[ CAS No. 609-12-1 ] {[proInfo.proName]}

Name: 609-12-1|Ethyl 2-bromo-3-methylbutanoate|98%
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SKU: A581854
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Quality Control of [ 609-12-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 609-12-1 ]

Product Details of [ 609-12-1 ]

CAS No. :	609-12-1	MDL No. :	MFCD00026855
Formula :	C₇H₁₃BrO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WNFUWONOILPKNX-UHFFFAOYSA-N
M.W :	209.08	Pubchem ID :	79068
Synonyms :

Calculated chemistry of [ 609-12-1 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.86
Num. rotatable bonds :	4
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.92
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.7 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.47
Log Po/w (XLOGP3) :	2.64
Log Po/w (WLOGP) :	1.97
Log Po/w (MLOGP) :	2.12
Log Po/w (SILICOS-IT) :	1.8
Consensus Log Po/w :	2.2

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.54
Solubility :	0.609 mg/ml ; 0.00291 mol/l
Class :	Soluble
Log S (Ali) :	-2.84
Solubility :	0.3 mg/ml ; 0.00144 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.09
Solubility :	1.7 mg/ml ; 0.00811 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.48

Safety of [ 609-12-1 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P501-P210-P234-P264-P280-P370+P378-P390-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P406-P405	UN#:	3265
Hazard Statements:	H314-H227-H290	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 609-12-1 ]

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

Upstream synthesis route of [ 609-12-1 ]
Downstream synthetic route of [ 609-12-1 ]

[ 609-12-1 ] Synthesis Path-Upstream 1~6

1
[ 64-17-5 ]
[ 10323-40-7 ]
[ 609-12-1 ]

Yield	Reaction Conditions	Operation in experiment
55%	for 36 h; Heating / reflux	A. Synthesis of 6-(3,5-dimethylbenzyl)-5-isopropyluracil (Compound of the Formula VI according to the Reaction Scheme 1 in which R¹is an isopropyl group and each of R²is a methyl group)To a solution of 2-bromo-3-methylbutanoic acid (3 g, 16.5 mmol) in ethanol (200 ml), was added concentrated sulfuric acid (4 ml). After 36 h under reflux ebullition, the reaction medium, returned to ambient temperature, was neutralized with an aqueous saturated sodium carbonate solution. After distillation of the ethanol, the reaction medium was extracted with dichloromethane (100 ml). The organic phase was dried over magnesium sulfate and the solvent was evaporated to give ethyl 2-bromo-3-methylbutanoate (1.91 g, 55percent).A suspension of Zn powder (31.5 g, 0.48 mol) in tetrahydrofuran (300 ml) was boiled under reflux, and then it was added thereto a few drops of ethyl 2-bromo-3-methylbutanoate to initiate the reaction. After 45 mn under reflux and under magnetic stirring, it was added thereto 3,5-dimethylphenylethanenitrile (13.2 g, 91 mmol), and then, dropwise, the remainder of ethyl 2-bromo-3-methylbutanoate (in total 19.1 g, 91 mmol). The ebullition was maintained for 15 mn, the mixture was then cooled, and then it was added thereto tetrahydrofuran (500 ml) and a 50percent aqueous potassium carbonate solution (100 ml). After 45 mn under vigorous stirring, the organic phase was separated by decantation and the aqueous phase was washed with tetrahydrofuran (2.x.100 ml). The collected organic phases were treated with 10percent aqueous hydrochloric acid solution (300 ml) for 45 mn. After elimination of tetrahydrofuran by distillation under reduced pressure, the residue was taken again with dichloromethane (300 ml), and the organic phase was washed with a saturated sodium monohydrogenocarbonate solution (100 ml), dried over magnesium sulfate and concentrated. The distillation of the residue (134° C., 10^-1mmHg) gave ethyl 3-methyl-2-(3,5-dimethylphenylacetyl)butanoate (13.2 g, 52percent).Metal sodium (23.8 g, 1.034 mol) was reacted with anhydrous ethanol (500 ml). To the clear obtained solution, was added thiourea (54.35 g, 714 mmol) and ethyl 3-methyl-2(3,5-dimethylphenylacetyl)butanoate (13.14 g, 47.6 mol). The reaction medium was maintained under reflux for 6 h, and then was concentrated in vacuo at 40.50° C. To the obtained residue was added concentrated hydrochloric acid (100 ml) and then the solution was brought to pH 4 with acetic acid. The obtained 6-dimethylbenzyl-5-isopropyl-2-thiouracil was dissolved in an aqueous 10percent chloroacetic acid solution (200 ml) and the solution was maintained under reflux for 24 h and then cooled to ambient temperature and the obtained precipitates were separated by filtration and washed with cold ethanol and then with ether, and then dried in vacuo at 40° C. to give 6-(3,5-dimethylbenzyl)-5-isopropyluracil (7 g, 54percent). Melting point: 213-214° C.

Reference： [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7574 - 7578
[2] Chemical and Pharmaceutical Bulletin, 1982, vol. 30, # 9, p. 3160 - 3166
[3] Journal of Medicinal Chemistry, 1994, vol. 37, # 8, p. 1177 - 1188
[4] Patent: US6911450, 2005, B1, . Location in patent: Page/Page column 15-16
[5] Journal of the American Chemical Society, 1954, vol. 76, p. 1137,1140

2
[ 32363-91-0 ]
[ 609-12-1 ]

Reference： [1] Patent: US4440947, 1984, A,

3
[ 26464-05-1 ]
[ 64-17-5 ]
[ 609-12-1 ]

Reference： [1] Russian Journal of General Chemistry, 2000, vol. 70, # 4, p. 516 - 517
[2] Journal fuer Praktische Chemie (Leipzig), 1924, vol. <2> 107, p. 260,262

4
[ 503-74-2 ]
[ 64-17-5 ]
[ 609-12-1 ]

Reference： [1] Journal of Labelled Compounds and Radiopharmaceuticals, 1978, vol. 14, # 5, p. 713 - 726
[2] Helvetica Chimica Acta, 1963, vol. 46, # 85, p. 766 - 780
[3] The Journal of organic chemistry, 1972, vol. 37, # 26, p. 4396 - 4399

5
[ 108-64-5 ]
[ 609-12-1 ]

Reference： [1] Tetrahedron Letters, 1971, p. 3995 - 3998

6
[ 56-23-5 ]
[ 7726-95-6 ]
[ 609-12-1 ]

Reference： [1] Journal of the American Chemical Society, 1949, vol. 71, p. 3107

[ 609-12-1 ] Synthesis Path-Downstream 1~76

1
[ 609-12-1 ]
[ 3019-89-4 ]
[ 63403-11-2 ]

Yield	Reaction Conditions	Operation in experiment
	at 160℃; Verseifung des gebildeten Aethylesters;

Reference： [1]Bischoff [Chemische Berichte, 1900, vol. 33, p. 1254]

2
[ 609-12-1 ]
[ 824-39-5 ]
α-(2-nitro-phenoxy)-isovaleric acid ethyl ester [ No CAS ]

Reference： [1]Chemische Berichte,1900,vol. 33,p. 1605

3
[ 609-12-1 ]
[ 13327-27-0 ]
[ 113455-85-9 ]

Reference： [1]Journal of the American Chemical Society,1956,vol. 78,p. 2642

4
[ 64-17-5 ]
[ 10323-40-7 ]
[ 609-12-1 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sulfuric acid; for 36h;Heating / reflux;	A. Synthesis of 6-(3,5-dimethylbenzyl)-5-isopropyluracil (Compound of the Formula VI according to the Reaction Scheme 1 in which R1 is an isopropyl group and each of R2 is a methyl group)To a solution of 2-bromo-3-methylbutanoic acid (3 g, 16.5 mmol) in ethanol (200 ml), was added concentrated sulfuric acid (4 ml). After 36 h under reflux ebullition, the reaction medium, returned to ambient temperature, was neutralized with an aqueous saturated sodium carbonate solution. After distillation of the ethanol, the reaction medium was extracted with dichloromethane (100 ml). The organic phase was dried over magnesium sulfate and the solvent was evaporated to give ethyl 2-bromo-3-methylbutanoate (1.91 g, 55%).A suspension of Zn powder (31.5 g, 0.48 mol) in tetrahydrofuran (300 ml) was boiled under reflux, and then it was added thereto a few drops of ethyl 2-bromo-3-methylbutanoate to initiate the reaction. After 45 mn under reflux and under magnetic stirring, it was added thereto 3,5-dimethylphenylethanenitrile (13.2 g, 91 mmol), and then, dropwise, the remainder of ethyl 2-bromo-3-methylbutanoate (in total 19.1 g, 91 mmol). The ebullition was maintained for 15 mn, the mixture was then cooled, and then it was added thereto tetrahydrofuran (500 ml) and a 50% aqueous potassium carbonate solution (100 ml). After 45 mn under vigorous stirring, the organic phase was separated by decantation and the aqueous phase was washed with tetrahydrofuran (2×100 ml). The collected organic phases were treated with 10% aqueous hydrochloric acid solution (300 ml) for 45 mn. After elimination of tetrahydrofuran by distillation under reduced pressure, the residue was taken again with dichloromethane (300 ml), and the organic phase was washed with a saturated sodium monohydrogenocarbonate solution (100 ml), dried over magnesium sulfate and concentrated. The distillation of the residue (134 C., 10-1 mmHg) gave ethyl 3-methyl-2-(3,5-dimethylphenylacetyl)butanoate (13.2 g, 52%).Metal sodium (23.8 g, 1.034 mol) was reacted with anhydrous ethanol (500 ml). To the clear obtained solution, was added thiourea (54.35 g, 714 mmol) and ethyl 3-methyl-2(3,5-dimethylphenylacetyl)butanoate (13.14 g, 47.6 mol). The reaction medium was maintained under reflux for 6 h, and then was concentrated in vacuo at 40.50 C. To the obtained residue was added concentrated hydrochloric acid (100 ml) and then the solution was brought to pH 4 with acetic acid. The obtained 6-dimethylbenzyl-5-isopropyl-2-thiouracil was dissolved in an aqueous 10% chloroacetic acid solution (200 ml) and the solution was maintained under reflux for 24 h and then cooled to ambient temperature and the obtained precipitates were separated by filtration and washed with cold ethanol and then with ether, and then dried in vacuo at 40 C. to give 6-(3,5-dimethylbenzyl)-5-isopropyluracil (7 g, 54%). Melting point: 213-214 C.

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 7574 - 7578
[2]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 3160 - 3166
[3]Journal of Medicinal Chemistry,1994,vol. 37,p. 1177 - 1188
[4]Patent: US6911450,2005,B1 .Location in patent: Page/Page column 15-16
[5]Journal of the American Chemical Society,1954,vol. 76,p. 1137,1140

5
[ 609-12-1 ]
[ 62-53-3 ]
<i>N</i>-phenyl-valine ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With potassium carbonate; In dimethyl sulfoxide; at 20 - 120℃; for 47h;	Ethyl 2-bromoisovalerate (112) (700 mg, 3.3 mmol) was dissolved in DMSO (7 mL), aniline (0.40 mL, 4.4 mmol), potassium carbonate (0.60 g, 4.4 mmol) were added, and the mixture was stirred at room temperature for 21 hr, at 80 C. for 6 hr, and at 120 C. for 20 hr. Ethyl acetate (30 mL), water (50 mL) were added and the mixture was partitioned. The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by moderate-pressure silica gel chromatography (silica gel 30 g, ethyl acetate/hexane=0/100-5/95) to give 113 (110 mg, 0.497 mmol, yield 15%) as a yellow liquid.

Reference： [1]Patent: US2020/165194,2020,A1 .Location in patent: Paragraph 0163-0164
[2]Chemische Berichte,1897,vol. 30,p. 2312
[3]Chemische Berichte,1897,vol. 30,p. 2312

6
[ 609-12-1 ]
[ 33367-55-4 ]

Yield	Reaction Conditions	Operation in experiment
	With Phenylcadmiumchlorid In diethyl ether
	Multi-step reaction with 3 steps 1.1: ethanol; potassium / 1 h / 20 °C / Inert atmosphere 1.2: 9 h / Inert atmosphere; Reflux 2.1: sulfuric acid / water / 16 h / 160 °C 2.2: 0.75 h / 50 °C 3.1: sulfuric acid / ethanol / 24 h / Reflux

Reference： [1]Jones,P.R.; Costanzo,S.J. [Journal of Organic Chemistry, 1973, vol. 38, p. 3189 - 3192]
[2]Current Patent Assignee: CHINA PETROCHEMICAL CORPORATION - EP2399902, 2011, A1

7
[ 609-12-1 ]
[ 5466-06-8 ]
[ 153261-32-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In tetrahydrofuran; ethanol 1.) -20 deg C, 20 min, 2.) -20 deg C -> room temperature, 3 h, 3.) room temperature, 1 h;
6.2 g	With sodium ethanolate In ethanol at -30℃; for 3h;
	Stage #1: 3-mercaptopropionic acid ethyl ester With sodium ethanolate In ethanol Stage #2: ethyl 2-bromoisovalerate In ethanol at -20℃;

Reference： [1]Kim, B. Moon; Lee, Hee-Yoon; Munson, Peter M.; Guare, James P.; McDonough, Colleen [Tetrahedron Letters, 1993, vol. 34, # 41, p. 6517 - 6520]
[2]Ghosh, Arun K.; Lee, Hee Yoon; Thompson, Wayne J.; Culberson, Chris; Holloway, M. Katharine; et al. [Journal of Medicinal Chemistry, 1994, vol. 37, # 8, p. 1177 - 1188]
[3]Current Patent Assignee: ABBVIE INC - EP1170289, 2002, A2 Location in patent: Page 53

8
[ 609-12-1 ]
[ 7695-47-8 ]
ethyl 3-methyl-2-(8-oxo-5,6,7,8-tetrahydro-1-naphthyloxy)butyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium phosphate In dimethyl sulfoxide at 60℃; for 3h;

Reference： [1]Sharshira, Essam Mohamed; Iwanami, Haruki; Okamura, Mutsuo; Hasegawa, Eietsu; Horaguchi, Takaaki [Journal of Heterocyclic Chemistry, 1996, vol. 33, # 1, p. 137 - 144]

9
[ 609-12-1 ]
[ 140-29-4 ]
[ 176519-53-2 ]

Reference： [1]Drug Research,2016,vol. 66,p. 181 - 188
[2]Journal of Medicinal Chemistry,1996,vol. 39,p. 2427 - 2431
[3]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 63 - 67
[4]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1461 - 1466
[5]Antimicrobial Agents and Chemotherapy,1998,vol. 42,p. 3225 - 3233
[6]Monatshefte fur Chemie,2008,vol. 139,p. 967 - 974

10
[ 609-12-1 ]
[ 39101-54-7 ]
[ 210645-97-9 ]

Yield	Reaction Conditions	Operation in experiment
52%		A. Synthesis of 6-(3,5-dimethylbenzyl)-5-isopropyluracil (Compound of the Formula VI according to the Reaction Scheme 1 in which R1 is an isopropyl group and each of R2 is a methyl group)To a solution of 2-bromo-3-methylbutanoic acid (3 g, 16.5 mmol) in ethanol (200 ml), was added concentrated sulfuric acid (4 ml). After 36 h under reflux ebullition, the reaction medium, returned to ambient temperature, was neutralized with an aqueous saturated sodium carbonate solution. After distillation of the ethanol, the reaction medium was extracted with dichloromethane (100 ml). The organic phase was dried over magnesium sulfate and the solvent was evaporated to give ethyl 2-bromo-3-methylbutanoate (1.91 g, 55%).A suspension of Zn powder (31.5 g, 0.48 mol) in tetrahydrofuran (300 ml) was boiled under reflux, and then it was added thereto a few drops of ethyl 2-bromo-3-methylbutanoate to initiate the reaction. After 45 mn under reflux and under magnetic stirring, it was added thereto 3,5-dimethylphenylethanenitrile (13.2 g, 91 mmol), and then, dropwise, the remainder of ethyl 2-bromo-3-methylbutanoate (in total 19.1 g, 91 mmol). The ebullition was maintained for 15 mn, the mixture was then cooled, and then it was added thereto tetrahydrofuran (500 ml) and a 50% aqueous potassium carbonate solution (100 ml). After 45 mn under vigorous stirring, the organic phase was separated by decantation and the aqueous phase was washed with tetrahydrofuran (2×100 ml). The collected organic phases were treated with 10% aqueous hydrochloric acid solution (300 ml) for 45 mn. After elimination of tetrahydrofuran by distillation under reduced pressure, the residue was taken again with dichloromethane (300 ml), and the organic phase was washed with a saturated sodium monohydrogenocarbonate solution (100 ml), dried over magnesium sulfate and concentrated. The distillation of the residue (134 C., 10-1 mmHg) gave ethyl 3-methyl-2-(3,5-dimethylphenylacetyl)butanoate (13.2 g, 52%).Metal sodium (23.8 g, 1.034 mol) was reacted with anhydrous ethanol (500 ml). To the clear obtained solution, was added thiourea (54.35 g, 714 mmol) and ethyl 3-methyl-2(3,5-dimethylphenylacetyl)butanoate (13.14 g, 47.6 mol). The reaction medium was maintained under reflux for 6 h, and then was concentrated in vacuo at 40.50 C. To the obtained residue was added concentrated hydrochloric acid (100 ml) and then the solution was brought to pH 4 with acetic acid. The obtained 6-dimethylbenzyl-5-isopropyl-2-thiouracil was dissolved in an aqueous 10% chloroacetic acid solution (200 ml) and the solution was maintained under reflux for 24 h and then cooled to ambient temperature and the obtained precipitates were separated by filtration and washed with cold ethanol and then with ether, and then dried in vacuo at 40 C. to give 6-(3,5-dimethylbenzyl)-5-isopropyluracil (7 g, 54%). Melting point: 213-214 C.

Reference： [1]Drug Research,2016,vol. 66,p. 181 - 188
[2]Patent: US6911450,2005,B1 .Location in patent: Page/Page column 16
[3]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 1461 - 1466
[4]Monatshefte fur Chemie,1999,vol. 130,p. 1499 - 1512
[5]Antimicrobial Agents and Chemotherapy,1998,vol. 42,p. 3225 - 3233

11
[ 609-12-1 ]
[ 696-63-9 ]
[ 212768-71-3 ]

Yield	Reaction Conditions	Operation in experiment
99%		2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was prepared according to the general method of Example 1. Starting from ethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of the product was isolated. Yield 99%; Light yellow oil; MS: 271 (M+H)+.
99%		Example 53N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-methyl-butyramide 2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from ethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was isolated. Yield 99%; Light yellow oil; MS: 269 (M+H)+.
99%		2-(4Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was prepared according to the general method of Example 1. Starting from ethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of the product was isolated. Yield 99%; Light yellow oil; MS: 271 (M+H)+.

99%

2-(4-Methoxy-phenylsulfanyl)-3methyl-butyric acid ethyl ester was prepared according to the general method as outlined in Example 1. Staring from ethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was isolated. Yield 99%; Light yellow oil; MS: 269 (M+H)+.

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 2361 - 2375
[2]Patent: EP970046,2003,B1 .Location in patent: Page 20
[3]Patent: EP970046,2003,B1 .Location in patent: Page 35
[4]Patent: US6342508,2002,B1 .Location in patent: Page column 22
[5]Patent: US6342508,2002,B1 .Location in patent: Page column 44

12
[ 609-12-1 ]
[ 654-01-3 ]
(Z)-3-Amino-4-(2,6-difluoro-phenyl)-2-isopropyl-but-2-enoic acid ethyl ester [ No CAS ]

Reference： [1]Medicinal Chemistry Research,2000,vol. 10,p. 30 - 39

13
[ 609-12-1 ]
[ 404392-16-1 ]

Reference： [1]Chemical and pharmaceutical bulletin,2003,vol. 51,p. 477 - 478

14
[ 609-12-1 ]
[ 132-75-2 ]
[ 640724-25-0 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2003,vol. 51,p. 779 - 789
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3173 - 3176
[3]Monatshefte fur Chemie,2008,vol. 139,p. 967 - 974
[4]European Journal of Medicinal Chemistry,2009,vol. 44,p. 1016 - 1023

15
[ 609-12-1 ]
[ 1218-89-9 ]
(3RS,4RS,5SR)-4-hydroxy-3-isopropyl-4,5-di-p-tolyldihydrofuran-2-one [ No CAS ]

Reference： [1]Organic Letters,2006,vol. 8,p. 3029 - 3032

16
[ 609-12-1 ]
[ 119-53-9 ]
(3RS,4RS,5SR)-4-hydroxy-3-isopropyl-4,5-diphenyldihydrofuran-2-one [ No CAS ]

Reference： [1]Organic Letters,2006,vol. 8,p. 3029 - 3032

17
[ 927175-29-9 ]
[ 609-12-1 ]
[ 927175-30-2 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 429 - 432

18
[ 927175-24-4 ]
[ 609-12-1 ]
[ 927175-25-5 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 429 - 432

19
[ 609-12-1 ]
[ 621-83-0 ]
[ 870709-55-0 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 429 - 432

20
[ 609-12-1 ]
[ 923016-97-1 ]
2-(5-methoxy-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}phenoxy)-3-methylbutanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		Example 18 A mixture of (2-hydroxy-4-methoxyphenyl){4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}methanone (400 mg), ethyl 2-bromo-3-methylbutanoate (302 mg), potassium carbonate (226 mg) and N,N-dimethylformamide (3 ml) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (1:4?1:1, v/v), and concentrated. The residue was dissolved in tetrahydrofuran (6 ml), ethanol (4 ml), water (4 ml) and lithium hydroxide monohydrate (116 mg) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with dil. hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (1:3?3:1, v/v), concentrated, and crystallized from ethyl acetate-hexane to give 2-(5-methoxy-2-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}phenoxy)-3-methylbutanoic acid (382 mg, yield 77%) as colorless crystals. melting point 87 - 88C. 1H-NMR (300 MHz, CDCl3) delta:1.06 (3 H, d, J=6.9 Hz), 1.14 (3 H, d, J=6.9 Hz), 2.36 - 2.46 (1 H, m), 2.47 (3 H, s), 3.86 (3 H, s), 4.85 (1 H, d, J=3.6 Hz), 5.10 (2 H, s), 6.58 (1 H, dd, J=2.4, 8.7 Hz), 6.65 (1 H, d, J=2.4 Hz), 7.11 (2 H, d, J=8.7 Hz), 7.38 (1 H, d, J=8.7 Hz), 7.42 - 7.47 (3 H, m), 7.87 (2 H, d, J=8.7 Hz), 7.99 - 8.04 (2 H, m).

Reference： [1]Patent: EP1911738,2008,A1 .Location in patent: Page/Page column 52

21
[ 609-12-1 ]
[ 13794-02-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 160 °C
	Multi-step reaction with 2 steps 1: N,N,N,N,N,N-hexamethylphosphoric triamide 2: sodium hydroxide / ethanol

Reference： [1]Bischoff [Chemische Berichte, 1900, vol. 33, p. 937]
[2]Current Patent Assignee: Hoffmann-La Roche - FR2323675, 1977, B1 [Chem.Abstr., 1977, vol. 87, # 67967][Chem.Abstr., 1977, vol. 87, # 67967]

22
[ 609-12-1 ]
[ 63403-13-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 160 °C 2: Verseifung
	Multi-step reaction with 2 steps 1: N,N,N,N,N,N-hexamethylphosphoric triamide 2: sodium hydroxide / ethanol

Reference： [1]Bischoff [Chemische Berichte, 1900, vol. 33, p. 1254]
[2]Current Patent Assignee: Hoffmann-La Roche - FR2323675, 1977, B1 [Chem.Abstr., 1977, vol. 87, # 67967][Chem.Abstr., 1977, vol. 87, # 67967]

23
[ 609-12-1 ]
[ 63403-11-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N,N,N,N,N,N-hexamethylphosphoric triamide 2: sodium hydroxide / ethanol

Reference： [1]Current Patent Assignee: Hoffmann-La Roche - FR2323675, 1977, B1 [Chem.Abstr., 1977, vol. 87, # 67967][Chem.Abstr., 1977, vol. 87, # 67967]

24
[ 609-12-1 ]
[ 4026-18-0 ]

Reference： [1]Helvetica Chimica Acta,1963,vol. 46,p. 766 - 780

25
[ 609-12-1 ]
[ 19552-10-4 ]
[ 796739-75-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 0℃; for 2h;	A solution of 2-bromo-3-methyllpropanoic acid ethyl ester (0.418 g, 2 mmol) and 4-bromobenzylthiol (0.402 g, 2 mmol) in DMF (5 mL) was cooled to 0 C and treated with K2CO3 (0. 414 G, 3. mmol). After stirring for 2 h, the reaction was quenched with 5% HC1 (15 mL) and diluted with ethyl acetate (50 mL). After seperation, the aqueous layer extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with sat. aq NACL, dried over MGS04 and concentrated. Purification by flash column chromatography (5% ethyl acetate in heptane) provided (4-bromophen-yl-4-methylsulfanyl)-3- methylbutanoic acid ethyl ester (660 MG, 90%) as white solid. 1H NMR (CDC13), 7.43 (d, J = 8 Hz, 2 H), 7.18 (d, J = 8 Hz, 2 H), 4.17 (q, J = 6 Hz, 2 H), 3.75 (s, 2 H), 2.85 (d, J = 9 Hz, 1 H), 2.04 (m, 1 H), 1.29 (t, J = 6 Hz, 3 H), 1.02 (d, J = 6 Hz, 3 H), 0.98 (d. J = 6 Hz, 3 H).

Reference： [1]Patent: WO2004/99170,2004,A2 .Location in patent: Page 76

26
[ 609-12-1 ]
[ 35320-67-3 ]
[ 936617-26-4 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; In acetone; for 72h;Heating / reflux;	EXAMPLE 11.12b: Compound (5-33) <n="173"/>KOH, THFZH2Oily-V-33[00438] 3-Methyl-2-(2-methyl~1H-indol-4'yloxy)-butyric acid ethyl ester (2): A mixture of 4-hydroxy-2-methylindoie (1) (1.5 g, 0.010 mole), 2-bromo-3-methyl-butyric acid ethyl ester (2.2 g, 0.010 mole) and potassium carbonate (excess) in acetone (50 mL) was refluxed for 3 days. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (20:1 Hex:EtOAc) to afford intermediate 2. Yield: 1.88 g, 71 %
71%	With potassium carbonate; In acetone; for 72h;Heating / reflux;	[00281] 3-Methyl-2-(2-methyl-1H-indol-4-yloxy)-butyric acid ethyl ester (2): A mixture of <strong>[35320-67-3]4-hydroxy-2-methylindole</strong> (1) (1.5 g, 0.010 mole), 2-bromo-3-methyl-butyric acid ethyl ester (2.2 g, 0.010 mole) and potassium carbonate (excess) in acetone (50 mL) was refluxed for 3 days. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (20:1 Hex:EtOAc) to afford intermediate 2. Yield: 1.88 g, 71 %
71%	With potassium carbonate; In acetone; for 72h;Heating / reflux;	A mixture of <strong>[35320-67-3]4-hydroxy-2-methylindole</strong> (1) (1.5 g, 0.010 mole), 2-bromo-3-methyl-butyric acid ethyl ester (2.2 g, 0.010 mole) and potassium carbonate (excess) in acetone (50 mL) was refluxed for 3 days. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (20:1 Hex:EtOAc) to afford intermediate 2. Yield: 1.88 g, 71%

Reference： [1]Patent: WO2007/56279,2007,A2 .Location in patent: Page/Page column 171-172; 206; 208; 211
[2]Patent: WO2007/56280,2007,A1 .Location in patent: Page/Page column 94; 96
[3]Patent: US2007/135385,2007,A1 .Location in patent: Page/Page column 77-78; 104-106

27
[ 609-12-1 ]
[ 936617-38-8 ]

Yield	Reaction Conditions	Operation in experiment
19%		[00242] 2-(1-Benzyl-2-methyl-1 H-indol-4-yloxy)-3-methyl-butyric acid ethyl ester 7:; 1- Benzyl-2-methyl-1 H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 ml_). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture ethyl-2-bromoisovalerate (0.344 ml_, 1.65 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 ml_) and washed with H2O (4 x 100 ml_) and brine (1 x 100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (10:1 Hexane:EtOAc) to afford a 1 :1 mixture of 7:ethyl-2-bromoisovalerate. Further purification by column chromatography (10:1 Hexane.epsilontOAc) afforded 7 (0.09 g, 19 %) as a yellow oil.

Reference： [1]Patent: WO2007/56275,2007,A2 .Location in patent: Page/Page column 83-84

28
[ 609-12-1 ]
[ 624734-34-5 ]
C₂₅H₃₆F₃N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 40℃;	Potassium carbonate (124 mg, 0.9 mmol) was added to a mixture of Intermediate 12 (105 mg, 0.3 mmol) and ethyl 2-bromo-3-methylbutanoate (82 mg, 0.39 mmol) in DMF (5 mL). The reaction was stirred for 40 C. overnight, then poured into ethyl acetate. The organic layer was washed three times with saturated sodium bicarbonate, dried over MgSO4 and concentrated to yield a residue that was purified by reverse phase HPLC. LC-MS for C25H36F3N3O3 calculated 483.58, found [M+H]+ 484.4.

Reference： [1]Patent: US2007/117797,2007,A1 .Location in patent: Page/Page column 44

29
[ 609-12-1 ]
[ 33666-91-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium iodide; In acetone;Heating / reflux;	11. 2-lodo-3-methyl-butyric acid ethyl ester; A mixture of 10 g commercially available ethyl-2-bromo isovalerate and 17.8 g sodium iodide in 150 ml acetone are heated to reflux over night. The solvent is removed under reduced pressure. Dichloromethane is added to the residue and the solution is washed with an aqueous solution (10 %) <n="127"/>of sodium thiosulfate and brine. The organic layer is dried and the solvent is removed under reduced pressure. 1 1.34 g (93 %) of the title compound are obtained as a yellowish oil. MS: m/z (M+) = 255.9
93%	With sodium iodide; In acetone;Heating / reflux;	A mixture of 10 g commercially available ethyl-2-bromo isovalerate and 17.8 g sodium iodide in 150 ml acetone are heated to reflux over night. The solvent is removed under reduced pressure. Dichloromethane is added to the residue and the solution is washed with an aqueous solution (10 %) of sodium thiosulfate and brine. The organic layer is dried and the solvent is removed under reduced pressure. 1 1.34 g (93 %) of the title compound are obtained as a yellowish oil. MS: m/z (M+) = 255.9
93%	With sodium iodide; In acetone;Heating / reflux;	A mixture of 10 g commercially available ethyl-2-bromo isovalerate and 17.8 g sodium iodide in 150 ml acetone are heated to reflux over night. The solvent is removed under reduced pressure. Dichloromethane is added to the residue and the solution is washed with an aqueous solution (10 %) of sodium thiosulfate and brine. The organic layer is dried and the solvent is removed under reduced pressure. 11.34 g (93 %) of the title compound are obtained as a yellowish oil. MS: m/z (M+) = 255.9

Reference： [1]Patent: WO2007/96395,2007,A1 .Location in patent: Page/Page column 125-126
[2]Patent: WO2009/24190,2009,A1 .Location in patent: Page/Page column 83
[3]Patent: WO2009/24613,2009,A1 .Location in patent: Page/Page column 81

30
[ 609-12-1 ]
[ 137-07-5 ]
C₁₃H₁₉NO₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 1 - 40℃; for 1.5h;	step 1 Production of 2-isopropyl-4H-benzo[1,4]thiazin-3-one 2-Aminobenzenethiol (1.63 g) and ethyl 2-bromo-3-methylbutyrate (2.09 g) were dissolved in dimethyl sulfoxide (20 mL), and potassium carbonate (1.78 g) was added. After stirring the mixture at room temperature for 1.5 hr, 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was dissolved in N,N-dimethylformamide (10 mL). Concentrated hydrochloric acid (0.13 mL) was added, and the mixture was stirred with heating at 80 C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was crystallized from n-hexane-ethyl acetate to give the title compound (850 mg) as a pale-yellow solid.

Reference： [1]Patent: US2007/197512,2007,A1 .Location in patent: Page/Page column 49

31
[ 609-12-1 ]
[ 367-21-5 ]
[ 866030-16-2 ]

Yield	Reaction Conditions	Operation in experiment
		2-[benzyl(3-chloro-4-fluorophenyl)amino]-3-methylbutan-1-ol (8-3); 3-chloro-4-fluoroaniline (1.03 g, 7.10 mmol), ethyl 2-bromo-3-methylbutanoate (2.97 g, 14.2 mmol), and diispropylethylamine (1.01 g, 7.81 mmol) were combined and heated to 150 C. for 1.5 h using a microwave. Ethylenediamine (1.28 g, 21.3 mmol) and CH2Cl2 (2 mL) were added to the reaction mixture which stirred for 10 min at 23 C. The mixture was acidified with 1N aqueous HCl and the product was extracted with CH2Cl2 (4×). The combined organic layers were dried with Na2SO4 and concentrated. The residue was purified by reverse-phase liquid chromatography (Semi Prep YMC C-18 Reverse Phase Column 5% CH3CN/H2O to 95% CH3CN/H2O with 0.1% TFA present) to get ethyl N-3-chloro-4-fluorophenyl)valinate (8-1). delta 6.93 (dd, J=8.85, 8.85 Hz, 1H), 6.64 (dd, J=5.95, 3.05 Hz, 1H), 6.47 (ddd, J=8.85, 3.05, 3.05 Hz, 1H), 4.19 (q, J=7.02 Hz, 2H), 3.73 (d, J=5.8 Hz, 1H), 2.10 (m, 1H), 1.26 (t, J=7.02 Hz, 3H), 1.04 (d, J=5.79 Hz, 3H), 1.01 (d, J=5.80 Hz, 3H).

Reference： [1]Patent: US2008/234281,2008,A1 .Location in patent: Page/Page column 24

32
[ 609-12-1 ]
[ 3215-64-3 ]
C₁₅H₁₉Cl₂NO₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4641 - 4652

33
[ 609-12-1 ]
[ 654-01-3 ]
C₁₅H₁₉F₂NO₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4641 - 4652

34
[ 609-12-1 ]
[ 75279-55-9 ]
C₁₅H₁₉ClFNO₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4641 - 4652

35
[ 609-12-1 ]
[ 1170192-98-9 ]
[ 1170193-01-7 ]

Yield	Reaction Conditions	Operation in experiment
		Reference Example 6; Ethyl 3-methyl-2-(5-phenyl-1,1-dioxothieno[2,3-d]isothiazol-2(3H)-yl)butyrate; The compound of Reference Example 5 (67 mg) and sodium hydride (13 mg, Wako Pure Chemical Industries, Ltd., containing 40% mineral oil) were dissolved in N,N-dimethylformamide (1 ml), and the resultant solution was stirred at 60 C. for 1 hour. Then, <strong>[609-12-1]ethyl 2-bromoisovalerate</strong> (68 mul, manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto and the reaction solution was further stirred for 24 hours. The reaction mixture was stood to cool to room temperature and then concentrated, and ethyl acetate (2 ml) and water (2 ml) were added thereto. A product was extracted with ethyl acetate, washed with saturated saline, dried with magnesium sulfate and then concentrated. The obtained residue was put into a silica gel column (hexane:ethyl acetate=5:1) to give 16 mg of the titled compound. LC-MS: HPLC retention time 4.94 minutes (LC Condition 2), m/z 380 (MH+)

Reference： [1]Patent: US2009/192154,2009,A1 .Location in patent: Page/Page column 102

36
[ 609-12-1 ]
[ 1761-61-1 ]
C₁₄H₁₇BrO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 0.67 g (3.3 mmol) 5-bromosalicylaldehyde in dimethylformamide (6 ml) 0.2 g sodium hydride (60 % suspension in mineral oil, 5 mmol) was added in small portions at 0 C. After stirring for about half an hour 1.05 g ethyl 2-bromo-3-methyl butyrat (5 mmol) was added slowly at room temperature and the mixture was allowed to stir at 90 C overnight. After cooling ice water (25 ml) and 1N sodium hydroxide solution was added until basic pH. The mixture was extracted three times with ethyl acetate, the comined organic layers were dried (MGS04) and evaporated. Short column filtration of the residue yielded the ester that was used for the next step without characterisation. The ester was dissolved in 2 ml of methanol and 2N aqueous sodium hydroxide solution (2 ml) was added. After stirring for 1 hour at room temperature the solvent was removed by rotary evaporation. Water (3 ml) and 4N hydrochloric acid was added until pH=4. The mixture was extracted three times with ethyl acetate, the combined organic layers were dried (MGS04) and evaporated to yield 0.125 g of the title compound as colourless oil. MS m/e (%): 299.0 (M-H+, 93); 301.0 (M-HT, 100).

Reference： [1]Patent: WO2004/100958,2004,A1 .Location in patent: Page 13

37
[ 609-12-1 ]
2-butyl-1-[(3'-hydroxybiphenyl-4-yl)methyl]-4-spirocyclohexyl-1H-imidazol-5(4H)-one [ No CAS ]
2-butyl-1-[(3'-((1-ethoxycarbonyl-1-(1,1-dimethylmethyl)-methyl)oxy)biphenyl-4-yl)methyl]-4-spirocyclohexyl-1H-imidazol-5(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.2%	With potassium carbonate; In acetonitrile;Reflux;	Method 14C: To a solution of phenol (1 eq) in acetonitrile was added potassium carbonate (3 eq), then brominated derivative (2 eq) drop by drop. The reaction mixture was stirred at reflux for 12 hours. The reaction mixture was filtered then were added again potassium carbonate (3 eq), then brominated derivative (2 eq). The reaction mixture was stirred again at reflux for 12 hours. Potassium carbonate was filtered and acetonitrile was evaporated under reduced pressure. The residue was chromatographed over silica gel.Example 14.4. 2-butyl-1-[(3'-((1-ethoxycarbonyl-1-(1,1-dimethylmethyl)-methyl)oxy)biphenyl-4-yl)methyl]-4-spirocyclohexyl-1H-imidazol-5(4H)-one Prepared following the general procedure previously described (Method 14C) using 2-butyl-1-[(3'-hydroxybiphenyl-4-yl)methyl]-4-spirocyclohexyl-1H-imidazol-5(4H)-one (example 13.1) and <strong>[609-12-1]ethyl 2-bromoisovalerate</strong>. The product was chromatographed over silica gel (elution gradient cyclohexane/ethyl acetate 9/1 to 7/3). The product was obtained as a yellow oil. Yield: 87.2% Rf (cyclohexane/ethyl acetate 60/40): 0.6 IR: nuCO 1725 and 1751 cm-1 NMR 1H (CDCl3): 0.88 (t, 3H, J=7.3 Hz); 1.11 (m, 6H); 1.26 (t, 3H, J=7.3 Hz); 1.35 (m, 2H); 1.71 (m, 12H); 2.33 (m, 3H); 4.24 (q, 2H, J=7.3 Hz); 4.42 (d, 1H, J=5.9 Hz); 4.73 (s, 2H); 6.86 (dd, 1H, J=8.2 Hz, J=1.7 Hz); 7.13 (m, 1H); 7.21 (m, 3H); 7.34 (t, 1. J=8.9 Hz); 7.54 (d, 2H, J=8.2 Hz).

Reference： [1]Patent: US2010/4159,2010,A1 .Location in patent: Page/Page column 96-97

38
[ 609-12-1 ]
[ 172732-78-4 ]
[ 936617-38-8 ]

Yield	Reaction Conditions	Operation in experiment
19%		[00485] 2-(1'Benzyl'2-methyl-1H-indol-4'yloxy)-3-methyl-butyric acid ethyl ester 7:1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 ml_). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture ethyl-2-bromoisovalerate (0.344 mL, 1.65 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 mL) and washed with H2O (4 x 100 mL) and brine (1 x 100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (10:1 Hexane:EtOAc) to afford a 1 :1 mixture of 7:ethyl-2-bromoisovalerate. Further purification by column chromatography (10:1 Hexane.epsilontOAc) afforded 7 (0.09 g, 19 %) as a yellow oil.
19%		[00241] 2-(1-Benzyl-2-methyl-1H-indol-4-yloxy)-3-methyl-butyric acid ethyl ester 7: 1- Benzyl-2-methyl-1 H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture ethyl-2-bromoisovalerate (0.344 mL, 1.65 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 mL) and washed with H2O (4 x 100 mL) and brine (1 x 100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (10:1 Hexane:EtOAc) to afford a 1 :1 mixture of 7:ethyl-2-bromoisovalerate. Further purification by column chromatography (10:1 Hexane:EtOAc) afforded 7 (0.09 g, 19 %) as a yellow oil.
19%		1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture ethyl-2-bromoisovalerate (0.344 mL, 1.65 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 mL) and washed with H2O (4×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (10:1 Hexane:EtOAc) to afford a 1:1 mixture of 7: ethyl-2-bromoisovalerate. Further purification by column chromatography (10:1 Hexane:EtOAc) afforded 7 (0.09 g, 19%) as a yellow oil.

Reference： [1]Patent: WO2007/56279,2007,A2 .Location in patent: Page/Page column 191; 192; 219; 220
[2]Patent: WO2007/56280,2007,A1 .Location in patent: Page/Page column 79-80
[3]Patent: US2007/135385,2007,A1 .Location in patent: Page/Page column 93-94; 114-115

39
[ 609-12-1 ]
[ 4435-14-7 ]
C₁₅H₂₇NO₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 694 - 697

40
[ 609-12-1 ]
[ 3215-64-3 ]
[ 1044749-08-7 ]

Reference： [1]Russian Journal of Organic Chemistry,2010,vol. 46,p. 1691 - 1694

41
[ 609-12-1 ]
[ 75279-55-9 ]
[ 1044749-11-2 ]

Reference： [1]Russian Journal of Organic Chemistry,2010,vol. 46,p. 1691 - 1694

42
[ 609-12-1 ]
[ 4604-72-2 ]
[ 1279106-15-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: pyridine / ethanol / 6 h / 100 °C / Sealed 2.1: sodium hydride / N,N-dimethyl-formamide / 0 °C 2.2: 0 - 25 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/71150, 2011, A1

43
[ 609-12-1 ]
[ 4604-72-2 ]
[ 1279106-14-7 ]

Yield	Reaction Conditions	Operation in experiment
16%	With pyridine; In ethanol; at 100℃; for 6h;Sealed;	A solution of pyrazine-2-carbothioamide (1 g, 7.19 mmol) in ethanol (10 ml) was treated with <strong>[609-12-1]ethyl 2-bromoisovalerate</strong> (2.25 g, 10.8 mmol), and pyridine (853 mg, 872 mul, 10.8 mmol) is combined to give a dark brown suspension. and heated to 100 C. for 6 hours in a sealed tube. The reaction mixture was cooled and concentrated to dryness under reduced pressure, and the resulting suspension is extracted with ethyl acetate (350 mL). The organic layers were combined, washed with saturated NaHCO3 (150 mL), saturated sodium chloride (2*20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo to give 5-isopropyl-2-pyrazin-2-yl-thiazol-4-ol (260 mgs, 16%) which was used directly without further purification.

Reference： [1]Patent: US2011/71150,2011,A1 .Location in patent: Page/Page column 40

44
[ 609-12-1 ]
[ 5331-91-9 ]
[ 1331734-08-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium; In ethanol;Inert atmosphere; Reflux;	General procedure: The heterocyclic thiol (1a-g) (3.0 mmol) and ethyl 2-bromoalkanoate (3.0 mmol), both dissolved in absolute EtOH (10 mL), were added to a solution of sodium (69.0 mg, 3.0 mmol) in absolute EtOH (10 mL), under nitrogen atmosphere. After stirring for 2-5 h at reflux, the solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with diethyl ether (3 × 20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent cyclohexane/ethyl acetate 95:5) to give 2a-g ester.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4869 - 4872

45
[ 609-12-1 ]
[ 1191465-55-0 ]
[ 1334758-82-5 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 824 - 827

46
[ 609-12-1 ]
[ 98429-31-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogensulfide; In ethanol; at 20℃; for 0.5h;Inert atmosphere; Reflux;	Step 1To a stirred solution of 0.25 g (1.20 mmol) of compound 77 in 20 mL of ethanol at room temperature under nitrogen was added 0.336 g (6.00 mmol) of sodium hydrogen sulfide. The reaction mixture was heated at reflux for 30 min and then cooled to room temperature. The reaction mixture was concentrated and the residue was partitioned between 20 mL of ethyl acetate and 20 mL of water. The layers were separated and the aqueous layer was extracted with two 15 mL portions of ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 0.195 g (100%) of crude 78 as an oil, which was used in the subsequent step without further purification

Reference： [1]Patent: WO2012/138678,2012,A1 .Location in patent: Page/Page column 96

47
[ 609-12-1 ]
[ 6674-22-2 ]
[ 28165-50-6 ]
[ 944355-67-3 ]

Yield	Reaction Conditions	Operation in experiment
50%	In 1-methyl-pyrrolidin-2-one	Procedure & NMR Data: 8-bromo-2-isopropyl-2H-benzo[b][1,4]oxazin-3(4H)-one Procedure & NMR Data: 1.52 g (8 mmol) of 2-bromo-6-aminophenol, 1.1 mL (7.2 mmol, 0.9 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 3.35 g (2 eq, 16 mmol) of ethyl 2-bromo-3-methylbutyrate in 1-methyl-2-pyrrolidinone (20 mL) were mixed. 1.1 g of P16 were obtained, yield 50%. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.12 (dd, J=8.0, 1.5 Hz, 1H), 6.74 (dd, J=8.0, 7.9 Hz, 1H), 6.67 (dd, J=7.9, 1.5 Hz, 1H), 4.39 (d, J=6.2 Hz, 1H), 2.19 (qq, J=6.9, 6.7 Hz, 1H), 1.07 (d, J=6.9 Hz, 3H), 1.00 (d, J=6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.90, 140.59, 127.78, 126.96, 122.95, 114.59, 110.84, 82.49, 29.98, 18.62, 17.58.
50%	In 1-methyl-pyrrolidin-2-one	8-bromo-2-isopropyl-2H-benzo[b][1,4]oxazin-3(4H)-one 8-bromo-2-isopropyl-2H-benzo[b][1,4]oxazin-3(4H)-one Procedure & NMR Data: 1.52 g (8 mmol) of 2-bromo-6-aminophenol, 1.1 mL (7.2 mmol, 0.9 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 3.35 g (2 eq, 16 mmol) of ethyl 2-bromo-3-methylbutyrate in 1-methyl-2-pyrrolidinone (20 mL) were mixed. 1.1 g of P16 were obtained, yield 50%. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.12 (dd, J=8.0, 1.5 Hz, 1H), 6.74 (dd, J=8.0, 7.9 Hz, 1H), 6.67 (dd, J=7.9, 1.5 Hz, 1H), 4.39 (d, J=6.2 Hz, 1H), 2.19 (qq, J=6.9, 6.7 Hz, 1H), 1.07 (d, J=6.9 Hz, 3H), 1.00 (d, J=6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.90, 140.59, 127.78, 126.96, 122.95, 114.59, 110.84, 82.49, 29.98, 18.62, 17.58.

Reference： [1]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; ECOLE NATIONALE SUPERIEURE DE CHIMIE DE RENNES - US2013/197218, 2013, A1 Location in patent: Page/Page column
[2]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; ECOLE NATIONALE SUPERIEURE DE CHIMIE DE RENNES - US8835628, 2014, B2 Location in patent: Page/Page column

48
[ 609-12-1 ]
[ 22246-66-8 ]
[ 1448190-07-5 ]

Yield	Reaction Conditions	Operation in experiment
23%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20 - 70℃; for 44h;Inert atmosphere; Cooling with ice;	Ethyl 2-(5-methoxy-l-oxoisoindolin-2-yl)-3-methylbutanoate Under an atmosphere of nitrogen, an ice-cooled solution of 5-methoxyisoindolin-l-one (commercially available from for example Chem Impex) (105 mg, 0.64 mmol) in DMF (2.5 mL) was treated with sodium hydride (60% w/w in mineral oil) (31 mg, 0.77 mmol). The mixture was warmed to ambient temperature, treated with ethyl 2-bromo-3-methylbutanoate (commercially available from for example Alfa Aesar) (135 mg, 0.64 mmol), stirred at ambient temperature for 2 hours, and then heated to 70 C for a further 18 hours. The mixture was then ice-cooled and treated with additional sodium hydride (60% w/w in mineral oil) (31 mg, 0.77 mmol), followed by ethyl 2-bromo-3-methylbutanoate (135 mg, 0.64 mmol) and stirred at 70 C for a further 24 hours. The cooled mixture was then cautiously treated with saturated aqueous ammonium chloride (20 mL) and the product was extracted with ethyl acetate (2 x 25 mL). The combined organic phase was washed with water (20 mL), brine (20 mL), filtered through a hydrophobic frit and evaporated to dryness. The product was purified by flash chromatography (20 g silica cartridge) using a gradient elution from 0% to 50% ethyl acetate in cyclohexane to afford the title compound (44 mg, 23% yield). LCMS RT= 1.01 min, ES+ve m/z 292 [M+H]+
23%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20 - 70℃; for 44h;Inert atmosphere; Cooling;	Under an atmosphere of nitrogen, an ice-cooled solution of 5-methoxyisoindolin-1-one (commercially available from for example Chem Impex) (105 mg, 0.64 mmol) in DMF (2.5 mL) was treated with sodium hydride (60% w/w in mineral oil) (31 mg, 0.77 mmol). The mixture was warmed to ambient temperature, treated with ethyl 2-bromo-3-methylbutanoate (commercially available from for example Alfa Aesar) (135 mg, 0.64 mmol), stirred at ambient temperature for 2 hours and then heated to 70 C. for a further 18 hours. The mixture was then ice-cooled and treated with additional sodium hydride (60% w/w in mineral oil) (31 mg, 0.77 mmol), followed by ethyl 2-bromo-3-methylbutanoate (135 mg, 0.64 mmol) and stirred at 70 C. for a further 24 hours. The cooled mixture was then cautiously treated with saturated aqueous ammonium chloride (20 mL) and the product was extracted with ethyl acetate (2*25 mL). The combined organic phase was washed with water (20 mL), brine (20 mL), filtered through a hydrophobic fit and evaporated to dryness. The product was purified by flash chromatography (20 g silica cartridge) using a gradient elution from 0% to 50% ethyl acetate in cyclohexane to afford the title compound (44 mg, 23% yield). LCMS RT=1.01 min, ES+ve m/z 292 [M+H]+

Reference： [1]Patent: WO2013/106646,2013,A2 .Location in patent: Page/Page column 203
[2]Patent: US2014/356322,2014,A1 .Location in patent: Paragraph 0456

49
[ 609-12-1 ]
[ 22246-66-8 ]
[ 1448190-08-6 ]

Yield	Reaction Conditions	Operation in experiment
21%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 18h;Inert atmosphere; Cooling with ice;	Ethyl 2-(6-methoxy-l-oxoisoindolin-2-yI)-3-methylbutanoate Under an atmosphere of nitrogen, an ice-cooled solution of 6-methoxyisoindolin-l-one (commercially available from for example Astatech) (105 mg, 0.64 mmol) in DMF (2.5 mL) was treated with sodium hydride (60% w/w in mineral oil) (31 mg, 0.77 mmol) and the mixture was allowed to warm to ambient temperature. The mixture was then treated with ethyl 2-bromo-3-methylbutanoate (commercially available from for example Alfa Aesar) (135 mg, 0.64 mmol) and the mixture was stirred for 18 hours then cautiously treated with saturated aqueous ammonium chloride (20 mL). The product was extracted with ethyl acetate (2 x 25 mL) and the combined organic phase was washed with water (20 mL), brine (20 mL), filtered through a hydrophobic frit and evaporated to dryness. The product was purified by flash chromatography (20 g silica cartridge) using a gradient elution from 0 to 50% ethyl acetate in cyclohexane to afford the title compound (40 mg, 21% yield). LCMS RT= 1.03 min, ES+ve m/z 292 [M+H]+
21%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 18h;Inert atmosphere; Cooling;	Under an atmosphere of nitrogen, an ice-cooled solution of <strong>[22246-66-8]6-methoxyisoindolin-1-one</strong> (commercially available from for example Astatech) (105 mg, 0.64 mmol) in DMF (2.5 mL) was treated with sodium hydride (60% w/w in mineral oil) (31 mg, 0.77 mmol) and the mixture was allowed to warm to ambient temperature. The mixture was then treated with ethyl 2-bromo-3-methylbutanoate (commercially available from for example Alfa Aesar) (135 mg, 0.64 mmol) and the mixture was stirred for 18 hours then cautiously treated with saturated aqueous ammonium chloride (20 mL). The product was extracted with ethyl acetate (2*25 mL) and the combined organic phase was washed with water (20 mL), brine (20 mL), filtered through a hydrophobic fit and evaporated to dryness. the product was purified by flash chromatography (20 g silica cartridge) using a gradient elution from 0 to 50% ethyl acetate in cyclohexane to afford the title compound (40 mg, 21% yield). LCMS RT=1.03 min, ES+ve m/z 292 [M+H]+

Reference： [1]Patent: WO2013/106646,2013,A2 .Location in patent: Page/Page column 203-204
[2]Patent: US2014/356322,2014,A1 .Location in patent: Paragraph 0457

50
[ 609-12-1 ]
[ 22246-66-8 ]
[ 1448189-57-8 ]

Reference： [1]Patent: WO2013/106646,2013,A2

51
[ 609-12-1 ]
[ 658683-16-0 ]
[ 1448190-09-7 ]

Yield	Reaction Conditions	Operation in experiment
15%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 29h;Inert atmosphere; Cooling with ice;	Ethyl 2-(7-chloro-l-oxoisoindolin-2-yl)-3-methylbutanoate Under a nitrogen atmosphere, an ice-cooled solution of 7-chloroisoindolin-l-one (commercially available from for example JW Pharm) (150 mg, 0.90 mmol) in DMF (2.5 mL) was treated with sodium hydride (60% w/w in mineral oil) (50 mg, 1.25 mmol). The mixture was allowed to warm to ambient temperature, then treated with ethyl 2-bromo-3- methylbutanoate (commercially available from for example Alfa Aesar) (187 mg, 0.90 mmol) and stirred for 5 hours. The mixture was then ice-cooled, treated with additional sodium hydride (60% w/w in mineral oil) (50 mg, 1.25 mmol) and ethyl 2-bromo-3-methylbutanoate (187 mg, 0.90 mmol) and the mixture was stirred at ambient temperature for a further 24 hours. The mixture was then cautiously treated with saturated aqueous ammonium chloride (20 mL), and the product was extracted with ethyl acetate (2 x 25 mL). The combined organic phase was washed with water (20 mL), brine (20 mL), filtered through a hydrophobic frit and evaporated to dryness. The product was purified by flash chromatography (20 g silica cartridge) using a gradient elution from 0 to 50% ethyl acetate in cyclohexane to afford the title compound (40 mg, 15% yield). LCMS RT= 1.07 min, ES+ve m/z 296 [M+H]+.

Reference： [1]Patent: WO2013/106646,2013,A2 .Location in patent: Page/Page column 205

52
[ 609-12-1 ]
[ 13169-73-8 ]
[ 1528751-84-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With caesium carbonate; In acetonitrile; at 20℃;	General procedure: The appropriate 2-aroylpyrrole derivative (9, 25.0 mmol) was dissolved in acetonitrile (375 mL). If the mixture did not become a solution (in the cases of 9j, 9k, 9n) 150 mL of CH2Cl2 was added. To this solution were added cesium carbonate (9.77 g, 30.0 mmol) and ethyl alpha-bromoalkanoate (ethyl bromoacetate, ethyl 2-bromopropionate or ethyl-2-bromobutyrate, 27.5 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was then filtered, evaporated, the residue was then dissolved in dichloromethane, extracted with water twice, dried over MgSO4, filtered and evaporated. The crude material was recrystallized or distilled.

Reference： [1]Tetrahedron,2014,vol. 70,p. 465 - 476

53
[ 16867-03-1 ]
[ 609-12-1 ]
[ 1559069-17-8 ]

Yield	Reaction Conditions	Operation in experiment
37%		To a suspension of NaH (0.77 g, i9.23 mmol) in DMF (15 mL) was added dropwise a solution of 2-amino-3-hydroxypyridine (3 g, 27.24 mmol) in DMF (15 mL) at room temperature over a period of 10 minutes and the mixture was stirred at room temperature for 20 minutes. To the mixture was added dropwise ethyl-2-bromo-isovalerate CAS [609-12-1] (2.63 mL, 16.03 mmol) over a period of 20 minutes, the reaction mixture was stirred at room temperature for 1 hour and at 80C for 2 hours. After cooling, cold water was added, and the mixture was extracted with EtOAc. The organic layer was successively washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromato15 graphy over silica gel (80 g, mobile phase gradient Heptane/EtOAc from 85/15 to70/30). Pure fractions were collected and the solvent was removed. Yielding:Intermediate Hi as a white powder, 1.14 g, (3 7%).
37%		Preparation of Intermediate IiTo a suspension of NaH (0.77 g, 19.23 mmol) in DMF (15 mL) was added dropwise a solution of 2-amino-3-hydroxypyridine (3 g, 27.24 mmol) in DMF (15 mL) at roomtemperature over a period of 10 minutes and the mixture was stirred at room temperature for 20 minutes. To the mixture was added dropwise ethyl-2-bromo- isovalerate CAS [609-12-1] (2.63 mL, 16.03 mmol) over a period of 20 minutes, the reaction mixture was stirred at room temperature for 1 hour and at 80C for 2 hours. After cooling, cold water was added, and the mixture was extracted with EtOAc. Theorganic layer was successively washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (80 g, mobile phase gradient Heptane/EtOAc from 85/15 to 70/30). Pure fractions were collected and the solvent was removed. Yielding:Intermediate Ii as a white powder, 1.14 g, (3 7%).

Reference： [1]Patent: WO2014/23814,2014,A1 .Location in patent: Page/Page column 59
[2]Patent: WO2014/23815,2014,A1 .Location in patent: Page/Page column 70; 71

54
[ 609-12-1 ]
[ 235106-12-4 ]
[ 1571821-40-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 50℃;	a) Ethyl 2-bromo-3-methylbutanoate (836 mg, 4 mmol), 4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazole (738 mg, 4 mmol), and K2CO3 (1.106 g, 8 mmol) were combined in 12 mL of 2:1 THF:DMF at 50 C. overnight. An additional 400 muL of alkylator was added and stirring continued overnight. The solids were filtered off washing with EtOAc and the volatiles were evaporated. The residue was diluted in EtOAc and washed with 2× brine (half-saturated). The organic layer was concentrated and the residue purified by normal phase flash chromatography (40 g column, eluting with 5% EtOAc in hexanes) to provide 870 mg (70%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 4.42 (d, J=10.2 Hz, 1H), 4.20 (q, J=7.4 Hz, 2H), 2.83 (m, 1H), 2.31 (s, 3H), 1.24 (t, J=7.4 Hz, 3H), 1.09 (d, J=6.7 Hz, 3H), 0.82 (d, J=6.6 Hz, 3H); MS: (ES) m/z calculated for C12H17ClF3N2O2 [M+H]+ 313.1, found 313.1. The regiochemistry of the system was confirmed by nOe between the alpha-methine proton and pyrazole methyl protons (and those of the isopropyl group).

Reference： [1]Patent: US2014/57937,2014,A1 .Location in patent: Paragraph 0170; 0171

55
[ 609-12-1 ]
[ 1746-23-2 ]
[ 1522362-04-4 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1932 - 1935
[2]Journal of Organic Chemistry,2019,vol. 84,p. 15677 - 15684

56
[ 609-12-1 ]
7-chloroisoindolin-1-one [ No CAS ]
[ 1448190-09-7 ]

Yield	Reaction Conditions	Operation in experiment
15%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 29h;Inert atmosphere; Cooling;	Under a nitrogen atmosphere, an ice-cooled solution of 7-chloroisoindolin-1-one (commercially available from for example JW Pharm) (150 mg, 0.90 mmol) in DMF (2.5 mL) was treated with sodium hydride (60% w/w in mineral oil) (50 mg, 1.25 mmol). The mixture was allowed to warm to ambient temperature, then treated with ethyl 2-bromo-3-methylbutanoate (commercially available from for example Alfa Aesar) (187 mg, 0.90 mmol) and stirred for 5 hours. The mixture was then ice-cooled, treated with additional sodium hydride (60% w/w in mineral oil) (50 mg, 1.25 mmol) and ethyl 2-bromo-3-methylbutanoate (187 mg, 0.90 mmol) and the mixture was stirred at ambient temperature for a further 24 hours. The mixture was then cautiously treated with saturated aqueous ammonium chloride (20 mL), and the product was extracted with ethyl acetate (2*25 mL). The combined organic phase was washed with water (20 mL), brine (20 mL), filtered through a hydrophobic fit and evaporated to dryness. The product was purified by flash chromatography (20 g silica cartridge) using a gradient elution from 0 to 50% ethyl acetate in cyclohexane to afford the title compound (40 mg, 15% yield). LCMS RT=1.07 min, ES+ve m/z 296 [M+H]+.

Reference： [1]Patent: US2014/356322,2014,A1 .Location in patent: Paragraph 0460

57
[ 609-12-1 ]
[ 120-83-2 ]
[ 63403-50-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;	General procedure: To stirred solutions of 2,4-dichlorophenol (2.50 g, 15.0 mmol)in DMF (25 mL) were added K2CO3 (2.60 g, 18.8 mmol) and the correspondingethyl 2-bromoalkyl esters (18.8 mmol). The mixtureswere stirred at 50 C for 16 h, then cooled to room temperatureand filtered to remove the inorganic solids. The filtrates were evaporatedunder high vacuum (<1 mmHg) to provide clear oils thatwere dissolved in absolute ethanol (25 mL). Aqueous solutions ofNaOH (2.0 M, 12 mL, 24 mmol) were added, and the combinedsolutions heated to reflux for 4 h. The resulting mixtures werecooled to room temperature and evaporated under reduced pressureto provide residues that were dissolved in water (75 mL).The aqueous solutions were acidified (pH 2) with aqueous HCl(2.0 M) to provide precipitates that were filtered, rinsed with water(20 mL), and dried under vacuum to provide the products 5b-e.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 1027 - 1043

58
[ 609-12-1 ]
3-fluoro-4-(1H-pyrazol-1-yl)phenol [ No CAS ]
ethyl 2-(3-fluoro-4-(1H-pyrazol-1-yl)phenoxy)-3-methylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.47 g	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h;	To a solution (50 mL) of ethyl 3-fluoro-4-(1H-pyrazol-1-yl)phenol (2.0 g) and 2-bromo-3-methylbutanoate (2.4 mL) in dimethylformamide was added potassium carbonate (2.33 g), and the mixture was stirred at 80C for 24 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.47 g). MS (API+): [M+H]+ 307.1.

Reference： [1]Patent: EP2873669,2015,A1 .Location in patent: Paragraph 0593

59
[ 609-12-1 ]
[ 22515-18-0 ]
ethyl 2-(4,4-difluoro-1-hydroxycyclohexyl)-3-methylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With zinc; In 1,4-dioxane; at 85℃; for 48h;	A mixture of 4,4-difluorocyclohexanone (1.00 g, 7.46 mmol), ethyl 2-bromo-3-methylbutanoate (1.56 g, 7.46 mmol), zinc powder (561 mg, 8.57 mmol) in dioxane (20 mL) is stirred at 85 oC for 2 days. After the removal of solvent, the filtrate is concentrated in vacuo. The residual oil is purified by column chromatography on silica gel eluting with 0-30% ethyl acetate in hexane to give the titled compound (1.46 g, 74% yield) as a pale yellow oil.

Reference： [1]Patent: WO2015/136947,2015,A1 .Location in patent: Paragraph 0192; 0193

60
[ 609-12-1 ]
[ 98-10-2 ]
2-bromo-3-methyl-N-(phenylsulfonyl)butanamide [ No CAS ]