[ CAS No. 2160-62-5 ] {[proInfo.proName]}

Name: 2160-62-5|5-Bromothiophene-2-carbonitrile|97%
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Quality Control of [ 2160-62-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 2160-62-5 ]

Product Details of [ 2160-62-5 ]

CAS No. :	2160-62-5	MDL No. :	MFCD04974080
Formula :	C₅H₂BrNS	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YVVHCBNJWHPMCQ-UHFFFAOYSA-N
M.W :	188.05	Pubchem ID :	3595059
Synonyms :

Calculated chemistry of [ 2160-62-5 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	36.73
TPSA :	52.03 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.54 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.76
Log Po/w (XLOGP3) :	2.68
Log Po/w (WLOGP) :	2.38
Log Po/w (MLOGP) :	1.19
Log Po/w (SILICOS-IT) :	3.2
Consensus Log Po/w :	2.24

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.16
Solubility :	0.131 mg/ml ; 0.000697 mol/l
Class :	Soluble
Log S (Ali) :	-3.42
Solubility :	0.0707 mg/ml ; 0.000376 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.61
Solubility :	0.466 mg/ml ; 0.00248 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.37

Safety of [ 2160-62-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 2160-62-5 ]

* 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 [ 2160-62-5 ]
Downstream synthetic route of [ 2160-62-5 ]

[ 2160-62-5 ] Synthesis Path-Upstream 1~7

1
[ 2160-63-6 ]
[ 2160-62-5 ]

Yield	Reaction Conditions	Operation in experiment
88%	With acetic anhydride; acetic acid In tetrahydrofuran at 20 - 70℃; for 10 h;	Preparation Example A+-20. 5-Bromo-thiophene-2-carbonitrile To a mixture of 5-bromo-thiophene-2-carbaldehyde oxime described in Preparation Example A+-19 (1.3g, 6.2mmol) and tetrahydrofuran (15mL) were acetic acid (1.4mL, 25mmol) and acetic anhydride (1.5mL, 15mmol) at room temperature, then, stirred at 50°C for 2 hours, and further stirred at 70°C for 8 hours. After cooling this reaction mixture, the solution was concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (heptane : ethyl acetate = 8 : 1), and the title compound (1.0g, 5.4mmol, 88percent) was obtained as a colorless solid. ¹H-NMR Spectrum (CDCl₃) δ(ppm) : 7.11 (1 H, d, J=4.0Hz), 7.40(1 H, d, J=4.0Hz).

Reference： [1] Patent: EP1782811, 2007, A1, . Location in patent: Page/Page column 51
[2] Bulletin de la Societe Chimique de France, 1967, p. 4115 - 4120
[3] Patent: WO2003/87103, 2003, A1, . Location in patent: Page/Page column 17
[4] Patent: WO2005/82899, 2005, A1, . Location in patent: Page/Page column 30
[5] Synlett, 2011, # 15, p. 2223 - 2227
[6] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 3, p. 778 - 781

2
[ 4701-17-1 ]
[ 2160-62-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	With tert.-butylhydroperoxide; ammonium acetate; iodine; sodium carbonate In ethanol at 50℃; for 15 h;	In a 25 mL two-necked round bottom flask equipped with a thermometer and a magnetic stirrer was added 4 mmol of 5-bromothiophene-2-carbaldehyde (1-20)), 6 mmol of NH4OAc, 4 mmol of Na2CO3, 4.4 mmol of TBHP, 0.1 mmol of I2, 5 mL of absolute ethanol Solvent, followed by placing the reaction flask in an oil bath preheated to 50 ° C and opening the magnetic stirrer for 15 h. The reaction solution By adding sodium thiosulfate solution, stirring, and then extracting with ether, separating the organic layer, and removing the solvent under reduced pressure, The eluate was collected with the mixture of ethyl acetate / petroleum ether in a volume ratio of 1: 100 as the eluent, and the eluate containing the target compound was collected. The solvent was distilled off to give 5-bromothiophene-2-carbonitrile with an isolated yield of 82percent.
58%	Stage #1: With hydroxylamine hydrochloride In pyridine; ethanol for 2 h; Nitrogen atmosphere; heating/reflux Stage #2: With copper diacetate In acetonitrile for 3 h; Heating / reflux	5-Bromo-2-thiophenecarbonitrile: A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL), and ethanol (500 mL) was heated under nitrogen at reflux for two hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an oil. The crude product was triturated twice with ice water and the solid obtained was collected on a filter. A mixture of a portion of the above solid (44.31 g, 215 mmol), copper (II) acetate monohydrate (4.2 g, 21 mmol) in acetonitrile (1.4 L) was heated at reflux for three hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5percent aqueous sulfuric acid (2.x.30 mL), water (2.x.30 mL), brine (20 mL), and dried (MgSO4). The solvent was removed in vacuo and the residue was dissolved in a minimum amount of chloroform (1 L) and allowed to crystallize. The crystals obtained was collected on a filter and the filtrate was concentrated and purified by a chromatography (silica gel, chloroform) to give the subtitled compound as an off-white solid (31.5 g combined, 58percent). IR (film) cm1 2200. 1H-NMR (CDCl3) δ 7.39-7.38 (d, 1H, J=4.1 Hz), 7.10 (d, 1H, J=4.0 Hz); MS (EI) m/z 187 (M+, 98percent) 189(M+, 100percent).
24%	With hydroxylamine-O-sulfonic acid In hexane; water; acetic anhydride; ethyl acetate	EXAMPLE 8 Preparation of 5-Bromo-2-Thiophenecarbonitrile STR97 Hydroxylamine-O-sulfonic acid (17.58 g, 157 mmol) is added to a solution of 5-bromo-2-thiophenecarboxaldehyde (15.00 g, 78.5 mmol) in water and acetonitrile. The reaction mixture is stirred for 17 hours, poured into water and extracted with ether and ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over MgSO₄ and concentrated in vacuo to give a brown, oily solid. A solution of the oily solid in acetic anhydride is refluxed for five hours, concentrated in vacuo, poured into water and extracted with ether. The combined organic extracts are washed sequentially with water, half-saturated sodium hydrogen carbonate solution and brine, dried over MgSO₄ and concentrated in vacuo to obtain a brown oil. Flash chromatography of the oil using silica gel and a 15percent ethyl acetate in hexane solution gives the title product as a yellow oil (3.60 g, 24percent).

24%	With hydroxylamine-O-sulfonic acid In hexane; water; acetic anhydride; ethyl acetate	EXAMPLE 8 Preparation of 5-Bromo-2-thiophenecarbonitrile STR97 Hydroxylamine-O-sulfonic acid (17.58 g, 157 mmol) is added to a solution of 5-bromo-2-thiophenecarboxaldehyde (15.0 g, 78.5 mmol) in water and acetonitrile. The reaction mixture is stirred for 17 hours, poured into water and extracted with ether and ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over MgSO₄ and concentrated in vacuo to give a brown, oily solid. A solution of the oily solid in acetic anhydride is refluxed for five hours, concentrated in vacuo, poured into water and extracted with ether. The combined organic extracts are washed sequentially with water, half-saturated sodium hydrogen carbonate solution and brine, dried over MgSO₄ and concentrated in vacuo to obtain a brown oil. Flash chromatography of the oil using silica gel and a 15percent ethyl acetate in hexane solution gives the title product as a yellow oil (3.6 g, 24percent).
16%	With pyridine; ammonium peroxydisulfate; tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinoxy In acetonitrile at 0.5℃; for 24 h; Molecular sieve; Sealed tube; Irradiation	General procedure: To an oven-dried 2 ml reaction vial equipped with a stir bar wasadded the aldehyde 3a (0.136 g, 1 mmol, 1 equiv) and pyridine(0.474 g, 6.0 mmol, 6 equiv), followed by acetonitrile (2 ml, 0.5M in 3a). The vial was then charged with Ru(bpy)3(PF6)2 (0.017g, 0.02 mmol, 0.02 equiv), 2 (0.043 g, 0.20 mmol, 0.20 equiv),(NH4)2S2O8(0.501 g, 2.2 mmol, 2.2 equiv), and activated 3 Åmolecular sieves (ca. 0.2 g), sealed with a cap, and irradiated inblue LED reactor for 24 h. In the absence of fan cooling, the temperatureof the reaction mixture plateaued at approximately 50°C . After the irradiation was complete, the reaction mixturewas quenched with EtOAc and transferred to a separatoryfunnel. Further EtOAc (30 ml) was added, followed by 0.5 MHCl(aq) (30 ml). The layers were separated, and the aqueous layerwas extracted with EtOAc (3 × 20 ml). The organic layers werethen combined and washed with 0.5 M 0.5 M HCl(aq) (2 × 20 ml),saturated aqueous sodium bicarbonate (2 × 20 ml), and finallybrine (20 ml). The organic layer was then dried over sodiumsulfate and the solvent removed in vacuo to afford the crudeproduct. The resulting crude mixture was adhered to silica gelusing 1.5 weight equivalents of SiO2(relative to the theoreticalyield). The dry-packed material was gently added on top of asilica gel plug. The plug was washed with an excess of hexanes(ca. 5 column volumes). The desired product was eluted off theplug via a 90:10 by volume mixture of hexanes/EtOAc (3–4column volumes). The solvent was removed in vacuo by rotaryevaporation affording the pure nitrile 3c (0.066 g, 50percent) as awhite solid.

Reference： [1] Journal of the American Chemical Society, 2011, vol. 133, # 34, p. 13437 - 13444
[2] Advanced Synthesis and Catalysis, 2016, vol. 358, # 7, p. 1157 - 1163
[3] RSC Advances, 2017, vol. 7, # 3, p. 1484 - 1489
[4] Patent: CN106748881, 2017, A, . Location in patent: Paragraph 0052
[5] Patent: US6355648, 2002, B1, . Location in patent: Page column 55
[6] Patent: US5480902, 1996, A,
[7] Patent: US5492925, 1996, A,
[8] Synlett, 2018, vol. 29, # 16, p. 2185 - 2190
[9] Journal of Materials Chemistry, 2000, vol. 10, # 9, p. 2069 - 2080
[10] Synlett, 2011, # 15, p. 2223 - 2227
[11] Angewandte Chemie - International Edition, 2015, vol. 54, # 14, p. 4241 - 4245
[12] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 3, p. 778 - 781
[13] Journal of Organic Chemistry, 2018,

3
[ 1003-31-2 ]
[ 2160-62-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; bromine; acetic anhydride In acetic acid at 20℃; for 3 h;	5-Bromo-2-thiophenecarbonitrile To a solution of the available 2-thiophenecarbonitrile (2.22 g, 20.3 [MMOL)] in a mixture of acetic acid (1.22 g, 20.3 [MMOL)] and acetic anhydride (8.3 g, 81.3 [MMOL)] was [ADDED NBS (3.62 G, 1.0 EQ. ) AND BROMINE (1.05 ML, 1.0 EQ. ) AND THE REACTION MIXTURE] was stirred at rt for 3 hours. Water and ice were added and also a saturated sodium bisulfite solution. After extraction with DCM, the organic layer was washed with a saturated [NAHC03] solution, dried over [NA2SO4] and evaporated. The title compound was obtained as a orange liquid (3.74 g, 20 [MMOL)] in a quantitative yield ; GC/MS : [M+] C5H2BrNS 188
75%	With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 6 h; Darkness	(1) Weighing 4 g 2-cyanothiophene (32.47 mmol) is dissolved in 30 ml DMF, taking 3.6 g NBS is slowly added to the mixture in stirring 15 min, all in the dark after adding the reaction under the room temperature condition 6 h. After the completion of the reaction methylene chloride and aqueous phase extraction purification, congeals the organic layer to dry column chromatography purification, the developing agent is the volume ratio of 1:3 of dichloromethane: petroleum ether mixed solvent, to obtain 4-bromo-2-cyanothiophene, the yield is 75percent.

Reference： [1] Patent: WO2004/6922, 2004, A1, . Location in patent: Page/Page column 53
[2] Patent: CN108530419, 2018, A, . Location in patent: Paragraph 0058; 0059
[3] Heterocycles, 1997, vol. 46, # 1, p. 489 - 501

4
[ 943325-65-3 ]
[ 2160-62-5 ]

Yield	Reaction Conditions	Operation in experiment
88%	With acetic anhydride; acetic acid In tetrahydrofuran at 20 - 70℃; for 10 h;	To a mixture of 5-bromo-thiophene-2-carbaldehyde oxime described in Preparation Example A+-19 (1.3g, 6.2mmol) and tetrahydrofuran (15mL) were acetic acid (1.4mL, 25mmol) and acetic anhydride (1.5mL, 15mmol) at room temperature, then, stirred at 50°C for 2 hours, and further stirred at 70°C for 8 hours. After cooling this reaction mixture, the solution was concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (heptane : ethyl acetate = 8 : 1), and the title compound (1.0g, 5.4mmol, 88percent) was obtained as a colorless solid. ¹H-NMR Spectrum (CDCl₃) δ(ppm) : 7.11 (1 H, d, J=4.0Hz), 7.40(1 H, d, J=4.0Hz).

Reference： [1] Patent: EP1669348, 2006, A1, . Location in patent: Page/Page column 59

5
[ 1003-31-2 ]
[ 79-24-3 ]
[ 18820-82-1 ]
[ 2160-62-5 ]

Reference： [1] Patent: US6696110, 2004, B1,

6
[ 3141-27-3 ]
[ 557-21-1 ]
[ 18853-40-2 ]
[ 2160-62-5 ]

Reference： [1] Synthesis, 2004, # 1, p. 23 - 25

7
[ 18791-75-8 ]
[ 2160-62-5 ]

Reference： [1] Journal of Organic Chemistry, 2018,

[ 2160-62-5 ] Synthesis Path-Downstream 1~88

1
[ 2160-63-6 ]
[ 2160-62-5 ]

Yield	Reaction Conditions	Operation in experiment
88%	With acetic anhydride; acetic acid; In tetrahydrofuran; at 20 - 70℃; for 10h;	Preparation Example A+-20. 5-Bromo-thiophene-2-carbonitrile To a mixture of 5-bromo-thiophene-2-carbaldehyde oxime described in Preparation Example A+-19 (1.3g, 6.2mmol) and tetrahydrofuran (15mL) were acetic acid (1.4mL, 25mmol) and acetic anhydride (1.5mL, 15mmol) at room temperature, then, stirred at 50C for 2 hours, and further stirred at 70C for 8 hours. After cooling this reaction mixture, the solution was concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (heptane : ethyl acetate = 8 : 1), and the title compound (1.0g, 5.4mmol, 88%) was obtained as a colorless solid. 1H-NMR Spectrum (CDCl3) delta(ppm) : 7.11 (1 H, d, J=4.0Hz), 7.40(1 H, d, J=4.0Hz).
	With pyridine; P,P-dichlorophenylphosphine oxide; In dichloromethane; at 0 - 20℃;	2-Bromothiophene-5-carboxaldehyde (5. 00g, 26.2 mmol) was dissolved in 150 mL of methanol/dichlonnethane (1: 4 by volume). Pyridine (4.25 mL, 52.4 mmol) and hydroxylamine hydrochloride (1.82 g, 26.2 mmol) were added sequentially. The mixture was stirred at room temperature, and then, after 2 h, the solvent was evaporated from the reaction mixture. The residue was dissolved in dichloromethane (180 mL) and pyridine (4.25 mL, 52.4 mmol) was added. The mixture was cooled to 0 C, then phenylphosphonic dichloride (10.20 g, 52.4 mmol) was added. Following, the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with saturated sodium bicarbonate, water, and brine. The organic layer was dried through MgS04, and then the solvent was evaporated. The compound was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound (5.15 g) as a pale solid.
	With acetic anhydride; at 100℃; for 17h;	Step b: Preparation of 2-bromo-5-cyanothiophene; 5-bromo-thiophen-2-yl-oxime (0.75 g) in acetic anhydride (5 mL) was heated to 100 C for about 17 hours. The reaction mixture was cooled and saturated sodium bicarbonate solution was added and stirred for about 30 minutes. The reaction mixture was extracted with dichloromethane, washed with sodium bicarbonate solution, water and brine. The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography 0-0.5% ethyl acetate in hexane to yield 0.25 g of product.

With [ruthenium(II)(eta6-1-methyl-4-isopropyl-benzene)(chloride)(mu-chloride)]2; In acetonitrile; at 80℃;

General procedure: To a solution of aldehyde1(1.0 equiv) in EtOH was added hydroxylamine hydrochloride (1.2 equiv) and sodium acetate (2.0 equiv). The mixture was stirred at room temperature for 12 h. EtOH was removedin vacuo. The residue was added water and extracted with ethyl acetate (3), washed with brine (3), dried over anhydrous Na2SO4and concentrated. The residue was subjected to silica gel chromatography with petroleum ether/EtOAc (5:1) to give2. To a solution of oxime (2, 1 equiv) in acetonitrile (80 mL) was added[Ru2(p-PriC6H4Me)2(-Cl)Cl]2(1.3g, 0.1 equiv) and refluxed for 4 h. The mixture was filtered and the filtrate was concentratedin vacuo. The residue was subjected to silica gel chromatography with petroleum ether/EtOAc (2:1) to give3.12

Reference： [1]Patent: EP1782811,2007,A1 .Location in patent: Page/Page column 51
[2]Bulletin de la Societe Chimique de France,1967,p. 4115 - 4120
[3]Patent: WO2003/87103,2003,A1 .Location in patent: Page/Page column 17
[4]Patent: WO2005/82899,2005,A1 .Location in patent: Page/Page column 30
[5]Synlett,2011,p. 2223 - 2227
[6]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 778 - 781

2
[ 2160-62-5 ]
[ 76371-66-9 ]

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

3
[ 2160-62-5 ]
[ 2160-56-7 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions II,1989,p. 1779 - 1782

4
[ 2160-62-5 ]
[ 74-86-2 ]
[ 123784-07-6 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1989,vol. 25,p. 570 - 575
Zhurnal Organicheskoi Khimii,1989,vol. 25,p. 633 - 639

5
[ 2160-62-5 ]
[ 128073-42-7 ]
(3R,4aS,6R,8aS)-6-[5-(1H-Tetrazol-5-yl)-thiophen-2-yl]-decahydro-isoquinoline-3-carboxylic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1161 - 1166

6
[ 2160-62-5 ]
[ 128073-42-7 ]
(3S,4aR,8aR)-6-(5-Cyano-thiophen-2-yl)-3,4,4a,5,8,8a-hexahydro-1H-isoquinoline-2,3-dicarboxylic acid 3-ethyl ester 2-methyl ester [ No CAS ]
(3S,4aS,8aR)-6-(5-Cyano-thiophen-2-yl)-3,4,4a,7,8,8a-hexahydro-1H-isoquinoline-2,3-dicarboxylic acid 3-ethyl ester 2-methyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1161 - 1166

7
[ 2160-62-5 ]
[ 128073-42-7 ]
(3S,4aR,8aR)-6-[5-(1H-Tetrazol-5-yl)-thiophen-2-yl]-3,4,4a,5,8,8a-hexahydro-1H-isoquinoline-2,3-dicarboxylic acid 3-ethyl ester 2-methyl ester [ No CAS ]
(3S,4aS,8aR)-6-[5-(1H-Tetrazol-5-yl)-thiophen-2-yl]-3,4,4a,7,8,8a-hexahydro-1H-isoquinoline-2,3-dicarboxylic acid 3-ethyl ester 2-methyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1161 - 1166

8
[ 1003-31-2 ]
[ 2160-62-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; bromine; acetic anhydride; In acetic acid; at 20℃; for 3h;	5-Bromo-2-thiophenecarbonitrile To a solution of the available 2-thiophenecarbonitrile (2.22 g, 20.3 [MMOL)] in a mixture of acetic acid (1.22 g, 20.3 [MMOL)] and acetic anhydride (8.3 g, 81.3 [MMOL)] was [ADDED NBS (3.62 G, 1.0 EQ. ) AND BROMINE (1.05 ML, 1.0 EQ. ) AND THE REACTION MIXTURE] was stirred at rt for 3 hours. Water and ice were added and also a saturated sodium bisulfite solution. After extraction with DCM, the organic layer was washed with a saturated [NAHC03] solution, dried over [NA2SO4] and evaporated. The title compound was obtained as a orange liquid (3.74 g, 20 [MMOL)] in a quantitative yield ; GC/MS : [M+] C5H2BrNS 188
75%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 6h;Darkness;	(1) Weighing 4 g <strong>[1003-31-2]2-cyanothiophene</strong> (32.47 mmol) is dissolved in 30 ml DMF, taking 3.6 g NBS is slowly added to the mixture in stirring 15 min, all in the dark after adding the reaction under the room temperature condition 6 h. After the completion of the reaction methylene chloride and aqueous phase extraction purification, congeals the organic layer to dry column chromatography purification, the developing agent is the volume ratio of 1:3 of dichloromethane: petroleum ether mixed solvent, to obtain 4-bromo-<strong>[1003-31-2]2-cyanothiophene</strong>, the yield is 75%.

Reference： [1]Patent: WO2004/6922,2004,A1 .Location in patent: Page/Page column 53
[2]Patent: CN108530419,2018,A .Location in patent: Paragraph 0058; 0059
[3]Heterocycles,1997,vol. 46,p. 489 - 501
[4]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2020,vol. 227

9
[ 3216-50-0 ]
[ 2160-62-5 ]
[ 163928-45-8 ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

10
[ 19983-18-7 ]
[ 2160-62-5 ]
[ 205529-40-4 ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

11
C₁₂H₈BrNO₂S [ No CAS ]
[ 2160-62-5 ]
[ 766-76-7 ]

Reference： [1]Journal of Organic Chemistry,1998,vol. 63,p. 8304 - 8309

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 18 5-Bromo-2-thiophenecarbonitrile A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (11.9 g, 500 mmol), pyridine (500 mL), and ethanol (500 mL) was heated under nitrogen at reflux for two hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an oil. The crude product was triturated twice with ice water and the solid obtained was collected on a filter. A mixture of a portion of the above solid (44.31 g, 215 mmol), copper (II) acetate monohydrate (4.2 g, 21 mmol) in acetonitrile (1.4L) was heated at reflux for three hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sulfuric acid (230 mL), water (230 mL), brine (20 mL), and dried (MgSO4). The solvent was removed in vacuo and the residue was dissolved in a minimum amount of chloroform (1L) and allowed to crystallize. The crystal obtained was collected on a filter and the filtrate was concentrated and purified by a chromatography (silica gel, chloroform) to give the title compound as an off-white solid (31.5 g combined, 58%). IR (film) cm-1 2200. 1H-NMR (CDCl3) delta7.39-7.38 (d, 1H, J=4.1 Hz), 7.10 (d, 1H, J=4.0 Hz); MS (EI) m/z 187 (M+, 98%) 189(M+, 100%).
		Production Example 28 5-Bromo-2-thiophene Carbonitrile To a solution of 8.2 g (43.1 mmol) of the compound of Production Example 27 in 40 ml of dimethylformamide were added 3.3 g (51.7 mmol) of hydroxylamine hydrochloride and 4.1 g (51.7 mmol) of pyridine followed by stirring at room temperature for 30 minutes. Then, 34.9 g (215.5 mmol) of 1,1'-carbonyldiimidazole were added thereto under ice-cooling followed by stirring at room temperature for 1 hour. Ice water was added to the reaction solution followed by extracting with ethyl acetate. The organic layer was washed with a 0.1N aqueous solution of hydrochloric acid, water and brine successively, and dried over magnesium sulfate. After it was concentrated, the resulting residue was purified by a silica gel column chromatography to give 6.7 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm); 7.45(1H,d,J=4.0 Hz), 7.84(1H, d, J=4.0 Hz).
		5-Bromo-2-thiophenecarbonitrile A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL), and ethanol (500 mL) was heated under nitrogen at reflux for two hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an oil. The crude product was triturated twice with ice water and the solid obtained was collected on a filter. A mixture of a portion of the above solid (44.31 g, 215 mmol), copper (II) acetate monohydrate (4.2 g, 21 mmol) in acetonitrile (1.4L) was heated at reflux for three hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sulfuric acid (230 mL), water (230 mL), brine (20 mL), and dried (MgSO4). The solvent was removed in vacuo and the residue was dissolved in a ninimum amount of chloroform (1L) and allowed to crystallize. The crystal obtained was collected on a filter and the filtrate was concentrated and purified by a chromatography (silica gel, chloroform) to give the subtitled compound as an off-white solid (31.5 g combined, 58%).: IR (film) cm-1 2200; 1H-NMR (CDCl3) delta7.39-7.38 (d, 1H, J=4.1 Hz), 7.10 (d, 1H, J=4.0 Hz); MS (EI) m/z 187 (M+, 98%) 189(M+, 100%).

		EXAMPLE 18 5-Bromo-2-thiophenecarbonitrile A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL), and ethanol (500 mL) was heated under nitrogen at reflux for two hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an oil. The crude product was triturated twice with ice water and the solid obtained was collected on a filter. A mixture of a portion of the above solid (44.31 g, 215 mmol), copper (II) acetate monohydrate (4.2 g, 21 mmol) in acetonitrile (1.4L) was heated at reflux for three hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sulfuric acid (230 mL), water (230 mL), brine (20 mL), and dried (MgSO4). The solvent was removed in vacuo and the residue was dissolved in a minimum amount of chloroform (1L) and allowed to crystallize. The crystal obtained was collected on a filter and the filtrate was concentrated and purified by a chromatography (silica gel, chloroform) to give the title compound as an off-white solid (31.5 g combined, 58%). IR (film) cm-2 2200. 1H-NMR (CDCl3) delta7.39-7.38 (d, 1H, J=4. 1 Hz), 7.10 (d, 1H, J=4.0 Hz); MS (EI) m/z 187 (M+, 98%) 189(M+, 100%).
		5-Bromo-2-thiophenecarbonitrile A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL), and ethanol (500 mL) was heated under nitrogen at reflux for two hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an oil. The crude product was triturated twice with ice water and the solid obtained was collected on a filter. A mixture of a portion of the above solid (44.31 g, 215 mmol), copper (II) acetate monohydrate (4.2 g, 21 mmol) in acetonitrile (1.4L) was heated at reflux for three hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sulfuric acid (230 mL), water (230 mL), brine (20 mL), and dried (MgSO4). The solvent was removed in vacuo and the residue was dissolved in a minimum amount of chloroform (1L) and allowed to crystallize. The crystal obtained was collected on a filter and the filtrate was concentrated and purified by a chromatography (silica gel, chloroform) to give the title compound as an off-white solid (31.5g combined, 58%).: IR (film) cm-12200; 1H-NMR (CDCl3) delta 7.39-7.38 (d, 1H, J=4.1 Hz), 7.10 (d, 1H, J=4.0 Hz); MS (EI) m/z 100%).
		17a 2-bromo-4-cyanothiophene 2-Bromo-5-cyanothiophene was prepared by standard chemistry well known to those versed in the art and is a colorless oil. 1 H-NMR (400 MHz, CDCl3) delta 7.85 (d, J=2.2 Hz, 1H), 7.25 (d, J=2.2 Hz, 1H) ppm.
		EXAMPLE 17 cis-[4-(4-cyanothien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-ol]17a) 2-bromo-4-cyanothiophene 2-Bromo-5-cyanothiophene was prepared by standard chemistry well known to those versed in the art and is a colorless oil. 1 H-NMR (400 MHz, CDCl3) delta 7.85 (d, J=2.2 Hz, 1H), 7.25 (d, J=2.2 Hz, 1H) ppm.
		Production Example 28 5-Bromo-2-thiophenecarbonitrile 3.3 g (51.7 mmol) of hydroxylamine hydrochloride and 4.1 g (51.7 mmol) of pyridine were added to a dimethylformamide solution (40 ml) containing 8.2 g (43.1 mmol) of the compound of Production Example 28 and the mixture was stirred at room temperature for 30 minutes. Then, 34.9 g (215.5 mmol) of 1,1'-carbonyldiimidazole was added under ice-cooling and the resulting mixture was stirred at room temperature for one hour. Ice-water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with an aqueous 0.1 N hydrochloric acid, water and brine, dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel chromatography, to give 6.7 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm): 7.45 (1H,d,J=4.0Hz), 7.84 (1H,d,J=4.0Hz)
		19a 2-bromo-5-cyanothiophene 2-Bromo-5-cyanothiophene was prepared by standard chemistry well known to those versed in the art and was a colorless oil, 1 H-NMR (400 MHz, CDCl3): delta 7.40 (d, J=4 Hz, 1H), 7.10 (d, J=4 Hz, 1H) ppm.
		PRODUCTION EXAMPLE 28 5-Bromo-2-thiophenecarbonitrile 3.3 g (51.7 mmol) of hydroxylamine hydrochloride and 4.1 g (51.7 mmol) of pyridine were added to a dimethylformamide solution (40 ml) containing 8.2 g (43.1 mmol) of the compound of Production Example 28 and the mixture was stirred at room temperature for 30 minutes. Then, 34.9 g (215.5 mmol) of 1,1'-carbonyldiimidazole was added under ice-cooling and the resulting mixture was stirred at room temperature for one hour. Ice-water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with an aqueous 0.1 N hydrochloric acid, water and brine, dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel chromatography, to give 6.7 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm): 7.45 (1H, d, J=4.0 Hz), 7.84 (1H, d, J=4.0 Hz)

13
[ 2160-62-5 ]
[ 179894-36-1 ]
[ 179899-05-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 415 - 418

14
[ 4701-17-1 ]
[ 2160-62-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	With tert.-butylhydroperoxide; ammonium acetate; iodine; sodium carbonate; In ethanol; at 50℃; for 15h;	In a 25 mL two-necked round bottom flask equipped with a thermometer and a magnetic stirrer was added 4 mmol of 5-bromothiophene-2-carbaldehyde (1-20)), 6 mmol of NH4OAc, 4 mmol of Na2CO3, 4.4 mmol of TBHP, 0.1 mmol of I2, 5 mL of absolute ethanol Solvent, followed by placing the reaction flask in an oil bath preheated to 50 C and opening the magnetic stirrer for 15 h. The reaction solution By adding sodium thiosulfate solution, stirring, and then extracting with ether, separating the organic layer, and removing the solvent under reduced pressure, The eluate was collected with the mixture of ethyl acetate / petroleum ether in a volume ratio of 1: 100 as the eluent, and the eluate containing the target compound was collected. The solvent was distilled off to give 5-bromothiophene-2-carbonitrile with an isolated yield of 82%.
58%		5-Bromo-2-thiophenecarbonitrile: A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL), and ethanol (500 mL) was heated under nitrogen at reflux for two hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an oil. The crude product was triturated twice with ice water and the solid obtained was collected on a filter. A mixture of a portion of the above solid (44.31 g, 215 mmol), copper (II) acetate monohydrate (4.2 g, 21 mmol) in acetonitrile (1.4 L) was heated at reflux for three hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sulfuric acid (2×30 mL), water (2×30 mL), brine (20 mL), and dried (MgSO4). The solvent was removed in vacuo and the residue was dissolved in a minimum amount of chloroform (1 L) and allowed to crystallize. The crystals obtained was collected on a filter and the filtrate was concentrated and purified by a chromatography (silica gel, chloroform) to give the subtitled compound as an off-white solid (31.5 g combined, 58%). IR (film) cm1 2200. 1H-NMR (CDCl3) delta 7.39-7.38 (d, 1H, J=4.1 Hz), 7.10 (d, 1H, J=4.0 Hz); MS (EI) m/z 187 (M+, 98%) 189(M+, 100%).
24%	With hydroxylamine-O-sulfonic acid; In hexane; water; acetic anhydride; ethyl acetate;	EXAMPLE 8 Preparation of 5-Bromo-2-Thiophenecarbonitrile STR97 Hydroxylamine-O-sulfonic acid (17.58 g, 157 mmol) is added to a solution of 5-bromo-2-thiophenecarboxaldehyde (15.00 g, 78.5 mmol) in water and acetonitrile. The reaction mixture is stirred for 17 hours, poured into water and extracted with ether and ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give a brown, oily solid. A solution of the oily solid in acetic anhydride is refluxed for five hours, concentrated in vacuo, poured into water and extracted with ether. The combined organic extracts are washed sequentially with water, half-saturated sodium hydrogen carbonate solution and brine, dried over MgSO4 and concentrated in vacuo to obtain a brown oil. Flash chromatography of the oil using silica gel and a 15% ethyl acetate in hexane solution gives the title product as a yellow oil (3.60 g, 24%).

24%	With hydroxylamine-O-sulfonic acid; In hexane; water; acetic anhydride; ethyl acetate;	EXAMPLE 8 Preparation of 5-Bromo-2-thiophenecarbonitrile STR97 Hydroxylamine-O-sulfonic acid (17.58 g, 157 mmol) is added to a solution of 5-bromo-2-thiophenecarboxaldehyde (15.0 g, 78.5 mmol) in water and acetonitrile. The reaction mixture is stirred for 17 hours, poured into water and extracted with ether and ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give a brown, oily solid. A solution of the oily solid in acetic anhydride is refluxed for five hours, concentrated in vacuo, poured into water and extracted with ether. The combined organic extracts are washed sequentially with water, half-saturated sodium hydrogen carbonate solution and brine, dried over MgSO4 and concentrated in vacuo to obtain a brown oil. Flash chromatography of the oil using silica gel and a 15% ethyl acetate in hexane solution gives the title product as a yellow oil (3.6 g, 24%).
16%	With pyridine; ammonium peroxydisulfate; tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinoxy; In acetonitrile; at 0.5℃; for 24h;Molecular sieve; Sealed tube; Irradiation;	General procedure: To an oven-dried 2 ml reaction vial equipped with a stir bar wasadded the aldehyde 3a (0.136 g, 1 mmol, 1 equiv) and pyridine(0.474 g, 6.0 mmol, 6 equiv), followed by acetonitrile (2 ml, 0.5M in 3a). The vial was then charged with Ru(bpy)3(PF6)2 (0.017g, 0.02 mmol, 0.02 equiv), 2 (0.043 g, 0.20 mmol, 0.20 equiv),(NH4)2S2O8(0.501 g, 2.2 mmol, 2.2 equiv), and activated 3 Amolecular sieves (ca. 0.2 g), sealed with a cap, and irradiated inblue LED reactor for 24 h. In the absence of fan cooling, the temperatureof the reaction mixture plateaued at approximately 50C . After the irradiation was complete, the reaction mixturewas quenched with EtOAc and transferred to a separatoryfunnel. Further EtOAc (30 ml) was added, followed by 0.5 MHCl(aq) (30 ml). The layers were separated, and the aqueous layerwas extracted with EtOAc (3 × 20 ml). The organic layers werethen combined and washed with 0.5 M 0.5 M HCl(aq) (2 × 20 ml),saturated aqueous sodium bicarbonate (2 × 20 ml), and finallybrine (20 ml). The organic layer was then dried over sodiumsulfate and the solvent removed in vacuo to afford the crudeproduct. The resulting crude mixture was adhered to silica gelusing 1.5 weight equivalents of SiO2(relative to the theoreticalyield). The dry-packed material was gently added on top of asilica gel plug. The plug was washed with an excess of hexanes(ca. 5 column volumes). The desired product was eluted off theplug via a 90:10 by volume mixture of hexanes/EtOAc (3-4column volumes). The solvent was removed in vacuo by rotaryevaporation affording the pure nitrile 3c (0.066 g, 50%) as awhite solid.

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 13437 - 13444
[2]Advanced Synthesis and Catalysis,2016,vol. 358,p. 1157 - 1163
[3]RSC Advances,2017,vol. 7,p. 1484 - 1489
[4]Patent: CN106748881,2017,A .Location in patent: Paragraph 0052
[5]Organic and Biomolecular Chemistry,2019,vol. 17,p. 9182 - 9186
[6]Patent: US6355648,2002,B1 .Location in patent: Page column 55
[7]Patent: US5480902,1996,A
[8]Patent: US5492925,1996,A
[9]Synlett,2018,vol. 29,p. 2185 - 2190
[10]Journal of Materials Chemistry,2000,vol. 10,p. 2069 - 2080
[11]Synlett,2011,p. 2223 - 2227
[12]Angewandte Chemie - International Edition,2015,vol. 54,p. 4241 - 4245
[13]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 778 - 781
[14]Journal of Organic Chemistry,2018,vol. 83,p. 14126 - 14137

15
[ 2160-62-5 ]
[ 145369-25-1 ]
2-(6-butylsulfanyl-2-naphthyl)-5-cyanothiophene [ No CAS ]

Reference： [1]Journal of Materials Chemistry,2000,vol. 10,p. 2069 - 2080

16
[ 2160-62-5 ]
[ 71-43-2 ]
[ 215361-51-6 ]

Reference： [1]Physical Chemistry Chemical Physics,2001,vol. 3,p. 2765 - 2770
[2]Physical Chemistry Chemical Physics,2001,vol. 3,p. 2765 - 2770

17
[ 2160-62-5 ]
[ 5720-07-0 ]
[ 200358-05-0 ]

Reference： [1]Journal of Materials Chemistry,2002,vol. 12,p. 2706 - 2721

18
[ 2160-62-5 ]
[ 304876-33-3 ]
5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-thiophene-2-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 86 5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-thiophene-2-carbonitrile Prepared according to the procedure for example 18 using (2'-oxo-[2,3-dihydro-3,3-dimethyl-1,3'-[3H]indol]-5'-yl)boronic acid (570 mg, 2.8 mmol) and 5-bromo-thiophene-2-carbonitrile (350 mg, 1.9 mmol) to afford the title compound (299 mg, 1.1 mmol, 60%) as an off-white solid: m.p. 255-256 C., 1H NMR (CDCl3) delta 1H NMR (CDCl3) delta 1.46 (s, 6H), 6.97 (d, J=8.1 Hz, 1H), 7.21 (d, J=3.9Hz, 1H), 7.39 (d, J=1.3 Hz, 1H), 7.47 (dd, J=8.1, 1.8Hz, 1H), 7.58 (d, J=3.9 Hz, 1H), 8.14 (s, 1H); MS (EI) m/z 268 (M)+.

Reference： [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 3487 - 3490
[2]Patent: US6462032,2002,B1

19
[ 2160-62-5 ]
[ 536-74-3 ]
5-phenylethynyl-thiophene-2-carbonitrile [ No CAS ]

Reference： [1]European Journal of Inorganic Chemistry,2003,p. 3895 - 3904
[2]Journal of Organic Chemistry,2003,vol. 68,p. 1503 - 1511

20
[ 3141-27-3 ]
[ 557-21-1 ]
[ 18853-40-2 ]
[ 2160-62-5 ]

Reference： [1]Synthesis,2004,p. 23 - 25

21
[ 2160-62-5 ]
[ 1001077-05-9 ]
C₂₄H₂₈N₄OS₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; di-isopropyl ether; at 80 - 90℃; for 2h;	N2 atmosphere. A mixture of intermediate (62) (0.0021 mol), 5-bromo-2-thiophene- carbonitrile (0.004 mol), Xantphos (O.lg) and Pd2(dba)3 (0.13 g) in 1,4-dioxane (20 ml) was degassed. DIPE was added and the reaction mixture was degassed again. The reaction mixture was stirred at 80-900C for 2 hours. After cooling, the reaction mixture was filtered over dicalite. The filtrate was concentrated and the residue was purified on silica gel using DCM/CH3OH(7N NH3) (from 100% to 99/1) as eluent. The product fractions were collected and evaporated to dryness. The residue was used as such in the next reaction, yielding 0.45g of intermediate (63).
0.45 g	With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; di-isopropyl ether; at 80 - 90℃; for 2h;Inert atmosphere;	e-1) Preparation of [0248] [0249] N2 atmosphere. A mixture of intermediate (62) (0.0021 mol), <strong>[2160-62-5]5-bromo-2-thiophene-carbonitrile</strong> (0.004 mol), Xantphos (0.1 g) and Pd2(dba)3 (0.13 g) in 1,4-dioxane (20 ml) was degassed. DIPE was added and the reaction mixture was degassed again. The reaction mixture was stirred at 80-90 C. for 2 hours. After cooling, the reaction mixture was filtered over dicalite. The filtrate was concentrated and the residue was purified on silica gel using DCM/CH3OH(7N NH3) (from 100% to 99/1) as eluent. The product fractions were collected and evaporated to dryness. The residue was used as such in the next reaction, yielding 0.45 g of intermediate (63).

Reference： [1]Patent: WO2008/3665,2008,A1 .Location in patent: Page/Page column 45
[2]Patent: US2013/324529,2013,A1 .Location in patent: Paragraph 0248; 0249

22
[ 2160-62-5 ]
(5-formylthiophen-2-yl)boronic acid [ No CAS ]
5'-cyano-5-formyl-2,2'-bithiophene [ No CAS ]

Reference： [1]Organic Letters,2007,vol. 9,p. 3201 - 3204

23
N-[(5S)-3-(3-fluoro-4-piperazin-1-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide trifluoroacetate [ No CAS ]
[ 2160-62-5 ]
(S)-N-[(3-{3-fluoro-4-[4-(5-cyano-thiophen-2-yl)-piperazin-1-yl]phenyl}-2-oxo-oxazolidin-5-yl)methyl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In DMF (N,N-dimethyl-formamide); at 95℃; for 10h;	Step c: Preparation of (S)-N- [ (3- {3-Fluoro-4- [4- (5-cyano-thiophen-2-yl)-piperazin-1- yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide; To (S)-N- (f3- [3-Fluoro-4- (piperazin-1-yl) phenyl]-2-oxo-oxazolidin-5-yllmethyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (0.5 g, 1.48 mmol) in dry dimethylformamide, 2-bromo-5-cyanothiophene (0.27g, 1.48 mmol), cesium carbonate (0.58g, 1. 78mmol), rac-2,2'bis (diphenylphosphino)-1, 1'-binaphthyl (0. 074g, 0.12 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.055 g, 0.06 mmol), were added and heated to 95 C for about 10 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated in vacuo. The residue was purified by column chromatography using 1-3 % methanol/dichloromethane to yield 0.037 g of the title compound. 'H NMR (DMSO) 8ppm : 8.25 (t, 1H), 7.64 (d, 1H), 7.51 (dd, 1H), 7.19 (dd, 1H), 7.13 (t, 1H), 6.32 (d, 1H), 4.72 (m, 1H), 4.1 (t, 1H), 3.70 (m, 2H), 3.14 (m, 4H), 1.83 (s, 3H) M+H = 444 m. p. = 204-207 C

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6714 - 6719
[2]Patent: WO2005/82899,2005,A1 .Location in patent: Page/Page column 30

24
[ 2160-62-5 ]
2-(5''-cyano-2',2''-bithienyl)-1H-anthra[1,2-d]imidazole-6,11-dione [ No CAS ]

Reference： [1]Organic Letters,2007,vol. 9,p. 3201 - 3204

25
[ 2160-62-5 ]
[ 301199-44-0 ]

Reference： [1]Journal of Materials Chemistry,2002,vol. 12,p. 2706 - 2721

26
[ 2160-62-5 ]
(E)-Hex-4-enoic acid 4-(5-cyano-thiophen-2-yl)-phenyl ester [ No CAS ]

Reference： [1]Journal of Materials Chemistry,2002,vol. 12,p. 2706 - 2721

27
[ 2160-62-5 ]
2-cyano-5-(4-[(E,E)-hexa-2,4-dienoyloxy]phenyl)thiophene [ No CAS ]

Reference： [1]Journal of Materials Chemistry,2002,vol. 12,p. 2706 - 2721

28
[ 2160-62-5 ]
(Z)-Hex-3-enoic acid 4-(5-cyano-thiophen-2-yl)-phenyl ester [ No CAS ]

Reference： [1]Journal of Materials Chemistry,2002,vol. 12,p. 2706 - 2721

29
[ 2160-62-5 ]
(E)-Hex-2-enoic acid 4-(5-cyano-thiophen-2-yl)-phenyl ester [ No CAS ]

Reference： [1]Journal of Materials Chemistry,2002,vol. 12,p. 2706 - 2721

30
[ 2160-62-5 ]
hex-5-enoic acid 4-(5-cyano-thiophen-2-yl)-phenyl ester [ No CAS ]

Reference： [1]Journal of Materials Chemistry,2002,vol. 12,p. 2706 - 2721

31
[ 2160-62-5 ]
2-cyano-5(4-[hexanoyloxy]phenyl)thiophene [ No CAS ]

Reference： [1]Journal of Materials Chemistry,2002,vol. 12,p. 2706 - 2721

32
[ 98-03-3 ]
benzylmagnesium halide [ No CAS ]
[ 2160-62-5 ]

Reference： [1]Journal of Materials Chemistry,2000,vol. 10,p. 2069 - 2080

33
[ 2160-62-5 ]
6-(5-Cyano-thien-2-yl)-1,2-dihydro-2,2,4-trimethylquinoline [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 415 - 418

34
[ 2160-62-5 ]
[ 150239-77-3 ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

35
[ 2160-62-5 ]
[ 146823-45-2 ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

36
[ 2160-62-5 ]
[ 205529-41-5 ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

37
[ 2160-62-5 ]
5'-Dimethylamino-[2,2']bithiophenyl-5-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

38
[ 2160-62-5 ]
5'-Pyrrolidin-1-yl-[2,2']bithiophenyl-5-carboxylic acid [ No CAS ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

39
[ 2160-62-5 ]
5'-Dimethylamino-[2,2']bithiophenyl-5-carboxylic acid cyclohexylamide [ No CAS ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

40
[ 2160-62-5 ]
[ 205529-43-7 ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

41
[ 2160-62-5 ]
(1R,2R)-1,2-cyclohexanediyl bis-(5'-dimethylamino)-(2.2'-bithiophene)-5-carboxylate [ No CAS ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

42
[ 2160-62-5 ]
(1R,2R)-N,N'-bis[5'-(dimethylamino)(2,2'-bithiophene)-5-carboxyl]cyclohexyldiamide [ No CAS ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

43
[ 2160-62-5 ]
5'-Dimethylamino-[2,2']bithiophenyl-5-carboxylic acid (2S,3R,4S,6R)-4-[1-(5'-dimethylamino-[2,2']bithiophenyl-5-yl)-meth-(E)-ylidene]-amino}-6-methoxy-2-methyl-tetrahydro-pyran-3-yl ester [ No CAS ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

44
[ 2160-62-5 ]
C₂₉H₃₂N₂O₆S₄ [ No CAS ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

45
[ 2160-62-5 ]
{5'-[(E)-Cyclohexyliminomethyl]-[2,2']bithiophenyl-5-yl}-dimethyl-amine [ No CAS ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

46
[ 2160-62-5 ]
Cyclohexyl-[1-(5'-pyrrolidin-1-yl-[2,2']bithiophenyl-5-yl)-meth-(E)-ylidene]-amine [ No CAS ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

47
[ 2160-62-5 ]
(2S,3R,4S,6R)-4-[1-(5'-Dimethylamino-[2,2']bithiophenyl-5-yl)-meth-(E)-ylidene]-amino}-6-methoxy-2-methyl-tetrahydro-pyran-3-ol [ No CAS ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

48
[ 2160-62-5 ]
(1R,2R)-N-[1-(5'-Dimethylamino-[2,2']bithiophenyl-5-yl)-meth-(E)-ylidene]-N'-[1-(5'-dimethylamino-[2,2']bithiophenyl-5-yl)-meth-(Z)-ylidene]-cyclohexane-1,2-diamine [ No CAS ]

Reference： [1]Heterocycles,1997,vol. 46,p. 489 - 501

49
[ 2160-62-5 ]
[ 79456-39-6 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions II,1989,p. 1779 - 1782

50
[ 2160-62-5 ]
5-methylsulfonyl-4-nitrothiophene-2-carbonitrile [ No CAS ]

Reference： [1]Journal of the Chemical Society. Perkin transactions II,1989,p. 1779 - 1782

51
[ 2160-62-5 ]
[ 304876-18-4 ]
5-(2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'yl)-2-thiophenecarbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0);	5-(2'-Oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3H]indo]-5'yl-2-thiophenecarbonitrile was prepared according to the procedure for Example 5 using <strong>[2160-62-5]5-bromo-2-thiophenecarbonitrile</strong> and (2'-oxo-2',3'-dihydrospiro[cyclohexane-1,3'-[3H]indol]-5'-yl) boronic acid: mp. 225-228 C.; 1H NMR (DMSO-d6) delta 1.63 (m, 8H), 1.90 (m, 2H) 6.91 (d, 1H, J=8.13 Hz), 7.55 (dd, 1H, J=8.13, 1.76 Hz), 7.60 (d, 1H, J=4.17 Hz), 7.75 (d, 1H, J=1.76 Hz), 7.93 (d, 1H, J=4.17 Hz), 10.51 (s, 1H); MS ((+)APCI) m/z 309 [M+H]+.

Reference： [1]Patent: US6355648,2002,B1 .Location in patent: Page column 55

52
[ 2160-62-5 ]
[ 924-88-9 ]
[ 777079-55-7 ]

Yield	Reaction Conditions	Operation in experiment
7.3%		6.01 G of sodium and 400 ml OF TERT-AMYL ALCOHOL are heated up to 100 C under a nitrogen atmosphere and stirred for 18 hours. The reaction mixture is allowed to cool to room temperature, 44. 66 G OF 2-CYANO-5-BROMOTHIOPHENE ARE added and heated up to 110C. As soon as the temperature has been reached, a solution OF 24. 3G OF DIISOPROPYL SUCCINATE and 100 mi of tert-amyl alcohol is added over 5 hours using a dropping funnel. When the addition has been completed, the reaction mixture is kept for 20 hours at 120C and cooled down to 65C. Then 300ML of water and 20 mi of acetic acid are added and the resultant pigment suspension is filtered at room temperature, washed with methanol and water until washings run colorless, and dried, affording 8. Og (7.3% of theory, based on dibutyl succinate) of 1,4- diketo-3, 6-BIS-2- (5-BROMOTHIOPHENE-YI)-PYRROLO- (3, 4-C)-PYRROLE. Example 3 is repeated, except using A-4 in place OF A-1, whereby a red solid is obtained (yield : 5%)

Reference： [1]Patent: WO2004/90046,2004,A1 .Location in patent: Page 58

53
[ 2160-62-5 ]
[ 64-17-5 ]
[ 57870-80-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; at -10℃;	Intermediate 117: 5-Bromo-thiophene-2-carboximidic acid ethyl ester A cooled (-10C) solution of 5-bromo-thiophene-2-carbonitrile (32. 5G, 0. 17MOL) in ethanol (250ML) was stirred whilst gaseous hydrochloric acid was bubbled through for 1.5 hours. After stirring for a further 2 hours the reaction mixture was left to stand overnight, before being evaporated to dryness to provide a residue. The residue was triturated with diethyl ether, to provide 5-BROMO-THIOPHENE-2-CARBOXIMIDIC acid ethyl ester (41g) as a white solid. LCMS (Method B): RT = 1.96 minutes; 234 & 236 (M+H) +.

Reference： [1]Patent: WO2005/14588,2005,A1 .Location in patent: Page/Page column 83

54
[ 2160-62-5 ]
[ 869854-23-9 ]
C₁₄H₁₀F₃NOS₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 110℃; for 2.5h;	To <strong>[2160-62-5]5-bromothiophene-2-carbonitrile</strong> (1.6 g, 8.3 mmol), (S)-1,1,1- trifluoro-2- (4-mercaptophenyl)propan-2-ol (1.8 g, 7.9 mmol) and Cs2C03 (3.1 g, 9.5 mmol) under nitrogen atmosphere was added DMF (8 mL). The reaction was warmed to 110 C and stirred for 2.5 h. The reaction was cooled to room temperature, poured onto 1 M HCI (80 mL), and extracted with CH2C12 (5 x 20 mL). The combined organics were dried with Na2S04 and concentrated in vacuo to obtain 2.6 g of the sulfide product.

Reference： [1]Patent: WO2005/110980,2005,A2 .Location in patent: Page/Page column 99

55
[ 2160-62-5 ]
[ 612499-04-4 ]

Yield	Reaction Conditions	Operation in experiment
85%		Preparation Example A+-21.C-(5-Bromo-thiophen-2-yl)-methylamine To a mixture of lithium aluminum hydride (1.6g, 41 mmol) and tetrahydrofuran (45mL) was aluminum chloride (6.1 g, 46mmol) on an ice bath, then, the solution was stirred for 1 hour at room temperature. The reaction solution was cooled to -20C, a solution of 5-bromo-thiophene-2-carbonitrile described in Preparation Example A+-20 (4.3g, 25mmol) in tetrahydrofuran (5mL) was added dropwise at the same temperature. After stirring at 2C for 20 minutes, the reaction solution was cooled to -10C, and while maintaining the internal temperature at 0Cor lower, tetrahydrofuran (300mL) and 28% aqueous ammonia solution (5mL) were added thereto. Anhydrous magnesium sulfate was added to the reaction solution, which was then filtered using a filter paper, and then, concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (ethyl acetate), and the title compound (840mg, 4.4mmol, 85%) was obtained as a colorless oil. 1H-NMR Spectrum (CDCl3) delta (ppm) : 3.99(2H, s), 6.67(1 H, d, J=3.7Hz), 6.88(1 H, d, J=3.7Hz).
85%		To a mixture of lithium aluminum hydride (1.6g, 41 mmol) and tetrahydrofuran (45mL) was aluminum chloride (6.1g, 46mmol) on an ice bath, then, the solution was stirred for 1 hour at room temperature. The reaction solution was cooled to -20C, a solution of 5-bromo-thiophene-2-carbonitrile described in Preparation Example A+-20 (4.3g, 25mmol) in tetrahydrofuran (5mL) was added dropwise at the same temperature. After stirring at 2C for 20 minutes, the reaction solution was cooled to -10C, and while maintaining the internal temperature at 0Cor lower, tetrahydrofuran (300mL) and 28% aqueous ammonia solution (5mL) were added thereto. Anhydrous magnesium sulfate was added to the reaction solution, which was then filtered using a filter paper, and then, concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (ethyl acetate), and the title compound (840mg, 4.4mmol, 85%) was obtained as a colorless oil. 1H-NMR Spectrum (CDCl3) delta(ppm) : 3.99(2H, s), 6.67(1H, d, J=3.7Hz), 6.88(1H, d, J=3.7Hz).

Reference： [1]Patent: EP1782811,2007,A1 .Location in patent: Page/Page column 51
[2]Patent: EP1669348,2006,A1 .Location in patent: Page/Page column 59-60

56
[ 943325-65-3 ]
[ 2160-62-5 ]

Yield	Reaction Conditions	Operation in experiment
88%	With acetic anhydride; acetic acid; In tetrahydrofuran; at 20 - 70℃; for 10h;	To a mixture of 5-bromo-thiophene-2-carbaldehyde oxime described in Preparation Example A+-19 (1.3g, 6.2mmol) and tetrahydrofuran (15mL) were acetic acid (1.4mL, 25mmol) and acetic anhydride (1.5mL, 15mmol) at room temperature, then, stirred at 50C for 2 hours, and further stirred at 70C for 8 hours. After cooling this reaction mixture, the solution was concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (heptane : ethyl acetate = 8 : 1), and the title compound (1.0g, 5.4mmol, 88%) was obtained as a colorless solid. 1H-NMR Spectrum (CDCl3) delta(ppm) : 7.11 (1 H, d, J=4.0Hz), 7.40(1 H, d, J=4.0Hz).

Reference： [1]Patent: EP1669348,2006,A1 .Location in patent: Page/Page column 59

57
[ 2160-62-5 ]
C₅H₂LiNS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In diethyl ether; hexane; at -78℃; for 0.0833333h;	n-Butyllithium (1.6M, 640 uL, 1.60 mmol) was added to a solution of 5-bromothiophene-2- carbonitrile (200 mg, 1.06 mmol) in anhydrous ether (10 mL) which was stirred at-78 C under nitrogen. After 5 minutes, tri-n-butylstannyl chloride (346 mg, 1.60 mmol) was added, then the solution was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched, and washed with IN sodium hydroxide, dried through MgS04, and then the solvent was evaporated to give a brown oily residue. Purification by flash chromatography using a gradient of ammoniated methanol in chloroform gave the sub-title compound as a yellow oil (296 mg).

Reference： [1]Patent: WO2003/87103,2003,A1 .Location in patent: Page/Page column 18

58
[ 2160-62-5 ]
[ 304853-90-5 ]
[ 304854-39-5 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 21 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [1,3]oxazin-6-yl)-thiophene-2-carbonitrile Prepared according to Procedure B from <strong>[2160-62-5]5-bromo-2-thiophenecarbonitrile</strong> and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. Off-white solid: mp 264-266 C. 1H-NMR (DMSO-d6) delta10.3 (s, 1H), 7.97 (d, 1H, J=7.9 Hz), 7.60-7.66 (m, 3H). 6.96 (d, 1H, J=8.1 Hz), 1.65 (S, 6H). MS (APCI) m/z 285 (M+H)+, 302 (M+NH4)+. Anal. Calc. For C15H12N2O2S: C, 63.36; H, 4.25; N, 9.85. Found: C, 63.01; H, 4.36; N, 9.39.
		EXAMPLE 21 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile Prepared according to Procedure B from <strong>[2160-62-5]5-bromo-2-thiophenecarbonitrile</strong> and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. Off-white solid: mp 264-266 C. 1H-NMR (DMSO-d6) delta10.3 (s, 1H), 7.97 (d, 1H, J=7.9 Hz), 7.60-7.66 (m, 3H). 6.96 (d, 1H, J=8.1 Hz), 1.65 (S, 6H). MS (APCI) m/z 285 (M+H)+, 302 (M+NH4)+. Anal. Calc. For C15H12N2O2S: C, 63.36; H, 4.25; N, 9.85. Found: C, 63.01; H, 4.36; N, 9.39.

Reference： [1]Patent: US2002/49204,2002,A1
[2]Patent: US6444668,2002,B1

59
[ 2160-62-5 ]
(spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-one-5-yl) boronic acid [ No CAS ]
[ 304875-52-3 ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In 1,2-dimethoxyethane; water;	EXAMPLE 78 5-(1,2-Dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitrile A solution of 2-bromo-5-cyanothiophene (0.5 g, 2.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3'-[3H]indol]-2'(1'H)-one-5-yl) boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (*3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.3 g, 40%) as a yellow solid. mp: 248 C.; 1H NMR (DMSO-d6) delta10.4 (s, 1H), 8.5 (d, 1H, J=1.4 Hz), 8.3 (d, 1H, J=1.4 Hz), 7.6 (s, 1H), 7.5 (dd, 1H, J=1.7, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.8 (m, 8H); MS [M-H]-=293.

Reference： [1]Patent: US6391907,2002,B1

60
[ 2160-62-5 ]
[ 211943-12-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium azide; triethylamine hydrochloride; In toluene; at 100 - 110℃;	To a solution of <strong>[2160-62-5]5-bromothiophene-2-carbonitrile</strong> (1.5 g) in toluene was added sodium azide (1.33 g) and triethylamine hydrochloride (2.89 g) and the reaction mixture was stirred overnight at 100-110 0C. The reaction mixture was filtered and the solid was washed with methanol. The filtrate was concentrated under vacuum to yield the title compound (1.8 g).

Reference： [1]Patent: WO2006/38100,2006,A1 .Location in patent: Page/Page column 83

61
[ 71-23-8 ]
[ 2160-62-5 ]
[ 892387-46-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In diethyl ether; at 20℃; for 72.5h;	Example 13. 3-f3-(5 -f pyridin-3- vDthiophen-2-vD- IH-1 ,2,4-triazol- 1 -yPquinuclidine. A mixture of 3-(3-(5-bromothiophen-2-yl)-lH-l,2,4-triazol-l-yl)quinuclidine (120 mg), pyridine-3-boronic acid (52 mg), cesium carbonate (234 mg) and bistriphenylphosphine palladium(II) chloride (13 mg) in 1,2-dimethoxyethane/water/ethanol (7:3:2, 2.5mL) was subjected to microwave irradiation at 150 0C for 10 minutes. After cooling to room temperature, the mixture was partitioned between chloroform (2 x 25 mL) and saturated aqueous potassium carbonate (2 x 25 mL). The organic extracts were combined, dried over potassium carbonate, filtered and evaporated to leave a yellow oil (110 mg). The product was purified by flash chromatography on basic alumina eluting with a chloroform to 1% MeOH/chloroform gradient followed by preparative supercritical fluid chromatography (Chiralpak AD, 17% MeOH, 0.5% DMEA in CO2) to afford the title compound, which was isolated as the dihydrochloride salt (10 mg). MS (AP+) 338 (MH+). 1H NMR (300.132 MHz, CDCl3) ? 8.93 (s, IH), 8.53 (d, J= 3.8 Hz, IH), 8.14 (s, IH), 7.90 (d, J- 7.9 Hz, IH), 7.68 (d, J- 3.8 Hz, IH), 7.36 (d, J= 3.8 Hz, 2H), 7.32 (dd, J= 8.0, 4.9 Hz, 2H), 4.45 (s, IH), 3.54 - 3.40 (m, 2H), 3.20 - 3.11 (m, IH), 3.01 - 2.84 (m, 4H), 2.24 (q, J= 2.9 Hz, IH), 1.88 - 1.70 (m, 4H), 1.53 - 1.43 (m, IH).The starting material, 5-bromothiophene-2-carboximidic acid ethyl ester hydrochloride, was prepared as follows: a. 5-Bromothiophene-2-carboximidic acid ethyl ester hydrochloride.A solution of 2-bromo-5-cyanothiophene (1.05 g) in diethyl ether (20 mL) and ethanol (1 mL) was treated with hydrogen chloride (g) for 30 min. The resulting mixture was stirred at room temperature for 72 hr to afford a white precipitate. The product was isolated by filtration, washed with cold diethyl ether (2 x 5 mL) and dried in vacuo to afford the title compound as a white solid (1.20 g). 1H NMR (300.132 MHz3 DMSO) ? 8.52 (s, IH), 7.56 (s, IH)3 4.61 (q, J= 7.0 Hz3 2H)3 1.42 (t, J= 7.0 Hz3 3H). 13C NMR (75.477 MHz3 DMSO) ? 164.21, 137.54, 133.31, 130.23, 124.13, 70.17, 13.85. b. 3-(3-(5-Bromothiophen-2-yl)-lH-l,2,4-triazol-l-yl)quinuclidme.A solution of l-(quinuclidin-3-yl)hydrazine dihydrochloride (213 mg) and 5- bromothiophene-2-carboximidic acid ethyl ester hydrochloride (284 mg) and triethylamine (313 mg) in methanol (5 mL) was stirred at room temperature for 22 hr. The solvent was then evaporated and the residue was suspended in triethyl orthoformate (10 mL) and pyridine (2 mL). The resulting mixture was heated to reflux for 16 hr, then was cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate (3 x 50 mL) and saturated aqueous potassium carbonate (2 x 20 mL). The organic extracts were combined, dried over potassium carbonate, filtered and evaporated to leave an amber oil (295 mg). The product was purified by flash chromatography on basic alumina eluting with a chloroform to 2% MeOH/chloroform gradient to afford the title compound as a clear oil (120 mg). MS (AP+) 339/341 (MH+). 1H NMR (300.132 MHz, CDCl3) ? 8.09 (s, IH), 7.41 (d, J= 3.8 Hz, IH)3 7.04 (d, J= 3.9 Hz, IH), 4.45 - 4.38 (m, IH), 3.45 - 3.42 (m, 2H), 3.18 - 3.06 (m, IH), 2.95 - 2.87 (m, 4H), 2.23 - 2.20 (m, IH), 1.82 - 1.73 (m, 4H), 1.58 (s, 3H). c. The l-(quinuclidin-3-yl)hydrazine dihydrochloride used above was prepared by methods described in J. Med. Chem., 35, 1280 (1992).

Reference： [1]Patent: WO2006/65217,2006,A1 .Location in patent: Page/Page column 27-28

62
[ 2160-62-5 ]
[ 153587-32-7 ]
4-(2-cyanothien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With ammonium chloride;copper(I) iodide; tetrakis(triphenylphosphine)palladium (0); In triethylamine;	19b 4-(2-cyanothien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-1-one (0.22 g, 0.7 mmol) and 2-bromo-5-cyanothiophene (0.13 g, 0.7 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.034 g, 4%) and copper(I) iodide (0.007 g, 6%), and the mixture was heated at 85-90 C. for 2 h. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluding with 2:8 ethyl acetate:hexanes, provided 4-(2-cyanothien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.06 g, 18%). This was combined with product (0.017 g) obtained in a second, similar reaction and was triturated from dichloromethane-hexanes to provide a white solid, mp 106-107 C. Anal. (C25 H25 NO3 S.0.5 H2 O) calcd: C, 70.07; H, 6.11; N, 3.27; found: C, 70.15; H, 5.84; N, 3.32.

Reference： [1]Patent: US5861421,1999,A

63
[ 2160-62-5 ]
[ 844496-26-0 ]

Reference： [1]Patent: WO2006/123639,2006,A1 .Location in patent: Page/Page column 136-137

64
[ 2160-62-5 ]
[ 211943-12-3 ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium azide; In methanol; N,N-dimethyl-formamide; at 20 - 100℃; for 7.5h;	General procedure: A mixture of benzonitrile (1 mmol), sodium azide (2 mmol), Ln(OTf)3-SiO2 (2008 mg) and DMF/MeOH (4:1, 5 mL) in a pressure vial was initially stirred at room temperature. After 30 min, the temperature of the reaction mixture was raised to 100 C and stirred for another 7 h. After consumption of 1a (as indicated by TLC), the catalyst was separated by filtration and the filtrate was treated with ethyl acetate (15 mL). The organic layer was washed with 4 N HCl (20 mL). The resultant organic layer was separated and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layer was washed with water (2 × 10 mL), dried over anhydrous sodium sulfate and concentrated to afford white crystalline solid.5-Phenyl-1H-tetrazole(3a)IR (KBr, cm-1): 3331, 2907, 2850, 2611, 1607, 1485, 1433, 1050, 828, 742. 1H NMR (300 MHz, CDCl3): 8.04-8.007 (m, 1H), 7.611-7.574 (m, 2H). 13C NMR (75 MHz, CDCl3): 156.03, 131.19, 129.08, 126.805, 123.924. MS: m/z = 146 [M]+.
	With sodium azide; triethylamine hydrochloride; In toluene; at 100℃;	Referential Example 6; 5-Bromothiophene-2-carbonitrile, sodium azide, and triethylamine hydrochloride were heated at 100C in toluene to obtain 5-(5-bromo-2-tienyl)-1H-tetrazole. ES: 231, 233.

Reference： [1]European Journal of Inorganic Chemistry,2010,p. 4643 - 4657
[2]Tetrahedron Letters,2014,vol. 55,p. 3557 - 3560
[3]Patent: EP1783124,2007,A1 .Location in patent: Page/Page column 16
[4]Journal of Materials Chemistry,2012,vol. 22,p. 11816 - 11825

65
[ 2160-62-5 ]
[ 876938-75-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 5; Under an argon atmosphere, 1.0 g of 4-bromo-1-isobutoxy-2-nitrobenzene, 1.0 g of bispinacolatodiboron, 1.2 g of potassium acetate, and 0.1 g of tetrakis(triphenylphosphine)palladium were heated at 100C for 4 days in toluene. Then, 658 mg of <strong>[2160-62-5]5-bromothiophene-2-carbonitrile</strong>, 0.1 g of tetrakis(triphenylphosphine)palladium, 10 ml of 1,4-dioxane, and 12 ml of a 2M aqueous sodium carbonate solution were added thereto, followed by heating at 100C for 4 hours under an argon atmosphere. After the reaction solution was diluted with water and ethyl acetate, the solution was filtrated through celite. The filtrate was extracted with ethyl acetate and the organic layer was washed with brine and then dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10) to obtain 522 mg of 5-(4-isobutoxy-3-nitrophenyl)thiophene-2-carbonitrile. Then, 214 mg of the compound, 0.13 g of triethylamine hydrochloride, and 60 mg of sodium azide were heated at 100C for 14 hours in 20 ml of toluene. Additionally, 0.13 g of triethylamine hydrochloride and 60 mg of sodium azide were added thereto, followed by heating at 100C for 4 hours. The reaction solution was extracted with water and the aqueous layer was acidified with 1M hydrochloric acid. The precipitate was collected by filtration, washed with water, dried, and purified by silica gel column chromatography (chloroform:methanol:acetic acid=94.7:5:0.3) to obtain 67 mg of 5-[5-(4-isobutoxy-3-nitrophenyl)-2-thienyl]-1H-tetrazole.

Reference： [1]Patent: EP1783124,2007,A1 .Location in patent: Page/Page column 19

66
[ 2160-62-5 ]
[ 5720-07-0 ]
[ 497-19-8 ]
[ 200358-05-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride;tetrakis(triphenylphosphine)palladium (0); In 1,2-dimethoxyethane; hexane; ethyl acetate;	A solution of 2-bromo-5-cyanothiophene (4.9 g), 4-methoxyphenyl boronic acid (4.7 g), 2M aqueous sodium carbonate solution (80 cm3), tetrakis(triphenylphosphine)palladium (0) (0.4 g) and dimethoxyethane (80 cm3) was heated under reflux for 6 h under an atmosphere of nitrogen. 20% Hydrochloric acid (200 cm3) was added and the resultant mixture extracted with diethyl ether (5100 cm3). The combined organic layers were washed with 20% hydrochloric acid (1100 cm3), brine (2*100 cm3) and then dried (MgSO4), filtered and evaporated down. The residue was purified by column chromatography on silica gel using a 9:1 hexane/ethyl acetate mixture as eluent and recrystallisation from ethanol to yield 4.5 g of 2-cyano-5-(4-methoxyphenyl)thiophene, K 58-60 C., I.

Reference： [1]Patent: US6696110,2004,B1

67
[ 2160-62-5 ]
[ 75-05-8 ]
[ 942590-32-1 ]

Yield	Reaction Conditions	Operation in experiment
		Potassium tert-butoxide (5.37 g) was added in portions to a solution of 5-bromo-2- thiophenecarbonitrile (3.0 g) in dry toluene (60 mL) and dry MeCN (1.66 mL) at room temperature under nitrogen. The solution was left to stir at room temperature for 2.5 h. Diethyl ether (100 mL) and saturated sodium carbonate solution (100 mL) were added and <n="93"/>the mixture was stirred vigorously for 5 mins. The layers were separated and the aqueous extracted further with diethyl ether (2 x 50 ml_). The combined organics were dried over sodium sulphate and were evaporated to give the title compound. MS calcd for (C7H5BrN2S + H)+: 229/331 MS found (electrospray): (M+H)+ = 229/331

Reference： [1]Patent: WO2007/71434,2007,A1 .Location in patent: Page/Page column 91-92

68
[ 1003-31-2 ]
[ 79-24-3 ]
[ 18820-82-1 ]
[ 2160-62-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In hexane; dichloromethane; chloroform;	A solution of 2-cyanothiophene (30.0 g), anhydrous <strong>[18820-82-1]pyridine hydrobromide</strong> (100 cm3) and nitroethane (13.5 g) was heated under reflux for 1 h under an atmosphere of nitrogen. The cooled reaction mixture was poured onto a mixture of chloroform (300 cm3) and 0.1M hydrochloric acid (300 cm3). The organic layer was separated off and the aqueous layer extracted with dichloromethane (250 cm3). The combined organic layers were washed with brine (2100 cm3), dried (MgSO4), filtered and then evaporated down. The residue was purified by column chromatography on silica gel using a 1:1 hexane/dichloromethane mixture as eluent to yield 12.8 g of 2-bromo-5-cyanothiophene as an oil.

Reference： [1]Patent: US6696110,2004,B1

69
[ 2160-62-5 ]
[ 36354-42-4 ]
[ 284660-96-4 ]

Reference： [1]European Journal of Inorganic Chemistry,2003,p. 3895 - 3904

70
[ 2160-62-5 ]
[ 304858-44-4 ]
5-(2,4,4-trimethyl-1,4-dihydro-2H-1,3-benzoxazin-6-yl)thiophene-2-carbonitrile [ No CAS ]

Reference： [1]Patent: US6358948,2002,B1 .Location in patent: Example 13

71
[ 2160-62-5 ]
[ 75-05-8 ]
[ 1094568-57-6 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 12(2E,Z)-3-Amino-3-(5-bromo-2-thienyl)-2-propenenitrileTo a solution of <strong>[2160-62-5]5-bromothiophene-2-carbonitrile</strong> (10.0 g, 53.2 mmol) in dry MeCN (5.56 mL) and dry toluene (200 mL) under nitrogen was added potassium te/f-butoxide (17.9 g, 159.6 mmol) in four equal portions over 45 mins. After 3 hours, diethyl ether (150 mL) and saturated sodium carbonate solution (150 mL) were added and the mixture stirred vigorously for 10 mins. The organic layer was extracted with more ether (2 x 50 mL), the combined organics were dried (hydrophobic frit) and evaporated to give the title compound. MS calcd for (C7H5BrN2S - H)": 228/230 MS found (electrospray): (M-H)" = 228/230

Reference： [1]Patent: WO2009/818,2008,A1 .Location in patent: Page/Page column 35

72
[ 2160-62-5 ]
[ 1163277-46-0 ]
[ 1163265-51-7 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;copper(l) iodide; (S)-[1,1']-binaphthalenyl-2,2'-diol; In 1-methyl-pyrrolidin-2-one; at 20 - 90℃; for 20h;	Example 34B(3R)-N-[(2Z)-3-(5-cyanothien-2-yl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-3-fluoropyrrolidine-1-carboxamide; Example 34A (46 mg, 0.20 mmol), copper (I) iodide (7.6 mg, 0.04 mmol), (S)-(-)-1,1'-bi(2-naphthol) (11.5 mg, 0.04 mmol), and cesium carbonate (78 mg, 0.24 mmol) were added to a reaction vial with a septum-containing cap, and flushed with nitrogen three times. Then <strong>[2160-62-5]5-bromothiophene-2-carbonitrile</strong> (27 muL, 0.24 mmol) and anhydrous 1-methyl-2-pyrrolidinone (0.20 mL) were added through the septum, the mixture was stirred a while at room temperature, and then heated in the dark first at 70 C. for 5 hours and then at 90 C. for 15 hours. Then the mixture was quenched with concentrated aqueous ammonium hydroxide (0.40 mL), mixed with 4:1 ethyl acetate/hexanes, and passed through diatomaceous earth with a 4:1 ethyl acetate/hexanes rinse. The aqueous phase was separated and back-extracted with 4:1 ethyl acetate/hexanes. The combined organic phases were washed with concentrated aqueous ammonium hydroxide, dried (sodium sulfate), concentrated, and chromatographed twice on silica (ethyl acetate/dichloromethane) to give the title compound.1H NMR (300 MHz, d4-MeOH) delta ppm 2.0-2.4 (2H), 2.33 (3H), 3.5-4.2 (4H), 5.2-5.5 (1H), 7.39 (1H), 7.64 (1H), 7.69 (1H); MS (ESI) m/z 337 (M+H)+.

Reference： [1]Patent: US2009/163470,2009,A1 .Location in patent: Page/Page column 27

73
[ 2160-62-5 ]
[ 122775-35-3 ]
[ 1067911-39-0 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6110 - 6120

74
[ 67-56-1 ]
[ 2160-62-5 ]
[ 1126601-61-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 3174 - 3176

75
tributyl(3-dodecylcyclopenta-1,3-dien-1-yl)stannane [ No CAS ]
[ 2160-62-5 ]
[ 1220883-07-7 ]

Reference： [1]Tetrahedron,2010,vol. 66,p. 1837 - 1845

76
[ 2160-62-5 ]
[ 123-25-1 ]
[ 777079-55-7 ]

Reference： [1]Tetrahedron,2010,vol. 66,p. 1837 - 1845

77
[ 2160-62-5 ]
tributyl(4-hexyl-2-thienyl)stannane [ No CAS ]
[ 1220883-06-6 ]

Reference： [1]Tetrahedron,2010,vol. 66,p. 1837 - 1845

78
C₇H₉BrNS⁽¹⁺⁾*Cl^(1-) [ No CAS ]
[ 2160-62-5 ]

Reference： [1]Synlett,2010,p. 1067 - 1070

79
[ 2160-62-5 ]
[ 150-76-5 ]
[ 915084-41-2 ]

Reference： [1]Patent: WO2006/123639,2006,A1 .Location in patent: Page/Page column 138

80
(E)-5-methylthiophen-2-carbaldehyde oxime [ No CAS ]
[ 2160-62-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In tetrahydrofuran; ethyl acetate; at 20℃;Inert atmosphere;	To a solution of aldoxime (0.01 mol) in THF (10 mL) was added T3P (15 mol %, 50% soln in EtOAc) and the resulting reaction mixture was stirred at room temperature for 1-2 h under nitrogen atmosphere. When the reaction was completed as confirmed by TLC, the solvent was removed under vacuum and the residue was diluted with water (20 mL). The product was extracted with ethyl acetate (2 × 20 mL) and the combined organic phase was washed with saturated NaHCO3 solution (1 × 10 mL) and brine. The organic phase was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford the desired nitriles in good purity.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 1074 - 1077

81
[ 2160-62-5 ]
[ 1305348-47-3 ]
[ 1305348-67-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90 - 100℃; for 24h;Inert atmosphere;	General procedure: Tetrakistriphenylphosphine palladium (0.288 g, 0.25 mmol) was added to a stirred mixture of the indole stannane 3 (2.29 g, 5 mmol) and the halo arylnitriles (<strong>[2160-62-5]5-bromothiophene-2-carbonitrile</strong> and 4-bromobenzonitrile) (5 mmol) in deaireated dioxane (20 mL) under a nitrogen atmosphere. The mixture was warmed to 90-100 C and stirred for 24 h. The solvent was evaporated under reduced pressure. The resultant solid was partitioned between ethyl acetate (200 mL) containing 5 mL of concentrated ammonia to destroy the palladium complex, washed with water, passed through celite, dried over sodium sulfate and evaporated. Purification was by column chromatography on silica gel, using hexanes/ethyl acetate (80:20, v/v) as the eluent.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2156 - 2167

82
[ 2160-62-5 ]
[ 1305348-47-3 ]
6-(4-amidinophenyl)-2-(5-amidinothien-2-yl)-1H-indole dihydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2156 - 2167

83
[ 2160-62-5 ]
[ 1028752-18-2 ]
[ 1305348-31-5 ]

Yield	Reaction Conditions	Operation in experiment
79%	With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90 - 100℃; for 24h;Inert atmosphere;	General procedure: Tetrakistriphenylphosphine palladium (0.288 g, 0.25 mmol) was added to a stirred mixture of the indole stannane 3 (2.29 g, 5 mmol) and the halo arylnitriles (<strong>[2160-62-5]5-bromothiophene-2-carbonitrile</strong> and 4-bromobenzonitrile) (5 mmol) in deaireated dioxane (20 mL) under a nitrogen atmosphere. The mixture was warmed to 90-100 C and stirred for 24 h. The solvent was evaporated under reduced pressure. The resultant solid was partitioned between ethyl acetate (200 mL) containing 5 mL of concentrated ammonia to destroy the palladium complex, washed with water, passed through celite, dried over sodium sulfate and evaporated. Purification was by column chromatography on silica gel, using hexanes/ethyl acetate (80:20, v/v) as the eluent.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2156 - 2167

84
[ 2160-62-5 ]
[ 1305348-84-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2156 - 2167

85
[ 2160-62-5 ]
5-(4-amidinophenyl)-2-(5-amidinothien-2-yl)-1H-indole dihydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2156 - 2167

86
[ 2160-62-5 ]
[2.2′-bithiophene]-5.5′-dicarbonitrile [ No CAS ]

Reference： [1]European Journal of Inorganic Chemistry,2010,p. 4643 - 4657

87
[ 2160-62-5 ]
[ 1269004-46-7 ]
[ 1269004-58-1 ]

Yield	Reaction Conditions	Operation in experiment
35%	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); tri tert-butylphosphoniumtetrafluoroborate; In tetrahydrofuran; water; at 80℃; for 2h;Inert atmosphere;	A degassed 3.1 mL H2O solution of K3PO4 (947 mg, 4.47 mmol) is added to a degassed 27 m L T H F s o l u t i o n o f 2 , 5-bis(2-ethylhexyl)-3,6-bis[5-(4,4,5,5-tetramethyl- (1 ,3,2)dioxoborolan-2-yl)-thiophen-2-yl]-2,5-dihydro-pynOlo[3,4-c]pyrrole-1 ,4-dione (1.14 g, 1.46 mmol), which can be synthesized in analogy to Example 37 of WO2009/047104, Pd2(dba)3 (39.0 mg , 0.04 mmol), P(i-Bu)3 chi HBF4 (23.0 mg , 0.08 mmol) and 2-bromo- thiophene-5-carbonitrile (1.1 g, 5.85 mmol) under argon atmosphere. After heating to 80 C for 2 h, the solvent is removed under vacuum. Column chromatography (CH2CI2) affordedA-18 as a dark blue solid.Mp 223-225 C.1H NMR (400 MHz, CD2CI2): 58.90 (d, 3J = 4.2 Hz, 2H), 7.60 (d, 3J = 4.0 Hz, 2H), 7.46 (d, 3J = 4.2 Hz, 2H), 7.31 (m, 3J = 4.2 Hz, 2H), 4.02 (m, 4H), 1.87 (m, 2H), 1.32 (m, 16H), 0.89 (m, 12H).13C NMR (101 MHz, CD2CI2): delta 162.0 (C), 143.5 (C), 140.1 (C), 139.9 (C), 136.8 (CH), 131.1 (C), 127.5 (CH), 125.4 (CH), 114.3 (C), 109.9 (C), 109.7 (C), 46.5 (CH2), 39.9 (CH),30.9 (CH2), 29.1 (CH2), 24.3 (CH2), 23.7 (CH2), 14.4 (CH3), 10.9 (CH3).HRMS (ESI): m/z calcd. for C40H43N4O2S4 [M+H]+ 739.2269, found 739.2261.Elemental analysis (%) calcd. for C40H42N4O2S4: C, 65.01 ; H, 5.73; N, 7.58; S, 17.35, found: C, 65.03; H, 5.76; N, 7.41 ; S, 17.39. UV/vis (CH2CI2): Wnm ( NM crrH) 586 (46600).

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 2426 - 2432
[2]Patent: WO2012/41849,2012,A1 .Location in patent: Page/Page column 46

88
[ 2160-62-5 ]
C₂₅H₃₂N₄O₄S₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2839 - 2863

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[ 2160-62-5 ] Synthesis Path-Upstream 1~7

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