[ CAS No. 58861-48-6 ] {[proInfo.proName]}

Name: 58861-48-6|2-(4-Fluorophenyl)thiophene|95%
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Quality Control of [ 58861-48-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 58861-48-6 ]

CAS No. :	58861-48-6	MDL No. :	MFCD06802535
Formula :	C₁₀H₇FS	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PURJRGMZIKXDMW-UHFFFAOYSA-N
M.W :	178.23	Pubchem ID :	21894783
Synonyms :

Calculated chemistry of [ 58861-48-6 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	11
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	49.71
TPSA :	28.24 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-4.66 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.42
Log Po/w (XLOGP3) :	3.84
Log Po/w (WLOGP) :	3.97
Log Po/w (MLOGP) :	3.37
Log Po/w (SILICOS-IT) :	4.64
Consensus Log Po/w :	3.65

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.98
Solubility :	0.0188 mg/ml ; 0.000106 mol/l
Class :	Soluble
Log S (Ali) :	-4.13
Solubility :	0.0132 mg/ml ; 0.0000743 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.46
Solubility :	0.00618 mg/ml ; 0.0000347 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	2.01

Safety of [ 58861-48-6 ]

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

Application In Synthesis of [ 58861-48-6 ]

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

Upstream synthesis route of [ 58861-48-6 ]
Downstream synthetic route of [ 58861-48-6 ]

[ 58861-48-6 ] Synthesis Path-Upstream 1~4

1
[ 58861-48-6 ]
[ 87604-18-0 ]
[ 1030825-20-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	With zinc(II) chloride In ethyl acetate for 6 h; Reflux; Large scale	Take 2-methyl-5-bromobenzyl chloride 110kg,Dissolved in 250kg of ethyl acetate,80kg of 2-p-fluorophenylthiophene was added,Zinc chloride 70kg,Heated to reflux reaction 6h,After the reaction was completed, the mixture was cooled to room temperature, 400 kg of water was added, extracted, and 200 kg of water was washed with anhydrous sulfurSodium soda, filtration, the filtrate recovery 100kg, crystallization was light yellow crystals 141kg, a yield of 78percent.

Reference： [1] Patent: CN107011316, 2017, A, . Location in patent: Paragraph 0006; 0013; 0015

2
[ 58861-48-6 ]
[ 1030825-20-7 ]

Reference： [1] Patent: WO2012/160218, 2012, A1,
[2] Patent: WO2016/16852, 2016, A1,
[3] Patent: CN107556287, 2018, A,

3
[ 58861-48-6 ]
[ 108440-70-6 ]
[ 898566-17-1 ]

Reference： [1] Patent: CN103980263, 2016, B, . Location in patent: Paragraph 0035; 0043; 0051
[2] Patent: US2010/99883, 2010, A1, . Location in patent: Page/Page column 40-41

4
[ 58861-48-6 ]
[ 898566-17-1 ]

Reference： [1] Patent: CN107556287, 2018, A,

[ 58861-48-6 ] Synthesis Path-Downstream 1~88

1
[ 371-42-6 ]
[ 58861-48-6 ]

Reference： [1]Journal of the American Chemical Society,1997,vol. 119,p. 12376 - 12377

Yield	Reaction Conditions	Operation in experiment
		Preparation 47 2-(4-Chlorophenyl)thiophene (1.52 g) was obtained in substantially the same manner as in Preparation 43. 1H-NMR (300 MHz, CDCl3, delta): 7.07(1H, dd, J=4, 4 Hz), 7.25-7.37(4H, m), 7.53(2H, d, J=8 Hz)

Yield	Reaction Conditions	Operation in experiment
		Preparation 55 2-(4-Trifluoromethylphenyl)thiophene (1.57 g) was obtained in substantially the same manner as in Preparation 43. 1H-NMR (300 MHz, CDCl3, delta): 7.10-7.14(1H, m), 7.34(1H, d, J=4 Hz), 7.40(1H, d, J=4 Hz), 7.62(2H, d, J=8 Hz), 7.71(2H, d, J=8 Hz)

Yield	Reaction Conditions	Operation in experiment
		Preparation 45 2-(3-Fluorophenyl)thiophene (1.12 g) was obtained in substantially the same manner as in Preparation 43. 1H-NMR (300 MHz, CDCl3, delta): 6.96(1H, t, J=8 Hz), 7.09(1H, t, J=4 Hz), 7.22-7.40(5H, m)

Yield	Reaction Conditions	Operation in experiment
		Preparation 52 2-(2-Fluorophenyl)thiophene (1.56 g) was obtained in substantially the same manner as in Preparation 43. 1H-NMR (300 MHz, CDCl3, delta): 6.96(1H, t, J=8 Hz), 7.09(1H, t, J=4 Hz), 7.22-7.40(5H, m)

Yield	Reaction Conditions	Operation in experiment
		Preparation 58 2-[3,4-(Methylenedioxy)phenyl]thiophene (1.53 g) was obtained in substantially the same manner as in Preparation 43. 1H-NMR (300 MHz, CDCl3, delta): 5.98(2H, s), 6.81(1H, d, J=8 Hz), 7.03(1H, t, J=4 Hz), 7.07-7.12(2H, m), 7.18(1H, d, J=4 Hz), 7.21(1H, d, J=4 Hz)

Yield	Reaction Conditions	Operation in experiment
		Preparation 62 2-(4-Ethoxyphenyl)thiophene (1.33 g) was obtained in substantially the same manner as in Preparation 43. 1H-NMR (300 MHz, CDCl3, delta): 1.40(3H, t, J=7 Hz), 4.05(2H, q, J=7 Hz), 6.90(2H, d, J=8 Hz), 7.02-7.04 (1H, m), 7.16-7.21 (2H, m), 7.51(2H, d, J=8 Hz)

Yield	Reaction Conditions	Operation in experiment
		Preparation 64 4-(2-Thienyl)benzonitrile (1.58 g) was obtained in substantially the same manner as in Preparation 43. 1H-NMR (300 MHz, CDCl3, delta): 7.13(1H, t, J=3 Hz), 7.40-7.48(2H, m), 7.51-7.82(4H, m)

Yield	Reaction Conditions	Operation in experiment
		Preparation 66 2-(4-Cyanomethylphenyl)thiophene (1.32 g) was obtained in substantially the same manner as in Preparation 43. 1H-NMR (300 MHz, CDCl3, delta): 3.78(2H,s), 7.10(1H, t, J=3 Hz), 7.30-7.38(4H, m), 7.52(2H, d, J=8 Hz)

Yield	Reaction Conditions	Operation in experiment
		Preparation 68 4-(2-Thienyl)phenol (10.2 g) was obtained in substantially the same manner as in Preparation 43. Mass (ESI): 175 (M-1) 1H-NMR (300 MHz, DMSO-d6, delta): 6.80(2H, d, J=8 Hz), 7.07(1H, t, J=3 Hz), 7.30(1H, d, J=3 Hz) 7.40(1H, d, J=3 Hz), 7.46(2H, d, J=8 Hz), 9.63(1H, brs)

11
[ 58861-48-6 ]
5-(4-fluoro-phenyl)-2-thiophenesulfonyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In 1,1-dichloroethane;	Preparation 44 2-(4-Fluorophenyl)thiophene (538 mg) was added to a solution of sulfur trioxide N,N-dimethylformamide complex in dichloroethane (5 ml). The reaction mixture was stirred at 50 C. for 3 hours and at 70 C. for 2 hours. Sulfur trioxide N,N-dimethylformamide complex (231 mg) was added to the reaction mixture and the mixture was stirred at 80 C. overnight. The reaction mixture was cooled to ambient temperature. Thionyl chloride (0.27 ml) was added to the reaction mixture and the mixture was stirred at 70 C. for 3 hours. The mixture was concentrated in vacuo and the residue was partitioned between AcOEt and ice water. The organic layer was washed with H2O, saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4 and concentrated in vacuo to give 694 mg of 5-(4-fluoro-phenyl)-2-thiophenesulfonyl chloride as a blue-gray solid. m.p.: 82-85 C. 1H-NMR (300 MHz, CDCl3, delta): 7.17(2H, t, J=8 Hz), 7.25(1H, d, J=1 Hz), 7.61(2H, d, J=3.8 Hz), 7.83(1H, d, J=1 Hz)

Reference： [1]Patent: US6333324,2001,B1

12
[ 3437-95-4 ]
[ 1765-93-1 ]
[ 58861-48-6 ]

Yield	Reaction Conditions	Operation in experiment
86.1%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In Dimethyl ether; water; at 100℃; for 0.5h;Microwave irradiation;	Step 1 2-(4-fluorophenyl)thiophene 2-iodothiophene (1.05 g, 5 mmol) was dissolved in 6 mL of mixed solution (dimethyl ether and water, v:v=2:1), followed by addition of 4-fluorophenylboronic acid 9a (700 mg, 5 mmol), potassium carbonate (1.38 g, 10 mmol) and tetrakis(triphenyl phosphine)palladium (173 mg, 0.15 mmol). The mixture was microwaved for 30 minutes at 100 C. Thereafter, the reaction mixture was extracted with ethyl acetate (20 mL*3) after 10 mL water were added. The organic extract was washed with saturated sodium chloride solution (20 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system C to obtain the title compound 2-(4-fluorophenyl)thiophene 9b (767 mg, white solid), yield: 86.1%.

Reference： [1]Chemical Communications,2008,p. 6318 - 6320
[2]Patent: US2013/130997,2013,A1 .Location in patent: Paragraph 0189
[3]Tetrahedron,2008,vol. 64,p. 4637 - 4643

13
potassim 4-fluorophenyltrifluoroborate [ No CAS ]
[ 403617-22-1 ]
[ 58861-48-6 ]

Reference： [1]Australian Journal of Chemistry,2008,vol. 61,p. 870 - 873

14
[ 58861-48-6 ]
[ 21900-41-4 ]
[ 1132832-75-7 ]

Yield	Reaction Conditions	Operation in experiment
		STEP B:In a separate 500 ml_ 3-necked round bottom flask was added AICI3 (15.O g, 0.11 mol) and 100 ml_ of CH2CI2. The suspension was cooled to -1 O0C in an ice bath then <strong>[58861-48-6]2-(4-fluorophenyl)thiophene</strong> (18.2 g, 0.10 mol) was added followed by addition of the mixture prepared as in STEP A above. After 30 minutes the ice bath was removed and the resulting mixture stirred at ambient temperature for 2-3 h. The resulting mixture was cooled to -120C and quenched by the slow addition of water (20 ml_), followed by 2N HCI (20 ml_) and heptane (100 ml_). A precipitate formed. The resulting mixture was stirred for 1 -2 h then filtered to give the title compound as a yellow solid.
		Synthesis of compound 43Ci8H12BrFOS M = 375.25 g.mof1 FN MR rCDCk 282.5MHz): - 111.3 (m, IF, Ar-F).Mass (GC-MS): 375.0 (97%); 376.0 (28%); 377.0 (100%); 416.0 (23%); 418.05-Bromo-2-methylbenzoic acid (725mg, 3.37mmol, leq) was suspended in dry dichloromethane (9.7mL). Oxalyl chloride (0.32mL, 3.74mmol, l . l eq) and N,N- dimethylformamide (0.013mL, 0.17mmol, 0.05eq) were then adde d at room temperature and the mixture was stirred for 6 hours. The solvent was then evaporated to give 5-bromo-2-methylbenzoyl chloride as yellow oil. This crude product was dissolved in dry dichloromethane (19.3mL), A1C13 (49.5mg, 3.71mmol, l . leq) and 42 (600mg, 3.37mmol, leq) were then added at 0C (internal temperature). The resultant mixture was stirred at this temperature for 30 minutes and then at room temperature overnight. The reaction mixture was poured into ice and water, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were gathered, dried over MgS04, filtered and concentrated. The rsidue was taken up with n- hexane to form a precipitate which was collected by filtration, washed with n-hexane and dried to afford compound 43 (69% yield) as yellowish crystals

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 6355 - 6360
[2]Patent: WO2009/35969,2009,A1 .Location in patent: Page/Page column 76
[3]Patent: WO2012/160218,2012,A1 .Location in patent: Page/Page column 71-72

15
[ 1003-09-4 ]
[ 460-00-4 ]
[ 58861-48-6 ]

Yield	Reaction Conditions	Operation in experiment
91.3%		Under nitrogen, a magnesium shoulder (11. lg, 0.457 mol), a solvent tetrahydrofuran (140 ml), a small amount of p-fluorobromobenzene (10 g, 0.057 mol), and an initiator iodine (0.1 g) were added to the 500 ml reaction flask. , until the color fades, when the determination is triggered, the temperature is controlled at 36-40 C, and parafluorobromobenzene 69.9 g, 0.4 mo 1) is added dropwise within 4 h, and the GC is controlled. After the reaction is completed,Keep warm at 40 C and stop stirring.A 1000 ml reaction flask was taken, and 2-bromothiophene (74.5 g, 0.457 mol) and solvent tetrahydrofuran (150 ml) were added under nitrogen atmosphere, and the mixture was replaced with nitrogen three times. The catalyst DPPE.NIC12 (0.48 g, 0.0009 mol) was added (after milling, 120 mesh) Between the 260 mesh screen, the particle size is 57-125mupi), the temperature is controlled at 20-25 C, the Grignard reagent prepared above is added dropwise, and the addition is completed in 5 hours, and the GC is controlled. After completion of the reaction, it was quenched with 5% EtOAc (EtOAc)EtOAc. Below 60 C, it was evaporated to dryness under reduced pressure and recrystallized from methanol: water = 2:1. After drying, a white solid was obtained: 74.2 g, the reaction yield was 91.3%, and the HPLC purity was 99.5 %.
87.6%		4.1 Format response In a 1000 ml four-necked flask, Nitrogen protection, First put the magnesium tablets 14 grams (0.58mol), THF 80 g, 2-bromothiophene 1 g, stirred. About 30 deg C, Began to trigger the reaction (with bubbles, the temperature naturally rose to 35-45 deg C). Cooling with cold water to 30 deg C, A mixture of 81 g (0.5 mol) of 2-bromothiophene and 1,16 g of THF was added dropwise, About two hours dripping finished. The dropping process controls the temperature at about 30 C. Drop finished, The reaction was carried out at 30 C for 30-60 minutes, sampling, Raw 2-bromothiophene <0.5% qualified. End.seal, stand-by.;_4.2 Coupling reaction In another 1000 ml four-necked flask. Nitrogen protection, Put THF 40 g, 93 g (0.53 mol) of fluorobromobenzene. Stir well. A solution of 5.5 g (0.005 mol) of tetrakis (triphenylphosphine) Heating up to 60 deg C, Start to add step on the format of liquid (just start dripping more obvious) control temperature of about 70-80 deg C drop. About 1 hour dripping end. 80 deg C reflux insulation reaction 5 hours. sampling, The raw material <0.5% is the reaction end point. End the reaction.;_4.3 hydrolysis The coupling solution was cooled to 50-60 C, In a 2000 ml hydrolyzate bottle, Add 250 ml of water. The coupling droplets are added to the water, To carry out hydrolysis. Control temperature <40 deg C. 20% sulfuric acid adjusted to pH 2 or so. Add activated carbon 5 grams decolorization adsorption impurities, filter. The filtrate is layered. The lower layer of organic layer was transferred to a 1000 ml distillation flask. The THF was recovered by distillation under reduced pressure at atmospheric pressure. To obtain about 85 g of crude 2- (4-fluorophenyl) thiophene, Add 90% methanol water 240 grams, Heating 60 all dissolved, 60 C for 30 minutes, Slowly cool to -10 deg C, Crystallization for two hours. Filter, Drained. Placed in a vacuum oven. 30-40 deg C under vacuum drying. Had a fine 78 grams. The content of GC 99.5% was 87.6%.
75%		26 g (1.08 mol) of magnesium (Mg) and 400 g of dry THF (tetrahydrofuran) were added to the reaction flask,Then add 1 g of 1,2-dibromoethane,Access to nitrogen protection to the system to achieve anaerobic state,And slowly stirring.175 g (1 mol)Fluorobromobenzene (IM 5) was dissolved in 300 g of THF,Dropping about 1/15 to the reaction flask,With the trigger trigger format,Exothermic and produce a lot of gas,The reaction was continued with the addition of a solution of p-fluorobromobenzene / THF.The dropping speed was controlled so that the reaction was semi-reflowed.Not too fast (severe reaction),It can not be too slow (to avoid the reaction to stop) After the drop is completed,Continue to react for about 1.5 h.After completion of the Grignard reaction,Cooled to below 25 C.Remove the remaining magnesium scrap (avoid 2-bromothiophene after formattingInto the thiophene impurities).Transfer the format reagent to a constant pressure drop funnel.160 g (0.98 mol) of 2-bromothiophene (IM 2) and 3 g of catalyst (Ni (dppp) 2Cl2)300 g THF was added to another reaction flask,Ice bath cooling at 10 C,Add the Grignard reagent.Attention to control the drop rate.Keep the temperature below 25 C.After dripping,An additional 3 g of catalyst was added to the reaction flask in portions.After the addition of the catalyst will also reflect the heat (the amount may make the reaction to reflux state).Add the catalyst after stirring for about 0.5h.The temperature was raised to 75 C and the reaction was refluxed overnight.HPLC for controlled reaction.Reaction is completed,Cooling the reaction solution to below 25 C,The reaction solution was slowly poured into a 2 L ice saturated aqueous ammonium chloride solution,Cooling conditions and with 1N dilute hydrochloric acid to adjust the PH value of 2-3,Separate the organic layer,The aqueous layer was extracted with 200 g of x2 ethyl acetate,Combined organic layer,Saturated brine washing,Dried over anhydrous sodium sulfate.filter,Concentrated dry solvent,The product was distilled off under reduced pressure IM3. The temperature was 110-120 C,The vacuum of the pump is 5 mmHg below the vacuum. White solid IM3 129g,Yield: 75%.

Example 8; 2(4-Fluorophenyl)-5,5-iodo-2-methylbenzyl)thiophene The following reactions were carried out under an argon atmosphere.Step A: 4-Fluoro-phenylmagnesium bromide2-Me-THF (80 ml, 0.1 L/mole) was added to Mg (19.44 g, 0.8 mol) and the resulting mixture was stirred slowly. 1-Bromo-4-fluoro-benzene (142.8 g, 0.816 mole) was dissolved in 2-Me-THF (200 ml, 0.25 L/mole) and 25 ml of this solution was added to the Mg mixture. The resulting mixture was heated to about 43 C., the remaining 1-bromo-4-fluorobenzene solution was added over about 40 minutes, while maintaining the mixture at reflux temperature. The addition funnel used to add the 1-bromo-4-fluorobenzene was rinsed with 2-methyl-THF (40 mL) and the rinse was added. The resulting mixture was stirred at 90 C. for 1 hour, then cooled to 20 C. to yield a brown-green solution containing 4-fluoro-phenylmagnesium bromide.Step B: 2-(4-Fluorophenyl)thiophene2-Bromothiophene (130.4 g, 0.8 mol) was dissolved in 2-Me-THF (240 ml, 0.3 L/mole) and the resulting mixture cooled to 2 C. NiCl2(dppe) (2.11 g, 4.0 mmol) was added followed by addition, over about 40 min. at 30 C., of the 4-fluoro-phenylmagnesium bromide solution prepared as in STEP A above to yield a dark red solution. The solution was then stirred at 22 C. for 1.5 hrs. A solution of acetic acid (91.7 ml, 1.6 mol) in water (240 ml, 0.3 L/mol) was then added and the resulting mixture stirred strongly for 15 min. The resulting layers were separated, the organic layer was washed with water (80 ml, 0.1 L/mol), then concentrated in vacuo at 75 C. to yield 2-(4-fluorophenyl)thiophene as a brown oil.

Reference： [1]Patent: CN108658929,2018,A .Location in patent: Page/Page column 4-9
[2]Patent: CN106167480,2016,A .Location in patent: Paragraph 0016; 0030-0065
[3]Patent: CN104418834,2017,B .Location in patent: Paragraph 0012-0016
[4]Patent: US2010/99883,2010,A1 .Location in patent: Page/Page column 40

16
[ 58861-48-6 ]
[ 108440-70-6 ]
[ 898566-17-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With aluminum (III) chloride;	optionally with intermediate or intermediate II as the first acylation reaction with 1.1 equivalents of thionyl chloride(P - fluorophenyl) - thiophene under the action of catalyst aluminum trichloride to form intermediate III. The yield is 80%.
		Step C: 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene; DCM (350 ml, 1 L/mol) was added to 91.7 g 5-iodo-2-methylbenzoic acid (91.7 g, 0.35 mol) and the resulting heterogeneous mixture stirred at 22 C. To the resulting mixture was then added thionyl chloride (42.5 g, 0.35 mol) via an addition funnel. The resulting mixture was warmed slowly to reflux temperature (over which time the mixture became a colorless solution and gas evolution was observed), then stirred for 1 hr, then cooled to 2 C. Aluminum chloride granules (56.0 g, 0.42 mol) were added to the resulting mixture, which was then stirred for 15 min at 2 C. A solution of <strong>[58861-48-6]2-(4-fluorophenyl)thiophene</strong> (0.35 mol, 89.7% w/w) in DCM (0.5 L/mol) was then added via addition funnel over 10 minutes, allowing the temperature to rise during addition to 20 C. The resulting mixture was stirred at 20 C. for 2 hrs, then cooled to 2 C. Additional aluminum chloride granules (107.3 g, 0.805 mol) were added and the resulting mixture stirred for 15 min. Acetonitrile (210 ml, 0.6 L/mol) was added via addition funnel over 20 minutes at T20 C. Tetramethyldisiloxane (131.6 g, 0.98 mol) was then added via addition funnel over 5 minutes. The resulting mixture was slowly warmed to reflux temperature (42 C.), maintained at reflux for 3 hours, allowed to cool to 22 C. and then stirred for 16 hrs. Water (420 ml, 1.2 L/mol) was added over 30 minutes at T35 C. and the resulting mixture stirred strongly for 15 min. The resulting layers were separated, the organic layer washed with water (70 ml, 0.2 L/mol), then concentrated in vacuo at 50 C. to yield the title compound as a residue.The residue (62.0 g, 0.1 mol theoretically) was suspended in a mixture of ethyl acetate (40 ml) and 2-propanol (50 ml). To the resulting mixture was added charcoal (1.2 g) and the resulting mixture heated to reflux, then stirred at reflux for 15 min. The resulting mixture was filtered warm over a filter aid, the filter washed with ethyl acetate (10 ml) and the combined filtrate and washes cooled to 2 C. over 16 hrs, over which time spontaneous crystallization was observed. The precipitate was filtered, washed with 2-propanol (50 ml) and dried in vacuo at 60 C. to yield 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene as a solid.

Reference： [1]Patent: CN103980263,2016,B .Location in patent: Paragraph 0035; 0043; 0051
[2]Patent: US2010/99883,2010,A1 .Location in patent: Page/Page column 40-41

17
[ 1003-09-4 ]
[ 352-13-6 ]
[ 58861-48-6 ]

Yield	Reaction Conditions	Operation in experiment
95%		The THF (10 mL) solvent of 2-bromothiophene (5 g, 30.7 mmol) was cooled to 2 C., NiCl 2 (dppe) (0.08 g, 0.15 mmol) was added, and stirring was continued at the same temperature for 40 minutes.Thereafter, a 19% THF solution (32 g, 30.7 mmol) of 4-fluorophenylmagnesium bromide was added dropwise to the reaction solution over 40 minutes so that the temperature of the reaction solution became 10 C. or less. Thereafter, the reaction solution was warmed to room temperature (23 C.) and stirred at 23 C. for 2 hours.Then, the reaction solution was cooled to 7 C., acetic acid (3.7 g, 61.4 mmol) and water (10 mL) were added dropwise over 15 minutes, and the mixture was stirred for 30 minutes. The resulting reaction solution is diluted with 50 mL of ice water, extracted with ethyl acetate / toluene = 5/1, washed with saturated brine, and concentrated.,2- (4-fluorophenyl) thiophene (5.2 g, yield 95%) was obtained as brown crystals.
		Example 16; 2-(4-Fluorophenyl)thiophene To a stirred solution of 2-bromothiophene (100 g, 613.3 mol) in dry THF (220 mL), at 50 C., under a nitrogen atmosphere were added Pd(OAc)2 (13.8 mg, 0.06 mmol) and 1,3-bis(diphenylphosphino)propane (25.3 mg, 0.06 mmol). After 5 minutes, 1.05 M 4-fluorophenylmagnesium bromide in THF (613 mL) was added over 6.0 hours (TOF=1750). The resulting mixture was stirred for 1 hour at 60 C., then cooled to 30 C. and slowly poured into a 2M HCl aqueous solution (600 mL) in an ice bath. DCM (300 mL) was added and the resulting mixture was separated, and washed with brine (200 mL). MgSO4 (20 g) and activated charcoal (10 g) were added and the resulting mixture was stirred. The mixture was then filtered, and the filtrate concentrated to yield the title compound as a residue, which was used without further purification.

Reference： [1]Patent: JP2019/81748,2019,A .Location in patent: Paragraph 0121; 0122; 0123; 0124; 0125
[2]Patent: US2010/99883,2010,A1 .Location in patent: Page/Page column 43-44

18
[ 1003-09-4 ]
[ 352-13-6 ]
[ 58861-48-6 ]
[ 398-23-2 ]
[ 492-97-7 ]

Reference： [1]Synlett,2011,p. 1324 - 1330

19
[ 58861-48-6 ]
[ 124-38-9 ]
[ 115933-30-7 ]

Reference： [1]Bulletin of the Chemical Society of Japan,2012,vol. 85,p. 369 - 371

20
[ 4466-24-4 ]
[ 58861-48-6 ]
[ 1401352-26-8 ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8230 - 8234

21
[ 6165-68-0 ]
[ 352-34-1 ]
[ 58861-48-6 ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 8230 - 8234
[2]Journal of the American Chemical Society,2012,vol. 134,p. 15241 - 15244
[3]Angewandte Chemie - International Edition,2014,vol. 53,p. 1809 - 1813
Angew. Chem.,2014,vol. 126,p. 1840 - 1844,5

22
[ 58861-48-6 ]
[ 1398124-14-5 ]

Reference： [1]Journal of the American Chemical Society,2012,vol. 134,p. 15241 - 15244

23
[ 58861-48-6 ]
[ 768-32-1 ]
[ 1415605-87-6 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 6186 - 6189

24
[ 1003-09-4 ]
[ 352-34-1 ]
[ 58861-48-6 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 6186 - 6189

25
[ 6165-68-0 ]
[ 460-00-4 ]
[ 58861-48-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In ethanol; water; at 90℃;Inert atmosphere;	Synthesis of compound 42C10H7FS M = 178.23 g.mol"1 19F NMR (CDCh 282.5MHz): -109.8 (m, IF, Ar-F).Mass (GC-MS): 133 (41%); 178 (100%)Into a freshly degassed mixture of EtOH (69mL) and H20 (9mL) was added Pd2dba3 (534mg, 0.58mmol, 0.025eq), PCy3 (660mg, 2.35mmol, O.leq), 2-thiophene boronic acid (3.00g, 23.4mmol, leq), K2C03 (6.48g, 46.9mmol, 2eq), and 4- bromofluorobenzene (5.17mL, 47.0mmol, 2eq). The resultant mixture was stirred overnight at 90C and then allowed to reach room temperature. MgS04 was added to quench water and the mixture was filtered on a pad of Celite using ethyl acetate. The filtrate was concentrated and purified on silica gel chromatography (cyclohexane/ ethyl acetate 100:0 to 95:5) to afford compound 42 (3.84g, 92% yield) as a white solid.

Reference： [1]Patent: WO2012/160218,2012,A1 .Location in patent: Page/Page column 71
[2]Chemistry - A European Journal,2015,vol. 21,p. 18407 - 18416
[3]Catalysis science and technology,2015,vol. 5,p. 2065 - 2071
[4]Angewandte Chemie - International Edition,2015,vol. 54,p. 5772 - 5776
Angew. Chem.,2015,vol. 127,p. 5864 - 5868,5
Angewandte Chemie,2015,vol. 127,p. 5864 - 5868,5

26
[ 58861-48-6 ]
[ 1030825-20-7 ]

Reference： [1]Patent: WO2012/160218,2012,A1
[2]Patent: WO2016/16852,2016,A1
[3]Patent: CN107556287,2018,A

27
[ 58861-48-6 ]
[ 1413373-77-9 ]

Reference： [1]Patent: WO2012/160218,2012,A1

28
[ 58861-48-6 ]
[ 501-65-5 ]
C₅₂H₃₅FS [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 282 - 285

29
[ 58861-48-6 ]
[ 264272-63-1 ]
[ 1428730-80-6 ]

Yield	Reaction Conditions	Operation in experiment
72%		3-Bromo-4-(methoxycarbonyl)benzoic acid (15 g, 57.90 mmol; obtained as described in Example 1) was dissolved in thionyl chloride (22 mL) and the reaction was heated to 652 c for 1 hour. The excess of thionyl chloride was evaporated to dryness and the desired acyl chloride was obtained as a yellow solid. A solution of this acyl chloride and <strong>[58861-48-6]2-(4-fluorophenyl)-thiophene</strong> (30 g, 168.32 mmol) in DCM (120 mL) was purged with N2 and cooled to 0^ C (inner temperature). A HCI gas trap was attached to the system and AICI3 (23.4 g, 175.49 mmol) was added portionwise, so that the inner temperature was around 0-5^ C. Afterwards, the reaction was warmed to room temperature and stirred for 3 hours. Then the reaction was poured into an ice/water mixture and the resulting phases were separated. The organic phase was washed with HCI 10% (x3), NaOH 10% (xl) and brine (xl). The organic fraction was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under vacuum to afford a yellow-orange solid Hexane was added to this solid and the mixture was vigorously stirred and filtered to obtain the desired compound as a yellow solid in 72% yield (17.63 g, 42.05 mmol).

Reference： [1]Patent: WO2013/45495,2013,A1 .Location in patent: Page/Page column 72; 73

30
[ 58861-48-6 ]
[ 21900-52-7 ]
[ 1358581-35-7 ]

Yield	Reaction Conditions	Operation in experiment
37.9%	With aluminum (III) chloride; In dichloromethane; at -10 - 20℃; for 16.5h;	Step 2 (5-bromo-2-chloro-phenyl)-[5-(4-fluorophenyl)-2-thienyl]methanone AlCl3 (1.5 g, 11 mmol) was dissolved in 10 mL methylene chloride and cooled to -10 C., followed by addition of 5-bromo-2-chloro-benzoyl chloride 2a (2.54 g, 10 mmol) and <strong>[58861-48-6]2-(4-fluorophenyl)thiophene</strong> 9b (1.78 g, 10 mmol). The reaction mixture was stirred for 30 minutes and then warmed to room temperature and stirred for another 16 hours. Thereafter, the reaction mixture was cooled to -10 C. The reaction mixture was extracted with ethyl acetate (50 mL*2) after a small amount of water and 20 mL 1 M hydrochloric acid were added. The organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound (5-bromo-2-chloro-phenyl)-[5-(4-fluorophenyl)-2-thienyl]methanone 9c (1.5 g, yellow solid), yield: 37.9%.

Reference： [1]Patent: US2013/130997,2013,A1 .Location in patent: Paragraph 0190

31
[ 58861-48-6 ]
[ 1358581-37-9 ]

Reference： [1]Patent: US2013/130997,2013,A1

32
[ 58861-48-6 ]
[ 1358581-40-4 ]

Reference： [1]Patent: US2013/130997,2013,A1

33
[ 58861-48-6 ]
[ 1358581-42-6 ]

Reference： [1]Patent: US2013/130997,2013,A1

34
[ 58861-48-6 ]
[ 1358581-43-7 ]

Reference： [1]Patent: US2013/130997,2013,A1

35
[ 58861-48-6 ]
[ 1358581-44-8 ]

Reference： [1]Patent: US2013/130997,2013,A1

36
[ 58861-48-6 ]
[ 1358581-46-0 ]

Reference： [1]Patent: US2013/130997,2013,A1

37
[ 58861-48-6 ]
[ 1358581-50-6 ]

Reference： [1]Patent: US2013/130997,2013,A1

38
[ 58861-48-6 ]
(1S,2S,3S,4R,5S)-5-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]

Reference： [1]Patent: US2013/130997,2013,A1

39
[ 58861-48-6 ]
diphenyliodonium tetrafluoroborate [ No CAS ]
[ 1415605-87-6 ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 1809 - 1813
Angew. Chem.,2014,vol. 126,p. 1840 - 1844,5

40
[ 517867-11-7 ]
[ 58861-48-6 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 302 - 305
[2]Organic Letters,2014,vol. 16,p. 302 - 305

41
[ 128400-42-0 ]
[ 58861-48-6 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 302 - 305

42
[ 1509927-78-9 ]
[ 58861-48-6 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 302 - 305

43
[ 58861-48-6 ]
C₈H₅BrClIO [ No CAS ]
C₁₈H₁₁BrFIOS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.16 g	With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 1.5h;	The acid B-30 (1.81 g, 5.31 mmol) was suspended in DCM (35 ml) and to the mixture were added oxalyl chloride (0.59 ml, 6.75 mmol) and DMF (18 uL). The mixture was stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure to give the benzoyl chloride as a white solid. This compound and <strong>[58861-48-6]2-(4-fluorophenyl)-thiophene</strong> were dissolved in DCM (40 ml), and to the mixture was added AlCl3 (939 mg, 6.37 mmol)) at 0 C. After stirring at that temperature for 30 min, the mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was poured into ice-water and the organic layer was separated, and the aqueous layer was extracted with DCM three times. The combined organic layers were washed with brine, dried with Na2SO4 and the drying agent was filtered off. The light yellow solid was washed with heptane three times to give 2.16 g (82%) C-30 as a yellow solid. 1H NMR (CDCl3) delta 7.90 (s, 1H), 7.63-7.68 (m, 2H), 7.59 (s, 1H), 7.38 (d, J=4.04 Hz, 1H), 7.27 (d, J=4.0 Hz, 1H), 7.10-7.17 (m, 2H), 2.32 (s, 3H). MS (ES) 524.8 (M+Na+).

Reference： [1]Patent: US2014/256657,2014,A1 .Location in patent: Paragraph 0506

44
[ 58861-48-6 ]
[ 95-92-1 ]
C₁₄H₁₁FO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[000764] To a solution of Compound 174C (890 mg, 5.0 mmol) in dry THF (50 mL) was added dropwise LDA (2.0 M, 3.0 mL, 6.0 mmol) under nitrogen at -70 C. After stirring for 30 min., diethyl oxalate (2.19 g, 15.0 mmol) was added as soon as possible. Then the mixture was stirred at -70 C for about 1 h. Then the mixture was quenched with sat. NH4C1 (10 mL), extracted with ethyl acetate (50 mL x 3), washed with water (5 mL) and brine (5 mL), and dried over sodium sulfate. The crude product was purified with flash column chromatography on silica gel (petroleum in ethyl acetate, 10% v/v) to furnish Compound 174D.

Reference： [1]Patent: WO2015/42397,2015,A1 .Location in patent: Paragraph 000764

45
[ 58861-48-6 ]
C₁₂H₇FO₃S [ No CAS ]

Reference： [1]Patent: WO2015/42397,2015,A1

46
[ 58861-48-6 ]
N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-(4-fluorophenyl)thiophen-2-yl)-2-oxoacetamide [ No CAS ]

Reference： [1]Patent: WO2015/42397,2015,A1

47
[ 58861-48-6 ]
C₁₄H₁₁F₃O₂S [ No CAS ]

Reference： [1]Patent: WO2015/42397,2015,A1

48
[ 58861-48-6 ]
C₁₂H₇F₃O₂S [ No CAS ]

Reference： [1]Patent: WO2015/42397,2015,A1

49
[ 58861-48-6 ]
N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-(4-fluorophenyl)thiophen-2-yl)acetamide [ No CAS ]

Reference： [1]Patent: WO2015/42397,2015,A1

50
[ 58861-48-6 ]
(Z)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-(4-fluorophenyl)thiophen-2-yl)-2-(hydroxyimino)acetamide [ No CAS ]

Reference： [1]Patent: WO2015/42397,2015,A1

51
[ 58861-48-6 ]
N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2,2-difluoro-2-(5-(4-fluorophenyl)thiophen-2-yl)acetamide [ No CAS ]

Reference： [1]Patent: WO2015/42397,2015,A1

52
[ 58861-48-6 ]
N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-(4-fluorophenyl)thiophen-2-yl)-2-oxoacetamide [ No CAS ]

Reference： [1]Patent: WO2015/42397,2015,A1

53
[ 58861-48-6 ]
N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-(4-fluorophenyl)thiophen-2-yl)-2-oxoacetamide [ No CAS ]

Reference： [1]Patent: WO2015/42397,2015,A1

54
[ 58861-48-6 ]
2,2-difluoro-N-((1R,2R)-1-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(5-(4-fluorophenyl)thiophen-2-yl)acetamide [ No CAS ]

Reference： [1]Patent: WO2015/42397,2015,A1

55
[ 58861-48-6 ]
[ 882-33-7 ]
2-(4-fluorophenyl)-5-(phenylthio)thiophene [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2015,vol. 54,p. 5772 - 5776
Angew. Chem.,2015,vol. 127,p. 5864 - 5868,5
Angewandte Chemie,2015,vol. 127,p. 5864 - 5868,5

56
[ 188290-36-0 ]
[ 371-40-4 ]
[ 58861-48-6 ]

Reference： [1]Chemistry - A European Journal,2015,vol. 21,p. 12894 - 12898
[2]Chemical Communications,2016,vol. 52,p. 9036 - 9039
[3]Journal of Materials Chemistry A,2017,vol. 5,p. 24920 - 24928

57
[ 58861-48-6 ]
[ 108440-70-6 ]
(5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With aluminum (III) chloride; In dichloromethane; at 0 - 30℃;	85 g (0.64 mol) of aluminum trichloride solids were quickly added to a 2 L reaction flask,Add 500 g of DCM,Stirring the ice salt bath cooling to below 0 ,Solid insoluble.150 g (0.53 mol) of 5-iodo-2-methylbenzoyl chloride (IM 6) was dissolved in DCM and added to the reaction flask, and the solid was gradually dissolved after stirring.100 g (0.56 mol) of IM3 obtained from Preparation 1 and 300 g of DCM were mixed together to dissolve sufficiently,move toDrop the funnel,When the temperature is less than 0 ,Began to drop into the reaction bottle.Natural warming,Then heated to 30 C and controlled by TLC and HPLC.After the reaction is complete,The reaction solution was poured into ice water,Release a large number of acid gases,Stirring under the stratification,The aqueous layer was washed with DCM300 g x2 for extraction,Combined organic layer,Washed twice with 1N aqueous hydrochloric acid solution,Washed with brine and dried over anhydrous sodium sulfate.filter,Concentrated dry,Then, after adding 300 g of toluene to heat and dissolve,The solid was cooled by cooling to 10 C with stirring.filter,Solid infrared light drying,To give 162 g of a yellow solid (IM7)Yield: 76%. HPLC content greater than 99%.
152 g	With aluminum (III) chloride; In dichloromethane; at 0 - 5℃;	Example 1: Preparation of compound of formula- II A mixture of 5-iodo-3-methyl benzoic acid (lOOgm), methylene dichloride (500ml) and dimethyl formamide (1.2ml) was stirred and to this oxalyl chloride (42.4ml) was added at 25-30C. The reaction mixture was stirred for a period of 4hr at a temperature of 25-30C. The reaction mixture was distilled and to the residue methylene dichloride were added to obtain a clear solution. The reaction mixture was cooled to 0-5C. To the reaction mixture, aluminium chloride (55.83gm) and 2-(4-fluorophenyl) thiophene (67.93gm) in methylene dichloride at 0-5C was added. The reaction mixture was stirred and to this mixture water was added and layers separated. The organic layer was distilled under vacuum at 35-40C and to this methanol was added to obtain a slurry. The slurry was stirred for 30min at 25-30C followed by filtration and washing with methanol. The product was dried at 40-45C to obtain 152gm of the product. 1H NMR (300Mhz, DMSO d6) having peaks at 2.4, 7.09, 7.17, 7.26 , 7.40 , 7.73-7.81, 7.83,8.01 .
65.09 g	With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 7.5h;Inert atmosphere;	Under nitrogen protection,5-iodo-2-methylbenzoyl chloride was dissolved in anhydrous dichloromethane ^ OmL) and cooledTo 0 C,To which anhydrous aluminum trichloride was added(30.08 g, (X 226 mol),After stirring at 0 C for 30 min,To this was added 2- (4-fluorophenyl) thiophene(33.518, 0.188111 O1). After the addition,The reaction was stirred at room temperature for 7 hours,11 ((B)Acid ethyl ester / petroleum ether = 1/10) at the end of the control reaction. The reaction was slowly poured into ice water (200 mL) to quench the reaction.The organic layer was separated, and the aqueous layer was extracted three times with dichloromethane (150 mL). The organic layers were combined, washed sequentially with water (200 mL) and brine(200 mL). And dried over anhydrous sodium sulfate. Filtration, rotary evaporator vacuum drying filtrate to be residues. The residue was removedWas dissolved in 95% ethanol / n-hexane (10/1, 300 mL), dissolved by heating, cooled to 5 C and stirred for 4 h,The yellow solid precipitated. After filtration, the filter cake was washed twice with cold 95% ethanol,And dried in vacuo to give the object product as a slightly yellow solid (65.09 g, yield 82%).

Reference： [1]Patent: CN104418834,2017,B .Location in patent: Paragraph 0017-0021
[2]Patent: WO2015/181692,2015,A1 .Location in patent: Paragraph 0190
[3]Patent: CN103570671,2016,B .Location in patent: Paragraph 0135
[4]Organic Process Research and Development,2018,vol. 22,p. 27 - 39

58
[ 58861-48-6 ]
[ 98-80-6 ]
[ 1415605-87-6 ]

Reference： [1]Chemistry - A European Journal,2015,vol. 21,p. 18407 - 18416

59
[ 58861-48-6 ]
[ 1030825-21-8 ]

Reference： [1]Patent: WO2016/16852,2016,A1

60
[ 58861-48-6 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2016/16852,2016,A1
[2]Patent: WO2016/83790,2016,A1
[3]Patent: WO2016/83790,2016,A1

61
[ 58861-48-6 ]
[ 866607-35-4 ]

Reference： [1]Patent: WO2016/16852,2016,A1
[2]Patent: WO2016/83790,2016,A1
[3]Patent: WO2016/83790,2016,A1

62
[ 58861-48-6 ]
[ 79669-49-1 ]
[ 1132832-75-7 ]

Yield	Reaction Conditions	Operation in experiment
93.2%		into the reaction flask add 30g of 5-bromo-2-methylbenzoic acid, 6mL DMF and 400mL Dichloromethane, stirring. Under the room temperature added the drops of 24.6g of thionyl chloride; after the drop is completed, the temperature is increased at 20-25 C; the reaction is monitored by TLC. After the reaction is completed, 25.2g of anhydrous aluminum chloride are added portion-wise into the reaction flask, stir for 30min, and cool down at 0-5 C, add the drops of 26.5g of a dichloromethane solution of <strong>[58861-48-6]2-(4-fluorophenyl)-thiophene</strong>; after dripping, warm up to 25-30 C and carry on reaction for 12 hours, TLC tracking reaction. After the reaction is over, the reaction solution is poured into 800mL ice water and quenched, stirring, static stratification. The aqueous phase is extracted with 300mL of dichloromethane; combine the organic phase, concentrated and then obtained Brown solid. The above solid is heated and dissolved with 8OOmL ethyl acetate, added the drops of 200mL of n-hexane, the crystals are stirred, filtered, and dried and then obtained 48.7g of a yellow solid product, yield is 93.2%.
80.4%		Oxalyl chloride (64.97 g) was slowly added to a solution of 5-bromo-2- methylbenzoic acid (100 g) in dichloromethane (1000 mL) and dimethylformamide (10 mL) at 25C to 30C under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for about one hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at a temperature of about 45 C under nitrogen atmosphere. The reaction mass obtained was dissolved in dichloromethane (1000 mL), and then cooled to 0C under nitrogen atmosphere. 2-(4-Fluorophenyl)thiophene (82.86 g; Example 1) and aluminum chloride (68 g) were added to the reaction mixture at 0C to 5C under nitrogen atmosphere. The reaction mixture was stirred for 60 minutes to 90 minutes at 10C to 15C under nitrogen atmosphere. After completion of the reaction, the reaction mixture was slowly added to water (1000 mL) at 0C to 10C. The reaction mixture was stirred at 25C to 30C for 10 to 15 minutes. The reaction mixture was allowed to settle for 15, minutes and then the layers were separated. Dichloromethane (200 mL) was added to the aqueous layer and the mixture was stirred for 10 minutes to 15 minutes. The mixture was allowed to settle for 15 minutes and then the layers were separated. The organic layers were combined, and then washed with an aqueous solution of sodium bicarbonate (50 g in 500 mL of de-ionized water). The organic layer was washed with an aqueous solution of sodium chloride (10 g in 200 mL of de-ionized water). The organic layer was concentrated under reduced pressure at a temperature of about 45C to obtain a residue. Hexanes (500 mL) were added to the residue, and then the reaction mixture was stirred for 15 minutes to 20 minutes at 25 C to 30C. The reaction mixture was cooled to 0C to 5C, and then stirred for 60 minutes to 120 minutes at the same temperature to obtain a solid. The solid was filtered under reduced pressure, then washed with hexanes (100 mL; pre-cooled), and then dried under reduced pressure at 40C to 45 C to obtain (5-bromo-2-methylphenyl)[5-(4-fluorophenyl)thiophen-2-yl]methanone. Yield: 80.4%
80%		In a 500-ml three-necked flask, 22 g (0.1 mol) of 2-methyl-5-bromobenzoic acid and 200 ml of dichloromethane were added, and 18.8 g (0.15 mol) of oxalyl chloride was slowly added dropwise with stirring, and the mixture was stirred at room temperature for 2 hours. The reaction was completely detected by TLC. Evaporation of excess oxalyl chloride under reduced pressure, cooling of the ice bath to -15C, addition of 200 ml of methylene chloride, 17.8 g (0.1 mol) of <strong>[58861-48-6]2-(4-fluorophenyl)thiophene</strong> prepared according to Example 3 and anhydrous trichlorin Aluminium 16g (0.12mol) was added and naturally warmed and controlled at a temperature of 25-35C for 4 hours. TLC detection reaction was completed, adding ice water 500ml to the reaction solution, stirring, standing to separate the organic layer, the aqueous layer was extracted with dichloromethane 100ml once, the organic phase was combined, the saturated saline solution was washed, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain (5-bromo-2-methylphenyl)[<strong>[58861-48-6]2-(4-fluorophenyl)thiophene</strong>]methanone as a crude product, which was recrystallized from acetone to give 30.1 g of the product. The yield was 80%, and the purity was 99.3% by HPLC. .

Reference： [1]Patent: CN104926803,2017,B .Location in patent: Paragraph 0037; 0048; 0058-0059
[2]Patent: WO2016/16852,2016,A1 .Location in patent: Page/Page column 6; 7
[3]Patent: CN107556287,2018,A .Location in patent: Paragraph 0046; 0047; 0048

63
[ 58861-48-6 ]
[ 1271-86-9 ]
(R<SUB>P</SUB>)-1-dimethylaminomethyl-2-(5-(4-fluorophenyl)thiophen-2-yl)ferrocene [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2016,vol. 138,p. 2544 - 2547

64
[ 289-95-2 ]
[ 58861-48-6 ]
6-(5-(4-fluorophenyl)thiophen-2-yl)-1,6-dihydropyrimidine [ No CAS ]

Reference： [1]MedChemComm,2016,vol. 7,p. 1093 - 1101

65
[ 58861-48-6 ]
[ 1449702-88-8 ]

Reference： [1]MedChemComm,2016,vol. 7,p. 1093 - 1101

66
[ 58861-48-6 ]
C₁₉H₁₉FN₂O₂S [ No CAS ]

Reference： [1]MedChemComm,2016,vol. 7,p. 1093 - 1101

67
[ 58861-48-6 ]
[ 54811-38-0 ]
(5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%		In a 500-ml three-necked flask, 28.5 g (0.1 mol) of 2-methyl-5-iodobenzoic acid and 200 ml of dichloromethane were added and DMF was added to the flask. 0.5ml, slowly stirring 8.8g (0.15mol) oxalyl chloride, stirring at room temperature for 2 hours, TLC detection reaction is complete, vacuum distillation The oxalyl chloride was added in excess, the ice bath was cooled to -15C, and 200 ml of methylene chloride was added. The 2-(4-fluorophenyl) prepared in Example 3 was added.Thiophene 17.8g (0.1mol) and anhydrous aluminum trichloride 16g (0.12mol), natural temperature rise after addition and temperature control 25-35C Reaction 4hour. The reaction was completed by TLC. 500 ml of ice water was added to the reaction solution. The organic layer was stirred and allowed to stand still. The aqueous layer was dichloromethan. The alkanes were extracted 100 ml once, and the organic phases were combined and washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain (5-Iodo-2-A The crude product of phenylphenyl)[<strong>[58861-48-6]2-(4-fluorophenyl)thiophene</strong>]methanone was recrystallized from acetone to obtain 34.2 g of the product, with a yield of 81%. Purity was determined by HPLC.99.3%.
222 g		To a reaction mixture of 150 gm of iodobenzoic acid in 750ml of dichloromethane and 3.0 ml DMF at 30C, 69.75 gm thionyl chloride was slowly charged. The reaction mixture was heated to reflux temperature of the solvent and stirred for 1 hour. The reaction mixture was cooled to 0C to 5C and was charged with 91 gm anhydrous AICI3, and 102 gm fluoro phenyl thiophene diluted in 300 ml dichloromethane. Stirred the reaction mixture at 30C for 1 hour. The reaction mixture was quenched in crushed ice water mixture at 0-5C. Organic layer was separated and washed with 750 ml saturated sodium bicarbonate solution. Dichloromethane was distilled under vacuum to obtain crude iodophenyl thiophene ketone. Crude iodophenyl thiophene ketone was recrystallized from 600 ml isopropanol to obtain 222 gm of lodophenyl thiophene ketone.

Reference： [1]Patent: CN107556287,2018,A .Location in patent: Paragraph 0049; 0050; 0051
[2]Patent: WO2016/83790,2016,A1 .Location in patent: Page/Page column 14

68
[ 58861-48-6 ]
[5-(4-fluorophenyl)thiophen-2-yl](5-iodo-2-methylphenyl)methanol [ No CAS ]

Reference： [1]Patent: WO2016/83790,2016,A1

69
[ 58861-48-6 ]
C₁₉H₁₆FIOS [ No CAS ]

Reference： [1]Patent: WO2016/83790,2016,A1

70
[ 58861-48-6 ]
C₃₃H₃₅FO₁₁S [ No CAS ]

Reference： [1]Patent: WO2016/83790,2016,A1

71
[ 58861-48-6 ]
C₃₂H₃₁FO₁₁S [ No CAS ]

Reference： [1]Patent: WO2016/83790,2016,A1

72
[ 96-43-5 ]
[ 1765-93-1 ]
[ 58861-48-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With C27H39Br2N3Pd; potassium hydroxide; In isopropyl alcohol; at 82℃; for 0.166667h;	General procedure: A two-necked 25.0mL flask fitted with a reflux condenser and septum was charged with aryl halide (1.0mmol), phenylboronic acid (1.2mmol), KOH (2.0mmol), diethyleneglycol-di-n-butylether (0.6mmol, internal standard), and the palladium-pyridine catalyst (0.01mol %) in isopropyl alcohol (1.0mL) was added. The mixture was heated to 82C under an air atmosphere. The conversion was monitored by gas chromatography.

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 10090 - 10094
[2]Tetrahedron,2018,vol. 74,p. 6829 - 6838

73
[ 58861-48-6 ]
(2S,3R,4R,5S,6R)-2-3-((5-(4-fluorophenyl)thiophen-[1,1-D₂]methyl)-4-methylphenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyrantriol [ No CAS ]