[ CAS No. 1004784-50-2 ]

Name: 1004784-50-2|4,4,5,5-Tetramethyl-2-(thieno[3,2-b]thiophen-2-yl)-1,3,2-dioxaborolane|95%
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Quality Control of [ 1004784-50-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1004784-50-2 ]

Product Details of [ 1004784-50-2 ]

CAS No. :	1004784-50-2	MDL No. :	MFCD24386909
Formula :	C₁₂H₁₅BO₂S₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZOGRODFFPRPMDQ-UHFFFAOYSA-N
M.W :	266.19	Pubchem ID :	58012946
Synonyms :

Calculated chemistry of [ 1004784-50-2 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	8
Fraction Csp3 :	0.5
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	76.18
TPSA :	74.94 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.28 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	3.73
Log Po/w (WLOGP) :	3.26
Log Po/w (MLOGP) :	2.15
Log Po/w (SILICOS-IT) :	4.19
Consensus Log Po/w :	2.67

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.12
Solubility :	0.0201 mg/ml ; 0.0000754 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.0
Solubility :	0.00269 mg/ml ; 0.0000101 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.21
Solubility :	0.0163 mg/ml ; 0.0000614 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.41

Safety of [ 1004784-50-2 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1004784-50-2 ]

* 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.

Downstream synthetic route of [ 1004784-50-2 ]

[ 1004784-50-2 ] Synthesis Path-Downstream 1~40

1
[ 1004784-50-2 ]
[ 1004784-48-8 ]
2,6-bis(thieno[3,2-b]thiophen-2-yl)-4,8-bis[(triisopropylsilanyl)-ethynyl]-1,5-dithia-s-indacene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate In tetrahydrofuran; water at 100 - 140℃; for 0.316667h; Microwave reaction;	4.2 To a 20-ml microwave reaction tube is charged 2,6-dibromo-4,8- bis[(triisopropylsilanyl)ethynyl]-1 ,5-dithia-s-indacene (0.20 g, 0.28 mmol), tetrakis(triphenylphosphine)palladium (0.05 g) and THF (10 ml), then 4,4,5,5-tetramethyl-2-( thieno[3,2-/>]thiophen-2-yl)-[1 ,3,2]- dioxaborolane (0.23 g, 0.86 mmol) and potassium carbonate solution (0.48 g, 3.5 mmol, in water 3 ml). This reaction mixture is degassed with nitrogen for 5 min, then heated in microwave reactor at100 0C for 120 s, 120 0C for 120 s and 140 0C for 900 s. The mixture is poured into water and the precipitate collected by filtration and purified by column chromatography, eluting with THF to give brown solid, which was recrystallised with THF/acetonitrile, to afford brown crystals (0.19 g, 83%). 1H NMR (300 Hz, CDCI3): δ (ppm) 7.65 (s, 2H, Ar-H), 7.51 (s, 2H, Ar-H), 7.39 (d, J = 5.1 Hz, 2H, Ar-H), 7.24 (d, J = 5.1 Hz, 2H, Ar-H), 1.27 (m, 42H, CH and CH3); 13C NMR (75 Hz, CDCI3): 140.2, 139.9, 139.32, 139.28, 139.1 , 138.9, 128.3, 119.6, 118.9, 117.8, 111.3, 102.4, 102.2, 18.8, 11.5.

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2008/11957, 2008, A1 Location in patent: Page/Page column 58

2
[ 251-41-2 ]
[ 61676-62-8 ]
[ 1004784-50-2 ]

Yield	Reaction Conditions	Operation in experiment
85.4%		[0602] To a solution of 148 (5 g, 35.65 mmol) in THF (70 mL) was added n-BuLi (1.6 M in hexanes, 23.4 mL, 37.4 mmol) at -70 C dropwise for 30 min with stirring under N2 atmosphere. After addition, the reaction was stirred at the same temperature for 30 min, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.29 g, 39.2 mmol). The reaction was allowed to warm to room temperature and stirred for 16 hrs. After quenched with saturated aq. NH4Cl solution at 0 oC, the mixture was extracted with EtOAc twice. The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness to give the title compound (8.1 g, 85.4% yield) as light green solid.
85.4%		To a solution of S1 (5 g, 35.65 mmol) in THE (70 mL) was added n-BuLi (1.6 M in hexanes, 23.4 mL, 37.4 mmol) at -70 dropwise for 30 min with stirring under N2atmosphere. After addition, the reaction was stirred at the same temperature for 30 min and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.29 g, 392 mmol) was added The reaction mixture was allowed to warm to room temperature and stirred for 16 hrs. After quenched with saturated aq. NH4Cl solution at 0 C., the mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4and to give the title compound (8.1 g, 85.40% yield) as light green solid.
73%		To a solution of thieno[3,2-jb]thiophene (4.08 g, 29.1 mmol) in THF (70 ml) is added BuLi (2.5 M in hexanes, 10.5 ml, 26.3 mmol) at -78 0C dropwise, with stirring, under N2. After complete addition, the mixture is stirred for 30 min at the same temperature, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolane (4.89 g, 26.3 mmol). The mixture is allowed to warm to room <n="59"/>temperature and stired overnight (~ 15h), then poured to a sat.aq. ammonium chloride solution. The product is extracted with ethyl actate (3 x 70 ml). The extracts are combined and washed with brine, then dried (Na2SO4). The solvent is removed under reduced pressure the residue is recrystallised with acetonitrile, to give deep blue crystals (5.14 g, 73%). 1H NMR (300 Hz1 CDCI3): delta (ppm) 7.76 (s, 1H1 Ar-H)1 7.42 (d, J = 5.3 Hz, 1 H, Ar-H), 7.21 (d, J = 5.3 Hz, 1 H, Ar- H)1 1.32 (s, 12H1 CH3); 13C NMR (75 Hz, CDCI3): delta (ppm) 145.7,140.9, 130.2, 129.1 , 119.5, 84.3, 24.8.

0.982 g thieno[3,2-b}thiophene (7.0 mmol) was dissolved in 40 mL THF under N2 and cooled to -78C. 7 ml BuLi (1.6 M in hexanes, 7.0 mmol) was added and the mixture wasstirred at -78C for 1 hour. Then 1.6 mL 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (7.7 mmol) was added and after 10 minutes stirring the mixture was allowed to warm up to room temperature. It was quenched with saturated aq. NH4CI solution, then extracted with THF, dried over Na2SO4, filtered and concentrated and purified via flash chromatography using heptane and EtOAc as eluents to give Preparation BA2.MS (El, 70 eV) m/z (% relative intensity, [ion]): 120 (19), 165 (25), 166 (100), 167 (44),180 (17), 206 (22), 223 (60), 266 (68, [Mt]).

Reference： [1]Patent: WO2017/35357,2017,A1 .Location in patent: Paragraph 0416; 0602
[2]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 0744
[3]Patent: WO2008/11957,2008,A1 .Location in patent: Page/Page column 57-58
[4]Patent: WO2015/97123,2015,A1 .Location in patent: Page/Page column 218

3
[ 251-41-2 ]
[ 1004784-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aluminum (III) chloride; boron trichloride; Dimethyl-p-toluidine / dichloromethane / 0.17 h / 20 °C / Inert atmosphere 2: triethylamine / 0.5 h / 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: aluminum (III) chloride; BCl₃*C₉H₁₃N / dichloromethane / 1 h / 20 °C / Schlenk technique; Inert atmosphere 2: triethylamine / 1 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Del Grosso, Alessandro; Helm, Matthew D.; Solomon, Sophia A.; Caras-Quintero, Dolores; Ingleson, Michael J. [Chemical Communications, 2011, vol. 47, # 46, p. 12459 - 12461]
[2]Bagutski, Viktor; Del Grosso, Alessandro; Carrillo, Josue Ayuso; Cade, Ian A.; Helm, Matthew D.; Lawson, James R.; Singleton, Paul J.; Solomon, Sophia A.; Marcelli, Tommaso; Ingleson, Michael J. [Journal of the American Chemical Society, 2013, vol. 135, # 1, p. 474 - 487]

4
[ 76-09-5 ]
C₆H₃BCl₂S₂ [ No CAS ]
[ 1004784-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine at 20℃; for 0.5h; Inert atmosphere;
	With triethylamine at 0 - 20℃; for 1h; Inert atmosphere;

5
[ 251-41-2 ]
[ 76-09-5 ]
[ 10294-34-5 ]
[ 1004784-50-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With AlCl₃; Me₂NTol In dichloromethane 1:1 mixt. of BCl3 and AlCl, pinacol (2.3-3.0 equiv.) and lutidine (15 equiv.) for 0.5 h;
0%	With AlCl₃; 2,6-lutidine In dichloromethane 1:1 mixt. of BCl3 and AlCl, pinacol (2.3-3.0 equiv.) and lutidine (15 equiv.) for 18 h;

Reference： [1]Del Grosso, Alessandro; Helm, Matthew D.; Solomon, Sophia A.; Caras-Quintero, Dolores; Ingleson, Michael J. [Chemical Communications, 2011, vol. 47, # 46, p. 12459 - 12461]
[2]Del Grosso, Alessandro; Helm, Matthew D.; Solomon, Sophia A.; Caras-Quintero, Dolores; Ingleson, Michael J. [Chemical Communications, 2011, vol. 47, # 46, p. 12459 - 12461]

6
[ 251-41-2 ]
[ 76-09-5 ]
[ 1004784-50-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: thieno[3,2-b]thiophene With aluminum (III) chloride; boron trichloride; Dimethyl-p-toluidine In dichloromethane at 20℃; for 0.166667h; Stage #2: 2,3-dimethyl-2,3-butane diol With triethylamine In dichloromethane at 20℃; for 0.5h;	23 Example 23 - Preparation of 5-(4 A5,5-tetramethyl-1 ,3,2-dioxaborolan-2-ylHhieno- r3.2-b1-thiophen-2-yl1. 1eq. BCI3, 1.2 eq.pinacol20°C, 30 mins[00126] BCI3 (1 M in dichloromethane) (0.2ml_, 1 eq, 0.2 mmol), Λ/,/V-dimethyl p- toluidine (31 μΙ_, 1 .2eq, 0.24mmol) and dry dichloromethane (0.2 mL) were added by syringe to a J. Youngs NMR tube. AICI3 (25mg, 1 eq. 0.2mmol) and thieno[3,2-b]thiophene (26mg, 1 eq. 0.2mmol) were added consecutively as solids. After 10 minutes, the NMR tube was charged with triethylamine (0.4ml_, 15eq 3mmol) followed by addition of pinacol (55mg, 2.5eq, 0.5mmol). The suspension was extracted into a Schlenk, the NMR tube was washed with dichloromethane (2ml_) and the resulting mixture was evaporated under vacuum. To the resulting solid, hexane (3ml_) was added and the mixture was sonicated for 1 minute. The solids were removed by filtration, upon washing with further hexane (3ml_), the extracts were combined and the volatiles removed in vacuum to give the crude product which was purified by flash chromatography through a short plug of neutral alumina using hexane as solvent to give a colourless crystalline solid. Isolated Yield: 81 %1 H-NMR (400MHz, CDCI3): 7.76 (s, 1 H), 7.48 (d, J= 5.2Hz, 1 H), 7.28 (d, J= 5.2 Hz, 1 H), 1 .36 (s, 12H).13C-NMR (100MHz, CDCI3): 145.6, 140.1 , 130.0, 129.0, 128.9, 1 19.5, 84.3, 24.9, 24.8. 1 1 B-NMR: 29.1

Reference： [1]Current Patent Assignee: UNIVERSITY OF MANCHESTER - WO2012/25760, 2012, A1 Location in patent: Page/Page column 48

7
[ 251-41-2 ]
[ 25240-59-9 ]
[ 1004784-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: thieno[3,2-b]thiophene With n-butyllithium In tetrahydrofuran at -78℃; Stage #2: pinacolboronic acid In tetrahydrofuran at -78℃;

Reference： [1]Lim, Kimin; Ju, Myung Jong; Na, Jongbeom; Choi, Hyeju; Song, Min Young; Kim, Byeonggwan; Song, Kihyung; Yu, Jong-Sung; Kim, Eunkyoung; Ko, Jaejung [Chemistry - A European Journal, 2013, vol. 19, # 29, p. 9442 - 9446]

8
[ 1004784-50-2 ]
[ 181765-86-6 ]
[ 1448993-76-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In tetrahydrofuran; water for 24h; Reflux;

9
[ 1004784-50-2 ]
[ 1448993-77-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran; water / 24 h / Reflux 2: sodium hydroxide / ethanol / Reflux

10
[ 1004784-50-2 ]
[ 1448993-78-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran; water / 24 h / Reflux 2: sodium hydroxide / ethanol / Reflux 3: N,N-dimethyl-formamide; thionyl chloride / benzene / 3 h / Reflux 4: tin(IV) chloride / benzene / 0 - 20 °C

11
[ 1004784-50-2 ]
[ 1448993-79-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran; water / 24 h / Reflux 2.1: sodium hydroxide / ethanol / Reflux 3.1: N,N-dimethyl-formamide; thionyl chloride / benzene / 3 h / Reflux 4.1: tin(IV) chloride / benzene / 0 - 20 °C 5.1: hydrazine hydrate / diethylene glycol / 2 h / 140 °C 5.2: 2 h / 110 °C

12
[ 1004784-50-2 ]
C₁₃H₆BrClOS₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran; water / 24 h / Reflux 2: sodium hydroxide / ethanol / Reflux 3: N,N-dimethyl-formamide; thionyl chloride / benzene / 3 h / Reflux

13
[ 1004784-50-2 ]
1,3-dibromo-4,6-N<SUP>4</SUP>, N<SUP>6</SUP>-dihexylbenzenediamine [ No CAS ]
C₃₀H₃₆N₂S₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; water; toluene at 90℃; Schlenk technique; Inert atmosphere;

Reference： [1]Zhang, Wanzheng; Zhang, Fan; Tang, Ruizhi; Fu, Yubin; Wang, Xinyang; Zhuang, Xiaodong; He, Gufeng; Feng, Xinliang [Organic Letters, 2016, vol. 18, # 15, p. 3618 - 3621]

14
[ 1004784-50-2 ]
[ 36210-57-8 ]
C₁₈H₁₂N₂S₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In ethanol; water; toluene at 90℃; Schlenk technique; Inert atmosphere;

Reference： [1]Zhang, Wanzheng; Zhang, Fan; Tang, Ruizhi; Fu, Yubin; Wang, Xinyang; Zhuang, Xiaodong; He, Gufeng; Feng, Xinliang [Organic Letters, 2016, vol. 18, # 15, p. 3618 - 3621]

15
[ 1004784-50-2 ]
[ 4181-20-8 ]
tris(4-(thieno[3,2-b]thiophen-2-yl)phenyl)amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; at 110℃; for 24h;Inert atmosphere;	General procedure: The tris (4-iodophenyl)amine (1.86 g, 3 mmol), 4,4,5,5-tetra-methyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (2.2 g, 10.5 mmol)and Pd(PPh3)4 (0.34 g, 0.3 mmol) were dissolved in 200 mL oftoluene. The solution was degased with N2 for 30 min and thendegasified solution of K2CO3 (6.73 g, 44.9 mmol) in 60 mL of H2Owas added. The mixture was refluxed for 24 h under inertatmosphere and cooled to rt. The compound was extracted indichloromethane, washed with water, dried over MgSO4 (anhd.)and evaporated. The purification was carried out using columnchromatography (silica gel, petroleum ether as eluent) to obtain ayellow solid.

Reference： [1]Electrochimica Acta,2017,vol. 230,p. 29 - 38

16
[ 251-41-2 ]
[ 25015-63-8 ]
[ 1004784-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium In tetrahydrofuran at -78℃;

Reference： [1]Potphode, Darshna D.; Mishra, Sarada P.; Sivaraman; Patri, Manoranjan [Electrochimica Acta, 2017, vol. 230, p. 29 - 38]

17
[ 1004784-50-2 ]
3-(thieno[3,2-b]thiophen-2-yl)cyclopent-2-enamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; cesium fluoride / water; 1,2-dimethoxyethane / 16 h / 70 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 2 h / Reflux; Inert atmosphere
	Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; cesium fluoride / water; 1,2-dimethoxyethane / 16 h / 70 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 2 h / Reflux

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35357, 2017, A1
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35353, 2017, A1

18
[ 1004784-50-2 ]
3-(thieno[3,2-b]thiophen-2-yl)cyclopentanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; cesium fluoride / water; 1,2-dimethoxyethane / 16 h / 70 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 2 h / Reflux; Inert atmosphere 3: palladium 10% on activated carbon; hydrogen; hydrogenchloride / water; ethanol / 32 h / 45 °C
	Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; cesium fluoride / water; 1,2-dimethoxyethane / 16 h / 70 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 2 h / Reflux 3: hydrogenchloride; palladium 10% on activated carbon; hydrogen / ethanol / 32 h / 45 °C

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35357, 2017, A1
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35353, 2017, A1

19
[ 1004784-50-2 ]
(2S,4R)-tert-butyl 4-fluoro-2-(3-(thieno[3,2-b]thiophen-2-yl)cyclopentylcarbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; cesium fluoride / water; 1,2-dimethoxyethane / 16 h / 70 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 2 h / Reflux; Inert atmosphere 3: palladium 10% on activated carbon; hydrogen; hydrogenchloride / water; ethanol / 32 h / 45 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35357, 2017, A1

20
[ 1004784-50-2 ]
(2S,4R)-tert-butyl 4-fluoro-2-((3-(thieno[3,2-b]thiophen-2-yl)cyclopentyl)carbamothioyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; cesium fluoride / water; 1,2-dimethoxyethane / 16 h / 70 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 2 h / Reflux; Inert atmosphere 3: palladium 10% on activated carbon; hydrogen; hydrogenchloride / water; ethanol / 32 h / 45 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 0 - 20 °C / Inert atmosphere 5: Lawessons reagent / toluene / 16 h / 0 - 80 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; cesium fluoride / water; 1,2-dimethoxyethane / 16 h / 70 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 2 h / Reflux 3: hydrogenchloride; palladium 10% on activated carbon; hydrogen / ethanol / 32 h / 45 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 0 - 20 °C 5: Lawessons reagent / toluene / 16 h / 0 - 80 °C

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35357, 2017, A1
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35353, 2017, A1

21
[ 1004784-50-2 ]
3-(1,3-dioxoisoindolin-2-yl)cyclopenta-1-en-1-yl trifluoromethanesulfonate [ No CAS ]
2-(3-(thieno[3,2-b]thiophen-2-yl)cyclopent-2-enyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.4%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; cesium fluoride In 1,2-dimethoxyethane; water at 70℃; for 16h; Inert atmosphere;	41.4 Step 4: 2-(3-(thieno[3,2-b]thiophen-2-yl)cyclopent-2-enyl)isoindoline-1,3-dione (154) [0605] To a mixture of 152 (6.3 g, 17.4 mmol) and 153 (4.8 g, 17.4 mmol) in DME/water (100 mL/30 mL) was added CsF (3.96 g, 26.1 mmol). The mixture was degassed under N2 for three times and then Pd(PPh3)4 was added in one portion under N2 atmosphere. The resulting mixture was degassed again and stirred at 70 oC under N2 atmosphere for 16 hrs. After cooled to room temperature, the mixture was filtered. The filter cake was washed with water and cooled ethanol, dried under vacuum to give the title compound (5.9 g, 96.4% yield) as pale solid. LC/MS (ESI) m/z: 352 [M+H]+.
96.4%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; cesium fluoride In 1,2-dimethoxyethane; water at 70℃; for 16h; Inert atmosphere;	6.4 Step 4: 2-(3-(Thieno[3,2-b]thiophen-2-yl)cyclopent-2-enyl)isoindoline-1,3-dione (S6) To a mixture of S5 (6.3 g, 17.4 mmol) and 2 (4.8 g, 17.4 mmol) in DME/water (100 mL/30 mL) was added CsF (3.96 g, 26.1 mmol). The mixture was degassed under N2three times and then Pd(PPh3)4was added in one portion under N2atmosphere. The resulting mixture was degassed again and stirred at 70° C. under N2atmosphere for 16 hrs. After cooling to room temperature, the mixture was filtered. The filter cake was washed with water and cooled, washed with ethanol and dried under vacuum to give the title compound (5.9 g, 96.4% yield) as pale solid, LCMS: LC/MS (ESI) m/z: 352 [M+H]+

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35357, 2017, A1 Location in patent: Paragraph 0605
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35353, 2017, A1 Location in patent: Paragraph 0747

22
[ 1004784-50-2 ]
(2S,4R)-tert-butyl 4-fluoro-2-(3-(thieno[3,2-b]thiophen-2-yl)cyclopentylcarbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; cesium fluoride / water; 1,2-dimethoxyethane / 16 h / 70 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 2 h / Reflux 3: hydrogenchloride; palladium 10% on activated carbon; hydrogen / ethanol / 32 h / 45 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35353, 2017, A1

23
[ 1004784-50-2 ]
[ 81090-53-1 ]
phenyl-bis(4-thieno[3,2-b]thiophen-2-ylphenyl)amine [ No CAS ]