[ CAS No. 24287-95-4 ] {[proInfo.proName]}

Name: 24287-95-4|2-Bromothiophene-3-carboxylic acid|96%
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Quality Control of [ 24287-95-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 24287-95-4 ]

Product Details of [ 24287-95-4 ]

CAS No. :	24287-95-4	MDL No. :	MFCD05865213
Formula :	C₅H₃BrO₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RVSXMPCELBYUSF-UHFFFAOYSA-N
M.W :	207.05	Pubchem ID :	12320971
Synonyms :

Calculated chemistry of [ 24287-95-4 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	38.98
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) :	-6.04 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.41
Log Po/w (XLOGP3) :	2.15
Log Po/w (WLOGP) :	2.21
Log Po/w (MLOGP) :	1.35
Log Po/w (SILICOS-IT) :	2.62
Consensus Log Po/w :	1.95

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.82
Solubility :	0.311 mg/ml ; 0.0015 mol/l
Class :	Soluble
Log S (Ali) :	-3.16
Solubility :	0.144 mg/ml ; 0.000694 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.9
Solubility :	2.61 mg/ml ; 0.0126 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.36

Safety of [ 24287-95-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H317-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 24287-95-4 ]

* 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 [ 24287-95-4 ]
Downstream synthetic route of [ 24287-95-4 ]

[ 24287-95-4 ] Synthesis Path-Upstream 1~12

1
[ 67-56-1 ]
[ 24287-95-4 ]
[ 76360-43-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	Reflux	Treat a solution of 2-bromo-3-thiophenecarboxylic acid (10.1 g, 49 mmol) in MeOH (100 mL) with sulfuric acid (2.5 mL, 45 mmol). Heat the reaction to reflux overnight. Concentrate the mixture under reduced pressure to remove the organic solvent and pour the resulting mixture into ice cold water. Extract the cold solution with EtOAc. Wash the combined organic extracts with water followed by a saturated aqueous sodium bicarbonate solution. Dry the organic solution over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to give the title compound 10.77 g (100percent). ¹H NMR (400.15 MHz, DMSO-d₆) δ 7.65 (d, J=6 Hz, 1H), 7.34 (d, J=6 Hz, 1H), 3.78 (s, 3H).
99%	for 6 h; Reflux	12.1 g (58.4 mmol) of Compound 1, 10 mL of concentrated sulfuric acid and 250 mL of methanol were placed in a reaction vessel and refluxed for 6 hours. The obtained reaction solution was poured into water and extracted with toluene. The liquid obtained by concentrating the obtained toluene solution was purified using a silica gel column to obtain Compound 2. [ The yield was 12.8 g and the yield was 99percent.
98%	Stage #1: With oxalyl dichloride In dichloromethane at 20℃; Stage #2: Heating / reflux	Process 10 2-bromo-3-thiophene carboxylic acid (1.0 eq, 12.56 g, 60.66 mmol) was suspended in CH₂Cl₂(200 ml). Oxalyl chloride (1.1 eq, 5.9 ml, 67.16 mmol) and 5 drops of DMF were added, inducing formation of gas. The mixture was stirred overnight at room temperature and the volatiles were removed in vacuo. The resulting solid was suspended in dry methanol (150 ml) and the mixture heated to ebullition. Evaporation of the solvents afforded methyl 2-bromo-3-thiophene carboxylate (13.16 g, 98percent yield) as a crude brown oil. LCMS (ES): 99percent pure, m/z not detected; ¹H NMR (CDCl₃, 400 MHz) δ 3.88 (s, 3H), 7.23 (d, J=5.6, 1H), 7.56 (d, J=5.6, 1H) ppm.

98%	Stage #1: With oxalyl dichloride In dichloromethane at 20℃; Stage #2: Heating	2-bromo-3-thiophene carboxylic acid (1.0 eq, 12.56 g, 60.66 mmol) was suspended in CH₂Cl₂(200 ml). Oxalyl chloride (1.1 eq, 5.9 ml, 67.16 mmol) and 5 drops of DMF were added, inducing formation of gas. The mixture was stirred overnight at room temperature and the volatiles were removed in vacuo. The resulting solid was suspended in dry methanol (150 ml) and the mixture heated to ebullition. Evaporation of the solvents afforded methyl 2-bromo-3-thiophene carboxylate (13.16 g, 98percent yield) as a crude brown oil. LCMS (ES): 99percent pure, m/z not detected; ¹H NMR (CDCl₃, 400 MHz) δ 3.88 (s, 3H), 7.23 (d, J=5.6, 1H), 7.56 (d, J=5.6, 1H) ppm.
71 g	at 20℃; for 3.5 h; Reflux	Treat a solution of 2-bromothiophene-3--carboxylic acid (65 g, 314 mmol) inMeOH (500 rnL) with thionyl chloride (1 3.5 g, i 13 mmoi) at room temperature. Stir the mixture for 30 minutes at room temperature and then heat the mixture to reflux for three hours. Allow the mixture to cool while stirring overnight. Concentrate the reaction mixture under reduced pressure. Add EtOAc and wash the resulting organic solution with saturated aqueous sodium bicarbonate. Separate the layers and back extract the aqueoussolution with additional EtOAc. Combine the organic solutions and thy over anhydroussodium sulfate. Filter the solution and concentrate the filtrate under reduced pressure.Purify the residue by silica gel column chromatography by loading the product onto a 220g pre-coiumn and eluting the pre-column onto a 330 g column with a gradient from 10-25percent EtOAc in DCM. Combine the appropriate fractions and concentrate under reducepressure to give the title compound 71 g. Use the material without further purification.1H NMR (400.15 MHz, DMSO-d6) ö 7.36-7.34 (d,J5.6 Hz, 1H), 7.22-7,20 (d, J5.6 Hz,1H), 3.87 (s, 3H).

Reference： [1] Patent: US2016/176896, 2016, A1, . Location in patent: Paragraph 0071
[2] Patent: KR2015/13550, 2015, A, . Location in patent: Paragraph 0319-0322
[3] Patent: US2009/93465, 2009, A1, . Location in patent: Page/Page column 46
[4] Patent: US2009/239859, 2009, A1, . Location in patent: Page/Page column 90
[5] Patent: WO2011/28827, 2011, A2, . Location in patent: Page/Page column 120
[6] Patent: US2011/230495, 2011, A1, . Location in patent: Page/Page column 37-38
[7] Patent: WO2014/176144, 2014, A1, . Location in patent: Page/Page column 43-44
[8] Patent: WO2015/18027, 2015, A1, . Location in patent: Page/Page column 46; 47
[9] Patent: WO2015/18029, 2015, A1, . Location in patent: Page/Page column 32
[10] Patent: WO2015/20930, 2015, A1, . Location in patent: Page/Page column 37
[11] Patent: WO2015/20933, 2015, A1, . Location in patent: Page/Page column 49
[12] Patent: WO2015/95442, 2015, A1, . Location in patent: Page/Page column 61; 62
[13] Patent: WO2015/95108, 2015, A1, . Location in patent: Page/Page column 45-46
[14] Patent: WO2016/65585, 2016, A1, . Location in patent: Page/Page column 50-51
[15] Patent: WO2016/100157, 2016, A2, . Location in patent: Page/Page column 33
[16] Patent: WO2016/69510, 2016, A1, . Location in patent: Page/Page column 45-46
[17] Patent: WO2016/106009, 2016, A1, . Location in patent: Page/Page column 16; 17
[18] Patent: WO2016/100161, 2016, A1, . Location in patent: Page/Page column 35
[19] Patent: WO2016/101119, 2016, A1, . Location in patent: Page/Page column 38; 39
[20] Patent: WO2016/101118, 2016, A1, . Location in patent: Page/Page column 29
[21] Patent: WO2016/95204, 2016, A1, . Location in patent: Page/Page column 33

2
[ 186581-53-3 ]
[ 24287-95-4 ]
[ 76360-43-5 ]

Reference： [1] Journal of Organic Chemistry, 2002, vol. 67, # 20, p. 6931 - 6937
[2] Journal of Organic Chemistry, 1951, vol. 16, p. 1864,1867

3
[ 24287-95-4 ]
[ 76360-43-5 ]

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 2, p. 635 - 654
[2] Patent: WO2011/25859, 2011, A1,

4
[ 24287-95-4 ]
[ 18107-18-1 ]
[ 76360-43-5 ]

Reference： [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 14, p. 3878 - 3882[2] Angew. Chem., 2013, vol. 125, # 14, p. 4132

5
[ 88-13-1 ]
[ 24287-95-4 ]

Yield	Reaction Conditions	Operation in experiment
66%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: With bromine In tetrahydrofuran; hexane at -78 - 20℃;	An oven-dried 100 mL round bottom flask was charged with compound 1 (2.00 g, 15.6 mmol) and tetrahydrofuran (THF; 30 mL). The solution was cooled to -78.0 °C and 2.50 M n-butyllithium in hexane (12.6 mL, 31.5 mmol) was slowly added dropwise. The reaction mixture was stirred for 30 min at -78.0 °C and bromine (0.86 mL, 16.4 mmol) was added dropwise. Stirring was continued for 1 h at -78.0 °C and the mixture was heated to room temperature. After stirring the mixture overnight, a small amount of dilute 1M HCl (50.0 mL) was added to quench the reaction and the solution was then concentrated. After extracting the resultant mixture using ether and water, the organic layer was dried with Na2SO4. The compound was recrystallized twice using a H2O/ether mixture to furnish the compound as faint yellow needles (2.13 g, yield 66.0percent; 1H NMR (500 MHz, DMSO‑d6, d (ppm)): 7.63-7.62 (d,J 5.8 Hz, 1H), 7.32-7.31 (d, J 5.8 Hz, 1H)).
50%	With carbon tetrabromide; lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2 h;	The reaction temperature was -78 , the reaction time was 2h, the yield was about 50percent. In a 1 L two-necked flask, 24.5 g of 3-methylthiophene (98 g mol-1,24.5 g, 250 mmol) was added and 400 mL of chloroform / glacial acetic acid (V: V = 1: / L,Favoring the inhibition of the bis-brominated product), 44.5 g of NBS (178 g mol-1, 44.5 g, 250 mmol) were added in portions in an ice-water bath.After the addition of NBS to continue stirring for 2-3 hours, TLC monitoring. After treatment: deionized water to quench the reaction, liquid separation, the organic phase was NaOH solution, washed with water, dried, concentrated vacuum pump with fractional distillation.

Reference： [1] Journal of Organic Chemistry, 2002, vol. 67, # 20, p. 6931 - 6937
[2] Polymer, 2018, vol. 146, p. 142 - 150
[3] Patent: CN106588868, 2017, A, . Location in patent: Paragraph 0025-0029; 0043; 0053-0055

6
[ 1860-99-7 ]
[ 24287-95-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	at 50℃; for 2 h;	In a 50 ml pear-shaped flask were placed 8 ml of deionized water, 0.6 g of NaOH (15 mmol) and 1.9 g of 2-bromo-3-thiophenecarboxaldehyde(190 g mol-1, 10 mmol),1.58 g of KMnO4 (158 g mol-1, 10 mmol) and stirred in a 50 ° C water bath for 2 hours.Hot filtration, extraction and separation, the aqueous phase was concentrated hydrochloric acid filtration to obtain a white solid, yield: 70percent.

Reference： [1] Patent: CN106588868, 2017, A, . Location in patent: Paragraph 0025; 0038; 0039; 0040; 0041
[2] Journal of the American Chemical Society, 1949, vol. 71, p. 333
[3] Bulletin de la Societe Chimique de France, 1967, p. 4115 - 4120

7
[ 1860-99-7 ]
[ 7758-19-2 ]
[ 24287-95-4 ]

Reference： [1] Patent: US5840917, 1998, A,

8
[ 616-44-4 ]
[ 24287-95-4 ]

Reference： [1] Patent: CN106588868, 2017, A,

9
[ 14282-76-9 ]
[ 24287-95-4 ]

Reference： [1] Patent: CN106588868, 2017, A,

10
[ 40032-76-6 ]
[ 24287-95-4 ]

Reference： [1] Patent: CN106588868, 2017, A,

11
[ 3199-44-8 ]
[ 24287-95-4 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1967, p. 4115 - 4120

12
[ 24287-95-4 ]
[ 75-65-0 ]
[ 21483-64-7 ]

Yield	Reaction Conditions	Operation in experiment
68%	at 65℃; for 4 h; Inert atmosphere	tert-Butyl 2-bromothiophen-3-ylcarbamate A round bottomed flask was charged with 2-bromothiophene-3-carboxylic acid (15.0 g, 72.4 mmol) and tert-butanol (188 mL). The suspension was placed under a nitrogen atmosphere and TEA (10.1 mL, 72.4 mmol) was added followed by diphenyl phosphoryl azide (14.2 mL, 65.9 mmol). The resulting mixture was heated to about 65° C. for about 4 h. The reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The remaining residue was purified by flash column chromatography on silica gel eluting with a gradient of 1-5percent EtOAc in heptane. The solvent was removed under reduced pressure to give tert-butyl 2-bromothiophen-3-ylcarbamate (12.4 g, 68percent yield): LC/MS (Table 1, Method a) R_t=2.46 min; MS m/z: 278 (M+H)⁺.

Reference： [1] Patent: US2011/152243, 2011, A1, . Location in patent: Page/Page column 45

[ 24287-95-4 ] Synthesis Path-Downstream 1~88

1
[ 24287-95-4 ]
[ 536-74-3 ]
6-phenyl-7-phenyl-ethyl-thieno[3,2-c]pyran-4-one [ No CAS ]
[ 886-66-8 ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 9554 - 9570

2
[ 24287-95-4 ]
[ 115-19-5 ]
6-(1-hydroxy-1-methyl-ethyl)-thieno[3,2-c]pyran-4-one [ No CAS ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 9554 - 9570

3
[ 24287-95-4 ]
[ 115-19-5 ]
6-(1-hydroxy-1-methyl-ethyl)-thieno[3,2-c]pyran-4-one [ No CAS ]
6-(1-hydroxy-1-methyl-ethyl)-7-(3-hydroxy-3-methyl-but-1-ynyl)-thieno[3,2-c]pyran-4-one [ No CAS ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 9554 - 9570

4
[ 24287-95-4 ]
[ 927-74-2 ]
6-(2-hydroxy-ethyl)-7-(4-hydroxy-but-1-ynyl)-thieno[3,2-c]pyran-4-one [ No CAS ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 9554 - 9570

5
[ 24287-95-4 ]
(2-bromo-3-thienyl)(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)methanone [ No CAS ]

Reference： [1]Molecules,2007,vol. 12,p. 60 - 73

6
[ 24287-95-4 ]
3-methyl-1-phenylthieno[3',2':5,6]pyrano[2,3-c]pyrazol-4(1H)-one [ No CAS ]

Reference： [1]Molecules,2007,vol. 12,p. 60 - 73

7
[ 24287-95-4 ]
octyl 2-bromothiophene-3-carboxylate [ No CAS ]

Reference： [1]Synthesis,2003,p. 2255 - 2258

8
[ 24287-95-4 ]
[ 91570-39-7 ]

Reference： [1]Journal of Organic Chemistry,2002,vol. 67,p. 6931 - 6937
[2]Journal of Organic Chemistry,1951,vol. 16,p. 1864,1867

9
[ 24287-95-4 ]
(2-Bromo-thiophen-3-yl)-(4-butyl-phenyl)-methanone [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1997,vol. 119,p. 9624 - 9631

10
[ 24287-95-4 ]
C₃₄H₃₀N₂S₃ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1997,vol. 119,p. 9624 - 9631

11
[ 24287-95-4 ]
[4'-tert-Butoxycarbonylamino-3,3''-bis-(4-butyl-benzoyl)-[2,2';5',2'']terthiophen-3'-yl]-carbamic acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1997,vol. 119,p. 9624 - 9631

12
[ 24287-95-4 ]
[ 19690-71-2 ]

Reference： [1]Journal of Organic Chemistry,1951,vol. 16,p. 1864,1867

13
[ 24287-95-4 ]
2-(2-methyl-6-nitro-phenyl)-thiophene-3-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1951,vol. 16,p. 1864,1867

14
[ 24287-95-4 ]
2-(2-methyl-6-nitro-phenyl)-thiophene-3-carboxylic acid amide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1951,vol. 16,p. 1864,1867

15
[ 24287-95-4 ]
[ 859492-59-4 ]

Reference： [1]Journal of Organic Chemistry,1951,vol. 16,p. 1864,1867

16
[ 3199-44-8 ]
[ 24287-95-4 ]

Reference： [1]Bulletin de la Societe Chimique de France,1967,p. 4115 - 4120

17
[ 24287-95-4 ]
[ 74-88-4 ]
[ 683251-61-8 ]

Yield	Reaction Conditions	Operation in experiment
85.1%	With potassium carbonate; at 20℃;	(1) A suspension of compound 1 (25.6 g, 116 mmol: Tetrahedron, 2000, 56, 7205), iodomethane (11.0 ml, 0.177 mmol) and potassium carbonate (24.0 g, 0.174 mmol) was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to give compound 2 (23.17 g, 85.1%) as an oily substance. MS·APCI (m/z): 252/254 ([M+NH4]+)

Reference： [1]Patent: US2006/135597,2006,A1 .Location in patent: Page/Page column 16

18
[ 1860-99-7 ]
[ 7758-19-2 ]
sodium dihydrogen phosphate [ No CAS ]
[ 24287-95-4 ]

Yield	Reaction Conditions	Operation in experiment
	With dihydrogen peroxide; In water; acetonitrile;	The crude product of 2-bromo-3-thiophenecarbaldehyde was dissolved in acetonitrile (50 ml), and sodium dihydrogen phosphate (1.0 g) in water (15 ml) and 30percent aqueous hydrogen peroxide (2.5 ml) were added. Further, sodium chlorite (2.7 g) in water (30 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide (2.7 g) and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-bromo-3-thiophenecarboxylic acid (2.89 g) as crystals. mp 151°-154° C.

Reference： [1]Patent: US5840917,1998,A

19
[ 24287-95-4 ]
[ 95-55-6 ]
N-(2-hydroxyphenyl)-5-bromo-3-thiophenecarboxamide [ No CAS ]
N-(2-hydroxyphenyl)-2-bromo-3-thiophenecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine; thionyl chloride; ethyl acetate; toluene;	STARTING MATERIAL SYNTHESIS EXAMPLE 68 2-Bromo-3-thiophenecarboxylic acid (30 g) was suspended in thionyl chloride (35 ml) and the mixture was stirred under reflux with heating for 1 hour. Thionyl chloride was evaporated under reduced pressure and the residue was dissolved in toluene (10 ml). This toluene solution was added dropwise to a solution of 2-aminophenol (19 g) in pyridine (100 ml) at 0 C. The mixture was stirred at room temperature for 20 minutes and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. This solution was washed with diluted hydrochloric acid and saturated aqueous sodium hydrogencarbonate solution, and the precipitated crystals were collected by filtration to give N-(2-hydroxyphenyl)-5-bromo-3-thiophenecarboxamide (21 g). The filtrate was concentrated and the precipitated crystals were collected by filtration to give N-(2-hydroxyphenyl)-2-bromo-3-thiophenecarboxamide (10 g). 1H-NMR(400 MHz, DMSO-d6) delta 6.82(1H, t, J=7.8 Hz, ArH), 6.91(1H, d, J=8.3 Hz, ArH), 7.00(1H, t, J=7.8 Hz, ArH), 7.40(1H, d, J=5.3 Hz, H of thiophene ring), 7.68(1H, d, J=5.9 Hz, H of thiophene ring), 7.81(1H, d, J=7.8 Hz, ArH), 9.30(1H, br, NH or OH), 9.87(1H, br, NH or OH).

Reference： [1]Patent: US6271225,2001,B1

20
[ 24287-95-4 ]
[ 50326-04-0 ]
2-bromo-N-[2-(4-chlorophenyl)-1-methylethyl]-N-cyclopropylthiophene-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine;benzotriazol-1-ol; In dichloromethane; at 20℃; for 49h;Heating / reflux;	300mg of N-[2-(4-chlorophenyl)-1-methylethyl]cyclopropanamine hydrochloride (1.218mmol), 265mg of <strong>[24287-95-4]2-bromothiophene-3-carboxylic acid</strong> (1.28mmol), 16mg of 1-hydroxybenzotriazole (0.12mmol), 256mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.34mmol) and 0.171ml of TEA (1.22mmol) are refluxed in 10ml of dichloromethane for one hour. After 48 hours at room temperature, the reaction is quenched with 5 ml of HCl 0.5M. After separation, the organic phase is washed with 5 ml of water and 5ml of a saturated solution of sodium bicarbonate, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product is flash-chromatographed on silica with heptane/EtOAc to yield to 190 mg of 2-bromo-N-[2-(4-chlorophenyl)-1-methylethyl]-N-cyclopropylthiophene-3-carboxamide (yield = 39%). [M+1]=399.

Reference： [1]Patent: EP1792901,2007,A1 .Location in patent: Page/Page column 29

21
[ 24287-95-4 ]
[ 17933-03-8 ]
[ 1108172-92-4 ]

Yield	Reaction Conditions	Operation in experiment
58%		A.4 Synthesis of 2-m-tolyl-thiophene-3-carboxylic acidA mixture of <strong>[24287-95-4]2-bromo-3-thiophenecarboxylic acid</strong> (1 g), 3-tolyl-boronic acid (656.65 mg), Pd(PPh3)4 (162.5 mg), aq 2M K2CO3 (11.7 mL) in a mixture of iPrOH (10 ml.) and toluene (10 mL ) was stirred at 800C under nitrogen for 5h. After cooling to rt, the reaction mixture was diluted with ether, washed with 2M NaOH. The aq. phase was acidified with 2N HCI until pH 1. The resulting white precipitate was filtered off, washed with cold water and dried in vacuo to yield the title compound (0.59 g, 58%) as a white solid. LC-MS: tR = 0.51 min; [M+H]+ = 218.99.
58%		A mixture of <strong>[24287-95-4]2-bromo-3-thiophenecarboxylic acid</strong> (1 g), 3-tolyl-boronic acid (656.65 mg), Pd(PPh3)4 (162.5 mg), aq 2M K2CO3 (11.7 mL) in a mixture of iPrOH (10 mL) and toluene (10 mL) was stirred at 80 C. under nitrogen for 5 h. After cooling to rt, the reaction mixture was diluted with ether, washed with 2M NaOH. The aq. phase was acidified with 2N HCl until pH 1. The resulting white precipitate was filtered off, washed with cold water and dried in vacuo to yield the title compound (0.59 g, 58%) as a white solid. LC-MS: tR=0.51 min; [M+H]+=218.99.

Reference： [1]Patent: WO2010/4507,2010,A1 .Location in patent: Page/Page column 65
[2]Patent: US2011/105491,2011,A1 .Location in patent: Page/Page column 32
[3]Patent: WO2009/16560,2009,A2 .Location in patent: Page/Page column 90

22
[ 67-56-1 ]
[ 24287-95-4 ]
[ 76360-43-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sulfuric acid;Reflux;	Treat a solution of <strong>[24287-95-4]2-bromo-3-thiophenecarboxylic acid</strong> (10.1 g, 49 mmol) in MeOH (100 mL) with sulfuric acid (2.5 mL, 45 mmol). Heat the reaction to reflux overnight. Concentrate the mixture under reduced pressure to remove the organic solvent and pour the resulting mixture into ice cold water. Extract the cold solution with EtOAc. Wash the combined organic extracts with water followed by a saturated aqueous sodium bicarbonate solution. Dry the organic solution over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure to give the title compound 10.77 g (100%). 1H NMR (400.15 MHz, DMSO-d6) delta 7.65 (d, J=6 Hz, 1H), 7.34 (d, J=6 Hz, 1H), 3.78 (s, 3H).
99%	With sulfuric acid; for 6.0h;Reflux;	12.1 g (58.4 mmol) of Compound 1, 10 mL of concentrated sulfuric acid and 250 mL of methanol were placed in a reaction vessel and refluxed for 6 hours. The obtained reaction solution was poured into water and extracted with toluene. The liquid obtained by concentrating the obtained toluene solution was purified using a silica gel column to obtain Compound 2. [ The yield was 12.8 g and the yield was 99%.
98%		Process 10 <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.0 eq, 12.56 g, 60.66 mmol) was suspended in CH2Cl2 (200 ml). Oxalyl chloride (1.1 eq, 5.9 ml, 67.16 mmol) and 5 drops of DMF were added, inducing formation of gas. The mixture was stirred overnight at room temperature and the volatiles were removed in vacuo. The resulting solid was suspended in dry methanol (150 ml) and the mixture heated to ebullition. Evaporation of the solvents afforded methyl 2-bromo-3-thiophene carboxylate (13.16 g, 98% yield) as a crude brown oil. LCMS (ES): 99% pure, m/z not detected; 1H NMR (CDCl3, 400 MHz) delta 3.88 (s, 3H), 7.23 (d, J=5.6, 1H), 7.56 (d, J=5.6, 1H) ppm.

98%		<strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.0 eq, 12.56 g, 60.66 mmol) was suspended in CH2Cl2 (200 ml). Oxalyl chloride (1.1 eq, 5.9 ml, 67.16 mmol) and 5 drops of DMF were added, inducing formation of gas. The mixture was stirred overnight at room temperature and the volatiles were removed in vacuo. The resulting solid was suspended in dry methanol (150 ml) and the mixture heated to ebullition. Evaporation of the solvents afforded methyl 2-bromo-3-thiophene carboxylate (13.16 g, 98% yield) as a crude brown oil. LCMS (ES): 99% pure, m/z not detected; 1H NMR (CDCl3, 400 MHz) delta 3.88 (s, 3H), 7.23 (d, J=5.6, 1H), 7.56 (d, J=5.6, 1H) ppm.
93.6%		To the solution of 2-bromo-3-thiophenic acid (5.0 g, 24.1 mmol) in dichloromethane (50 mL)) was slowly added dropwise oxalyl chloride (2.5 mL, 29.5 mmol) under ice-cooling, and the reaction mixture was at room temperature. Stir overnight. The solvent was removed by concentration, and the residue was dissolved in methanol (50 mL) and heated under reflux for 4 hours.The mixture was concentrated in vacuo to give Compound 2 (5.2 g, yield: 93.6%) as a yellow oil.
91%	With sulfuric acid;	Thiophene-2-bromo-3-carboxylic acid (10 g, 45 mmol) was placed in a 3 dry 3 -neck round bottom flask equipped with an argon inlet and a water condenser. Dry methanol (100 mL) was added to the flask along with a catalytic amount of cc. sulfuric acid (1 mL). The reaction completion was determined by taking aliquot for NMR analysis. When complete, the reaction was cooled to room temperature. The methanol was evaporated and the resulting product was purified via column chromatography, using a 100% hexane to 60%> hexane/ 40%> ethyl acetate gradient to yield clear slightly yellow oil (9 g, 91 >).Spectral data: 1H NMR (CDCI3, 300 MHz): deltaH3.89 (s, 3H), 7.23 (d, 5.76), 7.36 (d, 5.78Hz). 13C NMR (CDCI3, 75 MHz): delta 52.13, 120.15, 126.09, 129.48, 131.07, 162.61.
	With thionyl chloride; at 20℃; for 48.0h;Inert atmosphere;	Preparation 10 4-(3-Hydroxymethylthiophen-2-yl)piperidine-1-carboxylic Acid t-Butyl Ester 2-Bromothiophene-3-carboxylic acid (5.0 g, 24 mmol, 1 eq.) was dissolved in MeOH (100 mL) and the mixture was degassed and purged with nitrogen (2*). SOCl2 (15 mL, 0.2 mol, 8.3 eq.) was added dropwise and the resulting mixture was stirred for two days at room temperature. The mixture was then concentrated and DCM (150 mL) was added. Saturated NaHCO3 (20 mL) was added, and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was washed with saturated NaHCO3 (20 mL), water (20 mL), and saturated aqueous NaCl (20 mL), then dried over Na2SO4, filtered and concentrated to yield <strong>[24287-95-4]2-bromothiophene-3-carboxylic acid</strong> methyl ester (5.1 g) as a yellow oil.
	With hydrogenchloride; at 0 - 60℃;	Example 19 Step 1 : Potassium 2-(pyrimidin-2-yl)thiophene-3-carboxylate (11) A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2 mmol) in methanol (50 mL) was cooled to 0 C and saturated with gaseous HCl. The solution was heated to 60 C overnight, then concentrated in vacuo. The residue was redissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated, providing methyl 2-bromothiophene-3-carboxylate as yellow oil. LRMS m/z (M+H) 221.1 found, 221.0 required. A solution of methyl 2-bromothiophene-3-carboxylate (1.74 g, 7.87 mmol), 2-(tributylstannyl)pyrimidine (4.36 g, 11.81 mmol), cesium fluoride (4.78 g, 31.5 mmol), and copper(I) iodide (0.450 g, 2.36 mmol) in DMF (16 mL) in a pressure vessel was purged subsurface with nitrogen and treated with palladium tetrakis (0.455 g, 0.394 mmol). The mixture was sealed and heated at 120 C overnight. The reaction was partitioned between ethyl acetate and water and filtered through celite. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel gradient chromatography (0-30% ethyl acetate in hexanes), providing methyl 2-(pyrimidin-2-yl)thiophene-3-carboxylate as a yellow solid. LRMS m/z (M+H) 221.2 found, 221.1 required. A solution of methyl 2-(pyrimidin-2-yl)thiophene-3- carboxylate (0.695 g, 3.16 mmol) and potassium trimethylsilanolate (0.506 g, 3.94 mmol) in THF (16 mL) was stirred at RT overnight, then diluted with ether and filtered through a glass frit. The solids were washed with ether, and the filtrate was concentrated, providing the title compound as a beige solid. LRMS m/z (M+H) 207.3 found, 207.1 required.
	With hydrogenchloride; at 0 - 60℃;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2 mmol) in methanol (50 mL) was cooled to 0C and saturated with gaseous HCl. The solution was heated to 60C overnight, cooled and then concentrated in vacuo. The residue was redissolved in EtOAc, washed with saturated aqueous sodium bicarbonate and brine, dried over Na2SO4, filtered, and concentrated in vacuo, providing methyl 2-bromothiophene-3-carboxylate as yellow oil. LRMS m/z (M+H) 221.1 found, 221.0 required.
	With hydrogenchloride; at 0 - 60℃;	A solution of<strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2 mmol) inmethanol (50 mL) was cooled to 0 oc and saturated with gaseous HCl. The solution was heatedto 60 oc overnight, cooled and then concentrated in vacuo. The residue was redissolved inEtOAc, washed with saturated aqueous sodium bicarbonate and brine, dried over Na2S04,15 filtered, and concentrated in vacuo, providing methyl2-bromothiophene-3-carboxylate as yellowoil. LRMS m/z (M+H) 221.1 found, 221.0 required.
	With hydrogenchloride; at 0 - 60℃;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2 mmol) in methanol (50 mL) was cooled to 0 C and saturated with gaseous HCl. The solution was heated to 60 C overnight, cooled and then concentrated in vacuo. The residue was redissolved in EtOAc, washed with saturated aqueous sodium bicarbonate and brine, dried over Na2SO4, filtered, and concentrated in vacuo, providing methyl 2-bromothiophene-3-carboxylate as yellow oil. LRMS m/z (M+H) 221.1 found, 221.0 required.
	With hydrogenchloride; at 0 - 60℃;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2 mmol) in methanol (50 mL) was cooled to 0C and saturated with gaseous HC1. The solution was heated to 60C overnight, cooled and then concentrated in vacuo. The residue was redissolved in EtOAc, washed with saturated aqueous sodium bicarbonate and brine, dried over Na2SC>4, filtered, and concentrated in vacuo, providing methyl 2-bromothiophene-3-carboxylate as yellow oil. LRMS m/z (M+H) 221.1 found, 221.0 required.
	With hydrogenchloride; at 0 - 60℃;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2 mmol) in methanol (50 mL) was cooled to 0 C and saturated with gaseous HC1. The solution was heated to 60 C overnight, then concentrated in vacuo. The residue was redissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated, providing methyl 2-bromothiophene-3-carboxylate as yellow oil. LRMS m/z (M+H) 221.1 found, 221.0 required. A solution of methyl 2-bromothiophene-3-carboxylate (1.74 g, 7.87 mmol), 2-(tributylstannyl)pyrimidine (4.36 g, 11.81 mmol), cesium fluoride (4.78 g, 31.5 mmol), and copper(I) iodide (0.450 g, 2.36 mmol) in DMF (16 mL) in a pressure vessel was purged subsurface with nitrogen and treated with palladium tetrakis (0.455 g, 0.394 mmol). The mixture was sealed and heated at 120 C overnight. The reaction was partitioned between ethyl acetate and water and filtered through celite. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel gradient chromatography (0-30% ethyl acetate in hexanes), providing methyl 2- (pyrimidin-2-yl)thiophene-3-carboxylate as a yellow solid. LRMS m/z (M+H) 221.2 found, 221.1 required. A solution of methyl 2-(pyrimidin-2-yl)thiophene-3-carboxylate (0.695 g, 3.16 mmol) and potassium trimethylsilanolate (0.506 g, 3.94 mmol) in THF (16 mL) was stirred at RT overnight, then diluted with ether and filtered through a glass frit. The solids were washed with ether, and the filtrate was concentrated, providing the title compound as a beige solid. LRMS m/z (M+H) 207.3 found, 207.1 required.
	With hydrogenchloride; at 0 - 60℃;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2 mmol) in methanol (50 mL) was cooled to 0 C and saturated with gaseous HCI. The solution was heated to 60 C overnight, then concentrated in vacuo. The residue was redissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated, providing methyl 2-bromothiophene-3-carboxylate as yellow oil. LRMS m/z (M+H) 221.1 found, 221.0 required. A solution of methyl 2-bromothiophene-3-carboxylate (1.74 g, 7.87 mmol), 2-(tributylstannyl)pyrimidine (4.36 g, 11.81 mmol), cesium fluoride (4.78 g, 31.5 mmol), and copper(I) iodide (0.450 g, 2.36 mmol) in DMF (16 mL) in a pressure vessel was purged subsurface with nitrogen and treated with palladium tetrakis (0.455 g, 0.394 mmol). The mixture was sealed and heated at 120 C overnight. The reaction was partitioned between ethyl acetate and water and filtered through celite. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel gradient chromatography (0-30% ethyl acetate in hexanes), providing methyl 2-(pyrimidin-2-yl)thiophene-3-carboxylate as a yellow solid. LRMS m/z (M+H) 221.2 found, 221.1 required. A solution of methyl 2-(pyrimidin-2-yl)thiophene-3-carboxylate (0.695 g, 3.16 mmol) and potassium trimethylsilanolate (0.506 g, 3.94 mmol) in THF (16 mL) was stirred at RT overnight, then diluted with ether and filtered through a glass frit. The solids were washed with ether, and the filtrate was concentrated, providing the title compound as a beige solid. LRMS m/z (M+H) 207.3 found, 207.1 required.
	With hydrogenchloride; at 0 - 60℃;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2mmol) in methanol (50 mL) was cooled to 0C and saturated with gaseous HCI. The solution was heated to 60C overnight, then concentrated in vacuo. The residue was redissolved in EtOAc, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated, providing methyl 2-bromothiophene-3-carboxylate as an oil. LRMS m/z (M+H) 221.1, found, 221.0 required.
	With hydrogenchloride; at 0 - 60℃;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2 mmol) in methanol (50 mL) was cooled to 0 C and saturated with gaseous HC1. The solution was heated to 60 C overnight, cooled and then concentrated in vacuo. The residue was re-dissolved in EtOAc, washed with saturated aqueous sodium bicarbonate and brine, dried over Na2SO4,filtered, and concentrated in vacuo to provide the title compound. LRMS m/z (M+H) 221.1 found, 221.0 required.
	With hydrogenchloride; at 0 - 60℃;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2 mmol) in MeOH (50 mL) was cooled to 0C and saturated with gaseous HCI. The solution was heated to 60C overnight, then concentrated in vacuo. The residue was redissolved in EtOAc, washed with saturated, aqueous NaHCCh and brine, dried over sodium sulfate, filtered, and concentrated, providing methyl 2-bromothiophene-3-carboxylate as an oil. LRMS m/z (M+H) 221.1 found, 221.0 required. A solution of methyl 2-bromothiophene-3-carboxylate (1.74 g, 7.87 mmol), 2- (tributylstannyl)pyrimidine (4.36 g, 1 1.81 mmol), cesium fluoride (4.78 g, 31.5 mmol), and copper(I) iodide (0.450 g, 2.36 mmol) in DMF (16 mL) in a pressure vessel was purged subsurface with nitrogen and treated with palladium tetrakis (0.455 g, 0.394 mmol). The mixture was sealed and heated at 120C overnight. The reaction was partitioned between EtOAc and water and filtered through celite. The organic layer was washed with saturated, aqueous aHC03 and brine, dried over MgS04, filtered, and concentrated. The residue was purified by silica gel gradient chromatography (0-30% EtOAc in hexanes), providing methyl 2-(pyrimidin- 2-yl)thiophene-3-carboxylate as a solid. LRMS m/z (M+H) 221.2 found, 221.1 required. A solution of methyl 2-(pyrimidin-2-yl)thiophene-3-carboxylate (0.695 g, 3.16 mmol) and potassium trimethylsilanolate (0.506 g, 3.94 mmol) in THF (16 mL) was stirred at RT overnight, then diluted with ether and filtered through a glass frit. The solids were washed with ether, and the filtrate was concentrated, providing the title compound as a solid. LRMS m/z (M+H) 207.3 found, 207.1 required.
71 g	With thionyl chloride; at 20℃; for 3.5h;Reflux;	Treat a solution of 2-bromothiophene-3--carboxylic acid (65 g, 314 mmol) inMeOH (500 rnL) with thionyl chloride (1 3.5 g, i 13 mmoi) at room temperature. Stir the mixture for 30 minutes at room temperature and then heat the mixture to reflux for three hours. Allow the mixture to cool while stirring overnight. Concentrate the reaction mixture under reduced pressure. Add EtOAc and wash the resulting organic solution with saturated aqueous sodium bicarbonate. Separate the layers and back extract the aqueoussolution with additional EtOAc. Combine the organic solutions and thy over anhydroussodium sulfate. Filter the solution and concentrate the filtrate under reduced pressure.Purify the residue by silica gel column chromatography by loading the product onto a 220g pre-coiumn and eluting the pre-column onto a 330 g column with a gradient from 10-25% EtOAc in DCM. Combine the appropriate fractions and concentrate under reducepressure to give the title compound 71 g. Use the material without further purification.1H NMR (400.15 MHz, DMSO-d6) oe 7.36-7.34 (d,J5.6 Hz, 1H), 7.22-7,20 (d, J5.6 Hz,1H), 3.87 (s, 3H).
	With hydrogenchloride; at 0 - 60℃;	Intermediate E Step 1: Methyl 2-bromothiophene-3-carboxylate (El) A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2 mmol) in methanol (50 mL) was cooled to 0 C and saturated with gaseous HCl. The solution was heated to 60 C overnight, cooled and then concentrated in vacuo. The residue was re-dissolved in EtOAc, washed with saturated aqueous sodium bicarbonate and brine, dried over Na2SC>4, filtered, and concentrated in vacuo to provide the title compound. LRMS m/z (M+H) 221.1 found, 221.0 required.
	With hydrogenchloride; at 0 - 60℃;	A solution of 2.-brorno34hiophene carhoxylic acid (3,35 g, 16.2 mrnol) in methanol (50 mL) was cooling to () 0Q and saturated with gaseous HCI. The solution was heated to 60 C overnight, then concenirated in vacuo. The residue was redissoived in EtOAc, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium suifale, filtered, and concentrated, providing methyl 2-hrornothiophene-3carboxy1ate as yellow oil. LRMS m/z(M+H) 221.1 found, 221.0 required.
	With hydrogenchloride; at 60℃;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2 mmol) in methanol (50 mL) was cooled to 0 and saturated with gaseous HCl. The solution was heated at 60 overnight, then concentrated in vacuo. The residue was redissolved in EtOAc, washed with saturated, aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo, providing methyl 2-bromothiophene-3-carboxylate as a oil. LRMS m/z (M+H) 221.1 found, 221.0 required. A solution of methyl 2-bromothiophene-3-carboxylate (1.74 g, 7.87 mmol) , 2- (tributylstannyl) pyrimidine (4.36 g, 11.81 mmol) , cesium fluoride (4.78 g, 31.5 mmol) , and copper (I) iodide (0.450 g, 2.36 mmol) in DMF (16 mL) in a pressure vessel was purged subsurface with nitrogen and treated with palladium tetrakis (0.455 g, 0.394 mmol) . The mixture was sealed and heated at 120 overnight. The reaction was partitioned between EtOAc and water and filtered through celite. The organic layer was washed with saturated, aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-30EtOAc in hexanes) , providing methyl 2- (pyrimidin-2-yl) thiophene-3-carboxylate as a solid. LRMS m/z (M+H) 221.2 found, 221.1 required. A solution of methyl 2- (pyrimidin-2-yl) thiophene-3-carboxylate (0.695 g, 3.16 mmol) and potassium trimethylsilanolate (0.506 g, 3.94 mmol) in THF (16 mL) was stirred at RT overnight, then diluted with ether and filtered through a glass frit. The solids were washed with ether and concentrated, providing the title compound as a solid.
	With hydrogenchloride; at 0 - 60℃;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (3.35 g, 16.2 rnmol) in methanol (50 mL) was cooled to 0 DC and saturated with gaseous HC1. The solution was heatedto 60 C overnight, then concentrated in vacuo. The residue was redissoived in EtOAc. washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated, providing methyl 2-bromothiophene-3-carboxylate as an oil. LRIVIS niz (M+m 221.1 found, 221.0 required.

Reference： [1]Patent: US2016/176896,2016,A1 .Location in patent: Paragraph 0071
[2]Patent: KR2015/13550,2015,A .Location in patent: Paragraph 0319-0322
[3]Patent: US2009/93465,2009,A1 .Location in patent: Page/Page column 46
[4]Patent: US2009/239859,2009,A1 .Location in patent: Page/Page column 90
[5]Patent: CN110511220,2019,A .Location in patent: Paragraph 0220-0224
[6]Patent: WO2011/28827,2011,A2 .Location in patent: Page/Page column 120
[7]Patent: US2011/230495,2011,A1 .Location in patent: Page/Page column 37-38
[8]Patent: WO2014/176144,2014,A1 .Location in patent: Page/Page column 43-44
[9]Patent: WO2015/18027,2015,A1 .Location in patent: Page/Page column 46; 47
[10]Patent: WO2015/18029,2015,A1 .Location in patent: Page/Page column 32
[11]Patent: WO2015/20930,2015,A1 .Location in patent: Page/Page column 37
[12]Patent: WO2015/20933,2015,A1 .Location in patent: Page/Page column 49
[13]Patent: WO2015/95442,2015,A1 .Location in patent: Page/Page column 61; 62
[14]Patent: WO2015/95108,2015,A1 .Location in patent: Page/Page column 45-46
[15]Patent: WO2016/65585,2016,A1 .Location in patent: Page/Page column 50-51
[16]Patent: WO2016/100157,2016,A2 .Location in patent: Page/Page column 33
[17]Patent: WO2016/69510,2016,A1 .Location in patent: Page/Page column 45-46
[18]Patent: WO2016/106009,2016,A1 .Location in patent: Page/Page column 16; 17
[19]Patent: WO2016/100161,2016,A1 .Location in patent: Page/Page column 35
[20]Patent: WO2016/101119,2016,A1 .Location in patent: Page/Page column 38; 39
[21]Patent: WO2016/101118,2016,A1 .Location in patent: Page/Page column 29
[22]Patent: WO2016/95204,2016,A1 .Location in patent: Page/Page column 33

23
[ 24287-95-4 ]
[ 1619-34-7 ]
[ 1047675-19-3 ]

Yield	Reaction Conditions	Operation in experiment
		Production Example 7; To a solution of <strong>[24287-95-4]2-bromothiophene-3-carboxylic acid</strong> and TEA in toluene was added dropwise a solution of DPPA in toluene. The reaction liquid was stirred at room temperature for 40 minutes, and then stirred at 90C for 60 minutes. To this solution was added a solution of 3-quiclidinole in DMF, followed by heating under reflux for 15 hours. To the reaction liquid was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH) to obtain 1-azabicyclo[2.2.2]oct-3-yl(2-bromo-3-thienyl)carbamate as a pale brown solid.

Reference： [1]Patent: EP2119716,2009,A1 .Location in patent: Page/Page column 20

24
[ 24287-95-4 ]
[ 141-97-9 ]
[ 1233478-90-4 ]

Yield	Reaction Conditions	Operation in experiment
99%		2-(2-Ethoxy-2-oxoethyl)thiophene-3-carboxylic acid (31): Sodium (1.31 gm, 57 mmol) was placed in a oven dried flask & anhydrous ethanol (75 ml) was added slowly to keep the temperature between 40 - 50 0C. After 1 hr, sodium was completely dissolved. Ethyl acetoacetate (4.55 ml, 36 mmol) was added to the cold solution of sodium ethoxide. The reaction mixture was stirred for 5 min and then treated with <strong>[24287-95-4]2-bromo-thiophene 3-carboxylic acid</strong> (30) (5 gm, 24 mmol) and copper (247 mg, 3.9 mmol). The combined reaction mixture was refluxed for 13 hr. It was poured on water and the suspension was filtered. The pH was adjusted from 11.0 to 3 using concentrated HCl. Solid was filtered, washed with water and dried to give desired product (31) (5.1 gm, 99%). (23)

Reference： [1]Patent: WO2010/77663,2010,A2 .Location in patent: Page/Page column 77; 88

25
[ 24287-95-4 ]
[ 76360-43-5 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 635 - 654
[2]Patent: WO2011/25859,2011,A1

26
[ 24287-95-4 ]
dimethyl 2,2'-(thieno[3,2-b]thiophene-2,5-diyl)bis(thiophene-3-carboxylate) [ No CAS ]

Reference： [1]Patent: WO2011/28827,2011,A2

27
[ 24287-95-4 ]
[ 923980-65-8 ]

Reference： [1]Patent: US2011/112086,2011,A1

28
[ 24287-95-4 ]
[ 960202-50-0 ]

Reference： [1]Patent: US2011/112086,2011,A1

29
[ 24287-95-4 ]
[ 960202-51-1 ]

Reference： [1]Patent: US2011/112086,2011,A1

30
[ 24287-95-4 ]
[ 75-65-0 ]
[ 21483-64-7 ]

Yield	Reaction Conditions	Operation in experiment
68%	With diphenyl phosphoryl azide; triethylamine; at 65℃; for 4h;Inert atmosphere;	tert-Butyl 2-bromothiophen-3-ylcarbamate A round bottomed flask was charged with <strong>[24287-95-4]2-bromothiophene-3-carboxylic acid</strong> (15.0 g, 72.4 mmol) and tert-butanol (188 mL). The suspension was placed under a nitrogen atmosphere and TEA (10.1 mL, 72.4 mmol) was added followed by diphenyl phosphoryl azide (14.2 mL, 65.9 mmol). The resulting mixture was heated to about 65 C. for about 4 h. The reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The remaining residue was purified by flash column chromatography on silica gel eluting with a gradient of 1-5% EtOAc in heptane. The solvent was removed under reduced pressure to give tert-butyl 2-bromothiophen-3-ylcarbamate (12.4 g, 68% yield): LC/MS (Table 1, Method a) Rt=2.46 min; MS m/z: 278 (M+H)+.

Reference： [1]Patent: US2011/152243,2011,A1 .Location in patent: Page/Page column 45

31
[ 24287-95-4 ]
[ 1334394-52-3 ]

Reference： [1]Patent: US2011/230495,2011,A1

32
[ 24287-95-4 ]
[ 1334394-53-4 ]

Reference： [1]Patent: US2011/230495,2011,A1

33
[ 24287-95-4 ]
[ 1334394-54-5 ]

Reference： [1]Patent: US2011/230495,2011,A1

34
[ 24287-95-4 ]
4-(3-phenoxymethylthiophen-2-yl)piperidine trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2011/230495,2011,A1

35
[ 24287-95-4 ]
[ 1286279-49-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1758 - 1770

36
[ 24287-95-4 ]
[ 1286279-59-1 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1758 - 1770

37
[ 24287-95-4 ]
[ 1286279-64-8 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1758 - 1770

38
[ 24287-95-4 ]
[ 1286279-69-3 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1758 - 1770

39
[ 24287-95-4 ]
[ 1118-89-4 ]
[ 1286279-50-2 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1758 - 1770

40
[ 24287-95-4 ]
[ 1382312-83-5 ]

Reference： [1]Bulletin of the Korean Chemical Society,2012,vol. 33,p. 1375 - 1378

41
[ 24287-95-4 ]
[ 1382312-86-8 ]

Reference： [1]Bulletin of the Korean Chemical Society,2012,vol. 33,p. 1375 - 1378

42
[ 24287-95-4 ]
[ 1382313-25-8 ]

Reference： [1]Bulletin of the Korean Chemical Society,2012,vol. 33,p. 1375 - 1378

43
[ 24287-95-4 ]
[ 1382313-28-1 ]

Reference： [1]Bulletin of the Korean Chemical Society,2012,vol. 33,p. 1375 - 1378

44
[ 24287-95-4 ]
[ 1659-31-0 ]
[ 1382312-69-7 ]

Yield	Reaction Conditions	Operation in experiment
12 g	With dmap; In dichloromethane; at 20℃; for 1h;	Bis(2-pyridine)carbonate (17.44 g, 80.66 mmol) and DMAP (985.38 mg, 8.07 mmol) were added into a solution of Example 4A (16.7 g, 80.66 mmol) in dichloromethane (200 mL) at room temperature. The reaction solution was stirred at room temperature for 1h, and TLC showed completed reaction. The reaction solution was spin dried and directly purified by column chromatography (petroleum ether/ethyl acetate 10:1-5/1) to give the title compound (12 g, 42.23 mmol, yield of 52.36%, a brown liquid). 1H NMR (400 MHz, CDCl3) delta = 8.47 (dd, J=1.6, 4.8 Hz, 1H), 7.85 (dt, J=2.0, 7.6 Hz, 1H), 7.59 (d, J=5.6 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.22 (d, J=8.0 Hz, 1H).

Reference： [1]Bulletin of the Korean Chemical Society,2012,vol. 33,p. 1375 - 1378
[2]Bulletin of the Korean Chemical Society,2013,vol. 34,p. 1253 - 1256
[3]Patent: EP3418282,2018,A1 .Location in patent: Paragraph 0187-0188

45
[ 24287-95-4 ]
[ 110-83-8 ]
2-bromocyclohexyl 2-bromothiophene-3-carboxylate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 9541 - 9552,12

46
[ 24287-95-4 ]
[ 18107-18-1 ]
[ 76360-43-5 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 3878 - 3882
Angew. Chem.,2013,vol. 125,p. 4132

47
[ 24287-95-4 ]
C₈H₈O₃S [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 3878 - 3882
Angew. Chem.,2013,vol. 125,p. 4132

48
[ 24287-95-4 ]
methyl 2-vinyl-3-thiophenecarboxylate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 3878 - 3882
Angew. Chem.,2013,vol. 125,p. 4132

49
[ 24287-95-4 ]
2-vinyl-3-thiophenecarboxylic acid [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 3878 - 3882
Angew. Chem.,2013,vol. 125,p. 4132

50
[ 24287-95-4 ]
[ 137272-68-5 ]

Reference： [1]Bulletin of the Korean Chemical Society,2013,vol. 34,p. 1253 - 1256
[2]Patent: EP3418282,2018,A1

51
[ 24287-95-4 ]
[ 89-98-5 ]
C₁₃H₈BrClOS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium hydroxide; In methanol; ethanol; at 0 - 20℃; for 0.5h;	General procedure: A 0.5 N KOH solution (0.5 N in CH3OH, 6.0 mL, 3.0 mmol) was added to a mixture of 3c (467 mg, 3.0 mmol) and 4-methoxybenzaldehyde (408 mg, 3.0 mmol) in EtOH (15 mL) at 0 C. The mixture was stirred for 0.5 h between 0 C and room temperature. The resulting yellow solution containing white precipitate was quenched with 0.5 N HCl solution (6 mL). After evaporating the solvent, the mixture was poured into saturated NH4Cl solution (30 mL), extracted with dichloromethane(3 × 20 mL), and washed with brine (30 mL). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was recrystallized twice in 5% EtOAc/n-hexane to give 4ck (673mg, 82%).

Reference： [1]Bulletin of the Korean Chemical Society,2013,vol. 34,p. 1253 - 1256

52
[ 24287-95-4 ]
[ 89-98-5 ]
[ 1451143-79-5 ]

Reference： [1]Bulletin of the Korean Chemical Society,2013,vol. 34,p. 1253 - 1256

53
[ 24287-95-4 ]
[ 86-81-7 ]
C₁₆H₁₅BrO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium hydroxide; In methanol; ethanol; at 0 - 20℃; for 0.5h;	General procedure: A 0.5 N KOH solution (0.5 N in CH3OH, 6.0 mL, 3.0 mmol) was added to a mixture of 3c (467 mg, 3.0 mmol) and 4-methoxybenzaldehyde (408 mg, 3.0 mmol) in EtOH (15 mL) at 0 C. The mixture was stirred for 0.5 h between 0 C and room temperature. The resulting yellow solution containing white precipitate was quenched with 0.5 N HCl solution (6 mL). After evaporating the solvent, the mixture was poured into saturated NH4Cl solution (30 mL), extracted with dichloromethane(3 × 20 mL), and washed with brine (30 mL). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was recrystallized twice in 5% EtOAc/n-hexane to give 4ck (673mg, 82%).

Reference： [1]Bulletin of the Korean Chemical Society,2013,vol. 34,p. 1253 - 1256

54
[ 24287-95-4 ]
[ 86-81-7 ]
[ 1451143-80-8 ]

Reference： [1]Bulletin of the Korean Chemical Society,2013,vol. 34,p. 1253 - 1256

55
[ 98-03-3 ]
[ 24287-95-4 ]
C₁₁H₇BrOS₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium hydroxide; In methanol; ethanol; at 0 - 20℃; for 0.5h;	General procedure: A 0.5 N KOH solution (0.5 N in CH3OH, 6.0 mL, 3.0 mmol) was added to a mixture of 3c (467 mg, 3.0 mmol) and 4-methoxybenzaldehyde (408 mg, 3.0 mmol) in EtOH (15 mL) at 0 C. The mixture was stirred for 0.5 h between 0 C and room temperature. The resulting yellow solution containing white precipitate was quenched with 0.5 N HCl solution (6 mL). After evaporating the solvent, the mixture was poured into saturated NH4Cl solution (30 mL), extracted with dichloromethane(3 × 20 mL), and washed with brine (30 mL). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was recrystallized twice in 5% EtOAc/n-hexane to give 4ck (673mg, 82%).

Reference： [1]Bulletin of the Korean Chemical Society,2013,vol. 34,p. 1253 - 1256

56
[ 24287-95-4 ]
[ 63139-21-9 ]
2-(4-ethylphenyl)thiophene-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; isopropyl alcohol; toluene; at 80℃;Sealed tube; Inert atmosphere;	Step 1: 2-(4-ethylphenyl)thiophene-3-carboxylic acid Into a 50-mL sealed tube (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[24287-95-4]2-bromo-3-thiophenecarboxylic acid</strong> (3 g, 14.1 mmol), (4-ethylphenyl)boronic acid (2.28 g, 15.2 mmol), K2CO3 aqueous solution (35 mL, 2M, 70.2 mmol), Pd(PPh3)4 (496 mg, 0.429 mmol), IPA (30 mL) and toluene (30 mL). The resulting solution was stirred overnight at 80 C. in an oil bath. The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleum ether=1:6). The solids were filtered out and washed by 20 mL ethyl acetate. Collected the organic phases and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 2.33 g (71%) of 2-(4-ethylphenyl)thiophene-3-carboxylic acid as light yellow oil.
71%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; isopropyl alcohol; toluene; at 80℃;Sealed tube; Inert atmosphere;	Into a 50-mL sealed tube (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[24287-95-4]2-bromo-3-thiophenecarboxylic acid</strong> (3 g, 14.1 mmol), (4-ethylphenyl)boronic acid (2.28 g, 15.2 mmol), K2CO3 aqueous solution (35 mL, 2M, 70.2 mmol), Pd(PPh3)4 (496 mg, 0.429 mmol), IPA (30 mL) and toluene (30 mL). The resulting solution was stirred overnight at 80 C. in an oil bath. The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleum ether=1:6). The solids were filtered out and washed by 20 mL ethyl acetate. Collected the organic phases and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 2.33 g (71%) of 2-(4-ethylphenyl)thiophene-3-carboxylic acid as light yellow oil.
71%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; at 80℃;Sealed tube; Inert atmosphere;	Into a 50-mL sealed tube (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[24287-95-4]2-bromo-3-thiophenecarboxylic acid</strong> (3 g, 14.1 mmol), (4- ethylphenyl)boronic acid (2.28 g, 15.2 mmol), K2CO3 aqueous solution (35 mL, 2M, 70.2 mmol), Pd(PPh3)4 (496 mg, 0.429 mmol), IPA (30 mL) and toluene (30 mL). The resulting solution was stirred overnight at 80C in an oil bath. The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleum ether = 1 :6). The solids were filtered out and washed by 20 mL ethyl acetate. Collected the organic phases and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 2.33 g (71%) of 2-(4- ethylphenyl)thiophene-3-carboxylic acid as light yellow oil.

Reference： [1]Patent: US2014/275179,2014,A1 .Location in patent: Paragraph 1272
[2]Patent: US9067898,2015,B1 .Location in patent: Page/Page column 218
[3]Patent: WO2015/134039,2015,A1 .Location in patent: Page/Page column 247-248

57
[ 24287-95-4 ]
[ 63139-21-9 ]
(2-(4-ethylphenyl)thiophen-3-yl)methanol [ No CAS ]

Reference： [1]Patent: US2014/275179,2014,A1
[2]Patent: US9067898,2015,B1
[3]Patent: WO2015/134039,2015,A1

58
[ 288-36-8 ]
[ 24287-95-4 ]
(2-(2H)-1,2,3-triazol-2-yl)thiophene-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃;Inert atmosphere;	EXAMPLE 18 2-(2-[(3i?,6i?)-6-methyl -[2 2H ,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3- yl]oxy} pyridin-3 -yl)propan-2-ol 1 ,2,3-triazole, K2C03, Cul Step 1 : 2-(2H -l,2,3-Triazol-2-yl)thiophene-3-carboxylic acid (10) A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 mmol), 1Eta- 1,2,3-triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was purged subsurface with nitrogen and heated to 75 C for 4 nights. The reaction was diluted with water, washed with ether, and acidified with cone. HCl. The acidic aqueous solution was extracted 3x with ethyl acetate and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography [0-70% (1% acetic acid in ethyl acetate) in hexanes], providing the title compound as an off-white solid. LRMS m/z (M+H) 196.2 found, 196.1 required.
	With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 96h;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 mmol), 1H- 1,2,3-triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was sparged with nitrogen and heated to 75 C for 96 h. The cooled reaction mixture was diluted with water, washed with ether, and acidified with cone. HCl. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography [0-70% (1% acetic acid in EtOAc) in hexanes], to provide the title compound as an off-white solid. LRMS m/z (M+H) 196.2 found, 196.1 required.
	With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 96h;Inert atmosphere;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 mmol), 1H- 1,2,3-triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was sparged with nitrogen and heated to 75C for 96 h. The cooled reaction mixture was diluted with water, washed with ether, and acidified with cone. HC1. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography [0-70% (1% acetic acid in EtOAc) in hexanes], to provide the title compound as an off-white solid. LRMS m/z (M+H) 196.2 found, 196.1 required.

		A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 mmol), 1H-1,2,3- triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was purged subsurface with nitrogen and heated to 75 C for 96 h. The reaction was diluted with water, washed with ether, and acidified with cone. HCl. The acidic aqueous solution was extracted 3x with ethyl acetate and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography [0-70% (1% acetic acid in ethyl acetate) in hexanes], providing the title compound as an off-white solid. LRMS m/z (M+H) 196.2 found, 196.1 required.
	With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 96h;Inert atmosphere;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 mmol), 1H-1,2,3-triazole(0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was purged subsurface with nitrogen and heated to 75C for 96 h. The reaction was diluted with water, washed with ether, and acidified with conc. HC1. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silicagel gradient chromatography [0-70% (1% acetic acid in EtOAc) in hexanes], providing the title compound as a solid. LRMS m/z (M+H) 196.2 found, 196.1 required.
	With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 96h;Inert atmosphere;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 mmol), 1H- 1,2,3-triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was purged subsurface with nitrogen and heated at 75C for 96 h. The reaction was diluted with water, washed with ether, and acidified with cone. HCI. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography [0-70% (1% acetic acid in EtOAc) in hexanes], providing the title compound as a solid. LRMS m/z (M+H) 196.2 found, 196.1 required.
	With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 96h;Inert atmosphere;	A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 minol), 111-1,2,3- triazole (0.600 g, 8.69 rnmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide(0.138 g, 0.724 inmol) in DMF (36.2 mL) was purged subsurface with nitrogen and heated to75 C for 96 h. The reaction was diluted with water, washed with ether, and acidified with conc.HC1. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography [0-70% (1% acetic acid inEtOAc) in hexanesi, providing the title compound as an off-white solid. LRI?IS m/z (M+H)196.2 found, 196.1 required.
	With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 96h;Inert atmosphere;	A solution of 2-bromo-3-thiophene carboxyhc acid(i.50 g, 7.24 rnmol), 1JJ 1,2,3-triazole (0.600 g, 8.69 mmoi), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0138 g, 0.724 mmol) in DMF (36.2 mL) was purged subsurface with niLrogen and heated to75 C for 96 h. The reaction was diluted with water, washed with ether, and acidified with cone. HCI. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated, The crude material was purified by silica gel gradient chromatography [0-70% (1% acetic acid in EtOAc) in hexanesj, providing the title compound as a solid. LRMS rn/z (M+H) 196.2 found,196.1 required.

Reference： [1]Patent: WO2014/176144,2014,A1 .Location in patent: Page/Page column 42-43
[2]Patent: WO2015/20930,2015,A1 .Location in patent: Page/Page column 36
[3]Patent: WO2015/20933,2015,A1 .Location in patent: Page/Page column 48; 49
[4]Patent: WO2015/95108,2015,A1 .Location in patent: Page/Page column 48
[5]Patent: WO2016/65585,2016,A1 .Location in patent: Page/Page column 50
[6]Patent: WO2016/69510,2016,A1 .Location in patent: Page/Page column 44-45
[7]Patent: WO2016/101119,2016,A1 .Location in patent: Page/Page column 38
[8]Patent: WO2016/95204,2016,A1 .Location in patent: Page/Page column 32; 33

59
[ 24287-95-4 ]
potassium 2-(pyrimidin-2-yl)thiophene-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/176144,2014,A1
[2]Patent: WO2015/18027,2015,A1
[3]Patent: WO2015/18029,2015,A1
[4]Patent: WO2015/20930,2015,A1
[5]Patent: WO2015/95442,2015,A1
[6]Patent: WO2015/95108,2015,A1
[7]Patent: WO2016/65585,2016,A1
[8]Patent: WO2016/100157,2016,A2
[9]Patent: WO2016/69510,2016,A1
[10]Patent: WO2016/100161,2016,A1
[11]Patent: WO2016/101119,2016,A1
[12]Patent: WO2016/101118,2016,A1
[13]Patent: WO2016/95204,2016,A1

60
[ 24287-95-4 ]
methyl 2-(pyrimidin-2-yl)thiophene-3-carboxylate [ No CAS ]

61
[ 24287-95-4 ]
2-[2-({(3R,6R)-6-methyl-1-[(2-pyrimidin-2-ylthiophen-3-yl)carbonyl]piperidin-3-yl}oxy)pyridin-3-yl]propan-2-ol [ No CAS ]

Reference： [1]Patent: WO2014/176144,2014,A1

62
[ 7790-94-5 ]
[ 24287-95-4 ]
2-bromo-5-chlorosulfonyl-thiophene-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5856 mg	at 95℃; for 2h;Microwave irradiation;	2-bromo-3- thiophenecarboxylic acid (5000 mg, 24.15 mmol) was dissolved portion wise in chlorosulfonic acid (8 mL) in a microwave tube and heated at 95C for 2 hours. The reaction mixture was carefully added dropwise to a, ice/water (300 mL) mixture and stirred for 5 minutes. The formed precipitate was filtered off, rinsed with water and dried in vacuo at 50C, yielding 2-bromo-5- chlorosulfonyl-thiophene-3-carboxylic acid as a beige powder (5856 mg).) Compound 2 was synthesized similar as described for compound 1, starting from 2-bromo-5-chlorosulfonyl- thiophene-3-carboxylic acid instead of 5-(chlorosulfonyl)-3-thiophenecarboxylic acid. After work up, the compound was purified by silica gel column chromatography by gradient elution with 10 to 100 % EtOAc in heptanes. The obtained solid was recrystallized by adding water to a warm solution of crude compound 2 (11.4 g) in methanol (200 mL). After filtration and drying in vacuo at 50C, compound 2 was obtained as a beige powder (9850 mg). Method B; Rt: 0.98 min. m/z : 482.0 (M+NH4)+ Exact mass: 464.0. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.65 - 1.78 (m, 1 H), 1.96 - 2.10 (m, 1 H), 2.24 (d, J=1.8 Hz, 3 H), 3.46 (dd, J=9.0, 4.2 Hz, 1 H), 3.63 (td, J=8.1, 5.7 Hz, 1 H), 3.69 - 3.78 (m, 2 H), 3.81 - 3.91 (m, 1 H), 7.13 (t, J=9.2 Hz, 1 H), 7.51 (dt, J=7.6, 4.0 Hz, 1 H), 7.62 (dd, J=6.8, 2.2 Hz, 1 H), 7.87 (s, 1 H), 8.42 (d, J=6.2 Hz, 1 H), 10.38 (s, 1 H).

Reference： [1]Patent: WO2014/184365,2014,A1 .Location in patent: Page/Page column 18

63
[ 24287-95-4 ]
(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-2-methylpiperidin-1-yl)methanone [ No CAS ]

Reference： [1]Patent: WO2015/18027,2015,A1
[2]Patent: WO2015/20933,2015,A1

64
[ 24287-95-4 ]
ethyl 4-((3R,6R)-1-(2-(2H-1,2,3-triazol-2-yl)thiophene-3-carbonyl)-6-methylpiperidin-3-yl)thiazole-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/18027,2015,A1
[2]Patent: WO2015/20933,2015,A1

65
[ 24287-95-4 ]
(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl )((2R,5R)-5-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-2-methylpiperidin-1-yl)methanone [ No CAS ]

Reference： [1]Patent: WO2015/18027,2015,A1
[2]Patent: WO2015/20933,2015,A1

66
[ 24287-95-4 ]
[ 1612786-50-1 ]

Reference： [1]Patent: WO2015/18027,2015,A1
[2]Patent: WO2015/18029,2015,A1
[3]Patent: WO2015/20930,2015,A1
[4]Patent: WO2015/20933,2015,A1

67
[ 24287-95-4 ]
(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)((2R,5R)-5-(4-(2-hydroxypropan-2-yl)-5-methyloxazol-2-yl)-2-methylpiperidin-1-yl)methanone [ No CAS ]

Reference： [1]Patent: WO2015/18029,2015,A1
[2]Patent: WO2015/20930,2015,A1

68
[ 24287-95-4 ]
(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)((2R,5R)-5-(4-((R)-2-hydroxybutan-2-yl)-5-methyloxazol-2-yl)-2-methylpiperidin-1-yl)methanone [ No CAS ]

Reference： [1]Patent: WO2015/18029,2015,A1
[2]Patent: WO2015/20930,2015,A1

69
[ 24287-95-4 ]
(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)((2R,5R)-5-(4-((S)-2-hydroxybutan-2-yl)-5-methyloxazol-2-yl)-2-methylpiperidin-1-yl)methanone [ No CAS ]

Reference： [1]Patent: WO2015/18029,2015,A1
[2]Patent: WO2015/20930,2015,A1

70
[ 24287-95-4 ]
tert-butyl (Z)-2-methyl-1-oxo-3-phenyl-1,2,5,6-tetrahydrothieno[3,2-c]azocine-5-carboxylate [ No CAS ]

Reference： [1]Synthesis,2015,vol. 47,p. 1007 - 1015

71
[ 24287-95-4 ]
isopropyl (E)-2-[(2-tert-butoxycarbonyl)ethenyl]thiophene-3-carboxylate [ No CAS ]

Reference： [1]Synthesis,2015,vol. 47,p. 1007 - 1015

72
[ 24287-95-4 ]
tert-butyl 4-oxo-5-(2-oxo-2-phenylethyl)-5,6-dihydrocyclopenta[b]thiophene-5-carboxylate [ No CAS ]

Reference： [1]Synthesis,2015,vol. 47,p. 1007 - 1015

73
[ 24287-95-4 ]
tert-butyl 4-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate [ No CAS ]

Reference： [1]Synthesis,2015,vol. 47,p. 1007 - 1015

74
[ 24287-95-4 ]
isopropyl 2-[(2-tert-butoxycarbonyl)ethyl]thiophene-3-carboxylate [ No CAS ]

Reference： [1]Synthesis,2015,vol. 47,p. 1007 - 1015

75
[ 24287-95-4 ]
N<SUP>2</SUP>-methyl-5-(trifluoromethyl)pyridine-2,3-diamine [ No CAS ]
2-bromothiophene-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 2h;	A mixture of 1.91 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 2.07 g of 3-bromothiophene-2-carboxylic acid, 2.30 g of EDCI hydrochloride, 0.13 g of HOBt and 10 ml of pyridine was stirred at 80 C. for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3 g of <strong>[24287-95-4]2-bromothiophene-3-carboxylic acid</strong> (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide.

Reference： [1]Patent: US2015/94329,2015,A1 .Location in patent: Paragraph 1014

76
[ 24287-95-4 ]
2-bromo-N-methyl-N-phenylthiophene-3-carboxamide [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2015,vol. 357,p. 1525 - 1531

77
[ 24287-95-4 ]
(2-bromothiophen-3-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2015,vol. 357,p. 1525 - 1531

78
[ 24287-95-4 ]
5,6-dihydro-4H,8H-pyrido[3,2,1-ij]thieno[3,2-c]quinolin-8-one [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2015,vol. 357,p. 1525 - 1531

79
[ 24287-95-4 ]
4-[(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3-yl]oxy}furo[3,4-c]pyridin-1(3H)-one [ No CAS ]

Reference： [1]Patent: WO2015/95442,2015,A1

80
[ 24287-95-4 ]
2-({(3R,6R)-6-methyl-1-[(2-pyrimidin-2-ylthiophen-3-yl)carbonyl]piperidin-3-yl}sulfanyl)pyridine-4-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2015/95108,2015,A1

81
[ 24287-95-4 ]
[ 13524-04-4 ]
(RS)-1-(2-chlorophenyl)ethyl (2-bromothiophen-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With diphenylphosphoranyl azide; triethylamine; In toluene; for 1h;Inert atmosphere; Reflux;	To a solution of 4.44 g (21.4 mmol) of <strong>[24287-95-4]2-bromothiophene-3-carboxylic acid</strong> (Aldrich) in toluene (5 ml) was added dropwise 4.61 ml (33.1 mmol) of triethylamine under an argon atmosphere at room temperature while stirring, and the mixture was stirred at the same temperature for 5 minutes. Then, 3.4 ml (24 mmol) of (RS)-1-(2-chlorophenyl)ethanol (Tokyo Chemical Industry Co., Ltd.) and 5.30 ml (24.7 mmol) of diphenylphosphoryl azide were added, and the mixture was stirred for one hour under the heat-refluxing conditions. After completion of the reaction, to the reaction mixture was added water, and the mixture was extracted with toluene. The organic layer was washed with saturated brine, subsequently dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate = 100:0 to 75:25 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 6.80 g (18.9 mmol, yield 88%) of the title compound as a white solid. Mass spectrum (CI, m/z): 359 [M]+. 1 H-NMR spectrum (400 MHz, DMSO-d6, 75C) delta : 8.97 (1H, brs), 7.55 (1H, dd, J = 7.7, 1.6 Hz), 7.50 (1H, d, J = 5.8 Hz), 7.43 (1H, dd, J = 7.8, 1.4 Hz), 7.38 (1H, td, J = 7.5, 1.4 Hz), 7.32 (1H, td, J = 7.6, 1.8 Hz), 7.10 (1H, d, J = 5.9 Hz), 6.05 (1H, q, J = 6.5 Hz), 1.52 (3H, d, J = 6.5 Hz).

Reference： [1]Patent: EP2940013,2015,A1 .Location in patent: Paragraph 0503

82
[ 24287-95-4 ]
2-{4'-[1-(ethoxycarbonyl)cyclopropyl]-2-methoxy-[1,1'-biphenyl]-4-yl}-5-fluorothiophene-3-carboxylic acid [ No CAS ]