Name: 7226-23-5|1,3-Dimethyltetrahydropyrimidin-2(1H)-one|98%
Brand: Ambeed
SKU: A411176
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1
[ 1852-17-1 ]
[ 77-78-1 ]
[ 7226-23-5 ]

Reference： [1]Synthetic Communications,1988,vol. 18,p. 487 - 494

2
[ 1852-17-1 ]
[ 74-88-4 ]
[ 7226-23-5 ]

Reference： [1]Journal of Medicinal Chemistry,1981,vol. 24,p. 1089 - 1092

3
[ 2055-46-1 ]
[ 74-88-4 ]
[ 7226-23-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride for 5h; Heating;
81%	With 18-crown-6 ether; N-benzyl-N,N,N-triethylammonium chloride for 2h; Heating;

Reference： [1]Bogatsky, A. V.; Lukyanenko, N. G.; Kirichenko, T. I. [Synthesis, 1982, # 6, p. 464 - 465]
[2]Bogat-skii, A. V.; Luk'yanenko, N. G.; Kirichenko, T. I.; Limich, V. V.; Karpenko, L. P. [Journal of Organic Chemistry USSR (English Translation), 1984, vol. 20, # 1, p. 89 - 95][Zhurnal Organicheskoi Khimii, 1984, vol. 20, # 1, p. 101 - 108]

4
[ 201230-82-2 ]
[ 111-33-1 ]
[ 7226-23-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: carbon monoxide; 1,3-bis(methylamino)propane With selenium at 20℃; for 2h; neat (no solvent); Stage #2: With oxygen at 20℃; for 1h; neat (no solvent);
52%	With iodine; potassium carbonate In dichloromethane at 20℃;

Reference： [1]Location in patent: experimental part Mizuno, Takumi; Nakai, Takeo; Mihara, Masatoshi [Synthesis, 2010, # 24, p. 4251 - 4255]
[2]McCusker, Jennifer E.; Grasso, Cara A.; Main, Andrea D.; McEiwee-White, Lisa [Organic Letters, 1999, vol. 1, # 7, p. 961 - 964]

5
[ 7226-23-5 ]
[ 204138-31-8 ]
[ 54512-75-3 ]
[ 204138-83-0 ]

Yield	Reaction Conditions	Operation in experiment
	With chloro-trimethyl-silane; lithium bromide; iodine; magnesium;copper(I) iodide; In tetrahydrofuran; water; acetic acid;	a 7alpha-(5-Chloropentyl)-11beta-fluor-estr-4-ene-3,17-dione First 20% of a solution of 39 ml of <strong>[54512-75-3]1-bromo-5-chloropentane</strong> in 300 ml of THF is added under nitrogen to a suspension of 7.2 g of magnesium chips in 100 ml of THF. After the reaction has started, which can be achieved by adding iodine and dibromomethane, the residual solution is added in drops in such a way that the internal temperature does not exceed 35 C. In a second flask, 51.2 g of lithium bromide is added to a suspension of 28.1 g of copper(I) iodide in 130 ml of THF at 0 C., whereby the internal temperature climbs to 40 C. Without cooling, 49.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one is now added and stirred for 15 minutes at 40 C. A clear solution is obtained, which was added in drops to the Grignard solution that is cooled to -50 C. Then, it is stirred for 15 more minutes at -30 C. and mixed at -70 C. drop by drop with a solution of 25 g of 11beta-fluor-estra-4,6-diene-3,17-dione in 260 ml of THF, 26 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 59 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed -65 C. It is stirred for 30 minutes under cold conditions, then 34.7 ml of glacial acetic acid is added in drops, the cooling bath is removed and stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.5 l of water, diluted with the same amount of ethyl acetate, the precipitate is separated on Celite, rewashed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 22.1 g of 7alpha-(5-chloropentyl)-11beta-fluor-estr-4-ene-3,17-dione is obtained.
	With chloro-trimethyl-silane; lithium bromide; iodine; magnesium;copper(I) iodide; In tetrahydrofuran; acetic acid;	a 7alpha-(5-Chloropentyl)-11beta-fluoro-estr-4-ene-3,17-dione First, 20% of a solution of 39 ml of <strong>[54512-75-3]1-bromo-5-chloropentane</strong> in 300 ml of THF is added to a suspension of 7.2 g of magnesium chips in 100 ml of THF under nitrogen. After the reaction starts, which can be achieved by adding iodine and dibromomethane, the remaining solution is added in drops in such a way that the internal temperature does not exceed 35 C. In a second flask, 51.2 g of lithium bromide is added to a suspension of 28.1 g of copper(I) iodide in 130 ml of THF at 0 C., whereby the internal temperature climbs to 40 C. Without cooling, 49.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one is now added and stirred for 15 minutes at 40 C. A clear solution is obtained, which is added in drops to the Grignard solution that is cooled to -50 C. Then, it is stirred for 15 more minutes at -30 C. and mixed at -70 C. drop by drop with a solution of 25 g of 11beta-fluoro-estra-4,6-diene-3,17-dione in 260 ml of THF, 26 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 59 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed -65 C. It is stirred for 30 minutes cold, then 34.7 ml of glacial acetic acid is added in drops, the cooling bath is removed, and it is stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.51 of water, diluted with the same amount of ethyl acetate, the precipitate is separated on Celite, rewashed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 22.1 g of 7alpha-(5-chloropentyl)-11beta-fluoro-estr-4-ene-3,17-dione is obtained.

Reference： [1]Patent: US2003/69434,2003,A1
[2]Patent: US5866560,1999,A

6
[ 7226-23-5 ]
[ 204138-31-8 ]
[ 6294-17-3 ]
[ 204138-95-4 ]

Yield	Reaction Conditions	Operation in experiment
	With chloro-trimethyl-silane; lithium bromide; magnesium;copper(I) iodide; In tetrahydrofuran; water; acetic acid;	a 7alpha-(6-Chlorohexyl)-11beta-fluor-estr-4-ene-3,17-dione First 30 ml of a solution of 41 ml of <strong>[6294-17-3]1-bromo-6-chloro-hexane</strong> in 270 ml of THF is added under nitrogen to a suspension of 6.8 g of magnesium chips in 100 ml of THF. After the reaction has started, the residual solution is added in drops in such a way that the internal temperature does not exceed 35° C. In a second flask, 48.1 g of lithium bromide is added to a suspension of 26.4 g of copper(I) iodide in 120 ml of THF at 0° C., whereby the internal temperature climbs to 40° C. Without cooling, 46.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one is now added and stirred for 30 minutes at 40° C. A clear solution is obtained, which is added in drops to the Grignard solution that is cooled to -40° C. Then, it is stirred for 30 more minutes at -30° C. and mixed drop by drop at -50° C. with a solution of 23.5 g of 11beta-fluor-estra-4,6-diene-3,17-dione in 230 ml of THF, 24.6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 55 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed -40° C. It is stirred for 1 hour under cold conditions, then 32 ml of glacial acetic acid is added in drops, the cooling bath is removed and stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.5 l of water, diluted with the same amount of ethyl acetate, the precipitate is separated overnight on Celite, rewashed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 25.2 g of 7alpha-(6-chlorohexyl)-11beta-fluor-estr-4-ene-3,17-dione is obtained.

Reference： [1]Patent: US2003/69434,2003,A1

7
[ 7226-23-5 ]
[ 27935-87-1 ]
[ 16188-55-9 ]
[ 300355-05-9 ]

Yield	Reaction Conditions	Operation in experiment
35%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 9 3-Cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (3.2 mL, 23.16 mnmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to -78 C. under nitrogen and then treated with a lOM solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at -78 C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78 C. for 30 min and then allowed to warm to 25 C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1*100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93 C.; EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, found 264.1177.
35%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 61 3-Cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at -78 C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78 C. for 30 min and then allowed to warm to 25 C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93 C.; EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, found 264.1177.
35%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	(A) N-Benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at -78 C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78 C. for 30 min and then allowed to warm to 25 C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1*100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93 C.; EI-HRMS m/e calcd for C15H20S (M+) 264.1184, found 264.1177.

35%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 9 3-Cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at -78 C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then stirred at -78 C. for 30 min and then allowed to warm to 25 C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93 C.; EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, found 264.1177.
35%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 134 2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid amide A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at -78 C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then stirred at -78 C. for 30 min and then allowed to warm to 25 C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1*100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93 C.; EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, found 264.1177.
35%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 61 3-Cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry tetrahydrofuran (10.3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3.4 mL). The reaction mixture was allowed to stir at -78 C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.55 g, 12.13 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then stirred at -78 C. for 30 min and then allowed to warm to 25 C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1200 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g, 35%) as a cream solid: mp 91-93 C.; EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, found 264.1177.

Reference： [1]Patent: US2001/39344,2001,A1
[2]Patent: US2001/39344,2001,A1
[3]Patent: US2002/103199,2002,A1
[4]Patent: US6610846,2003,B1
[5]Patent: US6610846,2003,B1
[6]Patent: US6610846,2003,B1

8
[ 7226-23-5 ]
[ 27935-87-1 ]
[ 1878-68-8 ]
2-(4-bromophenyl)-3-cyclopentyl-propionic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With hydrogenchloride; n-butyllithium; diisopropylamine In tetrahydrofuran	7 3-Cyclopentyl-N-thiazol-2-yl-2-(4-thiophen-2-yl-phenyl)-propionamide EXAMPLE 7 3-Cyclopentyl-N-thiazol-2-yl-2-(4-thiophen-2-yl-phenyl)-propionamide A solution of diisopropylamine (7.7 mL, 54.88 mmol) in dry tetrahydrofuran (23 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrirnidinone (10 mL) was cooled to -78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (22.0 mL, 54.88 mmol). The reaction mixture was stirred at -78° C. for 30 min and then treated dropwise with a solution of 4-bromophenylacetic acid (5.62 g, 26.13 mmol) in dry tetrahydrofuran (23 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL). The reaction mixture turned dark in color and was allowed to stir at -78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (5.76 g, 27.44 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 24 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified using a 10% aqueous hydrochloric acid solution. The resulting aqueous layer was extracted with ethyl acetate (2*100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid (3.88 g, 50%) as a light yellow solid: mp 91-93° C.; EI-HRMS m/e calcd for C14H17BrO2 (M+) 296.0412, found 296.0417.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2002/2190, 2002, A1

9
[ 7226-23-5 ]
[ 27935-87-1 ]
[ 243977-23-3 ]
3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	(A) 3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooled to -78 C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of <strong>[243977-23-3]4-(trifluoromethylthio)phenylacetic acid</strong> (1.89 g, 8.00 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). The reaction mixture was allowed to stir at -78 C. for 55 min, at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 41 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (300 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1*100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid: mp 69-71 C.; EI-HRMS m/e calcd for C15H17F3O2S (M+) 318.0901, found 318.0912.
58%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	(A) 3-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooled to -78 C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of <strong>[243977-23-3]4-(trifluoromethylthio)phenylacetic acid</strong> (1.89 g, 8.00 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). The reaction mixture was allowed to stir at -78 C. for 55 min, at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 41 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1300 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid: mp 69-71 C.; EI-HRMS mle calcd for C15H17F3O2S (M+) 318.0901, found 318.0912.
58%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 62 {2-p-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylaminol-thiazol-4-yl}-acetic Acid Ethyl Ester A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooled to -78 C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of <strong>[243977-23-3]4-(trifluoromethylthio)phenylacetic acid</strong> (1.89 g, 8.00 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). The reaction mixture was allowed to stir at -78 C. for 55 min, at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 41 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1300 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid: mp 69-71 C.; EI-HRMS m/e calcd for C15H17F3O2S (M+) 318.0901, found 318.0912.

58%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 63 N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooled to -78 C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of <strong>[243977-23-3]4-(trifluoromethylthio)phenylacetic acid</strong> (1.89 g, 8.00 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). The reaction mixture was allowed to stir at -78 C. for 55 min, at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 41 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofiran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1300 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid: mp 69-71 C.; EI-HRMS m/e calcd for C15H17F3O2S (M+) 318.0901, found 318.0912.
58%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	(A) 3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooled to -78 C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of <strong>[243977-23-3]4-(trifluoromethylthio)phenylacetic acid</strong> (1.89 g, 8.00 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). The reaction mixture was allowed to stir at -78 C. for 55 min, at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 41 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1300 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid: mp 69-71 C.; EI-HRMS m/e calcd for C15H17F3O2S (M+) 318.0901, found 318.0912.
58%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	(A) 3-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooled to -78 C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of <strong>[243977-23-3]4-(trifluoromethylthio)phenylacetic acid</strong> (1.89 g, 8.00 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). The reaction mixture was allowed to stir at -78 C. for 55 min, at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 41 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1300 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid: mp 69-71 C.; EI-HRMS m/e calcd for C15H17F3O2S (M+) 318.0901, found 318.0912.
58%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 62 {2-[3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooled to -78 C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of <strong>[243977-23-3]4-(trifluoromethylthio)phenylacetic acid</strong> (1.89 g, 8.00 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). The reaction mixture was allowed to stir at -78 C. for 55 min, at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 41 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1300 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid: mp 69-71 C.; EI-HRMS m/e calcd for C15H17F3O2S (M+) 318.0901, found 318.0912.
58%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 63 N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) was cooled to -78 C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol). The resulting reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of <strong>[243977-23-3]4-(trifluoromethylthio)phenylacetic acid</strong> (1.89 g, 8.00 mmol) in dry tetrahydrofuran (7.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL). The reaction mixture was allowed to stir at -78 C. for 55 min, at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 41 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1300 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid: mp 69-71 C.; EI-HRMS m/e calcd for C15H17F3O2S (M+) 318.0901, found 318.0912.

Reference： [1]Patent: US2001/39344,2001,A1
[2]Patent: US2001/39344,2001,A1
[3]Patent: US2001/39344,2001,A1
[4]Patent: US2001/39344,2001,A1
[5]Patent: US6610846,2003,B1
[6]Patent: US6610846,2003,B1
[7]Patent: US6610846,2003,B1
[8]Patent: US6610846,2003,B1

10
[ 7226-23-5 ]
[ 300355-67-3 ]
[ 27935-87-1 ]
2-(3-bromo-4-methylsulfanylphenyl)-3-cyclopentylpropionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With n-butyllithium; diisopropylamine In tetrahydrofuran	24.A (A) A solution of diisopropylamine (4.8 mL, 34.27 mmol) in dry tetrahydrofuran (30 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to -78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (13.8 mL, 34.27 mmol). The resulting reaction mixture was stirred at -78° C. for 30 min and then treated dropwise with a solution of (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (8.57 g, 31.15 mmol) in dry tetrahydrofuran (30 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL). The resulting reaction mixture was allowed to stir at -78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (7.85 g, 37.38 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (300 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was extracted with ethyl acetate (3150 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (9.20 g, 83%) as a light yellow oil: EI-HRMS m/e calcd for C16H21BrO2S (M+) 356.0446, found 356.0435.
83%	With n-butyllithium; diisopropylamine In tetrahydrofuran	148.A (A) A solution of diisopropylamine (4.8 mL, 34.27 mmol) in dry tetrahydrofuran (30 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to -78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (13.8 mL, 34.27 mmol). The resulting reaction mixture was stirred at -78° C. for 30 min and then treated dropwise with a solution of (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (8.57 g, 31.15 mmol) in dry tetrahydrofuran (30 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL). The resulting reaction mixture was allowed to stir at -78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (7.85 g, 37.38 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (300 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was extracted with ethyl acetate (3150 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (9.20 g, 83%) as a light yellow oil: EI-HRMS m/e calcd for C16H21BrO2S (M+) 356.0446, found 356.0435.
57%	With n-butyllithium; diisopropylamine In tetrahydrofuran	73 2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide A solution of diisopropylamine (3.4 mL, 24.38 mmol) in dry tetrahydrofuran (21 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL) was cooled to -78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (9.8 mL, 24.38 mmol). The resulting reaction mixture was stirred at -78° C. for 30 min and then treated dropwise with a solution of (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (6.10 g, 22.17 mmol) in dry tetrahydrofuran (21 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). The resulting reaction mixture was allowed to stir at -78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (5.59 g, 26.60 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (300 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was extracted with ethyl acetate (3150 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (4.52 g, 57%) as a light yellow oil: EI-HRMS m/e calcd for C16H21BrO2S (M+) 356.0446, found 356.0435.

57%	With n-butyllithium; diisopropylamine In tetrahydrofuran	75 2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of diisopropylamine (3.4 mL, 24.38 mmol) in dry tetrahydrofuran (21 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL) was cooled to -78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (9.8 mL, 24.38 mmol). The resulting reaction mixture was stirred at -78° C. for 30 min and then treated dropwise with a solution of (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (6.10 g, 22.17 mmol) in dry tetrahydrofuran (21 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). The resulting reaction mixture was allowed to stir at -78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (5.59 g, 26.60 mmol) in a small amount of dry tetrahydrofliran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (300 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was extracted with ethyl acetate (3150 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (4.52 g, 57%) as a light yellow oil: EI-HRMS m/e calcd for C16H21BrO2S (M+) 356.0446, found 356.0435.
57%	With n-butyllithium; diisopropylamine In tetrahydrofuran	76 2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide A solution of diisopropylamine (3.4 mL, 24.38 mmol) in dry tetrahydrofuran (21 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL) was cooled to -78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (9.8 mL, 24.38 mmol). The reaction mixture was stirred at -78° C. for 30 min and then treated dropwise with a solution of (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (6.10 g, 22.17 mmol) in dry tetrahydrofuran (21 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). The resulting reaction mixture was allowed to stir at -78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (5.59 g, 26.60 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (300 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was extracted with ethyl acetate (3150 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (4.52 g, 57%) as a light yellow oil: EI-HRMS m/e calcd for C16H21BrO2S (M+) 356.0446, found 356.0435.
57%	With n-butyllithium; diisopropylamine In tetrahydrofuran	26 N-Benzothiazol-2-yl-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide A solution of diisopropylamine (3.4 mL, 24.38 mmol) in dry tetrahydrofuran (21 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL) was cooled to -78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (9.8 mL, 24.38 mmol). The reaction mixture was stirred at -78° C. for 30 min and then treated dropwise with a solution of (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (6.10 g, 22.17 mmol) in dry tetrahydrofuran (21 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). The resulting reaction mixture was allowed to stir at -78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (5.59 g, 26.60 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (300 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was extracted with ethyl acetate (3150 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (4.52 g, 57%) as a light yellow oil: EI-HRMS m/e calcd for C16H25BrO2S (M) 356.0446, found 356.0435.
57%	With n-butyllithium; diisopropylamine In tetrahydrofuran	72 2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of diisopropylamine (3.4 mL, 24.38 mmol) in dry tetrahydrofuran (21 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL) was cooled to -78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (9.8 mL, 24.38 mmol). The resulting reaction mixture was stirred at -78° C. for 30 min and then treated dropwise with a solution of (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (6.10 g, 22.17 mmol) in dry tetrahydrofuran (21 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). The resulting reaction mixture was allowed to stir at -78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (5.59 g, 26.60 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (300 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was extracted with ethyl acetate (3150 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (4.52 g, 57%) as a light yellow oil: EI-HRMS m/e calcd for C16H21BrO2S (M+) 356.0446, found 356.0435.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2002/103199, 2002, A1
[2]Current Patent Assignee: ROCHE HOLDING AG - US6610846, 2003, B1
[3]Current Patent Assignee: ROCHE HOLDING AG - US2001/39344, 2001, A1
[4]Current Patent Assignee: ROCHE HOLDING AG - US2001/39344, 2001, A1
[5]Current Patent Assignee: ROCHE HOLDING AG - US2001/39344, 2001, A1
[6]Current Patent Assignee: ROCHE HOLDING AG - US2002/103199, 2002, A1
[7]Current Patent Assignee: ROCHE HOLDING AG - US2001/39344, 2001, A1 Current Patent Assignee: ROCHE HOLDING AG - US6610846, 2003, B1

11
[ 7226-23-5 ]
(3,4-bis-methanesulfonyl-phenyl)-acetic acid methyl ester [ No CAS ]
[ 27935-87-1 ]
2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With n-butyllithium; diisopropylamine In tetrahydrofuran	80 2-(3,4-Bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide A solution of diisopropylamine (951 μL, 6.79 mmol) in dry tetrahydrofuran (6 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL) was cooled to -78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (2.5 mL, 6.79 mmol). The resulting reaction mixture was stirred at -78° C. for 30 min and then treated dropwise with a solution of (3,4-bis-methanesulfonyl-phenyl)-acetic acid methyl ester (1.89 g, 6.17 mmol) in dry tetrahydrofuran (12 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL). The resulting reaction mixture was allowed to stir at -78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (1.56 g, 7.40 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 64 h. The reaction mixture was quenched with water (150 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining residue was further diluted with water (100 mL) and then extracted with ethyl acetate (1250 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.61 g, 67%) as a yellow oil: EI-HRMS mle calcd for C17H24O6S2 (M) 388.1014, found 388.1014.
67%	With n-butyllithium; diisopropylamine In tetrahydrofuran	79 2-(3,4-Bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of diisopropylamine (951 μL, 6.79 mmol) in dry tetrahydrofuran (6 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL) was cooled to -78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (2.5 mL, 6.79 mmol). The resulting reaction mixture was stirred at -78° C. for 30 min and then treated dropwise with a solution of (3,4-bis-methanesulfonyl-phenyl)-acetic acid methyl ester (1.89 g, 6.17 mmol) in dry tetrahydrofuran (12 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL). The resulting reaction mixture was allowed to stir at -78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (1.56 g, 7.40 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 64 h. The reaction mixture was quenched with water (150 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining residue was further diluted with water (100 mL) and then extracted with ethyl acetate (1250 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.61 g, 67%) as a yellow oil: EI-HRMS m/e calcd for C17H24O6S2 (M+) 388.1014, found 388.1014.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2001/39344, 2001, A1
[2]Current Patent Assignee: ROCHE HOLDING AG - US2001/39344, 2001, A1 Current Patent Assignee: ROCHE HOLDING AG - US6610846, 2003, B1

12
[ 7226-23-5 ]
[ 27935-87-1 ]
[ 1798-06-7 ]
3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 10 3-Cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 25 3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-pyridin-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 28 3-Cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-3-yl-phenyl)-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.

70%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 29 3-Cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-4-yl-phenyl)-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 35 1-[3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionyl]-3-methyl Urea A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 36 1-[3-Cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionyl]-3-methyl-urea A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 37 1-{3-Cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionyl}-3-methyl-urea A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stiffed at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 5 8.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 5 3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EL-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 8 3-Cyclopentyl-2-(4-pyridin-3-yl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EL-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
70%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 9 3-Cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 1 3-Cyclopentyl-2-(4-ethynyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofiran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2800 mL). The combined organic extracts were washed with water (1600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 10 3-Cyclopentyl-2-(4-pyrimidin-5-ylethynyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2800 mL). The combined organic extracts were washed with water (1600 mL), a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 3 3-Cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2800 mL). The combined organic extracts were washed with water (1600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 4 3-Cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and was acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2800 mL). The combined organic extracts were washed with water (1600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 5 3-Cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and was acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2800 mL). The combined organic extracts were washed with water (1600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 6 3-Cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2800 mL). The combined organic extracts were washed with water (1600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 7 3-Cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2800 mL). The combined organic extracts were washed with water (1600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS In/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 8 3-Cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2800 mL). The combined organic extracts were washed with water (1600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
57.8%	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	EXAMPLE 9 3-Cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2800 mL). The combined organic extracts were washed with water (1600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.

Reference： [1]Patent: US2002/2190,2002,A1
[2]Patent: US2002/2190,2002,A1
[3]Patent: US2002/2190,2002,A1
[4]Patent: US2002/2190,2002,A1
[5]Patent: US2002/2190,2002,A1
[6]Patent: US2002/2190,2002,A1
[7]Patent: US2002/2190,2002,A1
[8]Patent: US2002/2190,2002,A1
[9]Patent: US2002/2190,2002,A1
[10]Patent: US2002/2190,2002,A1
[11]Patent: US2001/53851,2001,A1
[12]Patent: US2001/53851,2001,A1
[13]Patent: US2001/53851,2001,A1
[14]Patent: US2001/53851,2001,A1
[15]Patent: US2001/53851,2001,A1
[16]Patent: US2001/53851,2001,A1
[17]Patent: US2001/53851,2001,A1
[18]Patent: US2001/53851,2001,A1
[19]Patent: US2001/53851,2001,A1

13
[ 7226-23-5 ]
[ 27935-87-1 ]
[ 111601-67-3 ]
[ 372509-76-7 ]

Yield	Reaction Conditions	Operation in experiment
51%	With n-butyllithium; diisopropylamine In tetrahydrofuran	18 3-Cyclopentyl-2-(4-morpholin-4-yl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (344 μL, 2.45 mmol) in dry tetrahydrofuran (2.9 mL) was cooled to -78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (981 μL, 2.45 mmol). The reaction mixture was stirred at -78° C. for 15 min and then treated dropwise with a solution of (4-morpholin-4-yl-phenyl)-acetic acid methyl ester (549.9 mg, 2.34 mmol) in dry tetrahydrofuran (2 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The resulting reaction mixture was allowed to stir at -78° C. for 30 min, at which time, a solution of iodomethylcyclopentane (540.0 mg, 2.57 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 67 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a saturated aqueous sodium chloride solution (1*100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid methyl ester (381.4 mg, 51%) as a white solid: mp 68-70° C.; EI-HRMS m/e calcd for C19H27NO3 (M+) 317.1991, found 317.2001.
51%	With n-butyllithium; diisopropylamine In tetrahydrofuran	39 1-[3-Cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionyl]-3-methyl-urea A solution of diisopropylamine (344 μL, 2.45 mmol) in dry tetrahydrofuran (2.9 mL) was cooled to -78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (981 μL, 2.45 mmol). The reaction mixture was stirred at -78° C. for 15 min and then treated dropwise with a solution of (4-morpholin-4-yl-phenyl)-acetic acid methyl ester (549.9 mg, 2.34 mmol) in dry tetrahydrofuran (2 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The resulting reaction mixture was allowed to stir at -78° C. for 30 min, at which time, a solution of iodomethylcyclopentane (540.0 mg, 2.57 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then allowed to warn to 25° C. where it was stirred for 67 h. The reaction mixture was quenched with water and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was diluted with ethyl acetate (200 mL). The organic phase was washed with a saturated aqueous sodium chloride solution (1*100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid methyl ester (381.4 mg, 51%) as a white solid: mp 68-70° C.; EI-HRMS m/e calcd for C19H27NO3 (M+) 317.1991, found 317.2001.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2002/2190, 2002, A1
[2]Current Patent Assignee: ROCHE HOLDING AG - US2002/2190, 2002, A1

14
[ 7226-23-5 ]
[ 300355-18-4 ]
[ 27935-87-1 ]
[ 300355-19-5 ]

Yield	Reaction Conditions	Operation in experiment
68%	With n-butyllithium; diisopropylamine In tetrahydrofuran	13 (2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (29.2 mL, 0.21 mol) in dry tetrahydrofuran (186 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (62 mL) was cooled to -78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (83.4 mL, 0.21 mol). The yellow-orange reaction mixture was stirred at -78° C. for 35 min and then slowly treated with a solution of 4-(methanesulfonyl)phenyl acetic acid methyl ester (45.35 g, 0.20 mol) in dry tetrahydrofuran (186 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (62 mL). The reaction mixture turned dark in color. The reaction mixture was then stirred at -78° C. for 50 min, at which time, a solution of iodomethylcyclopentane (50.08 g, 0.24 mol) in a small amount of dry tetrahydrofuran was added slowly. The reaction mixture was then stirred at -78° C. for 50 min, and then allowed to warm to 25° C., where it was stirred for 36 h. The reaction mixture was quenched with water (100 mL), and the resulting reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The remaining residue was diluted with ethyl acetate (1.5 L). The organic phase was washed with a saturated aqueous sodium chloride solution (1*500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid methyl ester (41.79 g, 68%) as a yellow viscous oil: EI-HRMS m/e calcd for C16H22O4S (M+) 310.1239, found 310.1230.
68%	With n-butyllithium; diisopropylamine In tetrahydrofuran	13 (2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (29.2 mL, 0.21 mol) in dry tetrahydrofuran (186 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (62 mL) was cooled to -78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (83.4 mL, 0.21 mol). The yellow-orange reaction mixture was stirred at -78° C. for 35 min and then slowly treated with a solution of 4-(methanesulfonyl)phenyl acetic acid methyl ester (45.35 g, 0.20 mol) in dry tetrahydrofuran (186 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (62 mL). The reaction mixture turned dark in color. The reaction mixture was then stirred at -78° C. for 50 min, at which time, a solution of iodomethylcyclopentane (50.08 g, 0.24 mol) in a small amount of dry tetrahydrofuran was added slowly. The reaction mixture was then stirred at -78° C. for 50 min, and then allowed to warm to 25° C. where it was stirred for 36 h. The reaction mixture was quenched with water (100 mL), and the resulting reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The remaining residue was diluted with ethyl acetate (1.5 L). The organic phase was washed with a saturated aqueous sodium chloride solution (1*500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid methyl ester (41.79 g, 68%) as a yellow viscous oil: EI-HRMS m/e calcd for C16H22O4S (M+) 310.1239, found 310.1230.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2001/39344, 2001, A1
[2]Current Patent Assignee: ROCHE HOLDING AG - US6610846, 2003, B1

15
[ 7226-23-5 ]
[ 588939-37-1 ]
[ 27935-87-1 ]
[ 144-55-8 ]
[ 588939-42-8 ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium hydroxide; n-butyllithium; diisopropylamine In tetrahydrofuran	125 3-Cyclopentyl-2-(4-methoxymethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (0.37 mL, 2.62 mmol) in tetrahydrofuran (2 mL) was cooled to -78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (1.05 mL, 2.62 mmol). This solution was stirred at -78° C. for 30 min and then treated with a solution of (4-methoxymethylsulfanyl-phenyl)-acetic acid (223 mg, 1.05 mmol) in tetrahydrofuran (1.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL). The reaction mixture was allowed to stir at -78° C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (328 mg, 1.56 mmol). The reaction mixture was allowed to slowly warm to 25° C. where it was stirred for 18 h. At this time, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and then concentrated in vacuo. The residue was treated with a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The aqueous layer was then acidified with concentrated hydrochloric acid. This solution was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methoxymethylsulfanyl-phenyl)-propionic acid (202 mg, 65%) as an off-white solid: mp 167-170° C.; EI-HRMS m/e calcd for C16H22O3S (M+) 294.1290, found 294.1288.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US6610846, 2003, B1

16
[ 7226-23-5 ]
[ 204138-31-8 ]
[ 75-77-4 ]
[ 6294-17-3 ]
[ 204138-95-4 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium bromide; magnesium;copper(I) iodide; In tetrahydrofuran; acetic acid;	a 7alpha-(6-Chlorohexyl)-11beta-fluoro-estr-4-ene-3,17-dione First 30 ml of a solution that consists of 41 ml of <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> in 270 ml of THF is added to a suspension of 6.8 g of magnesium chips in 100 ml of THF. After the reaction starts, the remaining solution is added in drops in such a way that the internal temperature does not exceed 35° C. In a second flask, 48.1 g of lithium bromide is added to a suspension of 26.4 g of copper(I) iodide in 120 ml of THF at 0° C., whereby the internal temperature climbs to 40° C. Without cooling, 46.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one is now added and stirred for 30 minutes at 40° C. A clear solution is obtained, which is added in drops to the Grignard solution that is cooled to -40° C. Then, it is stirred for 30 more minutes at -30° C. and mixed drop by drop at -50° C. with a solution of 23.5 g of 11beta-fluoro-estra-4,6-diene-3,17-dione in 230 ml of THF, 24.6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 55 ml of trimethyl-chlorosilane in such a way that the internal temperature does not exceed -40° C. It is stirred for 1 hour cold, then 32 ml of glacial acetic acid is added in drops, the cooling bath is removed and stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.51 of water, diluted with the same amount of ethyl acetate, the precipitate is separated on Celite, rewashed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 25.2 g of 7alpha-(6-chlorohexyl)-11beta-fluoro-estr-4-ene-3,17-dione is obtained.

Reference： [1]Patent: US5866560,1999,A

17
[ 7226-23-5 ]
sodium chloride (brine) [ No CAS ]
lithium tetrahydroaluminate (LTHA) [ No CAS ]
[ 85514-43-8 ]
[ 142-62-1 ]
2-butyl-7-(tert-butyldimethylsilyloxy)-1-heptanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12.03 g (69%)	With sodium hydroxide; potassium hydrogensulfate; diisopropylamine In tetrahydrofuran; diethyl ether	1 2-Butyl-7-(tert-butyldimethylsilyloxy)-1-heptanol 2-Butyl-7-(tert-butyldimethylsilyloxy)-1-heptanol To a solution of diisopropylamine (16.8 ml, 120 mmol) in anhydrous tetrahydrofuran (THF) (125 ml) held at -30 to -40° C., n-butlyllithium (120 mmol, 50 ml of a 2.4 M solution in hexanes) was added dropwise. The resulting solution was stirred for 15 min and hexanoic acid (6.97 g, 60 mmol) in a little THF was added dropwise keeping the temperature below 0° C. The milky white suspension was stirred at 0° C. for 10 min and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU) (9.5 ml, 78 mmol, 1.2 to 1.3* the amount of hexanoic acid on a molar basis) was added and the mixture allowed to come to room temperature (22° C.) over one hour. The solution was chilled to 0° C. and 1-bromo-5-(tert-butyldimethylsilyloxy)pentane (14.35 g, 60 mmol) was added. After stirring at room temperature for 12 h, the reaction was quenched by addition of 100 ml of a saturated solution of KHSO4 (100 ml). The organic layer was diluted with ethyl ether (250 ml) and washed with a solution of saturated sodium chloride (brine) (4100 ml), dried over anhydrous MgSO4. The drying agent was removed by filtration and the solvent removed by evaporation yielding a red oil (15 g). This oil was dissolved in anhydrous ethyl ether (50 ml) and added to a suspension of lithium tetrahydroaluminate (LTHA) (4.55 g, 120 mmol) in 125 ml of anhydrous ether. The reaction mixture was heated under reflux for 8 h, chilled and decomposed with 10% NaOH (100 ml). The mixture was extracted with ether (3100 ml) and the combined extracts washed with water and dried over anhydrous K2 CO3. Removal of the solvent in vacuo and purification of the residual oil by preparative medium-pressure liquid chromatography (PMPLC) on Merck 60 silica gel (0.040-0.063 mm) yielded 12.03 g (69%) of 2-butyl-7-(tert-butyldimethylsilyloxy)-1-heptanol.

Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES - US6054141, 2000, A

18
[ 7226-23-5 ]
imidazopyridine [ No CAS ]
[ 272-97-9 ]
[ 170499-26-0 ]
[ 170497-69-5 ]

Yield	Reaction Conditions	Operation in experiment
	With NaH; sodium bromide; In tetrahydrofuran; methanol;	Step 3: 1-N,N-Dimethylcarbamoyl-6-(4-fluorophenyl)-3-{4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methyl]benzoyl}indole. To a solution of imidazo[4,5-c]pyridine (407 mg, 3.06 mmol) in THF (15 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2-1H-pyrimidinone (5 mL) was added NaH (110 mg, 4.59 mmol) in a single portion and the resulting solution was stirred for 1 hour at ambient temperature. In a separate flask, NaBr (630 mg, 6.11 mmol) was added to a solution of 6-(4-fluorophenyl)-3-(4-chloromethylbenzoyl)indole-1-carboxylic acid dimethylamide (1.33 g, 3.06 mmol), prepared as in step 2, in THF (15 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2-1H-pyrimidinone (5 mL). The resulting yellow suspension was stirred for 1 hour at ambient temperature, after which the imidazopyridine solution was added dropwise via syringe. The reaction mixture was stirred for 3 hours at ambient temperature and then was partitioned between brine and ethyl acetate. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (2%, then 4% methanol/CH2 Cl2) provided 1-N,N-dimethylcarbamoyl-6-(4-fluorophenyl)-3-{4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methyl]benzoyl}indole. (228 mg). mp 257-259 C. 1 H NMR (DMSO-d6, 300 MHz) delta2.59 (s, 3H), 3.03 (s, 6H), 5.67 (s, 2H), 7.25-7.35 (m, 4H), 7.6-7.7 (m, 2H), 7.7-7.8 (m, 2H), 7.8-7.9 (m, 3H), 8.15 (s, 1H), 8.30 (d, 1H, J=8.4 Hz), 8.3 1 (d, 1H, J=5.7 Hz), 8.87 (s, 1H). MS (DCI/NH3) m/e 532 (M+H)+. Anal calcd for C32 H26 FN5 O2.0.8H2 O: C, 70.39; H, 5.09; N, 12.83. Found: C, 70.38; H, 5.39; N, 12.82.

Reference： [1]Patent: US5486525,1996,A

19
[ 7226-23-5 ]
[ 101990-45-8 ]
[ 141872-21-1 ]
Ethyl 2-[N-(6-bromopyridin-3-ylmethyl)-N-propyl]amino}pyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium; 1,1,1,3,3,3-hexamethyl-disilazane; In tetrahydrofuran; ethyl acetate; Petroleum ether;	EXAMPLE VIII Ethyl 2-[N-(6-bromopyridin-3-ylmethyl)-N-propyl]amino}pyridine-3-carboxylate STR29 3.2 ml of a 1.6N solution of n-butyllithium are added at -20 C. to a solution of 0.87 g (5.4 mmol) of hexamethyldisilazane in 5.5 ml of THF. The solution prepared in this way is added dropwise at from -10 C. to 0 C. to a solution of 1.07 g (5.13 mmol) of ethyl 2-propylaminopyridine-3-carboxylate and 1.25 g of 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU) in 4 ml of THF. After stirring at this temperature for 10 min, 2 g (8 mmol) of <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> dissolved in 12 ml of THF are added slowly dropwise. After removing the cooling bath, the mixture is stirred at 20 C. for 36 h. After that, 2 drops of conc. hydrochloric acid are added, the solvent is removed in vacuo, and the residue is taken up in ethyl acetate, which is then washed three times with water. The organic phase is dried over sodium sulphate and concentrated, and the residue is purified on silica gel using petroleum ether/ethyl acetate (20:1). Yield: 1.14 g (59% of theory) Rf =0.35 (petroleum ether/ethyl acetate=5:1)

Reference： [1]Patent: US5594010,1997,A

20
[ 7226-23-5 ]
ammonium chloride [ No CAS ]
[ 106-95-6 ]
[ 6725-44-6 ]
[ 173457-29-9 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; diisopropylamine; In tetrahydrofuran;	a. Methyl 2-(3,4-dichlorophenyl)-4-pentenoate. A solution of diisopropylamine (12.75 g) in tetrahydrofuran was cooled to -10 C. and was treated dropwise with a solution of n-butyllithium in hexanes (50 mL of a 2.44M solution). The resulting solution was cooled to -78 C. and was treated dropwise with <strong>[6725-44-6]methyl 3,4-dichlorophenylacetate</strong> (25.0 g) to afford a deep yellow solution. To this solution was added 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (16.15 g) followed by allyl bromide (15.24 g). The reaction mixture was allowed to warm to room temperature, was quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic extracts were washed (saturated aqueous ammonium chloride, brine), dried, and evaporated to leave an amber oil. Purification by fractional distillation afforded the pentoate as a clear liquid (23.08 g); (bp 125-130 C., 1.1 Pa); NMR: 7.41 (d,1), 7.39 (d,1), 7.15 (dd,1), 5.65 (m,1), 5.10-5.00 (m,3), 3.67 (s,3), 3.59 (m,1), 2.77(m,1), 2.48 (m,1).

Reference： [1]Patent: US5635509,1997,A

21
[ 7226-23-5 ]
[ 70-23-5 ]
[ 50551-10-5 ]
[ 187724-98-7 ]

Yield	Reaction Conditions	Operation in experiment
	In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethyl acetate	1 EXAMPLE 1 The starting material is obtained as follows: Stage 1.1: At 0-5° C., 56.0 g (0.43 mol) of ethyl 2-amidinoacetate [for preparation see: Liebigs Ann. Chem., 1561 (1981)] are initially introduced into 172 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. 56.0 ml (0.45 mol) of ethyl bromopyruvate are added dropwise in the course of 30 min and the mixture is then warmed to 60° C. for 3 h. The dark-brown reaction solution is poured onto 1 liter of ice water and extracted with 1 liter of ethyl acetate and twice with 0.5 liter of ethyl acetate each time. The organic phases are washed 3 times with 0.5 liter of water and 0.5 liter of brine, dried (Na2SO4) and evaporated. Column chromatography (SiO2, hexane/ethyl acetate [1:1]) and crystallization from diethyl ether-hexane yields 2-amino-3,5-bis(ethoxycarbonyl)-1H-pyrrole; m.p. 147-149° C.; MS: (M)+=226.

Reference： [1]Current Patent Assignee: Novartis AG - US6180636, 2001, B2

22
[ 7226-23-5 ]
[ 3056-17-5 ]
[ 938050-90-9 ]

Yield	Reaction Conditions	Operation in experiment
87.5%	In acetone; at 56℃; for 0.25 - 0.5h;Heating / reflux;Product distribution / selectivity;	Example-l: Preparation of 2',3'-Didehydro-3'-deoxythymidine-N,N-dimethyl propylene urea solvate (Stavudine DMPU solvate) 3',4'-anhydrothymidine (25 g, 0.116 mole) is suspended in acetonitrile (300 ml). The slurry is stirred and potassium tert-butoxide (25 g, 0.2232 mole) is added. The resulting <n="8"/>solution is heated to 60-65C for 2 hrs. The solution is cooled to 5-10C, separated salt is filtered under nitrogen atmosphere and immediately dissolved in methanol (200 ml). pH of the solution is adjusted to 6.5 with cone. HCl and cooled to 2O0C. The precipitated KCl is filtered and washed with methanol (25 ml). The combined filtrate and wash are concentrated under vacuum. To the residue acetone (250ml), is added and heated to reflux for 0.5 hrs. Reaction mass is filtered while hot and washed with hot acetone (25 ml). Combined filtrate and wash are mixed with N, N-dimethylpropyleneurea (27 ml) and concentrated until about 100 ml of acetone remained. The solution is allowed to cool to 0-5C, filtered, washed with acetone (25 ml) to give a total of 27.6 g (70.2%) of the title compound.; Method C:Crude Stavudine (25 g, 97.7% pure, 0.1116 mole), DMPU (37.5 g, 1.5 parts) are added to acetone (50 ml) and heated to 56C for dissolution. The obtained solution is stirred for 15 min. at 56C and cooled to 6-80C. The precipitated product is filtered, washed with acetone and dried to give 34.4 g of Stavudine DMPU solvate (87.5%) with a chromatographic purity 99.93%.
87.5%	In acetone; at 6 - 56℃; for 0.25h;Product distribution / selectivity;	EXAMPLE-1 Preparation of 2',3'-Didehydro-3'-deoxythymidine-N,N-dimethyl propylene urea Solvate (Stavudine DMPU Solvate) 3',4'-anhydrothymidine (25 g, 0.116 mole) is suspended in acetonitrile (300 ml). The slurry is stirred and potassium tert-butoxide (25 g, 0.2232 mole) is added. The resulting solution is heated to 60-65 C. for 2 hrs. The solution is cooled to 5-10 C., separated salt is filtered under nitrogen atmosphere and immediately dissolved in methanol (200 ml). pH of the solution is adjusted to 6.5 with conc. HCl and cooled to 20 C. The precipitated KCl is filtered and washed with methanol (25 ml). The combined filtrate and wash are concentrated under vacuum. To the residue acetone (250 ml), is added and heated to reflux for 0.5 hrs. Reaction mass is filtered while hot and washed with hot acetone (25 ml). Combined filtrate and wash are mixed with N,N-dimethylpropyleneurea (27 ml) and concentrated until about 100 ml of acetone remained. The solution is allowed to cool to 0-5 C., filtered, washed with acetone (25 ml) to give a total of 27.6 g (70.2%) of the title compound. Method C:Crude Stavudine (25 g, 97.7% pure, 0.1116 mole), DMPU (37.5 g, 1.5 parts) are added to acetone (50 ml) and heated to 56 C. for dissolution. The obtained solution is stirred for 15 min. at 56 C. and cooled to 6-8 C. The precipitated product is filtered, washed with acetone and dried to give 34.4 g of Stavudine DMPU solvate (87.5%) with a chromatographic purity 99.93%.
86.7%	In isopropyl alcohol; at 70 - 75℃; for 0.25h;Product distribution / selectivity;	Method B:Crude Stavudine (25 g, 96.7% pure, 0.1116 mole), N,N,-dimethyl propylene urea (37.5 g, 1.5 parts) are added to isopropanol (50 ml, 2 volumes) and heated to 70-750C for dissolution. The obtained solution is stirred for 15 min. at 75C and cooled to 6-80C. The precipitated product is filtered, washed with IPA and dried to give 34.1 g of Stavudine DMPU solvate (86.7%) with a chromatographic purity of 99.91%

86.7%	In isopropyl alcohol; at 6 - 75℃; for 0.25h;Product distribution / selectivity;	Method B:Crude Stavudine (25 g, 96.7% pure, 0.1116 mole), N,N,-dimethyl propylene urea (37.5 g, 1.5 parts) are added to isopropanol (50 ml, 2 volumes) and heated to 70-75 C. for dissolution. The obtained solution is stirred for 15 min. at 75 C. and cooled to 6-8 C. The precipitated product is filtered, washed with IPA and dried to give 34.1 g of Stavudine DMPU solvate (86.7%) with a chromatographic purity of 99.91%
84.9%	at 85 - 90℃;Product distribution / selectivity;	General procedureStavudine-N,N-DimethyI propylene urea (DMPU) solvate from crude StavudineMethod A:Crude Stavudine (25 g, 95.79% pure, 0.116 mole) is dissolved in N,N-Dimethyl propylene urea (30.0 g, 1.2 parts) at 85-9O0C. The solution is allowed to cool to room temperature. The mixture is further cooled to 6-8C and maintained for 2 hrs. The crystals are filtered, washed with acetone (2 x 12 ml) and dried to give white Stavudine.DMPU solvate (33.5 g, 84.9%) with a chromatographic purity of 99.87%.MP: 120 and SOR [alpha]2S= -27.5 (c=l; water) <n="9"/>The Bruker Avance 300 MHz IH NMR spectrum in DMSO d6 showed delta 1.72 (s,3H, Stavudine, CH3), 1.86 (m,2H); 2.75 (s,2x 3H, N(CH3)2); 3.2 (m,4H, 2 x CH2); 3.60 (m,2H, 2 x H-5'); 4.77 (s,lH,H-4); 5.02 (t,-OH); 5.91 (dd, IH, H-2'); 6.39 (dl, IH, H-3'); 6.82 (d,lH,H-l'); 7.64 (s,lH,H-6); 11.30 (s, IH5NH). The Stavudine position of the above spectrum agrees with the literature values (J.Med. Chem. 32 461 (1989).
84.9%	at 6 - 90℃; for 2h;Product distribution / selectivity;	Method A:Crude Stavudine (25 g, 95.79% pure, 0.116 mole) is dissolved in N,N-Dimethyl propylene urea (30.0 g, 1.2 parts) at 85-90 C. The solution is allowed to cool to room temperature. The mixture is further cooled to 6-8 C. and maintained for 2 hrs. The crystals are filtered, washed with acetone (2×12 ml) and dried to give white Stavudine.DMPU solvate (33.5 g, 84.9%) with a chromatographic purity of 99.87%.MP: 120 and SOR [alpha]25=-27.5 (c=1; water)The Bruker Avance 300 MHz 1H NMR spectrum in DMSO d6 showed delta 1.72 (s, 3H, Stavudine, CH3), 1.86 (m, 2H); 2.75 (s, 2×3H, N(CH3)2); 3.2 (m, 4H, 2×CH2); 3.60 (m, 2H, 2×H-5'); 4.77 (s, 1H, H-4); 5.02 (t, -OH); 5.91 (dd, 1H, H-2'); 6.39 (dl, 1H, H-3'); 6.82 (d, 1H, H-1'); 7.64 (s, 1H, H-6); 11.30 (s, 1H, NH). The Stavudine position of the above spectrum agrees with the literature values (J. Med. Chem. 32 461 (1989).

Reference： [1]Patent: WO2007/60689,2007,A2 .Location in patent: Page/Page column 6-7; 8
[2]Patent: US2008/312428,2008,A1 .Location in patent: Page/Page column 3; 4
[3]Patent: WO2007/60689,2007,A2 .Location in patent: Page/Page column 8
[4]Patent: US2008/312428,2008,A1 .Location in patent: Page/Page column 4
[5]Patent: WO2007/60689,2007,A2 .Location in patent: Page/Page column 7-8
[6]Patent: US2008/312428,2008,A1 .Location in patent: Page/Page column 3-4

23
[ 7226-23-5 ]
[ 7790-44-5 ]
4H(C₃H₆N₂CO(CH₃)2)2⁽¹⁺⁾*Sb₈I₂₈^(4-)*2C₆H₅Cl={H(C₃H₆N₂CO(CH₃)2)2}4Sb₈I₂₈*2C₆H₅Cl [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With AgBF₄ In tetrahydrofuran under N2; addn. of DMPU to SbI3 in THF, color changed from yellow to orange, addn. of AgBF4 dissolved in THF, pptn. of yellow compd., stirred for 1 h; filtered (Celite), filtrate reduced by vacuum, addn. of hexane, solvent diffusion over some ds. at -30°C resulted in orange oil, crystals obtained by solvent diffusion of Et2O into C6H5Cl soln. of oil over some days at room temp.; elem. anal.;

Reference： [1]Carmalt, Claire J.; Norman, Nicholas C.; Farrugia, Louis J. [Polyhedron, 1993, vol. 12, p. 2081 - 2090]

24
[ 7226-23-5 ]
[ 529-19-1 ]
[ 80783-98-8 ]
[ 636598-42-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; 2-Methylbenzonitrile With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.333333h; Stage #2: N-methoxy-N-methylcyclohexanecarboxamide In tetrahydrofuran at -78℃; for 1h;	1 Example 1 [8-] {N- [3-(2-Cyanophenyl)-4-cyclohexyl-4-oxobutyl]-N-methyl-2-aminoethoxy}- [QUINOLINE] [2- (2-CYCLOHEXYL-2-OXOETHYL)-BENZONITRILE] (Compound la) To a solution of 0.47 g of 2-tolunitrile in 4 ml of THF was added 0.535 ml of 1,3- dimethyl-3,4, 5,6-tetrahydro-2 [(1H)] pyrimidinone (DMPU) and the mixture was cooled at- [78°C] ; 2.22 ml of a 2M sol. [OF LDA] in THF was then dropped during 5 min. , then the reaction mixture was stirred at the same temperature for 15 min. followed by dropwise addition of 0.757 g of N-methyl-N-methoxycyclohexanecarboxamide in 4 ml of THF. After 1 h stirring [AT-78°C,] the reaction mixture was quenched with a 10% aq. sol. of [NH4CI.] The temperature was allowed to rise at r. t. and the mixture was extracted with EtOAc [(2X20ML),] washed with 30 ml of brine, dried on [NA2S04] and evaporated to dryness in vacuo. The crude was purified by flash chromatography (PE-EtOAc 90: 10) to afford 0.34 g of the title compound. ['H-NMR] [(CDCL3,] [¢] : 1.10-2. 05 [(M,] [1OH)] ; 2.45-2. 60 [(M,] 1H) ; 4,00 [(M,] 2H); 7.20-7. 43 [(M,] 2H); 7.48-7. 70 [(M,] [2H) ;]

Reference： [1]Current Patent Assignee: RECORDATI SPA - WO2003/106421, 2003, A2 Location in patent: Page 29

25
[ 7226-23-5 ]
[ 86-74-8 ]
[ 2236-52-4 ]
[ 207447-27-6 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate In hexane; water; toluene	1.1 Synthesis of 9-(4'-iodobiphenyl-4-yl)-9H-carbazole [Step 1] Synthesis of 9-(4'-iodobiphenyl-4-yl)-9H-carbazole A synthesis scheme (C-1) of 9-(4'-iodobiphenyl-4-yl)-9H-carbazole is shown below. Initially, 49 g (120 mmol) of diiodobiphenyl, 17 g (100 mmol) of carbazole, 1.0 g (5.0 mmol) of copper(I) iodide, 1.3 g (5.0 mmol) of 18-crown-6-ether, 10 g (75 mmol) of potassium carbonate, 40 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (abbreviation: DMPU) were put in a 500 mL three-neck flask, and the atmosphere of the flask was substituted by nitrogen. The mixture was stirred at 170° C. for 6.5 hours. After stirring, water was added to the mixture and the mixture was filtrated to give a precipitate. The precipitate was washed with 1M hydrochloric acid, water, an aqueous solution of sodium hydrogen carbonate, and water in this order, and then was recrystallized from a mixture solution of toluene and hexane. The resulting solid was recrystallized from chloroform to give 40 g of the target substance, white powder of 9-(4'-iodobiphenyl-4-yl)-9H-carbazole in a yield of 89%.

Reference： [1]Current Patent Assignee: SEMICONDUCTOR ENERGY LABORATORY CO.,LTD. - US2009/284143, 2009, A1

26
[ 7226-23-5 ]
[ 13465-09-3 ]
[ 1224633-26-4 ]

Reference： [1]Inorganica Chimica Acta,2010,vol. 363,p. 988 - 994

27
[ 7226-23-5 ]
[ 13813-23-5 ]
[ 1226451-93-9 ]

Yield	Reaction Conditions	Operation in experiment
	In neat (no solvent) anhyd. lanthanoid (III) iodide was dissolved to saturation in freshly distilled urea-compound, carefully heated in an oil bath not exceeding 323K, let to slowly cool to room temp.;

Reference： [1]Lundberg, Daniel; Persson, Ingmar; Eriksson, Lars; D'Angelo, Paola; De Panfilis, Simone [Inorganic Chemistry, 2010, vol. 49, # 10, p. 4420 - 4432]

28
[ 7226-23-5 ]
[ 7790-87-6 ]
hexakis(N,N'-dimethylpropyleneurea)cerium(III) iodide - N,N'-dimethylpropyleneurea (1:3) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In neat (no solvent) anhyd. lanthanoid (III) iodide was dissolved to saturation in freshly distilled urea-compound, carefully heated in an oil bath not exceeding 323K, let to slowly cool to room temp.;

Reference： [1]Lundberg, Daniel; Persson, Ingmar; Eriksson, Lars; D'Angelo, Paola; De Panfilis, Simone [Inorganic Chemistry, 2010, vol. 49, # 10, p. 4420 - 4432]

29
[ 7226-23-5 ]
[ 13813-43-9 ]
hexakis(N,N'-dimethylpropyleneurea)thulium(III) iodide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In neat (no solvent) anhyd. lanthanoid (III) iodide was dissolved to saturation in freshly distilled urea-compound, carefully heated in an oil bath not exceeding 323K, let to slowly cool to room temp.;

Reference： [1]Lundberg, Daniel; Persson, Ingmar; Eriksson, Lars; D'Angelo, Paola; De Panfilis, Simone [Inorganic Chemistry, 2010, vol. 49, # 10, p. 4420 - 4432]

30
[ 7226-23-5 ]
[ 375-80-4 ]
[ 557-20-0 ]
[(1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone)₂Zn((CF₂)₆)₂Zn(1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone)₂] [ No CAS ]

Reference： [1]Organometallics,2013,vol. 32,p. 7552 - 7558

31
[ 7226-23-5 ]
cadmium(II) nitrate tetrhydrate [ No CAS ]
[ 127-19-5 ]
[ 4371-28-2 ]
[Cd₂(3,3’,5,5’-biphenyltetracarboxylate)(dimethylacetamide)₂(1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone)_0.5(H₂O)_0.5](1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone)_0.5}_n [ No CAS ]

Reference： [1]Dalton Transactions,2017,vol. 47,p. 700 - 707

32
[ 7226-23-5 ]
[ 14325-24-7 ]
[ 29261-33-4 ]
[ 7732-18-5 ]
C₃₂H₂₀MnN₈O₂*C₃₄H₁₆MnN₁₀*4C₆H₁₂N₂O [ No CAS ]

Reference： [1]European Journal of Inorganic Chemistry,2018,vol. 2018,p. 3344 - 3353

33
[ 7226-23-5 ]
(±)N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) [ No CAS ]
[ 7732-18-5 ]
[ 107264-00-6 ]
C₃₆H₅₆CoN₂O₄⁽¹⁺⁾*2C₆H₁₂N₂O*CF₃O₃S^(1-) [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 12056 - 12068

34
[ 7226-23-5 ]
[ 1093759-68-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hexane; pentane / 2 h / -20 - 20 °C 2: [2,2]bipyridinyl; copper(l) chloride / dimethyl sulfoxide / 8 h / 60 °C / Inert atmosphere; Sealed tube
	Multi-step reaction with 2 steps 1: hexane; pentane / 2 h / -20 - 20 °C 2: tetrakis(acetonitrile)copper(I)tetrafluoroborate; bathophenanthroline; potassium acetate / dimethyl sulfoxide / 12 h / 20 °C / Inert atmosphere; Glovebox

Reference： [1]Zeng, Xiaojun; Yan, Wenhao; Zacate, Samson B.; Chao, Tzu-Hsuan; Sun, Xiaodong; Cao, Zhi; Bradford, Kate G. E.; Paeth, Matthew; Tyndall, Sam B.; Yang, Kundi; Kuo, Tung-Chun; Cheng, Mu-Jeng; Liu, Wei [Journal of the American Chemical Society, 2019, vol. 141, # 29, p. 11398 - 11403]
[2]Cai, Aijie; Liu, Wei; Wang, Yufei; Yan, Wenhao; Yang, Dongqi; Yang, Kundi; Zacate, Samson B.; Zeng, Xiaojun [Angewandte Chemie - International Edition, 2020, vol. 59, # 38, p. 16398 - 16403][Angew. Chem., 2020, vol. 132, # 38, p. 16540 - 16545,6]

35
[ 7226-23-5 ]
[ 111-33-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium hydroxide at 160℃; Large scale;	3-4 Example 4: (1) to one with mechanical stirring, thermometer, 2050 g of 1,3-dimethyltetrahydro-2-pyrimidinone was added to a 3000 mL four-necked flask of a reflux condenser. 450 g of finely divided potassium hydroxide powder, Slowly heat to 160 ° C to react. The crude N,N'-dimethyl-1,3-propanediamine formed by the reaction was distilled off while heating. (2) After distilling to a system temperature of 170 ° C, no more distillate is distilled out. Down to room temperature, Vacuum filtration with a Buchner funnel, Removing the formed potassium carbonate solid, The filtrate was used as the starting material for the next batch of reaction. (3) adding 90 g of potassium hydroxide to the crude distilled product for half an hour, Liquid separation, organic phase pump distillation, Collect fractions of 65-68 ° C / 3.3 kPa, 340 g of N,N'-dimethyl-1,3-propanediamine were obtained, gas phase purity: 99.2%, yield: 83%.

Reference： [1]Current Patent Assignee: QINGXIAN KERUIXI MEDICINE TECH - CN110128276, 2019, A Location in patent: Paragraph 0015-0020

36
[ 7226-23-5 ]
[ 14325-24-7 ]
[ 29261-33-4 ]
[ 7732-18-5 ]
[(manganese phthalocyanine)(H₂O)₂(1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidin-7-one)₄]·[2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethanate] [ No CAS ]

Reference： [1]Dalton Transactions,2019,vol. 48,p. 17252 - 17257

37
[ 7218-04-4 ]
3-(((3-acetamido-4-methoxy-2-methyl-4-oxobutan-2-yl)disulfanecarbonyl)(methyl)amino)-N-methylpropan-1-aminium trifluoroacetate [ No CAS ]
[ 7226-23-5 ]
[ 463-58-1 ]
[ 5545-17-5 ]
C₁₃H₂₂N₂O₆S₂ [ No CAS ]
[ 76480-10-9 ]

Reference： [1]Journal of the American Chemical Society,2020,vol. 142,p. 4309 - 4316

38
[ 123183-72-2 ]
[ 7226-23-5 ]

Reference： [1]Angewandte Chemie - International Edition,2020,vol. 59,p. 4176 - 4181
Angew. Chem.,2020,vol. 132,p. 4205 - 4210,6
[2]Angewandte Chemie - International Edition,2020,vol. 59,p. 4176 - 4181
Angew. Chem.,2020,vol. 132,p. 4205 - 4210,6

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

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CAS No. :	7226-23-5	MDL No. :	MFCD00006550
Formula :	C₆H₁₂N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GUVUOGQBMYCBQP-UHFFFAOYSA-N
M.W :	128.17	Pubchem ID :	81646
Synonyms :		Chemical Name :	1,3-Dimethyltetrahydropyrimidin-2(1H)-one

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.83
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	43.05
TPSA :	23.55 Å²

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.17 cm/s

[ CAS No. 7226-23-5 ] {[proInfo.proName]}

Quality Control of [ 7226-23-5 ]

Related Doc. of [ 7226-23-5 ]

Product Details of [ 7226-23-5 ]

Calculated chemistry of [ 7226-23-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 7226-23-5 ]

Application In Synthesis of [ 7226-23-5 ]

[ 7226-23-5 ] Synthesis Path-Downstream 1~38

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Log Po/w (iLOGP) :	1.69
Log Po/w (XLOGP3) :	-0.13
Log Po/w (WLOGP) :	-0.39
Log Po/w (MLOGP) :	0.41
Log Po/w (SILICOS-IT) :	0.05
Consensus Log Po/w :	0.33

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Log S (ESOL) :	-0.55
Solubility :	35.9 mg/ml ; 0.28 mol/l
Class :	Very soluble
Log S (Ali) :	0.09
Solubility :	157.0 mg/ml ; 1.23 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.29
Solubility :	66.3 mg/ml ; 0.518 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.49

Signal Word:	Danger	Class:	N/A
Precautionary Statements:	P201-P202-P264-P270-P280-P301+P312+P330-P305+P351+P338+P310-P308+P313-P405-P501	UN#:	N/A
Hazard Statements:	H302-H318-H361	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