[ CAS No. 685892-23-3 ]

Name: 685892-23-3|Methyl 2-bromo-6-chlorobenzoate|95%
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Quality Control of [ 685892-23-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 685892-23-3 ]

Product Details of [ 685892-23-3 ]

CAS No. :	685892-23-3	MDL No. :	MFCD03789160
Formula :	C₈H₆BrClO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XSNZTSBNXMQBRI-UHFFFAOYSA-N
M.W :	249.49	Pubchem ID :	2759827
Synonyms :

Calculated chemistry of [ 685892-23-3 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	50.43
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.42 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.35
Log Po/w (XLOGP3) :	1.98
Log Po/w (WLOGP) :	2.89
Log Po/w (MLOGP) :	3.24
Log Po/w (SILICOS-IT) :	3.01
Consensus Log Po/w :	2.69

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.87
Solubility :	0.335 mg/ml ; 0.00134 mol/l
Class :	Soluble
Log S (Ali) :	-2.16
Solubility :	1.73 mg/ml ; 0.00695 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.95
Solubility :	0.0282 mg/ml ; 0.000113 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.69

Safety of [ 685892-23-3 ]

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 [ 685892-23-3 ]

* 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 [ 685892-23-3 ]
Downstream synthetic route of [ 685892-23-3 ]

[ 685892-23-3 ] Synthesis Path-Upstream 1~6

1
[ 93224-85-2 ]
[ 74-88-4 ]
[ 685892-23-3 ]

Yield	Reaction Conditions	Operation in experiment
99.4%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3.66667 h;	To a solution 2-bromo-6-chlorobenzoic acid (9.5 g, 0.041 mol) and potassium carbonate (8.6 g, 0.061 mol) in N,N-dimethylformamide (50 mL) was added methyl iodide (11.2 g, 0.081 mol) dropwise over a 10 minute period. The reaction mixture was stirred at RT for 3.5 hours and was subsequently diluted with water (500 mL). The aqueous phase was back-extracted with EtOAc (3*300 mL). The organic layers were combined, washed with 1M HCl aq (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (10.0 g, 99.4percent). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.413 (d, J=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.137 (t, J=8 Hz, 1H), 3.9 (s, 3H).

Reference： [1] Patent: US2014/256734, 2014, A1, . Location in patent: Paragraph 0238-0240
[2] Journal of the American Chemical Society, 2015, vol. 137, # 13, p. 4445 - 4452
[3] Organic Process Research and Development, 2005, vol. 9, # 6, p. 764 - 767

2
[ 93224-85-2 ]
[ 77-78-1 ]
[ 685892-23-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: With lithium hydroxide monohydrate In tetrahydrofuran at 25℃; for 1 h; Stage #2: at 85℃; for 21 h;	LiOH.H₂0 (180 mg, 4.24 mmol) was added to a solution of 2-bromo-6-chlorobenzoic acid (i-la) (1.0 g, 4.24 mmol) in THF (30 ml). The mixture was stirred at 25 °C for lh. Then the Me₂S0₄ (1.1 g, 8.48 mmol) was added to the reaction mixture. The mixture was warmed to 85 °C and stirred at 85 °C for 21 h. After cooled, H₃.H₂0 was added dropwise to the mixture until pH=7-8. The solution was poured into water and THF was evaporated. The water layer was extracted with EA (60 ml). The organic layer was dried over Na₂S0₄ and concentrated to obtain 800 mg (75percent) of the title compound. LCMS (ESI): calc'd for C₈H₆BrC10₂ [M+H]⁺: 251, found: 251.

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7232 - 7246
[2] Patent: WO2014/26327, 2014, A1, . Location in patent: Page/Page column 52

3
[ 616-42-2 ]
[ 93224-85-2 ]
[ 685892-23-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: With lithium hydroxide monohydrate In tetrahydrofuran at 25℃; for 1 h; Stage #2: at 85℃; for 21 h;	LiOH.H20 (180 mg,4.24 mmol) was added to a solution of 2-bromo-6-chlorobenzoic acid (i-la) (1.0 g, 4.24mmol) in THF (30 ml). The mixture was stirred at 25 °C for lh. Then the Me2SO4 (1.1 g, 8.48mmol) was added to the reaction mixture. The mixture was warmed to 85 °C and stirred at 85°C for 21 h. After cooling, NH3.H20 was added dropwise to the mixture until pH=7-8. Thesolution was poured into water and THF was evaporated. The water layer was extracted withEA (60 ml). The organic layer was dried over Na2SO4 and concentrated to obtain 800 mg(75percent) of the title compound. LCMS (ESI): calc’d for C8H6BrC1O2 [M+H]: 251, found: 251.

Reference： [1] Patent: WO2014/28589, 2014, A2, . Location in patent: Page/Page column 56

4
[ 93224-85-2 ]
[ 18107-18-1 ]
[ 685892-23-3 ]

Reference： [1] Patent: US2003/220375, 2003, A1,

5
[ 67-56-1 ]
[ 93224-85-2 ]
[ 685892-23-3 ]

Reference： [1] Letters in Drug Design and Discovery, 2016, vol. 13, # 9, p. 968 - 981

6
[ 108-37-2 ]
[ 108-18-9 ]
[ 79-22-1 ]
[ 31603-49-3 ]
[ 685892-23-3 ]

Reference： [1] Organic Process Research and Development, 2005, vol. 9, # 6, p. 764 - 767

[ 685892-23-3 ] Synthesis Path-Downstream 1~69

1
[ 81-46-9 ]
[ 685892-23-3 ]
2-(4-benzoylamino-9,10-dioxo-9,10-dihydro-[1]anthrylamino)-6-chloro-benzoic acid methyl ester [ No CAS ]

Reference： [1]Patent: DE652773,1936,
Fortschr. Teerfarbenfabr. Verw. Industriezweige,vol. 24,p. 871

2
[ 81-46-9 ]
[ 685892-23-3 ]
<i>N</i>-(9-chloro-5,8,14-trioxo-5,8,13,14-tetrahydro-naphth[2,3-<i>c</i>]acridin-6-yl)-benzamide [ No CAS ]

Reference： [1]Patent: DE652773,1936,
Fortschr. Teerfarbenfabr. Verw. Industriezweige,vol. 24,p. 871

3
[ 592-31-4 ]
[ 685892-23-3 ]
3-butyl-5-chloroquinazoline-2,4(1H,3H)-dione [ No CAS ]

Reference： [1]Organic Letters,2006,vol. 8,p. 5089 - 5091

4
[ 845829-93-8 ]
[ 685892-23-3 ]
[ 1048975-24-1 ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium carbonate;palladium diacetate; tris-(o-tolyl)phosphine; In tetrahydrofuran; water; at 20℃;	Intermediate 4; 4'-{(R)-1-[(3-Amino-oxetane-3-carbonyl)-amino]-ethyl}-3-chloro-3'-fluoro-biphenyl-2-carboxylic acid methyl ester Step A: 4'-((R)-1-tert-Butoxycarbonylamino-ethyl)-3-chloro-3'-fluoro-biphenyl-2-carboxylic acid methyl ester A mixture of {(R)-1-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (600 mg, 1.64 mmol, intermediate 13), <strong>[685892-23-3]methyl 2-bromo-6-chlorobenzoate</strong> (430 mg, 1.72 mmol) [CAS 685892-23-3; commercially available], tri-o-tolyl-phosphane (100 mg, 329 mumol), potassium carbonate (568 mg, 4.11 mmol) and palladium(II) acetate (18.4 mg, 82.1 mumol) in THF (20.0 ml) and water (1.18 ml) was stirred at room temperature over night. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined extracts were washed with water and brine, dried with Na2SO4 and concentrated in vacuo. The remaining residue was purified by chromatography (silica gel; DCM/EtOAc 100:0-90:10) and the title compound was obtained as colorless oil (385 mg, 58%). MS: 466.1 [M-H+OAc]-.
58%	With potassium carbonate; tris-(o-tolyl)phosphine;palladium diacetate; In tetrahydrofuran; water; at 20℃;	Step A: 4'-((R)- l-tert-Butoxycarbonylamino-ethyl)-3-chloro-3'-fluoro-biphicarboxylic acid methyl ester A mixture of {(R)-l-[2-fluoro-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]- ethylj-carbamic acid tert-butyl ester (600 mg, 1.64 mmol, intermediate 13), methyl 2- bromo-6-chlorobenzoate (430 mg, 1.72 mmol) [CAS 685892-23-3; commercially available], tri-o-tolyl-phosphane (100 mg, 329 muiotaetaomicron), potassium carbonate (568 mg, 4.11 mmol) and palladium(II) acetate (18.4 mg, 82.1 muiotaetaomicron) in THF (20.0 ml) and water (1.18ml) was stirred at room temperature over night. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined extracts were washed with water and brine, dried with Na2S04 and concentrated in vacuo. The remaining residue was purified by chromatography (silica gel; DCM / EtOAc 100:0-90: 10) and the title compound was obtained as colorless oil (385 mg, 58%). MS: 466.1 [M-H+OAc]".

Reference： [1]Patent: US2012/165338,2012,A1 .Location in patent: Page/Page column 17
[2]Patent: WO2012/89601,2012,A1 .Location in patent: Page/Page column 42-43
[3]Journal of Medicinal Chemistry,2007,vol. 50,p. 272 - 282

5
C₁₇H₂₈BFN₂O₃S [ No CAS ]
[ 685892-23-3 ]
[ 943975-48-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3608 - 3612

6
[ 685892-23-3 ]
[ 943975-64-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3608 - 3612

7
[ 685892-23-3 ]
C₂₁H₁₈ClF₄N₃O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3608 - 3612

8
[ 93224-85-2 ]
[ 18107-18-1 ]
[ 685892-23-3 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol;	To a solution of 2-bromo-6-chlorobenzoic acid (17.7 g, 75.2 mmol) in methanol (200 mL) at 0 C. was added (trimethylsilyl)diazomethane (2M in hexanes, 100 mL, 0.200 mol). The solution was stirred at 0 C. for 1.5 hours, then warmed to room temperature and washed with aqueous sodium bicarbonate and brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to silica gel chromatography eluted with 0-5% ethyl acetate in hexanes to provide methyl 2-bromo-6-chlorobenzoate as a pale yellow oil that gave proton NMR spectra consistent with theory.

Reference： [1]Patent: US2003/220375,2003,A1

9
tert-butyl (1R)-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl]ethylcarbonate [ No CAS ]
[ 685892-23-3 ]
[ 6163-58-2 ]
[ 1048975-24-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;palladium diacetate; In tetrahydrofuran; water; ethyl acetate;	A mixture of <strong>[685892-23-3]methyl 2-bromo-6-chlorobenzoate</strong> (2.25 g, 9.03 mmol), tert-butyl (1R)-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethylcarbonate (see Example 11, 3.00 g, 8.21 mmol), potassium carbonate (2.84 g, 20.5 mmol), tri-o-tolylphosphine (0.10 g, 0.33 mmol), and palladium acetate (0.018 g, 0.08 mmol) in 40 mL of THF and 4 mL of water was heated in a sealed flask at 100 C. for 4 h. The mixture was then cooled and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-10% ethyl acetate and hexane to provide methyl 4'-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-chloro-3'-fluoro-1,1'-biphenyl-2-carboxylate that gave proton NMR spectra consistent with theory.

Reference： [1]Patent: US2003/220375,2003,A1

10
[ 89466-08-0 ]
[ 685892-23-3 ]
7-chloro-6H-benzo[c]chromen-6-one [ No CAS ]

Reference： [1]Journal of Combinatorial Chemistry,2010,vol. 12,p. 664 - 669

11
[ 93224-85-2 ]
[ 77-78-1 ]
[ 685892-23-3 ]

Yield	Reaction Conditions	Operation in experiment
75%		LiOH.H20 (180 mg, 4.24 mmol) was added to a solution of 2-bromo-6-chlorobenzoic acid (i-la) (1.0 g, 4.24 mmol) in THF (30 ml). The mixture was stirred at 25 C for lh. Then the Me2S04 (1.1 g, 8.48 mmol) was added to the reaction mixture. The mixture was warmed to 85 C and stirred at 85 C for 21 h. After cooled, H3.H20 was added dropwise to the mixture until pH=7-8. The solution was poured into water and THF was evaporated. The water layer was extracted with EA (60 ml). The organic layer was dried over Na2S04 and concentrated to obtain 800 mg (75%) of the title compound. LCMS (ESI): calc'd for C8H6BrC102 [M+H]+: 251, found: 251.

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246
[2]Patent: WO2014/26327,2014,A1 .Location in patent: Page/Page column 52

12
[ 685892-23-3 ]
[ 1338224-15-9 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

13
[ 685892-23-3 ]
[ 1338224-16-0 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

14
[ 685892-23-3 ]
[ 1338224-12-6 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

15
[ 685892-23-3 ]
[ 1338224-13-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

16
[ 685892-23-3 ]
C₁₆H₁₂ClN₃O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

17
[ 685892-23-3 ]
C₁₅H₁₀ClN₃O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

18
[ 685892-23-3 ]
[ 1338223-95-2 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

19
[ 685892-23-3 ]
[ 1338223-98-5 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

20
[ 685892-23-3 ]
[ 1338223-99-6 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

21
[ 685892-23-3 ]
[ 1338224-01-3 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

22
[ 685892-23-3 ]
[ 20771-95-3 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

23
[ 685892-23-3 ]
[ 97674-02-7 ]
C₁₂H₁₃ClO₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7232 - 7246

24
[ 685892-23-3 ]
(1R)-1-[3'-chloro-3-fluoro-2'-(methoxycarbonyl)-1,1'-biphenyl-4-yl]ethanamine hydrochloride [ No CAS ]

Reference： [1]Patent: US2012/165338,2012,A1
[2]Patent: WO2012/89601,2012,A1

25
[ 685892-23-3 ]
[ 1384171-62-3 ]

Reference： [1]Patent: US2012/165338,2012,A1
[2]Patent: WO2012/89601,2012,A1

26
[ 685892-23-3 ]
[ 1384171-61-2 ]

Reference： [1]Patent: US2012/165338,2012,A1
[2]Patent: WO2012/89601,2012,A1

27
[ 93224-85-2 ]
[ 74-88-4 ]
[ 685892-23-3 ]

Yield	Reaction Conditions	Operation in experiment
99.4%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3.66667h;	To a solution 2-bromo-6-chlorobenzoic acid (9.5 g, 0.041 mol) and potassium carbonate (8.6 g, 0.061 mol) in N,N-dimethylformamide (50 mL) was added methyl iodide (11.2 g, 0.081 mol) dropwise over a 10 minute period. The reaction mixture was stirred at RT for 3.5 hours and was subsequently diluted with water (500 mL). The aqueous phase was back-extracted with EtOAc (3*300 mL). The organic layers were combined, washed with 1M HCl aq (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (10.0 g, 99.4%). 1H NMR (400 MHz, CDCl3) delta ppm 7.413 (d, J=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.137 (t, J=8 Hz, 1H), 3.9 (s, 3H).

Reference： [1]Patent: US2014/256734,2014,A1 .Location in patent: Paragraph 0238-0240
[2]Journal of the American Chemical Society,2015,vol. 137,p. 4445 - 4452
[3]Organic Process Research and Development,2005,vol. 9,p. 764 - 767
[4]Advanced Synthesis and Catalysis,2019,vol. 361,p. 983 - 988

28
[ 108-37-2 ]
[ 108-18-9 ]
[ 79-22-1 ]
[ 31603-49-3 ]
[ 685892-23-3 ]

Reference： [1]Organic Process Research and Development,2005,vol. 9,p. 764 - 767

29
[ 685892-23-3 ]
[ 1562375-26-1 ]
[ 1562375-27-2 ]

Reference： [1]Patent: WO2014/28597,2014,A2
[2]Patent: US2015/191434,2015,A1

30
[ 685892-23-3 ]
[ 1562374-41-7 ]

Reference： [1]Patent: WO2014/28597,2014,A2
[2]Patent: US2015/191434,2015,A1

31
[ 685892-23-3 ]
[ 1561771-92-3 ]

Reference： [1]Patent: WO2014/28597,2014,A2
[2]Patent: WO2014/28589,2014,A2
[3]Patent: US2015/191434,2015,A1
[4]Patent: WO2017/75182,2017,A1
[5]Patent: US2018/16239,2018,A1
[6]Patent: US2018/305320,2018,A1
[7]Patent: JP2018/531957,2018,A

32
[ 685892-23-3 ]
[ 1561771-96-7 ]

Reference： [1]Patent: WO2014/28597,2014,A2
[2]Patent: WO2014/28600,2014,A2
[3]Patent: WO2014/28589,2014,A2
[4]Patent: US2015/191434,2015,A1
[5]Patent: WO2017/75182,2017,A1
[6]Patent: US2018/16239,2018,A1
[7]Patent: US2018/305320,2018,A1
[8]Patent: JP2018/531957,2018,A

33
[ 685892-23-3 ]
[ 1561772-02-8 ]

Reference： [1]Patent: WO2014/28597,2014,A2
[2]Patent: WO2014/28600,2014,A2
[3]Patent: WO2014/28589,2014,A2
[4]Patent: US2015/191434,2015,A1

34
[ 685892-23-3 ]
[ 411235-57-9 ]
[ 1561771-86-5 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃;Inert atmosphere;	Step 1. Preparation of methyl 2-chloro-6-cyclopropylbenzoate (i-Sb).Methyl 2-bromo-6-chlorobenzoate (i-5a) (1.0 g, 4.0 mmol), cyclopropylboronic acid (516 mg, 6.0 mmol), Pd(OAc)2 (90 mg, 0.4 mmol), Cy3P (224 mg, 0.8 mmol) and K3P04 (2.5 g, 12.0mmol) were mixed in toluene (20 ml) and H20 (2.5 ml). The mixture was stirred at 100C overnight under N2 atmosphere. The mixture was cooled down and poured into water (50 ml). The mixture was extracted with EA (50 ml). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography(PetroleumlEtOAc 15/1) to give 0.6 g (7 1%) of the title compound. LCMS (ESI) calc?d for C11H11C102 [M+H]: 211, found: 211.
71%	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene;Inert atmosphere;	Methyl 2-bromo-6-chlorobenzoate (1.0 g, 4.0 mmol), cyclopropylboronic acid (516 mg, 6.0mmol), Pd(OAc)2 (90 mg, 0.4 mmol), Cy3P (224 mg, 0.8 mmol) and K3P04 (2.5 g, 12.0mmol) were stirred overnight in toluene (20 ml) and H20 (2.5 ml) under an atmosphere of N2(g). The mixture was cooled to room temperature and poured into water (50 ml). The mixturewas then extracted with EA (50 ml). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (PetroleumlEtOAc 15/1) to give 0.6 g (71%) of the title compound. LCMS (ESI) calc?d for C11H11C102 [M+H]: 211, found: 211.
71%	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃;Inert atmosphere;	Step 1. Preparation of methyl 2-chloro-6-cyclopropylbenzoate (i-5b) [0272] Methyl 2-bromo-6-chlorobenzoate (i-5a) (1.0 g, 4.0 mmol), cyclopropylboronic acid (516 mg, 6.0 mmol), Pd(OAc)2 (90 mg, 0.4 mmol), Cy3P (224 mg, 0.8 mmol) and K3PO4 (2.5 g, 12.0 mmol) were mixed in toluene (20 ml) and H2O (2.5 ml). The mixture was stirred at 100 C. overnight under N2 atmosphere. The mixture was cooled down and poured into water (50 ml). The mixture was extracted with EA (50 ml). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (Petroleum/EtOAc 15/1) to give 0.6 g (71%) of the title compound. LCMS (ESI) calc'd for C11H11ClO2 [M+H]+: 211. found: 211.

52%	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃;Inert atmosphere;	Methyl 2-bromo-6- chlorobenzoate (i-lb) (0.8 g, 3.2 mmol), cyclopropylboronic acid (330 mg, 3.84 mmol), Pd(OAc)2 (72 mg, 0.32 mmol), Cy3P (180 mg, 0.64 mmol) and K3P04 (2.0 g, 9.6 mmol) were mixed in toluene (12 ml) and H20 (1.2 ml). The reaction mixture was stirred at 100 C for overnight under N2 atmosphere. After cooled, the mixture was poured into water (30 ml) and extracted with EA (50 ml). The organic layer was dried over Na2S04 and concentrated to obtain a residue. The residue was purified by chromatography on silica gel (PE/EA=10: 1) to obtain 350 mg (52%) of the title compound. LCMS (ESI): calc'd for CnHnC102 [M+H] : 211, found: 211.
52%	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃;Inert atmosphere;	Methyl 2-bromo-6-chlorobenzoate (i-lb) (0.8 g, 3.2 mmol), cyclopropylboronic acid (330 mg, 3.84 mmol), Pd(OAc)2 (72 mg, 0.32 mmol), Cy3P (180 mg, 0.64 mmol) and K3PO4 (2.0 g, 9.6 mmol) were mixed in toluene (12 ml) and H20 (1.2 ml). The reaction mixture was stirred at 100 C overnight under N2 atmosphere. After cooling, the mixture was poured into water (30 ml) and extracted with EA (50 ml). The organic layer was dried over Na2SO4 and concentrated to obtain a residue. The residue was purified by chromatography on silica gel (PE/EA=10:1) to obtain 350 mg (52%) of the title compound. LCMS (ESI): calc?d for C11H11C102 [M+H]:211, found: 211.
	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 14h;Inert atmosphere;	Step 1. Preparation of methyl 2-chloro-6-cvclopropylbenzoate (i-la) [00137] Methyl 2-bromo-6-chlorobenzoate (1.0 g, 4.0 mmol), cyclopropylboronic acid (516 mg, 6.0 mmol), Pd(OAc)2 (90 mg, 0.4 mmol), Cy3P ( 224 mg, 0.8 mmol) and K3PO4 (2.5 g, 12.0 mmol) were mixed in toluene (20 mL) and H2O (2.5 mL). The mixture was stirred at 100C for 14h under N2 atmosphere. The mixture was cooled down and poured into water. The mixture was extracted with EtOAc and the organic layer was dried over Na2SC>4 and concentrated. The residue was purified by flash chromatography (Petroleum/EtOAc 15/1) to give the title compound. MS: 211 (M+l).
	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 14h;Inert atmosphere;	Methyl 2-bromo-6-chlorobenzoate (1.0 g, 4.0 mmol), cyclopropylboronic acid (516 mg, 6.0 mmol), Pd(OAc)2 (90 mg, 0.4 mmol), Cy3P (224 mg, 0.8 mmol) and K3PO4 (2.5 g, 12.0 mmol) were mixed in toluene (20 ml) and H2O (2.5 ml). The mixture was stirred at 100 C. for 14 h under N2 atmosphere. The mixture was cooled down and poured into water. The mixture was extracted with EtOAc and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (Petroleum/EtOAc 15/1) to give title compound. LCMS (ESI) calc'd for CHHHClO2 [M+H]+: 211, found: 211.
	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 14h;Inert atmosphere;	Methyl 2-bromo-6-chlorobenzoate (1.0 g, 4.0 mmol), cyclopropylboronic acid (516 mg, 6.0 mmol), Pd(OAc)2 (90 mg, 0.4 mmol), Cy3P (224 mg, 0.8 mmol) and K3PO4 (2.5 g, 12.0 mmol) were mixed in toluene (20 mL) and H2O (2.5 mL). The mixture was stirred at 100 C. for 14 h under N2 atmosphere. The mixture was cooled down and poured into water. The mixture was extracted with EtOAc and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (Petroleum/EtOAc 15/1) to give the title compound. MS: 211 (M+1).
	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 14h;Inert atmosphere;	Methyl 2-bromo-6-chlorobenzoate (1.0 g, 4.0 mmol), cyclopropylboronic acid (516 mg, 6.0 mmol), Pd (OAc) 2 (90 mg, 0.4mmol), Cy3 P (224 mg, 0.8 mmol) and K3 PO4 (2.5 g, 12.0 mmol) were mixed in toluene (20 mL) and H2 O (2.5 mL). The mixture was stirred under N 2 atmosphere at 100 C. for 14 hours. The mixture was cooled and poured into water. The mixture was extracted with EtOAc and the organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by flash chromatography (petrol / EtOAc 15/1) to give the title compound.

Reference： [1]Patent: WO2014/28597,2014,A2 .Location in patent: Page/Page column 46; 47
[2]Patent: WO2014/28589,2014,A2 .Location in patent: Page/Page column 72
[3]Patent: US2015/191434,2015,A1 .Location in patent: Paragraph 0272
[4]Patent: WO2014/26327,2014,A1 .Location in patent: Page/Page column 52-53
[5]Patent: WO2014/28589,2014,A2 .Location in patent: Page/Page column 56; 57
[6]Patent: WO2017/75182,2017,A1 .Location in patent: Paragraph 00137
[7]Patent: US2018/16239,2018,A1 .Location in patent: Paragraph 0178; 0179
[8]Patent: US2018/305320,2018,A1 .Location in patent: Paragraph 0154; 0155
[9]Patent: JP2018/531957,2018,A .Location in patent: Paragraph 0019

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[ 685892-23-3 ]
[ 1562453-25-1 ]

Reference： [1]Patent: WO2014/26327,2014,A1
[2]Patent: WO2014/28589,2014,A2

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[ 685892-23-3 ]
[ 1562453-52-4 ]

Reference： [1]Patent: WO2014/26327,2014,A1
[2]Patent: WO2014/28589,2014,A2

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[ 685892-23-3 ]
[ 1562448-86-5 ]

Reference： [1]Patent: WO2014/26327,2014,A1
[2]Patent: WO2014/28589,2014,A2

38
[ 685892-23-3 ]
[ 1561772-12-0 ]

Reference： [1]Patent: WO2014/28600,2014,A2
[2]Patent: WO2014/28589,2014,A2
[3]Patent: WO2017/75182,2017,A1
[4]Patent: US2018/16239,2018,A1
[5]Patent: US2018/305320,2018,A1
[6]Patent: JP2018/531957,2018,A

39
[ 685892-23-3 ]
[ 1561772-67-5 ]

Reference： [1]Patent: WO2014/28600,2014,A2

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[ 685892-23-3 ]
[ 1561770-26-0 ]

Reference： [1]Patent: WO2014/28600,2014,A2

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[ 685892-23-3 ]
(3S,4R and 3R,4S)-ethyl 3-((tert-butyldiphenylsilyl)oxy)-1-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)piperidine-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/28600,2014,A2

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[ 685892-23-3 ]
[ 1561773-14-5 ]
[ 1561773-19-0 ]

Reference： [1]Patent: WO2014/28600,2014,A2

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[ 685892-23-3 ]
[ 1561770-82-8 ]

Reference： [1]Patent: WO2014/28600,2014,A2

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[ 685892-23-3 ]
(3R,4R and 3S,4S)-ethyl 1-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)-3-hydroxy-4-methylpiperidine-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/28600,2014,A2

45
[ 685892-23-3 ]
(3R,4R and 3S,4S)-1-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)-3-hydroxy-4-methylpiperidine-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2014/28600,2014,A2

46
[ 685892-23-3 ]
[ 1561773-34-9 ]
[ 1561773-30-5 ]

Reference： [1]Patent: WO2014/28600,2014,A2

47
[ 685892-23-3 ]
[ 1561771-14-9 ]

Reference： [1]Patent: WO2014/28600,2014,A2

48
cyclobutylzinc(II) bromide [ No CAS ]
[ 685892-23-3 ]
[ 1561772-06-2 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 70℃; for 12h;Inert atmosphere;	Step 1. Preparation of methyl 2-chloro-6-cyclobutylbenzoate (i-llb).A mixture of <strong>[685892-23-3]methyl 2-bromo-6-chlorobenzoate</strong> (i-ha) (750 mg, 3 mmol), (PPh3)4Pd (345 mg, 0.3 mmol) and cyclobutylzinc bromide (12 ml in THF, 6 mmol) were mixed under N2 protection. The mixture was stirred at 70C for 12 h under N2. The mixture was extracted with EtOAc and water. The organic phase was washed with brine, dried over Na2SO4, filtered, concentrated, and purified with chromatography (PE: EtOAc = 50:1) to give 350 mg (61% inLCMS, contained some PPh3) of the title compound. LCMS (ESI) calc?d for C12H13C102 [M+H]: 225, found: 225.
350 mg	With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 70℃; for 12h;Inert atmosphere;	A mixture of <strong>[685892-23-3]methyl 2-bromo-6-chlorobenzoate</strong> (750 mg g, 3 mmol), (PPh3)4Pd (345 mg, 0.3mmol) and cyclobutylzinc bromide (12 ml in THF, 6 mmol) was stirred at 70C for 12 hunder N2. The mixture was extracted with EA and water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography (PE: EtOAc = 50:1) afforded 350 mg (61% in LCMS, contained some PPh3) of the title compound. LCMS (ESI) calc?d for C12H13C102 [M+H]: 225, found: 225.
	With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 70℃; for 12h;Inert atmosphere;	Step 1. Preparation of methyl 2-chloro-6-cvclobutylbenzoate (i-lOa) [00172] A mixture of <strong>[685892-23-3]methyl 2-bromo-6-chlorobenzoate</strong> (750 mg, 3 mmol), (PPh3)4Pd (345 mg, 0.3 mmol) and cyclobutylzinc bromide (0.5M in THF, 12mL) were mixed under N2 protection. The mixture was stirred at 70C for 12 h under N2. The mixture was extracted with EtOAc and water. The organic phase was washed with brine, dried over Na2SC>4, filtered, and concentrated. The residue was purified with flash chromatography (PE: EtOAc = 50: 1) to give the title compound. MS: 225 (M+l).

	With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 70℃; for 12h;Inert atmosphere;	A mixture of <strong>[685892-23-3]methyl 2-bromo-6-chlorobenzoate</strong> (750 mg, 3 mmol), (PPh3)4Pd (345 mg, 0.3 mmol) and cyclobutylzinc bromide (0.5M in THF, 12 mL) were mixed under N2 protection. The mixture was stirred at 70 C. for 12 h under N2. The mixture was extracted with EtOAc and water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified with flash chromatography (PE:EtOAc=50:1) to give the title compound. MS: 225 (M+1).
	With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 70℃; for 12h;Inert atmosphere;	A mixture of <strong>[685892-23-3]methyl 2-bromo-6-chlorobenzoate</strong> (750 mg, 3 mmol), (PPh 3) 4 Pd (345 mg, 0.3 mmol) and cyclobutyl zinc bromide (0.5 M in THF, 12 mL) was mixed under N 2 protection. The mixture was stirred under N 2 at 70 C. for 12 h. The mixture was extracted with EtOAc and water. The organic phase was washed with brine, dried over Na 2 SO 4, filtered and concentrated. The residue was purified by flash chromatography (PE: EtOAc = 50: 1) to give the title compound.

Reference： [1]Patent: WO2014/28600,2014,A2 .Location in patent: Page/Page column 49
[2]Patent: WO2014/28589,2014,A2 .Location in patent: Page/Page column 70
[3]Patent: WO2017/75182,2017,A1 .Location in patent: Paragraph 00172
[4]Patent: US2018/305320,2018,A1 .Location in patent: Paragraph 0198; 0199
[5]Patent: JP2018/531957,2018,A .Location in patent: Paragraph 0154

49
[ 685892-23-3 ]
[ 411235-57-9 ]
[ 1561771-92-3 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium phosphate; palladium diacetate; In water; toluene; at 100℃; for 14h;Inert atmosphere;	Step 1. Preparation of methyl 2-chloro-6-cyclopropylbenzoate (i-9a).Methyl 2-bromo-6-chlorobenzoate (1.0 g, 4.0 mmol), cyclopropylboronic acid (516 mg, 6.0mmol), Pd(OAc)2 (90 mg, 0.4 mmol), Cy3P (224 mg, 0.8 mmol) and K3P04 (2.5 g, 12.0mmol) were mixed in toluene (20 ml) and H20 (2.5 ml). The mixture was stirred at 100C for14h under N2 atmosphere. The mixture was cooled down and poured into water (50 ml). The mixture was extracted with EtOAc (50 ml). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (PetroleumlEtOAc 15/1) to give 0.6 g (71%) of the title compound. LCMS (ESI) calc?d for C11H11C102 [M+H]: 211,found:211.

Reference： [1]Patent: WO2014/28600,2014,A2 .Location in patent: Page/Page column 47

50
[ 685892-23-3 ]
[ 1562995-59-8 ]