[ CAS No. 17100-63-9 ] {[proInfo.proName]}

Name: 17100-63-9|Methyl 4-bromo-3-methoxybenzoate|97%
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Quality Control of [ 17100-63-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 17100-63-9 ]

Product Details of [ 17100-63-9 ]

CAS No. :	17100-63-9	MDL No. :	MFCD08436018
Formula :	C₉H₉BrO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XLKDKHRGIJWOSN-UHFFFAOYSA-N
M.W :	245.07	Pubchem ID :	14570117
Synonyms :

Calculated chemistry of [ 17100-63-9 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	51.91
TPSA :	35.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.81 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.6
Log Po/w (XLOGP3) :	2.8
Log Po/w (WLOGP) :	2.24
Log Po/w (MLOGP) :	2.36
Log Po/w (SILICOS-IT) :	2.39
Consensus Log Po/w :	2.48

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.27
Solubility :	0.133 mg/ml ; 0.000541 mol/l
Class :	Soluble
Log S (Ali) :	-3.2
Solubility :	0.154 mg/ml ; 0.000627 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.46
Solubility :	0.085 mg/ml ; 0.000347 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 17100-63-9 ]

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 [ 17100-63-9 ]

* 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 [ 17100-63-9 ]
Downstream synthetic route of [ 17100-63-9 ]

[ 17100-63-9 ] Synthesis Path-Upstream 1~12

1
[ 106291-80-9 ]
[ 77-78-1 ]
[ 17100-63-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate In acetone for 3 h; Heating / reflux	Step B. Methyl 4-bromo-3-methoxybenzoate A solution of methyl 4-bromo-3-hydroxybenzoate of Step A (27 mmol), potassium carbonate (33 mmol), and dimethyl sulfate (32 mmol) in acetone (40 mL) was stirred at reflux temperature under nitrogen atmosphere for three hours. The mixture was cooled and 5 mL of water was added. The acetone was evaporated and 30 mL of water was added. The product was extracted into dichloromethane. The organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound (6.5 g, 99percent) as a hard, white crystalline solid.
99%	With potassium carbonate In acetone for 3 h; Heating / reflux	Step B. Methyl 4-bromo-3-methoxybenzoate; A solution of 4-bromo-3-hydroxybenzoic acid of Step A (27 mmol), potassium carbonate (33 mmol) and dimethyl sulfate (32 mmol), in acetone (40 mL) was stirred at reflux temperature under nitrogen atmosphere for three hours. The mixture was cooled and 5 mL of water was added. The acetone was evaporated and 30 mL of water was added. The product was extracted into dichloromethane. The organic solution was dried over anhydrous magnesium sulfate, and evaporated to provide the title compound (6.5 g; 99percent) as a hard, white, crystalline solid.
99%	With potassium carbonate In acetone for 3 h; Reflux	Method A: Potassium carbonate (4.56 g, 33.0 mmol) was added to asolution of methyl 4-bromo-3-hydroxybenzoate (12, 6.24 g,27.0 mmol) in acetone (40 mL). Dimethyl sulfate (3.03 mL, 32.0 mmol)was added and the mixture was heated to reflux for 3 h. At roomtemp., deionized water was added (5 mL) and acetone was distilled off in vacuo. Theremaining aq. phase was extracted with dichloromethane (3 x 100 mL), the combinedorganic layer was dried with magnesium sulfate, filtered and the solvent wasremoved in vacuo yielding a colourless solid. Yield: 6.59 g (26.9 mmol, >99percent) (ref.[5]:99percent).Method B: Potassium carbonate (2.54 g, 18.4 mmol) was added to a solution of 4-bromo-3-hydroxybenzoic acid (11, 1.00 g, 4.61 mmol) in N,N-dimethylformamide (10 mL). Methyl iodide (863 µL, 13.8 mmol) was added and the mixture was stirred for 16 h at room temp. Deionized water (50 mL) was added and the aq. phase was extracted with tert-butyl methyl ether (3 x 100 mL). The combined organic layer was washed with brine (100 mL) and dried with magnesium sulfate. After filtration, the solvent was evaporated in vacuo yielding a colourless solid. Yield: 938 mg(3.83 mmol, 83percent) (ref.[3]: 91percent). M. p. 53 °C.1H NMR (500 MHz, CDCl3): δ = 7.61 (d, 1H,3J = 8.2 Hz, Ar-H-5), 7.55(d, 1H,4J = 1.8 Hz, Ar-H-2), 7.51 (dd, 1H,3J = 8.2 Hz,4J = 1.8 Hz, Ar-H-6), 3.95 (s,3H, OCH3), 3.92 (s, 3H, CO2CH3) ppm.13C NMR (125 MHz, CDCl3): δ = 166.4 (s,CO2Me), 155.9 (s, Ar-C-3), 133.3 (d, Ar-C-5), 130.6 (s, Ar-C-1), 122.9 (d, Ar-C-6),117.5 (s, Ar-C-4), 112.4 (d, Ar-C-2), 56.4 (q, OCH3), 52.4 (q, CO2CH3) ppm. HRMS(EI): m/z = calcd. 243.9735; found 243.9744 (Δ 4.01 ppm).

Reference： [1] Patent: US2006/199806, 2006, A1, . Location in patent: Page/Page column 23
[2] Patent: US2006/287522, 2006, A1, . Location in patent: Page/Page column 24
[3] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273
[4] Yakugaku Zasshi, 1930, vol. 50, p. 224,227; dtsch. Ref. S. 26[5] Chem.Abstr., 1930, p. 3513
[6] Indian Journal of Chemistry, 1973, vol. 11, p. 1081 - 1083

2
[ 14348-38-0 ]
[ 74-88-4 ]
[ 17100-63-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h;	Method A: Potassium carbonate (4.56 g, 33.0 mmol) was added to asolution of methyl 4-bromo-3-hydroxybenzoate (12, 6.24 g,27.0 mmol) in acetone (40 mL). Dimethyl sulfate (3.03 mL, 32.0 mmol)was added and the mixture was heated to reflux for 3 h. At roomtemp., deionized water was added (5 mL) and acetone was distilled off in vacuo. Theremaining aq. phase was extracted with dichloromethane (3 x 100 mL), the combinedorganic layer was dried with magnesium sulfate, filtered and the solvent wasremoved in vacuo yielding a colourless solid. Yield: 6.59 g (26.9 mmol, >99percent) (ref.[5]:99percent).Method B: Potassium carbonate (2.54 g, 18.4 mmol) was added to a solution of 4-bromo-3-hydroxybenzoic acid (11, 1.00 g, 4.61 mmol) in N,N-dimethylformamide (10 mL). Methyl iodide (863 µL, 13.8 mmol) was added and the mixture was stirred for 16 h at room temp. Deionized water (50 mL) was added and the aq. phase was extracted with tert-butyl methyl ether (3 x 100 mL). The combined organic layer was washed with brine (100 mL) and dried with magnesium sulfate. After filtration, the solvent was evaporated in vacuo yielding a colourless solid. Yield: 938 mg(3.83 mmol, 83percent) (ref.[3]: 91percent). M. p. 53 °C.1H NMR (500 MHz, CDCl3): δ = 7.61 (d, 1H,3J = 8.2 Hz, Ar-H-5), 7.55(d, 1H,4J = 1.8 Hz, Ar-H-2), 7.51 (dd, 1H,3J = 8.2 Hz,4J = 1.8 Hz, Ar-H-6), 3.95 (s,3H, OCH3), 3.92 (s, 3H, CO2CH3) ppm.13C NMR (125 MHz, CDCl3): δ = 166.4 (s,CO2Me), 155.9 (s, Ar-C-3), 133.3 (d, Ar-C-5), 130.6 (s, Ar-C-1), 122.9 (d, Ar-C-6),117.5 (s, Ar-C-4), 112.4 (d, Ar-C-2), 56.4 (q, OCH3), 52.4 (q, CO2CH3) ppm. HRMS(EI): m/z = calcd. 243.9735; found 243.9744 (Δ 4.01 ppm).

Reference： [1] Angewandte Chemie - International Edition, 2008, vol. 47, # 44, p. 8482 - 8486
[2] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273

3
[ 106291-80-9 ]
[ 74-88-4 ]
[ 17100-63-9 ]

Yield	Reaction Conditions	Operation in experiment
10 g	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;	To a stirred solution of methyl 4-bromo-3-hydroxybenzoate (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 mg). The mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 10 g of the title compound, that was used without further purification. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 3.82 (s, 3H), 3.87 (s, 3H), 7.41 (dd, 1 H), 7.47 (d, 1 H), 7.67 (d, 1 H).
10 g	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;	To a stirred solution of methyl 4-bromo-3-hydroxybenzoate (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 mg). The mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent wasremoved in vacuum to give 10 g of the title compound, that was used without further purification.1H-NMR (400MHz, DMSO-d6): O [ppm] = 3.82 (5, 3H), 3.87 (5, 3H), 7.41 (dd, 1H),7.47 (d, 1H), 7.67 (d, 1H).
10 g	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;	To a stirred solution of methyl 4-bromo-3-hydroxybenzoate (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 mg). The mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 10 g of the title compound, that was used without further purification. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=3.82 (s, 3H), 3.87 (s, 3H), 7.41 (dd, 1H), 7.47 (d, 1H), 7.67 (d, 1H).

Reference： [1] Journal of Materials Chemistry C, 2016, vol. 4, # 19, p. 4269 - 4277
[2] Patent: WO2004/89874, 2004, A1, . Location in patent: Page 46
[3] Patent: WO2011/64328, 2011, A1, . Location in patent: Page/Page column 79
[4] Patent: WO2012/143329, 2012, A1, . Location in patent: Page/Page column 89
[5] Patent: WO2013/87579, 2013, A1, . Location in patent: Page/Page column 96
[6] Patent: WO2014/9219, 2014, A1, . Location in patent: Page/Page column 70; 71
[7] Patent: WO2014/195276, 2014, A1, . Location in patent: Page/Page column 98-99
[8] Patent: WO2014/198594, 2014, A1, . Location in patent: Page/Page column 94
[9] Patent: US2015/148542, 2015, A1, . Location in patent: Paragraph 0338-0340

4
[ 67-56-1 ]
[ 56256-14-5 ]
[ 17100-63-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	for 24 h; Reflux	General procedure: The benzoic acid (1-4 g)was dissolved in methanol (25-75 mL),before conc. H2SO4 (2-6 mL) was added dropwise while stirring.The reaction mixture was heated to reflux and stirred for 24 h. Thereaction mixture was quenched in a saturated aq NaHCO3 solution(100-200 mL) ensuring neutral to basic pH, and the aqueous phase was extracted with CH2Cl2 (4 x 50 mL). The combined organic phases were washed with saturated aq NaCl solution (25-50 mL),dried over anhydrous Na2SO4 and filtered. Concentration yielded the target compound in high yield and purity. Methyl 4-bromo-3-methoxybenzoate was prepared as described in Section 4.5, starting with 4-bromo-3-methoxybenzoic acid (845 mg, 3.67 mmol). The procedure yielded 808 mg(3.30 mmol, 90percent) of methyl 4-bromo-3-methoxybenzoate a white crystalline product;
69%	at 0 - 20℃; for 16 h; Inert atmosphere	Methyl 4-bromo-3-methoxybenzoate (0284) To a solution of 4-bromo-3-methoxybenzoic acid (10.0 g, 43.28 mmol) in methanol (400 mL) was added acetyl chloride (19 mL, 266.25 mmol) dropwise at 0° C. The resulting solution was then stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with ethyl aceate in hexane (0percent to 5percent gradient) to yield methyl 4-bromo-3-methoxybenzoate as white solid (7.3 g, 69percent). MS: m/z=245.0 [M+H]⁺.

Reference： [1] European Journal of Medicinal Chemistry, 2016, vol. 107, p. 255 - 274
[2] Patent: US2016/376283, 2016, A1, . Location in patent: Paragraph 0283; 0284

5
[ 3556-83-0 ]
[ 17100-63-9 ]

Reference： [1] Patent: US6350774, 2002, B1, . Location in patent: Page column 33

6
[ 14348-38-0 ]
[ 77-78-1 ]
[ 17100-63-9 ]

Reference： [1] Patent: US2003/45557, 2003, A1,

7
[ 14348-38-0 ]
[ 17100-63-9 ]

Reference： [1] Chemische Berichte, 1941, vol. 74, p. 79,94
[2] Indian Journal of Chemistry, 1973, vol. 11, p. 1081 - 1083
[3] Patent: EP1104754, 2001, A1,
[4] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273

8
[ 99-06-9 ]
[ 17100-63-9 ]

Reference： [1] Indian Journal of Chemistry, 1973, vol. 11, p. 1081 - 1083
[2] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273
[3] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273

9
[ 19438-10-9 ]
[ 17100-63-9 ]

Reference： [1] Journal of Materials Chemistry C, 2016, vol. 4, # 19, p. 4269 - 4277

10
[ 186581-53-3 ]
[ 106291-80-9 ]
[ 17100-63-9 ]

Reference： [1] Chemische Berichte, 1941, vol. 74, p. 79,94

11
[ 17100-63-9 ]
[ 17100-64-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	With lithium aluminium tetrahydride In tetrahydrofuran at -40℃; for 2 h; Inert atmosphere	To a mixture of methyl 4-bromo-3-methoxy-benzoate (3.00 g, 12.24 mmol) in THF (40) was added LiAlH₄ (1.39 g, 36.72 mmol) at -40°C under N₂, then the mixture was stirred at -40°C for 2 hours. To the mixture was added 0 (1.76 g) dropwise at -40 °C, then the mixture was stirred at 0 °C for 0.5 hour and 50 °C for 0.5 hour, filtered through Celite, and eluted by THF (100 mL x 2). The filtrate was concentrated. The residue was dissolved in EtOAc (200 mL), washed with water (30 mL x 2) and brine (50 mL), dried over Na₂S0₄, filtered and concentrated to afford the crude product of compound 17-2 (2.50 g, 11.52 mmol, 94percent yield) as an oil, *H NMR (400MHz, DMSO-d₆) δ_Η = 7.49 (d, 1H), 7.06 (s, 1H), 6.84 (d, 1H), 5.29 (t, 1H), 4.47 (d, 2H), 3.83 (s, 3H).
2.5 g	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at -40℃; for 2 h; Stage #2: With water In tetrahydrofuran at -40 - 50℃; for 1 h;	To a mixture of A-26 (3.00 g, 12.24 mmol) in THF (40 mL) was added LiAlH4 (1.39 g, 36.72 mmol) at -40C under N2, and the mixture was stirred at -40C for 2 hours. To the mixture was added _0 (1.76 g) dropwise at -40 C, and the mixture was stirred at 0 C for 0.5 hour, followed by stirring at 50 C for 0.5 hour. The mixture was then filtered through Celite, eluted by THF (100 mL x 2), concentrated, dissolved in EtOAc (200 mL), washed with water (30 mL x 2) and brine (50 mL), dried over Na2S04, filtered and concentrated to give A-27 (2.50 g, 11.52 mmol) as an oil. 1H NMR (400MHz DMSO-d6) _ = 7.49 (d, 1H), 7.06 (s, 1H), 6.84 (d, 1H), 5.29 (t, 1H), 4.47 (d, 2H), 3.83 (s, 3H).

Reference： [1] Patent: WO2018/98491, 2018, A1, . Location in patent: Page/Page column 96
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 7, p. 2382 - 2391
[3] CrystEngComm, 2017, vol. 19, # 4, p. 603 - 607
[4] Patent: WO2018/98499, 2018, A1, . Location in patent: Page/Page column 137

12
[ 17100-63-9 ]
[ 56256-14-5 ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium hydroxide In methanol; water at 20℃; for 6 h;	Aq. sodium hydroxide (2 M, 40 mL) was added to a solution of methyl 4-bromo-3-methoxy-benzoate (13, 6.52 g, 27.1 mmol) in methanol (200 mL) and the mixture was stirred for 6 h at room temp. Deionized water (100 mL) was added and methanol was distilled off in vacuo.The remaining aq. phase was washed with dichloromethane (3 x 100 mL) and acidified with hydrochloric acid (6 M). The precipitate was filtered off and was washed thoroughly with water yielding a colourless solid. Yield: 4.10 g (17.8 mmol, 66percent)(ref[5]: 89percent). M. p.: 220 °C.1H NMR (500 MHz, DMSO-d6): δ = 13.21 (br. s, 1H,CO2H), 7.71 (d, 1H,3J = 8.2 Hz, Ar-H-5), 7.54 (d, 1H,4J = 1.8 Hz, Ar-H-2), 7.46 (dd,1H,3J = 8.2 Hz,4J = 1.8 Hz, Ar-H-6), 3.91 (s, 3H, OCH3) ppm.13C NMR (125 MHz,DMSO-d6): δ = 167.1 (s, CO2H), 155.9 (s, Ar-C-3), 133.6 (d, Ar-C-5), 132.1 (s, Ar-C-1), 123.2 (d, Ar-C-6), 116.5 (s, Ar-C-4), 113.0 (d, Ar-C-2), 56.8 (q, OCH3) ppm. MS(EI, 70 eV): m/z = 230/232 (100/98) [M]+·.
56%	With hydrogenchloride; lithium hydroxide In tetrahydrofuran; methanol	To a solution of 4-bromo-3-methoxy-benzoic acid methyl ester (6.875 mmol, 1.676 mL) in a mixture 1:1 of THF/MeOH (15 ML), lithium hydroxide (7.553 mmol, 0.180 g) was added, and the reaction was stirred at RT overnight before distillation of volatiles. The residue was diluted with water, acidified with a solution of HCl (1N), and stirred for 1 hour. The formed precipitate was filtered off, and washed with water and petroleum ether to give 4-bromo-3-methoxy-benzoic acid. Yield: 56percent.
10.1 g	With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 1 h;	To a stirred solution of methyl 4-bromo-3-methoxybenzoate (11.2 g) in THF (130 mL), methanol (45 mL) and water (45 mL) was added a 1 M solution of lithium hydroxide in water (140 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuum. Water was added and 1 N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by filtration, washed with water and dried in vacuum to give 10.1 g of the title compound, that was used without further purification. ¹H-NMR (300MHz, DMSO-d₆): δ [ppm] = 3.87 (s, 3H), 7.42 (dd, 1 H), 7.50 (d, 1 H), 7.68 (d, 1 H), 13.21 (br. s., 1 H).

10.1 g	With lithium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 1 h;	To a stirred solution of methyl 4-bromo-3-methoxybenzoate (11.2 g) in THF (130 mL), methanol (45 mL) and water (45 mL) was added a 1 M solution of lithium hydroxide in water (140 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuum. Water was added and I N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by filtration, washed with waterand dried in vacuum to give 10.1 g of the title compound, that was used without further purification.1H-NMR (300MHz, DMSO-d6): a [ppm] = 3.87 (5, 3H), 7.42 (dd, 1H), 7.50 (d, 1H),7.68 (d, 1H), 13.21 (br. s., 1H).
10.1 g	With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 1 h;	To a stirred solution of methyl 4-bromo-3-methoxybenzoate (11.2 g) in THF (130 mL), methanol (45 mL) and water (45 mL) was added a 1 M solution of lithium hydroxide in water (140 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuum. Water was added and 1 N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by filtration, washed with water and dried in vacuum to give 10.1 g of the title compound, that was used without further purification. ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=3.87 (s, 3H), 7.42 (dd, 1H), 7.50 (d, 1H), 7.68 (d, 1H), 13.21 (br. s., 1H).

Reference： [1] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273
[2] Patent: US2003/45557, 2003, A1,
[3] Patent: WO2011/64328, 2011, A1, . Location in patent: Page/Page column 79-80
[4] Patent: WO2012/143329, 2012, A1, . Location in patent: Page/Page column 89
[5] Patent: WO2013/87579, 2013, A1, . Location in patent: Page/Page column 96; 97
[6] Patent: WO2014/9219, 2014, A1, . Location in patent: Page/Page column 71
[7] Patent: WO2014/195276, 2014, A1, . Location in patent: Page/Page column 99
[8] Patent: WO2014/198594, 2014, A1, . Location in patent: Page/Page column 94; 95
[9] Patent: US2015/148542, 2015, A1, . Location in patent: Paragraph 0341-0343

[ 17100-63-9 ] Synthesis Path-Downstream 1~46

2
[ 106291-80-9 ]
[ 77-78-1 ]
[ 17100-63-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In acetone; for 3h;Heating / reflux;	Step B. Methyl 4-bromo-3-methoxybenzoate A solution of <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> of Step A (27 mmol), potassium carbonate (33 mmol), and dimethyl sulfate (32 mmol) in acetone (40 mL) was stirred at reflux temperature under nitrogen atmosphere for three hours. The mixture was cooled and 5 mL of water was added. The acetone was evaporated and 30 mL of water was added. The product was extracted into dichloromethane. The organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound (6.5 g, 99%) as a hard, white crystalline solid.
99%	With potassium carbonate; In acetone; for 3h;Heating / reflux;	Step B. Methyl 4-bromo-3-methoxybenzoate; A solution of 4-bromo-3-hydroxybenzoic acid of Step A (27 mmol), potassium carbonate (33 mmol) and dimethyl sulfate (32 mmol), in acetone (40 mL) was stirred at reflux temperature under nitrogen atmosphere for three hours. The mixture was cooled and 5 mL of water was added. The acetone was evaporated and 30 mL of water was added. The product was extracted into dichloromethane. The organic solution was dried over anhydrous magnesium sulfate, and evaporated to provide the title compound (6.5 g; 99%) as a hard, white, crystalline solid.
> 99%	With potassium carbonate; In acetone; for 3h;Reflux;	Method A: Potassium carbonate (4.56 g, 33.0 mmol) was added to asolution of <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> (12, 6.24 g,27.0 mmol) in acetone (40 mL). Dimethyl sulfate (3.03 mL, 32.0 mmol)was added and the mixture was heated to reflux for 3 h. At roomtemp., deionized water was added (5 mL) and acetone was distilled off in vacuo. Theremaining aq. phase was extracted with dichloromethane (3 x 100 mL), the combinedorganic layer was dried with magnesium sulfate, filtered and the solvent wasremoved in vacuo yielding a colourless solid. Yield: 6.59 g (26.9 mmol, >99%) (ref.[5]:99%).Method B: Potassium carbonate (2.54 g, 18.4 mmol) was added to a solution of 4-bromo-3-hydroxybenzoic acid (11, 1.00 g, 4.61 mmol) in N,N-dimethylformamide (10 mL). Methyl iodide (863 muL, 13.8 mmol) was added and the mixture was stirred for 16 h at room temp. Deionized water (50 mL) was added and the aq. phase was extracted with tert-butyl methyl ether (3 x 100 mL). The combined organic layer was washed with brine (100 mL) and dried with magnesium sulfate. After filtration, the solvent was evaporated in vacuo yielding a colourless solid. Yield: 938 mg(3.83 mmol, 83%) (ref.[3]: 91%). M. p. 53 C.1H NMR (500 MHz, CDCl3): delta = 7.61 (d, 1H,3J = 8.2 Hz, Ar-H-5), 7.55(d, 1H,4J = 1.8 Hz, Ar-H-2), 7.51 (dd, 1H,3J = 8.2 Hz,4J = 1.8 Hz, Ar-H-6), 3.95 (s,3H, OCH3), 3.92 (s, 3H, CO2CH3) ppm.13C NMR (125 MHz, CDCl3): delta = 166.4 (s,CO2Me), 155.9 (s, Ar-C-3), 133.3 (d, Ar-C-5), 130.6 (s, Ar-C-1), 122.9 (d, Ar-C-6),117.5 (s, Ar-C-4), 112.4 (d, Ar-C-2), 56.4 (q, OCH3), 52.4 (q, CO2CH3) ppm. HRMS(EI): m/z = calcd. 243.9735; found 243.9744 (Delta 4.01 ppm).

Reference： [1]Patent: US2006/199806,2006,A1 .Location in patent: Page/Page column 23
[2]Patent: US2006/287522,2006,A1 .Location in patent: Page/Page column 24
[3]Beilstein Journal of Organic Chemistry,2016,vol. 12,p. 2267 - 2273
[4]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1930,vol. 50,p. 224,227; dtsch. Ref. S. 26
Chem.Abstr.,1930,p. 3513
[5]Indian Journal of Chemistry,1973,vol. 11,p. 1081 - 1083

3
[ 17100-63-9 ]
[ 83011-43-2 ]
[ 2556-05-0 ]

Reference： [1]Chemische Berichte,1965,vol. 98,p. 1879 - 1892

4
[ 17100-63-9 ]
[ 93830-58-1 ]
[ 859140-23-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 3927 - 3954

5
[ 17100-63-9 ]
3-methoxy-4-(pyridin-4-yl)benzoic acid hydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 3927 - 3954

6
[ 14348-38-0 ]
[ 17100-63-9 ]

Yield	Reaction Conditions	Operation in experiment
		[Referential Example 40] Methyl 4-bromo-3-methoxybenzoate In the same manner as in Referential Example 17, a reaction was conducted using <strong>[14348-38-0]4-bromo-3-hydroxybenzoic acid</strong> as a starting material, whereby the title compound was obtained. 1H-NMR (CDCl3) delta: 3.92(3H,s), 3.96(3H,s), 7.51(1H,dd,J=8.3,2.0Hz), 7.55(1H,d,J=2.0Hz), 7.61(1H,d,J=8.8Hz).

Reference： [1]Chemische Berichte,1941,vol. 74,p. 79,94
[2]Indian Journal of Chemistry,1973,vol. 11,p. 1081 - 1083
[3]Patent: EP1104754,2001,A1
[4]Beilstein Journal of Organic Chemistry,2016,vol. 12,p. 2267 - 2273

7
potassium cyanide [ No CAS ]
[ 17100-63-9 ]
methyl 4-Cyanomethyl-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	18-crown-6 ether; In tetrahydrofuran; at 65℃; for 20h;	AIBN (274 mg) was added to a stirred suspension of methyl 3-methoxy-4-methylbenzoate (20.10 g, 112.0 mmol) and NBS (23.84 g, 134 mmol) in CCl4 (730 mL), and the resultant mixture was heated to reflux for 3 h. At room temperature, the mixture was diluted with hexanes (350 mL) before it was filtered and concentrated to give 28.59 g (crude yield 99%) of the brominated product. Part of the crude brominated product (8.10 g) was dissolved in anhydrous THF (70 mL). 18-Crown-6 (413 mg, 1.56 mmol) was added followed by KCN (3.05 g, 46.9 mmol); then the resulting mixture was heated at 65 C. for 20 h. The reaction mixture was diluted with H2O (50 mL) and EtOAc (250 mL), then the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give an oily residue, which was chromatographed on silica [gradient 5-20% EtOAc in hexanes] to provide 2.50 g of the cyanomethyl compound (39%) as a white solid. IR (KBr) 2260, 1714, cm-1; FDMS m/e 205 (M+).

Reference： [1]Patent: US6350774,2002,B1 .Location in patent: Page column 33

8
[ 3556-83-0 ]
[ 17100-63-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 3h;Heating / reflux;	AIBN (274 mg) was added to a stirred suspension of methyl 3-methoxy-4-methylbenzoate (20.10 g, 112.0 mmol) and NBS (23.84 g, 134 mmol) in CCl4 (730 mL), and the resultant mixture was heated to reflux for 3 h. At room temperature, the mixture was diluted with hexanes (350 mL) before it was filtered and concentrated to give 28.59 g (crude yield 99%) of the brominated product. Part of the crude brominated product (8.10 g) was dissolved in anhydrous THF (70 mL). 18-Crown-6 (413 mg, 1.56 mmol) was added followed by KCN (3.05 g, 46.9 mmol); then the resulting mixture was heated at 65 C. for 20 h. The reaction mixture was diluted with H2O (50 mL) and EtOAc (250 mL), then the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give an oily residue, which was chromatographed on silica [gradient 5-20% EtOAc in hexanes] to provide 2.50 g of the cyanomethyl compound (39%) as a white solid. IR (KBr) 2260, 1714, cm-1; FDMS m/e 205 (M+).

Reference： [1]Patent: US6350774,2002,B1 .Location in patent: Page column 33

9
[ 585544-30-5 ]
[ 17100-63-9 ]
5'-[(cyclopropylamino)carbonyl]-3'-fluoro-2'-methyl-2-(methyloxy)-4-biphenylcarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In water; isopropyl alcohol; at 90℃; for 3h;	Intermediate 7 (980mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (1.14g) and tetrakis (triphenylphosphine) palladium (0) (231mg) were combined in isopropanol (36ml) and aqueous sodium hydrogen carbonate (1 M, 12ml) was added. The reaction was stirred under nitrogen for 3 hours at 90C. The solvent was evaporated under vacuum and the resulting gel dissolved in ethyl ACETATE/CHLOROFORM (1: 1, 150MI) and washed with water (2X100ML). The organic layer was dried using a hydrophobic filter and evaporated in vacuo. The solid was purified using biotage (40g, Si), eluting with a gradient of ethyl acetate in cyclohexane (10-20%) to give 5 - [ (CYCLOPROPYLAMINO) CARBONYL]-3 -FLUORO- 2 -METHYL-2- (METHYLOXY)-4-BIPHENYLCARBOXYLIC acid (791mg). LC-MS : Rt 3.03min, MH+ 344.

Reference： [1]Patent: WO2004/89874,2004,A1 .Location in patent: Page 46

10
[ 106291-80-9 ]
[ 74-88-4 ]
[ 17100-63-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone; at 20℃; for 22h;	4-Bromo-3-hydroxybenzoic acid (1g) was dissolved in methanol (50MOI), concentrated sulphuric acid (330)) was added, and the reaction mixture heated at reflux for 16 hours. The reaction mixture was neutralised to pH7 using aqueous sodium hydroxide solution (2M) and the methanol evaporated under vacuum. The mixture was partitioned between water (50MI) and ethyl acetate/chloroform (1: 1, 2X100ML). The organics were combined, dried using a hydrophobic filter and the solvent evaporated to give a pale brown solid (1g). This solid was dissolved in acetone (25MUT) and potassium carbonate (680mg) added. Methyl iodide (366mul) was added dropwise and the mixture stirred under nitrogen at 20C for 22 hours. The reaction was quenched with aqueous sodium hydroxide solution (2M, 1. 1ML) and the solvent evaporated. The resulting solid was partitioned between water (100ML) and ethyl ACETATE/CHLOROFORM (1: 1, 2X100ML). The organic layers were combined, washed with water (100ml), dried over a hydrophobic filter, and the solvent evaporated to LEAVE METHYL 4-BROMO-3- (METHYLOXY) benzoate as a green-brown solid (980mg). LC-MS: Rt 3. 13min.
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	Intermediate [Example Int15.1methyl 4-bromo-3-methoxybenzoateTo a stirred solution of <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 mg). The mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 10 g of the title compound, that was used without further purification.1H-NMR (400MHz, DMSO-d6): delta [ppm]= 3.82 (s, 3H), 3.87 (s, 3H), 7.41 (dd, 1 H), 7.47 (d, 1 H), 7.67 (d, 1 H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	Intermediate Example Int 10.1meth l 4-bromo-3-methoxybenzoateTo a stirred solution of <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 mg). The mixture was stirred at r.t. for 2 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 10 g of the title compound, that was used without further purification.1H-NMR (400MHz, DMSO-d6): delta [ppm]= 3.82 (s, 3H), 3.87 (s, 3H), 7.41 (dd, 1 H), 7.47 (d, 1 H), 7.67 (d, 1 H).

	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a stirred solution of <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 mg). The mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 10 g of the title compound, that was used without further purification. 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 3.82 (s, 3H), 3.87 (s, 3H), 7.41 (dd, 1H), 7.47 (d, 1H), 7.67 (d, 1H).
10 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a stirred solution of <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 mg). The mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 10 g of the title compound, that was used without further purification. 1H-NMR (400MHz, DMSO-d6): delta [ppm] = 3.82 (s, 3H), 3.87 (s, 3H), 7.41 (dd, 1 H), 7.47 (d, 1 H), 7.67 (d, 1 H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a stirred solution of <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 g). The mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 10 g of the title compound, that was used without further purification.1H-NMR (400MHz, DMSO-d6): delta [ppm] = 3.82 (s, 3H), 3.87 (s, 3H), 7.41 (dd, 1 H), 7.47 (d, 1 H), 7.67 (d, 1 H).
10 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a stirred solution of <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 mg). The mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent wasremoved in vacuum to give 10 g of the title compound, that was used without further purification.1H-NMR (400MHz, DMSO-d6): O [ppm] = 3.82 (5, 3H), 3.87 (5, 3H), 7.41 (dd, 1H),7.47 (d, 1H), 7.67 (d, 1H).
10 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a stirred solution of <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 mg). The mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 10 g of the title compound, that was used without further purification. 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=3.82 (s, 3H), 3.87 (s, 3H), 7.41 (dd, 1H), 7.47 (d, 1H), 7.67 (d, 1H).

Reference： [1]Journal of Materials Chemistry C,2016,vol. 4,p. 4269 - 4277
[2]Patent: WO2004/89874,2004,A1 .Location in patent: Page 46
[3]Patent: WO2011/64328,2011,A1 .Location in patent: Page/Page column 79
[4]Patent: WO2012/143329,2012,A1 .Location in patent: Page/Page column 89
[5]Patent: WO2013/87579,2013,A1 .Location in patent: Page/Page column 96
[6]Patent: WO2014/9219,2014,A1 .Location in patent: Page/Page column 70; 71
[7]Patent: WO2014/195276,2014,A1 .Location in patent: Page/Page column 98-99
[8]Patent: WO2014/198594,2014,A1 .Location in patent: Page/Page column 94
[9]Patent: US2015/148542,2015,A1 .Location in patent: Paragraph 0338-0340

11
[ 17100-63-9 ]
[ 56256-14-5 ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium hydroxide; In methanol; water; at 20℃; for 6h;	Aq. sodium hydroxide (2 M, 40 mL) was added to a solution of methyl 4-bromo-3-methoxy-benzoate (13, 6.52 g, 27.1 mmol) in methanol (200 mL) and the mixture was stirred for 6 h at room temp. Deionized water (100 mL) was added and methanol was distilled off in vacuo.The remaining aq. phase was washed with dichloromethane (3 x 100 mL) and acidified with hydrochloric acid (6 M). The precipitate was filtered off and was washed thoroughly with water yielding a colourless solid. Yield: 4.10 g (17.8 mmol, 66%)(ref[5]: 89%). M. p.: 220 C.1H NMR (500 MHz, DMSO-d6): delta = 13.21 (br. s, 1H,CO2H), 7.71 (d, 1H,3J = 8.2 Hz, Ar-H-5), 7.54 (d, 1H,4J = 1.8 Hz, Ar-H-2), 7.46 (dd,1H,3J = 8.2 Hz,4J = 1.8 Hz, Ar-H-6), 3.91 (s, 3H, OCH3) ppm.13C NMR (125 MHz,DMSO-d6): delta = 167.1 (s, CO2H), 155.9 (s, Ar-C-3), 133.6 (d, Ar-C-5), 132.1 (s, Ar-C-1), 123.2 (d, Ar-C-6), 116.5 (s, Ar-C-4), 113.0 (d, Ar-C-2), 56.8 (q, OCH3) ppm. MS(EI, 70 eV): m/z = 230/232 (100/98) [M]+·.
56%	With hydrogenchloride; lithium hydroxide; In tetrahydrofuran; methanol;	To a solution of 4-bromo-3-methoxy-benzoic acid methyl ester (6.875 mmol, 1.676 mL) in a mixture 1:1 of THF/MeOH (15 ML), lithium hydroxide (7.553 mmol, 0.180 g) was added, and the reaction was stirred at RT overnight before distillation of volatiles. The residue was diluted with water, acidified with a solution of HCl (1N), and stirred for 1 hour. The formed precipitate was filtered off, and washed with water and petroleum ether to give 4-bromo-3-methoxy-benzoic acid. Yield: 56%.
		Intermediate [Example Int15.24-bromo-3-methoxybenzoic acidTo a stirred solution of methyl 4-bromo-3-methoxybenzoate (11.2 g) in THF (130 mL), methanol (45 mL) and water (45 mL) was added a 1 M solution of lithium hydroxide in water (140 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuum. Water was added and 1 N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by filtration, washed with water and dried in vacuum to give 10.1 g of the title compound, that was used without further purification.1 H-NMR (300MHz, DMSO-d6): delta [ppm]= 3.87 (s, 3H), 7.42 (dd, 1 H), 7.50 (d, 1 H), 7.68 (d, 1 H), 13.21 (br. s., 1 H).

		Intermediate Example Int 10.24-bromo-3-methoxybenzoic acidTo a stirred solution of methyl 4-bromo-3-methoxybenzoate (1 1 .2 g) in THF (1 30 mL), methanol (45 mL) and water (45 mL) was added a 1M solution of lithium hydroxide in water (140 mL). The mixture was stirred at r.t. for 1 h. The solvent was removed in vacuum. Water was added and 1 N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by filtration, washed with water and dried in vacuum to give 10.1 g of the title compound, that was used without further purification. 1H-NMR (300MHz, DMSO-d6): delta [ppm]= 3.87 (s, 3H), 7.42 (dd, 1 H), 7.50 (d, 1 H), 7.68 (d, 1 H), 13.21 (br. s., 1 H). Intermediate Example Int10.3
	With water; lithium hydroxide; In tetrahydrofuran; methanol;	To a stirred solution of methyl 4-bromo-3-methoxybenzoate (11.2 g) in THF (130 mL), methanol (45 mL) and water (45 mL) was added a 1 M solution of lithium hydroxide in water (140 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuum. Water was added and 1 N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by filtration, washed with water and dried in vacuum to give 10.1 g of the title compound, that was used without further purification. 1H-NMR (300MHz, DMSO-d6): delta [ppm]= 3.87 (s, 3H), 7.42 (dd, 1 H), 7.50 (d, 1 H), 7.68 (d, 1 H), 13.21 (br. s., 1 H).
10.1 g	With water; lithium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 1h;	To a stirred solution of methyl 4-bromo-3-methoxybenzoate (11.2 g) in THF (130 mL), methanol (45 mL) and water (45 mL) was added a 1 M solution of lithium hydroxide in water (140 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuum. Water was added and 1 N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by filtration, washed with water and dried in vacuum to give 10.1 g of the title compound, that was used without further purification. 1H-NMR (300MHz, DMSO-d6): delta [ppm] = 3.87 (s, 3H), 7.42 (dd, 1 H), 7.50 (d, 1 H), 7.68 (d, 1 H), 13.21 (br. s., 1 H).
	With water; lithium hydroxide; In tetrahydrofuran; at 20℃; for 1h;	To a stirred solution of methyl 4-bromo-3-methoxybenzoate (11.2 g) in THF (130 ml_), methanol (45 mL) and water (45 mL) was added a 1 M solution of lithium hydroxide in water (140 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuum. Water was added and 1 N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by filtration, washed with water and dried in vacuum to give 10.1 g of the title compound, that was used without further purification.1H-NMR (300MHz, DMSO-d6): delta [ppm] = 3.87 (s, 3H), 7.42 (dd, 1 H), 7.50 (d, 1 H), 7.68 (d, 1 H), 13.21 (br. s., 1 H).
10.1 g	With lithium hydroxide; In tetrahydrofuran; methanol; water; at 20℃; for 1h;	To a stirred solution of methyl 4-bromo-3-methoxybenzoate (11.2 g) in THF (130 mL), methanol (45 mL) and water (45 mL) was added a 1 M solution of lithium hydroxide in water (140 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuum. Water was added and I N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by filtration, washed with waterand dried in vacuum to give 10.1 g of the title compound, that was used without further purification.1H-NMR (300MHz, DMSO-d6): a [ppm] = 3.87 (5, 3H), 7.42 (dd, 1H), 7.50 (d, 1H),7.68 (d, 1H), 13.21 (br. s., 1H).
10.1 g	With water; lithium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 1h;	To a stirred solution of methyl 4-bromo-3-methoxybenzoate (11.2 g) in THF (130 mL), methanol (45 mL) and water (45 mL) was added a 1 M solution of lithium hydroxide in water (140 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuum. Water was added and 1 N hydrochloric acid was added with ice bath cooling until pH 4 was reached. The precipitated solid was collected by filtration, washed with water and dried in vacuum to give 10.1 g of the title compound, that was used without further purification. 1H-NMR (300 MHz, DMSO-d6): delta [ppm]=3.87 (s, 3H), 7.42 (dd, 1H), 7.50 (d, 1H), 7.68 (d, 1H), 13.21 (br. s., 1H).

Reference： [1]Beilstein Journal of Organic Chemistry,2016,vol. 12,p. 2267 - 2273
[2]Patent: US2003/45557,2003,A1
[3]Patent: WO2011/64328,2011,A1 .Location in patent: Page/Page column 79-80
[4]Patent: WO2012/143329,2012,A1 .Location in patent: Page/Page column 89
[5]Patent: WO2013/87579,2013,A1 .Location in patent: Page/Page column 96; 97
[6]Patent: WO2014/9219,2014,A1 .Location in patent: Page/Page column 71
[7]Patent: WO2014/195276,2014,A1 .Location in patent: Page/Page column 99
[8]Patent: WO2014/198594,2014,A1 .Location in patent: Page/Page column 94; 95
[9]Patent: US2015/148542,2015,A1 .Location in patent: Paragraph 0341-0343

12
[ 14348-38-0 ]
[ 77-78-1 ]
[ 17100-63-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone;	To a solution of <strong>[14348-38-0]4-bromo-3-hydroxybenzoic acid</strong> (14.480 mmol, 2.600 g) in acetone (180 mL), potassium carbonate (62.988 mmol, 8.710 g) and dimethylsulfate (31.422 mmol, 2.970 mL) were added. The reaction was stirred at RT for 30 minutes and evaporated to dryness. The residue was then diluted with water and extracted with ethyl acetate. The collected organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. 4-Bromo-3-methoxy-benzoic acid methyl ester was isolated by chromatography on silica gel eluding with cyclohexane containing from 0% to 20% ethyl acetate. Yield: 47%.

Reference： [1]Patent: US2003/45557,2003,A1

13
[ 700-58-3 ]
[ 17100-63-9 ]
[ 205986-50-1 ]

Yield	Reaction Conditions	Operation in experiment
1.23 g (3.39 mmol, 84.7%)	With triethylamine; In tetrahydrofuran; hexane; dichloromethane; water;	REFERENCE EXAMPLE 1 1,1-(bicyclo[3.3.1]nonan-3,7-diyl)-2-(4-bromo-3-methoxyphenyl)-2-methoxyethene (Compound [3]) STR6 In an atmosphere of nitrogen, 4.8 g (31 mmol) of titanium trichloride was added to 80 ml of tetrahydrofuran in a 500 ml three-necked eggplant type flask equipped with a three way stop-cock, a condenser stopped with a balloon, and a 50 ml dropping funnel. The above mixture was stirred in the atmosphere of nitrogen at room temperature for about 10 minutes. To this mixture, 0.61 g (16.1 mmol) of lithium aluminum hydride was added under ice cooling. After the generation of hydrogen ceased, the mixture was further stirred for about 10 minutes. 2.1 ml (15 mmol) of triethylamine was then added to this reaction mixture. This mixture was further refluxed for about 15 minutes. To this reaction mixture, under refluxing, a solution of 1.21 g (8.0 mmol) of 2-adamantanone and 990 mg (4.0 mmol) of <strong>[17100-63-9]methyl 4-bromo-3-methoxybenzoate</strong> in 25 ml of tetrahydrofuran was added dropwise over a period of 20 minutes. The above reaction mixture was further refluxed for 3 hours and then allowed to cool to room temperature. 30 ml of distilled water was added to the reaction mixture. The mixture was extracted with 200 ml of ethyl acetate. The ethyl acetate extract layer was washed twice with 200 ml of distilled water, dried over magnesium sulfate, and then concentrated. The residue was chromatographed on silica gel and eluted with a mixed solvent of hexane and dichloromethane (50:1), whereby 1,1-(bicyclo[3.3.1]nonan-3,7-diyl)-2-(4-bromo-3-methoxy-phenyl)-2-methoxyethene (Compound [3]) was obtained in the form of a colorless oil in a yield of 1.23 g (3.39 mmol, 84.7%). 1 H-NMR(400 MHz, CDCl3): delta1.61-2.17 (m, 12H), 2.63 (mp, 1H, alpha-methyne), 3.24 (mp, 1H, alpha-methyne), 3.30 (s, 3H, OMe), 3.89 (s, 3H, ArOMe), 6.76-7.49 (m, 3H, ArOMe), 6.76-7.49 (m, 3H, ArH) ppm IR (KRr): 2923, 2847, 1569, 1457, 1395, 1247, 1206, 1095, 1048, 1026, 866, 822, 795, 764 cm-1

Reference： [1]Patent: US5929254,1999,A

14
[ 17100-63-9 ]
[ 16419-60-6 ]
[ 175152-49-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 105℃; for 7h;	A solution consisting of toluene (100 mL), ethanol (50 mL), and water (50 mL) was sparged with dry nitrogen for 45 minutes. To the mixture was added <strong>[17100-63-9]methyl 4-bromo-3-methoxybenzoate</strong> of step B (26.5 mmol), o-tolylboronic acid (29.1 mmol), and sodium carbonate (112.5 mmol). The mixture was sparged with nitrogen for an additional ten minutes. Terakis(triphenylphosphine)palladium(0) (1 mmol) was added to the mixture, which was then heated at 105 C. for 6 hours. The mixture was cooled and the organic phase was washed three times in sequence with saturated aqueous sodium carbonate and brine. The organics were dried over anhydrous sodium sulfate, filtered, and evaporated to an oil. Flash chromatography of the residue on silica gel using dichloromethane/ hexane (3:1) yielded the title compound as a clear oil (6.7 g, 99%).
99%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 105℃; for 6h;	Step C. 2-Methoxy-2'-methyl-1,1'-biphenyl-4-carboxylic acid methyl ester; A solution consisting of toluene (100 mL), ethanol (50 mL), and water (50 mL), was sparged with dry nitrogen gas for 45 minutes. To the solvent mixture was added 4-bromo-3-methoxybenzoic acid methyl ester of Step B (26.5 mmol), o-tolylboronic acid (29.1 mmol), and sodium carbonate (112.5 mmol). The mixture was sparged with nitrogen gas for an additional ten minutes. Tetrakis(triphenylphosphine)palladium(0) (1 mmol) was added to the mixture which was then heated at 105 C. for 6 hours. The mixture was cooled and the phases separated. The organic phase was washed three times with a sequence of saturated aqueous sodium carbonate, and brine. The organics were dried over anhydrous sodium sulfate, and evaporated to an oil. Chromatography on silica gel using dichloromethane and hexane (3:1) provided the title compound as a clear oil (6.7g, 99%).
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; for 2h;Heating / reflux;	A suspension of <strong>[17100-63-9]methyl 4-bromo-3-methoxybenzoate</strong> (Combi-blocks CA-4192; 2.5 g; 10.2 mmol; 1 eq.), o-tolylboronic acid (Aldrich 393606; 1.53 g; 11 .2 mmol; 1.1 eq.), potassium carbonate (7.05 g; 51 mmol; 5 eq.) and Pd(PPh3)4 (1.18 g; 1 .02 mmol; 0.1 eq.) in toluene (12.5 mL) and water (12.5 mL) was refluxed for 2 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of celite which was further washed with touene (200 mL). The filtrate was concentrated in vacuo and the residue taken up in Ethyl acetate (500 mL). The organic layer was washed with sat. aq. NaHCO3 (150 mL), water (150 mL) and brine (150 mL) then dried over magnesium sulfate and concentrated in vacuo. The residue (2.5 g; 9.75 mmol; 1 eq.) was taken up in EtOH (75 mL), sodium hydroxide (5M; 5.85 mL; 29.3 mmol; 3 <n="69"/>eq.) was added and the reaction mixture was stirred at 600C for two hours. After concentration in vacuo, the residue was taken up in water (400 ml_) and the aqueous phase was washed withEthyl acetate then acidified to pH 2 with cone. HCI. The solution was concentrated to ca. 80 ml_ and the precipitate filtered off and dried to afford the title compound (1.95 g, 79%) as a beige solid.HPLC (Method A) : Rt 4.05 min (purity 97.3%). LC/MS : 240.9 (M-H)".

Reference： [1]Patent: US2006/199806,2006,A1 .Location in patent: Page/Page column 23
[2]Patent: US2006/287522,2006,A1 .Location in patent: Page/Page column 24
[3]Patent: WO2009/43890,2009,A1 .Location in patent: Page/Page column 67-68
[4]ChemMedChem,2015,vol. 10,p. 688 - 714

15
[ 17100-63-9 ]
[ 14047-29-1 ]
[ 149-73-5 ]
[ 934666-70-3 ]

Reference： [1]Angewandte Chemie - International Edition,2008,vol. 47,p. 8482 - 8486

16
[ 14348-38-0 ]
[ 74-88-4 ]
[ 17100-63-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 12h;	Procedure M: To a mixture of 2-<strong>[14348-38-0]4-bromo-3-hydroxybenzoic acid</strong> (2.5 g, 23.0 mmol) in DMF (10 mL), were added Cs2CO3 (12.0 g, 69.0 mmol) and methyl iodide (4.1 g, 57.5 mmol). The reaction mixture was stirred at 50 for 12 h. It was then diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (DCM/MeOH 4:1, v/v) to give methyl 4-bromo-3- methoxybenzoate as a white solid (2.4 g, 85%). LC-MS (ESI): m/z (M)+ = 245.11, 247.16.
83%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	Method A: Potassium carbonate (4.56 g, 33.0 mmol) was added to asolution of methyl 4-bromo-3-hydroxybenzoate (12, 6.24 g,27.0 mmol) in acetone (40 mL). Dimethyl sulfate (3.03 mL, 32.0 mmol)was added and the mixture was heated to reflux for 3 h. At roomtemp., deionized water was added (5 mL) and acetone was distilled off in vacuo. Theremaining aq. phase was extracted with dichloromethane (3 x 100 mL), the combinedorganic layer was dried with magnesium sulfate, filtered and the solvent wasremoved in vacuo yielding a colourless solid. Yield: 6.59 g (26.9 mmol, >99%) (ref.[5]:99%).Method B: Potassium carbonate (2.54 g, 18.4 mmol) was added to a solution of <strong>[14348-38-0]4-bromo-3-hydroxybenzoic acid</strong> (11, 1.00 g, 4.61 mmol) in N,N-dimethylformamide (10 mL). Methyl iodide (863 muL, 13.8 mmol) was added and the mixture was stirred for 16 h at room temp. Deionized water (50 mL) was added and the aq. phase was extracted with tert-butyl methyl ether (3 x 100 mL). The combined organic layer was washed with brine (100 mL) and dried with magnesium sulfate. After filtration, the solvent was evaporated in vacuo yielding a colourless solid. Yield: 938 mg(3.83 mmol, 83%) (ref.[3]: 91%). M. p. 53 C.1H NMR (500 MHz, CDCl3): delta = 7.61 (d, 1H,3J = 8.2 Hz, Ar-H-5), 7.55(d, 1H,4J = 1.8 Hz, Ar-H-2), 7.51 (dd, 1H,3J = 8.2 Hz,4J = 1.8 Hz, Ar-H-6), 3.95 (s,3H, OCH3), 3.92 (s, 3H, CO2CH3) ppm.13C NMR (125 MHz, CDCl3): delta = 166.4 (s,CO2Me), 155.9 (s, Ar-C-3), 133.3 (d, Ar-C-5), 130.6 (s, Ar-C-1), 122.9 (d, Ar-C-6),117.5 (s, Ar-C-4), 112.4 (d, Ar-C-2), 56.4 (q, OCH3), 52.4 (q, CO2CH3) ppm. HRMS(EI): m/z = calcd. 243.9735; found 243.9744 (Delta 4.01 ppm).

Reference： [1]Angewandte Chemie - International Edition,2008,vol. 47,p. 8482 - 8486
[2]Patent: WO2019/213570,2019,A1 .Location in patent: Paragraph 0331; 0623-0625
[3]Beilstein Journal of Organic Chemistry,2016,vol. 12,p. 2267 - 2273

17
[ 17100-63-9 ]
[ 177735-11-4 ]
[ 1141473-69-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; for 5h;Heating / reflux;	A suspension of <strong>[17100-63-9]methyl 4-bromo-3-methoxybenzoate</strong> (2.5 g; 10.2 mmol; 1.00 eq.), 4-methyl-3- thiopheneboronic acid (Aldrich 542393; 1.59 g; 11.2 mmol; 1.1 eq.), potassium carbonate (7.05 <n="70"/>g; 51 mmol; 5 eq.) and Pd(PPh3)4 (1.18 g; 1 mmol; 0.1 eq.) in toluene (12.5 ml_) and water (12.5 ml.) was refluxed for 5 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of celite which was further washed with touene (200 ml_). The filtrate was concentrated in vacuo and the residue taken up in Ethyl acetate (400 ml_). The organic layer was washed with sat. aq. NaHCC>3 (100 ml_), water (100 ml_) and brine (100 ml_) then dried over magnesium sulfate and concentrated in vacuo. The residue (2.3 g; 8.77 mmol; 1 eq.) was taken up in EtOH (69 ml_), sodium hydroxide (5M; 5.26 ml 26.3 mmol; 3 eq.) was added and the reaction mixture was stirred at 6O0C for one hour. After concentration in vacuo, the residue was taken up in water (200 ml_) and the aqueous phase was washed with Ethyl acetate then acidified to pH 2 with cone. HCI. The solution was concentrated to ca. 100 ml_ and the precipitate filtered off and dried to afford the title compound (1.81 g, 71 %) as a brown solid. HPLC (Method A) : Rt 3.99 min (purity 97.4%). LC/MS : 246.9 (M-H)".
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; for 3h;Inert atmosphere; Reflux;	imethyl 3-methoxy-4-(4-methyl-3-thienyl)benzoateMethyl 4-bromo-3-methoxybenzoate (Combi-Blocks, 2.50 g; 10.20 mmol) and 4-methyl-3- thiopheneboronic acid (1.59 g; 1 1.22 mmol), potassium carbonate (7.04 g; 51 mmol), tetrakis(triphenylphosphine)palladium(0) (1.17 g; 1.02 mmol) were mixed in toluene (10 ml_) and water (10 ml_) under N2 atmosphere. The reaction mixture was degassed with N2for 10 min and was heated under reflux for 3 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene. The filtrate was concentrated under vacuum to afford brown oil. It was taken in EtOAc and the organic layer was washed with a saturated aqueous solution of NaHCO3, water and brine. It was dried over MgSO4, filtered off and concentrated under vacuum giving a brown oil. LC/MS (Method A): 262.8 (M+H)+. HPLC (Method A) Rt 4.79 min (Purity: 63.0%).

Reference： [1]Patent: WO2009/43890,2009,A1 .Location in patent: Page/Page column 68-69
[2]Patent: WO2010/69949,2010,A1 .Location in patent: Page/Page column 69

18
[ 474010-72-5 ]
[ 17100-63-9 ]
[ 1173176-98-1 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4481 - 4487

19
[ 17100-63-9 ]
[ 73183-34-3 ]
3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 4h;Inert atmosphere;	A mixture of <strong>[17100-63-9]methyl 4-bromo-3-methoxybenzoate</strong> (3.0 g, 12.2 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4.8 g, 19 mmol), Pd(dppf)Ch (450 mg, 0.6 mmol) and potassium acetate (1.9 g, 19.0 mmol) in dioxane (50 mL) was stirred at 80 C under an N2 atmosphere for 4 h. The reaction was filtered through a pad of Celite, and the filter cake washed with EtOAc (10 mL x 3). The filtrate was concentrated under vacuum and the residue purified by silica gel column chromatography using 15: 1 petroleum ether/ethyl acetate to afford methyl 3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoate (2.5 g, 70% yield) as a white solid. MS Calcd.: 292.1, MS Found: 293.4 [M+l] +.
69%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere;	methyl 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0285) To a solution of <strong>[17100-63-9]methyl 4-bromo-3-methoxybenzoate</strong> (7.3 g, 29.79 mmol) in dioxane (150 mL) was added 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (8.3 g, 32.69 mmol), Pd(dppf)Cl2.CH2Cl2 (2.4 g, 2.94 mmol) and potassium acetate (8.76 g, 89.26 mmol) at room temperature. The reaction mixture was stirred for 16 h at 80 C., cooled to room temperature, and treated with water (100 mL). The resulting solution was extracted with ethyl acetate (250 mL×3). The organic phases were combined, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate in hexane (0% to 10% gradient) to yield methyl 3-methoxy-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate as yellow oil (6.0 g, 69%). MS: m/z=293.0 [M+H]+.
50%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 100℃; for 1h;Microwave irradiation; Inert atmosphere; Sealed tube;	Preparation 19: methyl 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzoate; 1 ,1 '-Bis(diphenylphospino)ferrocene-palladium dichloride (157 mg, 0.204 mmol), <strong>[17100-63-9]methyl 4-bromo-3-methoxybenzoate</strong> (1000 mg, 4.08 mmol), bis(pinacolato)diboron (1140 mg, 4.49 mmol), potassium acetate (843 mg, 8.16 mmol) and dioxane (3 ml_) were combined in a microwave vial and bubbled with nitrogen for 5 min. The vial was sealed and heated to 1000C in a microwave reactor for 60 min. The reaction was cooled to room temperature, filtered through celite and partitioned between ethyl acetate (10 mL) and water (10 mL). The phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated to give an off-white solid. The solid was purified by silica gel column chromatography eluting with a gradient of 0%-50% ethyl acetate/ heptane to obtain the title compound (600 mg, 50 %) 1 H NMR (400 MHz,DMSO-cfe) delta ppm 1.26 (s, 12 H) 3.78 (s, 3 H) 3.84 (s, 3 H) 7.41 (d, J=1.37 Hz, 1 H) 7.50 (dd, J=7.61 , 1.37 Hz, 1 H) 7.62 (d, J=7.61 Hz, 1 H).

	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 6h;Inert atmosphere;	General procedure: Preparation 3 7-Cvclopropyl-4-r4-fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyll-7/-/- imidazor4,5-clpyridazine A mixture of 4-(3-bromo-4-fluorophenyl)-7-cyclopropyl-7/-/-imidazo[4,5-c]pyridazine (Preparation 8, 820 mg, 2.461 mmol), bispinacolatodiboron (938 mg, 3.692 mmol) and potassium acetate (483 mg, 4.922 mmol) in dioxane (20 ml_) was degassed with nitrogen before the addition of 1 ,1 '-bis(di-phenylphosphino)ferrocene palladium (II) dichloride (201 mg, 0.246 mol). The reaction was heated to 100C for 3 hours before cooling and filtering through celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified using silica gel column chromatography eluting with 0-2% MeOH in EtOAc followed by trituration with EtOAc to afford the title compound as an off-white solid (510 mg, 55%). 1 H NMR (400 MHz, CDCI3): delta ppm 1.25-1.34 (m, 4H), 1.39 (s, 12H), 3.67-3.73 (m, 1 H), 7.21-7.26 (s, 1 H), 8.25 (s, 1 H), 8.40-8.44 (m, 2H), 9.40 (s, 1 H). MS m/z 299 [M+H]+ Boronic acid, MS m/z 381 [M+H]+ Boronate ester
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In toluene; at 110℃; for 3h;Inert atmosphere;	Compound 61-1 (200 mg, 0.816 mmol),Bis (pinacolato) diboron(246 mg, 0.979 mmol), Pd (dppf) 2Cl2 (66 mg, 0.0816 mmol) and potassium acetate (240 mg, 2.448 mmol) were dissolved in 20 mL of toluene,Nitrogen replacement 3 times,Heated to 110 C,The mixture was reacted for 3 hours,Cooled to room temperature,filter,The filtrate was used directly in the next step without separation.

Reference： [1]Patent: WO2020/86533,2020,A1 .Location in patent: Page/Page column 98
[2]Patent: US2016/376283,2016,A1 .Location in patent: Paragraph 0283; 0285
[3]Patent: WO2010/116282,2010,A1 .Location in patent: Page/Page column 58-59
[4]Patent: WO2015/189744,2015,A1 .Location in patent: Page/Page column 57-58; 69
[5]Patent: CN104844471,2017,B .Location in patent: Paragraph 0537; 0538; 0539

20
[ 17100-63-9 ]
[ 4612-26-4 ]
1,4-di(4-methoxycarbonyl-2-methoxyphenyl)benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃;	1,4-di(4-carboxy-2-hydroxyphenyl)benzene (di-OH-TPDC) was synthesized following a procedure we previously reported (Fig. S1) [11-13]. First, 10.2mmol (1.69g) of benzene-1,4-diboronic acid, 20.4 mmol(4.99 g) of <strong>[17100-63-9]methyl 4-bromo-3-methoxybenzoate</strong>, and 0.6 mmol (0.69 g) of Pd(PPh3)4 were slowly added to a mixed solution of THF (80 mL) and K2CO3 (15 ml, 2 M dissolved in deionized water) at 80 C. After stirring this mixture over night, this was filtered, washed using methanol, and then dried at 60 C to yield 1,4-di(4-methoxycarbonyl-2-methoxyphenyl)benzene (1). Second, 12.3 mmol (5.0 g)of 1 was added to a mixed solution of THF (200 mL) and NaOH (200 mL, 1 M dissolved in deionized water) at 80 C under stirring. After refluxing this suspension for 5 h, the resulting mixture was diluted using deionized water until a salt included in this mixture was dissolved completely.This was subsequently acidified using 1 M HCl, filtered, washed using methanol, and dried at 60 C to yield 1,4-di(4-carboxy-2-methoxyphenyl)benzene(2). Third, 2 was added to 30 mL of BBr3 solution(1 M dissolved in deionized water)at room temperature and stirred over night.This mixture was filtered, washed using deionized water, and recrystallized under the mixture of DMF and deionized water to finally yield di-OH-TPDC (3). 3 was stored in a glove box purged with Ar gas (99.999%). The successful synthesis of 1, 2, and, 3 was confirmed by 1H-NMR and differential scanning calorimetry (DSC) under a N2 atmosphere (30 mLmin-1) showing distinguishable melting point of each chemical [11-13].

Reference： [1]Inorganica Chimica Acta,2011,vol. 370,p. 76 - 81
[2]Journal of Solid State Chemistry,2015,vol. 230,p. 110 - 117

21
[ 17100-63-9 ]
[ 56256-15-6 ]

Reference： [1]Patent: WO2011/64328,2011,A1
[2]Patent: WO2012/143329,2012,A1
[3]Patent: WO2014/198594,2014,A1
[4]Beilstein Journal of Organic Chemistry,2016,vol. 12,p. 2267 - 2273

22
[ 17100-63-9 ]
[ 1309682-43-6 ]

Reference： [1]Patent: WO2011/64328,2011,A1
[2]Patent: WO2013/87579,2013,A1
[3]Patent: WO2014/9219,2014,A1
[4]Patent: WO2014/195276,2014,A1
[5]Patent: US2015/148542,2015,A1

23
[ 111-34-2 ]
[ 17100-63-9 ]
C₁₅H₂₀O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;1,3-bis-(diphenylphosphino)propane; palladium diacetate; In methanol; at 90℃;Inert atmosphere; Microwave irradiation; Sealed vial;	Example 206methyl 4-acetyl-3-methoxybenzoateMethyl 4-bromo-3-methoxybenzoate (0.53 g, 2.2 mmol), 1,3-bis(diphenylphosphino)propane (0.050 g, 0.12 mmol), sodium carbonate (0.510 g, 4.81 mmol) and palladium (II) acetate (0.024 g, 0.11 mmol) were combined in a 5 mL microwave vial. The vial was sealed and purged with argon. Methanol (2.50 mL, 61.7 mmol) and n-butyl vinyl ether (1.12 mL, 8.74 mmol) were added by syringe, and the mixture was sonicated under argon flow for several minutes, then heated to 90 C. over night. Upon cooling to room temperature, celite (1 g) was added. The mixture was diluted with methanol (5 mL) and the slurry was then filtered. The filter cake was washed with methanol and to the pale red/brown methanolic filtrate was added 6M aqueous HCl (2.5 mL). The solution turned yellow and then turbid white over stirring at room temperature (0.5 h). The solvent was removed under reduced pressure and the residue obtained was partitioned between ethyl acetate (50 mL) and half-saturated aqueous sodium bicarbonate solution (25 mL). The aqueous phase was extracted with ethyl acetate (30 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (15-85% EtOAc/hexanes gradient) to afford the title compound (0.396 g, 87%). LC-MS: (FA) ES+209; 1H NMR (300 MHz, DMSO) delta 7.69-7.53 (m, 3H), 3.94 (s, 3H), 3.88 (s, 3H), 2.54 (s, 3H).

Reference： [1]Patent: US2011/212969,2011,A1 .Location in patent: Page/Page column 134

24
[ 17100-63-9 ]
[ 17100-64-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	With lithium aluminium tetrahydride; In tetrahydrofuran; at -40℃; for 2h;Inert atmosphere;	To a mixture of methyl 4-bromo-3-methoxy-benzoate (3.00 g, 12.24 mmol) in THF (40) was added LiAlH4 (1.39 g, 36.72 mmol) at -40°C under N2, then the mixture was stirred at -40°C for 2 hours. To the mixture was added 0 (1.76 g) dropwise at -40 °C, then the mixture was stirred at 0 °C for 0.5 hour and 50 °C for 0.5 hour, filtered through Celite, and eluted by THF (100 mL x 2). The filtrate was concentrated. The residue was dissolved in EtOAc (200 mL), washed with water (30 mL x 2) and brine (50 mL), dried over Na2S04, filtered and concentrated to afford the crude product of compound 17-2 (2.50 g, 11.52 mmol, 94percent yield) as an oil, *H NMR (400MHz, DMSO-d6) deltaEta = 7.49 (d, 1H), 7.06 (s, 1H), 6.84 (d, 1H), 5.29 (t, 1H), 4.47 (d, 2H), 3.83 (s, 3H).
2.5 g		To a mixture of A-26 (3.00 g, 12.24 mmol) in THF (40 mL) was added LiAlH4 (1.39 g, 36.72 mmol) at -40C under N2, and the mixture was stirred at -40C for 2 hours. To the mixture was added _0 (1.76 g) dropwise at -40 C, and the mixture was stirred at 0 C for 0.5 hour, followed by stirring at 50 C for 0.5 hour. The mixture was then filtered through Celite, eluted by THF (100 mL x 2), concentrated, dissolved in EtOAc (200 mL), washed with water (30 mL x 2) and brine (50 mL), dried over Na2S04, filtered and concentrated to give A-27 (2.50 g, 11.52 mmol) as an oil. 1H NMR (400MHz DMSO-d6) _ = 7.49 (d, 1H), 7.06 (s, 1H), 6.84 (d, 1H), 5.29 (t, 1H), 4.47 (d, 2H), 3.83 (s, 3H).

Reference： [1]Patent: WO2018/98491,2018,A1 .Location in patent: Page/Page column 96
[2]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 2382 - 2391
[3]CrystEngComm,2017,vol. 19,p. 603 - 607
[4]Patent: WO2018/98499,2018,A1 .Location in patent: Page/Page column 137

25
[ 17100-63-9 ]
[ 75-16-1 ]
[ 1403330-20-0 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 20℃; for 1h;Reflux;	Intermediate Example Int 10.292-(4-bromo-3-methoxyphenyl)propan-2-olTo a stirred solution of Int 10.1 (5.3 g) in THF (250 mL) was added methyl magnesium bromide (21 .5 mL; c = 3.0 M) at r.t. and the mixture was heated to reflux for 1 h. A half-saturated aqueous solution of ammounim chloride was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 3.09 g of the title compound.
3.09 g	In tetrahydrofuran; for 1h;Reflux;	To a stirred solution of <strong>[17100-63-9]methyl 4-bromo-3-methoxybenzoate</strong> (5.3 g) in THF (250 mL) was added methyl magnesium bromide (21.5 mL; c = 3.0 M) at room temperature and the mixture was heated to reflux for 1 h. A half-saturatedaqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chLoride soLution, dried (sodium suLfate) and the soLvent was removed in vacuum. Silicagel chromatography gave 3.09 g of the title compound.
960 mg	In tetrahydrofuran; at -30 - 25℃; for 8h;	To a solution of <strong>[17100-63-9]methyl 4-bromo-3-methoxy-benzoate</strong> (1.00 g, 4.08 mmol) in THF (30 mL) was added MeMgBr (3 M, 10.88 mL) dropwise at -30C. The reaction mixture was allowed to warm to 25 C and stirred for 8 hours. The mixture was quenched with sat.NH4Cl (200 mL) at 0 C and extracted with EtOAc (200 mL x 2). The organic layers were concentrated to afford A-127 (960.00 mg) as a solid. H NMR (400MHz DMSO-d6) _ = 7.45 (d, 1H), 7.19 (d, 1H), 6.95 (dd, 1H), 5.12 (s, 1H), 3.84 (s, 3H), 1.42 (s, 6H).

Reference： [1]Patent: WO2012/143329,2012,A1 .Location in patent: Page/Page column 135-136
[2]Patent: WO2014/198594,2014,A1 .Location in patent: Page/Page column 97
[3]Patent: WO2018/98499,2018,A1 .Location in patent: Page/Page column 206

26
[ 17100-63-9 ]
[ 762183-54-0 ]
[ 1563217-32-2 ]

Yield	Reaction Conditions	Operation in experiment
	With chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2?,4?,6?-tri-1-propyl-1,1?-biphenyl][2-(2-aminoethyl)phenyl]palladium(II); sodium t-butanolate; In 1,2-dimethoxyethane; at 95℃;Inert atmosphere;	Stepl: To a solution of compound 38c-2 (3.5 g, 14.3 mmol, 1.0 eq.) in DME (30 mL) were added l-cyclopropylpropan-2-amine (1.7 g, 17.2 mmol, 1.2 eq.), i-BuONa (3.0 g, 31.5 mmol, 2.2 eq.) and pre-Pd-brettphos (0.46 g, 0.572 mmol, 0.04 eq.) under N2, and then the mixture was stirred at 95 C under N2 overnight. TLC (PE/EA = 15/1) showed that the reaction was complete. The reaction mixture was concentrated in vacuum. The residue was portioned between EA (150 mL) and water (300 mL). The aqueous layer was separated and extracted with EA (150 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography, eluted by PE/EA (50/1 ~ 35/1) to give compound 38c-3 as an oil. 'HNMR: (400 MHz, CDC13) delta: 7.65 (dd, / = 8.4, 1.2 Hz, IH), 7.42 (d, / = 1.2 Hz, IH), 6.58 (d, / = 8.4 Hz, IH), 4.69 (br, IH), 3.91 (s, 3H), 3.88 (s, 3H), 3.70-3.51 (m, IH), 1.62-1.56 (m, IH), 1.42- 1.38 (m, IH), 1.49 (d, / = 6.0 Hz, 3H), 0.77-0.75 (m, IH), 0.52-0.49 (m, 2H), 0.13-0.09 (m, 2H).

Reference： [1]Patent: WO2014/28669,2014,A1 .Location in patent: Paragraph 00739

27
[ 17100-63-9 ]
[ 42182-27-4 ]
[ 1620677-23-7 ]

Yield	Reaction Conditions	Operation in experiment
65.38%		To the solution of <strong>[42182-27-4]2-aminoisonicotinonitrile</strong> (1.4g, 11.75mmol) in toluene (60mL) was added Al(Me)3 (5.87ml, 11.75mmol) at room tempereture. After stiring for 30min, methyl 4-bromo-3-methoxybenzoate (2.88g, 11.75mmol) was added. The reaction was refluxed for 3h. The mixture was quenched with IN HC1 and partitioned with H20 (45 mL) and EA (10 mL*3). The EA layer was dried, filtered, concentrated, and purified by column chromatography on silica gel (PE: EA = 0-60percent) to give 4-bromo-N-(4- cyanopyridin-2-yl)-3-methoxybenzamide (2.55g, 65.38percent>) as a white solid. 1H NMR (400MHz, CDCls) delta= 8.69 (s, 1H), 8.65 (br. s., 1H), 8.49 (dd, J=0.8, 5.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.33 - 7.29 (m, 2H), 4.01 (s, 3H).
65.38%		(a) 4-bromo-N-(4-cyanopyridin-2-yl)-3-methoxybenzamide To the solution of <strong>[42182-27-4]2-aminoisonicotinonitrile</strong> (1.4 g, 11.75 mmol) in toluene (60 mL) was added Al(Me)3 (5.87 ml, 11.75 mmol) at room temperature. After stirring for 30 min, methyl 4-bromo-3-methoxybenzoate (2.88 g, 11.75 mmol) was added. The reaction was refluxed for 3 h. The mixture was quenched with 1N HCl and partitioned with H2O (45 mL) and EA (10 mL*3). The EA layer was dried, filtered, concentrated, and purified by column chromatography on silica gel (PE: EA=0-60percent) to give 4-bromo-N-(4-cyanopyridin-2-yl)-3-methoxybenzamide (2.55 g, 65.38percent) as a white solid. 1H NMR (400 MHz, CDCl3) delta=8.69 (s, 1H), 8.65 (br. s., 1H), 8.49 (dd, J=0.8, 5.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.33-7.29 (m, 2H), 4.01 (s, 3H).
65.38%		To the solution of <strong>[42182-27-4]2-aminoisonicotinonitrile</strong> (1.4g, 11.75mmol) in toluene (60mL) was added Al(Me)3 (5.87ml, 11.75mmol) at room tempereture. After stiring for 30min, methyl 4-bromo-3-methoxybenzoate (2.88g, 11.75mmol) was added. The reaction was refluxed for 3h. The mixture was quenched with IN HCl and partitioned with H20 (45 mL) and EA (10 mL*3). The EA layer was dried, filterted, concentrated, and purified by column chromatography on silica gel (PE: EA = 0-60percent) to give 4-bromo-N-(4- cyanopyridin-2-yl)-3-methoxybenzamide (2.55g, 65.38percent) as a white solid. 1H NMR (400MHz, CDC13 ) delta = 8.69 (s, 1H), 8.65 (br. s., 1H), 8.49 (dd, J=0.8, 5.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.33 - 7.29 (m, 2H), 4.01 (s, 3H).

Reference： [1]Patent: WO2014/114185,2014,A1 .Location in patent: Page/Page column 152; 153
[2]Patent: US2014/206681,2014,A1 .Location in patent: Paragraph 0861
[3]Patent: WO2014/113932,2014,A1 .Location in patent: Page/Page column 109

28
[ 552846-17-0 ]
[ 17100-63-9 ]
[ 1623119-26-5 ]

Yield	Reaction Conditions	Operation in experiment
69%		Intermediate 1A: methyl 3-methoxy-4-(1H-pyrazol-4-yl)benzoate [0251] To a solution of methyl 4-bromo-3-methoxybenzoate (1.32 g, 5.39 mmol) in dioxane (30 mL) and water (5 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.901 g, 6.46 mmol), potassium phosphate (2.86 g, 13.47 mmol) and PdCl2(dppf) (0.197 g, 0.269 mmol) at RT. The reaction was stirred under argon at 100 C. for 3 hrs. The reaction mixture was diluted with EtOAc, washed with H2O. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in DCM (10 mL) and TFA (5 mL) was added. The reaction was stirred at RT for 1.5 hrs. Solvent was removed. The residue was taken into EtOAc, which was washed with NaHCO3 (3×) and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography. Desired product was isolated as white solid (0.86 g, 69% yield). LCMS (ESI) m/z: 233.0 (M+H)+; 1H NMR (400 MHz, CDCl3) delta 8.13 (s, 2H), 7.73-7.66 (m, 1H), 7.66-7.56 (m, 2H), 3.98 (s, 3H), 3.94 (s, 3H).
69%		To a solution of methyl 4-bromo-3-methoxybenzoate (1.32 g, 5.39 mmol) in dioxane (30 mL) and water (5 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.90 1 g, 6.46 mmol), potassium phosphate (2.86 g, 13.47 mmol) and PdC12(dppf) (0.197 g, 0.269 mmol) at rt. The reaction was stirred under argon at 100 C for 3 hrs. The reaction mixture was diluted with EtOAc, washed with H20. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in DCM (10 mL) and TFA (5 mL) wasadded. The reaction was stirred at rt for 1.5 hrs. Solvent was removed. The residue was taken into EtOAc, which was washed with NaHCO3 (3x) and brine, dried over Na2504, filtered and concentrated. The crude product was purified by normal phase chromatography. Desired product was isolated as white solid (0.86 g, 69% yield).LCMS(ESI) m/z: 233.0 (M+H) ?H NMR (400MHz, CDC13) oe 8.13 (s, 2H), 7.73 - 7.66(m, 1H), 7.66 - 7.56 (m, 2H), 3.98 (s, 3H), 3.94 (s, 3H).
69%		Intermediate 1A: Methyl 3-methoxy-4-(1H-pyrazol-4-yl)benzoateTo a solution of methyl 4-bromo-3-methoxybenzoate (1.32 g, 5.39 mmol) in dioxane (30 mL) and water (5 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.901 g, 6.46 mmol), potassium phosphate (2.86 g, 13.47 mmol) and PdCl2(dppf) (0.197 g, 0.269 mmol) at rt. The reaction was stirred under argon at 100 C for 3 h. The reaction mixture was diluted with EtOAc, washed with H2O. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in DCM (10 mL) and TFA (5 mL) was added. The reaction was stirred at rt for 1.5 h. The solvent was removed. The residue was taken into EtOAc, which was washed with NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography. The desired product was isolated as white solid (0.86g, 69% yield). LCMS(ESI) m/r. 233.0 (M+H)+; 1H NMR (400MHz, CDCl3) delta 8.13 (s, 2H), 7.73 - 7.66 (m, 1H), 7.66 - 7.56 (m, 2H), 3.98 (s, 3H), 3.94 (s, 3H).

Reference： [1]Patent: US2014/243338,2014,A1 .Location in patent: Paragraph 0250; 0251
[2]Patent: WO2016/10950,2016,A1 .Location in patent: Page/Page column 242
[3]Patent: WO2016/28971,2016,A1 .Location in patent: Page/Page column 57
[4]Patent: WO2017/123860,2017,A1 .Location in patent: Page/Page column 165

29
[ 17100-63-9 ]
[ 1220219-73-7 ]
methyl 4-(5-chloro-6-fiuoropyridin-3-yl)-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With tetrakis(triphenylphosphine) palladium(0); cyclopentyl methyl ether; sodium carbonate; at 100℃;Inert atmosphere;	EXAMPLE 772: 4-(5-CHLORO-6-(3,5-DICHLOROPHENOXY)PYRIDIN-3-YL)-3- METHOXY-N-(N-METHYLSULFAMOYL)BENZAMIDESTEP 1 : METHYL 4-(5-CHLORO-6-FLUOROPYRIDIN-3-YL)-3-METHOXYBENZOATE[00267] To a flask charged with methyl 4-bromo-3 -methoxybenzoate (2.00 g, 8.16 mmol, Astatech), 3-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (2.206 g, 8.57 mmol), and Pd(Ph3P)4(0.943 g, 0.816 mmol) was added cyclopentyl methyl ether (20.40 ml) and 2M Na2C03(20.40 ml, 40.8 mmol) and the mixture heated to 100 C overnight and stirred under nitrogen affording a yellow solution. Upon cooling to room temperature a precipitate formed which was collected by vacuum filtration and washed with water. The solid was stirred in 30 ml MeOH for 1.5 hr and the solid was collected by vacuum filtration and washed with MeOH affording clean product as a white solid, methyl 4-(5-chloro- 6-fiuoropyridin-3-yl)-3 -methoxybenzoate (2.41 g, 8.15 mmol, 100 % yield). MS m/z: [M+l]+= 296.1.

Reference： [1]Patent: WO2015/51043,2015,A1 .Location in patent: Paragraph 00267

30
[ 67-56-1 ]
[ 56256-14-5 ]
[ 17100-63-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sulfuric acid; for 24h;Reflux;	General procedure: The benzoic acid (1-4 g)was dissolved in methanol (25-75 mL),before conc. H2SO4 (2-6 mL) was added dropwise while stirring.The reaction mixture was heated to reflux and stirred for 24 h. Thereaction mixture was quenched in a saturated aq NaHCO3 solution(100-200 mL) ensuring neutral to basic pH, and the aqueous phase was extracted with CH2Cl2 (4 x 50 mL). The combined organic phases were washed with saturated aq NaCl solution (25-50 mL),dried over anhydrous Na2SO4 and filtered. Concentration yielded the target compound in high yield and purity. Methyl 4-bromo-3-methoxybenzoate was prepared as described in Section 4.5, starting with <strong>[56256-14-5]4-bromo-3-methoxybenzoic acid</strong> (845 mg, 3.67 mmol). The procedure yielded 808 mg(3.30 mmol, 90%) of methyl 4-bromo-3-methoxybenzoate a white crystalline product;
69%	With acetyl chloride; at 0 - 20℃; for 16h;Inert atmosphere;	Methyl 4-bromo-3-methoxybenzoate (0284) To a solution of <strong>[56256-14-5]4-bromo-3-methoxybenzoic acid</strong> (10.0 g, 43.28 mmol) in methanol (400 mL) was added acetyl chloride (19 mL, 266.25 mmol) dropwise at 0 C. The resulting solution was then stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with ethyl aceate in hexane (0% to 5% gradient) to yield methyl 4-bromo-3-methoxybenzoate as white solid (7.3 g, 69%). MS: m/z=245.0 [M+H]+.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 107,p. 255 - 274
[2]Patent: US2016/376283,2016,A1 .Location in patent: Paragraph 0283; 0284

31
[ 17100-63-9 ]
[ 25015-63-8 ]
3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; dichloro bis(acetonitrile) palladium(II); triethylamine; In 1,4-dioxane; at 80℃;Inert atmosphere;	General procedure: The methyl benzoate (200-1500 mg), PdCl2(CH3CN)2 (0.02 eq)and SPhos (0.08 eq) were added to a pressure tube. Then, 1,4-dioxane (0.5-3.5 mL) and Et3N (0.5-2 mL) were added under N2 atmosphere, followed by dropwise addition of HBpin (1.5 eq) while stirring under N2 atmosphere. The reaction mixture was heated to 80 C and stirred for 5-20 h. After cooling to rt, the reaction mixturewas filtered through a Celite pad. If further purificationwasperformed, it is specified in each specific example. 4.6.3 Methyl 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate fx9 The target compound was prepared as described in Section 4.6 , starting with <strong>[17100-63-9]methyl 4-bromo-3-methoxybenzoate</strong> (501 mg, 2.05 mmol). The crude oil (600 mg) was used without further purification. 1H NMR spectroscopy confirmed the presence of 54% of the desired product by comparison with the literature [54] . 1H NMR (600 MHz, DMSO-d6) delta: 7.65-7.63 (m, 1H), 7.54-7.52 (m, 1H), 7.44-7.43 (m, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 1.28 (s, 12H).

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 107,p. 255 - 274

32
[ 17100-63-9 ]
[ 1614246-94-4 ]
methyl 5'-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2'-fluoro-2-methoxybiphenyl-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis(tri-t-butylphosphine)palladium(0); N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 18h;Inert atmosphere;	Preparation 10 Methyl 5'-(7-ethyl-7H-imidazo[4,5-clpyridazin-4-yl)-2'-fluoro-2-methoxybiphenyl-4- carboxylate and 5'-(7-ethyl-7H-imidazor4,5-clpyridazin-4-yl)-2'-fluoro-2- methoxybiphenyl-4-carboxylic acid 7-Ethyl-4-(4-fluoro-3-chlorophenyl)-7/-/-imidazo[4,5-c]pyridazine (Preparation 7, 200 mg, 0.723 mmol), methyl-3-methoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoate (Preparation 29, 300 mg, 1.027 mmol) dicyclohexyl(2',4',6'-triisopropyl- [1 , 1'-biphenyl]-2-yl)phosphine (35 mg, 0.073 mmol), palladium (II) acetate (8 mg, 0.036 mmol) and potassium carbonate (280 mg, 2.029 mmol) were mixed in 2-methyl- 2-butanol (6 ml_) and water (3 ml_) under nitrogen and heated to 110C for 18 hours. The reaction was cooled and partitioned between water (50 ml_) and EtOAc (50 ml_). The aqueous layer was separated and extracted further with EtOAc (10 ml_). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was triturated with tert-butylmethylether (2 ml_) to afford methyl 5'- (7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2'-fluoro-2-methoxybiphenyl-4-carboxylate (125 mg, 43%). 1 H NMR (400 MHz, CDCI3): delta ppm 1 .69 (t, 3H), 3.89 (s, 3H), 3.96 (s, 3H), 4.55-4.61 (q, 2H), 7.35 (t, 1 H), 7.43 (d, 1 H), 7.69 (s, 1 H), 7.75 (d, 1 H), 8.22-8.24 (dd, 1 H), 8.28- 8.33 (m, 2H), 9.39 (s, 1 H). 19F NMR (376 MHz, CDCI3): delta ppm -110.5 MS m/z 407 [M+H]+ The combined aqueous layers were acidified with 1 M aqueous citric acid to pH=4 and extracted with EtOAc twice (50 ml_, 10 ml_). The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was triturated with tert- butyldimethylether to afford 5'-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2'-fluoro-2- methoxybiphenyl-4-carboxylic acid (125 mg, 43%). 1 H NMR (400 MHz, DMSO-d6): delta ppm 1.53 (t, 3H), 3.82 (s, 3H), 4.46-4.52 (q, 2H), 7.46-7.53 (m, 2H), 7.62-7.68 (m, 2H), 8.44-8.49 (m, 2H), 8.85 (s, 1 H), 9.54 (s, 1 H). 19F NMR (376 MHz, CDCI3): delta ppm -11 1.5 MS m/z 393 [M+H]+ Methyl 5'-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2'-fluoro-2-methoxybiphenyl-4- carboxylate may also be prepared according to the following method: A solution of 7-ethyl-4-[4-fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]- 7H-imidazo[4,5-c]pyridazine (Preparation 4, 50 mg, 0.136 mmol) and methyl-3- bromo-4-methoxybenzoate (33 mg, 0.136 mmol) in DIPEA (0.4 ml_) and DMF (2 ml_) was degassed with nitrogen before the addition of bis (tri-tert- butylphosphine)palladium (0) (7 mg,0.014 mmol) and heating to 90C for 18 hours. The reaction was cooled, diluted with EtOAc (20 ml_) and washed with brine (20 ml_). The organic layer was collected, concentrated in vacuo and purified using silica gel column chromatography eluting with EtOAc to afford the title compound. 5'-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2'-fluoro-2-methoxybiphenyl-4-carboxylic acid may also be prepared according to the following method: A mixture of methyl 5'-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)-2'-fluoro-2- methoxybiphenyl-4-carboxylate (55 mg, 0.136 mmol) and LiOH (3.6 mg, 0.150 mmol) in THF (2 ml_) and water (1 ml_) was stirred at room temperature for 3 hours. Further LiOH (7.2 mg, 0.299 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was concentrated in vacuo, dissolved in DCM and 1 M HCI was added until pH=7. The organic layer was separated, the aqueous layer extracted with DCM, and the organic extracts combined, dried over Na2S04 and concentrated in vacuo to afford the title compound.

Reference： [1]Patent: WO2015/189744,2015,A1 .Location in patent: Page/Page column 61-62

33
[ 17100-63-9 ]
[ 102362-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: copper(l) iodide; potassium iodide / N,N-dimethyl-formamide / 8 h / 140 °C / Inert atmosphere 2: sodium hydroxide / methanol / 1 h / 80 °C

Reference： [1]Jiao, Yan; Li, Ming; Wang, Ning; Lu, Tao; Zhou, Liang; Huang, Yan; Lu, Zhiyun; Luo, Daibing; Pu, Xuemei [Journal of Materials Chemistry C, 2016, vol. 4, # 19, p. 4269 - 4277]

34
[ 17100-63-9 ]
copper(l) cyanide [ No CAS ]
[ 210037-76-6 ]

Reference： [1]Journal of Materials Chemistry C,2016,vol. 4,p. 4269 - 4277

35
[ 621-59-0 ]
[ 17100-63-9 ]
2.2'-Dimethoxy-4-methoxycarbonyl-5'-formyldiphenylether [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With pyridine; potassium carbonate; copper(II) oxide; for 12h;Reflux;	General procedure: A mixture of 2-(1,3-dioxan-2-yl)phenol (14, 10g, 0.05mol) [38], 3-bromo-benzaldehyde (16, 8.8g, 0.05mmol), potassium carbonate (13.5g, 0.09mol) and cupric oxide (0.95g, 5.9mmol) in pyridine (50mL) was stirred under reflux for 12h. The pyridine was distilled off in vacuo and the residue was extracted with ethyl acetate (200mL). The solution was concentrated and the residue was purified by flash column chromatograph (Al2O3), eluting with a 2:1 solution of petroleum ether-DCM to afford 19 (12.6g, 81%) as a yellow solid.
63%	With pyridine; potassium carbonate; copper(II) oxide; for 12h;Reflux;	General procedure: A mixture of phenol (0.05 mol) (compounds 3, 8, 67, and 97-98), bromo-benzaldehyde (1.05 equiv.) (compounds 1-2, 9-12,48, 56, and 66), potassium carbonate (2 equiv.) and cupric oxide(0.3 equiv.) in pyridine (50 mL) was stirred under reflux for 12 h.The pyridine was distilled off in vacuo and the residue wasextracted with EtOAc (200 mL). The solution was concentrated andthe residue was purified by flash column chromatography (SiO2 orAl2O3), eluting with a hexane-DCM mixture, to yield the pureproduct as a solid in moderate yield.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 121,p. 484 - 499
[2]European Journal of Medicinal Chemistry,2017,vol. 129,p. 186 - 208

36
[ 17100-63-9 ]
4-bromo-Ν-α-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(2H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
methyl 4'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(2H-tetrazol-5-yl)phenyl]amino}propyl]-2-methoxybiphenyl-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%		Bis (pinacolato) diborane (1.82 g, 7.2 mmol), 4-bromo-3-methoxy-methylbenzoate (1.64 g, 6.7mmol) and potassium acetate (1:41 g, 14.4 mmol) were initially charged in toluene 37.5 mL,purged with argon and with 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (196 mg, 0:24 mmol) The reaction mixture was stirred for 3 h at 110 C. Then the addition of 4-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(2H-tetrazol-5-yl)phenyl]-L-phenylalaninamide (3000 mg, 4.8 mmol), aqueoussodium carbonate solution (1 g of sodium carbonate in 4.8 ml water, 9.6 mmol), [l, l-bis(diphenylphosphino) - ferrocene] -dichloropalladium dichloromethane complex (121 mg, 0:15mmol) and ethanol (15 ml). The reaction mixture was stirred t 100 C and over night at RT for 5 h. followed by celite filtration, silica gel and included in, and rapid silica gel chromatography purification. The combined product-containing liquid, and concentrate under reduced pressure. To obtain 5.1 gram as (94% theoretical value) of the title compound

Reference： [1]Patent: TW2016/5810,2016,A .Location in patent: Paragraph 0223

37
[ 1200126-06-2 ]
[ 17100-63-9 ]
methyl 4-(2-(1,3-dioxan-2-yl)-6-methoxyphenoxy)-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With pyridine; potassium carbonate; copper(II) oxide; for 12h;Reflux;	General procedure: A mixture of phenol (0.05 mol) (compounds 3, 8, 67, and 97-98), bromo-benzaldehyde (1.05 equiv.) (compounds 1-2, 9-12,48, 56, and 66), potassium carbonate (2 equiv.) and cupric oxide(0.3 equiv.) in pyridine (50 mL) was stirred under reflux for 12 h.The pyridine was distilled off in vacuo and the residue wasextracted with EtOAc (200 mL). The solution was concentrated andthe residue was purified by flash column chromatography (SiO2 orAl2O3), eluting with a hexane-DCM mixture, to yield the pureproduct as a solid in moderate yield.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 129,p. 186 - 208

38
[ 942070-45-3 ]
[ 17100-63-9 ]
tert-butyl 3-(2-methoxy-4-(methoxycarbonyl)phenyl)-1H-indole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.7%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; for 3.5h;Inert atmosphere;	To a solution of methyl 4-iodo-3-methoxybenzoate (9) (0.5 g, 1.71 mmol) and <strong>[942070-45-3]tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate</strong>(0.70 g, 2.05 mmol) in 1,4-dioxane (10.0 mL) was added 2.0 mL of water. The reaction mixture was degassed with argon for about30 min. After that Pd(dppf)Cl2.DCM (0.069 g, 0.085 mmol) andNa2CO3 (0.36 g, 3.42 mmol) were added to the reaction mixture andagain degassed with argon for another 20 min. The reactionmixturewas stirred under reflux for 3 h. After cooled down to roomtemperature, the mixture was extracted with EtOAc, washed withbrine, dried over Na2SO4, and concentrated under reduced pressure.The crude product was purified by column chromatography(Hexane/EtOAc 4:6) to afford 10 as a yellow solid (0.52 g, 79.7%).1H NMR (500 MHz, CDCl3) delta 8.15 (d, J 5.0 Hz, 1H), 7.85 (s, 1H), 7.65(d, J 10.0 Hz, 2H), 7.56 (d, J 10.0 Hz, 2H), 7.32 (d, J 10.0 Hz, 1H),7.28 (s, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 1.62 (s, 9H).

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 139,p. 644 - 656

39
[ 5765-65-1 ]
[ 17100-63-9 ]
C₁₃H₁₇NO₄ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 8551 - 8562

40
[ 17100-63-9 ]
[ 24850-33-7 ]
methyl 4-allyl-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 80℃; for 4h;Inert atmosphere;	To a solution of <strong>[17100-63-9]methyl 4-bromo-3-methoxybenzoate</strong> (28.00 g, 114.25 mmol, 1.00 equiv.) in N,N-dimethylformamide (400 mL) was added allyl(tributyl)stannane (38.53 mL, 125.68 mmol, 1.10 equiv.) and Pd(PPh3)4(13.20 g, 11.43 mmol, 0.10 equiv.). The mixture was degassed under vacuum and purged with nitrogen 3 times and the resulting mixture stirred at 80C for 4 hours under a nitrogen atmosphere. Water (25 mL) and sodium fluoride (5 g) were added, the resultant mixture was stirred at 25C for 30 minutes and then filtered. The filter cake was washed with ethyl acetate (20 mL x2). The combined filtrate was extracted with ethyl acetate (250 ml x3). The organic phase was combined and washed with brine (100 mL x2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ethenethyl acetate 1000: 1 to 800: 1) to give the desired product as colourless oil (21.2 g, 90%); 1H NMR (DMSO, 400 MHz) delta 7.51 (dd, = 8.0 Hz, = 1.6 Hz, 1H), 7.45 (s, 1H), 7.21 (d, = 7.6 Hz, 1H), 5.96 - 5.89 (m, 1H), 5.06 - 5.01 (m, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.36 (s, 2H)

Reference： [1]Patent: WO2018/144620,2018,A1 .Location in patent: Paragraph 00400

41
(4-chloro-3-(trifluoromethyl)phenyl)boronic acid [ No CAS ]
[ 17100-63-9 ]
methyl 4'-chloro-2-methoxy-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxylate [ No CAS ]