅H₁₂FNO₂ [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: dmap / Isopropyl acetate / 80 °C / Inert atmosphere 2.1: phosphorus pentachloride; α-picoline / toluene / 40 °C / Inert atmosphere 3.1: triethylamine / toluene; water / Inert atmosphere 4.1: palladium diacetate; (S)-(6,6'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(bis(3,5-dimethylphanyl))phosphine; potassium acetate; copper(II) bis(tetrafluoroborate); carbon monoxide / methanol; tetrahydrofuran / 18 h / 70 °C / 1810.07 Torr 5.1: toluene / 45 °C / Inert atmosphere 6.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 6.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

43
C₁₇H₁₄F₄N₂O₂ [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: phosphorus pentachloride; α-picoline / toluene / 40 °C / Inert atmosphere 2.1: triethylamine / toluene; water / Inert atmosphere 3.1: palladium diacetate; (S)-(6,6'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(bis(3,5-dimethylphanyl))phosphine; potassium acetate; copper(II) bis(tetrafluoroborate); carbon monoxide / methanol; tetrahydrofuran / 18 h / 70 °C / 1810.07 Torr 4.1: toluene / 45 °C / Inert atmosphere 5.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 5.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

44
C₁₇H₁₂F₄N₂O [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: triethylamine / toluene; water / Inert atmosphere 2.1: palladium diacetate; (S)-(6,6'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(bis(3,5-dimethylphanyl))phosphine; potassium acetate; copper(II) bis(tetrafluoroborate); carbon monoxide / methanol; tetrahydrofuran / 18 h / 70 °C / 1810.07 Torr 3.1: toluene / 45 °C / Inert atmosphere 4.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 4.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

45
C₁₈H₁₉BrFN₃O₂ [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: phosphorus pentachloride / acetonitrile 2.1: potassium hexamethylsilazane / N,N-dimethyl acetamide / 60 °C / Inert atmosphere 3.1: C₁₄H₁₈N₂O₆Pd₂S₂; (1R)-1-[(1R)-1-[bis[3,5-bis(trifluoromethyl)-phenyl]phosphino]ethyl]-2-[2-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-phenyl]ferrocene; cesium formate / N,N-dimethyl-formamide / 12 h / 60 °C / Inert atmosphere 4.1: toluene / 45 °C / Inert atmosphere 5.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 5.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

46
C₁₈H₁₈BrClFN₃O [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium hexamethylsilazane / N,N-dimethyl acetamide / 60 °C / Inert atmosphere 2.1: C₁₄H₁₈N₂O₆Pd₂S₂; (1R)-1-[(1R)-1-[bis[3,5-bis(trifluoromethyl)-phenyl]phosphino]ethyl]-2-[2-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-phenyl]ferrocene; cesium formate / N,N-dimethyl-formamide / 12 h / 60 °C / Inert atmosphere 3.1: toluene / 45 °C / Inert atmosphere 4.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 4.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

47
C₁₂H₁₂F₃NO₃ [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium hexamethylsilazane / N,N-dimethyl acetamide / 60 °C / Inert atmosphere 2.1: C₁₄H₁₈N₂O₆Pd₂S₂; (1R)-1-[(1R)-1-[bis[3,5-bis(trifluoromethyl)-phenyl]phosphino]ethyl]-2-[2-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-phenyl]ferrocene; cesium formate / N,N-dimethyl-formamide / 12 h / 60 °C / Inert atmosphere 3.1: toluene / 45 °C / Inert atmosphere 4.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 4.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

48
[ 349-65-5 ]
[ 917389-32-3 ]

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 1097 - 1103

49
(S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydroxide In tetrahydrofuran at 60℃; for 10h;
	Multi-step reaction with 2 steps 1.1: toluene / 45 °C / Inert atmosphere 2.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 2.2: 5 h / 60 °C / Inert atmosphere
22 mg	With water; sodium hydroxide In tetrahydrofuran at 60℃; for 10h;	15 Synthesis of (S)-2-(8-fluoro-3-(2-meth oxy-5-(tr ifluo romethy 1) p heny l)-2-(4-(3 - metiioxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl) acetic acid 0.22 mL of an aqueous solution of 1M NaOH is added to a solution of (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin- 1 -y l)-3 ,4-dihy droquinazolin-4-y l)acetate (26 mg, 0.0443 mmol) in THF 0.5 ml. The reaction mixture is stirred at room temperature for 15-20 minutes, then heated at 60°C for 10 hours. The mixture is cooled to room temperature, and H2O (5 mL) and EtaO (5 mL) are added. The organic phase is eliminated and acidified with an aqueous solution of 0.5 M HC1 until pH 5-6 is reached. The aqueous phase is extracted with Et2O (5 mLx3). The combined organic phases are washed with a saturated aqueous solution of NaCl and dried with Na2SO4. The drying agent is filtered and evaporated to residue to obtain 22 mg of (S)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxy- phenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl) acetic acid as a ’white solid. 1H NMR (300 MHz, d6-DMSO): δ=12.54 (br s, 1H), 7.54 (dd, >8.6, 1.2, 1H), 7.40 (br s, 1H), 7.23 (d, >8.6, 1H), 7.10 - 6.99 (m, 2H), 6.86 (m, 2H), 6.46 - 6.34 (m, 3H), 4.88 (m, 1H), 3.80 (s, 3H), 3.68 (s, 3H), 3.43 (br m, 4H), 2.97 - 2.75 (m, 5H), 2.44 (m, 1H).

22 mg

With water; sodium hydroxide In tetrahydrofuran at 60℃; for 10h;

15 Synthesis of (S)-2-(8-fluoro-3-(2-meth oxy-5-(tr ifluo romethy 1) p heny l)-2-(4-(3 - metiioxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl) acetic acid 0.22 mL of an aqueous solution of 1M NaOH is added to a solution of (S)-methyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin- 1 -y l)-3 ,4-dihy droquinazolin-4-y l)acetate (26 mg, 0.0443 mmol) in THF 0.5 ml. The reaction mixture is stirred at room temperature for 15-20 minutes, then heated at 60°C for 10 hours. The mixture is cooled to room temperature, and H2O (5 mL) and EtaO (5 mL) are added. The organic phase is eliminated and acidified with an aqueous solution of 0.5 M HC1 until pH 5-6 is reached. The aqueous phase is extracted with Et2O (5 mLx3). The combined organic phases are washed with a saturated aqueous solution of NaCl and dried with Na2SO4. The drying agent is filtered and evaporated to residue to obtain 22 mg of (S)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxy- phenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl) acetic acid as a ’white solid. 1H NMR (300 MHz, d6-DMSO): δ=12.54 (br s, 1H), 7.54 (dd, >8.6, 1.2, 1H), 7.40 (br s, 1H), 7.23 (d, >8.6, 1H), 7.10 - 6.99 (m, 2H), 6.86 (m, 2H), 6.46 - 6.34 (m, 3H), 4.88 (m, 1H), 3.80 (s, 3H), 3.68 (s, 3H), 3.43 (br m, 4H), 2.97 - 2.75 (m, 5H), 2.44 (m, 1H).

Reference： [1]Wang, Pu-Sheng; Shen, Meng-Lan; Wang, Tian-Ci; Lin, Hua-Chen; Gong, Liu-Zhu [Angewandte Chemie - International Edition, 2017, vol. 56, # 50, p. 16032 - 16036][Angew. Chem., 2017, vol. 129, # 50, p. 16248 - 16252,5]
[2]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]
[3]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1 Location in patent: Page/Page column 25
[4]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1 Location in patent: Page/Page column 25

50
C₂₈H₂₈F₄N₄O₂ [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: palladium diacetate; (S)-(6,6'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(bis(3,5-dimethylphanyl))phosphine; potassium acetate; copper(II) bis(tetrafluoroborate); carbon monoxide / methanol; tetrahydrofuran / 18 h / 70 °C / 1810.07 Torr 2.1: toluene / 45 °C / Inert atmosphere 3.1: disodium hydrogenphosphate; tert-butyl methyl ether / water / 2 h 3.2: 5 h / 60 °C / Inert atmosphere

Reference： [1]Humphrey, Guy R.; Dalby, Stephen M.; Andreani, Teresa; Xiang, Bangping; Luzung, Michael R.; Song, Zhiguo Jake; Shevlin, Michael; Christensen, Melodie; Belyk, Kevin M.; Tschaen, David M. [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1097 - 1103]

51
[ 1018853-56-9 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: dichloromethane / 4 h / 0 - 20 °C 2.1: bis(dibenzylideneacetone)-palladium⁽⁰⁾; 2,5-Dimethyl-1,4-benzoquinone; o-fluoro-benzoic acid; (R,2R)-1-(2,6-bis(3,5-bis(trifluoromethyl)phenyl)-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yl)-2-methylpiperidine / tert-butyl methyl ether / 48 h / 0 - 25 °C / Schlenk technique 3.1: magnesium / methanol / 0.5 h / 20 °C / Sonication 4.1: 9-bora-bicyclo[3.3.1]nonane / tetrahydrofuran / 12 h / 0 - 45 °C 4.2: 1 h / 20 °C 5.1: potassium phosphate; N,N`-dimethylethylenediamine; copper(l) iodide / 1,4-dioxane / 24 h / 110 °C / Schlenk technique; Inert atmosphere 6.1: rhodium(III) chloride hydrate; sodium periodate / water; ethyl acetate; acetonitrile / 0.33 h / 0 °C 6.2: 0.5 h / 20 °C 7.1: 10 wt% Pd(OH)2 on carbon; hydrogen; trifluoroacetic acid / 12 h / 60 °C 8.1: trichlorophosphate; dmap / toluene / 12 h / 100 °C / Inert atmosphere 8.2: 24 h / 100 °C 9.1: sodium hydroxide / tetrahydrofuran / 10 h / 60 °C

Reference： [1]Wang, Pu-Sheng; Shen, Meng-Lan; Wang, Tian-Ci; Lin, Hua-Chen; Gong, Liu-Zhu [Angewandte Chemie - International Edition, 2017, vol. 56, # 50, p. 16032 - 16036][Angew. Chem., 2017, vol. 129, # 50, p. 16248 - 16252,5]

52
N-((2-allyl-6-fluorophenyl)(benzyl)carbamoyl)-2-methylbenzenesulfonamide [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: bis(dibenzylideneacetone)-palladium⁽⁰⁾; 2,5-Dimethyl-1,4-benzoquinone; o-fluoro-benzoic acid; (R,2R)-1-(2,6-bis(3,5-bis(trifluoromethyl)phenyl)-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yl)-2-methylpiperidine / tert-butyl methyl ether / 48 h / 0 - 25 °C / Schlenk technique 2.1: magnesium / methanol / 0.5 h / 20 °C / Sonication 3.1: 9-bora-bicyclo[3.3.1]nonane / tetrahydrofuran / 12 h / 0 - 45 °C 3.2: 1 h / 20 °C 4.1: potassium phosphate; N,N`-dimethylethylenediamine; copper(l) iodide / 1,4-dioxane / 24 h / 110 °C / Schlenk technique; Inert atmosphere 5.1: rhodium(III) chloride hydrate; sodium periodate / water; ethyl acetate; acetonitrile / 0.33 h / 0 °C 5.2: 0.5 h / 20 °C 6.1: 10 wt% Pd(OH)2 on carbon; hydrogen; trifluoroacetic acid / 12 h / 60 °C 7.1: trichlorophosphate; dmap / toluene / 12 h / 100 °C / Inert atmosphere 7.2: 24 h / 100 °C 8.1: sodium hydroxide / tetrahydrofuran / 10 h / 60 °C

Reference： [1]Wang, Pu-Sheng; Shen, Meng-Lan; Wang, Tian-Ci; Lin, Hua-Chen; Gong, Liu-Zhu [Angewandte Chemie - International Edition, 2017, vol. 56, # 50, p. 16032 - 16036][Angew. Chem., 2017, vol. 129, # 50, p. 16248 - 16252,5]

53
(S)-1-benzyl-8-fluoro-3-(o-tolylsulfonyl)-4-vinyl-3,4-dihydroquinazolin-2(1H)-one [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: magnesium / methanol / 0.5 h / 20 °C / Sonication 2.1: 9-bora-bicyclo[3.3.1]nonane / tetrahydrofuran / 12 h / 0 - 45 °C 2.2: 1 h / 20 °C 3.1: potassium phosphate; N,N`-dimethylethylenediamine; copper(l) iodide / 1,4-dioxane / 24 h / 110 °C / Schlenk technique; Inert atmosphere 4.1: rhodium(III) chloride hydrate; sodium periodate / water; ethyl acetate; acetonitrile / 0.33 h / 0 °C 4.2: 0.5 h / 20 °C 5.1: 10 wt% Pd(OH)2 on carbon; hydrogen; trifluoroacetic acid / 12 h / 60 °C 6.1: trichlorophosphate; dmap / toluene / 12 h / 100 °C / Inert atmosphere 6.2: 24 h / 100 °C 7.1: sodium hydroxide / tetrahydrofuran / 10 h / 60 °C

Reference： [1]Wang, Pu-Sheng; Shen, Meng-Lan; Wang, Tian-Ci; Lin, Hua-Chen; Gong, Liu-Zhu [Angewandte Chemie - International Edition, 2017, vol. 56, # 50, p. 16032 - 16036][Angew. Chem., 2017, vol. 129, # 50, p. 16248 - 16252,5]

54
(S)-1-benzyl-8-fluoro-4-vinyl-3,4-dihydroquinazolin-2(1H)-one [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: 9-bora-bicyclo[3.3.1]nonane / tetrahydrofuran / 12 h / 0 - 45 °C 1.2: 1 h / 20 °C 2.1: potassium phosphate; N,N`-dimethylethylenediamine; copper(l) iodide / 1,4-dioxane / 24 h / 110 °C / Schlenk technique; Inert atmosphere 3.1: rhodium(III) chloride hydrate; sodium periodate / water; ethyl acetate; acetonitrile / 0.33 h / 0 °C 3.2: 0.5 h / 20 °C 4.1: 10 wt% Pd(OH)2 on carbon; hydrogen; trifluoroacetic acid / 12 h / 60 °C 5.1: trichlorophosphate; dmap / toluene / 12 h / 100 °C / Inert atmosphere 5.2: 24 h / 100 °C 6.1: sodium hydroxide / tetrahydrofuran / 10 h / 60 °C

Reference： [1]Wang, Pu-Sheng; Shen, Meng-Lan; Wang, Tian-Ci; Lin, Hua-Chen; Gong, Liu-Zhu [Angewandte Chemie - International Edition, 2017, vol. 56, # 50, p. 16032 - 16036][Angew. Chem., 2017, vol. 129, # 50, p. 16248 - 16252,5]

55
(S)-1-benzyl-8-fluoro-4-(2-hydroxyethyl)-3,4-dihydroquinazolin-2(1H)-one [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium phosphate; N,N`-dimethylethylenediamine; copper(l) iodide / 1,4-dioxane / 24 h / 110 °C / Schlenk technique; Inert atmosphere 2.1: rhodium(III) chloride hydrate; sodium periodate / water; ethyl acetate; acetonitrile / 0.33 h / 0 °C 2.2: 0.5 h / 20 °C 3.1: 10 wt% Pd(OH)2 on carbon; hydrogen; trifluoroacetic acid / 12 h / 60 °C 4.1: trichlorophosphate; dmap / toluene / 12 h / 100 °C / Inert atmosphere 4.2: 24 h / 100 °C 5.1: sodium hydroxide / tetrahydrofuran / 10 h / 60 °C

Reference： [1]Wang, Pu-Sheng; Shen, Meng-Lan; Wang, Tian-Ci; Lin, Hua-Chen; Gong, Liu-Zhu [Angewandte Chemie - International Edition, 2017, vol. 56, # 50, p. 16032 - 16036][Angew. Chem., 2017, vol. 129, # 50, p. 16248 - 16252,5]

56
(S)-1-benzyl-8-fluoro-4-(2-hydroxyethyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-2(1H)-one [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: rhodium(III) chloride hydrate; sodium periodate / water; ethyl acetate; acetonitrile / 0.33 h / 0 °C 1.2: 0.5 h / 20 °C 2.1: 10 wt% Pd(OH)2 on carbon; hydrogen; trifluoroacetic acid / 12 h / 60 °C 3.1: trichlorophosphate; dmap / toluene / 12 h / 100 °C / Inert atmosphere 3.2: 24 h / 100 °C 4.1: sodium hydroxide / tetrahydrofuran / 10 h / 60 °C

Reference： [1]Wang, Pu-Sheng; Shen, Meng-Lan; Wang, Tian-Ci; Lin, Hua-Chen; Gong, Liu-Zhu [Angewandte Chemie - International Edition, 2017, vol. 56, # 50, p. 16032 - 16036][Angew. Chem., 2017, vol. 129, # 50, p. 16248 - 16252,5]

57
methyl (S)-2-(1-benzyl-8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 10 wt% Pd(OH)2 on carbon; hydrogen; trifluoroacetic acid / 12 h / 60 °C 2.1: trichlorophosphate; dmap / toluene / 12 h / 100 °C / Inert atmosphere 2.2: 24 h / 100 °C 3.1: sodium hydroxide / tetrahydrofuran / 10 h / 60 °C

Reference： [1]Wang, Pu-Sheng; Shen, Meng-Lan; Wang, Tian-Ci; Lin, Hua-Chen; Gong, Liu-Zhu [Angewandte Chemie - International Edition, 2017, vol. 56, # 50, p. 16032 - 16036][Angew. Chem., 2017, vol. 129, # 50, p. 16248 - 16252,5]

58
[ 1170692-57-5 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: zinc(II) chloride; sodium cyanoborohydride / methanol / 2 h / 0 - 50 °C 2.1: dichloromethane / 4 h / 0 - 20 °C 3.1: bis(dibenzylideneacetone)-palladium⁽⁰⁾; 2,5-Dimethyl-1,4-benzoquinone; o-fluoro-benzoic acid; (R,2R)-1-(2,6-bis(3,5-bis(trifluoromethyl)phenyl)-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yl)-2-methylpiperidine / tert-butyl methyl ether / 48 h / 0 - 25 °C / Schlenk technique 4.1: magnesium / methanol / 0.5 h / 20 °C / Sonication 5.1: 9-bora-bicyclo[3.3.1]nonane / tetrahydrofuran / 12 h / 0 - 45 °C 5.2: 1 h / 20 °C 6.1: potassium phosphate; N,N`-dimethylethylenediamine; copper(l) iodide / 1,4-dioxane / 24 h / 110 °C / Schlenk technique; Inert atmosphere 7.1: rhodium(III) chloride hydrate; sodium periodate / water; ethyl acetate; acetonitrile / 0.33 h / 0 °C 7.2: 0.5 h / 20 °C 8.1: 10 wt% Pd(OH)2 on carbon; hydrogen; trifluoroacetic acid / 12 h / 60 °C 9.1: trichlorophosphate; dmap / toluene / 12 h / 100 °C / Inert atmosphere 9.2: 24 h / 100 °C 10.1: sodium hydroxide / tetrahydrofuran / 10 h / 60 °C

Reference： [1]Wang, Pu-Sheng; Shen, Meng-Lan; Wang, Tian-Ci; Lin, Hua-Chen; Gong, Liu-Zhu [Angewandte Chemie - International Edition, 2017, vol. 56, # 50, p. 16032 - 16036][Angew. Chem., 2017, vol. 129, # 50, p. 16248 - 16252,5]

59
[ 791117-40-3 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 2.1: water; sodium hydrogencarbonate / ethyl acetate 2.2: 3 - 18 h / 20 °C 2.3: pH 7.0 - 7.5
	Multi-step reaction with 3 steps 1.1: sodium hydroxide; water / 1,4-dioxane / 2 h / 20 °C 2.1: sulfuric acid / 26 h / Heating / reflux 3.1: water; sodium hydrogencarbonate / ethyl acetate 3.2: 18 h / 20 °C 3.3: pH 7 - 14

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

60
[ 791116-51-3 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sulfuric acid / 26 h / Heating / reflux 2.1: water; sodium hydrogencarbonate / ethyl acetate 2.2: 18 h / 20 °C 2.3: pH 7 - 14
	Multi-step reaction with 3 steps 1.1: sulfuric acid / 6 h / Heating / reflux 2.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 3.1: water; sodium hydrogencarbonate / ethyl acetate 3.2: 18 h / 20 °C 3.3: pH 7 - 14
	Multi-step reaction with 3 steps 1.1: sulfuric acid / 6 h / Heating / reflux 2.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 3.1: water; sodium hydrogencarbonate / ethyl acetate 3.2: 3 - 18 h / 20 °C 3.3: pH 7.0 - 7.5

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[3]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

61
[ 917389-37-8 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: methanol; sodium methylate / acetonitrile / 60 h / Heating / reflux 1.2: pH 7 - 7.5 2.1: sulfuric acid / 26 h / Heating / reflux 3.1: water; sodium hydrogencarbonate / ethyl acetate 3.2: 18 h / 20 °C 3.3: pH 7 - 14
	Multi-step reaction with 3 steps 1.1: methanol; sodium methylate / acetonitrile / 77 h / Heating / reflux 1.2: pH 7 - 13 2.1: sulfuric acid / 26 h / Heating / reflux 3.1: water; sodium hydrogencarbonate / ethyl acetate 3.2: 18 h / 20 °C 3.3: pH 7 - 14
	Multi-step reaction with 4 steps 1.1: methanol; sodium methylate / acetonitrile / 60 h / Heating / reflux 1.2: pH 7 - 7.5 2.1: sulfuric acid / 6 h / Heating / reflux 3.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 4.1: water; sodium hydrogencarbonate / ethyl acetate 4.2: 18 h / 20 °C 4.3: pH 7 - 14

	Multi-step reaction with 4 steps 1.1: methanol; sodium methylate / acetonitrile / 60 h / Heating / reflux 1.2: pH 7 - 7.5 2.1: sulfuric acid / 6 h / Heating / reflux 3.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 4.1: water; sodium hydrogencarbonate / ethyl acetate 4.2: 3 - 18 h / 20 °C 4.3: pH 7.0 - 7.5
	Multi-step reaction with 4 steps 1.1: methanol; sodium methylate / acetonitrile / 77 h / Heating / reflux 1.2: pH 7 - 13 2.1: sulfuric acid / 6 h / Heating / reflux 3.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 4.1: water; sodium hydrogencarbonate / ethyl acetate 4.2: 18 h / 20 °C 4.3: pH 7 - 14
	Multi-step reaction with 4 steps 1.1: methanol; sodium methylate / acetonitrile / 77 h / Heating / reflux 1.2: pH 7 - 13 2.1: sulfuric acid / 6 h / Heating / reflux 3.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 4.1: water; sodium hydrogencarbonate / ethyl acetate 4.2: 3 - 18 h / 20 °C 4.3: pH 7.0 - 7.5

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[3]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[4]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[5]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[6]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

62
[ 348-54-9 ]
[ 917389-37-8 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: acetonitrile / 4 h / 82 °C 2.1: sulfuric acid; acetic acid / palladium diacetate / 20 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 56 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 6.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 7.1: water; sodium hydrogencarbonate / ethyl acetate 7.2: 18 h / 20 °C 7.3: pH 7 - 14

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

63
[ 917389-24-3 ]
[ 917389-37-8 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sulfuric acid; acetic acid / palladium diacetate / 20 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 56 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 5.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 6.1: water; sodium hydrogencarbonate / ethyl acetate 6.2: 18 h / 20 °C 6.3: pH 7 - 14

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

64
[ 917389-23-2 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: triethylamine / dichloro bis(acetonitrile) palladium(II); tris-(o-tolyl)phosphine / Isobutyronitrile / 16 - 22 h / 90 - 102 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 4.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 5.1: water; sodium hydrogencarbonate / ethyl acetate 5.2: 3 - 18 h / 20 °C 5.3: pH 7.0 - 7.5
	Multi-step reaction with 6 steps 1.1: triethylamine / dichloro bis(acetonitrile) palladium(II); tris-(o-tolyl)phosphine / Isobutyronitrile / 16 - 22 h / 90 - 102 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 4.1: sodium hydroxide; water / 1,4-dioxane / 2 h / 20 °C 5.1: sulfuric acid / 26 h / Heating / reflux 6.1: water; sodium hydrogencarbonate / ethyl acetate 6.2: 18 h / 20 °C 6.3: pH 7 - 14

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

65
[ 917389-26-5 ]
[ 917389-37-8 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 56 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 4.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 5.1: water; sodium hydrogencarbonate / ethyl acetate 5.2: 18 h / 20 °C 5.3: pH 7 - 14

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

66
[ 917389-35-6 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: water; sodium hydrogencarbonate / ethyl acetate 1.2: 18 h / 20 °C 1.3: pH 7.0 - 7.5 2.1: methanol; sodium methylate / acetonitrile / 60 h / Heating / reflux 2.2: pH 7 - 7.5 3.1: sulfuric acid / 26 h / Heating / reflux 4.1: water; sodium hydrogencarbonate / ethyl acetate 4.2: 18 h / 20 °C 4.3: pH 7 - 14
	Multi-step reaction with 4 steps 1.1: water; sodium hydrogencarbonate / ethyl acetate 1.2: 18 h / 20 °C 1.3: pH 7.0 - 7.5 2.1: methanol; sodium methylate / acetonitrile / 77 h / Heating / reflux 2.2: pH 7 - 13 3.1: sulfuric acid / 26 h / Heating / reflux 4.1: water; sodium hydrogencarbonate / ethyl acetate 4.2: 18 h / 20 °C 4.3: pH 7 - 14
	Multi-step reaction with 5 steps 1.1: water; sodium hydrogencarbonate / ethyl acetate 1.2: 18 h / 20 °C 1.3: pH 7.0 - 7.5 2.1: methanol; sodium methylate / acetonitrile / 60 h / Heating / reflux 2.2: pH 7 - 7.5 3.1: sulfuric acid / 6 h / Heating / reflux 4.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 5.1: water; sodium hydrogencarbonate / ethyl acetate 5.2: 18 h / 20 °C 5.3: pH 7 - 14

	Multi-step reaction with 5 steps 1.1: water; sodium hydrogencarbonate / ethyl acetate 1.2: 18 h / 20 °C 1.3: pH 7.0 - 7.5 2.1: methanol; sodium methylate / acetonitrile / 60 h / Heating / reflux 2.2: pH 7 - 7.5 3.1: sulfuric acid / 6 h / Heating / reflux 4.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 5.1: water; sodium hydrogencarbonate / ethyl acetate 5.2: 3 - 18 h / 20 °C 5.3: pH 7.0 - 7.5
	Multi-step reaction with 5 steps 1.1: water; sodium hydrogencarbonate / ethyl acetate 1.2: 18 h / 20 °C 1.3: pH 7.0 - 7.5 2.1: methanol; sodium methylate / acetonitrile / 77 h / Heating / reflux 2.2: pH 7 - 13 3.1: sulfuric acid / 6 h / Heating / reflux 4.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 5.1: water; sodium hydrogencarbonate / ethyl acetate 5.2: 18 h / 20 °C 5.3: pH 7 - 14
	Multi-step reaction with 5 steps 1.1: water; sodium hydrogencarbonate / ethyl acetate 1.2: 18 h / 20 °C 1.3: pH 7.0 - 7.5 2.1: methanol; sodium methylate / acetonitrile / 77 h / Heating / reflux 2.2: pH 7 - 13 3.1: sulfuric acid / 6 h / Heating / reflux 4.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 5.1: water; sodium hydrogencarbonate / ethyl acetate 5.2: 3 - 18 h / 20 °C 5.3: pH 7.0 - 7.5

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[3]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[4]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[5]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[6]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

67
[ 16588-75-3 ]
[ 917389-37-8 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: acetonitrile / 38 - 45 h / 35 - 88 °C 2.1: triethylamine / dichloro bis(acetonitrile) palladium(II); tris-(o-tolyl)phosphine / Isobutyronitrile / 16 - 22 h / 90 - 102 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 5.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 6.1: water; sodium hydrogencarbonate / ethyl acetate 6.2: 18 h / 20 °C 6.3: pH 7 - 14
	Multi-step reaction with 7 steps 1.1: acetonitrile / 4 h / 82 °C 2.1: sulfuric acid; acetic acid / palladium diacetate / 20 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetone / 4 h / 56 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; trichlorophosphate / chlorobenzene / 9.17 - 9.33 h / 120 - 130 °C / Heating / reflux 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 1,4-dioxane; chlorobenzene / 22 h / 20 °C / Heating / reflux 6.1: ethyl acetate / 19.5 - 75.5 h / 0 - 20 °C / Resolution of racemate 7.1: water; sodium hydrogencarbonate / ethyl acetate 7.2: 18 h / 20 °C 7.3: pH 7 - 14

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2006/133822, 2006, A1

68
[ 917389-32-3 ]
sodium (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide In ethanol; di-isopropyl ether at 50℃; for 3.41667h;	01-04 Example 01 : Preparation of sodium (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1- yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetate The title compound was prepared from (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1- yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid (letermovir) according to the method described in WO 2013127971 A1.333.1 g of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5- (trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid are dissolved in 1300 ml of a mixture of ethanol and diisopropyl ether (1 :1) in a 2000 ml three-neck flask. 21.9 g (546.84 mmol) of NaOH are added as a solid to the solution. The mixture is heated for 25 min to an inner temperature of 50 °C, and this yields a clear orange-coloured solution. The solution thus obtained is stirred for 3 hours at this temperature, and a thin suspension is formed already after 1 hour. The reaction mixture is then cooled down for 10 hours at a cooling rate of 3 °C/hour to an inner temperature of 20 °C and then stirred for a further 5 hours at this temperature. The total volume of the reaction mixture is reduced under vacuum to approximately 750 ml_ and the suspension obtained in this way is stirred at 20 °C for 2 hours. Next, 250 ml_ diisopropyl ether is added over a period of 10 min to the reaction mixture obtained and the mixture is stirred for further 2 hours. The crystalline product which is obtained is vacuumed off by a suction device, washed 2* with - in each case - 250 ml_ diisopropyl ether, and dried in a vacuum drying cabinet for 20 hours at 20 °C. and 160 mbar. The crystalline solid obtained in this way is then dried for 10 min at 90 °C. in an IR dryer and then again for further 16 hours at 60 °C in the vacuum drying cabinet. In this way a total of 274.4 g (86% of the theoretical yield) of the desired crystalline sodium salt of letermovir ethanol monohydrate is obtained.
	With sodium hydroxide In di-isopropyl ether; Isopropyl acetate; lithium hydroxide monohydrate at 50℃; for 4h;	01; 02 Example 02. Preparation of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)pi- perazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate tri hydrate in 500 g scale. 499 g of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5- (trifluoromethyl)phenyl]-4/-/-quinazolin-4-yl]acetic acid are dissolved in a 1 : 2 mixture of isopropyl acetate and diisopropyl ether at 50 °C (0.75 L / 1.5 L), followed by addition of ca. 1.5 equivalents of NaOH (aqueous solution, 1 g / ml_, 50 ml_) and the solution is seeded with sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5- (trifluoromethyl)phenyl]-4/-/-quinazolin-4-yl]acetate trihydrate (0.5 - 1 % w/w with respect to the base). The suspension is stirred for 4 hours at 50 °C (stir rate: 150 rpm, glass anchor shaft). Abundant white solid precipitates within the first hour. The reactor is gradually cooled down (50 °C to 20 °C in 1 hour) and its contents are filtered under vacuum and washed thrice with diisopropyl ether. The obtained white solid is dried under reduced pressure (2 - 3 mBar) at 50 °C for 15 hours. 510 g of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-trifluoromethyl)phenyl]-4/-/-quinazolin-4-yl]acetic acid trihydrate have been obtained.
	With anhydrous sodium carbonate In lithium hydroxide monohydrate for 3h; Heating;	1-2 (1) Add 500 g of letermovir and 500 g of anhydrous sodium carbonate to the reaction flask, add 5 L of deionized water to the reaction flask, stir and heat, and keep at a temperature of 50-60 °C for 3 hours to prepare Aqueous solution containing letermovir sodium salt; (2) The temperature of the aqueous solution containing letermovir sodium salt prepared in step (1) was lowered to below 30°C, and a mixed solvent of 2L dichloromethane and 200mL ethanol was added to the above aqueous solution, stirred evenly, and allowed to stand. 1-2 hours, separate the layers, keep the organic phase, continue to add a mixed solvent of 2 L of dichloromethane and 200 mL of ethanol to the aqueous layer, let stand, separate the layers, combine the two organic phases, wash the organic phase with 1 L of saturated brine, After stirring evenly, let it stand for 2-3 hours, separate layers, continue to retain the organic phase, add 2kg of anhydrous sodium sulfate to the organic phase, dry overnight, filter, take the organic phase, and distill at atmospheric pressure, when the organic phase remains about 1.4L , add 1.4 L of isopropyl ether, stir for 2 hours, filter, and dry the filter cake under vacuum at a temperature of 50-60 ° C for 24-48 hours to obtain the crude product of letermovir sodium salt; (3) At room temperature, add 350 g of the crude Letermovir sodium salt product prepared in step (2) into the flask, add 1.8 L of dichloromethane to the flask, stir to dissolve, and after about 1 hour, filter and remove Insoluble matter, a clear mother liquor was obtained, 2.5L of isopropyl ether was added to the clear mother liquor, a white solid was precipitated, and after stirring for 15 minutes, the filter was filtered, and the filter cake was washed with isopropyl ether, and the filter cake was placed under vacuum at 50-60°C Drying under certain conditions for 24-48 hours, the refined product of letermovir sodium salt was obtained.

Reference： [1]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2021/170879, 2021, A1 Location in patent: Page/Page column 33-34; 36
[2]Current Patent Assignee: AICURIS GMBH & CO. KG - WO2021/170874, 2021, A1 Location in patent: Page/Page column 22; 27-29; 31
[3]Current Patent Assignee: SHANDONG CHENGCHUANG BLUE SEA PHARMACEUTICAL TECH - CN114031560, 2022, A Location in patent: Paragraph 0026-0033

69
ethyl (2-((S)-3-((S)-4-benzyl-2- thioxothiazolidin-3-yl)-1-((2-methoxy-5- (trifluoromethyl)phenyl)amino)-3-oxopropyl)-6- fluorophenyl)carbamate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 3.1: potassium carbonate / acetone / 0.08 h / 20 °C 3.2: Reflux 4.1: trichlorophosphate / chlorobenzene / 3.5 h / Reflux 4.2: 18 h / 115 - 120 °C / Reflux 4.3: 2 h / Reflux 5.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 5 steps 1.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 3.1: potassium carbonate / acetone / 0.08 h / 20 °C 3.2: Reflux 4.1: trichlorophosphate; dmap / toluene / 100 °C / Reflux 4.2: 24 h / 100 °C 5.1: sodium hydroxide; water / tetrahydrofuran / 10 h / 60 °C
	Multi-step reaction with 5 steps 1.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 3.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 3.2: 18 h / 20 °C 4.1: trichlorophosphate / chlorobenzene / 3.5 h / Reflux 4.2: 18 h / 115 - 120 °C / Reflux 4.3: 2 h / Reflux 5.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr

	Multi-step reaction with 5 steps 1.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 3.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 3.2: 18 h / 20 °C 4.1: trichlorophosphate; dmap / toluene / 100 °C / Reflux 4.2: 24 h / 100 °C 5.1: sodium hydroxide; water / tetrahydrofuran / 10 h / 60 °C
	Multi-step reaction with 5 steps 1.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 3.1: potassium carbonate / acetone / 0.08 h / 20 °C 3.2: Reflux 4.1: phosphorus pentachloride / dichloromethane / 2 h / Reflux 4.2: 3 h / 120 - 130 °C / Reflux 5.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 5 steps 1.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 3.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 3.2: 18 h / 20 °C 4.1: phosphorus pentachloride / dichloromethane / 2 h / Reflux 4.2: 3 h / 120 - 130 °C / Reflux 5.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr

Reference： [1]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[2]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[3]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[4]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[5]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[6]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1

70
(S)-3-(2-((ethoxycarbonyl)amino)-3-fluorophenyl)-3-((2-methoxy-5-(trifluoro-methyl)phenyl)amino)propanoic acid [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 2.1: potassium carbonate / acetone / 0.08 h / 20 °C 2.2: Reflux 3.1: trichlorophosphate / chlorobenzene / 3.5 h / Reflux 3.2: 18 h / 115 - 120 °C / Reflux 3.3: 2 h / Reflux 4.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 2.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 2.2: 18 h / 20 °C 3.1: trichlorophosphate / chlorobenzene / 3.5 h / Reflux 3.2: 18 h / 115 - 120 °C / Reflux 3.3: 2 h / Reflux 4.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 2.1: potassium carbonate / acetone / 0.08 h / 20 °C 2.2: Reflux 3.1: phosphorus pentachloride / dichloromethane / 2 h / Reflux 3.2: 3 h / 120 - 130 °C / Reflux 4.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr

	Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 2.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 2.2: 18 h / 20 °C 3.1: phosphorus pentachloride / dichloromethane / 2 h / Reflux 3.2: 3 h / 120 - 130 °C / Reflux 4.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 2.1: potassium carbonate / acetone / 0.08 h / 20 °C 2.2: Reflux 3.1: trichlorophosphate; dmap / toluene / 100 °C / Reflux 3.2: 24 h / 100 °C 4.1: sodium hydroxide; water / tetrahydrofuran / 10 h / 60 °C
	Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 2.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 2.2: 18 h / 20 °C 3.1: trichlorophosphate; dmap / toluene / 100 °C / Reflux 3.2: 24 h / 100 °C 4.1: sodium hydroxide; water / tetrahydrofuran / 10 h / 60 °C

Reference： [1]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[2]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[3]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[4]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[5]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[6]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1

71
(S)-2-(8-fluoro-3-(2-methoxy-5- (trifluoromethyl)phenyl)-2-oxo-1,2,3,4- tetrahydroquinazolin-4-yl)acetic acid [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / acetone / 0.08 h / 20 °C 1.2: Reflux 2.1: trichlorophosphate / chlorobenzene / 3.5 h / Reflux 2.2: 18 h / 115 - 120 °C / Reflux 2.3: 2 h / Reflux 3.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 3 steps 1.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 1.2: 18 h / 20 °C 2.1: trichlorophosphate / chlorobenzene / 3.5 h / Reflux 2.2: 18 h / 115 - 120 °C / Reflux 2.3: 2 h / Reflux 3.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 3 steps 1.1: potassium carbonate / acetone / 0.08 h / 20 °C 1.2: Reflux 2.1: phosphorus pentachloride / dichloromethane / 2 h / Reflux 2.2: 3 h / 120 - 130 °C / Reflux 3.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr

	Multi-step reaction with 3 steps 1.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 1.2: 18 h / 20 °C 2.1: phosphorus pentachloride / dichloromethane / 2 h / Reflux 2.2: 3 h / 120 - 130 °C / Reflux 3.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 3 steps 1.1: potassium carbonate / acetone / 0.08 h / 20 °C 1.2: Reflux 2.1: trichlorophosphate; dmap / toluene / 100 °C / Reflux 2.2: 24 h / 100 °C 3.1: sodium hydroxide; water / tetrahydrofuran / 10 h / 60 °C
	Multi-step reaction with 3 steps 1.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 1.2: 18 h / 20 °C 2.1: trichlorophosphate; dmap / toluene / 100 °C / Reflux 2.2: 24 h / 100 °C 3.1: sodium hydroxide; water / tetrahydrofuran / 10 h / 60 °C

Reference： [1]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[2]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[3]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[4]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[5]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[6]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1

72
(S)-benzyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: phosphorus pentachloride / dichloromethane / 2 h / Reflux 1.2: 3 h / 120 - 130 °C / Reflux 2.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 2 steps 1.1: trichlorophosphate / chlorobenzene / 3.5 h / Reflux 1.2: 18 h / 115 - 120 °C / Reflux 1.3: 2 h / Reflux 2.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr

Reference： [1]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[2]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1

73
(S)-benzyl-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolm-4-yl)acetate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	With 5%-palladium/activated carbon; hydrogen In tetrahydrofuran; water at 25℃; for 2h;	12; 13; 14 Synthesis of (S)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3- methoxyphenyl)piperazin-1-yI)-3,4-dihydroqainazolm-4-yl) acetic acid 5% Pd/C, 50% wet (1.0 g), suspended in H2O (15 mL), is added to a solution of (S)-benzyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxy phenyl)- piperazin- 1 -yl)-3,4-dihydroquinazolin-4-yl)acetate (10.0 g) in THF (165 mL). The mixture is placed in a hydrogen atmosphere (3 bars) and left under stirring at 25 °C for 2 hours. The catalyst is filtered through cellulose, and the solution is concentrated to residue. Acetone (26 mL) is added, the mixture is filtered through cellulose, and the solution is dripped into in 232 mL of water. The mixture is left under stirring for 18 hours, and the solid is filtered and stove-dried at 55°C under vacuum. 7.5 g (87% yield) of (S)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3- methoxyphenyl)piperazin- 1 -y I)-3 ,4-dihydroquinazolin-4-y 1) acetic acid is obtained as a white solid. 1H NMR (300 MHz, d6-DMSO): δ=12.54 (br s, 1H), 7.54 (dd, J=8.6, 1.2, 1H), 7.40 (br s, 1H), 7.23 (d, J=8.6, 1H), 7.10 - 6.99 (m, 2H), 6.86 (m, 2H), 6.46 - 6.34 (m, 3H), 4.88 (m, 1H), 3.80 (s, 3H), 3.68 (s, 3H), 3.43 (br m, 4H), 2.97 - 2.75 (m, 5H), 2.44 (m, 1H).
87%	With 5%-palladium/activated carbon; hydrogen In tetrahydrofuran; water at 25℃; for 2h;	12; 13; 14 Synthesis of (S)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3- methoxyphenyl)piperazin-1-yI)-3,4-dihydroqainazolm-4-yl) acetic acid 5% Pd/C, 50% wet (1.0 g), suspended in H2O (15 mL), is added to a solution of (S)-benzyl 2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxy phenyl)- piperazin- 1 -yl)-3,4-dihydroquinazolin-4-yl)acetate (10.0 g) in THF (165 mL). The mixture is placed in a hydrogen atmosphere (3 bars) and left under stirring at 25 °C for 2 hours. The catalyst is filtered through cellulose, and the solution is concentrated to residue. Acetone (26 mL) is added, the mixture is filtered through cellulose, and the solution is dripped into in 232 mL of water. The mixture is left under stirring for 18 hours, and the solid is filtered and stove-dried at 55°C under vacuum. 7.5 g (87% yield) of (S)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3- methoxyphenyl)piperazin- 1 -y I)-3 ,4-dihydroquinazolin-4-y 1) acetic acid is obtained as a white solid. 1H NMR (300 MHz, d6-DMSO): δ=12.54 (br s, 1H), 7.54 (dd, J=8.6, 1.2, 1H), 7.40 (br s, 1H), 7.23 (d, J=8.6, 1H), 7.10 - 6.99 (m, 2H), 6.86 (m, 2H), 6.46 - 6.34 (m, 3H), 4.88 (m, 1H), 3.80 (s, 3H), 3.68 (s, 3H), 3.43 (br m, 4H), 2.97 - 2.75 (m, 5H), 2.44 (m, 1H).

Reference： [1]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1 Location in patent: Page/Page column 22-24
[2]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1 Location in patent: Page/Page column 22-24

74
ethyl N-(2-fluoro-6-formylphenyl)carbamate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: toluene / 24 h / 20 °C 2.1: titanium tetrachloride / dichloromethane / 0.25 h / 0 °C 2.2: 2 h / -60 °C 2.3: 8 h / -60 °C 3.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 5.1: potassium carbonate / acetone / 0.08 h / 20 °C 5.2: Reflux 6.1: trichlorophosphate; dmap / toluene / 100 °C / Reflux 6.2: 24 h / 100 °C 7.1: sodium hydroxide; water / tetrahydrofuran / 10 h / 60 °C
	Multi-step reaction with 7 steps 1.1: toluene / 24 h / 20 °C 2.1: titanium tetrachloride / dichloromethane / 0.25 h / 0 °C 2.2: 2 h / -60 °C 2.3: 8 h / -60 °C 3.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 5.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 5.2: 18 h / 20 °C 6.1: trichlorophosphate; dmap / toluene / 100 °C / Reflux 6.2: 24 h / 100 °C 7.1: sodium hydroxide; water / tetrahydrofuran / 10 h / 60 °C
	Multi-step reaction with 7 steps 1.1: toluene / 24 h / 20 °C 2.1: titanium tetrachloride / dichloromethane / 0.25 h / 0 °C 2.2: 2 h / -60 °C 2.3: 8 h / -60 °C 3.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 5.1: potassium carbonate / acetone / 0.08 h / 20 °C 5.2: Reflux 6.1: phosphorus pentachloride / dichloromethane / 2 h / Reflux 6.2: 3 h / 120 - 130 °C / Reflux 7.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr

	Multi-step reaction with 7 steps 1.1: toluene / 24 h / 20 °C 2.1: titanium tetrachloride / dichloromethane / 0.25 h / 0 °C 2.2: 2 h / -60 °C 2.3: 8 h / -60 °C 3.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 5.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 5.2: 18 h / 20 °C 6.1: phosphorus pentachloride / dichloromethane / 2 h / Reflux 6.2: 3 h / 120 - 130 °C / Reflux 7.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 7 steps 1.1: toluene / 24 h / 20 °C 2.1: titanium tetrachloride / dichloromethane / 0.25 h / 0 °C 2.2: 2 h / -60 °C 2.3: 8 h / -60 °C 3.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 5.1: potassium carbonate / acetone / 0.08 h / 20 °C 5.2: Reflux 6.1: trichlorophosphate / chlorobenzene / 3.5 h / Reflux 6.2: 18 h / 115 - 120 °C / Reflux 6.3: 2 h / Reflux 7.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 7 steps 1.1: toluene / 24 h / 20 °C 2.1: titanium tetrachloride / dichloromethane / 0.25 h / 0 °C 2.2: 2 h / -60 °C 2.3: 8 h / -60 °C 3.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 5.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 5.2: 18 h / 20 °C 6.1: trichlorophosphate / chlorobenzene / 3.5 h / Reflux 6.2: 18 h / 115 - 120 °C / Reflux 6.3: 2 h / Reflux 7.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr

Reference： [1]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[2]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[3]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[4]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[5]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[6]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1

75
ethyl (2-fluoro-6-(((2-methoxy-5-(trifluoromethyl)phenyl)imino)methyl)phenyl)carbamate [ No CAS ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: titanium tetrachloride / dichloromethane / 0.25 h / 0 °C 1.2: 2 h / -60 °C 1.3: 8 h / -60 °C 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 4.1: potassium carbonate / acetone / 0.08 h / 20 °C 4.2: Reflux 5.1: phosphorus pentachloride / dichloromethane / 2 h / Reflux 5.2: 3 h / 120 - 130 °C / Reflux 6.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 6 steps 1.1: titanium tetrachloride / dichloromethane / 0.25 h / 0 °C 1.2: 2 h / -60 °C 1.3: 8 h / -60 °C 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 4.1: potassium carbonate / acetone / 0.08 h / 20 °C 4.2: Reflux 5.1: trichlorophosphate; dmap / toluene / 100 °C / Reflux 5.2: 24 h / 100 °C 6.1: sodium hydroxide; water / tetrahydrofuran / 10 h / 60 °C
	Multi-step reaction with 6 steps 1.1: titanium tetrachloride / dichloromethane / 0.25 h / 0 °C 1.2: 2 h / -60 °C 1.3: 8 h / -60 °C 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 4.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 4.2: 18 h / 20 °C 5.1: phosphorus pentachloride / dichloromethane / 2 h / Reflux 5.2: 3 h / 120 - 130 °C / Reflux 6.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr

	Multi-step reaction with 6 steps 1.1: titanium tetrachloride / dichloromethane / 0.25 h / 0 °C 1.2: 2 h / -60 °C 1.3: 8 h / -60 °C 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 4.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 4.2: 18 h / 20 °C 5.1: trichlorophosphate; dmap / toluene / 100 °C / Reflux 5.2: 24 h / 100 °C 6.1: sodium hydroxide; water / tetrahydrofuran / 10 h / 60 °C
	Multi-step reaction with 6 steps 1.1: titanium tetrachloride / dichloromethane / 0.25 h / 0 °C 1.2: 2 h / -60 °C 1.3: 8 h / -60 °C 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 4.1: potassium carbonate / acetone / 0.08 h / 20 °C 4.2: Reflux 5.1: trichlorophosphate / chlorobenzene / 3.5 h / Reflux 5.2: 18 h / 115 - 120 °C / Reflux 5.3: 2 h / Reflux 6.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr
	Multi-step reaction with 6 steps 1.1: titanium tetrachloride / dichloromethane / 0.25 h / 0 °C 1.2: 2 h / -60 °C 1.3: 8 h / -60 °C 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 0 - 5 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 22 h / Reflux 4.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3.5 h / 20 °C 4.2: 18 h / 20 °C 5.1: trichlorophosphate / chlorobenzene / 3.5 h / Reflux 5.2: 18 h / 115 - 120 °C / Reflux 5.3: 2 h / Reflux 6.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; water / 2 h / 25 °C / 2250.23 Torr

Reference： [1]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[2]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[3]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[4]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[5]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1
[6]Current Patent Assignee: P&R SPA - WO2022/18625, 2022, A1

76
[ 75-30-9 ]
[ 917389-32-3 ]
[ 2872586-94-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 0 - 25℃; Inert atmosphere;	8.2 2. Preparation of isopropyl ester impurities Add 0.71g of the compound of formula I, 0.4g of K2CO3 and 7mL of DMF into a 25mL three-necked flask, under nitrogen protection,Cool down to 0°C, add 0.31g isopropane iodide dropwise, transfer to room temperature or 25°C to continue the reaction, stir overnight, take samples for monitoring, and the reaction is complete.Add 14mL of water and 7mL of ethyl acetate to the reaction solution, stir for 5min, let stand for liquid separation, wash the upper organic layer with water (14mL×3), concentrate, and dry under vacuum at 40°C to obtain the compound of formula II

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - CN115403528, 2022, A Location in patent: Paragraph 0093; 0097-0099

77
[ CAS Unavailable ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
83.2 %	Stage #1: C₃₁H₃₂F₄N₄O₄*C₁₈H₁₄O₈ With sodium hydrogencarbonate In ethyl acetate Stage #2: With water; lithium hydroxide at 30℃;	7 Embodiment 7 prepares final product compound I Add 4.5g of Int7 to 17.5ml of ethyl acetate, add 12.7g of saturated aqueous sodium bicarbonate solution, react for 1h, and separate the water phase. The organic phase was concentrated. Acetone and LiOH aqueous solution (0.5 g LiOH and 20 ml purified water) were added to the concentrate. React at 30°C for 4h. Add to 95ml of purified water. The pH was adjusted to 6.0 with 1M HCl. After suction filtration, the wet product was rinsed with purified water and dried to obtain 2.7 g of the product, with a yield of 83.2%, a purity of 99.8%, and an ee value of 99.86%.

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - CN115850192, 2023, A Location in patent: Paragraph 0003;

78
[ 2921059-75-6 ]
[ 917389-32-3 ]

Yield	Reaction Conditions	Operation in experiment
83.2 %	Stage #1: C₃₁H₃₂F₄N₄O₄*C₂₀H₁₈O₈ With sodium hydrogencarbonate In ethyl acetate Stage #2: With water; lithium hydroxide at 30℃;	7 Embodiment 7 prepares final product compound I Add 4.5g of Int7 to 17.5ml of ethyl acetate, add 12.7g of saturated aqueous sodium bicarbonate solution, react for 1h, and separate the water phase. The organic phase was concentrated. Acetone and LiOH aqueous solution (0.5 g LiOH and 20 ml purified water) were added to the concentrate. React at 30°C for 4h. Add to 95ml of purified water. The pH was adjusted to 6.0 with 1M HCl. After suction filtration, the wet product was rinsed with purified water and dried to obtain 2.7 g of the product, with a yield of 83.2%, a purity of 99.8%, and an ee value of 99.86%.

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - CN115850192, 2023, A Location in patent: Paragraph 0003; 0091-0092

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CAS No. :	917389-32-3	MDL No. :	MFCD22572725
Formula :	C₂₉H₂₈F₄N₄O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FWYSMLBETOMXAG-QHCPKHFHSA-N
M.W :	572.55	Pubchem ID :	45138674
Synonyms :	AIC246;MK-8228;Prevymis;MK-8828

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
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
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 917389-32-3 ] {[proInfo.proName]}

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Application In Synthesis of [ 917389-32-3 ]

[ 917389-32-3 ] Synthesis Path-Downstream 1~78

Precautionary Statements-General

Prevention

Response

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Disposal

Physical hazards

Health hazards

Environmental hazards

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