[ CAS No. 29421-99-6 ] {[proInfo.proName]}

Name: 29421-99-6|4-Bromo-5-methylthiophene-2-carboxylic acid|97%
Brand: Ambeed
SKU: A378787
Price: 10.0 USD
Availability: InStock
Rating: 99 (27 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 29421-99-6

Structure of 29421-99-6 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 29421-99-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 29421-99-6 ]

SDS Specification

Alternatived Products of [ 29421-99-6 ]

Product Details of [ 29421-99-6 ]

CAS No. :	29421-99-6	MDL No. :	MFCD01859873
Formula :	C₆H₅BrO₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JUPQMRVILHTCOF-UHFFFAOYSA-N
M.W :	221.07	Pubchem ID :	818889
Synonyms :

Calculated chemistry of [ 29421-99-6 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	43.94
TPSA :	65.54 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) :	-5.84 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.67
Log Po/w (XLOGP3) :	2.55
Log Po/w (WLOGP) :	2.52
Log Po/w (MLOGP) :	1.69
Log Po/w (SILICOS-IT) :	3.03
Consensus Log Po/w :	2.29

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.12
Solubility :	0.167 mg/ml ; 0.000757 mol/l
Class :	Soluble
Log S (Ali) :	-3.57
Solubility :	0.059 mg/ml ; 0.000267 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.29
Solubility :	1.14 mg/ml ; 0.00516 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.49

Safety of [ 29421-99-6 ]

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

Application In Synthesis of [ 29421-99-6 ]

* 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 [ 29421-99-6 ]
Downstream synthetic route of [ 29421-99-6 ]

[ 29421-99-6 ] Synthesis Path-Upstream 1~6

1
[ 1918-79-2 ]
[ 29421-99-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With iron(III) chloride; bromine In acetic acid at 25℃; for 5 h;	A solution of bromine (725 uL, 14.1 mmol) in AcOH (2.8 ml.) was added dropwise to δ-methyl^-thiophenecarboxylic acid (2 g, 14.1 mmol) and FeCI₃ (456 mg, 2.81 mmol) in AcOH (28 ml.) at 25 ⁰C. After 5h, the solution was poured onto ice and the precipitate was filtered and washed with water affording the title compound (3 g, quant.) as a yellow powder: LCMS (ES) m/z 222 (M+H)⁺.

Reference： [1] Patent: WO2008/98104, 2008, A1, . Location in patent: Page/Page column 81
[2] Patent: WO2010/93885, 2010, A1, . Location in patent: Page/Page column 36-37
[3] Patent: WO2017/176961, 2017, A1, . Location in patent: Paragraph 00768

2
[ 29421-73-6 ]
[ 29421-99-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With hydrogenchloride; n-butyllithium; carbon dioxide In tetrahydrofuran; cyclohexane	a) 4-Bromo-5-methylthiophene-2-carboxylic acid A solution of 27.65 g (108 mmol) of 2-methyl-3,5-dibromothiophene (prepared by the method of Kano, S.et al., Heterocycles 20(10):2035, 1983) was dissolved in dry tetrahydrofuran (280 mL), cooled to -78° C. and 2 M n-butyl lithium in cyclohexane (54 mL, 108 mmol) was added over 10 min. After stirring 20 min at -78° C., dry carbon dioxide gas was bubbled through the solution for 1.5 h as the mixture was allowed to warm to room temperature. To this 6 N hydrochloric acid (100 mL) was added carefully. The layers were separated and the aqueous layer was extracted with diethyl ether (4*50 mL). The combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. The solvents were removed in vacuo to give 4-bromo-5-methylthiophene-2-carboxylic acid (22.4 g, 94percent) as an off-white solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ13.34 (br s, 1 H), 7.61 (s, 1 H), 2.41 (s, 3 H).
94%	With hydrogenchloride; n-butyllithium; carbon dioxide In tetrahydrofuran; cyclohexane	a) 4-Bromo-5-methylthiophene-2-carboxylic acid A solution of 27.65 g (108 mmol) of 2-methyl-3,5-dibromothiophene (prepared by the method of Kano, S. et al., Heterocycles 20(10):2035, 1983) was dissolved in dry tetrahydrofuran (280 mL), cooled to -78° C. and 2 M n-butyl lithium in cyclohexane (54 mL, 108 mmol) was added over 10 min. After stirring 20 min at -78° C., dry carbon dioxide gas was bubbled through the solution for 1.5 h as the mixture was allowed to warm to room temperature. To this 6 N hydrochloric acid (100 mL) was added carefully. The layers were separated and the aqueous layer was extracted with diethyl ether (4*50 mL). The combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. The solvents were removed in vacuo to give 4-bromo-5-methylthiophene-2-carboxylic acid (22.4 g, 94percent) as an off-white solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 13.34 (br s, 1H), 7.61 (s, 1H), 2.41 (s, 3H).
90%	With hydrogenchloride; n-butyllithium In tetrahydrofuran; cyclohexane; water	a) 4-Bromo-5-methylthiophene-2-carboxylic acid A stirred solution of 1 g (3.9 mmol) of 2-methyl-3,5-dibromothiophene (prepared by the method of Kano, S.et al., Heterocycles 20(10):2035, 1983) in dry tetrahydrofuran (10 mL) was cooled to -78° C. and 2 M n-butyllithium in cyclohexane (1.93 mL, 3.87 mmol) was added over 3 min. After stirring 3 min at -78° C., the mixture was added to tetrahydrofuran (100 mL) with dry ice suspended. This mixture was allowed to stir and warm to room temperature. To this, 6 N hydrochloric acid (50 mL) was added carefully. Then, water (50 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (4*30 mL). The combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate. The solvents were removed in vacuo to give an 85/15 mixture of 4-bromo-5-methylthiophene-2-carboxylic acid and 5-bromothiophene-2-carboxylic acid (780 mg, 90percent) as a tan solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ13.33 (br s, 1 H), 7.62 (s, 1 H), 7.56 and 7.34 (AB quartet, 0.35H, J=3.9 Hz), 2.41 (s, 3 H). Gas Chromotography/Mass spectroscopy (m/z): Calcd. for C₆H₅O₂SBr, 220.9 and 222.9 (M+H), found 221.3 and 223.3. Calcd. for C₅H₃O₂SBr, 206.9 and 208.9 (M+H), found 207.3 and 209.3.

90%

With hydrogenchloride; n-butyllithium In tetrahydrofuran; cyclohexane; water

a)
4-Bromo-5-methylthiophene-2-carboxylic acid

A stirred solution of 1 g (3.9 mmol) of 2-methyl-3,5-dibromothiophene (prepared by the method of Kano, S. et al., Heterocycles 20(10):2035, 1983) in dry tetrahydrofuran (10 mL) was cooled to -78° C. and 2 M n-butyllithium in cyclohexane (1.93 mL, 3.87 mmol) was added over 3 min.
After stirring 3 min at -78° C., the mixture was added to tetrahydrofuran (100 mL) with dry ice suspended.
This mixture was allowed to stir and warm to room temperature.
To this, 6 N hydrochloric acid (50 mL) was added carefully.
Then, water (50 mL) was added and the layers were separated.
The aqueous layer was extracted with diethyl ether (4*30 mL).
The combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate.
The solvents were removed in vacuo to give an 85/15 mixture of 4-bromo-5-methylthiophene-2-carboxylic acid and 5-bromothiophene-2-carboxylic acid (780 mg, 90percent) as a tan solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 13.33 (br s, 1H), 7.62 (s, 1H), 7.56 and 7.34 (AB quartet, 0.35H, J=3.9 Hz), 2.41 (s, 3H).
Gas Chromotography/Mass spectroscopy (m/z): Calcd. for C₆H₅O₂SBr, 220.9 and 222.9 (M+H), found 221.3 and 223.3. Calcd. for C₅H₃O₂SBr, 206.9 and 208.9 (M+H), found 207.3 and 209.3.

Reference： [1] Patent: US2002/37915, 2002, A1,
[2] Patent: US6291514, 2001, B1,
[3] Patent: US2002/37915, 2002, A1,
[4] Patent: US6291514, 2001, B1,
[5] Justus Liebigs Annalen der Chemie, 1934, vol. 513, p. 281,291

3
[ 124-38-9 ]
[ 29421-99-6 ]

Reference： [1] Patent: WO2007/124546, 2007, A1, . Location in patent: Page/Page column 57

4
[ 29421-73-6 ]
[ 124-38-9 ]
[ 29421-99-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 3, p. 491 - 495

5
[ 1256286-44-8 ]
[ 29421-99-6 ]

Reference： [1] Synthesis, 2010, # 17, p. 2965 - 2968

6
[ 554-14-3 ]
[ 29421-99-6 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1934, vol. 513, p. 281,291
[2] Justus Liebigs Annalen der Chemie, 1934, vol. 513, p. 281,291

[ 29421-99-6 ] Synthesis Path-Downstream 1~72

1
[ 29421-73-6 ]
[ 29421-99-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With hydrogenchloride; n-butyllithium; carbon dioxide; In tetrahydrofuran; cyclohexane;	a) 4-Bromo-5-methylthiophene-2-carboxylic acid A solution of 27.65 g (108 mmol) of 2-methyl-3,5-dibromothiophene (prepared by the method of Kano, S.et al., Heterocycles 20(10):2035, 1983) was dissolved in dry tetrahydrofuran (280 mL), cooled to -78 C. and 2 M n-butyl lithium in cyclohexane (54 mL, 108 mmol) was added over 10 min. After stirring 20 min at -78 C., dry carbon dioxide gas was bubbled through the solution for 1.5 h as the mixture was allowed to warm to room temperature. To this 6 N hydrochloric acid (100 mL) was added carefully. The layers were separated and the aqueous layer was extracted with diethyl ether (4*50 mL). The combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. The solvents were removed in vacuo to give 4-bromo-5-methylthiophene-2-carboxylic acid (22.4 g, 94%) as an off-white solid. 1H-NMR (DMSO-d6; 300 MHz) delta13.34 (br s, 1 H), 7.61 (s, 1 H), 2.41 (s, 3 H).
94%	With hydrogenchloride; n-butyllithium; carbon dioxide; In tetrahydrofuran; cyclohexane;	a) 4-Bromo-5-methylthiophene-2-carboxylic acid A solution of 27.65 g (108 mmol) of 2-methyl-3,5-dibromothiophene (prepared by the method of Kano, S. et al., Heterocycles 20(10):2035, 1983) was dissolved in dry tetrahydrofuran (280 mL), cooled to -78 C. and 2 M n-butyl lithium in cyclohexane (54 mL, 108 mmol) was added over 10 min. After stirring 20 min at -78 C., dry carbon dioxide gas was bubbled through the solution for 1.5 h as the mixture was allowed to warm to room temperature. To this 6 N hydrochloric acid (100 mL) was added carefully. The layers were separated and the aqueous layer was extracted with diethyl ether (4*50 mL). The combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. The solvents were removed in vacuo to give 4-bromo-5-methylthiophene-2-carboxylic acid (22.4 g, 94%) as an off-white solid. 1H-NMR (DMSO-d6; 300 MHz) delta 13.34 (br s, 1H), 7.61 (s, 1H), 2.41 (s, 3H).
90%	With hydrogenchloride; n-butyllithium; In tetrahydrofuran; cyclohexane; water;	a) 4-Bromo-5-methylthiophene-2-carboxylic acid A stirred solution of 1 g (3.9 mmol) of 2-methyl-3,5-dibromothiophene (prepared by the method of Kano, S.et al., Heterocycles 20(10):2035, 1983) in dry tetrahydrofuran (10 mL) was cooled to -78 C. and 2 M n-butyllithium in cyclohexane (1.93 mL, 3.87 mmol) was added over 3 min. After stirring 3 min at -78 C., the mixture was added to tetrahydrofuran (100 mL) with dry ice suspended. This mixture was allowed to stir and warm to room temperature. To this, 6 N hydrochloric acid (50 mL) was added carefully. Then, water (50 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (4*30 mL). The combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate. The solvents were removed in vacuo to give an 85/15 mixture of 4-bromo-5-methylthiophene-2-carboxylic acid and 5-bromothiophene-2-carboxylic acid (780 mg, 90%) as a tan solid. 1H-NMR (DMSO-d6; 300 MHz) delta13.33 (br s, 1 H), 7.62 (s, 1 H), 7.56 and 7.34 (AB quartet, 0.35H, J=3.9 Hz), 2.41 (s, 3 H). Gas Chromotography/Mass spectroscopy (m/z): Calcd. for C6H5O2SBr, 220.9 and 222.9 (M+H), found 221.3 and 223.3. Calcd. for C5H3O2SBr, 206.9 and 208.9 (M+H), found 207.3 and 209.3.

90%

With hydrogenchloride; n-butyllithium; In tetrahydrofuran; cyclohexane; water;

a) 4-Bromo-5-methylthiophene-2-carboxylic acid A stirred solution of 1 g (3.9 mmol) of 2-methyl-3,5-dibromothiophene (prepared by the method of Kano, S. et al., Heterocycles 20(10):2035, 1983) in dry tetrahydrofuran (10 mL) was cooled to -78 C. and 2 M n-butyllithium in cyclohexane (1.93 mL, 3.87 mmol) was added over 3 min. After stirring 3 min at -78 C., the mixture was added to tetrahydrofuran (100 mL) with dry ice suspended. This mixture was allowed to stir and warm to room temperature. To this, 6 N hydrochloric acid (50 mL) was added carefully. Then, water (50 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (4*30 mL). The combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate. The solvents were removed in vacuo to give an 85/15 mixture of 4-bromo-5-methylthiophene-2-carboxylic acid and 5-bromothiophene-2-carboxylic acid (780 mg, 90%) as a tan solid. 1H-NMR (DMSO-d6; 300 MHz) delta 13.33 (br s, 1H), 7.62 (s, 1H), 7.56 and 7.34 (AB quartet, 0.35H, J=3.9 Hz), 2.41 (s, 3H). Gas Chromotography/Mass spectroscopy (m/z): Calcd. for C6H5O2SBr, 220.9 and 222.9 (M+H), found 221.3 and 223.3. Calcd. for C5H3O2SBr, 206.9 and 208.9 (M+H), found 207.3 and 209.3.

Reference： [1]Patent: US2002/37915,2002,A1
[2]Patent: US6291514,2001,B1
[3]Patent: US2002/37915,2002,A1
[4]Patent: US6291514,2001,B1
[5]Justus Liebigs Annalen der Chemie,1934,vol. 513,p. 281,291

2
[ 29421-99-6 ]
[ 95-55-6 ]
[ 245416-14-2 ]

Reference： [1]Russian Chemical Bulletin,1999,vol. 48,p. 1003 - 1005

4
[ 29421-73-6 ]
[ 124-38-9 ]
[ 29421-99-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 491 - 495

5
[ 29421-99-6 ]
[ 18107-18-1 ]
[ 237385-15-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 491 - 495

6
[ 29421-99-6 ]
[ 478165-96-7 ]

Reference： [1]Chemistry of Heterocyclic Compounds,2002,vol. 38,p. 165 - 176
[2]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 491 - 495

7
[ 124-38-9 ]
[ 29421-99-6 ]

Yield	Reaction Conditions	Operation in experiment
74.4%		Compound 2 was carbonylated with BuIi and dry ice to give compound 3 in 74.4% yield and the carboxylate was esterified to give compound 4 in 75.1% yield.

Reference： [1]Patent: WO2007/124546,2007,A1 .Location in patent: Page/Page column 57

8
[ 29421-99-6 ]
[ 237385-15-8 ]

Yield	Reaction Conditions	Operation in experiment
75.1%		Compound 2 was carbonylated with BuIi and dry ice to give compound 3 in 74.4% yield and the carboxylate was esterified to give compound 4 in 75.1% yield.

Reference： [1]Patent: WO2007/124546,2007,A1 .Location in patent: Page/Page column 57

9
[ 29421-99-6 ]
[ 302777-33-9 ]

Reference： [1]Chemistry of Heterocyclic Compounds,2002,vol. 38,p. 165 - 176

10
[ 29421-99-6 ]
[ 302777-31-7 ]

Reference： [1]Chemistry of Heterocyclic Compounds,2002,vol. 38,p. 165 - 176

11
[ 29421-99-6 ]
2-(4-bromo-5-methyl-2-thienyl)-5-(6-methoxy-2-benzothiazolyl)-1,3,4-oxadiazole [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2002,vol. 38,p. 165 - 176

12
[ 29421-99-6 ]
[ 478165-99-0 ]

Reference： [1]Chemistry of Heterocyclic Compounds,2002,vol. 38,p. 165 - 176

13
[ 29421-99-6 ]
[ 302777-35-1 ]

Reference： [1]Chemistry of Heterocyclic Compounds,2002,vol. 38,p. 165 - 176

14
[ 29421-99-6 ]
[ 237385-16-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 491 - 495
[2]Patent: WO2007/124546,2007,A1

15
[ 29421-99-6 ]
[ 237385-21-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 491 - 495

16
[ 29421-99-6 ]
[ 237385-22-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 491 - 495

17
[ 29421-99-6 ]
[ 237385-17-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 491 - 495

18
[ 29421-99-6 ]
[ 237385-23-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 491 - 495

19
[ 29421-99-6 ]
5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 491 - 495

20
[ 29421-99-6 ]
[ 288397-85-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 491 - 495

21
[ 29421-99-6 ]
[ 237385-20-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 491 - 495

22
[ 29421-99-6 ]
4-[4-(3,4-dimethoxy-phenyl)-thiazol-2-yl]-5-methyl-thiophene-2-carboxamidine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 491 - 495

23
[ 29421-99-6 ]
1-[2-methyl-5-(benzoxazol-2-yl)thien-3-yl]heptafluorocyclopentene [ No CAS ]

Reference： [1]Russian Chemical Bulletin,1999,vol. 48,p. 1003 - 1005

24
[ 29421-99-6 ]
[ 245416-11-9 ]

Reference： [1]Russian Chemical Bulletin,1999,vol. 48,p. 1003 - 1005
[2]Russian Chemical Bulletin,1999,vol. 48,p. 1003 - 1005

25
[ 554-14-3 ]
[ 29421-99-6 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1934,vol. 513,p. 281,291
[2]Justus Liebigs Annalen der Chemie,1934,vol. 513,p. 281,291

26
[ 29421-99-6 ]
[ 79-37-8 ]
[ 237385-21-6 ]

Yield	Reaction Conditions	Operation in experiment
32%	With pyridine; In N-methyl-acetamide; dichloromethane; isopropyl alcohol;	b) Isopropyl 4-bromo-5-methylthiophene-2-carboxylate A solution of 5 g (22.6 mmol) of <strong>[29421-99-6]4-bromo-5-methylthiophene-2-carboxylic acid</strong> was dissolved in dry dichloromethane (200 mL) and reacted with oxalyl chloride (2 mL, 22.6 mmol) and dimethylformamide (100 muL) stirring on an ice bath for 30 min and then at room temperature for 2.5 h. The solvents were removed in vacuo and the residue was passed through silica gel, eluding off with hexanes:ethyl acetate 7/3 (v:v), ethyl acetate, and dichloromethane. The solvents were removed in vacuo and the resulting oil dissolved in dry dichloromethane (100 mL). This solution was reacted with dry pyridine (9 mL, 113 mmol) and dry isopropanol (40 mL, 522 mmol) for 88 h. The solvents were removed in vacuo and the residue partitioned between sodium bicarbonate (150 mL) and dichloromethane (75 mL). The aqueous layers were extracted with dichloromethane (2*20 mL), and the combined organic layers were washed with sodium bicarbonate (30 mL), brine (30 mL), and dried over anhydrous sodium sulfate. The solvents were removed in vacuo. The residue was purified by column chromatography eluding with hexanes:ethyl acetate 9/1 (v:v) to give isopropyl 4-bromo-5-methylthiophene-2-carboxylate (1.91 g, 32%) as a pale yellow oil. 1H-NMR (DMSO-d6; 300 MHz) delta7.66 (s, 1 H), 5.07 (septet, 1 H, J=6.2 Hz), 2.42 (s, 3 H), 1.29 (d, 6 H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C9H11O2SBr 264.2 (M+H), found 264.8.
32%	With pyridine; In N-methyl-acetamide; dichloromethane; isopropyl alcohol;	b) Isopropyl 4-bromo-5-methylthiophene-2-carboxylate A solution of 5 g (22.6 mmol) of <strong>[29421-99-6]4-bromo-5-methylthiophene-2-carboxylic acid</strong> was dissolved in dry dichloromethane (200 mL) and reacted with oxalyl chloride (2 mL, 22.6 mmol) and dimethylformamide (100 muL) stirring on an ice bath for 30 min and then at room temperature for 2.5 h. The solvents were removed in vacuo and the residue was passed through silica gel, eluding off with hexanes:ethyl acetate 7/3 (v:v), ethyl acetate, and dichloromethane. The solvents were removed in vacuo and the resulting oil dissolved in dry dichloromethane (100 mL). This solution was reacted with dry pyridine (9 mL, 113 mmol) and dry isopropanol (40 mL, 522 mmol) for 88 h. The solvents were removed in vacuo and the residue partitioned between sodium bicarbonate (150 mL) and dichloromethane (75 mL). The aqueous layers were extracted with dichloromethane (2*20 mL), and the combined organic layers were washed with sodium bicarbonate (30 mL), brine (30 mL), and dried over anhydrous sodium sulfate. The solvents were removed in vacuo. The residue was purified by column chromatography eluding with hexanes:ethyl acetate 9/1 (v:v) to give isopropyl 4-bromo-5-methylthiophene-2-carboxylate (1.91 g, 32%) as a pale yellow oil. 1H-NMR (DMSO-d6; 300 MHz) delta 7.66 (s, 1H), 5.07 (septet, 1H, J=6.2 Hz), 2.42 (s, 3H), 1.29 (d, 6H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C9H11O2SBr 264.2 (M+H), found 264.8.

Reference： [1]Patent: US2002/37915,2002,A1
[2]Patent: US6291514,2001,B1

27
[ 7311-63-9 ]
[ 29421-99-6 ]
[ 18107-18-1 ]
[ 237385-15-8 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol;	b) Methyl 4-bromo-5-methylthiophene-2-carboxylate A solution of 780 mg (3.5 mmol) of an 85/15 mixture of <strong>[29421-99-6]4-bromo-5-methylthiophene-2-carboxylic acid</strong> and 5-bromothiophene-2-carboxylic acid was dissolved in methanol (50 mL) and treated with 9 ml (18 mmol) 2 M trimethylsilyldiazomethane in hexanes (Aldrich, Milwaukee, Wis., USA). Evaporation of the solvents gave an 8/2 mixture of methyl 4-bromo-5-methylthiophene-2-carboxylate and methyl 5-bromothiophene-2-carboxylate (858 mg, quantitive yield) as a brown oil. Gas Chromotography/Mass spectroscopy (m/z): Calcd. for C7H7O2SBr, 234.9 and 236.9 (M+H), found 235.3 and 237.3. Calcd. for C6H4O2SBr, 220.9 and 222.9 (M+H), found 221.3 and 223.3.
	In methanol;	b) Methyl 4-bromo-5-methylthiophene-2-carboxylate A solution of 780 mg (3.5 mmol) of an 85/15 mixture of <strong>[29421-99-6]4-bromo-5-methylthiophene-2-carboxylic acid</strong> and 5-bromothiophene-2-carboxylic acid was dissolved in methanol (50 mL) and treated with 9 ml (18 mmol) 2 M trimethylsilyldiazomethane in hexanes (Aldrich, Milwaukee, Wis., U.S.A.). Evaporation of the solvents gave an 8/2 mixture of methyl 4-bromo-5-methylthiophene-2-carboxylate and methyl 5-bromothiophene-2-carboxylate (858 mg, quantitive yield) as a brown oil. Gas Chromotography/Mass spectroscopy (m/z): Calcd. for C7H7O2SBr, 234.9 and 236.9 (M+H), found 235.3 and 237.3. Calcd. for C6H4O2SBr, 220.9 and 222.9 (M+H), found 221.3 and 223.3.

Reference： [1]Patent: US2002/37915,2002,A1
[2]Patent: US6291514,2001,B1

28
[ 67-56-1 ]
[ 29421-99-6 ]
[ 237385-15-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	sulfuric acid; at 50℃;	Preparation 3; Preparation of methyl 4-bromo-5-methyl-2-thiophenecarboxylate; A solution of <strong>[29421-99-6]4-bromo-5-methyl-2-thiophenecarboxylic acid</strong> (3 g, 13.6 mmol) in MeOH (67 ml.) and H2SO4 (3 ml.) was stirred at 50 0C. After 12h, the solution was added to ice-H2O and the pH was adjusted to -11. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and used directly yielding the title compound (3 g, 94%) as an orange solid: LCMS (ES) m/z 236 (M+H)+.
94%	With sulfuric acid; at 50℃; for 12h;	A solution of <strong>[29421-99-6]4-bromo-5-methyl-2-thiophenecarboxylic acid</strong> (3 g, 13.6 mmol) in MeOH (67 mL) and H2SO4 (3 mL) was stirred at 50 0C. After 12h, the solution was added to ice-H2O and the pH was adjusted to -1 1. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and used directly yielding the title compound (3 g, 94%) as an orange solid: LCMS (ES) m/z 236 (M+H)+.
	With sulfuric acid;Reflux;	INTERMEDIATE S; Methyl 5-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate; Step 1. Methyl 4-bromo-5-methylthiophene~2-carboxylate; To a stirred solution of <strong>[29421-99-6]4-bromo-5-methylthiophene-2-carboxylic acid</strong> (45 g, 204 mmol) in methanol (225 mL) was added concentrated H2SO4 (4.0 g, 41 mmol). The reaction mixture was heated to reflux overnight, cooled to room temperature, poured into saturated NaHCO3 (800 mL), and left to stir for 30 min. The precipitate was filtered, washed with water, and dried under high- vacuum to afford the title compound. 1H NMR (500 MHz, CDCl3) delta 7.61 (s, 1H); 3.88 (s, 3H); 2.45 (s, 3H). LRMS (APCI) calc'd for (C7H8BrO2S) [M+H]+, 234.9; found 234.9.

Reference： [1]Patent: WO2010/93885,2010,A1 .Location in patent: Page/Page column 37
[2]Patent: WO2008/98104,2008,A1 .Location in patent: Page/Page column 81
[3]Patent: WO2010/83145,2010,A1 .Location in patent: Page/Page column 31

29
[ 1918-79-2 ]
[ 29421-99-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With iron(III) chloride; bromine; In acetic acid; at 25℃; for 5h;	A solution of bromine (725 uL, 14.1 mmol) in AcOH (2.8 ml.) was added dropwise to delta-methyl^-thiophenecarboxylic acid (2 g, 14.1 mmol) and FeCI3 (456 mg, 2.81 mmol) in AcOH (28 ml.) at 25 0C. After 5h, the solution was poured onto ice and the precipitate was filtered and washed with water affording the title compound (3 g, quant.) as a yellow powder: LCMS (ES) m/z 222 (M+H)+.
	With iron(III) chloride; bromine; acetic acid; at 25℃;	Preparation 2; Preparation of 4-bromo-5-methyl-2-thiophenecarboxylic acid; A solution of bromine (725 uL, 14.1 mmol) in AcOH (2.8 ml.) was added dropwise to delta-methyl^-thiophenecarboxylic acid (2 g, 14.1 mmol) and FeCI3 (456 mg, 2.81 mmol) in AcOH (28 ml.) at 25 0C. After 5h, the solution was poured onto ice and the precipitate was filtered and washed with water affording the title compound (3 g, quant.) as a yellow powder: LCMS (ES) m/z 222 (M+H)+.
	With iron(III) chloride; bromine; In acetic acid; at 25℃; for 5h;	To a mixture of 5-methylthiophene-2-carboxylic acid (2 g, 14.1 mmol) and FeCl3 (456 mg, 2.81 mmol) in AcOH (28 mL) was added a solution of Br2 (725 uL, 14.1 mmol) in AcOH (2.8 mL) at 25 C. After 5 h, the mixture was poured into ice and the precipitate was filtered and washed with water affording 4-bromo-5-methylthiophene-2-carboxylic acid (2.7 g, 87 %) as a yellow solid.1H NMR (500 MHz, CDCl3) delta 13.33 (s, 1H), 7.61 (s, 1H), 2.41 (s, 3H). LC-MS m/z: 220.9 [M+H]+. LCMS: Purity (254nm): 92.7%; tR = 1.76 min.

Reference： [1]Patent: WO2008/98104,2008,A1 .Location in patent: Page/Page column 81
[2]Patent: WO2010/93885,2010,A1 .Location in patent: Page/Page column 36-37
[3]Patent: WO2017/176961,2017,A1 .Location in patent: Paragraph 00768

30
[ 1445-45-0 ]
[ 29421-99-6 ]
[ 237385-15-8 ]

Yield	Reaction Conditions	Operation in experiment
	at 100℃; for 0.666667h;Microwave irradiation;	In a 5 mL microwave vial was added <strong>[29421-99-6]4-bromo-5-methyl-2-thiophenecarboxylic acid</strong> (41) (1.03 g, 4.66 mmol) and trimethyl orthoacetate (1.53 ml, 13.98 mmol), neat. The system was heated at 40 min at 100 C. The reaction was then partitioned between water and DCM. The organic was dried over sodium sulfate and concentrated. The crude material 42 was used directly in the next step. MS APCI: [M + H]+ m/z 236.1.
	at 100℃;Microwave irradiation;	Scheme 5.Commercially available <strong>[29421-99-6]4-bromo-5-methyl-2-thiophenecarboxylic acid</strong> 33 (1.03 g, 4.66 mmol) and trimethyl orthoacetate (1.53 ml, 13.98 mmol) were heated at 40 min at 100 C in a microwave reactor to yield ethyl ester 34. Boronic ester 35 was generated via a palladium- mediated coupling with bispinacolatodi boron.

Reference： [1]Patent: WO2009/14620,2009,A1 .Location in patent: Page/Page column 89; 26
[2]Patent: WO2010/17046,2010,A1 .Location in patent: Page/Page column 45

31
[ 1256286-44-8 ]
[ 29421-99-6 ]

Reference： [1]Synthesis,2010,p. 2965 - 2968

32
[ 29421-99-6 ]
4-bromo-5-methylthiophene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.7 g		To a mixture of <strong>[29421-99-6]4-bromo-5-methylthiophene-2-carboxylic acid</strong> (2.21 g, 10 mmol), HOBt (1.49 g, 11 mmol), EDCI (2.11 g, 11 mmol) and DIPEA (1.9 g, 15 mmol) in DMF (10 mL) stirred at RT for 0.5 h was added NH4Cl (1.6 g, 30 mmol). The reaction mixture was stirred at RT for 10 h, and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with NaOH (1N, 40 mL × 3), HCl (1N, 40 mL × 3), and brine (50 mL) and dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo, and the residue was crystallized with Et2O (10 mL) to afford 4-bromo-5-methylthiophene-2-carboxamide (1.7 g, 76%) as a white solid.1H NMR (500 MHz, DMSO-d6) delta 7.96 (s, 1H), 7.69 (s, 1H), 7.50 (s, 1H), 2.38 (s, 3H). LC-MS m/z: 220.0 [M+H]+. LCMS: Purity (254 nm): 96.0%; tR = 1.60 min.

Reference： [1]Patent: WO2017/176961,2017,A1 .Location in patent: Paragraph 00769

33
[ 29421-99-6 ]
4-bromo-5-methylthiophene-2-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2017/176961,2017,A1

34
[ 29421-99-6 ]
[ 1314941-27-9 ]

Reference： [1]Patent: WO2017/176961,2017,A1

35
[ 29421-99-6 ]
C₂₀H₁₈BrF₃N₂O₃S₂ [ No CAS ]

Reference： [1]Patent: CN106317050,2017,A

36
[ 29421-99-6 ]
C₂₀H₁₆BrF₃N₂O₃S₂ [ No CAS ]

Reference： [1]Patent: CN106317050,2017,A

37
[ 29421-99-6 ]
C₂₆H₃₁BrF₃N₃O₂S₂ [ No CAS ]

Reference： [1]Patent: CN106317050,2017,A

38
[ 29421-99-6 ]
C₁₂H₁₁F₃N₂OS [ No CAS ]
C₁₈H₁₄BrF₃N₂O₂S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere;	1.73 g (6 mmol) of the compound (2b), 1.33 g (6 mmol) of the compound (3b), 2.43 g (18 mmol) of HOBT,HBTU 6.83 g (18 mmol) was added to a 100 ml round bottom flask,Under nitrogen, 40 ml of double distilled DMF was added and DIPEA was added8.92 ml (54 mmol), stirred at room temperature for 4 h.After the reaction was completed, the reaction mixture was diluted with 200 ml of ethyl acetate and washed with water (50 ml × 5) to remove DMF. The organic phase was dried over anhydrous Na 2 SO 4 for 1 h,The filtrate was spin-dried to give 2.21 g of a white solid (4b) in 75% yield.

Reference： [1]Patent: CN106317050,2017,A .Location in patent: Paragraph 0052; 0054; 0055

39
[ 29421-99-6 ]
[ 956118-34-6 ]

Reference： [1]Patent: WO2007/124546,2007,A1

40
[ 29421-99-6 ]
4-[3-(butan-2-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl]-N-cyclopropyl-5-methylthiophene-2-carboxamide [ No CAS ]

Reference： [1]ChemMedChem,2019,vol. 14,p. 2093 - 2101

41
[ 29421-99-6 ]
[ 765-30-0 ]
[ 909187-29-7 ]

Reference： [1]ChemMedChem,2019,vol. 14,p. 2093 - 2101

42
[ 29421-99-6 ]
[ 1047629-43-5 ]