1280786-80-2|5-Bromo-3-chloro-2-fluorobenzaldehyde| Ambeed

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Quality Control of [ 1280786-80-2 ] Purity: 98% SDS Specification

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Product Details of [ 1280786-80-2 ]

CAS No. :	1280786-80-2
Formula :	C₇H₃BrClFO
M.W :	237.45
SMILES Code :	O=CC1=CC(Br)=CC(Cl)=C1F
MDL No. :	MFCD18783162
InChI Key :	PLYXMAYYYOIEJW-UHFFFAOYSA-N
Pubchem ID :	51051363

Safety of [ 1280786-80-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H317-H319
Precautionary Statements:	P280-P305+P351+P338

Application In Synthesis of [ 1280786-80-2 ]

* 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 [ 1280786-80-2 ]

[ 1280786-80-2 ] Synthesis Path-Downstream 1~35

1
[ 1280786-80-2 ]
C₇H₄BrClFNO [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 279 - 282.

2
[ 60811-21-4 ]
[ 33513-42-7 ]
[ 1280786-80-2 ]

Yield	Reaction Conditions	Operation in experiment
76%		To a solution of diisopropylamine (4.02 g, 5.66 ml, 39.7 mmol, Eq: 1.04) in THF (28 ml)was added dropwise (10 mm) at -20 C n-butyllithium, 1.6 M in hexane (24.8 ml, 39.7 mmol, Eq:1.04) and stuffed at 0 C for 20 minutes. The mixture was cooled to -78 C followed by dropwise addition (20 minutes) of 4-bromo-2-chloro-1-fluorobenzene (8 g, 38.2 mmol, Eq: 1) and the yellow suspension was stirred at -78 C for 45 mm. Then was added dropwise (5 minutes - exotherm) N,N-dimethylformamide (4.19 g, 4.44 ml, 57.3 mmol, Eq: 1.5), the cooling bath wasremoved and the mixture was allowed to warm to -20 C to give complete conversion. At -20 C the clear solution was quenched with sat NH4C1 (80 ml) and extracted with TBME (80 ml). The aqueous layer was extracted again with TBME (40 ml). The organic layers were dried and evaporated. The residue (9.03 g, 100%) was purified by flash chromatography (silica gel) to give 5-bromo-3-chloro-2-fluorobenzaldehyde (6.88 g, 76%) as a white solid.GC-MS: mlz = 236.9 (M + H)+ (monoisotopic mass 235.90)
70.6%		To a solution of dissoprppylamine (5.1 mL, 36.0 mmol, 1.5 eq.) in anhydrous THF (15 mL) was added n-BuLi (19.2 mL, 28.8 mmol, 1.2eq.) dropwise at -78C under N2 atmosphere, then was added the 4-bromo-2-chloro-1-fluorobenzene (5 g, 24.0 mmol, 1.0 eq.) at -78C 1 h later. The mixture was stirred at -78C for 45 minutes, then was added DMF (2.8 mL, 36.0 mmol, 1.5 eq.), warmed to -3 0C until TLC showed that the reaction was completed. The reaction was quenched with H20 (100 mL), then adjusted to pH=2-3, extracted with EA (50 mLx3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (PE/EA=100: 1) to provide 5-bromo-3-chloro-2-fluorobenzaldehyde (4.0 g, 70.6%) as yellow solid.
70.6%		To a solution of dissoprppylamine (5.1 mL, 36.0 mmol, 1.5 eq.) in anhydrous THF (15 mL) was added n-BuLi (19.2 mL, 28.8 mmol, 1.2eq.) dropwise at -78C under N2 atmosphere, then was added the 4-bromo-2-chloro-l-fluorobenzene (5 g, 24.0 mmol, 1.0 eq.) at -78C 1 h later. The mixture was stirred at -78C for 45 minutes, then was added DMF (2.8 mL, 36.0 mmol, 1.5 eq. ), warmed to -30C until TLC showed that the reaction was completed. The reaction was quenched with H20 (100 mL), then adjusted to pH 2-3, extracted with EA (50 mLx3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and evaporated. The residue was purified by column chromatography (PE/EA=100: 1) to provide 5-bromo-3-chloro-2-fluoroben low solid.

46%		4-Bromo-2-chloro-l- fluorobenzene (1; 16 g, 76.5 mmol) was dissolved in 50 mL of THF. The reaction mixture was cooled down to -78 C. A solution of LDA in THF (2 M, 38.2 mL, 76.4 mmol) was added dropwise over 20 min. The reaction mixture was stirred at -78 C for 10 min. DMF (8.4 mL) was added dropwise. The reaction mixture was allowed to warm -20 C and quenched with 30 mL of saturated ammonium chloride aqueous solution, extracted with methyl tert- at l ether (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (5-10% EtO Ac/petroleum ether) to afford 8.4 g of 5-bromo-3-chloro-2-fluorobenzaldehyde (2) as white solid (yield: 46%). 1H MR (400 MHz, DMSO-i) δ 10.10 (s, 1H), 8.26 (s, 1H), 7.93 (s, 1H).
46%		[00367] Synthesis of 5-bromo-3-chloro-2-fluorobenzaldehyde (26): 4-Bromo-2-chloro- 1-fluorobenzene (25, 16 g, 76.5 mmol) was dissolved in 50 mL of THF. The reaction mixture was cooled down to -78 C. A solution of LDA in THF (2 M, 38.2 mL, 76.4 mmol) was added dropwise over 20 min. The reaction mixture was stirred at -78 C for 10 min. DMF (8.4 mL) was added dropwise. The reaction mixture was allowed to warm -20 C, quenched with 30 mL of saturated ammonium chloride aqueous solution and extracted with methyl fei -butyl ether (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (5-10% EtOAc/petroleum ether) to afford 8.4 g of 5-bromo-3-chloro-2-fluorobenzaldehyde (26) as white solid (yield: 46%). 1H MR (400 MHz, OMSO-d6) δ 10.10 (s, 1H), 8.26 (s, 1H), 7.93 (s, 1H).
46%		4-Bromo-2-chloro-l-fluorobenzene (16 g, 76.5 mmol) was dissolved in 50 mL of THF. The reaction mixture was cooled to -78 C. A solution of LDA in THF (2 M, 38.2 mL, 76.4 mmol) was added dropwise over 20 min. The reaction mixture was stirred at -78 oC for 10 min. DMF (8.4 mL) was added dropwise. The reaction mixture was allowed to warm -20 C. The reaction was quenched with 30 mL of saturated ammonium chloride aqueous solution and the mixture was extracted with methyl tert-butyl ether (50 mL X 3). The combined organic fractions were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give crude product which was purified by silica gel chromatography (5-10% EtO Ac/petroleum ether) to afford 8.4 g of 5-bromo-3-chloro-2-fluorobenzaldehyde (23) (yield: 46%). 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.26 (s, 1H), 7.93 (s, 1H).
40%		To a dry-ice/ethanol cooled solution of compound S1 (20.0 g, 0.95 mol) in THF (200 mL) was added 2 M LDA (52 mL, 1.05 mol) dropwise over 30 min. After addition, the reaction mixture was stirred at this temperature for 30 min followed by the addition of DMF (10.5 g, 1.43 mol). The reaction was stirred for 30 min and warmed to room temperature slowly. The reaction mixture was then quenched with aq. NH4Cl (100 mL) and extracted with ethyl acetate (500 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluted with petroleum ether/ethyl acetate=1:0 to 50:1) to give compound S2 (10 g, yield 40%) as a yellow oil.
		3-chloro-4-fluoro bromobenzene (6.3 g, 30 mmol) and tetrahydrofuran (60 mL) were added to a reaction flask, and cooled to -73 C. under an argon atmosphere. A solution of LDA in tetrahydrofuran/n-hexane (2 mol/L, 18 mL, 36 mmol) was added dropwise. The resulting mixture was stirred at a certain temperature for 1.5 h, and then DMF (12.4 mL, 161 mmol) was added dropwise. After the addition, the reaction solution was stirred at a certain temperature until raw materials substantially disappeared as detected by HPLC. The reaction solution was added to a mixture of water (40 mL), concentrated hydrochloric acid (30 mL) and methyl tert-butyl ether (60 mL), and the mixture was separated into layers. Methyl tert-butyl ether (30 mL) was added to the aqueous phase for extraction. The organic phases were combined, and concentrated under reduced pressure to constant weight to give a crude product (7.0 g, yield: 98%), and the crude product became light yellow when cooled to room temperature, which was directly used in the next step.

References: [1]Patent: WO2017/72062,2017,A1 .Location in patent: Page/Page column 228.
[2]Patent: WO2017/98328,2017,A2 .Location in patent: Paragraph 00232.
[3]Patent: WO2018/229543,2018,A2 .Location in patent: Paragraph 00203.
[4]Patent: WO2016/100515,2016,A1 .Location in patent: Paragraph 00314.
[5]Patent: WO2017/31204,2017,A1 .Location in patent: Paragraph 00367.
[6]Patent: WO2017/117447,2017,A1 .Location in patent: Paragraph 0273.
[7]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 0585.
[8]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 279 - 282.
[9]Patent: US2020/369676,2020,A1 .Location in patent: Paragraph 0834-0844.

3
[ 60811-21-4 ]
[ 33513-42-7 ]
[ 1280786-80-2 ]
6-bromo-2-chloro-3-fluorobenzaldehyde [ No CAS ]

References: [1]Journal of Organic Chemistry,2011,vol. 76,p. 993 - 996.

4
[ 1280786-80-2 ]
5-bromo-7-chlorobenzo[b]thiophene-2-carboxylic acid [ No CAS ]

References: [1]Patent: WO2016/100515,2016,A1 .
[2]Patent: WO2017/31204,2017,A1 .
[3]Patent: WO2017/117447,2017,A1 .
[4]Patent: WO2018/210988,2018,A1 .

5
[ 1280786-80-2 ]
5-bromo-7-chlorobenzo[b]thiophene-2-carboxamide [ No CAS ]

References: [1]Patent: WO2016/100515,2016,A1 .
[2]Patent: WO2017/31204,2017,A1 .
[3]Patent: WO2017/117447,2017,A1 .

6
[ 1280786-80-2 ]
7-chloro-5-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)benzo[b]thiophene-2-carbonitrile [ No CAS ]

References: [1]Patent: WO2016/100515,2016,A1 .
[2]Patent: WO2017/31204,2017,A1 .
[3]Patent: WO2017/117447,2017,A1 .

7
[ 1280786-80-2 ]
(4-(2-(aminomethyl)-7-chlorobenzo[b]thiophen-5-yl)phenyl)(4,4-difluoropiperidin-1-yl)methanone [ No CAS ]

References: [1]Patent: WO2016/100515,2016,A1 .

8
[ 1280786-80-2 ]
tert-butyl (7-chloro-5-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)benzo[b]thiophen-2-yl)methylcarbamate [ No CAS ]

References: [1]Patent: WO2016/100515,2016,A1 .

9
[ 1280786-80-2 ]
tert-butyl (5-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)-7-(4-fluorophenyl)benzo[b]thiophen-2-yl)methylcarbamate [ No CAS ]

References: [1]Patent: WO2016/100515,2016,A1 .

10
[ 1280786-80-2 ]
(4-(2-(aminomethyl)-7-(4-fluorophenyl)benzo[b]thiophen-5-yl)phenyl)(4,4-difluoropiperidin-1-yl)methanone [ No CAS ]

References: [1]Patent: WO2016/100515,2016,A1 .
[2]Patent: WO2017/31204,2017,A1 .
[3]Patent: WO2017/117447,2017,A1 .

11
[ 1280786-80-2 ]
(E)-3-(6-aminopyridin-3-yl)-N-((5-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)-7-(4-fluorophenyl)benzo[b]thiophen-2-yl)methyl)acrylamide [ No CAS ]

References: [1]Patent: WO2016/100515,2016,A1 .

12
[ 1280786-80-2 ]
5-bromo-7-chlorobenzo[b]thiophene-2-carbonitrile [ No CAS ]

References: [1]Patent: WO2016/100515,2016,A1 .
[2]Patent: WO2017/31204,2017,A1 .
[3]Patent: WO2017/117447,2017,A1 .

13
[ 1280786-80-2 ]
7-chloro-5-(4-(morpholine-4-carbonyl)phenyl)benzo[b]thiophene-2-carbonitrile [ No CAS ]

References: [1]Patent: WO2016/100515,2016,A1 .

14
[ 1280786-80-2 ]
C₂₀H₁₉ClN₂O₂S [ No CAS ]

References: [1]Patent: WO2016/100515,2016,A1 .

15
[ 1280786-80-2 ]
(E)-3-(6-aminopyridin-3-yl)-N-((7-chloro-5-(4-(morpholine-4-carbonyl)phenyl)benzo[b]thiophen-2-yl)methyl)acrylamide [ No CAS ]

References: [1]Patent: WO2016/100515,2016,A1 .

16
[ 1280786-80-2 ]
[ 2365-48-2 ]
methyl 5-bromo-7-chlorobenzo[b]thiophene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 2.5h;	To a cooled (0C) mixture of <strong>[1280786-80-2]5-bromo-3-chloro-2-fluorobenzaldehyde</strong> (1.000 g, 4.13 mmol) and potassium carbonate (873 mg, 6.19 mmol) in DMF (10 mL) is added dropwise methyl 2-mercaptoacetate (0.466 mL, 4.95 mmol) and the resulting mixture is stirred at RT for 1.5h, and then at 60C for lh. The RM is treatedwith water and stirred at RT for 15 mm. The resulting suspension is filtered and the obtained solid is washed with water and dried under high vacuum to give methyl 5-bromo-7-chlorobenzo[b]thiophene-2-carboxylate as a colorless solid (1.137 g, 90%). LC-MS B: tR = 1.11 mm; no ionization.
39%		NaH (1.8 g, 45 mmol, 60% dispersion in mineral oil) was suspended in 50 mL of DMF. The mixture was cooled down to 0 C. Methyl 2-mercaptoacetate (3.6 g, 35 mmol) was added dropwise. The reaction mixture was stirred at 0 C for 30 min. 5-Bromo-3-chloro-2- fluorobenzaldehyde (2; 5.5 g, 23 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated at 140 C for 16 h. After cooling down to room temperature, the reaction mixture was poured into iced water (100 mL), extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (2% EtO Ac/petroleum ether) to afford 2.7 g of methyl 5-bromo-7-chlorobenzo[£]thiophene-2-carboxylate (3) as yellow solid (yield: 39%). 1H MR (400 MHz, OMSO-d6) δ 8.30 (d, J = 2 Hz, 1H), 8.25 (s, 1H), 7.94 (d, J = 2 Hz, 1H), 3.92 (s, 3H).
39%		[00368] Synthesis of methyl 5-bromo-7-chlorobenzo[ ]thiophene-2-carboxylate (27): NaH (1.8 g, 45 mmol, 60% dispersion in mineral oil) was suspended in 50 mL of DMF. The mixture was cooled to 0 C. Methyl 2-mercaptoacetate (3.6 g, 35 mmol) was added dropwise. The reaction mixture was stirred at 0 C for 30 min. 5-Bromo-3-chloro-2- fluorobenzaldehyde (26; 5.5 g, 23 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated at 140 C for 16 h. After cooling down to room temperature, the reaction mixture was poured into iced water (100 mL), extracted with EtOAc (100 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give crude product, which was purified by silica gel chromatography (2% EtOAc/petroleum ether) to afford 2.7 g of methyl 5-bromo-7-chlorobenzo[£]thiophene-2-carboxylate (27) as yellow solid (yield: 39%). 1H MR (400 MHz, OMSO-d6) δ 8.30 (d, J= 2 Hz, 1H), 8.25 (s, 1H), 7.94 (d, J= 2 Hz, 1H), 3.92 (s, 3H).

39%

NaH (1.8 g, 45 mmol, 60% dispersion in mineral oil) was suspended in 50 mL of DMF. The mixture was cooled to 0 oC. Methyl 2-mercaptoacetate (3.6 g, 35 mmol) was added dropwise. The reaction mixture was stirred at 0 oC for 30 min. 5-Bromo-3- chloro-2-fluorobenzaldehyde (23) (5.5 g, 23 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated at 140 oC for 16 h. After cooling to room temperature the reaction mixture was poured into ice-water (100 mL), and extracted with EtOAc (100 mL X 3). The combined organic fractions were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give crude product which was purified by silica gel chromatography (2%EtO Ac/petroleum ether) to afford 2.7 g of methyl 5-bromo-7-chlorobenzo[b]thiophene- 2-carboxylate (24) (yield: 39%). 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 2 Hz, 1H), 8.25 (s, 1H), 7.94 (d, J = 2 Hz, 1H), 3.92 (s, 3H).

References: [1]Patent: WO2018/210988,2018,A1 .Location in patent: Page/Page column 145.
[2]Patent: WO2016/100515,2016,A1 .Location in patent: Paragraph 00315.
[3]Patent: WO2017/31204,2017,A1 .Location in patent: Paragraph 00368.
[4]Patent: WO2017/117447,2017,A1 .Location in patent: Paragraph 00273.

17
[ 1280786-80-2 ]
((1-bromo-4-chloro-naphthalene-7-yl)methyl)triphenylphosphonium bromide [ No CAS ]
C₁₈H₉Br₂Cl₂F [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		Under nitrogen, (1-bromo-4-chloro-7-naphthyl) triphenylphosphonium bromide (71.5g, 120mmol) and potassium tert-butoxide (20.2g, 180mmol) was added to 400mL of tetrahydrofuran, and the resulting mixture was refluxed for 5 hours to give an orange mixture, it was cooled to 0 C, <strong>[1280786-80-2]5-bromo-3-chloro-2-fluorobenzaldehyde</strong> (27.5g, 125mmol) was added to a solution of tetrahydrofuran, naturally came to room temperature and the reaction was continued for 12 hours, and the residue was filtered off short silica gel column in methylene chloride was filtered, to give 4-bromo-6-[2-(5-bromo-3-ethoxy-2-chlorophenyl)vinyl]-1-chloronaphthalene (mixture of cis and trans isomers) 38.1 g, yield 67% .

References: [1]Patent: CN103183711,2016,B .Location in patent: Paragraph 0201; 0205.

18
[ 1280786-80-2 ]
((1-bromo-3-chloro-naphthalene-7-yl)methyl)triphenylphosphonium bromide [ No CAS ]
1-bromo-7-(2-(5-bromo-3-chloro-2-fluorophenyl)vinyl)-3-chloronaphthalene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		Under nitrogen, ((1-bromo-3-chloro-naphthalene-7-yl)methyl)triphenylphosphonium bromide (71.5g, 120mmol) and potassium tert-butoxide (20.2g, 180 mmol) was added to 400mL of tetrahydrofuran, and the resulting mixture was refluxed for 5 hours to give an orange mixture, it was cooled to 0 C, 3-bromo-5-chloro-6-fluorobenzaldehyde (28.5g, 125mmol) in tetrahydrofuran, allowed to naturally rise and the reaction was continued for 12 hours at room temperature, concentrated and the residue over a short silica gel column (dichloromethane) to give 1-bromo-7-(2-(5-bromo-3-chloro-2-fluorophenyl)vinyl)-3-chloronaphthalene (mixture of cis and trans isomers) 45 g, 77% yield.

References: [1]Patent: CN103183711,2016,B .Location in patent: Paragraph 0233; 0238.

19
[ 1280786-80-2 ]
5-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)-7-(4-fluorophenyl)benzo[b]thiophene-2-carbonitrile [ No CAS ]

References: [1]Patent: WO2017/31204,2017,A1 .
[2]Patent: WO2017/117447,2017,A1 .

20
[ 1280786-80-2 ]
(1S,2S)-2-(6-aminopyridin-3-yl)-N-((5-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)-7-(4-fluorophenyl)benzo[b]thiophen-2-yl)methyl)cyclopropanecarboxamide [ No CAS ]

References: [1]Patent: WO2017/31204,2017,A1 .

21
[ 1280786-80-2 ]
[ 1514304-24-5 ]

Yield	Reaction Conditions	Operation in experiment
96.6%	With methanol; sodium tetrahydroborate; at 20℃; for 2h;	To a solution of <strong>[1280786-80-2]5-bromo-3-chloro-2-fluorobenzaldehyde</strong> (4.7 g, 19.9 mmol, 1.0 eq.) in CH3OH (30 mL) was added NaBH4 (2.3 g, 59.7 mmol, 3.Oeq,) in portions. The mixture was stirred at r.t. for 2 h until TLC showed that the reaction was completed, then concentrated under reduced pressure. The residue was dissolved in EA (60 mL), washed with brine (60 mLx3), dried over anhydrous Na2SO4 and concentrated to provide (5-bromo-3- chloro-2-fluorophenyl)methanol (4.6 g, 96.6%).
96.6%	With methanol; sodium tetrahydroborate; at 20℃; for 2h;	To a solution of <strong>[1280786-80-2]5-bromo-3-chloro-2-fluorobenzaldehyde</strong> (4.7 g, 19.9 mmol, 1.0 eq.) in CH3OH (30 mL) was added NaBH4 (2.3 g, 59.7 mmol, 3.0eq,) in portions. The mixture was stirred at r.t. for 2 h until TLC showed that the reaction was completed, then concentrated under reduced pressure. The residue was dissolved in EA (60 mL), washed with brine (60 mLx3), dried over anhydrous Na2S04 and concentrated to provide (5-bromo-3-chloro-2-fluorophenyl)methanol (4.6 g, 96.6%).
55%	With sodium tetrahydroborate; In tetrahydrofuran; for 1h;Cooling with ice;	To an ice-water cooled solution of compound S2 (18.0 g, 0.076 mol) in THF (150 mL) was added NaBH4(4.3 g, 0.114 mol). The reaction mixture was stirred at this temperature for 1 h. Then the reaction mixture was quenched slowly with aq. NH4Cl and extracted with ethyl acetate (500 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by column chromatography on silica gel (eluted with petroleum ether/ethyl acetate=100:1 to 20:1) to give compound S3 (10 g, yield 55%) as a white solid.

References: [1]Patent: WO2017/98328,2017,A2 .Location in patent: Paragraph 00233.
[2]Patent: WO2018/229543,2018,A2 .Location in patent: Paragraph 00204.
[3]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 0586.

22
[ 1280786-80-2 ]
2-(5-bromo-3-chloro-2-fluorobenzyl)isoindoline-1,3-dione [ No CAS ]

References: [1]Patent: WO2017/35353,2017,A1 .
[2]Patent: WO2017/98328,2017,A2 .
[3]Patent: WO2018/229543,2018,A2 .

23
[ 1280786-80-2 ]
[ 1386459-84-2 ]

References: [1]Patent: WO2017/35353,2017,A1 .

24
[ 1280786-80-2 ]
(2S,4R)-tert-butyl 2-(5-bromo-3-chloro-2-fluorobenzylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2017/35353,2017,A1 .

25
[ 1280786-80-2 ]
(2S,4R)-tert-butyl 2-(3-chloro-2-fluoro-5-vinylbenzylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2017/35353,2017,A1 .

26
[ 1280786-80-2 ]
(2S,4R)-N-(3-chloro-2-fluoro-5-vinylbenzyl)-4-fluoropyrrolidine-2-carboxamide trifluoroacetate [ No CAS ]

References: [1]Patent: WO2017/35353,2017,A1 .

27
[ 1280786-80-2 ]
copper(l) cyanide [ No CAS ]
3-chloro-4-fluoro-5-formylbenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	In 1-methyl-pyrrolidin-2-one; at 170℃; for 0.5h;Microwave irradiation;	To the stirred solution of <strong>[1280786-80-2]5-bromo-3-chloro-2-fluorobenzaldehyde</strong> (1.5g, 6.3mmol) in NMP (1 1.5m1) was added CuCN (680mg, 7.59mmol) and heated at 170C for 30 mm under microwave condition. Then reaction mass was diluted with water and extracted with ethyl acetate. The separated organic layer was washed with water, brine solution, dried over sodiumsulfate and evaporated under reduced pressure to get the crude. The crude thus obtained was purified by normal silica column using 5-15% ethyl acetate in hexane to get 3-chloro-4-fluoro-5- formylbenzonitrile (562 mg, 48%) as yellow solid.

References: [1]Patent: WO2017/72062,2017,A1 .Location in patent: Page/Page column 257; 258.

28
[ 1280786-80-2 ]
ethyl 2-({4-bromo-2-chloro-6-[(1Z)-[(2-methylpropane-2-sulfinyl)imino]methyl]phenyl}sulfanyl)pyridine-3-carboxylate [ No CAS ]