[ CAS No. 3943-74-6 ] {[proInfo.proName]}

Name: 3943-74-6|Methyl 4-hydroxy-3-methoxybenzoate|98%
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Quality Control of [ 3943-74-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 3943-74-6 ]

CAS No. :	3943-74-6	MDL No. :	MFCD00008438
Formula :	C₉H₁₀O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BVWTXUYLKBHMOX-UHFFFAOYSA-N
M.W :	182.17	Pubchem ID :	19844
Synonyms :		Chemical Name :	Methyl 4-hydroxy-3-methoxybenzoate

Calculated chemistry of [ 3943-74-6 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	46.24
TPSA :	55.76 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.16 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.13
Log Po/w (XLOGP3) :	1.76
Log Po/w (WLOGP) :	1.19
Log Po/w (MLOGP) :	1.06
Log Po/w (SILICOS-IT) :	1.23
Consensus Log Po/w :	1.47

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.22
Solubility :	1.09 mg/ml ; 0.006 mol/l
Class :	Soluble
Log S (Ali) :	-2.55
Solubility :	0.515 mg/ml ; 0.00283 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.03
Solubility :	1.72 mg/ml ; 0.00942 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.67

Safety of [ 3943-74-6 ]

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

Application In Synthesis of [ 3943-74-6 ]

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

Upstream synthesis route of [ 3943-74-6 ]
Downstream synthetic route of [ 3943-74-6 ]

[ 3943-74-6 ] Synthesis Path-Upstream 1~21

1
[ 3943-74-6 ]
[ 60547-92-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 20, p. 5427 - 5436
[2] Patent: US2017/95570, 2017, A1,
[3] Patent: WO2018/195245, 2018, A1,

2
[ 121-34-6 ]
[ 3943-74-6 ]
[ 6702-50-7 ]

Reference： [1] Patent: US6384080, 2002, B1,

3
[ 3943-74-6 ]
[ 4998-07-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 13, p. 3529 - 3542

4
[ 3943-74-6 ]
[ 61032-42-6 ]

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[2] Patent: US2014/235634, 2014, A1,
[3] Patent: CN105541736, 2016, A,
[4] ChemMedChem, 2016, vol. 11, # 20, p. 2327 - 2338
[5] MedChemComm, 2017, vol. 8, # 5, p. 1069 - 1092
[6] Patent: WO2006/117552, 2006, A1,

5
[ 3943-74-6 ]
[ 100-39-0 ]
[ 61032-41-5 ]

Reference： [1] Patent: EP1153920, 2001, A1,
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 24, p. 6796 - 6805
[3] Patent: US2007/149523, 2007, A1,

6
[ 3943-74-6 ]
[ 61032-41-5 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 20, p. 5427 - 5436
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2989 - 2992
[3] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[4] Patent: US2014/235634, 2014, A1,
[5] Patent: CN105541736, 2016, A,
[6] ChemMedChem, 2016, vol. 11, # 20, p. 2327 - 2338
[7] MedChemComm, 2017, vol. 8, # 5, p. 1069 - 1092
[8] Patent: US2017/95570, 2017, A1,
[9] Patent: WO2006/117552, 2006, A1,
[10] Patent: WO2018/195245, 2018, A1,

7
[ 5368-81-0 ]
[ 3943-74-6 ]
[ 6342-70-7 ]
[ 2905-82-0 ]

Reference： [1] Journal of Organic Chemistry, 2015, vol. 80, # 16, p. 8084 - 8095

8
[ 5368-81-0 ]
[ 3943-74-6 ]
[ 6342-70-7 ]
[ 2905-82-0 ]

Reference： [1] Journal of Organic Chemistry, 2015, vol. 80, # 16, p. 8084 - 8095

9
[ 3943-74-6 ]
[ 63603-09-8 ]

Reference： [1] Journal of the American Chemical Society, 1983, vol. 105, # 15, p. 5015 - 5024
[2] Patent: WO2011/27106, 2011, A1,
[3] Patent: US2012/149737, 2012, A1,

10
[ 3943-74-6 ]
[ 15785-54-3 ]

Reference： [1] Journal of the American Chemical Society, 1995, vol. 117, # 16, p. 4722 - 4723

11
[ 3943-74-6 ]
[ 100-39-0 ]
[ 56441-97-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;	General Procedure 1: Syntheses of 4-chloroquinazolines with alkylamino sidechains: 4-Chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline, 4-Chloro-7-methoxy-6-[3-(4-methyl-piperazin-1-yl)propoxy]quinazoline and 4-Chloro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinazoline.; Step 1. To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100° C. for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na₂SO₄, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
100%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;	Step 1. To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100°C for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na₂SO₄, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
100%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;	Syntheses of Intermediates. General procedure 1: Syntheses of 4-chloroquinazolines with alkylamino sidechains: 4-Chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline, 4-Chloro-7-methoxy-6-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline and 4-Chloro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinazoline. Step 1. To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100°C for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na₂SO₄, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.

100%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;	Step 1. To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100° C. for 3 h. After cooling to r. t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na₂SO₄, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
99%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;	Step 1. To a solution of methyl vanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100°C for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na₂SO₄, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate (10.8 g, 39.7 mmol, 99 percent) as a grey solid which was used without further purification. LC/ESI-MS: m/z = 273 [M+H]⁺; R_t = 3.82 min.
99%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;	Step 1. To a solution of methyl vanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100° C. for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na₂SO₄, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate (10.8 g, 39.7 mmol, 99percent) as a grey solid which was used without further purification. LC/ESI-MS: m/z=273 [M+H]⁺; R_t=3.82 min.
97%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 5 h;	4.1.3 Methyl 4-benzyloxy-3-methoxybenzoate (11) To a solution of methyl vanillate (10) (1.82 g, 10 mmol) in DMF (10 mL) were added K₂CO₃ (1.38 g, 10 mmol) and benzyl bromide (2.05 g, 12 mmol). The mixture was heated at 60 °C for 5 h. After cooling to room temperature, water was added and the product was extracted with CH₂Cl₂. The organic phase was washed with water and brine. After drying over Na₂SO₄, the solvent was removed to yield intermediate 11 as a white solid. Yield: 97percent, mp: 77-79 °C.
95%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2 h;	Step 2a. Methyl 4-(benzyloxy)-3-methoxybenzoate (Compound 202) To a mixture of compound 201 (18.2 g, 0.1 mol), potassium carbonate (34.55 g, 0.25 mol) in N,N-dimethylformamide was added benzylbromide (14.5 ml, 0.105 mol) dropwise. The reaction was then heated to 60° C. and stirred for 2 hours. The mixture was cooled to room temperature and was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate 500 mL. The organic layer was washed with water and brine (100 mL), dried over MgSO₄, filtered and concentrated to give the title compound 202 as a white solid (26 g, 95percent): LCMS: 273 [M+1]⁺.
95%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6 h;	A 250 mL, round-bottomed flask with a stirring bar, a solution of 4-hydroxy-3-methoxybenzoic acid (20 g, 118.94 mmol) was added slowly to a solution of methanol (100 mL) and concentrated sulfuric acid (10 mL). After being stirred for 12 h at reflux, saturated solution of sodium bicarbonate was added to adjust the pH to 7. Dichloromethane was added and the mixture was then filtered and the organic phase evaporated on a rotary evaporator and to obtain the compound 2 (20.37 g, 94 percent). Compound 2 (20.4 g, 111.98 mmol) was added into a 500 mL, round-bottomed flask with a stirring bar, then benzyl bromide (18 mL), potassium carbonate (22 g, 156.8 mmol), DMF (200 mL) were added. It was stirred for 6 h at 80 °C. Then the reaction system was poured into right amount of water, white solid (3) was obtained by filtration (28.97 g, 95 percent). Compound 3 (16.54 g, 60.74 mmol) was dissolved in CH₃COOH (50 mL) and then added into a 250 mL, round bottomed flask with a stirring bar. Then HNO₃ (25 mL) was added into the system slowly to keep the temperature of the reaction above 5 °C. The reaction temperature was raised to 50 °C and kept for another 2 h. After that the system was poured into water and pale yellow solid (I) was obtained^6-8(18.3 g, 95percent, m.p.: 134-135 °C).
91%	With potassium carbonate In acetone at 45℃; for 3.5 h;	To a mechanically stirred solution of methyl vanillate (103.5 g, 0.568 mol) and benzyl bromide (101.36 ml, 0.852 mol) in acetone (800 ml) at room temperature powdered K₂CO3 (196.25 g, 1.4 mol) is added The reaction is heated to 45° C for 3.5 hours, cooled and filtered. The filtrate is concentrated in vacuo and the residue dissolved in EtOAc (300 ml) and washed with water (100 ml) three times saturated. NaHCψ3 (100 ml x 2), and brine. The organic layer is dried over Na₂SO₄ and concentrated in vacuo to provide 224.72g of a white solid. The solid is then triturated in hexane (300 ml) and filtered to provide methyl 4-(benzyloxy)-3-methoxybenzoate (141.45 g, 91percent).
86.6%	With potassium carbonate In acetone for 12 h; Heating / reflux	D) 4-Benzyloxy-3-methoxy benzoic acid methyl ester; Potassium carbonate (3.45 g; 25 mmol) was added to a solution of 4-hydroxy- 3-methoxy benzoic acid methyl ester (3.6 g; 20 mmol) and benzyl bromide (3.42 g; 20 mmol) in acetone (100 ml). The reaction mixture was refluxed for 12 hrs. After the removal of the solvent under reduced pressure, the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The ethyl acetate layer was washed with water (50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 4.64 g of 4-benzyloxy-3-methoxy benzoic acid methyl ester (Yield = 86.6percent)
82.2%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;	A solution of methyl 4-hydroxy-3-methoxybenzoate 38 (3.0 g, 16.5 mmol) in DMF (100 mL) was added benzyl bromide (4.22 g, 24.7 mmol) and K₂CO₃ (4.56 g, 32.9 mmol). The reaction mixture was stirred at 100° C. for 3 h. The mixture was concentrated in vacuo and was dissolved in water (50 mL), extracted with EtOAC (30 mL*2), washed with NaCl (30 mL), dried over Na₂SO₄. It was concentrated and purified by silica chromatography (0-30percent EtOAc in petroleum ether) to give methyl 4-(benzyloxy)-3-methoxybenzoate 39 (3.8 g, 13.5 mmol, 82.2percent yield) as a white solid. LCMS (5-95AB/1.5 min): RT=0.787 min, [M+H]+ 272.9

Reference： [1] Patent: US2007/21446, 2007, A1, . Location in patent: Page/Page column 14
[2] Patent: EP1785420, 2007, A1, . Location in patent: Page/Page column 18
[3] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 18, p. 6728 - 6737
[4] Patent: EP1746096, 2007, A1, . Location in patent: Page/Page column 23
[5] ChemMedChem, 2016, vol. 11, # 20, p. 2327 - 2338
[6] Patent: US2007/149523, 2007, A1, . Location in patent: Page/Page column 13
[7] Patent: EP1674466, 2006, A1, . Location in patent: Page/Page column 26
[8] Patent: EP1674467, 2006, A1, . Location in patent: Page/Page column 26
[9] Patent: US2006/142570, 2006, A1, . Location in patent: Page/Page column 16
[10] MedChemComm, 2017, vol. 8, # 5, p. 1069 - 1092
[11] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 24, p. 6796 - 6805
[12] Patent: US2009/76044, 2009, A1, . Location in patent: Page/Page column 26
[13] Asian Journal of Chemistry, 2015, vol. 27, # 7, p. 2647 - 2650
[14] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 20, p. 5427 - 5436
[15] Patent: WO2008/109613, 2008, A1, . Location in patent: Page/Page column 214
[16] Patent: WO2005/113489, 2005, A1, . Location in patent: Page/Page column 93
[17] Patent: US2017/95570, 2017, A1, . Location in patent: Paragraph 0571; 0572
[18] Synlett, 2010, # 5, p. 753 - 756
[19] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2989 - 2992
[20] Patent: EP1489077, 2004, A1, . Location in patent: Page 40
[21] Patent: US2006/135782, 2006, A1, . Location in patent: Page/Page column 23
[22] Patent: WO2010/85747, 2010, A1, . Location in patent: Page/Page column 53
[23] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[24] RSC Advances, 2016, vol. 6, # 46, p. 40238 - 40249
[25] Patent: WO2006/117552, 2006, A1, . Location in patent: Page/Page column 63-65

12
[ 3943-74-6 ]
[ 100-44-7 ]
[ 56441-97-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 3 h;	A mixture of methyl vanillate (300.0 g, 1.65 mol), benzyl chloride (230 mL, 1.81 mol) and potassium carbonate (345 g, 2.5 mol) in N,N-dimethyl formamide (1000 mL) was heated to 100° C. for three hours. The reaction was cooled to room temperature, poured into ice water (1500 mL) and stirred for 1 h. The resultant solid was filtered and washed by water (300 mL×3), then dried to give 119 (440 g, yield=98.0percent) as a white solid
97%	With potassium carbonate In acetonitrile at 90℃; for 2 h; Inert atmosphere	under the protection of nitrogen added in the reaction bottle 10.0g3-methoxy-4-hydroxy benzoic acid, 19.0g potassium carbonate, 7.0g benzyl chloride and 80 ml of acetonitrile, the mixture to the 90 °C reflux reaction 2 hours, using n-hexane: ethyl acetate = 4 volume ratio: 1 as a developing solvent of TLC analysis of the mixture; complete reaction of raw materials, cooling filter, by 150 ml ethyl acetate wash the filter cake, filtrate turns on lathe does, column chromatography, using hexane: ethyl acetate = 5 volume ratio: 1 of the mixed solution to elute, get 14.5g pure white solid (compound a), yield 97.0percent;

Reference： [1] Patent: US2014/235634, 2014, A1, . Location in patent: Paragraph 0390; 0391
[2] Patent: CN105541736, 2016, A, . Location in patent: Paragraph 0044; 0045
[3] ACS Chemical Biology, 2012, vol. 7, # 3, p. 552 - 562
[4] Journal of the Chemical Society, 1950, p. 864,866

13
[ 3943-74-6 ]
[ 27883-60-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2989 - 2992

14
[ 3943-74-6 ]
[ 84211-30-3 ]

Reference： [1] Journal of the American Chemical Society, 1995, vol. 117, # 16, p. 4722 - 4723
[2] ChemMedChem, 2015, vol. 10, # 1, p. 116 - 133

15
[ 3943-74-6 ]
[ 162364-72-9 ]

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056
[2] Patent: CN105541736, 2016, A,
[3] Patent: WO2006/117552, 2006, A1,

16
[ 3943-74-6 ]
[ 263149-10-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 21, p. 2477 - 2480

17
[ 3943-74-6 ]
[ 380844-49-5 ]

Reference： [1] Heterocycles, 2014, vol. 89, # 12, p. 2806 - 2813

18
[ 3943-74-6 ]
[ 162012-72-8 ]

Reference： [1] Patent: US2014/235634, 2014, A1,
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 24, p. 6796 - 6805
[3] Patent: US2007/149523, 2007, A1,

19
[ 3943-74-6 ]
[ 1320288-19-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 17, p. 6139 - 6150

20
[ 3943-74-6 ]
[ 824-94-2 ]
[ 1354549-24-8 ]

Reference： [1] ACS Chemical Biology, 2012, vol. 7, # 3, p. 552 - 562

21
[ 3943-74-6 ]
[ 1481677-78-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8931 - 8942

[ 3943-74-6 ] Synthesis Path-Downstream 1~88

1
[ 67-56-1 ]
[ 121-34-6 ]
[ 3943-74-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride for 12h; Reflux;	3-Methoxy-4-(3-methylphenoxy)benzoic Acid (18h) Methyl 4-hydroxy-3- methyoxybenzoate was prepared in quantitative yield by Fischer esterification of the corresponding benzoic acid (3.04 g, 18.1 mmol) refluxed 12 h in methanol (50 mL) with catalytic dry HC1 (2 mL, 2 M in ether). The phenol (546.6 mg, 3 mmol) was combined with 3-iodotoluene (654 mg, 1.0 eq) and Cu20 (515 mg, 1.2 eq) in collidine (1 mL). The mixture was heated to 200 °C for 1 h in a sealed tube. The resulting solution was extracted with ether and washed with 2 N HC1. Silica gel (up to 50% EtOAc in hexanes) gave the desired intermediate ether (435 mg, 53%). The methyl ester was saponified with LiOH (3 eq) in dioxane/water (1 :1, 9.6 mL) at r.t. The resulting solution was acidified with 2 N H2S04, concentrated, filtered and washed with water to give 18h (355 mg, 46%). NMR (CDC13) δ , 3.96 (s, 3H).
100%	With hydrogenchloride In diethyl ether Reflux;	3-Methoxy-4-(3-methylphenoxy)benzoic Acid (18h). Methyl 4-hydroxy-3-methyoxybenzoate was prepared in quantitative yield by Fischer esterification of the corresponding benzoic acid (3.04 g, 18.1 mmol) refluxed 12 h in methanol (50 mL) with catalytic dry HCl (2 mL, 2 M in ether). The phenol (546.6 mg, 3 mmol) was combined with 3-iodotoluene (654 mg, 1.0 eq) and Cu2O (515 mg, 1.2 eq) in collidine (1 mL). The mixture was heated to 200° C. for 1 h in a sealed tube. The resulting solution was extracted with ether and washed with 2 N HCl. Silica gel (up to 50% EtOAc in hexanes) gave the desired intermediate ether (435 mg, 53%). The methyl ester was saponified with LiOH (3 eq) in dioxane/water (1:1, 9.6 mL) at r.t. The resulting solution was acidified with 2 N H2SO4, concentrated, filtered and washed with water to give 18h (355 mg, 46%). 1H NMR (CDCl3) δ, 3.96 (s, 3H).
100%	With thionyl chloride at 0 - 20℃; Inert atmosphere;	4 [0502] Preparation of Compound Int-1-1 [0503] To a solution of vanillic acid (50.0 g, 0.30 mol) in MeOH (700 mL) was added dropwise SOCl2 (207 mL, 2.85 mol) and stirred at 0°C. under N2 atmosphere. The reaction mixture was allowed warm up to room temperature and stirred overnight. The mixture was concentrated under reduced pressure and the pH was adjusted to 7-8. The mixture was extracted with distilled water (100 mL) and EA (200 mL2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Int-1-1 (54.2 g, quant) [0504] 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J=6.4, 1.6 Hz, 1H), 7.55 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.05 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H).

100%	With thionyl chloride at 0℃; for 2h; Reflux; Inert atmosphere;
100%	With thionyl chloride at 0 - 20℃; for 15h; Inert atmosphere;	2 Preparation of compound Int-l-l To a solution of vanillic acid (50.0 g, 0.30 mol) in MeOH (700 mL) was added dropwise SOCl2 (207 mL, 2.85 mol) at 0 °C under N2 atmosphere. After stirring for 15 hours at room temperature, the reaction was adjusted to have pH of 7 to 8 with saturated aqueous NaHCCb solution and then diluted with distilled water (100 mL) and EA (400 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Int-l-l (54.2 g, quant). NMR (400 MHz, CDCb) d 7.64 (dd, = 6.4, 1.6 Hz, 1H), 7.55 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.05 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H)
100%	With thionyl chloride at 20℃; for 72h; Inert atmosphere;	4 4-Hydroxy-3-methoxybenzoic acid methyl ester (10) Under argon, at room temperature, to a suspension of isovanillic acid (10.0 g, 59 mmol) in absolute methanol (100 mL) was added dropwise thionyl chloride (3.9 mL, 53.1 mmol). The resulting mixture was stirred at room temperature for 72 hours then concentrated under reduced pressure. The solid residue was poured into cold H2O (40 mL) and basified, under stirring, with saturated aqueous solution of NaHCCL until pH7-8. The remaining precipitate was collected by filtration affording 4- hydroxy-3-methoxybenzoic acid methyl ester (10) (10.8 g, quantitative) as a light brown solid. 1 H NMR (250 MHz, CDCL) d 7.63 (dd, J = 8.3 and 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H) and 3.88 (s, 3H); LCMS C9H10O4 Rt = 5.248 min, ESI+ m/z = 182.9 (M+H).
100%	With thionyl chloride at 0 - 20℃; Inert atmosphere;	29 Preparation of compound L-12-1 To a solution of vanillic acid (50.0 g, 0.30 mol) in MeOH (700 mL) was added dropwise SOCh (207 mL, 2.85 mol) and the resulting mixture was stirred at 0 °C under N2 atmosphere, and then stirred overnight at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure. The reaction was adjusted to pH 7 to 8 with saturated aqueous NaHCCb solution and then diluted with distilled water (100 mL) and EA (200 mL x 2). The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound L-12-1 (54.2 g, quant) NMR (400 MHz, CDCb) d 7.64 (dd, J= 6.4, 1.6 Hz, 1H), 7.55 (s, 1H), 6.94 (d, J= 8.4 Hz, 1H), 6.05 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H).
100%	With thionyl chloride at 0 - 20℃; for 15h; Inert atmosphere;	4.4.8.7 Preparation of compound lnt-1 -1 To a solution of vanillic acid (50.0 g, 0.30 mol) in MeOH (700 mL) was added dropwise SOCl2(207 mL, 2.85 mol) at 0 °C under N2 atmosphere. After stirring for 15 hours at room temperature, the reaction was adjusted to have pH of 7 to 8 with saturated aqueous NaHCO3solution and then diluted with distilled water (100 mL) and EA (400 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Int-1-1 (54.2 g, quant).1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J= 6.4, 1.6 Hz, 1H), 7.55 (s, 1H), 6.94 (d, J= 8.4Hz, 1H), 6.05 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H).
98%	With thionyl chloride at 20℃;
98%	With sulfuric acid Reflux;	6.1 (1) Synthesis of methyl 4-hydroxy-3-methoxybenzoate (9) (1) Synthesis of methyl 4-hydroxy-3-methoxybenzoate (9) To a solution of 4-hydroxy-3-methoxybenzoic acid (0.1 g, 0.59 mmol) in 10 mL of methanol was added 0.3 mL of conc. sulfuric acid, and refluxed overnight. The pH of the solution was shifted into an alkaline zone by addition of 5% aqueous NaHCO3 solution. Following extraction with EtOAc, the extract was washed with a saturated NaCl aqueous solution. It was dried over MgSO4 and the solvent was removed by concentration under reduced pressure to afford the compound 9 (0.107 g, 98%). Yellow oil; 1H NMR (400 MHz, Acetone-d6) δ 8.390 (s, 1H), 7.561 (d, J=8.0, 7.538 (s, 1H), 6.911 (d, J=8.4, 1H), 6.516 (s, 2H), 3.904 (s, 3H), 3.831 (s, 3H).
98%	With sulfuric acid Reflux;	Synthesis of methyl 4-hydroxy-3-methoxybenzoate. To a solution of 4-hydroxy-3-methoxybenzoic acid (0.1 g, 0.59 mmol) in 10 mL ofmethanol was added 0.3 mL of conc. Sulfuric acid, andrefluxed overnight. The pH of the solution was shifted intoan alkaline zone by addition of 5 % aqueous NaHCO3solution. Following extraction with EtOAc, the extract waswashed with a saturated NaCl aqueous solution. It wasdried over MgSO4 and the solvent was removed by concentrationunder reduced pressure to afford the methyl4-hydroxy-3-methoxybenzoate (0.107 g, 98 %).Yellow oil; 1H NMR (400 MHz, acetone-d6) δ 8.390 (s,1H), 7.561 (d, J = 8.0, 1H), 7.538 (s, 1H), 6.911 (d,J = 8.4, 1H), 6.516 (s, 2H), 3.904 (s, 3H), 3.831 (s, 3H).
96%	With hydrogenchloride In lithium hydroxide monohydrate Reflux;
96.1%	With thionyl chloride at 0 - 65℃; for 8h;	6.1 Example 6 (1) Place 40.0g (0.24mol) of vanillic acid in a 500mL three-necked flask, add 200mL of methanol, cool down to 0°C in an ice bath, drop 20.8mL (0.28mol) of thionyl chloride, control the dripping speed to keep the temperature below 10 °C, the dropwise addition was completed for 1 h, and the temperature was raised to 65 °C and refluxed for 7 h. MeOH and remaining thionyl chloride were evaporated under reduced pressure, the residue was dissolved in 200 mL of DCM, washed twice with 60 mL of saturated sodium bicarbonate, once with 60 mL of saturated NaCl, and dried over anhydrous sodium sulfate for 12 h. Suction filtration, the filtrate was evaporated to dryness, and the obtained light blue liquid was left for 10 min to solidify to obtain methyl 4-hydroxy-3-methoxybenzoate (near white solid, 41.6 g, yield 96.1%).
94%	With sulfuric acid for 12h; Reflux;	Synthesis of compound I: A 250 mL, round-bottomed flask with a stirring bar, a solution of 4-hydroxy-3-methoxybenzoic acid (20 g, 118.94 mmol) was added slowly to a solution of methanol (100 mL) and concentrated sulfuric acid (10 mL). After being stirred for 12 h at reflux, saturated solution of sodium bicarbonate was added to adjust the pH to 7. Dichloromethane was added and the mixture was then filtered and the organic phase evaporated on a rotary evaporator and to obtain the compound 2 (20.37 g, 94 %). Compound 2 (20.4 g, 111.98 mmol) was added into a 500 mL, round-bottomed flask with a stirring bar, then benzyl bromide (18 mL), potassium carbonate (22 g, 156.8 mmol), DMF (200 mL) were added. It was stirred for 6 h at 80 °C. Then the reaction system was poured into right amount of water, white solid (3) was obtained by filtration (28.97 g, 95 %). Compound 3 (16.54 g, 60.74 mmol) was dissolved in CH3COOH (50 mL) and then added into a 250 mL, round bottomed flask with a stirring bar. Then HNO3 (25 mL) was added into the system slowly to keep the temperature of the reaction above 5 °C. The reaction temperature was raised to 50 °C and kept for another 2 h. After that the system was poured into water and pale yellow solid (I) was obtained6-8 (18.3 g, 95%, m.p.: 134-135 °C).
94.36%	With hydrogenchloride at 70℃; for 10h;
93%	With sulfuric acid for 16h; Heating;
93%	With sulfuric acid
92%	With sulfuric acid for 2h; Reflux;	1.3.1 4-Hydroxy-3-methoxy-benzoic acid methyl ester (2) To a solution of vanillic acid 1 (3.00 g, 17.9 mmol) in methanol (100 mL) was added H2SO4 (98%, 2.5 mL). The mixture was heated under reflux for two hours, and after cooling was extracted three times with dichloromethane (3 x 50 mL). The combined organic layer was washed successively with 2 M NaHCO3 (20 mL) and brine (20 mL), followed by drying over anhydrous sodium sulphate, and concentrated under vacuum to yield compound 2 as colourless liquid (3.00 g, 16.5 mmol, 92%). M.p.: 62-65 °C (69-70 °C)1; 1H NMR: (400 MHz, CDCl3): δ 7.62-7.59 (dd, 1H, J = 8.4 Hz, 2.0 Hz, Ar), 7.52 (d, 1H, J = 1.2 Hz, Ar), 6.91 (d, 1H, J = 8.4 Hz, Ar), 3.89 (s, 3H, CH3OAr), 3.86 (s, 3H, COOCH3); 13C NMR: (400 MHz, CDCl3): 166.9 (C=O), 150.0, 146.2, 124.1, 122.1, 114.1, 111.7 (Ar), 56.0 (CH3OAr), 51.9 (COOCH3); ESI-TOF-HRMS: [M-H]+ calculated for C9H9O4: 181.0501, found 181.0508.
91.5%	With hydrogenchloride In lithium hydroxide monohydrate for 12h; Heating / reflux;	12.C C) 4-Hydroxy-3-methoxy benzoic acid methyl ester; A solution of 4-hydroxy-3methoxy benzoic acid (7.2 g) in methanol (150 ml) was refluxed in presence of concentrated hydrochloric acid (0.5 ml) for 12 hrs. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate (200 ml) and washed with water (50 ml) 10 % sodium bicarbonate solution (2 x 50 ml), water (50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 7.25 g of 4-hydroxy-3-methoxy benzoic acid methyl ester. (Yield = 91.5 %). 'H NMR CDC13 7.65 (lH, d, J 8Hz) 7.55 (1H, s) 6.95 (1H, d, J 8Hz) 6.15 (1H, bs, - OH) 3.95 (3H, s) 3.9 (3H, s).
90%	With sulfuric acid for 8h; Reflux;	3.1 4.3.1 Synthesis of methylvanillate Vanillic acid (15.0 g, 0.09 mol) was dissolved in methanol (75 mL). Sulfuric acid (2.1 mL) was added and the mixture was stirred and warmed to reflux for 8 h. After evaporation of methanol, the solid was dissolved in ethylacetate (60 mL), washed with a NaHCO3 solution (30 mL), water (2 times) and brine (1 time). The organic phase was evaporated under reduced pressure. Yield: 90%. 1H NMR (400 MHz, CDCl3, δ (ppm)): δ 7.45 (m, 2H, Ar), 6.88 (d, 1H, Ar), 3.81 (s, 3H, OCH3), 3.79 (s, 3H, OCH3 ester). 13C NMR (400 MHz, CDCl3, δ (ppm)): δ 166,03 (OCH3 ester), 151.22 (Ar-C), 147.20 (Ar-C), 123.38 (Ar-C), 120.30 (Ar-C), 115.13 (Ar-C), 112.42 (Ar-C), 55.27 (OCH3), 51.60 (OCH3 ester).
90.5%	With sulfuric acid for 48h; Reflux;	Synthesis of methyl 4-hydroxy-3-methoxybenzoate (1) To a 500 mL three-necked flask was added 4-hydroxy-3-methoxybenzoic acid (20.0 g, 0.19 mol)Methanol 250mL, concentrated sulfuric acid 0.8mL,Heated to reflux, after about 48h to stop the reaction.The methanol was distilled off, water was added to the residue, neutralized with a saturated K2CO3 solution,Extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate,Filtered, and the mother liquor was concentrated under reduced pressure to give a brown oil, washed with petroleum ether:Ethyl acetate (8: 1) was recrystallized,To give a white solid (1) (19.6 g, 90.5%),
90.1%	With sulfuric acid Reflux;	3.1 General procedure for the synthesis of compounds General procedure: A mixture of organic acid (0.5 g) and methanol (100 ml) was heated under reflux in presence of sulphuric acid (0.8 ml) until the completion of the reaction which was checked by single spot TLC. Then, methanol was removed under reduced pressure a half and the solution was diluted with 20 ml of water. The product was extracted with ethyl acetate (30 ml). The organic phase was neutralized successively with NaHCO3 5%and water, dried over anhydrous Na2SO4, and filtered. The ethyl acetate phase was separated, which on evaporation yielded the ester derivatives
89%	With sulfuric acid Heating;
88.1%	With sulfuric acid at 100℃; for 2.5h; Autoclave;	1.4 4) Synthesis of vanillic acid methyl ester 20.0 g Vanillic acid was dissolved in 250 mL of methyl alcohol, then 1 mL of concentrated sulfuric acid was added, and the mixture was stirred for 2.5 hours in a 100 ° C high pressure autoclave. The reaction solution was concentrated to 50 mL and dropped into 300 mL of 0 ° C water, and white crystals were precipitated. By filtration and drying, 19.1 g of the desired product was obtained. Yield: 88.1%, Melting point: 64 °C
88.5%	With hydrogenchloride In lithium hydroxide monohydrate at 70℃; for 12h;	Synthesisof methyl 4-hydroxy-3-methoxybenzoate (2) To a solution ofvanillic acid (6.58 g, 39.13 mmol) in MeOH (50 ml) was added hydrochloric acid(4.4 ml). After stirring at 70 °C for 12 h, the solvent was removed undervacuum, affording an oily residue that was purified by flash chromatography.Elution with CH2Cl2/petroleum ether (3:1) afforded 2as a white solid (6.31 g, 88.5%), mp: 61.3-63.2°C.
87%	With hydrogenchloride In lithium hydroxide monohydrate at 70℃; for 12h;	1.1 The preparation of 6-methoxy-7-(3-N-morpholinylpropoxy)-3-nitro-4-N-anilino-quinoline is as follows: Step 1: 1 g of vanillic acid (5.95 mmol) was placed in a 50 mL round-bottomed flask. After 10 mL of methanol was added to dissolve the solution, 0.6 mL of concentrated hydrochloric acid was added and the mixture was heated to reflux at 70° C. for 12 hours. After completion of the reaction, 0.87 g of compound a, ie methyl vanillate, was obtained in a yield of 87%. Multiple reactions accumulate the mass of this compound.
85.4%	With thionyl chloride at 20℃; for 20h;
68.2%	With sulfuric acid Reflux;	Synthesis of 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-3-methoxybenzoic acid (27a) To a solution of vanilic acid (0.67g, 4mmol) in 9ml of anhydrous methanol 0.25ml of Conc. Sulfuric acid (3.0mL) was added and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature,the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 5%sodium bicarbonate, water and brine. Then it was dried over sodium sulfate, filtered, and concentrated to get awhite solid (0.49 g, 68.2%). Methyl 4-hydroxy-3-methoxybenzoate (0.36g, 2mmol) and triphenylphosphine(2.62g, 10mmol) dissolved in 30 mL of dry THF at 0 °C. To the stirred mixture was added dropwise, over a periodof 2 h, a solution of N-(tertbutyloxycarbonyl)piperidin-4-ol (2.0g, 10 mmol) and DIAD (2.5g, 10 mmol) in 20mL of dry THF. The reaction mixture was stirred for 5 days at room temperature and monitored by TLC(Ethylacetate:Hexane-35:65) to see the consumption of starting material. The reaction mixture was diluted with50 mL of ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3, dried over MgSO4, andconcentrated to give a semisolid. This material was suspended in 100-200 mL of hexane/ethyl acetate (9:1),stirred, and filtered to remove triphenylphosphine oxide. Evaporation of the filtrate under reduced pressureyielded an oil that was purified by Flash column (hexane/ethyl acetate 6.5:3.5) to give an oil that solidified onstanding. This oil was then hydrolyzed to the free carboxylic acid using a similar procedure reported for thesynthesis of 11a.
63%	With sulfuric acid for 24h; Reflux; Inert atmosphere;
	With hydrogenchloride
	With sulfuric acid for 24h;
	With sulfuric acid
	With hydrogenchloride at 20℃;
	With sulfuric acid
	With sulfuric acid Heating;
	With sulfuric acid for 12h; Heating;
	With sulfuric acid at 40℃; for 2h;
	With sulfuric acid Reflux;
	With hydrogenchloride In diethyl ether for 12h; Reflux;
	With sulfuric acid for 12h; Reflux;
	With hydrogenchloride In lithium hydroxide monohydrate for 2h; Reflux;
	With thionyl chloride at 25℃; for 15h; Cooling with ice;	3 Example 3 Preparation of Intermediate 3 5.502 g (2.73 mmol) of vanillic acid was weighed into a reaction flask containing 50 mL of anhydrous methanol.Then, 3 ml of SOCl2 was gradually added dropwise in an ice bath, and then the reaction solution was stirred at room temperature overnight.When the reaction was completed by TLC, the reaction mixture was concentrated under reduced pressure to give a white solid.White solid purity 95%,No further purification was carried out.
	With sulfuric acid Reflux;	general procedure for the preparations of the methyl ferulate (2) and methyl vanillate (5) General procedure: To a stirred mixture of corresponding acids (5 mmol) in dry methanol (15 mL) was added concentrated sulfuric acid (0.027 mL, 0.5 mmol), and the reaction mixture was refluxed until the acid had completely reacted, as indicated by TLC. After cooling to 25 °C, ethyl acetate was added and the mixture washed with water and brine. The ethyl acetate layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with (petroleum ether/EtOAc = 8:1) to afford the corresponding esters (90% yields), the 1H NMR data were in accordance with literature data (Yoshioka T et al. 2004).
	With sulfuric acid for 8h; Reflux;	4 Methyl Vanillate Synthesis 15 g of vanillic acid (0.09 mol) were dissolved in 75 mL of methanol. 2.1 mL of sulfuric acid were added and the mixture is stirred and warm to reflux for 8 h. After evaporation of methanol, the solid is dissolved in 60 mL of ethylacetate, washed with 30 mL of NaHCO3 solution, water (2 times) and brine (1 time). The organic phase is evaporated under reduced pressure.
	With sulfuric acid for 8h; Reflux;
	With sulfuric acid for 10h; Reflux;
	With sulfuric acid Reflux;
	With thionyl chloride In methanol for 24h; Reflux;

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2
[ 3943-74-6 ]
[ 42590-00-1 ]

Yield	Reaction Conditions	Operation in experiment
78%	With HNO₃; glacial acetic acid at 0 - 20℃; for 2h;
78%	With HNO₃; glacial acetic acid at 20℃; for 2h; Cooling with ice;	77.1 Methyl 4-hydroxy-3-methoxy-5-nitrobenzoate 77b The compound 4-hydroxy-3-methoxybenzoic acid methyl ester 77a (20.48 g, 112.4, mmol) was dissolved in glacial acetic acid (100 mL), nitric acid (9.4 mL) was slowly added under an ice bath, and the reaction was returned to room temperature for 2 hours. Ice water was added to the reaction solution, and the solid was filtered and drained to obtain compound 77b (20 g) with a yield of 78%.
75%	With HNO₃; glacial acetic acid at 0 - 20℃;	1.1 Step 1; Preparation of methyl 4-hvdroxy-3-methoxy-5-nitrobenzoate (2) To a stirred solution of methyl-4-hydroxy-3-methoxybenzoate (1, 20 g, 109.7 mmol) in CH3COOH (100 mL) was added HNO3 (5.9 mL, 94.4 mmol) under 0°C drop wise and then reaction mixture was stirred at room temperature for 4-5 h (reaction condition a). To the reaction mixture ice cold water was added and the reaction mixture was filtered to obtain the precipitate which was dried using high vacuum to get the product as yellow solid (18 g, 75% yield). MS (ESI): mass calcd. for C9H9N06, 227.04; m/z found, 228 [M+H]+.

74%	With HNO₃; glacial acetic acid In glacial acetic acid for 2h; Ambient temperature;
73%	With HNO₃; glacial acetic acid at 20℃; for 0.25h; Inert atmosphere;
70%	With HNO₃; glacial acetic acid at 20℃; for 2h;	c (c) Preparation of methyl 3-nitro-4-hydroxy-5-methoxybenzoate 3-methoxy-4-hydroxybenzoate (28.6g, 0.16mol) was dissolved in 150 ml of glacial acetic acid, at zero degrees, a concentrated solution of concentrated nitric acid in glacial acetic acid (10.5 mL, 0.16 mol, 60 ml of concentrated nitric acid) was added, and the precipitate was gradually precipitated in the reaction mixture, and reacted at room temperature for 2 hours.The precipitate was filtered, washed with distilled water until the filtrate is nearly colorless, to give a yellow solid, after recrystallization from ethyl acetate, methyl 3-nitro-4-hydroxy-5-methoxybenzoate was obtained in 25.4 g, yield 70%
66%	With HNO₃; glacial acetic acid at 20℃; for 5h; Cooling with ice;	1.1 Step 1: Synthesis of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate Methyl 4-hydroxy-3-methoxybenzoate (25.4 g, 0.139 mol) was dissolved in glacial acetic acid (100 mL), and a mixed solution of nitric acid (10.2 mL) and acetic acid (52 mL) was slowly added dropwise on an ice bath, about 1 The hour is added. The reaction solution was slowly warmed to room temperature and stirred for 4 hours. Filter, the filter cake was washed with water, n-hexane and diethyl ether.Drying gave the product as a yellow solid (21.0 g, yield: 66%).
59%	With HNO₃; glacial acetic acid at 25℃; for 3h; Inert atmosphere;	100 Intermediate K-l Methyl 4-hydroxy-3-methoxy-5-nitrobenzoate To a solution of methyl vanillate (8.00 g, 43.9 mmol) in acetic acid (20 mL) was added HNO3 (3.69 g, 52.7 mmol) at 25 °C for 3 h. The resulting solid was filtered and washed with FLO (3 x 100 mL), then dried under vacuum to afford methyl 4-hydroxy-3- methoxy-5-nitro- benzoate (6.20 g, 59%) as a light yellow solid; NMR (400MHz, CDCI3) S= 11.09 (br, 1H), 8.46 (d , J= 1.9 Hz, 1H), 7.78 (A, J= 1.9 Hz, 1H), 4.03 (s, 3H), 3.97 (s, 3H).
58%	With HNO₃; glacial acetic acid at 0 - 20℃; for 3h;
35%	With HNO₃ In dichloromethane; lithium hydroxide monohydrate at -60℃; for 2.5h;	115.i Synthesis 1 154-(3,4-Dichloro-5-isopropoxybenzamido)-2-methylbenzoic acid (AAA-113)A solution of methyl 4-hydroxy-3-methoxybenzoate (1) (10 g, 55 mmol) in DCM (100 mL) was cooled to -60°C and fuming nitric acid (24.5 mL, 549 mmol) was added dropwise over 30 min. The reaction mixture was stirred at -60°C for 2 h then added slowly to iced water (200 mL) with stirring. The precipitate was collected, washed with ice cold water and dried under suction to afford methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2) (4.4 g, 35% yield) as a bright yellow solid: 1H NMR (400 MHz, CDCI3) δ: 1 1.08 (1 H, d), 8.45 (1 H, d), 7.77 (1 H, d), 4.01 (3H, s), 3.95 (3H, s).
35%	With HNO₃ In dichloromethane at -60℃; for 2.5h;	115.i A solution of methyl 4-hydroxy-3-methoxybenzoate (1) (10 g, 55 mmol) in DCM (100 mL) was cooled to -60° C. and fuming nitric acid (24.5 mL, 549 mmol) was added dropwise over 30 min. The reaction mixture was stirred at -60° C. for 2 h then added slowly to iced water (200 mL) with stirring. The precipitate was collected, washed with ice cold water and dried under suction to afford methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2) (4.4 g, 35% yield) as a bright yellow solid: 1H NMR (400 MHz, CDCl3) δ: 11.08 (1H, d), 8.45 (1H, d), 7.77 (1H, d), 4.01 (3H, s), 3.95 (3H, s).
	With diethyl ether; HNO₃
	With HNO₃; glacial acetic acid
	With HNO₃; NaNO₂ In 1,4-dioxane; lithium hydroxide monohydrate at 40℃; for 7h;	2b Example 2b Preparation of 4-hydroxy-5-methoxy-3-nitrobenzoic acid Vanillic acid methyl ester (33g) and sodium nitrite (0.625g) are charged. Water (158mL) and 1,4-dioxane (158mL) are added at room temperature. The reaction mixture is heated to 40 °C. Nitric acid (65%) (15.75g) is added in the course of three hours and the resulting mixture is stirred for 4h after addition. The reaction mixture is sampled for completion. The water/nitric-acid/dioxane azeotrope is distilled off in vacuum at 40 °C. The resulting product suspension is quenched by addition of sodium hydroxide solution (50% , 33.2 mL) and then stirred for 16h. The quench mixture is sampled for completion. Then, HCl (18,5%, 70.2mL.) is added until the pH is below 1. The product is filtered off and washed with water (27.9mL). The product is then dried in vacuum at 50 °C. The overall yield was 81 % of a 97.3 % pure product.
	With sulfuric acid; HNO₃	11 Example 11 4-chloro-3-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-ylamino)-7, 8dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methoxy-N-methylbe nzamide (I-11) Compound Ia-11 was synthesized according to the process described in the patent application . Compound Ib-11 was synthesized with reference to Example 1. In a glass sealed tube, Compound Ib-11 (9mmol) was dissolved in 30ml ethanol, and a methylamine alcohol solution (15ml) was added. The mixture was reacted at 50°C overnight to produce Compound Ib-11' (7.2mmol). With reference to the procedure of Example 10, methyl vanillate, N-BOC-4-piperidinone, N-ethylpiperazine and 2-chloro-5-nitropyridine were used as starting materials to synthesize and produce Compound Ik-11. Compound Ik-11 (1.0 mmol) was dissolved in 15ml dichloromethane, and a HCl gas was introduced for 30min. The mixture was concentrated to produce Compound Im-11 (1.0 mmol). Compound Im-11 (1.0 mmol) and Compound Ib-11' (1.05 mmol) were suspended in 10ml dioxane, and cesium carbonate (4.5 mmol) was added. The mixture was stirred evenly, Pd2(dba)3 (0.1 mmol) and BINAP (0.12 mmol) were added. The mixture was reacted under the nitrogen protection at 100°C for 48 hours, cooled to room temperature and filtered. The filtrate was concentrated to an oily substance, and an appropriate amount of methanol was added. A solid separated out. The mixture was filtered to remove the solid (BINAP), and the filtrate was separated by thin layer chromatography to produce Compound I-11 (0.2mmol) in a yield of 20%. H1-NMR (deuterated DMSO) : δ9.3(s, 1H), δ8.57(s, 1H), δ8.48(s, 1H), δ8.26(s, 1H), δ7.89(s, 1H), δ7.35(d, 2H), δ6.85(s, 1H), δ4.13(s, 2H), δ3.91(s, 3H), δ3.42(m, 2H), δ3.20(t, 4H), δ2.82(t, 2H), δ2.68(s, 3H), δ2.49(m, 4H)δ2.35(m, 2H), δ1.05(t, 3H). H1-NMR (deuterated DMSO) for intermediate Ib-11': δ8.65(s, 1H), δ7.92(s, 1H), δ7.6(s, 1H), δ3.91(s, 3H), δ2.78(d, 3H). ESI(+)m/z: 537

Reference： [1]Wang, Lin; Gong, Jianxian; Deng, Lujiang; Xiang, Zheng; Chen, Zhixing; Wang, Yuefan; Chen, Jiahua; Yang, Zhen [Organic Letters, 2009, vol. 11, # 8, p. 1809 - 1812]
[2]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - WO2021/249475, 2021, A1 Location in patent: Page/Page column 155; 156
[3]Current Patent Assignee: JUBILANT PHARMOVA LTD - WO2019/58393, 2019, A1 Location in patent: Paragraph 000144
[4]Meyers; Babiak; Campbell; et al. [Journal of the American Chemical Society, 1983, vol. 105, # 15, p. 5015 - 5024]
[5]Hillisch, Alexander; Gericke, Kersten M.; Allerheiligen, Swen; Roehrig, Susanne; Schaefer, Martina; Tersteegen, Adrian; Schulz, Simone; Lienau, Philip; Gnoth, Mark; Puetter, Vera; Hillig, Roman C.; Heitmeier, Stefan [Journal of Medicinal Chemistry, 2020, vol. 63, # 21, p. 12574 - 12594]
[6]Current Patent Assignee: SHAOXING UNIVERSITY - CN110016016, 2019, A Location in patent: Paragraph 0028; 0035; 0036
[7]Current Patent Assignee: NANJING TRANSTHERA BIOSCIENCES - CN110194770, 2019, A Location in patent: Paragraph 0398; 0399; 0400; 0401; 0402
[8]Current Patent Assignee: ROCHE HOLDING AG - WO2019/105915, 2019, A1 Location in patent: Page/Page column 67; 115-116
[9]Howard, Nigel I.; Dias, Marcio V.B.; Peyrot, Fabienne; Chen, Liuhong; Schmidt, Marco F.; Blundell, Tom L.; Abell, Chris [ChemMedChem, 2015, vol. 10, # 1, p. 116 - 133]
[10]Current Patent Assignee: UNIVERSITY OF LONDON - WO2011/27106, 2011, A1 Location in patent: Page/Page column 151-152
[11]Current Patent Assignee: UNIVERSITY OF LONDON - US2012/149737, 2012, A1 Location in patent: Page/Page column 88-89
[12]Klemenc [Monatshefte fur Chemie, 1914, vol. 35, p. 95]
[13]Schkeryantz, Jeffrey M.; Danishefsky, Samuel J. [Journal of the American Chemical Society, 1995, vol. 117, # 16, p. 4722 - 4723]
[14]Current Patent Assignee: Bial - Sgps, S.A - WO2013/89573, 2013, A1 Location in patent: Page/Page column 19
[15]Current Patent Assignee: ALLIST PHARMACEUTICALS INC - EP3466948, 2019, A1 Location in patent: Paragraph 0092-0096

3
[ 3943-74-6 ]
[ 50522-19-5 ]

Yield	Reaction Conditions	Operation in experiment
94.5%	With sodium persulfate In water at 80℃; for 1.5h;	1.5 5) Synthesis of dehydro divanillic acid methyl ester 20.0 g of methyl vanillate, 1.2 g of iron (III) sulfate, 20.0 g of sodium persulfate and 400 mL of water were added and the mixture was stirred at 80 ° C for 1.5 hours. The solid was recovered by filtration. And washed with water (50 mL × 3 times) and ethyl acetate (50 mL × 2 times). Finally, recrystallization in acetone (twice) gave 18.8 g of the title compound. Yield: 94.5%, Melting point: 230 ° C
90%	With laccase from Trametes versicolor; oxygen In acetone at 20℃; for 24h; Green chemistry; Enzymatic reaction;	General procedure for dimerization: synthesis of dimers 1-7 Dimethyl divanillate (4): MW = 362 g/mol, yield: 90%. 1H NMR (400 MHz, CDCl3, δ (ppm)): δ 9.60 (s, 2H, HO), 7.46 (s, 4H, Ar), 3.90 (s, 6H, OCH3), 3.80 (s, 6H, OCH3 ester). 13C NMR (400 MHz, CDCl3, δ (ppm)): δ 166,04 (OCH3 ester), 148.60 (Ar-C), 147.27 (Ar-C), 125.25 (Ar-C), 123.93(Ar-C), 119.21 (Ar-C), 110.89 (Ar-C), 55.97 (OCH3), 51.75(OCH3 ester).
90%	With laccase from Trametes versicolor; oxygen In acetone at 20℃; for 24h; Enzymatic reaction;	4 Example 4: Preparation of Compound (4) A solution of 1.5 g of compound of methylvanillate in 20 mL of acetone was added to 180 mL of NaOAc buffer (0.1 M, pH 5.0). The solution was saturated in O2 for 5 min. Laccase from Trametes versicolor (20 U, 12.4 mg) was added and the reaction was stirred at room temperature for 24 hours. The precipitate was filtered, washed with water and dried under vacuum (at 100° C. overnight). Compound (4) is prepared from methylvanillate with a yield of 90%.

72%	With dipotassium peroxodisulfate; ammonium ferrous sulfate hexahydrate In water for 0.5h;
51%	With [bis(acetoxy)iodo]benzene In acetonitrile at 25℃; for 18h; Cooling with ice; Darkness;
51%	With [bis(acetoxy)iodo]benzene
51%	With [bis(acetoxy)iodo]benzene
40%	With [bis(acetoxy)iodo]benzene In acetonitrile at 25℃; for 24h;
35.4%	With dihydrogen peroxide; horseradish peroxidase In water; acetone at 20℃; Enzymatic reaction;
	With sodium persulfate; water; iron(II) sulfate
	With [bis(acetoxy)iodo]benzene

Reference： [1]Current Patent Assignee: TEIJIN LIMITED - JP2017/171591, 2017, A Location in patent: Paragraph 0059
[2]Llevot, Audery; Grau, Etienne; Carlotti, Stéphane; Grelier, Stéphane; Cramail, Henri [Journal of Molecular Catalysis B: Enzymatic, 2016, vol. 125, p. 34 - 41]
[3]Current Patent Assignee: UNIVERSITY OF BORDEAUX 1; INSTITUT POLYTECHNIQUE DE BORDEAUX; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - US10155969, 2018, B2 Location in patent: Page/Page column 20
[4]De Vasconcelos, Debora Naliati; Lima, Angélica Nakagawa; Philot, Eric Allison; Scott, Ana Lígia; Ferreira Boza, Izabelle Amorim; De Souza, Aguinaldo Robinson; Morgon, Nelson Henrique; Ximenes, Valdecir Farias [RSC Advances, 2019, vol. 9, # 35, p. 19983 - 19992]
[5]Scholtes, Jan Felix; Trapp, Oliver [Angewandte Chemie - International Edition, 2019, vol. 58, # 19, p. 6306 - 6310][Angew. Chem., 2019, vol. 131, # 19, p. 6372 - 6376,5]
[6]Scholtes, Jan Felix; Trapp, Oliver [Chemistry - A European Journal, 2019, vol. 25, # 50, p. 11707 - 11714]
[7]Scholtes, Jan Felix; Trapp, Oliver [Chirality, 2019, vol. 31, # 12, p. 1028 - 1042]
[8]Wells, Geoffrey; Seaton, Angela; Steven, Malcolm F. G. [Journal of Medicinal Chemistry, 2000, vol. 43, # 8, p. 1550 - 1562]
[9]Enomoto, Yukiko; Iwata, Tadahisa [Polymer, 2020, vol. 193]
[10]Erdtman [Svensk Kemisk Tidskrift, 1935, vol. 47, p. 223,227]
[11]Scholtes, Jan Felix; Trapp, Oliver [Organometallics, 2019, vol. 38, # 20, p. 3955 - 3960]

4
[ 3943-74-6 ]
[ 100-44-7 ]
[ 56441-97-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3.0h;	A mixture of methyl vanillate (300.0 g, 1.65 mol), benzyl chloride (230 mL, 1.81 mol) and potassium carbonate (345 g, 2.5 mol) in N,N-dimethyl formamide (1000 mL) was heated to 100 C. for three hours. The reaction was cooled to room temperature, poured into ice water (1500 mL) and stirred for 1 h. The resultant solid was filtered and washed by water (300 mL×3), then dried to give 119 (440 g, yield=98.0%) as a white solid
97%	With potassium carbonate; In acetonitrile; at 90℃; for 2.0h;Inert atmosphere;	under the protection of nitrogen added in the reaction bottle 10.0g3-methoxy-4-hydroxy benzoic acid, 19.0g potassium carbonate, 7.0g benzyl chloride and 80 ml of acetonitrile, the mixture to the 90 C reflux reaction 2 hours, using n-hexane: ethyl acetate = 4 volume ratio: 1 as a developing solvent of TLC analysis of the mixture; complete reaction of raw materials, cooling filter, by 150 ml ethyl acetate wash the filter cake, filtrate turns on lathe does, column chromatography, using hexane: ethyl acetate = 5 volume ratio: 1 of the mixed solution to elute, get 14.5g pure white solid (compound a), yield 97.0%;

Reference： [1]Patent: US2014/235634,2014,A1 .Location in patent: Paragraph 0390; 0391
[2]Patent: CN105541736,2016,A .Location in patent: Paragraph 0044; 0045
[3]ACS Chemical Biology,2012,vol. 7,p. 552 - 562
[4]Journal of the Chemical Society,1950,p. 864,866

5
[ 3943-74-6 ]
[ 2150-43-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With aluminium(III) iodide; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In acetonitrile at 80℃; for 18h;
90%	With aluminium(III) iodide; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In acetonitrile at 80℃; for 18h;	4-6; 3-4 Example 4 (Demethylation of methyl vanillate) Add acetonitrile (40ml), aluminum triiodide (2.242g, 5.5mmol)) and N,N-dimethylformamide dimethyl acetal (0.894g, 7.5mmol) into a 100ml round bottom flask. After stirring for 15 min, methyl vanillate (0.911g, 5mmol) was added, and stirring was continued at 80°C for 18h. After the reaction was completed, it was quenched with 2M dilute hydrochloric acid (10ml), and then extracted three times with ethyl acetate (50ml). Phase, first washed with saturated sodium thiosulfate aqueous solution (10ml), then dried over anhydrous magnesium sulfate, filtered, the filtrate was removed with a rotary evaporator to remove the solvent, and the residue was passed through flash column chromatography (eluent is petroleum ether/ethyl acetate Ester=4:1, volume ratio) was purified to obtain 0.757 g of methyl 3,4-dihydroxybenzoate (white solid, yield 90%).
88%	With aluminium(III) iodide; ethyl acetate; diisopropyl-carbodiimide In acetonitrile at 20℃; for 96h; chemoselective reaction;	Methyl protocatechuate (2) General procedure: To a suspension of AlI3 (2.75 mmol, 1.1 eq.) in CH3CN (20 mL) was added asolution of DIC (190 mg, 1.5 mmol, 0.6 eq.) and methyl vanillate (454 mg, 2.5 mmol) in EA (20 mL, desiccated by MgSO4). After stirred for 2 h at 20 °C, the mixture was was acidified with HCl (2 mol/L, 5 mL), and extracted with EA (3 × 50 mL). The organic phases were combined, washed with saturated aq Na2S2O3 (10 mL) and brine (10 mL), and was dried (MgSO4). The solvent was removed on a rotary evaporator and the residue was purified by flash column chromatography (PE/EA = 2 : 1) to afford 2 (0.349 g, 82%) as a white solid

73%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In water; carbonic acid dimethyl ester at 20℃; Stage #2: With sodium oxalate In water; carbonic acid dimethyl ester chemoselective reaction;
25%	With oxygen; copper(II) perchlorate; ascorbic acid In water; acetone at 40℃; for 50h;

Reference： [1]Sang, Dayong; Yue, Huaxin; Zhao, Zhengdong; Yang, Pengtao; Tian, Juan [Journal of Organic Chemistry, 2020, vol. 85, # 10, p. 6429 - 6440]
[2]Current Patent Assignee: JINGCHU UNIVERSITY OF TECHNOLOGY - CN111620764, 2020, A Location in patent: Paragraph 0041-0057
[3]Tian, Juan; Yi, Cuicui; Fang, Huasheng; Sang, Dayong; He, Zhoujun; Wang, Jiahui; Gan, Yongjiang; An, Qing [Tetrahedron Letters, 2017, vol. 58, # 36, p. 3522 - 3524]
[4]Location in patent: experimental part Bernini, Roberta; Barontini, Maurizio; Mosesso, Pasquale; Pepe, Gaetano; Willfoer, Stefan M.; Sjoeholm, Rainer E.; Eklund, Patrik C.; Saladino, Raffaele [Organic and Biomolecular Chemistry, 2009, vol. 7, # 11, p. 2367 - 2377]
[5]Aihara, Kazuhiro; Higuchi, Tsunehiko; Hirobe, Masaaki [Chemical and pharmaceutical bulletin, 1988, vol. 36, # 2, p. 837 - 840]

6
[ 67-56-1 ]
[ 3943-74-6 ]
[ 292638-85-8 ]
[ 124692-20-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: methanol; 4-hydroxy-3-methoxybenzoic acid methyl ester With iodobenzene; 3-chloro-benzenecarboperoxoic acid Stage #2: acrylic acid methyl ester In methanol at 20℃; for 0.5h;	General procedure for the Diels-Alder reaction of MOBs 1b-9b with dienophiles Method B General procedure: To a stirred solution of iodobenzene (30 mol %) in dry methanol (2 mL) dry m-CPBA (249 mg, 1 mmol, 2 equiv) was added followed by the addition of methanolic solution (1 mL) of guaiacol derivatives (0.5 mmol). To the resulting yellow colour solution dienophile (10 mmol, 20 equiv) was added and the reaction mixture was stirred at room temperature for 20 min to 3 h. After the completion of the reaction as monitored by TLC, the solvent was evaporatedin vacuo. The mixture was washed with a saturated aqueous solution of NaHCO3 and extracted twice (2 x 20 mL) with CH2Cl2.The combined organic layers were washed with brine, filtered, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc (10-20%) in hexanes to afford the pure cycloadducts 12a-d-19a-d. NMR data of the compounds from the current study are comparable with that of the compounds reported in the literature.22
	With thallium(III) nitrate Yield given. Multistep reaction;

Reference： [1]Taneja, Neha; Peddinti, Rama Krishna [Tetrahedron Letters, 2016, vol. 57, # 35, p. 3958 - 3963]
[2]Liao, Chun-Chen; Wei, Ching-Peng [Tetrahedron Letters, 1989, vol. 30, # 17, p. 2255 - 2256]

7
[ 3943-74-6 ]
[ 106-95-6 ]
[ 171002-53-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In acetone at 40℃; for 16h; Inert atmosphere;	Methyl 4-(allyloxy)-3-methoxybenzoate Allyl bromide (0.5 mL, 58 mmol) was added to a suspension of methyl vanillate (4) (10.0 g, 55 mmol) and potassium carbonate (16.8 g, 122 mmol) in acetone (55 mL) and the mixture stirred for 16 hours at 40°C. The suspension was filtered and the filter cake rinsed with acetone. The filtrate was concentrated under reduced pressure to afford the title compound 5 as a white crystalline solid (12.2 g, 55 mmol, 100%) requiring no purification and whose spectral data matched that reported in the literature;1 Rf 0.28 (20% EtOAc in Pet. Spirits); mp 54-55 °C; IR (thin film) 2999, 2951, 2854, 1716, 1599, 1513, 1342, 1272 cm-1; 1H NMR (500 MHz, C6D6) d 7.63 (dd, J = 8.4, 1.9 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.07 (ddd, J = 22.6, 10.7, 5.4 Hz, 1H), 5.41 (dd, J = 17.3, 1.4 Hz, 1H), 5.31 (dd, J = 10.5, 1.1 Hz, 1H), 4.66 (d, J = 5.4 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H); 13C NMR (126 MHz, C6D6) d 167.0, 153.2, 150.3, 133.7, 124.0, 123.9 117.7, 113.6, 112.0, 69.7, 55.7, 51.9; MS (ESI) m/z 223 [M+H]+, 245 [M+Na]+; HRMS (ESI) calcd for C12H14O4 [M+Na]+ 245.0784, found 245.0784.
95%	With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 2h;	508.a A solution of methyl 4-hydroxy-3-methoxybenzoate (2.0 g, 10.98 mmol), allyl bromide (1.58 g, 13.18 mmol) and K2CO3(3.10 g, 22.50 mmol) in DMF (20 mL), was stirred for 2 hr at 40C. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase chromatography (MeCN/H2O, 0% to 100%, 30 min) to give the desired compound as a yellow oil (2.3 g, 95%). ESI-MS m/z: 223.10 [M+H]+.
92%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: allyl bromide In N,N-dimethyl-formamide at 20℃; for 18h;

With sodium hydride 1.) DMF, r.t., 2 h; 2.) r.t., 24 h; Multistep reaction;

Reference： [1]Aumann, Kylee M.; Hungerford, Natasha L.; Coster, Mark J. [Tetrahedron Letters, 2011, vol. 52, # 51, p. 6988 - 6990]
[2]Current Patent Assignee: ENANTA PHARMACEUTICALS INC - WO2021/66922, 2021, A1 Location in patent: Page/Page column 202; 203
[3]Wilson, Stuart C.; Howard, Philip W.; Forrow, Stephen M.; Hartley, John A.; Adams, Lesley J.; Jenkins, Terence C.; Kelland, Lloyd R.; Thurston, David E. [Journal of Medicinal Chemistry, 1999, vol. 42, # 20, p. 4028 - 4041]
[4]Wilson; Howard; Thurston [Tetrahedron Letters, 1995, vol. 36, # 35, p. 6333 - 6336]

8
[ 3943-74-6 ]
[ 106-96-7 ]
3-methoxy-4-(prop-2-yn-1-yloxy)benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate In N,N-dimethyl-formamide for 3h; Ambient temperature;
95%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With potassium carbonate In N,N-dimethyl-formamide for 0.5h; Stage #2: propargyl bromide In N,N-dimethyl-formamide at 25℃; for 2h;	110.1 Step - 1: Methyl 3-methoxy-4-(prop-2-yn-1-yloxy)benzoate To a stirred solution of methyl 4-hydroxy-3-methoxybenzoate (70 g, 384 mmol) (commercially available) in DMF (500 ml) was added K2CO3 (80 g, 576 mmol) and stirred for 30 min followed by addition of 80% 3-bromoprop-1-yne in toluene (43.6 ml, 384 mmol) drop wise at ambient temperature. The resulting mixture was stirred for 2 h at 25°C. After completion of reaction, reaction mass was cooled to 0°C and ice cold water (1000 ml) was added slowly, solid compound got precipitated was filtered, residue was washed with water (500 ml x 2) and dried under vacuum to afford methyl 3-methoxy-4-(prop-2-yn-1-yloxy)benzoate (80 g, 95% yield) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ 7.59 (dd, J = 8.4, 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.90 (d, J = 2.4 Hz, 2H), 3.83 (s, 6H), 3.62 (t, J = 2.4 Hz, 1H).
93%	With potassium carbonate In N,N-dimethyl-formamide

91%	With potassium carbonate In acetone Inert atmosphere; Reflux;	4 3-Methoxy-4-(prop-2-yn-l-yloxy)benzoic acid methyl ester (11) Under argon, to a suspension of (10) (1.82 g, 10 mmol) and potassium carbonate (4.88 g, 40 mmol) in acetone (30 mL), was injected propargyl bromide (2.6 mL, 30 mmol). The resulting mixture was refluxed overnight and directly filtrated without any work up. The filtrate was concentrated under reduced pressure and the residue was crystallized from MeOH (20 mL) to afford 3-methoxy-4-(prop- 2-yn-l-yloxy)benzoic acid methyl ester (11) (2.0 g, 91%) as a light brown plates. 'H NMR (300 MHz, CDCL) d 7.66 (dd, / = 8.4 and 2.0 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.04 (d, / = 8.5 Hz, 1H), 4.82 (d, /= 2.4 Hz, 2H), 3.92 (s, 3H), 3.89 (s, 3H) and 2.53 (t, / = 2.4 Hz, 1H); LCMS Ci2Hi204Rt = 6.044 min, ESI+ m/z = 221.1 (M+H).
90%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With potassium carbonate In acetone for 0.5h; Reflux; Stage #2: propargyl bromide In acetone; toluene for 4h; Reflux;	1.3.2 Synthesis of 3-methoxy-4-prop-2-ynyloxy-benzoic acid methyl ester (3) A solution of 4-hydroxy-3-methoxy-benzoic acid methyl ester 2 (3.00 g, 16.5 mmol) in acetone (100 mL) was treated with K2CO3 (3.42 g, 24.9 mmol). The resulting reaction mixture was stirred under reflux for 30 minutes after which propargyl bromide was added (2 mL of 80 wt % solution in toluene, 16.5 mmol). After stirring for 4 h under reflux, the reaction mixture was concentrated under vacuum. The residue was then taken up in ethyl acetate, washed successively with water (3 x 50 mL) and brine (25 mL), dried over anhydrous sodium sulphate and concentrated under vacuum to provide compound 3 as white powdered solid (3.27 g, 14.9 mmol, 90%).2 M.p.: 85-88 °C; 1H NMR: (400 MHz, CDCl3): δ 7.66-7.64 (dd, 1H, J = 8.4 Hz, 2.0 Hz, Ar), 7.54 (d, 1H, J = 1.6 Hz, Ar), 7.02 (d, 1H, J = 8.4 Hz, Ar), 4.80 (d, 2H, J = 2.4 Hz, CH2OAr), 3.90 (s, 3H, CH3OAr), 3.87 (s, 3H, COOCH3), 2.52-2.50 (t, 1H, J = 2.4 Hz, C≡CH); 13C NMR: (400 MHz, CDCl3): 166.7 (C=O), 150.6, 149.1, 123.8, 123.1, 112.6, 112.4 (Ar), 77.7 (C≡CH), 76.3 (C≡CH), 56.5 (CH2OAr), 55.9 (CH3OAr), 52.0 (COOCH3); ESI-TOF-HRMS: [M+H]+ calculated for C12H13O4: 221.0814, found 221.0811.
85%	With potassium carbonate In acetone for 6h; Reflux;
78%	With potassium carbonate In acetone; toluene for 7h; Reflux;	8 Methyl 3-methoxy-4-hydroxybenzoate 1 (18.22 g, 0.100 mol) was dissolved in acetone (200 niL) and potassium carbonate (48.8 g, 0.400 mol) was added. Propargyl bromide (80% 9N toluene, 26 mL, 0.30 mol) was added, and the mixture was heated at reflux with stirring for 7 h. The mixture was filtered while hot, the filtrate was evaporated to dryness, and the residue was recrystallized from methanol. [0174] Yield = 17.25 g, 0.0784 mol, 78% , white needles, mp 87-88°C. 1H- NMR: 7.672 (dd, 1 H, C6-H, J= 8.5,2.0 Hz); 7.568 (d, 1 H, C2-H, J= 2 Hz); 7.044(d, 1 H, C5-H, J = 8.5); 4.825 (d, 2H, J= 2.5 Hz); 3.927 (s, 3H); 3.897(s, 3H); 2.54 (t, 1H, J = 2.5 Hz). C12H12O4: CaIc. C = 65.45; H = 5.59.Obs. C = 65.34; H = 5.65.
78%	With potassium carbonate In acetone; toluene for 7h; Reflux;	Methyl 3-methoxy-4-(prop-2-ynyloxy)benzoate 3 Methyl 3-methoxy-4-hydroxybenzoate 1 (18.22 g, 0.100 mol) was dissolved in acetone (200 mL) and potassium carbonate (48.8 g, 0.400 mol) was added. Propargyl bromide (80% 9N toluene, 26 mL, 0.30 mol) was added, and the mixture was heated at reflux with stirring for 7 h. The mixture was filtered while hot, the filtrate was evaporated to dryness, and the residue was recrystallized from methanol, yielding 17.25 g, 0.0784 mol, 78% , white needles, mp 87-88°C. 1H-NMR: 7.672 (dd, 1 H, C6-H, J= 8.5,2.0 Hz); 7.568 (d, 1 H, C2-H, J= 2 Hz); 7.044(d, 1 H, C5-H, J = 8.5); 4.825 (d, 2H, J= 2.5 Hz); 3.927 (s, 3H); 3.897(s, 3H); 2.54 (t, 1H, J = 2.5 Hz). C12H12O4: Calc. C = 65.45; H = 5.59.Obs. C = 65.34; H = 5.65.

Reference： [1]Ishikawa, Tsutomu; Mizutani, Akiko; Miwa, Chizue; Oku, Yumie; Komano, Naoko; Takami, Atsuya; Watanabe, Toshiko [Heterocycles, 1997, vol. 45, # 11, p. 2261 - 2272]
[2]Current Patent Assignee: LUPIN LIMITED - WO2021/105960, 2021, A1 Location in patent: Page/Page column 190-191
[3]Awino, Joseph K.; Zhao, Yan [Chemistry - A European Journal, 2015, vol. 21, # 2, p. 655 - 661]
[4]Current Patent Assignee: PAOLI CALMETTES INSTITUTE; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; AIX-MARSEILLE UNIVERSITY - WO2021/74392, 2021, A1 Location in patent: Page/Page column 37; 38
[5]Belay, Yonas; Coetzee, Louis-Charl; Williams, D. Bradley G.; Muller, Alfred [Tetrahedron Letters, 2019, vol. 60, # 6, p. 501 - 503]
[6]Maddali, Narendra Kumar; Viswanath, I. V. Kasi; Murthy; Bera, Rabin; Takhi, Mohamed; Rao, Nethinti Sundara; Gudla, Vanajakshi [Medicinal Chemistry Research, 2019, vol. 28, # 4, p. 559 - 570]
[7]Current Patent Assignee: NORTHEASTERN UNIVERSITY IN BOSTON, MASSACHUSETTS - WO2010/85747, 2010, A1 Location in patent: Page/Page column 54-55
[8]Pham, Helen Trinh; Hanson, Robert N.; Olmsted, Sandra L.; Kozhushnyan, Anton; Visentin, Adam; Weglinsky, Paul J.; Massero, Chris; Bailey, Kristen [Tetrahedron Letters, 2011, vol. 52, # 10, p. 1053 - 1056]

9
[ 3943-74-6 ]
[ 358-23-6 ]
[ 175153-75-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 2,4,6-trimethyl-pyridine In dichloromethane at -78 - 20℃; for 4h;	230.a Example 230; 2?-(2-Aminomethyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5?-hydroxy-2,4?-dimethoxy-biphenyl-4-carboxylic acid; Step a To a solution of 4-hydroxy-3-methoxy-benzoic acid methyl ester (75 g, 410 mmol) and 2,4,6-collidine (75 g, 620 mmol) in dichloromethane (750 mL) was added trifluoromethanesulfonic anhydride (94 mL, 560 mmol)at ?78 C. under nitrogen. After the addition, the reaction was warmed to room temperature, stirred for 4 h and quenched with saturated aqueous copper sulfate (500 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2?250 mL). The organic phases were combined, dried and concentrated under reduced pressure. The residue was purified by column chromatography (4:1 hexane/EtOAc) to yield 3-methoxy-4-trifluoromethane-sulfonyloxy-benzoic acid methyl ester (129 g, quantitative as an oil that crystallized upon standing.
100%	With pyridine In dichloromethane at 0℃; for 0.333333h;
99%	With pyridine In dichloromethane at 0℃; for 4h;

95%	With pyridine In dichloromethane at 0℃; for 0.5h;
94%	With pyridine In dichloromethane at 0 - 20℃; for 1.5h;
93%	With tripotassium phosphate tribasic In toluene for 0.5h;
92%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 0℃;
91%	With pyridine In dichloromethane at -5 - 20℃; for 0.5h; Inert atmosphere; Sealed tube;
90%	With pyridine In dichloromethane at 0℃; for 1h;
	With pyridine In dichloromethane at 0 - 20℃;	2a Synthesis of 3-methoxy-4-boronicacid-benzoic acid methyl ester: [00176] 1.0g of 4-hydroxy-3-methoxybenzoic acid methyl ester (5.5mmol) was dissolved in 20 ML OF DICHLOROMETHANE and stirred at 0°C. To the reaction mixture was added 0. 66MOL of ANHYDROUS pyridine (8. 25MMOL), followed by 1. 39M1 OF TRIFLIC anhydride (8. 25MOL). The reaction mixture was warmed to room temperature and allowed to stir until completion (monitored by LC-MS/TLC). The mixture was poured into A separator funnel and washed with water three times. The organic layer was washed with brine, dried over MGS04, filtered and evaporated under vacuum to give the INFLATE (used as crude for boronoic acid formation). [00177] The TRIFLATE (5. 5MOL) was dissolved in acetonitrile (30MOL) and placed into an 80ml microwave vessel. To the solution was added 1. 5 EQ of Bis (PINACOLATO) DIBORON (8. 25MMOL ; 2. 08G). The mixture was stirred on A magnetic stir plate until dissolution. To the mixture was added KOAC (16. 5MOL ; 1. 62g) and 134mg of [1, 1- Bis (DIPHENYLPHOSPHINO) ferrocene] DICHLOROPALLADIUM (II) (0. 03mol%). The reaction mixture was heated at 160°C for 2 X 600S. After completion (monitored by LC-MS), the acetonitrile was evaporated to give A black solid. The solid was dissolved in EtOAc and washed with water, brine and dried over MGS04. After filtration, the solvent was evaporated under vacuum. The solid material was then dissolved in chloroform and filtered through silica. The chloroform was evaporated to give A dark green solid (used as crude for the next reaction)
	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With pyridine In dichloromethane at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: trifluoromethylsulfonic anhydride In dichloromethane at 20℃; Inert atmosphere;
	With triethylamine In dichloromethane at 0 - 20℃;	2. General Procedure for Synthesis of Aryl Triflates General procedure: To a solution of phenols (1.0 equiv, 0.5 M) in CH2Cl2 was added Et3N (2 equiv) at 0 °C. The mixture was allowed to stirred at 0 °C for 5 min followed by dropwise addition of Tf2O (1.5 equiv). The reaction mixture was warmed to room temperature and stirred until full consumption of starting materials (monitored by TLC). The resulting mixture was concentrated under reduced pressure and purified by flash column chromatography.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2003/225110, 2003, A1 Location in patent: Page 70
[2]Kurata, Haruto; Kusumi, Kensuke; Otsuki, Kazuhiro; Suzuki, Ryo; Kurono, Masakuni; Komiya, Takaki; Hagiya, Hiroshi; Mizuno, Hirotaka; Shioya, Hiroki; Ono, Takeji; Takada, Yuka; Maeda, Tatsuo; Matsunaga, Norikazu; Kondo, Tetsu; Tominaga, Sachiko; Nunoya, Ken-Ici; Kiyoshi, Hidekazu; Komeno, Masaharu; Nakade, Shinji; Habashita, Hiromu [Journal of Medicinal Chemistry, 2017, vol. 60, # 23, p. 9508 - 9530]
[3]Dodo, Kosuke; Aoyama, Atsushi; Noguchi-Yachide, Tomomi; Makishima, Makoto; Miyachi, Hiroyuki; Hashimoto, Yuichi [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 8, p. 4272 - 4285]
[4]Eicher, Theophil; Fey, Sabine; Puhl, Werner; Buechel, Edwin; Speicher, Andreas [European Journal of Organic Chemistry, 1998, # 5, p. 877 - 888]
[5]Fujii, Kana; Morita, Daichi; Onoda, Kenji; Kuroda, Teruo; Miyachi, Hiroyuki [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2324 - 2327]
[6]Mori, Akinori; Mizusaki, Tomoteru; Ikawa, Takashi; Maegawa, Tomohiro; Monguchi, Yasunari; Sajiki, Hironao [Chemistry - A European Journal, 2007, vol. 13, # 5, p. 1432 - 1441]
[7]Campeau, Louis-Charles; Parisien, Mathieu; Jean, Annie; Fagnou, Keith [Journal of the American Chemical Society, 2006, vol. 128, # 2, p. 581 - 590]
[8]Sun, Youwen; Zhang, Guozhu [Chinese Journal of Chemistry, 2018, vol. 36, # 8, p. 708 - 711]
[9]Sawada, Hiromi; Onoda, Kenji; Morita, Daichi; Ishitsubo, Erika; Matsuno, Kenji; Tokiwa, Hiroaki; Kuroda, Teruo; Miyachi, Hiroyuki [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6563 - 6568]
[10]Current Patent Assignee: EVOTEC AG - WO2005/32493, 2005, A2 Location in patent: Page/Page column 42-43
[11]Zhang, Liangwei; Liu, Long; Huang, Tianzeng; Dong, Qizhi; Chen, Tieqiao; Chen, Tieqiao [Organometallics, 2020, vol. 39, # 11, p. 2189 - 2196]
[12]Xu, Tianhao; Zhou, Xiangbing; Han, Yuhui; Zhang, Liangwei; Liu, Long; Huang, Tianzeng; Li, Chunya; Tang, Zhi; Wan, Shungang; Chen, Tieqiao [Tetrahedron Letters, 2022, vol. 97]

10
[ 100-42-5 ]
[ 67-56-1 ]
[ 3943-74-6 ]
methyl (1S*,4R*,7R*)-3,3-dimethoxy-2-oxo-7-phenylbicyclo[2.2.2]oct-5-en-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With [bis(acetoxy)iodo]benzene at 50℃; for 1h;
86%	With [bis(acetoxy)iodo]benzene at 50℃; for 4h;
85%	Stage #1: methanol; 4-hydroxy-3-methoxybenzoic acid methyl ester With iodobenzene; 3-chloro-benzenecarboperoxoic acid Stage #2: styrene In methanol at 20℃; for 0.75h;	General procedure for the Diels-Alder reaction of MOBs 1b-9b with dienophiles Method B General procedure: To a stirred solution of iodobenzene (30 mol %) in dry methanol (2 mL) dry m-CPBA (249 mg, 1 mmol, 2 equiv) was added followed by the addition of methanolic solution (1 mL) of guaiacol derivatives (0.5 mmol). To the resulting yellow colour solution dienophile (10 mmol, 20 equiv) was added and the reaction mixture was stirred at room temperature for 20 min to 3 h. After the completion of the reaction as monitored by TLC, the solvent was evaporatedin vacuo. The mixture was washed with a saturated aqueous solution of NaHCO3 and extracted twice (2 x 20 mL) with CH2Cl2.The combined organic layers were washed with brine, filtered, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc (10-20%) in hexanes to afford the pure cycloadducts 12a-d-19a-d. NMR data of the compounds from the current study are comparable with that of the compounds reported in the literature.22

Reference： [1]Gao, Shih-Yu; Lin, Yen-Lin; Rao, Polisetti Dharma; Liao, Chun-Chen [Synlett, 2000, # 3, p. 421 - 423]
[2]Gao, Shih-Yu; Ko, San; Lin, Yen-Lin; Peddinti, Rama Krishna; Liao, Chun-Chen [Tetrahedron, 2001, vol. 57, # 2, p. 297 - 308]
[3]Taneja, Neha; Peddinti, Rama Krishna [Tetrahedron Letters, 2016, vol. 57, # 35, p. 3958 - 3963]

11
[ 3943-74-6 ]
[ 75-26-3 ]
[ 3535-27-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 2477 - 2480

12
[ 3943-74-6 ]
[ 109-64-8 ]
[ 343308-46-3 ]

Yield	Reaction Conditions	Operation in experiment
88.8%	With potassium carbonate In acetonitrile at 80 - 85℃; for 8h; Heating / reflux;	II-16; III-5 [Example II-16] Preparation of methyl 4-(3-bromopropoxy)-3-methoxybenzoate In a 100 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 10.2 g (54.9 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 12.5 g (60.4 mmol) of 1,3-dibromopropane (purity: 99 wt.%), 8.5 g (60.4 mmol) of potassium carbonate (purity: 98 wt.%), and 30 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85°C in an argon gas atmosphere for 8 hours. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (gel: Wako gel C-200, eluent: n-hexane), to give 15.1 g (isolated yield: 88.8%, purity: 98% in terms of area percentage by high performance liquid chromatography) of methyl 4-(3-bromopropoxy)-3-methoxybenzoate as a white crystalline product. Methyl 4-(3-bromopropoxy)-3-methoxybenzoate had the following characteristics. m.p.: 65-66°C 1H-NMR (CDCl3, δ (ppm)): 2.01-2.43 (2H, m), 3.61-3.65 (2H, m), 3.89 (3H, s), 3.93 (3H, s), 4.19 (2H, t, J=6.0Hz), 6.90 (1H, d, J=6.0Hz), 7.55 (1H, s), 7.67 (1H, d, J=6.0Hz); [Reference Example III-5] Preparation of methyl 4-(3-bromopropoxy)-3-methoxybenzoate In a 100 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 10.2 g (54.9 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 12.4 g (60.4 mmol) of 1,3-dibromopropane, 8.3 g (60.4 mmol) of potassium carbonate (purity: 98 wt.%), and 30 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85°C in an argon gas atmosphere for 8 hours. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (gel: Wako gel C-200, eluent: n-hexane), to give 15.1 g (isolated yield: 88.8%, purity: 98% in terms of area percentage by high performance liquid chromatography) of methyl 4-(3-bromopropoxy)-3-methoxybenzoate as a white crystalline product. Methyl 4-(3-bromopropoxy)-3-methoxybenzoate had the following characteristics. m.p.: 65-66°C 1H-NMR (CDCl3, δ (ppm)): 2.01-2.43 (2H, m), 3.61-3.65 (2H, m), 3.89 (3H, s), 3.93 (3H, s), 4.19 (2H, t, J=6.0Hz), 6.90 (1H, d, J=6.0Hz), 7.55 (1H, s), 7.67 (1H, d, J=6.0Hz)
86%	With potassium carbonate In acetone for 48h; Heating;
86%	With potassium carbonate In acetone for 48h; Heating;

82%	With potassium carbonate In acetone for 48h; Heating;
	With potassium carbonate In acetone for 48h; Reflux;

Reference： [1]Current Patent Assignee: UBE INDUSTRIES LIMITED - EP1477481, 2004, A1 Location in patent: Page 23-24; 27-28
[2]Kamal, Ahmed; Murali Mohan Reddy; Rajasekhar Reddy; Laxman [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 2, p. 385 - 394]
[3]Kamal, Ahmed; Ramesh; Laxman; Ramulu; Srinivas; Neelima; Kondapi, Anand K.; Sreenu; Nagarajaram [Journal of Medicinal Chemistry, 2002, vol. 45, # 21, p. 4679 - 4688]
[4]Kamal, Ahmed; Laxman; Ramesh; Srinivas; Ramulu [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 15, p. 1917 - 1919]
[5]Kamal, Ahmed; Pogula, Praveen Kumar; Khan, Mohammed Naseer Ahmed; Seshadri, Bobburi Naga; Sreekanth, Kokkonda [Medicinal Chemistry, 2013, vol. 9, # 5, p. 651 - 659]

13
[ 110-52-1 ]
[ 3943-74-6 ]
[ 343308-47-4 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate In acetone for 48h; Heating;
82%	With potassium carbonate In acetone Heating;
59%	With potassium hydroxide In dimethyl sulfoxide for 1.16667h;	General procedure for the synthesis of bromobutoxy benzoates 3a-n. General procedure: Method B: powdered KOH (60 mmol) was added to DMSO (40 mL). The obtained suspension wasstirred for 5 min. Appropriate phenol (20 mmol) was added, followed by 1,4-dibromobutane (40mmol) after further 10 min. After stirring for 1 h, the reaction mixture was poured into water andextracted with ethyl acetate (3 × 100 mL). The combined organic extracts were washed with brine (2× 100 mL) and dried over anhydrous sodium sulfate. After rotary evaporation, the residue waspurified by flash chromatography using mixtures of cyclohexane /ethyl acetate. By use of thisprocedure, the following compounds were prepared.

	With potassium carbonate In acetone for 48h; Reflux;
	With potassium carbonate In acetonitrile at 85℃; for 6h; Inert atmosphere;

Reference： [1]Kamal, Ahmed; Murali Mohan Reddy; Rajasekhar Reddy; Laxman [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 2, p. 385 - 394]
[2]Kamal, Ahmed; Ramesh; Laxman; Ramulu; Srinivas; Neelima; Kondapi, Anand K.; Sreenu; Nagarajaram [Journal of Medicinal Chemistry, 2002, vol. 45, # 21, p. 4679 - 4688]
[3]Sorrenti, Valeria; Pittalà, Valeria; Romeo, Giuseppe; Amata, Emanuele; Dichiara, Maria; Marrazzo, Agostino; Turnaturi, Rita; Prezzavento, Orazio; Barbagallo, Ignazio; Vanella, Luca; Rescifina, Antonio; Floresta, Giuseppe; Tibullo, Daniele; Di Raimondo, Francesco; Intagliata, Sebastiano; Salerno, Loredana [European Journal of Medicinal Chemistry, 2018, vol. 158, p. 937 - 950]
[4]Kamal, Ahmed; Pogula, Praveen Kumar; Khan, Mohammed Naseer Ahmed; Seshadri, Bobburi Naga; Sreekanth, Kokkonda [Medicinal Chemistry, 2013, vol. 9, # 5, p. 651 - 659]
[5]Dhanya, Raveendra-Panickar; Sheffler, Douglas J.; Dahl, Russell; Davis, Melinda; Lee, Pooi San; Yang, Li; Nickols, Hilary Highfield; Cho, Hyekyung P.; Smith, Layton H.; D'Souza, Manoranjan S.; Conn, P. Jeffrey; Der-Avakian, Andre; Markou, Athina; Cosford, Nicholas D.P. [Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4154 - 4172]

14
[ 111-24-0 ]
[ 3943-74-6 ]
[ 169286-59-3 ]

Yield	Reaction Conditions	Operation in experiment
84.5%	With potassium carbonate In acetone for 6h; Inert atmosphere; Reflux;	1 The phenol compound (2.20 g, 12.1 mmol) is dissolved in acetone (dried through a pad of Na2S04, 48.4 mL) and to this solution is added 1,5-dibromopentane (49.4 mL, 36.3 mmol) and K2C03(6.69 g, 48.4 mmol). The reaction is heated to reflux under Ar for 6 hrs. The reaction is cooled to RT and the solid is filtered out. The filtrate is concentrated and purified with CombiFlash in 0-30% EtOAc/p-ether to obtained EC1851 (3.3893 g, yield 84.5%) as a solid. LCMS: [M+H]+m/z =331. 1H NMR (CDC13, δ in ppm): 7.65 (dd, J = 8.5, 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.50 Hz, 1H), 4.08 (t, J = 6.50 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.44 (t, J = 6.5 Hz, 2H), 1.95 (m, 4H), 1.65 (m, 2H).
84.5%	With potassium carbonate In acetone for 6h; Inert atmosphere; Reflux;	The phenol compound (2.2044g, 12.1 mmol) was dissolved in acetone (dried through a pad of Na2SO4, 48.4 mL) and to this solution was added 1,5-dibromopentane (49.4 mL, 36.3 mmol) and K2C03 (6.69 g, 48.4 mmol). The reaction was heated to reflux under Ar for 6 hrs. Thereaction was cooled to RT and the solid was filtered out. The filtrate was concentrated and purified with CombiFlash in 0-30% EtOAc/p-ether to obtained EC1851 (3.3893 g, yield 84.5%) as a solid. LCMS: [M+H] mlz =331. ‘H NMR (CDC13, ö in ppm): 7.65 (dd, I = 8.5, 2.0 Hz, 1H), 7.54 (d, I = 2.0 Hz, 1H), 6.86 (d, I = 8.50 Hz, 1H), 4.08 (t, I = 6.50 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.44 (t, I = 6.5 Hz, 2H), 1.95 (m, 4H), 1.65 (m, 2H).
84.5%	With potassium carbonate In acetone for 6h; Reflux; Inert atmosphere;

84.5%	With potassium carbonate In acetone for 6h; Reflux; Inert atmosphere;	7 Example 7: Synthesis of FA-PBD inhibitor (compound 25) The phenol compound (2.20 g, 12.1 mmol) was dissolved in acetone (driedthrough a pad of Na2S04, 48.4 mL) and to this solution was added 1,5-dibromopentane (49.4mL, 36.3 mmol) and K2C03 (6.69 g, 48.4 mmol). The reaction was heated to reflux under Ar5 for 6 hrs. The reaction was cooled toRT and the solid was filtered out. The filtrate was10concentrated and purified with CombiFlash in 0-30% EtOAc/p-ether to obtained compound 13(3.3893 g, yield 84.5%) as a solid. LCMS: [M+Ht m/z =331. 1H NMR (CDCh, 8 in ppm): 7.65(dd, J = 8.5, 2.0 Hz, lH), 7.54 (d, J = 2.0 Hz, lH), 6.86 (d, J = 8.50 Hz, lH), 4.08 (t, J = 6.50Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.44 (t, J = 6.5 Hz, 2H), 1.95 (m, 4H), 1.65 (m, 2H).
83%	With potassium carbonate In acetone for 48h; Heating;
83%	With potassium carbonate In acetone Heating;
82%	With potassium carbonate In acetone for 6h; Heating / reflux;	14 Compound 15. To a solution of methyl vanillate (9.109 g, 50 mmol) in acetone (200 mL) were added K2CO3 (27.64 g, 200 mmol) and 1,5-dibromopentane (20.4 mL, 150 mmol). The resulting mixture was heated to reflux. After 6h, TLC showed no starting material left. The mixture was cooled to rt, and the solid was removed by filtration. The filtrate was concentrated. Purification by flash chromatography (silica gel, 8:2 hexanes/EtOAc) afforded 4-(5-bromopentyloxy)-3-methoxy-benzoic acid methyl ester 15 as white solid (13.65 g, 82%): 1H-NMR (300 MHz, CDCl3) δ 1.60 - 1.66 (m, 2H), 1.85 - 1.97 (m, 4H), 3.42 (t, J = 5.0 Hz, 2H), 3.87 (s, 3H), 3.89 (s, 3H), 4.06 (t, J = 5.0 Hz, 2H), 6.85 (d, J = 6.3 Hz, 1 H), 7.52 (d, J = 1.5 Hz, 1 H), 7.63 (dd, J = 6.3, 1.5 Hz, 1H); EIMS m/z 353 and 355 ([M]++Na).
	With potassium carbonate In acetone for 48h; Reflux;

Reference： [1]Current Patent Assignee: PURDUE UNIVERSITY SYSTEM; NOVARTIS AG; Novartis (w/o Sandoz) - WO2016/85967, 2016, A1 Location in patent: Page/Page column 48
[2]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2016/148674, 2016, A1 Location in patent: Page/Page column 100; 115
[3]Vlahov, Iontcho R.; Qi, Longwu; Kleindl, Paul J.; Santhapuram, Hari K.; Felten, Albert; Parham, Garth L.; Wang, Kevin; You, Fei; Vaughn, Jeremy F.; Hahn, Spencer J.; Klein, Hanna F.; Vetzel, Marilynn; Reddy, Joseph A.; Nelson, Melissa; Nicoson, Jeff; Leamon, Christopher P. [Bioconjugate Chemistry, 2017, vol. 28, # 12, p. 2921 - 2931]
[4]Current Patent Assignee: PURDUE UNIVERSITY SYSTEM; NOVARTIS AG; Novartis (w/o Sandoz) - WO2017/205661, 2017, A1 Location in patent: Page/Page column 51; 52
[5]Kamal, Ahmed; Murali Mohan Reddy; Rajasekhar Reddy; Laxman [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 2, p. 385 - 394]
[6]Kamal, Ahmed; Ramesh; Laxman; Ramulu; Srinivas; Neelima; Kondapi, Anand K.; Sreenu; Nagarajaram [Journal of Medicinal Chemistry, 2002, vol. 45, # 21, p. 4679 - 4688]
[7]Current Patent Assignee: SANOFI - EP1813614, 2007, A1 Location in patent: Page/Page column 43
[8]Kamal, Ahmed; Pogula, Praveen Kumar; Khan, Mohammed Naseer Ahmed; Seshadri, Bobburi Naga; Sreekanth, Kokkonda [Medicinal Chemistry, 2013, vol. 9, # 5, p. 651 - 659]

15
[ 3943-74-6 ]
[ 100-39-0 ]
[ 56441-97-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3.0h;	General Procedure 1: Syntheses of 4-chloroquinazolines with alkylamino sidechains: 4-Chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline, 4-Chloro-7-methoxy-6-[3-(4-methyl-piperazin-1-yl)propoxy]quinazoline and 4-Chloro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinazoline.; Step 1. To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100 C. for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
100%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3.0h;	Step 1. To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100C for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
100%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3.0h;	Syntheses of Intermediates. General procedure 1: Syntheses of 4-chloroquinazolines with alkylamino sidechains: 4-Chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline, 4-Chloro-7-methoxy-6-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline and 4-Chloro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinazoline. Step 1. To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100C for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.

100%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3.0h;	Step 1. To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100 C. for 3 h. After cooling to r. t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
99%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3.0h;	Step 1. To a solution of methyl vanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100C for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate (10.8 g, 39.7 mmol, 99 %) as a grey solid which was used without further purification. LC/ESI-MS: m/z = 273 [M+H]+; Rt = 3.82 min.
99%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3.0h;	Step 1. To a solution of methyl vanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100 C. for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate (10.8 g, 39.7 mmol, 99%) as a grey solid which was used without further purification. LC/ESI-MS: m/z=273 [M+H]+; Rt=3.82 min.
98%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 6.0h;Inert atmosphere;	[0506] To a solution of compound Int-1-1 (54.2 g, 0.30 mol) in DMF (200 mL) was added K2CO3 (61.6 g, 0.45 mol) and benzyl bromide (39.0 mL, 0.33 mol) under N2 atmosphere. After stirring for 6 h at 100C., the mixture was cooled to room temperature and diluted with distilled water (100 mL) and EA (200 mL2). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Int-1-2 (79.8 g, 98%). [0507] 1H NMR (400 MHz, CDCl3) delta 7.60 (dd, J=6.4, 2.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.44-7.31 (m, 5H), 6.89 (d, J=8.4 Hz, 1H), 5.22 (s, 2H), 3.94 (s, 3H), 3.88 (s, 3H).
97%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5.0h;	4.1.3 Methyl 4-benzyloxy-3-methoxybenzoate (11) To a solution of methyl vanillate (10) (1.82 g, 10 mmol) in DMF (10 mL) were added K2CO3 (1.38 g, 10 mmol) and benzyl bromide (2.05 g, 12 mmol). The mixture was heated at 60 C for 5 h. After cooling to room temperature, water was added and the product was extracted with CH2Cl2. The organic phase was washed with water and brine. After drying over Na2SO4, the solvent was removed to yield intermediate 11 as a white solid. Yield: 97%, mp: 77-79 C.
95%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2.0h;	Step 2a. Methyl 4-(benzyloxy)-3-methoxybenzoate (Compound 202) To a mixture of compound 201 (18.2 g, 0.1 mol), potassium carbonate (34.55 g, 0.25 mol) in N,N-dimethylformamide was added benzylbromide (14.5 ml, 0.105 mol) dropwise. The reaction was then heated to 60 C. and stirred for 2 hours. The mixture was cooled to room temperature and was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate 500 mL. The organic layer was washed with water and brine (100 mL), dried over MgSO4, filtered and concentrated to give the title compound 202 as a white solid (26 g, 95%): LCMS: 273 [M+1]+.
95%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 6.0h;	A 250 mL, round-bottomed flask with a stirring bar, a solution of 4-hydroxy-3-methoxybenzoic acid (20 g, 118.94 mmol) was added slowly to a solution of methanol (100 mL) and concentrated sulfuric acid (10 mL). After being stirred for 12 h at reflux, saturated solution of sodium bicarbonate was added to adjust the pH to 7. Dichloromethane was added and the mixture was then filtered and the organic phase evaporated on a rotary evaporator and to obtain the compound 2 (20.37 g, 94 %). Compound 2 (20.4 g, 111.98 mmol) was added into a 500 mL, round-bottomed flask with a stirring bar, then benzyl bromide (18 mL), potassium carbonate (22 g, 156.8 mmol), DMF (200 mL) were added. It was stirred for 6 h at 80 C. Then the reaction system was poured into right amount of water, white solid (3) was obtained by filtration (28.97 g, 95 %). Compound 3 (16.54 g, 60.74 mmol) was dissolved in CH3COOH (50 mL) and then added into a 250 mL, round bottomed flask with a stirring bar. Then HNO3 (25 mL) was added into the system slowly to keep the temperature of the reaction above 5 C. The reaction temperature was raised to 50 C and kept for another 2 h. After that the system was poured into water and pale yellow solid (I) was obtained6-8 (18.3 g, 95%, m.p.: 134-135 C).
91%	With potassium carbonate; In acetone; at 45℃; for 3.5h;	To a mechanically stirred solution of methyl vanillate (103.5 g, 0.568 mol) and benzyl bromide (101.36 ml, 0.852 mol) in acetone (800 ml) at room temperature powdered K2CO3 (196.25 g, 1.4 mol) is added The reaction is heated to 45 C for 3.5 hours, cooled and filtered. The filtrate is concentrated in vacuo and the residue dissolved in EtOAc (300 ml) and washed with water (100 ml) three times saturated. NaHCtheta3 (100 ml x 2), and brine. The organic layer is dried over Na2SO4 and concentrated in vacuo to provide 224.72g of a white solid. The solid is then triturated in hexane (300 ml) and filtered to provide methyl 4-(benzyloxy)-3-methoxybenzoate (141.45 g, 91%).
86.6%	With potassium carbonate; In acetone; for 12.0h;Heating / reflux;	D) 4-Benzyloxy-3-methoxy benzoic acid methyl ester; Potassium carbonate (3.45 g; 25 mmol) was added to a solution of 4-hydroxy- 3-methoxy benzoic acid methyl ester (3.6 g; 20 mmol) and benzyl bromide (3.42 g; 20 mmol) in acetone (100 ml). The reaction mixture was refluxed for 12 hrs. After the removal of the solvent under reduced pressure, the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The ethyl acetate layer was washed with water (50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 4.64 g of 4-benzyloxy-3-methoxy benzoic acid methyl ester (Yield = 86.6%)
82.2%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3.0h;	A solution of methyl 4-hydroxy-3-methoxybenzoate 38 (3.0 g, 16.5 mmol) in DMF (100 mL) was added benzyl bromide (4.22 g, 24.7 mmol) and K2CO3 (4.56 g, 32.9 mmol). The reaction mixture was stirred at 100 C. for 3 h. The mixture was concentrated in vacuo and was dissolved in water (50 mL), extracted with EtOAC (30 mL*2), washed with NaCl (30 mL), dried over Na2SO4. It was concentrated and purified by silica chromatography (0-30% EtOAc in petroleum ether) to give methyl 4-(benzyloxy)-3-methoxybenzoate 39 (3.8 g, 13.5 mmol, 82.2% yield) as a white solid. LCMS (5-95AB/1.5 min): RT=0.787 min, [M+H]+ 272.9
	With potassium carbonate; In acetone; for 4.0h;Heating / reflux;	(1) Benzyl bromide (3.59 ml) and potassium carbonate (5.69 g) were added to an acetone (50 ml) solution of methyl 4-hydroxy-3-methoxybenzoate (5.00 g), and heated at reflux for 4 hours. After removing solid matter by filtration and concentrating the filtrate under reduced pressure, the residue was dissolved in ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure, thereby giving 7.47 g of methyl 4-benzyloxy-3-methoxybenzoate.(2) An aqueous 2 M sodium hydroxide solution (13.72 ml) was added to an ethanol (15 ml) solution of the above-obtained 4-benzyloxy compound (7.47 g), and heated at reflux for 2 hours. After evaporating the solvent under reduced pressure, 2M hydrochloric acid was added, and the thus-precipitated crystals were filtered, thereby giving 7.00 g of the desired compound.
	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3.0h;	To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100 C. for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
	With potassium carbonate; In acetone;	Commercially available methyl 4-hydroxy-3-methoxy-benzoate 1 was converted in 5 steps to 4-(3-fluoroanilino)-6-methoxy-7-benzyloxy-quinazolme 15 (35% overall yield).[17,18] The only significant modification involved an improved workup of the nickel chloride hexahydrate-sodium borohydride reduction of the nitro intermediate. Debenzylation with trifluoroacetic acid to give the 7-hydroxy intermediate 16, followed by alkylation with propargyl bromide in acetonitrile, gave 13 in a 65% yield for 2 steps. This method involved an additional step, and the overall yield was greater. In addition, the final 7-hydroxy intermediate 16 could be used to generate other products [19].
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4.0h;	To a solution of methyl vanillate (5.0 g, 27.4 mmol) in DMF (50 ml) was added K2CO3 (4.92 g, 35.6 mmol) and benzyl bromide (3.9 ml, 32.9 mmol). The reaction was stirred at room temperature, under nitrogen, for 4 hours, poured into water (100 ml) and stirred for 30 minutes. The aqueous layer was extracted with EtOAc and the organic washed with saturated aqueous NaHCO3, water, brine, dried (MgSO4) and concentrated. The residue was recrystallised from heptane to provide the title compound as a cream coloured solid (6.35 g). LC/MS purity: 100 %, m/z 566 [M+H]+. 1H NMR (400 MHz, CDCI3) delta: 7.60 (1H, dd, J=8.2, 8.5 Hz), 7.56 (1H, d, J=2.2 Hz), 7.45-7.41 (2H, m), 7.40-7.35 (2H, m), 7.34-7.29 (1 H, m), 6.89 (1 H, d, J=8.5 Hz), 5.22 (2H, s), 3.94 (3H, s), 3.88 (3H, s).
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72.0h;	To a solution of compound 1 (500 g, 2.74 mol) in DMF (2.50 L) was added K2C03 (757.39 g, 5.48 mol) in one portion, following BnBr (702.93 g, 4.11 mol, 488.15 mL) was added to the mixture in portions, the mixture was stirred at 20 C for 72 h. TLC (petroleum ether: ethyl acetate = 5: 1) showed that the reaction was completed. The mixture was quenched by pouring into ice-water (3 L) and the precipitated solid was collected by filtration, the filter cake was triturated with petroleum (500 mL x 2). Filtered and dried under vacuum to give compound 2 (1.00 kg, crude) as a white solid which was used in the next step without any further purification. (0193) 1H NMR: (CDC13 400MHz): delta 7.62-7.59 (dd, J1= 2.0 Hz, J2 = 8.4 Hz, 1H), 7.57-7.56 (d, / = 2.0 Hz, 1H), 7.44-7.26 (m, 5H), 6.91-6.89 (d, J = 8.4 Hz, 1H), 5.21 (s, 2H), 3.94 (s, 3H), 3.88 (s, 3H).

Reference： [1]Patent: US2007/21446,2007,A1 .Location in patent: Page/Page column 14
[2]Patent: EP1785420,2007,A1 .Location in patent: Page/Page column 18
[3]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 6728 - 6737
[4]Patent: EP1746096,2007,A1 .Location in patent: Page/Page column 23
[5]ChemMedChem,2016,vol. 11,p. 2327 - 2338
[6]Patent: US2007/149523,2007,A1 .Location in patent: Page/Page column 13
[7]Patent: EP1674466,2006,A1 .Location in patent: Page/Page column 26
[8]Patent: US2006/142570,2006,A1 .Location in patent: Page/Page column 16
[9]MedChemComm,2017,vol. 8,p. 1069 - 1092
[10]Patent: US2019/367488,2019,A1 .Location in patent: Paragraph 0505-0507
[11]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 6796 - 6805
[12]Patent: US2009/76044,2009,A1 .Location in patent: Page/Page column 26
[13]Asian Journal of Chemistry,2015,vol. 27,p. 2647 - 2650
[14]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5427 - 5436
[15]Patent: WO2008/109613,2008,A1 .Location in patent: Page/Page column 214
[16]Patent: WO2005/113489,2005,A1 .Location in patent: Page/Page column 93
[17]Patent: US2017/95570,2017,A1 .Location in patent: Paragraph 0571; 0572
[18]Synlett,2010,p. 753 - 756
[19]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2989 - 2992
[20]Patent: EP1489077,2004,A1 .Location in patent: Page 40
[21]Patent: US2006/135782,2006,A1 .Location in patent: Page/Page column 23
[22]Patent: WO2010/85747,2010,A1 .Location in patent: Page/Page column 53
[23]Tetrahedron Letters,2011,vol. 52,p. 1053 - 1056
[24]RSC Advances,2016,vol. 6,p. 40238 - 40249
[25]Patent: WO2006/117552,2006,A1 .Location in patent: Page/Page column 63-65
[26]Patent: WO2018/195245,2018,A1 .Location in patent: Page/Page column 26

16
[ 3943-74-6 ]
[ 63558-65-6 ]
4-(5-iodo-pyrimidin-4-yloxy)-3-methoxy-benzoic acid methyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 8235 - 8239

17
[ 3943-74-6 ]
[ 166815-96-9 ]
[ 906565-52-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester; N-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: N-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine In N,N-dimethyl-formamide at 120℃; for 5h;
86%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.0025h; Stage #2: N-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine In N,N-dimethyl-formamide for 3h; Reflux;	1 Synthesis of methyl 4-(N-Boc-4-piperidinylmethoxy)-3-methoxybenzoate Methyl trioxalate (1g, 5.49mmol) was weighted into a 100 mL eggplant-shaped bottle, and anhydrous potassium carbonate (1.52g, 10.98mmol) and about 50 mL of DMF were added, and stirred for about 15 min at room temperature. Tert-butyl tert-butyl-4-((tosyloxy)methyl)piperidine-1-carboxylate (2.75g, 7.41mmol) was added, heated to 95°C and refluxed for 3h. The reaction was confirmed as being completed by TLC. The reaction mixture was extracted with saturated sodium chloride/ethyl acetate and dried over anhydrous sodium sulfate. Most of the solvent was removed in vacuo, and the residual DMF was removed by a diaphragm pump at 70°C for about 20 minutes. The crude product was separated by silica gel-column chromatography (petroleum ether / ethyl acetate = 8: 1) to obtain 2 g of methyl 4-(N-Boc-4-piperidinylmethoxy)-3-methoxybenzoate with a yield of 86%. 1H NMR(400MHz, DMSO): δ 7.57 (d, J = 8.4Hz, 1H), 7.45 (s, 1H), 7.07 (d, J = 8.4Hz, 1H), 3.97 (d, J = 12Hz, 2H), 3.9 (d, J= 6.4Hz, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 2.74 (s, 2H), 1.95-1.85 (m, 1H), 1.75 (d, J = 8.4Hz, 2H), 1.4 (s, 9H), 1.15 (m, 2H).
	With potassium carbonate In N,N-dimethyl-formamide

Reference： [1]Li, Qiannan; Zhang, Tao; Li, Shiliang; Tong, Linjiang; Li, Junyu; Su, Zhicheng; Feng, Fang; Sun, Deheng; Tong, Yi; Wang, Xia; Zhao, Zhenjiang; Zhu, Lili; Ding, Jian; Li, Honglin; Xie, Hua; Xu, Yufang [ACS Medicinal Chemistry Letters, 2019, vol. 10, # 6, p. 869 - 873]
[2]Current Patent Assignee: EAST CHINA UNIVERSITY OF SCIENCE AND TECHNOLOGY; CHINESE ACADEMY OF SCIENCES; Shanghai Institute of Materia Medica (in: CAS) - EP3778586, 2021, A1 Location in patent: Paragraph 0060-0061
[3]Boschelli, Diane H.; Ye, Fei; Wu, Biqi; Wang, Yanong D.; Barrios Sosa, Ana Carolina; Yaczko, Deanna; Powell, Dennis; Golas, Jennifer M.; Lucas, Judy; Boschelli, Frank [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 21, p. 3797 - 3800]

18
[ 3943-74-6 ]
[ 111-29-5 ]
[ 145325-42-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; for 1h; Stage #2: 1 ,5-pentanediol In tetrahydrofuran for 0.5h;	Methyl vanillate (2.18g, 11.98 mmol) and Ph3P (4.71 g, 17.97 mmol) in THF (20 mL) wascooled to 0°C and to which was added DIAD (2.59 mL, 13.18 mmol) dropwise. The reactionwas stirred at 0°C for 1 hr. 1,5-petanediol (0.6 mL, 5.75 mmol) in THF (20 mL) was added over 30 mm. The reaction was stuffed overnight and prESlpitate formed and was collected with filtration. The filtrate was concentrated to form more solid. The solid was combined and triturated with MeOH (5 mL) to give qite clean product EC1624 1.74 g in yield of 70%. ‘HNMR (CDC13, ö in ppm): 7.66(m 2H), 7.62(m, 2H), 6.87(m, 2H), 4.10(m, 4H), 3.89(m, 12H),1.95(m, 4H), 1.69(m, 2H). ‘3C NMR: 166.88, 152.50, 148.86, 132.12, 132.04, 131.88, 128.52,128.42, 123.50, 122.55, 112.35, 111.46, 68.67, 56.03, 51.93, 28.73, 22.52, 21.92.
70%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; for 1h; Stage #2: 1 ,5-pentanediol In tetrahydrofuran	4.1 Step 1: Preparation of Compound 3. Methyl vanillate (2.18g, 11.98 mmol) and Ph3P (4.71 g, 17.97 mmol) in THF (20 mL) was cooled to 0°C and to which was added DIAD (2.59 mL, 13.18 mmol) dropwise. The reaction was stirred at 0°C for 1 hr. 1,5-petanediol (0.6 mL, 5.75 mmol) in THF (20 mL) wasadded over 30 mm. The reaction was stirred overnight and prESlpitate formed and was collected with filtration. The filtrate was concentrated to form more solid. The solid was combined and triturated with MeOH (5 mL) to give qite clean product Compound 3 1.74 g in yield of 70%. ‘H NMR (CDC13, in ppm): 7.66(m 2H), 7.62(m, 2H), 6.87(m, 2H), 4.10(m, 4H), 3.89(m, 12H), 1.95(m, 4H), 1.69(m, 2H). ‘3C NMR: 166.88, 152.50, 148.86, 132.12,132.04, 131.88, 128.52, 128.42, 123.50, 122.55, 112.35, 111.46, 68.67, 56.03, 51.93, 28.73,22.52, 21.92.
52%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃;

Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0℃; for 1h; Stage #2: 1 ,5-pentanediol In tetrahydrofuran at 20℃;

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2016/148674, 2016, A1 Location in patent: Page/Page column 100; 110
[2]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2017/172930, 2017, A1 Location in patent: Page/Page column 109; 110
[3]Current Patent Assignee: ASTRAZENECA PLC - EP1193270, 2002, A2 Location in patent: Page 55, 113-114
[4]Gregson, Stephen J.; Howard, Philip W.; Gullick, Darren R.; Hamaguchi, Anzu; Corcoran, Kathryn E.; Brooks, Natalie A.; Hartley, John A.; Jenkins, Terence C.; Patel, Sejal; Guille, Matthew J.; Thurston, David E. [Journal of Medicinal Chemistry, 2004, vol. 47, # 5, p. 1161 - 1174]

19
[ 3943-74-6 ]
[ 504-63-2 ]
[ 130107-96-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 2h; Inert atmosphere; Stage #2: trimethyleneglycol In tetrahydrofuran at 0 - 20℃; for 120h;	a (a) 1',3'-Bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane (3) (a) 1',3'-Bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane (3) Diisopropyl azodicarboxylate (71.3 mL, 73.2 g, 362 mmol) was added drop-wise over a period of 60 min to an overhead stirred solution of methyl vanillate 2 (60.0 g, 329 mmol) and Ph3P (129.4 g, 494 mmol) in anhydrous THF (800 mL) at 0-5°C (ice/acetone) under a nitrogen atmosphere. The reaction mixture was allowed to stir at 0-5°C for an additional 1 hour after which time a solution of 1 ,3-propanediol (1 1.4 mL, 12.0 g, 158 mmol) in THF (12 mL) was added drop-wise over a period of 20 min. The reaction mixture was allowed to warm to room temperature and stirred for 5 days. The resulting white precipitate 3 was collected by vacuum filtration, washed with THF and dried in a vacuum desiccator to constant weight. Yield = 54.7 g (84% based on 1 ,3-propanediol). Purity satisfactory by LC/MS (3.20 min (ES+) m/z (relative intensity) 427 [M + Na]+ , 10); 1H NMR (400 MHz, CDCI3) δ 7.64 (dd, 2H, J = 1.8, 8.3 Hz), 7.54 (d, 2H, J = 1.8 Hz), 6.93 (d, 2H, J = 8.5 Hz), 4.30 (t, 4H, J = 6.1 Hz), 3.90 (s, 6H), 3.89 (s, 6H), 2.40 (p, 2H, J = 6.0 Hz).
84%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 1h; Inert atmosphere; Stage #2: trimethyleneglycol In tetrahydrofuran at 0 - 20℃; for 120h;	1.B.a (a) 1 3 ‘-Bis[2-methoxy-4- (methoxycarbonyl)phenoxy]propane (3) Diisopropyl azodicarboxylate (71.3 mL, 73.2 g, 362 mmol) was added drop-wise over a period of 60 mm to an overhead stirred solution of methyl vanillate 2 (60.0 g, 329mmol) and Ph3P (129.4 g, 494 mmol) in anhydrous THF (800 mL) at 0-5°C (ice/acetone) under a nitrogen atmosphere. The reaction mixture was allowed to stir at 0-5°C for an additional 1 hour after which time a solution of 1,3-propanediol (11.4 mL, 12.0 g, 158 mmol) in THF (12 mL) was added drop-wise over a period of 20 mm. The reaction mixture was allowed to warm to room temperature and stirred for 5 days. The resultingwhite precipitate 3 was collected by vacuum filtration, washed with THF and dried in a vacuum desiccator to constant weight. Yield = 54.7 g (84% based on 1 ,3-propanediol). Purity satisfactory by LC/MS (3.20 mm (ES+) m/z (relative intensity) 427 ([M + Na], 10); ‘H NMR (400 MHz, CDC13) ö 7.64 (dd, 2H, J= 1.8, 8.3 Hz), 7.54 (d, 2H, J 1.8 Hz), 6.93 (d, 2H, J= 8.5 Hz), 4.30 (t, 4H, J= 6.1 Hz), 3.90 (s, 6H), 3.89 (s, 6H), 2.40 (p,2H,J6.OHz).
84%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 120h; Inert atmosphere;	a (a) 1 ',3'-Bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane (3) Diisopropyl azodicarboxylate (71 .3 ml_, 73.2 g, 362 mmol) was added drop-wise over a period of 60 min to an overhead stirred solution of methyl vanillate 2 (60.0 g, 329 mmol) and Ph3P (129.4 g, 494 mmol) in anhydrous THF (800 ml.) at 0-5°C (ice/acetone) under a nitrogen atmosphere. The reaction mixture was allowed to stir at 0-5°C for an additional 1 hour after which time a solution of 1 ,3-propanediol (1 1.4 ml_, 12.0 g, 158 mmol) in THF (12 ml.) was added drop-wise over a period of 20 min. The reaction mixture was allowed to warm to room temperature and stirred for 5 days. The resulting white precipitate 3 was collected by vacuum filtration, washed with THF and dried in a vacuum desiccator to constant weight. Yield = 54.7 g (84% based on 1 ,3-propanediol). Purity satisfactory by LC/MS (3.20 min (ES+) m/z (relative intensity) 427 ([M + Na]+ , 10); 1 H NMR (400 MHz, CDCIs) δ 7.64 (dd, 2H, J = 1 .8, 8.3 Hz), 7.54 (d, 2H, J = 1.8 Hz), 6.93 (d, 2H, J = 8.5 Hz), 4.30 (t, 4H, J = 6.1 Hz), 3.90 (s, 6H), 3.89 (s, 6H), 2.40 (p, 2H, J = 6.0 Hz).

84%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 2h; Inert atmosphere; Stage #2: trimethyleneglycol In tetrahydrofuran at 20℃; for 120h; Inert atmosphere;	12.a 3’-Bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane (3) Diisopropyl azodicarboxylate (71 .3 mL, 73.2 g, 362 mmol) was added drop-wise over aperiod of 60 mm to an overhead stirred solution of methyl vanillate 2 (60.0 g, 329 mmol) andPh3P (129.4 g, 494 mmol) in anhydrous THF (800 mL) at 0-5°C (ice/acetone) under anitrogen atmosphere. The reaction mixture was allowed to stir at 0-5°C for an additional Ihour afterwhich time a solution of 1,3-propanediol (11.4 mL, 12.0 g, 158 mmol) in THF (12mL) was added drop-wise over a period of 20 mm. The reaction mixture was allowed towarm to room temperature and stirred for 5 days. The resulting white precipitate 3 wascollected by vacuum filtration, washed with THF and dried in a vacuum desiccator to constant weight. Yield = 54.7 g (84% based on 1,3-propanediol). Purity satisfactory by LC/MS (3.20 mm (ES+) m/z (relative intensity) 427 ([M + Na], 10); 1H NMR (400 MHz, CDCI3) 57.64 (dd, 2H, J 1.8, 8.3 Hz), 7.54 (d, 2H, J 1.8 Hz), 6.93 (d, 2H, J 8.5 Hz),4.30 (t, 4H, J= 6.1 Hz), 3.90 (s, 6H), 3.89 (s, 6H), 2.40 (p, 2H, J= 6.0 Hz).
84%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 2h; Inert atmosphere; Stage #2: trimethyleneglycol In tetrahydrofuran at 0 - 20℃; for 120h; Inert atmosphere;	10.a (a) 1',3'-bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane (3) [0461] Diisopropyl azodicarboxylate (71.3 mL, 73.2 g, 362 mmol) was added drop-wise over a period of 60 min to an overhead stirred solution of methyl vanillate 2 (60.0 g, 329 mmol) and Ph3P (129.4 g, 494 mmol) in anhydrous THF (800 mL) at 0-5°C (ice/acetone) under a 163 nitrogen atmosphere. The reaction mixture was allowed to stir at 0-5 °C for an additional 1 hour after which time a solution of 1,3-propanediol (11.4 mL, 12.0 g, 158 mmol) in THF (12 mL) was added drop-wise over a period of 20 min. The reaction mixture was allowed to warm to room temperature and stirred for 5 days. The resulting white precipitate 3 was collected by vacuum filtration, washed with THF and dried in a vacuum desiccator to constant weight. Yield = 54.7 g (84% based on 1,3-propanediol). Purity satisfactory by LC/MS (3.20 min (ES+) m/z (relative intensity) 427 ([ + Na]+', 10); 1H NMR (400 MHz, CDC13) δ 7.64 (dd, 2H, / = 1.8, 8.3 Hz), 7.54 (d, 2H, / = 1.8 Hz), 6.93 (d, 2H, / = 8.5 Hz), 4.30 (t, 4H, / = 6.1 Hz), 3.90 (s, 6H), 3.89 (s, 6H), 2.40 (p, 2H, J = 6.0 Hz).
84%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 2h; Inert atmosphere; Stage #2: trimethyleneglycol In tetrahydrofuran at 0 - 20℃;	Synthesis of Intermediate 12 (a) 1’, 3’-Bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane (3)Diisopropyl azodicarboxylate (71.3 mL, 73.2 g, 362 mmol) was added drop-wise over a period of 60 mm to an overhead stirred solution of methyl vanillate 2 (60.0 g, 329 mmol) and Ph3P (129.4 g, 494 mmol) in anhydrous THF (800 mL) at 0-5°C (ice/acetone) under a nitrogen atmosphere. The reaction mixture was allowed to stir at 0-5°C for an additional 1 hour afterwhich time a solution of 1,3-propanediol (11.4 mL, 12.0 g, 158 mmol) in THF (12 mL) was added drop-wise over a period of 20 mm. The reaction mixture was allowed to warm to room temperature and stirred for 5 days. The resulting white precipitate 3 was collected by vacuum filtration, washed with THF and dried in a vacuum desiccator to constant weight. Yield = 54.7 g (84% based on 1 ,3-propanediol). Purity satisfactory by LC/MS (3.20 mm (ES+) m/z (relative intensity) 427 ([M + Na], 10); 1H NMR (400 MHz, CDCI3) O 7.64 (dd, 2H, J 1.8, 8.3 Hz), 7.54 (d, 2H, J= 1.8 Hz), 6.93 (d, 2H, J= 8.5 Hz), 4.30 (t, 4H, J= 6.1 Hz), 3.90 (5, 6H), 3.89 (5, 6H), 2.40 (p, 2H, J= 6.0 Hz).
84%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 2h; Inert atmosphere; Stage #2: trimethyleneglycol In tetrahydrofuran at 20℃; for 120h; Inert atmosphere;	1.b.i 1',3'-Bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane Diisopropyl azodicarboxylate (71.3 ml_, 73.2 g, 362 mmol) was added drop-wise over a period of 60 min to an overhead stirred solution of methyl vanillate 4 (60 g, 329 mmol) and Ph3P (129.4 g, 494 mmol) in anhydrous THF (800 mL) at 0-5 °C (ice/acetone) under a nitrogen atmosphere. The reaction mixture was allowed to stir at 0-5 °C for an additional 1 h after which time a solution of 1 ,3-propanediol (1 1 .4 mL, 12.0 g, 158 mmol) in THF (12 mL) was added drop-wise over a period of 20 min. The reaction mixture was allowed to warm to room temperature and stirred for 5 days. The resulting white precipitate 3 was collected by vacuum filtration, washed with THF and dried in a vacuum desiccator to constant weight. Yield = 54.68 g (84% based on 1 ,3-propanediol). Analytical Data: Purity satisfactory by LC/MS 3.20 min (ES+) m/z (relative intensity) 427 [M + Na]+ , 10); 1H NMR (400 MHz, CDCIs) δ 57.64 (dd, 2H, J = 1 .8, 8.3 Hz), 7.54 (d, 2H, J = 1 .8 Hz), 6.93 (d, 2H, J = 8.5 Hz), 4.30 (t, 4H, J = 6.1 Hz), 3.90 (s, 6H), 3.89 (s, 6H), 2.40 (p, 2H, J = 6.0 Hz).
84%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 2h; Inert atmosphere; Stage #2: trimethyleneglycol In tetrahydrofuran at 0 - 20℃; for 120h;	1.c.i (i) 1 ',3'-Bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane (5) Diisopropyl azodicarboxylate (71.3 ml_, 73.2 g, 362 mmol) was added drop-wise over a period of 60 min to an overhead stirred solution of methyl vanillate 4 (60 g, 329 mmol) and Ph3P (129.4 g, 494 mmol) in anhydrous THF (800 mL) at 0-5 °C (ice/acetone) under a nitrogen atmosphere. The reaction mixture was allowed to stir at 0-5 °C for an additional 1 h after which time a solution of 1 ,3-propanediol (1 1 .4 mL, 12.0 g, 158 mmol) in THF (12 mL) was added drop-wise over a period of 20 min. The reaction mixture was allowed to warm to room temperature and stirred for 5 days. The resulting white precipitate 3 was collected by vacuum filtration, washed with THF and dried in a vacuum desiccator to constant weight. Yield = 54.68 g (84% based on 1 ,3-propanediol). Analytical Data: Purity satisfactory by LC/MS 3.20 min (ES+) m/z (relative intensity) 427 [M + Na]+ , 10); 1H NMR (400 MHz, CDCIs) δ 57.64 (dd, 2H, J = 1 .8, 8.3 Hz), 7.54 (d, 2H, J = 1 .8 Hz), 6.93 (d, 2H, J = 8.5 Hz), 4.30 (t, 4H, J = 6.1 Hz), 3.90 (s, 6H), 3.89 (s, 6H), 2.40 (p, 2H, J = 6.0 Hz).
84%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With (Z)-N-[(propan-2-yloxy)carbonyl]imino}(propan-2-yloxy)formamide; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 1h; Inert atmosphere; Stage #2: trimethyleneglycol In tetrahydrofuran at 20℃; for 120h;	1b.i (I) 1 ‘,3’-Bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane (5) Diisopropyl azodicarboxylate (71.3 mL, 73.2 g, 362 mmol) was added drop-wise over aperiod of 60 mm to an overhead stirred solution of methyl vanillate 4 (60 g, 329 mmol) andPh3P (129.4 g, 494 mmol) in anhydrous THF (800 mL) at 0-5 00 (ice/acetone) under anitrogen atmosphere. The reaction mixture was allowed to stir at 05 00 for an additional 1 h after which time a solution of 1,3-propanediol (11.4 mL, 12.0 g, 158 mmol) in THF (12mL) was added drop-wise over a period of 20 mm. The reaction mixture was allowed to warm to room temperature and stirred for 5 days. The resulting white precipitate 3 was collected by vacuum filtration, washed with THF and dried in a vacuum desiccator toconstant weight. Yield = 54.68 g (84% based on 1,3-propanediol). Analytical Data: Puritysatisfactory by LC/MS 3.20 mm (ES+) m/z (relative intensity) 427 ([M + Na], 10); 1H NMR(400 MHz, ODd3) 6 67.64 (dd, 2H, J = 1.8, 8.3 Hz), 7.54 (d, 2H, J = 1.8 Hz), 6.93 (d, 2H, J= 8.5 Hz), 4.30 (t, 4H, J = 6.1 Hz), 3.90 (s, 6H), 3.89 (s, 6H), 2.40 (p, 2H, J = 6.0 Hz).
84%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 2h; Inert atmosphere; Stage #2: trimethyleneglycol In tetrahydrofuran at 20℃; for 120h;	b.i (i) 1 ‘,3’-Bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane (15) Diisopropyl azodicarboxylate (71.3 mL, 73.2 g, 362 mmol) was added drop-wise over aperiod of 60 mm to an overhead stirred solution of methyl vanillate 14 (60 g, 329 mmol) andPh3P (129.4 g, 494 mmol) in anhydrous THF (800 mL) at 0-5 °C (ice/acetone) under anitrogen atmosphere. The reaction mixture was allowed to stir at 0-5 °C for an additional 1h after which time a solution of 1,3-propanediol (11.4 mL, 12.0 g, 158 mmol) in THF (12mL) was added drop-wise over a period of 20 mm. The reaction mixture was allowed towarm to room temperature and stirred for 5 days. The resulting white precipitate 13 was collected by vacuum filtration, washed with THF and dried in a vacuum desiccator to constant weight. Yield = 54.68 g (84% based on 1 ,3-propanediol). Analytical Data: Purity satisfactory by LC/MS 3.20 mm (ES+) m/z (relative intensity) 427 ([M + Na], 10); 1H NMR (400 MHz, ODd3) 6 67.64 (dd, 2H, J = 1.8, 8.3 Hz), 7.54 (d, 2H, J = 1.8 Hz), 6.93 (d, 2H, J = 8.5 Hz), 4.30 (t, 4H, J = 6.1 Hz), 3.90 (s, 6H), 3.89 (s, 6H), 2.40 (p, 2H, J = 6.0 Hz).
83%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran	21 Preparation of bis-ester (7) Refering to FIGs.33A and 33B, Phenol 6 (80 g, 0.4 mol), PPh3 (172.9 g, 0.66 mol) and 1,3-propanediol (15.2 mL, 0.21 mol) were dissolved in anhydrous THF (1.6 L) and DEAD (79.6 mL, 0.48 mol) was added dropwise. Reaction mixture was stirred overnight. White precipitate was filtered off, washed with methanol and dried thoroughly to afford 7 (70.9 g, 83% yield).1H NMR (500 MHz, DMSO-d6) : 7.62 (d, J 8.2 Hz, 2H), 7.48 (s, 2H), 7.12 (d, J 8.2 Hz, 2H), 4.22 (m, 4H), 3.82 (s, 6H), 2.15 (m, 2H). LC/MS: retention time 3.11 min. (ESI) C21H24O8 calculated for [M+H] + 405; found 405.
	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0℃; for 1h; Stage #2: trimethyleneglycol In tetrahydrofuran at 20℃;
54.7 g	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 2h; Inert atmosphere; Stage #2: trimethyleneglycol In tetrahydrofuran at 20℃; for 120h; Inert atmosphere;	3’-Bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane (3) Diisopropyl azodicarboxylate (71 .3 mL, 73.2 g, 362 mmol) was added drop-wise over aperiod of 60 mm to an overhead stirred solution of methyl vanillate 2 (60.0 g, 329 mmol) andPh3P (129.4 g, 494 mmol) in anhydrous THF (800 mL) at 0-5°C (ice/acetone) under anitrogen atmosphere. The reaction mixture was allowed to stir at 0-5°C for an additional Ihour afterwhich time a solution of 1,3-propanediol (11.4 mL, 12.0 g, 158 mmol) in THF (12mL) was added drop-wise over a period of 20 mm. The reaction mixture was allowed towarm to room temperature and stirred for 5 days. The resulting white precipitate 3 wascollected by vacuum filtration, washed with THF and dried in a vacuum desiccator to constant weight. Yield = 54.7 g (84% based on 1,3-propanediol). Purity satisfactory by LC/MS (3.20 mm (ES+) m/z (relative intensity) 427 ([M + Na], 10); 1H NMR (400 MHz, CDCI3) 57.64 (dd, 2H, J 1.8, 8.3 Hz), 7.54 (d, 2H, J 1.8 Hz), 6.93 (d, 2H, J 8.5 Hz),4.30 (t, 4H, J= 6.1 Hz), 3.90 (s, 6H), 3.89 (s, 6H), 2.40 (p, 2H, J= 6.0 Hz).
54.7 g	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 2h; Inert atmosphere; Stage #2: trimethyleneglycol In tetrahydrofuran at 20℃; for 120h; Inert atmosphere;	12.a 3’-Bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane (3) Diisopropyl azodicarboxylate (71 .3 mL, 73.2 g, 362 mmol) was added drop-wise over aperiod of 60 mm to an overhead stirred solution of methyl vanillate 2 (60.0 g, 329 mmol) andPh3P (129.4 g, 494 mmol) in anhydrous THF (800 mL) at 0-5°C (ice/acetone) under anitrogen atmosphere. The reaction mixture was allowed to stir at 0-5°C for an additional Ihour afterwhich time a solution of 1,3-propanediol (11.4 mL, 12.0 g, 158 mmol) in THF (12mL) was added drop-wise over a period of 20 mm. The reaction mixture was allowed towarm to room temperature and stirred for 5 days. The resulting white precipitate 3 wascollected by vacuum filtration, washed with THF and dried in a vacuum desiccator to constant weight. Yield = 54.7 g (84% based on 1,3-propanediol). Purity satisfactory by LC/MS (3.20 mm (ES+) m/z (relative intensity) 427 ([M + Na], 10); 1H NMR (400 MHz, CDCI3) 57.64 (dd, 2H, J 1.8, 8.3 Hz), 7.54 (d, 2H, J 1.8 Hz), 6.93 (d, 2H, J 8.5 Hz),4.30 (t, 4H, J= 6.1 Hz), 3.90 (s, 6H), 3.89 (s, 6H), 2.40 (p, 2H, J= 6.0 Hz).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2014/57073, 2014, A1 Location in patent: Page/Page column 111
[2]Current Patent Assignee: ASTRAZENECA PLC; ABBVIE INC - WO2014/130879, 2014, A2 Location in patent: Page/Page column 111
[3]Current Patent Assignee: ASTRAZENECA PLC - WO2015/52321, 2015, A1 Location in patent: Page/Page column 109
[4]Current Patent Assignee: ASTRAZENECA PLC - WO2015/52535, 2015, A1 Location in patent: Page/Page column 40; 41
[5]Current Patent Assignee: ASTRAZENECA PLC - WO2015/155345, 2015, A1 Location in patent: Paragraph 0461
[6]Current Patent Assignee: CANCER RESEARCH UK - WO2015/159076, 2015, A1 Location in patent: Page/Page column 150
[7]Current Patent Assignee: ASTRAZENECA PLC - WO2017/137553, 2017, A1 Location in patent: Page/Page column 99
[8]Current Patent Assignee: ASTRAZENECA PLC - WO2017/137555, 2017, A1 Location in patent: Page/Page column 97-98
[9]Current Patent Assignee: ASTRAZENECA PLC; AUVEN THERAPEUTICS HOLDING LP - WO2017/137556, 2017, A1 Location in patent: Page/Page column 37
[10]Current Patent Assignee: ASTRAZENECA PLC - WO2018/69490, 2018, A1 Location in patent: Page/Page column 139; 140
[11]Current Patent Assignee: CELLERANT THERAPEUTICS INC - WO2018/53552, 2018, A2 Location in patent: Paragraph 000547-000550
[12]Gregson, Stephen J.; Howard, Philip W.; Gullick, Darren R.; Hamaguchi, Anzu; Corcoran, Kathryn E.; Brooks, Natalie A.; Hartley, John A.; Jenkins, Terence C.; Patel, Sejal; Guille, Matthew J.; Thurston, David E. [Journal of Medicinal Chemistry, 2004, vol. 47, # 5, p. 1161 - 1174]
[13]Current Patent Assignee: ASTRAZENECA PLC - WO2015/52533, 2015, A1 Location in patent: Page/Page column 41 Current Patent Assignee: ASTRAZENECA PLC - WO2015/52534, 2015, A1 Location in patent: Page/Page column 41
[14]Current Patent Assignee: ASTRAZENECA PLC - WO2015/52532, 2015, A1 Location in patent: Page/Page column 43

20
[ 56441-97-5 ]
[ 3943-74-6 ]

Reference： [1]Synlett,2004,p. 522 - 524

21
[ 3943-74-6 ]
[ 17102-64-6 ]
methyl (2aRS,5SR,5aRS,8aRS,8bRS)-8a-methoxy-5-methyl-8-oxo-2a,5,5a,8,8a,8b-hexahydro-2H-benzo[cd]isobenzofuran-5a-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester; Sorbyl alcohol With bis-[(trifluoroacetoxy)iodo]benzene In tetrahydrofuran at 20℃; for 6h; Stage #2: With trimethyl orthoformate In 1,3,5-trimethyl-benzene at 200℃; for 8h;

Reference： [1]Hsu, Po-Yi; Peddinti, Rama Krishna; Chittimalla, Santhosh Kumar; Liao, Chun-Chen [Journal of Organic Chemistry, 2005, vol. 70, # 23, p. 9156 - 9167]

22
[ 3943-74-6 ]
[ 627-42-9 ]
[ 870959-66-3 ]

Reference： [1]Journal of Organic Chemistry,2006,vol. 71,p. 3599 - 3607

23
[ 3943-74-6 ]
[ 106-93-4 ]
[ 871813-86-4 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate In acetone for 48h; Heating;
61%	With potassium carbonate In N,N-dimethyl-formamide at 45℃; for 2h;	102.a Example 102 step a (Method O) A solution of methyl 4-hydroxy-3-methoxybenzoate (3 g, 16.47 mmol), K2CO3(6.8 g, 49.57 mmol), 1,2-dibromoethane (15.5 g, 82.34 mmol) in DMF (30 mL) was stirred for 2 hours at 45C. The resulting solution was quenched with water and extracted with EtOAc. The combined organics were dried, concentrated and purified by reverse phase C18 column chromatography (MeCN/H2O) to afford desired product as a light-yellow solid (3 g, 61%).
32%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 6h;

Reference： [1]Kamal, Ahmed; Murali Mohan Reddy; Rajasekhar Reddy; Laxman [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 2, p. 385 - 394]
[2]Current Patent Assignee: ENANTA PHARMACEUTICALS INC - WO2021/66922, 2021, A1 Location in patent: Page/Page column 101; 102
[3]Hu, Lan; Zhao, Yan [Organic and Biomolecular Chemistry, 2018, vol. 16, # 31, p. 5580 - 5584]

24
[ 3943-74-6 ]
[ 109-70-6 ]
[ 111627-40-8 ]

Yield	Reaction Conditions	Operation in experiment
99.5%	With potassium carbonate; sodium chloride In propan-2-one at 55 - 60℃; for 5h; Heating / reflux;	II-15 [Example II-15] Preparation of methyl 4-(3-chloropropoxy)-3-methoxybenzoate In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt.%), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt.%), 1.02 g (17.5 mmol) of sodium chloride, and 10 mL of acetone. The resulting mixture was refluxed under stirring at 55-60°C in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.41 g (reaction yield: 99.5%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
99.3%	With potassium carbonate In propan-2-one; acetonitrile at 75 - 79℃; for 5h; Heating / reflux;	II-13 [Example II-13] Preparation of methyl 4-(3-chloropropoxy)-3-methoxybenzoate In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt.%), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt.%), 5 mL of acetone, and 5 mL of acetonitrile. The resulting mixture was refluxed under stirring at 79-75°C in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.41 g (reaction yield: 99.3%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
98.2%	With potassium chloride; potassium carbonate In propan-2-one at 55 - 60℃; for 10h; Heating / reflux;	II-14 [Example II-14] Preparation of methyl 4-(3-chloropropoxy)-3-methoxybenzoate In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt.%), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt.%), 1.02 g (13.7 mmol) of potassium chloride, and 10 mL of acetone. The resulting mixture was refluxed under stirring at 55-60°C in an argon gas atmosphere for 10 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.39 g (reaction yield: 98.2%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.

97%	With potassium carbonate In acetonitrile at 80 - 85℃; for 5 - 8h; Heating / reflux;	II-3; II-7; II-8; III-3 [Example II-3] Preparation of methyl 4-(3-chloropropoxy)-3-methoxybenzoate In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 1.15 g (7.14 mmol) of 3-bromo-1-chloropropane (purity: 98 wt.%), 0.85 g (6.04 mmol) of potassium carbonate (purity: 98 wt.%), and 30 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85°C for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. To the concentrate was added n-heptane, to precipitate a crystalline product. The crystalline product was collected by filtration and dried under reduced pressure, to obtain 1.34 g (isolated yield: 97.8%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate as a white crystalline product. Methyl 4-(3-chloropropoxy)-3-methoxybenzoate had the following characteristics. m.p.: 98-99°C 1H-NMR (CDCl3, δ (ppm)): 2.27-2.35 (2H, m), 3.75-3.79 (2H, m), 3.85 (3H, s), 3.91 (3H, s), 4.22 (2H, t, J=6.0Hz), 6.95 (1H, d, J=6.0Hz), 7.57 (1H, s), 7.67 (1H, d, J=6.0Hz); [Example II-7] Preparation of methyl 4-(3-chloropropoxy)-3-methoxybenzoate In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt.%), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt.%), and 10 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85°C in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.38 g (reaction yield: 97.0%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.; [Example II-8] Preparation of methyl 4-(3-chloropropoxy)-3-methoxybenzoate In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 3.17 g (19.8 mmol) of 3-bromo-1-chloropropane (purity: 98 wt.%), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt.%), and 10 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85°C in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.41 g (reaction yield: 98.9%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.; [Reference Example III-3] Preparation of methyl 4-(3-chloropropoxy)-3-methoxybenzoate In a 100 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 10.2 g (54.9 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 11.2 g (71.4 mmol) of 3-bromo-1-chloropropane, 8.3 g (60.4 mmol) of potassium carbonate, and 30 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85°C for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. To the concentrate was added n-heptane, to precipitate a crystalline product. The crystalline product was collected by filtration and dried under reduced pressure, to obtain 14.3 g (isolated yield: 97.8%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate as a white crystalline product. Methyl 4-(3-chloropropoxy)-3-methoxybenzoate had the following characteristics. m.p.: 98-99°C 1H-NMR (CDCl3, δ (ppm)): 2.27-2.35 (2H, m), 3.75-3.79 (2H, m), 3.85 (3H, s), 3.91 (3H, s), 4.22 (2H, t, J=6.0Hz), 6.95 (1H, d, J=6.0Hz), 7.57 (1H, s); 7.67 (1H, d, J=6.0Hz)
97.2%	With potassium carbonate In propan-2-one at 55 - 60℃; for 5h; Heating / reflux;	II-12 [Example II-12] Preparation of methyl 4-(3-chloropropoxy)-3-methoxybenzoate In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt.%), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt.%), and 10 mL of acetone. The resulting mixture was refulxed under stirring at 55-60°C in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.38 g (reaction yield: 97.2%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
97.9%	With potassium carbonate In N,N-dimethyl-formamide at 50℃;	3 Compound 1 To a solution of methyl vanillate (150 g, 0.82 mol) in dry N,N-dimethylformamide (DMF) (1200 mL) was added 1-bromo-3-chloropropane (259.6 g, 1.65 mol) and K2CO3 (341 g, 2.47 mol). The mixture was stirred at 50° C. overnight. The reaction mixture was poured into water (300 mL) filtered, the solid was washed with water (500 mL) then hexane (250 mL), and dried to give 209 g (yield=97.9%) of 1 as a white solid
95.4%	With potassium carbonate In butanone at 77 - 82℃; for 2h; Heating / reflux;	II-9 [Example II-9] Preparation of methyl 4-(3-chloropropoxy)-3-methoxybenzoate In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt.%), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt.%), and 10 mL of methyl ethyl ketone. The resulting mixture was refluxed under stirring at 77-82°C in an argon gas atmosphere for 2 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.36 g (reaction yield: 95.4%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
94%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h;
94%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h;	5.1.6. Methyl 4-(3-chloropropoxy)-3-methoxybenzoate (12) A mixture of methyl 4-hydroxy-3-methoxybenzoate (91 g,0.5 mol), 1-bromo-3-chloropropane (94.5 g, 0.6 mol), and K2CO3 (103.5 g, 0.75 mol) in DMF (300 mL) was heated at 70 °C for 2 h. The mixture was cooled to room temperature, then poured slowly into ice water (4 L) while stirring constantly. The precipitate obtained was filtered, washed with cold water and dried to yield 12 (121 g, 94%) as white powder, mp: 99-100 °C ([47], mp: 98-99 °C).
93%	With potassium carbonate for 2h; Microwave irradiation; Reflux;
92.85%	With potassium carbonate In propan-2-one at 70℃; for 10h;
91%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 1h; Green chemistry;
91%	With potassium carbonate In N,N-dimethyl-formamide Heating;
91%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 1h;	Methyl 4-(3-Chloropropoxy)-3-methoxybenzoate (14) 1-Bromo-3-chloropropane (404 g, 2.57 mol) was added dropwise to a stirred mixture ofmethyl vanillate (13, 360 g, 1.98 mol) and potassium carbonate (415 g, 3.0 mol) in DMF(1.8 kg) at 60 °C. The reaction mixture was stirred at this temperature for another 1 h then cooled to room temperature, and poured slowly into ice-water (8 kg) while stirring constantly. The solid formed was collected, washed with cold water (0.8 kg £ 2), and dried at 60 °C for 4 h. The white product was digested by stirring and heating with 2:1 hexane/EtOAc (1 kg) at 60 °C for 2 h then cooled to room temperature. The resulting solid was collected and washed with 1:1 hexane/EtOAc (300 g £ 2), dried at 50 °C for4 h to afford 14 (466 g, 91%) as a white solid, mp 106.5 - 107 °C. 1H NMR (CDCl3): d2.292.35 (m, 2 H, ClCH2CH2CH2O), 3.78 (t, J D 6.4 Hz, 2 H, ClCH2CH2CH2O), 3.90(s, 3 H, OCH3), 3.91 (s, 3 H, OCH3), 4.23 (t, J D 6.0 Hz, 2 H, ClCH2CH2CH2O), 6.91 (d,J D 8.4 Hz, 1 H, ArH), 7.55 (d, J D 2.0 Hz, 1 H, ArH), 7.67 (dd, J D 2.0, 8.4 Hz, 1 H,ArH). MS-ESI (m/z): 281.0 (MCNa)C.Anal. Calcd for C12H15ClO4: C, 55.71; H, 5.84; Found: C, 55.93; H, 5.80.
90%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 1h;
88%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 15h;	27.27A.1 Example 27; Preparation of l-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3- morpholinopropoxy)quinazolin-4-yloxy')phenyl)urea; [00747] Example 27 A Step 1 : To a solution of 4-(3-chloro-propoxy)-3- methoxy-benzoic acid methyl ester (12 g, 65.8 mmol) and potassium carbonate (36.3 g, 263 mmol) in DMF (100 mL) was added l-bromo-3-chloro-propane (32.5 mL, 329 mmol). The mixture was stirred at ambient temperature for 15 hours. Completion of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and the ethyl acetate layer was washed with water and brine. The organic layer was dried (Na2SO4) and concentrated to afford 4-(3-chloropropoxy)-3-methoxy- benzoic acid methyl ester (15 g, 88%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.65 (d, 1H), 7.52 (s, 1H), 6.88 (d, 1H), 4.20 (t, 2H), 3.90 (s, 6H), 3.75 (t, 2H), 2.30 (q, 2H).
86.5%	With potassium carbonate In methanol at 62 - 67℃; for 10h;	II-10 [Example II-10] Preparation of methyl 4-(3-chloropropoxy)-3-methoxybenzoate In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt.%), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt.%), and 30 mL of methanol. The resulting mixture was under stirring at 62-67°C in an argon gas atmosphere for 10 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.23 g (reaction yield: 86.5%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
85%	With Cs₂CO₃ In propan-2-one at 20℃; for 72h;
85%	With Cs₂CO₃ In propan-2-one at 20℃; for 72h;	10.1 Example 10; N-(3-{4-[3-chloro-4-(1-ethyl-4,5-dimethyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-3-cyano-6-methoxy-quinolin-7-yloxy}-propyl)-benzenesulfonamide; Step 1. Methyl 4-(3-chloropropoxy)-3-methoxybenzoate; To a stirred solution of methyl vanillate (2.00 g, 11.0 mmol) in acetone (50 mL) was added Cs2CO3 (3.94 g, 12.1 mmol) followed by 3-chloro-1-propyl bromide (2.16 mL, 22.0 mmol). The solution was stirred at room temperature for 3 days. The solution was then diluted with H2O (50 mL) and extracted with Et2O (2×200 mL). The organic layer was washed with brine, dried over MgSO4, filtered and then concentrated to afford the product (0.290 g, 85%) as a solid; 1H NMR (DMSO-d6) δ 2.10-2.20 (m, 2H), 3.74 (t, J=6.5 Hz, 2H), 3.77 (s, 6H), 4.12 (t, J=6.0 Hz, 2H), 7.06 (d, J=8.5 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.53 (dd, J=2.1, 8.5 Hz, 1H); mass spectrum [(+) ESI], m/z 259 (M+H).
85.2%	With potassium carbonate In acetonitrile at 50℃; for 40h;	6.2 (2) Place 31.0g (0.17mol) methyl 4-hydroxy-3-methoxybenzoate in a 1L three-necked flask, add 300mL CH3CN, 54.55g (0.26mol) 1-bromo-3-chloropropane and 70.49g (0.51mol) potassium carbonate was heated to 50°C for 40h, the reaction was stopped, filtered with suction, distilled under reduced pressure, the residue was dissolved in 300 mL of DCM, washed twice with 200 mL of water, and dried over anhydrous sodium sulfate for 12 h. Suction filtration, the obtained filtrate was evaporated to dryness under reduced pressure, and the obtained light red semi-solid (45.3 g) was recrystallized with 135 mL of acetone to obtain methyl 4-(3-chloropropoxy)-3-methoxybenzoate (white block crystal, 37.33g, yield 85.2%), the recrystallization filtrate was recovered and applied mechanically.
80.7%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 12h;	Synthesis of Methyl 3-Methoxy-4- (3-chloropropoxy) benzoate (2) A solution of 4.22 g (23 mmol) of methyl 4-hydroxy-3-methoxybenzoate (1), 5.06 g (32.4 mmol) of 1-bromo-3-chloropropane was dissolved in 20 mL of DMF,10.24 g (74.2 mmol) of potassium carbonate was added,100 & lt; 0 & gt; C for 12 h.After the reaction solution was cooled to room temperature, the reaction solution was poured into 500 mL of ice water,Stir for 30min. Filtration gave 5.85 g of an off-white solid.Ethyl acetate to give 4.85 g of the desired product as a white product,Yield 80.7%,
79.13%	With potassium carbonate In propan-2-one; acetonitrile at 70℃; for 10h;	Synthesisof methyl 4-(3-chloropropoxy)-3-methoxybenzoate(3) A stirred solution ofcompound 2 (6.30 g, 34.64 mmol) andanhydrous potassium carbonate (9.66 g, 0.07 mmol) in CH3CN (50 ml)was added dropwise with an acetone solution of 1-bromo-3-chloropropane (10.85g, 0.07 mmol). Upon completion of the addition, the reaction mixture wasstirred at 70 °C for 10 h. The solid was removed by filtration, and thefiltrate was concentrated, obtaining an oily residue that was purified by flashchromatography. Elution with CH2Cl2/petroleum ether (1:4)afforded 3 as a white solid (7.09 g, 79.13%), mp: 100.6-102.1°C.
74%	With potassium carbonate In propan-2-one at 65℃; for 12h;	1.2 Step 2: Put 1 g (5.5 mmol) of compound a into a 50 mL round bottom flask and dissolve it with acetone.Then 1.5 g of anhydrous potassium carbonate and 1.2 g (8.7 mml) of 1-bromo-3-chloropropane are added and the mixture is heated to reflux at 65[deg.] C. for 12 hours. After completion of the reaction, the reaction mixture was filtered while hot, the organic solvent was evaporated to dryness and purified to obtain 0.74 g of compound b in a yield of 74%. Multiple reactions accumulate the mass of this compound.
59.8%	With potassium carbonate In N,N-dimethyl-formamide at 52 - 57℃; for 5h; Heating / reflux;	II-11 [Example II-11] Preparation of methyl 4-(3-chloropropoxy)-3-methoxybenzoate In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt.%), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt.%), and 10 mL of N,N-dimethylformamide. The resulting mixture was refluxed under stirring at 52-57°C in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 0.85 g (reaction yield: 59.8%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
	With N,N,N-tributyl-1-butanaminium iodide; potassium carbonate In propan-2-one for 2h; Heating;
137.8 g (97%)	With potassium carbonate In propan-2-one	31 4-(3-Chloropropoxy)-3-methoxybenzoic acid methyl ester PREPARATION 31 4-(3-Chloropropoxy)-3-methoxybenzoic acid methyl ester A mixture of 100 g (0.549 mole) of methylvanillate, 172.8 g (1.1 mole) of 1-bromo-3-chloropropane and 228 g (1.65 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered, and the filtrate concentrated to give a white solid as residue. The solid was triturated with petroleum ether, collected by filtration, and dried to yield 137.8 g (97%) of white powder which was recrystallized from isopropyl alcohol, m.p. 104°-105° C. Analysis: Calculated for C12 H15 ClO4: C, 55.71; H, 5.84. Found: C, 55.87; H, 5.94.
137.8 g (97%)	With potassium carbonate In propan-2-one	4 4-(3-Chloropropoxy)-3-methoxybenzoic acid methyl ester PREPARATION 4 4-(3-Chloropropoxy)-3-methoxybenzoic acid methyl ester A mixture of 100 g (0.549 mole) of methyl vanillate, 172.8 g (1.1 mole) of 1-bromo-3-chloropropane and 228 g (1.65 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered, and the filtrate concentrated to give a white solid as residue. The solid was triturated with petroleum ether, collected by filtration, and dried to yield 137.8 g (97%) of the title compound as a white powder, mp 104°-105° C. (2-propanol). Analysis: Calculated for C12 H15 ClO4: C, 55.71; H, 5.84. Found: C, 55.87; H, 5.94.
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h;
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h;
	With potassium carbonate In N,N-dimethyl-formamide Heating;	4.1.2.1 4.1.2.1 Synthesis of methyl 4-(3-chloropropoxy)-3-methoxybenzoate (2) To a stirred solution of methyl vanillate 1 (10.0g, 0.055mol) in DMF (300mL) were added K2CO3 (10.4g, 0.066mol) and 1-bromo-3-chloropropane (11.4g, 0.082mol). The mixture was heated at 60°C for 5h. After the reaction mixture was cooled to room temperature and poured into ice water (400mL). After being stirred for 1h, the respective product was filtered off, washed with ice water and dried to obtain the crude intermediate 2 as a white solid, which was used without purification. Yield: 97%, m.p.: 98-100°C.
	With potassium carbonate In N,N-dimethyl-formamide at 70℃;
130.8 g	With potassium carbonate In N,N-dimethyl-formamide	4.1 Step 1. Synthesis of methyl 3-methoxy-4-(3-chloropropoxy)benzoate (II-1) Methyl 3-methoxy-4-hydroxybenzoate (100.0 g, 0.55 mol) was dissolved in 600 mL of DMF at room temperature.Add anhydrous potassium carbonate (151.6 g, 1.10 mol),After stirring for 15 min, 1,3-bromochloropropane was added and the addition was completed.Stir at room temperature for 3 h. Pour the reaction solution into 2 L of ice water and filter by suction.Dry to give a white solid 130.8g
	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃;

Reference： [1]Current Patent Assignee: UBE INDUSTRIES LIMITED - EP1477481, 2004, A1 Location in patent: Page 23
[2]Current Patent Assignee: UBE INDUSTRIES LIMITED - EP1477481, 2004, A1 Location in patent: Page 23
[3]Current Patent Assignee: UBE INDUSTRIES LIMITED - EP1477481, 2004, A1 Location in patent: Page 23
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[13]Wang, Han; Zhu, Chunping; Zhu, Guoqing; Tian, Xin; Shen, Yongjia; Mao, Yongjun [Heterocycles, 2014, vol. 89, # 12, p. 2806 - 2813]
[14]Mao, Yongjun; Tian, Xin; Jiang, Luobin; Zhu, Guoqing; Wang, Han [Organic Preparations and Procedures International, 2015, vol. 47, # 3, p. 207 - 213]
[15]Location in patent: experimental part Yin, Xiao Jia; Xu, Guan Hong; Sun, Xu; Peng, Yan; Ji, Xing; Jiang, Ke; Li, Fei [Molecules, 2010, vol. 15, # 6, p. 4261 - 4266]
[16]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - WO2009/117080, 2009, A1 Location in patent: Page/Page column 188-188
[17]Current Patent Assignee: UBE INDUSTRIES LIMITED - EP1477481, 2004, A1 Location in patent: Page 22
[18]Location in patent: experimental part Miller, Lori M.; Mayer, Scott C.; Berger, Dan M.; Boschelli, Diane H.; Boschelli, Frank; Di, Li; Du, Xuemei; Dutia, Minu; Floyd, Middleton B.; Johnson, Mark; Kenny, Cynthia Hess; Krishnamurthy, Girija; Moy, Franklin; Petusky, Susan; Tkach, Diane; Torres, Nancy; Wu, Biqi; Xu, Weixin [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 1, p. 62 - 66]
[19]Current Patent Assignee: PFIZER INC - US2009/264427, 2009, A1 Location in patent: Page/Page column 15
[20]Current Patent Assignee: UNIV SHENYANG PHARMACEUTICAL - CN114409636, 2022, A Location in patent: Paragraph 0125; 0127
[21]Current Patent Assignee: XUZHOU MEDICAL COLLEGE - CN106083836, 2016, A Location in patent: Paragraph 0088; 0089; 0090
[22]Zhu, Jun; Wang, Li-Ning; Cai, Rong; Geng, Shang-Qi; Dong, Ya-Fei; Liu, Yu-Ming [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 11, p. 1325 - 1329]
[23]Current Patent Assignee: TIANJIN UNIVERSITY OF TECHNOLOGY - CN107721923, 2018, A Location in patent: Paragraph 0025; 0028
[24]Current Patent Assignee: UBE INDUSTRIES LIMITED - EP1477481, 2004, A1 Location in patent: Page 23
[25]Knesl, Petr; Roeseling, Dirk; Jordis, Ulrich [Molecules, 2006, vol. 11, # 4, p. 286 - 297]
[26]Current Patent Assignee: PFIZER INC - US4950674, 1990, A
[27]Current Patent Assignee: PFIZER INC - US5070087, 1991, A
[28]Location in patent: experimental part Wu, Xiaoqing; Li, Mingdong; Qu, Yang; Tang, Wenhua; Zheng, Youguang; Lian, Jiqin; Ji, Min; Xu, Liang [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 11, p. 3812 - 3822]
[29]Location in patent: experimental part Wu, Xiaoqing; Li, Mingdong; Tang, Wenhua; Zheng, Youguang; Lian, Jiqin; Xu, Liang; Ji, Min [Chemical Biology and Drug Design, 2011, vol. 78, # 6, p. 932 - 940]
[30]Chang, Jin; Ren, Hongyu; Zhao, Mingxia; Chong, Yan; Zhao, Wenwen; He, Yong; Zhao, Yunling; Zhang, Huabei; Qi, Chuanmin [European Journal of Medicinal Chemistry, 2017, vol. 138, p. 669 - 688]
[31]Zheng, You-Guang; Wu, Xiao-Qing; Su, Jun; Jiang, Ping; Xu, Liang; Gao, Jian; Cai, Bin; Ji, Min [Journal of Enzyme Inhibition and Medicinal Chemistry, 2017, vol. 32, # 1, p. 954 - 959]
[32]Current Patent Assignee: ZUNYI MEDICAL UNIVERSITY - CN109134451, 2019, A Location in patent: Paragraph 0108-0111
[33]An, Lin; Gao, Cai-Yun; Li, Cheng-Lin; Liu, Yi; Meng, Long; Wu, Xiao-Qing; Xu, Liang; Zhang, Ling; Zhang, Wu-Qi; Zheng, You-Guang [European Journal of Medicinal Chemistry, 2020, vol. 202]

25
[ 3943-74-6 ]
[ 281191-65-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With 2,2'-azinobis(3-ethylbenzthiazolinesulfonate); laccase; potassium iodide In dimethyl sulfoxide at 20℃; for 36h; Enzymatic reaction;
29%	With N-iodo-succinimide; trifluoroacetic acid for 3h;	99 N-Iodosuccinimide (1.2 g, 5.5 mmol) was added portion wise to a solution of methyl vanillate (1.0 g, 5.5 mmol) in trifluoroacetic acid (10 mL). The reaction was monitored by LC/MS and judged complete after 3 h. The reaction was concentrated to remove the TFA then diluted with EA. The organic layer was washed with sodium thiosulfate and brine, dried and concentrated to afford 17-1 (0.50 g, 29%). LC/MS: m/z 308.95 [M+H]+.
27.2%	With N-iodo-succinimide; trifluoroacetic acid at 20℃; for 3h;	8.8a Step 8a: Preparation of methyl 4-hydroxy-3-iodo-5-methoxybenzoate (compound 0204-23): Methyl 4-hydroxy-3-methoxybenzoate (0202-23)(1.82 g, 0.01 mol, 1.0 eq.)Dissolved in 15 ml of trifluoroacetic acid,N-Iodosuccinimide (2.7 g, 0.012 mole, 1.2 equivalents) was added,The reaction was stirred at room temperature for 3 hours.Add water, extract with ethyl acetate, dry, and concentrate under reduced pressure.Purification by silica gel column chromatography (eluent: petroleum ether: dichloromethane = 4:3),The product as a white solid was obtained methyl 4-hydroxy-3-iodo-5-methoxybenzoate (840 mg, yield: 27.2%).

25%	With N-iodo-succinimide; trifluoroacetic acid
	With N-iodo-succinimide In tetrahydrofuran at 0℃; for 1h;	9.a a) 4-Hydroxy-3-iodo-5-methoxybenzoic acid methyl ester To a solution of 4-hydroxy-3-methoxybenzoic acid methyl 25 ester (5.0 g) in tetrahydrofuran (20 mL) was added N-iodosuccinimide (6.17 g) at 0° C., and the mixiture was stirred for 1 hour. The precipitated solid was filtered, washed with water, and dried to give the title compound (9.60 g).

Reference： [1]Sdahl, Mark; Conrad, Jürgen; Braunberger, Christina; Beifuss, Uwe [RSC Advances, 2019, vol. 9, # 34, p. 19549 - 19559]
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2016/244460, 2016, A1 Location in patent: Paragraph 0630; 0631
[3]Current Patent Assignee: GUANGZHOU BEBETTER MEDICINE TECH - CN107383024, 2017, A Location in patent: Paragraph 0167
[4]Appendino, Giovanni; Ech-Chahad, Abdellah; Minassi, Alberto; Bacchiega, Sara; Petrocellis, Luciano De; Marzo, Vincenzo Di [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 1, p. 132 - 135]
[5]Current Patent Assignee: JAPAN TOBACCO INC - US2006/89392, 2006, A1 Location in patent: Page/Page column 45

26
[ 3943-74-6 ]
[ 39149-80-9 ]
C₁₆H₂₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;Microwave irradiation;	(2) Preparation of 2-(2-methoxy-4-(methoxycarbonyl)phenoxy)propanoic acid (A02): Methyl 4-hydroxy-3-methoxybenzoate (1.09 g, 5.98 mmol) and tert-butyl 2-bromopropanoate (1.25 g, 0.97 mL, 5.98 mmol) and cesium carbonate (1.95 g, 5.98 mmol) were added into DMF (10 mL) in a 20 mL microwave vial equipped with a stir bar and sealed. The mixture was heated in Biotage microwave synthesizer for 1 hour at 100° C. The solvent was removed and the remained sticky oil was dissolved in DCM (7 mL) and TFA (7 mL). The mixture was stirred overnight. The reaction mixture was neutralized with sodium bicarbonate and organic layer was separated from the mixture. The aqueous layer washed with DCM (2*10 mL), combined organics and acidified to around pH5 with 2N HCl. Aqueous was extracted with DCM and then with ethyl acetate, dried with sodium sulfate and concentrated to an oil. The crude product was dissolved in DCM (4 mL) and a pure product (0.530 g) precipitate out from the solution by adding diethyl ether (4 mL).

Reference： [1]Patent: US2007/287730,2007,A1 .Location in patent: Page/Page column 12-13

27
[ 3943-74-6 ]
[ 214470-57-2 ]

Reference： [1]Molecules,2006,vol. 11,p. 286 - 297
[2]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 2825 - 2828
[3]Journal of Medicinal Chemistry,2011,vol. 54,p. 6139 - 6150
[4]Chemical Biology and Drug Design,2011,vol. 78,p. 932 - 940
[5]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 806 - 810
[6]European Journal of Medicinal Chemistry,2013,vol. 63,p. 702 - 712
[7]Journal of Medicinal Chemistry,2013,vol. 56,p. 8931 - 8942
[8]ChemMedChem,2014,vol. 9,p. 549 - 553
[9]Patent: US2014/235634,2014,A1
[10]Organic Preparations and Procedures International,2015,vol. 47,p. 207 - 213
[11]European Journal of Medicinal Chemistry,2017,vol. 138,p. 669 - 688
[12]Journal of Enzyme Inhibition and Medicinal Chemistry,2017,vol. 32,p. 954 - 959
[13]Patent: CN106083836,2016,A
[14]Patent: WO2017/142947,2017,A1
[15]Patent: CN107721923,2018,A
[16]Patent: EP973746,2003,B1
[17]Patent: WO2009/117080,2009,A1
[18]Patent: CN109134451,2019,A
[19]Patent: WO2019/36384,2019,A1
[20]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 1325 - 1329
[21]Bioorganic Chemistry,2019,vol. 93
[22]European Journal of Medicinal Chemistry,2020,vol. 202

28
[ 3943-74-6 ]
[ 61032-41-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5427 - 5436
[2]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2989 - 2992
[3]Tetrahedron Letters,2011,vol. 52,p. 1053 - 1056
[4]Patent: US2014/235634,2014,A1
[5]Patent: CN105541736,2016,A
[6]ChemMedChem,2016,vol. 11,p. 2327 - 2338
[7]MedChemComm,2017,vol. 8,p. 1069 - 1092
[8]Patent: US2017/95570,2017,A1
[9]Patent: WO2006/117552,2006,A1
[10]Patent: WO2018/195245,2018,A1
[11]Patent: WO2008/109613,2008,A1
[12]Patent: US2019/367488,2019,A1
[13]Patent: WO2020/89687,2020,A2

29
[ 3943-74-6 ]
[ 27883-60-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2989 - 2992
[2]Patent: US2019/367488,2019,A1

30
[ 3943-74-6 ]
[ 263149-10-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 2477 - 2480

31
[ 3943-74-6 ]
[ 214470-68-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 2477 - 2480
[2]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 2825 - 2828
[3]Heterocycles,2014,vol. 89,p. 2806 - 2813

32
[ 3943-74-6 ]
[ 15785-54-3 ]

Reference： [1]Journal of the American Chemical Society,1995,vol. 117,p. 4722 - 4723

33
[ 3943-74-6 ]
[ 84211-30-3 ]

Reference： [1]Journal of the American Chemical Society,1995,vol. 117,p. 4722 - 4723
[2]ChemMedChem,2015,vol. 10,p. 116 - 133

34
[ 3943-74-6 ]
[ 58885-58-8 ]
[ 174665-00-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃;
73%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃;	7; 9 EXAMPLE 7Synthesis of a Resin-bound 8-aminopropyl PBD Scaffold (30)(see FIG. 9)Overall Synthetic Strategy Boc Amino Ester (22) EXAMPLE 7Synthesis of a Resin-bound 8-aminopropyl PBD Scaffold (30)(see FIG. 9)Overall Synthetic Strategy [00143] The o-nitrobenzylchloroformate resin 2 can also immobilize more complicated amines other than simple anthranilic acids, greatly facilitating the preparation of molecules such as the PBD C8-amino scaffold 30. As in the previous strategy, the Fmoc protected scaffold 29 was prepared by oxidizing the primary alcohol resin 28. This resin was obtained by loading the o-nitrobenzylchloroformate resin 2 with the amino alcohol 27. The amino alcohol was prepared by a Tin (II) chloride mediated reduction of the nitro alcohol 26; use of hydrogenation conditions to reduce the nitro group were avoided due to the presence of the Fmoc group in 26. The nitro alcohol in turn was furnished in this case by coupling pyrrolidine methanol 5 to the o-nitrobenzoic acid 25, although other functionalised prolines could also be employed in the coupling reaction. The Fmoc o-nitrobenzoic acid was obtained via Fmoc protection of the amino acid 24 produced by hydrolysis of the ester 23. Other nitrogen protecting groups may be substituted for Fmoc as long as the cleavage conditions involved are compatible with the presence of an o-nitrobenzyl carbamate linker (eg. Boc, Alloc, Teoc etc). Finally, the amino ester was prepared by nitration of 22 which was obtained by a Mitsunobu etherification of commercially available methyl vanillate.Boc Amino Ester (22) [00144] A solution diethylazidodicarboxylate (3.38 g, 19.4 mmol) in THF (50 mL) was added dropwise to a solution of methylvanillate (3.53 g, 19.4 mmol), N-Boc-propanolamine (3.4 g, 19.4 mmol) and triphenylphosphine (5.09 g, 19.4 mmol) in THF (50 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stir overnight. Excess solvent was removed by rotary evaporation under reduced pressure and the residue triturated with toluene. Precipitated triphenylphosphine oxide was removed by vacuum filtration and the filtrate concentrated in vacuo. The residue was subjected to flash column chromatography (silica gel, petroleum ether 40-60/ethyl acetate, 80/20) and removal of excess eluent afforded the pure product 22 (4.8 g, 73% yield.). 1H NMR (270 MHz, CDCl3) δ 7.65 (dd, J=8.43, 2.02 Hz, 1H), 7.54 (d, J=2.02 Hz, 1H), 6.86 (d, J=8.43 Hz, 1H), 5.55 (bs, 1H), 4.15 (t, J=5.87 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.41-3.35 (m, 2H), 2.09-2.00 (m, 2H) and 1.46 (s, 9H). 13C NMR (68.7 MHz, CDCl3) δ 166.9, 156.1, 152.1, 148.8, 123.5, 122.8, 112.0, 111.2, 79.0, 68.2, 55.9, 52.0, 38.9, 29.2 and 28.5.Synthesis of Methyl 4-[N-(tert-butoxycarbonyl)]aminotropyloxy-3-methoxybenzoate 44 [00168] A solution of DEAD (18.3 g, 105.3 mmol) in freshly distilled THF (50 ml) was added dropwise to a mechanically stirred solution of triphenylphosphine (27.6 g, 105.3 mmol), methyl vanillate 43 (19.2 g, 105.3 mmol), and Boc-amino-1-propanol 42 (18.4 g, 105.3 mmol) in freshly distilled THF (250 mL), at 0° C. under a nitrogen atmosphere. Following the addition of DEAD the reaction mixture was allowed to stir at room temperature overnight and the progress of reaction was monitored by TLC (50% EtOAc/pet-ether). The solvent was removed by evaporation under reduced pressure and the residue was triturated with Et2O (300 mL). This led to the precipitation of some of the TPO and diethyl hydrazinedicarboxylate which were removed by filtration and the filtrate was washed with 1 N aqueous NaOH (150 mL), H2O (2×150 mL), brine (2×150 mL) and dried over MgSO4. Excess solvent was removed by evaporation under reduced pressure. The title compound was purified by column chromatography (80% pet-ether/EtOAc) to give a beige solid (30 g, 85%). [00169] mp=79-82° C.; 1H-NMR (CDCl3, 270 MHz): δ 1.46 (s, 9H, CH3), 2.0-2.08 (m, 2H, H2'), 3.38 (dd, 2H, J=5.68, 6.04 Hz H3'), 3.90 (s, 3H, OCH3ether), 3.93 (s, 3H, OCH3ethex), 4.14 (t, 2H, J=5.95 Hz, H3'), 5.58 (br, 1H, NH), 6.86 (d, 1H, J=8.42 Hz, H5), 7.55 (d, 1H, J=1.83 Hz, H2), 7.65 (dd, 1H, J=2.02, 8.42 Hz, H6); 13C-NMR (CDCl3, 68.7 MHz): δ 28.5 (C), 29.2 (C2'), 38.9 (C3'), 52.0 (OCH3aster), 55.8 (OCH3ether), 68.1 (C1'), 78.9 (Cquater), 111.3 (C5), 112.0 (C2), 122.84 (Carom), 123.5 (C6), 148.8 (Carom), 152.1 (Carom), 156.1 (NCO), 166.8 (CO); MS (E/I) m/z (relative intensity): 339 (M+, 11), 266 (13), 182 (42), 151 (27), 102 (100); HRMS (E/I) exact mass calcd. for C17H25NO6: m/e 339.1682, obsd m/e 339.1733; IR (Nujol) ν: (cm-1) 3362, 2923, 2854, 1712, 1684, 1599, 1520, 1464, 1377, 1272, 1217, 1132, 1045, 1022, 872, 780, 762, 722.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - EP1193270, 2002, A2 Location in patent: Page 87, 128
[2]Current Patent Assignee: ASTRAZENECA PLC - US6747144, 2004, B1 Location in patent: Page column 24; 28-29

35
[ 6940-78-9 ]
[ 3943-74-6 ]
methyl 4-(4-chlorobutoxy)-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In acetonitrile at 80 - 85℃; for 8h; Heating / reflux;	II-18; III-9 [Example II-18] Preparation of methyl 4-(4-chlorobutoxy)-3-methoxybenzoate In a 100 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 10.2 g (54.9 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 12.6 g (71.4 mmol) of 4-bromo-1-chlorobutane (purity: 99 wt.%), 8.5 g (60.4 mmol) of potassium carbonate (purity: 98 wt.%), and 300 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85°C for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (gel: Wako gel C-200, eluent: n-hexane), to give 13.6 g (isolated yield: 90.0%, purity: 99% in terms of area percentage by high performance liquid chromatography) of methyl 4-(4-chlorobutoxy)-3-methoxybenzoate as a colorless liquid. Methyl 4-(4-chlorobutoxy)-3-methoxybenzoate was a new compound and had the following characteristics. 1H-NMR (CDCl3, δ (ppm)): 1.96-2.07 (4H, m), 3.61-3.67 (2H, m), 3.89 (3H, s), 3.93 (3H, s), 4.13 (2H, t, J=6.0Hz), 6.87 (1H, d, J=6.0Hz), 7.55 (1H, s), 7.64 (1H, d, J=7Hz) In a 100 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 10.2 g (54.9 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 12.5 g (71.4 mmol) of 4-bromo-1-chlorobutane, 8.3 g (60.4 mmol) of potassium carbonate (purity: 98 wt.%), and 300 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85°C for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (gel: Wako gel C-200, eluent: n-hexane), to give 13.6 g (isolated yield: 90.0%, purity: 99% in terms of area percentage by high performance liquid chromatography) of methyl 4-(4-chlorobutoxy)-3-methoxybenzoate as a colorless liquid. Methyl 4-(4-chlorobutoxy)-3-methoxybenzoate had the following characteristics. 1H-NMR (CDCl3, δ (ppm)): 1.96-2.07 (4H, m), 3.61-3.67 (2H, m), 3.89 (3H, s), 3.93 (3H, s), 4.13 (2H, t, J=6.0Hz), 6.87 (1H, d, J=6.0Hz), 7.55 (1H, s), 7.64 (1H, d, J=7Hz)

Reference： [1]Current Patent Assignee: UBE INDUSTRIES LIMITED - EP1477481, 2004, A1 Location in patent: Page 24; 29

36
[ 3943-74-6 ]
[ 107-04-0 ]
[ 214470-56-1 ]

Yield	Reaction Conditions	Operation in experiment
97.8%	With potassium carbonate In acetonitrile at 80 - 85℃; for 8h; Heating / reflux;	II-1; III-1 [Example II-1] Preparation of methyl 4-(2-chloroethoxy)-3-methoxybenzoate In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.00 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 1.04 g (7.14 mmol) of 2-bromo-1-chloroethane (purity: 98 wt.%), 0.85 g (6.04 mmol) of potassium carbonate (purity: 98 wt.%), and 30 mL of acetonitrile. The resulting mixture was reflued under stirring at 80-85°C for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. To the concentrate was added 20 mL of n-heptane, to precipitate a crystalline product. The crystalline product was collected by filtration and dried under reduced pressure, to obtain 1.34 g (isolated yield: 97.8%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of methyl 4-(2-chloroethoxy)-3-methoxybenzoate as a white crystalline product. Methyl 4-(2-chloroethoxy)-3-methoxybenzoate had the following characteristics. m.p.: 61-62°C 1H-NMR (CDCl3, δ (ppm)): 3.65-3.69 (2H, m), 3.82 (3H, s), 3.90 (3H, s), 4.35 (2H, t, J=3.0Hz), 6.95 (1H, d, J=6.0Hz), 7.57 (1H, s), 7.67 (1H, d, J=6.0Hz); [Reference Example III-1] Preparation of methyl 4-(2-chloroethoxy)-3-methoxybenzoate In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.00 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt.%), 1.02 g (7.14 mmol) of 2-bromo-1-chloroethane, 0.83 g (6.04 mmol) of potassium carbonate, and 30 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85°C for 8 hours in an argon gas atmosphere. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. To the concentrate was added 20 mL of n-heptane, to precipitate a crystalline product. The crystalline product was collected by filtration and dried under reduced pressure, to obtain 1.34 g (isolated yield: 97.8%) of methyl 4-(2-chloroethoxy)-3-methoxybenzoate as a white crystalline product. Methyl 4-(2-chloroethoxy)-3-methoxybenzoate had the following characteristics. m.p.: 61-62°C 1H-NMR (CDCl3, δ (ppm)): 3.65-3.69 (2H, m), 3.82 (3H, s), 3.90 (3H, s), 4.35 (2H, t, J=3.0Hz), 6.95 (1H, d, J=6.0Hz), 7.57 (1H, s), 7.67 (1H, d, J=6.0Hz)
97%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 3h;	4-(2-Chloro-ethoxy)-3-methoxy-benzoic acid methyl ester. To a mixture of 4-hydroxy-3-methoxy-benzoic acid methyl ester (10 g, 54.8 mmol) and potassium carbonate (22.75 g, 164.4 mmol) in DMF (100 mL) was added 1-bromo-2-chloroethane (22.7 mL, 274 mmol). The mixture was heated at 70°C for 3h, and then diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to afford 4-(2-chloro-ethoxy)-3-methoxy-benzoic acid methyl ester as a white solid (13.1 gm, 97%). 1H NMR (300 MHz, CDCl3) δ 7.65 (d, 1H), 7.55 (s, 1H), 6.90 (d, 1H), 4.35 (t, 2H), 3.90 (m, 8H).
	With tetrabutylammomium bromide; potassium carbonate for 4h; Reflux;

Reference： [1]Current Patent Assignee: UBE INDUSTRIES LIMITED - EP1477481, 2004, A1 Location in patent: Page 20; 25
[2]Holladay, Mark W.; Campbell, Brian T.; Rowbottom, Martin W.; Chao, Qi; Sprankle, Kelly G.; Lai, Andiliy G.; Abraham, Sunny; Setti, Eduardo; Faraoni, Raffaella; Tran, Lan; Armstrong, Robert C.; Gunawardane, Ruwanthi N.; Gardner, Michael F.; Cramer, Merryl D.; Gitnick, Dana; Ator, Mark A.; Dorsey, Bruce D.; Ruggeri, Bruce R.; Williams, Michael; Bhagwat, Shripad S.; James, Joyce [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5342 - 5346]
[3]Dabirian, Sara; Dogaheh, Mahtab Ghasemi; Ghasemi, Saeed; Moghadam, Fatemeh Azmian; Mojabi, Mohammad; Yousefbeyk, Fatemeh [Australian Journal of Chemistry, 2021, vol. 74, # 10, p. 730 - 739]

37
[ 3943-74-6 ]
[ 17392-83-5 ]
[ 845655-00-7 ]

Yield	Reaction Conditions	Operation in experiment
71%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 18h; Cooling with ice;	1 Diisopropyl azodicarboxylate (4mL, 20mmol) in tetrahydrofuran (15mL) was added dropwise to an ice-cooled solution of f methyl vanillate ( 3.64g, 20mmol), (R)-methyl lactate (2.08g, 20mmol) and triphenyl phosphine (5.24g, 20mmol) in tetrahydrofuran (30mL) and the reaction mixture was stirred at room temperature for 18 hours. The solvent was then evaporated under reduced pressure and the residue was stirred in a mixture of diethyl ether (50mL) and hexane (50mL). The resulting precipitate was filtered off and the filtrate was concentrated in vacuo. P urification of the residue by column chromatography on silica gel, eluting with hexane: ethyl acetate, 85 : 15 to 75 : 25 afforded the title compound in 71 % yield, 3.8g LRMS (ES+): m/z [M+H]+ 269
71%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 18h;	6 3-Methoxy-4-[(1S)-1-methoxycarbonyl-ethoxy]-benzoic acid methyl ester Preparation 6 3-Methoxy-4-[(1S)-1-methoxycarbonyl-ethoxy]-benzoic acid methyl ester Diisopropyl azodicarboxylate (4 mL, 20 mmol) in tetrahydrofuran (15 mL) was added dropwise to an ice-cooled solution of methyl vanillate (3.64 g, 20 mmol), methyl (R)-lactate (2.08 g, 20 mmol) and triphenyl phosphine (5.24 g, 20 mmol) in tetrahydrofuran (30 mL) and the reaction mixture was stirred at room temperature for 18 hours. The solvent was then evaporated under reduced pressure and the residue was stirred in a mixture of diethyl ether (50 mL) and hexane (50 mL). The resulting precipitate was filtered off and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluding with hexane:ethyl acetate, 85:15 to 75:25 afforded the title compound in 71% yield, 3.8 g LRMS (ES+): m/z [M+H]+ 269

Reference： [1]Current Patent Assignee: PFIZER INC - WO2005/121094, 2005, A1 Location in patent: Page/Page column 35
[2]Current Patent Assignee: PFIZER INC - US2005/43300, 2005, A1 Location in patent: Page/Page column 33

38
[ 632-02-0 ]
[ 3943-74-6 ]
[ 5137-55-3 ]
[ 111627-40-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone;	EXAMPLE 66 4-(3-Chloro-propoxy)-5-methoxy-benzoic Acid Methyl Ester A mixture of 102.4 g (411.7 mmol) of 3-chloropropyl p-toluene sulfonate, 75 g (411.7 mmol) of 4-hydroxy-5-methoxy-benzoic acid methyl ester, 75.7 g (547.5 mmol) of potassium carbonate, and 1.66 g (4.1 mmol) of methyl-tricapryl ammonium chloride in 900 ml of acetone was stirred rapidly at reflux for 18 hr. The mixture was filtered and the solvent was removed giving 106 g of the tile compound after recrystallization from a chloroform-hexane mixture.
	With potassium carbonate; In acetone;	EXAMPLE 66 4-(3-Chloro-propoxy)-5-methoxy -benzoic acid methyl ester A mixture of 102.4 g (411.7 mmol) of 3-chloropropyl p-toluene sulfonate, 75 g (411.7 mmol) of 4-hydroxy-5-methoxy -benzoic acid methyl ester, 75.7 g (547.5 mmol) of potassium carbonate, and 1.66 g (4.1 mmol) of methyl-tricapryl ammonium chloride in 900 ml of acetone was stirred rapidly at reflux for 18 hr. The mixture was filtered and the solvent was removed giving 106 g of the tile compound after recrystallization from a chloroform-hexane mixture.
	With potassium carbonate; In acetone;	EXAMPLE 46 4-(3-Chloro-propoxy)-5-methoxy-benzoic acid methyl ester A mixture of 102.4 g (411.7 mmol) of 3-chloropropyl p-toluene sulfonate, 75 g (411.7 mmol) of 4-hydroxy-5-methoxy-benzoic acid methyl ester, 75.7 g (547.5 mmol) of potassium carbonate, and 1.66 g (4.1 mmol) of methyl-tricapryl ammonium chloride in 900 ml of acetone was stirred rapidly at reflux for 18 hr. The mixture was filtered and the solvent was removed giving 106 g of the tile compound after recrystallization from a chloroform-hexane mixture.

With potassium carbonate; In acetone;

Example 66 4-(3-Chloro-propoxy)-5-methoxy-benzoic acid methyl ester A mixture of 102.4 g (411.7 mmol) of 3-chloropropyl p-toluene sulfonate, 75 g (411.7 mmol) of 4-hydroxy-5-methoxy -benzoic acid methyl ester, 75.7 g (547.5 mmol) of potassium carbonate, and 1.66 g (4.1 mmol) of methyl-tricapryl ammonium chloride in 900 ml of acetone was stirred rapidly at reflux for 18 hr. The mixture was filtered and the solvent was removed giving 106 g of the tile compound after recrystallization from a chloroform-hexane mixture.

Reference： [1]Patent: US6384051,2002,B1
[2]Patent: US6002008,1999,A
[3]Patent: US6288082,2001,B1
[4]Patent: EP1263503,2005,B1

39
[ 121-34-6 ]
[ 3943-74-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With sulfuric acid; sodium hydrogencarbonate; mercury In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate	1 Preparation of methyl 4-hydroxy-3-methoxybenzoate (methyl vanillate) EXAMPLE 1 Preparation of methyl 4-hydroxy-3-methoxybenzoate (methyl vanillate) 50 g of vanillic acid and 250 ml of methanol were introduced into a reactor provided with a magnetic stirrer, a coolant and a thermometer. 40 ml of 96% concentrated sulfuric acid was introduced dropwise using a dropping funnel; cooling was carried out if the alcohol boiled. The mixture was refluxed for 2 hours with stirring. The mixture was cooled to room temperature, poured into 100 ml of ice water, and the alcohol was evaporated off under reduced pressure (200 mm of mercury=2.6104 Pa). The aqueous phase was extracted three times with ethyl ether. The combined organic phases were washed with a saturated solution of sodium bicarbonate until the pH was neutral, then washed once with water to eliminate the salts. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure (200 mm of mercury=2.6104 Pa) to obtain the crude ester. The methyl ester was distilled at 118° C. under a reduced pressure of 2 mm of mercury (266 PA), then crystallized from petroleum ether (80°-120° C. fraction) to provide methyl vanillate having a purity of more than 97% in a yield of 82%. The methyl vanillate has a spicy vanilla scent, different than vanillin.

Reference： [1]Current Patent Assignee: SOLVAY - US5686406, 1997, A

40
[ 3943-74-6 ]
[ 100-39-0 ]
[ 61032-41-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; sodium sulfate; In water; N,N-dimethyl-formamide;	Production Example 25: Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate Commercially available methyl vanillate (50 g) and potassium carbonate (76 g) were dissolved in N,N-dimethylformamide (200 ml). Benzyl bromide (33 ml) was added dropwise to the solution over a period of 10 min. The mixture was stirred at room temperature overnight. Water (200 ml) was added thereto, followed by extraction with ethyl acetate. Saturated brine was then added to the organic layer, and the mixture was extracted with ethyl acetate. Sodium sulfate was added to the organic layer to dry the organic layer. Next, the organic layer was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was dried through a vacuum pump to give 68 g of a white solid.

Reference： [1]Patent: EP1153920,2001,A1
[2]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 6796 - 6805
[3]Patent: US2007/149523,2007,A1

41
[ 3943-74-6 ]
[ 7051-34-5 ]
[ 1040724-12-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With potassium carbonate; sodium iodide In acetone at 20℃; for 0.5h; Stage #2: cyclopropylcarbinyl bromide In acetone for 48h; Heating / reflux;	a a) 4-Cyclopropyhnethoxy~3-methoxy-benzoic acid methyl ester 4-hydroxy-3-methoxy-benzoic acid methyl ester (1.0 g, 5.5 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.5 eq) and K2CO3 (1.0 g, 2.0 eq) were added and the mixture was stirred at room temperature for 30 min. (Bromomethyl)cyclopropane (0.53 mL, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and it was extracted with DCM and dried. The title product (1.21 g, yield 93%) was recovered and used without further purification.C13H16O4
93%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With potassium carbonate; sodium iodide In acetone at 20℃; for 0.5h; Stage #2: cyclopropylcarbinyl bromide In acetone for 48h; Heating / reflux;	a 4-hydroxy-3-methoxy-benzoic acid methyl ester (1.0 g, 5.5 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.5 eq) and K2CO3 (1.0 g, 2.0 eq) were added and the mixture was stirred at room temperature for 30 min. (Bromomethyl)cyclopropane (0.53 mL, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and it was extracted with DCM and dried. The title product (1.21 g, yield 93%) was recovered and used without further purification. C13H16O4

Reference： [1]Current Patent Assignee: SIENA BIOTECH S.P.A. SOCIETA' IN LIQUIDAZIONE; PFIZER INC - WO2008/87529, 2008, A1 Location in patent: Page/Page column 56-57
[2]Current Patent Assignee: PFIZER INC - WO2009/91832, 2009, A1 Location in patent: Page/Page column 55-56

42
[ 74-96-4 ]
[ 3943-74-6 ]
[ 3535-24-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h;	6.6A.1 EXAMPLE 6; Preparation of 1 -(5-fer/-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4- yloxylphenyllurea hydrochloride; [00666] Example 6A Step 1 : A mixture of methyl vanillate (6.376 g, 35 mmol), bromoethane (4.359 g, 40 mmol), and K2CO3 (5.528 g, 40 mmol) in DMF (40 mL) was heated at 70 °C for 2 hours. The reaction mixture was quenched with water, filtered, washed with water, and dried under vacuum with P2O5 to give methyl 4- ethoxy-3-methoxybenzoate as white solid (7.123 g, 97%). 1H NMR (300 MHz, CDCl3) δ 7.66 (dd, 1H), 7.55 (d, 1H), 6.88 (d, 1H), 4.17 (q, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.50 (t, 3H); LC-MS (ESI) m/z 211 (M + H)+.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - WO2009/117080, 2009, A1 Location in patent: Page/Page column 166

43
[ 3943-74-6 ]
2,3,4,6-tetra-O-acetyl-d-glucopyranosyl trichloroacetimidate [ No CAS ]
[ 72500-10-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester; 2,3,4,6-tetra-O-acetyl-d-glucopyranosyl trichloroacetimidate In dichloromethane at 0℃; Molecular sieve; Inert atmosphere; Stage #2: With boron trifluoride diethyl etherate In dichloromethane for 3h; Molecular sieve; Inert atmosphere;	A typical procedure for the phenol O-glycosylation with glycosyl imidates as donors in the presence of BF3 Et2O or TMSOTf (Tables 1 and 2). General procedure: A mixture of imidate 1 (100 mg, 0.2 mmol), phenol 2i (26 mg, 0.17 mmol), and freshly activated 4 Å molecular sieve in anhydrous CH2Cl2 (5 mL) was stirred under Ar at 0 °C for 10 min, TMSOTf (2 μL, 0.02 mmol) or BF3·Et2O (1 μL, 0.02 mmol) was then added through a syringe. The stirring continued for 3 h, Et3N (1 mL) was then added, and the resulting mixture was filtered through Celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography to give phenol glycoside 3iɑ (22 mg, 26%) and 3iβ (43 mg, 53%) or 3iβ only (82 mg, 100%).
	With boron trifluoride diethyl etherate In dichloromethane

Reference： [1]Li, Yali; Mo, Huaping; Lian, Gaoyan; Yu, Biao [Carbohydrate Research, 2012, vol. 363, p. 14 - 22]
[2]Location in patent: experimental part Kojima, Masaru; Nakamura, Yutaka; Ito, Shun; Takeuchi, Seiji [Tetrahedron Letters, 2009, vol. 50, # 45, p. 6143 - 6149]

44
[ 67-56-1 ]
[ 9005-53-2 ]
[ 3943-74-6 ]
[ 884-35-5 ]
[ 121-33-5 ]
[ 134-96-3 ]

Yield	Reaction Conditions	Operation in experiment
	With oxygen;phosphomolybdic acid; In water; at 170℃; under 3825.38 Torr;	Experiments 01-11 and Blank Sample (see Table 1):In a typical experiment, 9.13 g of the POM H3PMo12O40 were dissolved in 100 ml of water or a water/alcohol mixture, which corresponds formally to a 0.05 molar solution. This was then transferred into a 500 ml autoclave (Premex Reactor AG, Lengnau, Switzerland). Before the closure of the reactor, 1 g of pulverulent lignin was added. The reaction mixture was then contacted three times with 5 bar of oxygen or nitrogen and vented, in order to displace the air initially present. Finally, the reactor was filled with 5 bar of oxygen or 10 bar of nitrogen. The reaction mixture was heated to 170 C. at a rate of 8 K/min at a stirrer speed of 1200 rad/min. The mixture was kept at 170 C. for 20 minutes. The liquid phase was removed after 20 minutes. This was followed by the sampling through a water-cooled cooling coil. The sample was filtered once and then extracted three times with 10 ml of chloroform. 30 mul of n-decane were added to the organic phase as an internal standard for the GC-MS analysis (Fisons instruments GC8000/MD800; column from Restek Rtx-5MS 30 m×0.25 mm×0.25 mum).In experiments 03, 04, 08, 09, 10 and 11, free-radical scavengers (methanol, ethanol) were used.In experiment 02, a second liquid phase in the form of 30 ml of chloroform was added before the closure of the reactor.In experiment 05, 9.45 g of the POM Na3PMo12O40 were used. In the blank sample, no POM was used.Experiment 12 and Wu et al. (G. X. Wu, M. Heitz, E. Chornet, Ind. Eng. Chem. Res. 33, 718 (March, 1994)) (see table 1):The experimental method in experiment 12 is kept analogous to Wu et al. 10 g of lignin were dissolved in 100 ml of a 3 molar sodium hydroxide solution. The solution was added to a 500 ml autoclave, and the catalyst system consisting of 500 mg of copper sulfate and 50 mg of iron chloride was added. The reactor was closed and filled three times with oxygen at 10 bar and emptied, in order to displace the air originally present. Subsequently, the reaction vessel was placed under pressure with 13.2 bar of oxygen. The reaction mixture was heated to 170 C. at a rate of 8 K/min at a stirrer speed of 1200 rad/min. The mixture was kept at 170 C. for 20 minutes. The liquid phase was withdrawn after 20 minutes. The sampling was effected through a water-cooled cooling coil.In experiment 01, lignin was treated in a 0.05 molar aqueous H3PMo12O40 solution under inert gas. In the course of this, the color of the solution changed from yellowish to dark blue. This shows clearly that the polymolybdate used was reduced. By means of GC-MS analysis, 0.56 mg of lignin-based products (principally vanillin) was quantified.The yield of lignin-based products could be increased by approx. 30% by in situ extraction (cf. experiment 01 with experiment O2). To this end, a second liquid phase (chloroform) was added to the reaction mixture. This has a higher solubility for the desired degradation products and can therefore withdraw any products formed from the actual reaction medium (aqueous POM solution) before possible further reactions destroy the products formed again.The degradation of lignin with 0.05 molar H3PMo12O40 solution under oxygen (experiment 06) likewise increased the yield compared to the degradation under inert gas (experiment 01). After the experiment under oxygen, in contrast to the experiment under inert gas, only slight discoloration of the solution to yellow-greenish was detected, i.e. the polyoxomolybdate was reduced only very slightly, if at all. This leads to the suspicion that the POM is reoxidizable under the conditions used and, in this case, oxygen is consumed by the POM during the degradation of lignin.Experiment 07 shows that various lignin types can be used and that the yield of chemicals here is within the same order of magnitude. According to the manufacturer, the lignin from Aldrich (batch No. 09724CE) is a softwood lignin (principally from spruce wood), which was obtained in the Kraft process. The lignin from the Granit process was, in contrast, obtained from plants utilized in agriculture and therefore has a different chemical structure.In experiment 05, the POM used was the sodium salt Na3PMo12O40 corresponding to H3PMo12O40. The yield of chemicals is noticeably higher in this experiment. It is therefore found that changes in the POM system used which are slight from a chemical point of view can affect the yield of desired products. The use of a very substantially optimal POM system is therefore of crucial significance for the attainment of high yields.The positive effect of the free-radical scavenger with regard to the yield of chemicals was demonstrated in experiments 03 and 04 compared to experiment 01 and the blank sample. In experiments 03 and 04, ethanol and methanol were used as free-radical scavengers. Using the free-radical scavengers, the yield was enhanced from 0.56 mg to 1.17 mg in the case of ethanol and to 2.38 mg in the case of methanol.In the case of t...

Reference： [1]Patent: US2010/121110,2010,A1 .Location in patent: Page/Page column 5-8

45
[ 67-56-1 ]
[ 9005-53-2 ]
[ 3943-74-6 ]
[ 121-33-5 ]

Yield	Reaction Conditions	Operation in experiment
	With oxygen In water at 170℃;	10 Experiments 01-11 and Blank Sample (see Table 1):In a typical experiment, 9.13 g of the POM H3PMo12O40 were dissolved in 100 ml of water or a water/alcohol mixture, which corresponds formally to a 0.05 molar solution. This was then transferred into a 500 ml autoclave (Premex Reactor AG, Lengnau, Switzerland). Before the closure of the reactor, 1 g of pulverulent lignin was added. The reaction mixture was then contacted three times with 5 bar of oxygen or nitrogen and vented, in order to displace the air initially present. Finally, the reactor was filled with 5 bar of oxygen or 10 bar of nitrogen. The reaction mixture was heated to 170° C. at a rate of 8 K/min at a stirrer speed of 1200 rad/min. The mixture was kept at 170° C. for 20 minutes. The liquid phase was removed after 20 minutes. This was followed by the sampling through a water-cooled cooling coil. The sample was filtered once and then extracted three times with 10 ml of chloroform. 30 μl of n-decane were added to the organic phase as an internal standard for the GC-MS analysis (Fisons instruments GC8000/MD800; column from Restek Rtx-5MS 30 m×0.25 mm×0.25 μm).In experiments 03, 04, 08, 09, 10 and 11, free-radical scavengers (methanol, ethanol) were used.In experiment 02, a second liquid phase in the form of 30 ml of chloroform was added before the closure of the reactor.In experiment 05, 9.45 g of the POM Na3PMo12O40 were used. In the blank sample, no POM was used.Experiment 12 and Wu et al. (G. X. Wu, M. Heitz, E. Chornet, Ind. Eng. Chem. Res. 33, 718 (March, 1994)) (see table 1):The experimental method in experiment 12 is kept analogous to Wu et al. 10 g of lignin were dissolved in 100 ml of a 3 molar sodium hydroxide solution. The solution was added to a 500 ml autoclave, and the catalyst system consisting of 500 mg of copper sulfate and 50 mg of iron chloride was added. The reactor was closed and filled three times with oxygen at 10 bar and emptied, in order to displace the air originally present. Subsequently, the reaction vessel was placed under pressure with 13.2 bar of oxygen. The reaction mixture was heated to 170° C. at a rate of 8 K/min at a stirrer speed of 1200 rad/min. The mixture was kept at 170° C. for 20 minutes. The liquid phase was withdrawn after 20 minutes. The sampling was effected through a water-cooled cooling coil.In experiment 01, lignin was treated in a 0.05 molar aqueous H3PMo12O40 solution under inert gas. In the course of this, the color of the solution changed from yellowish to dark blue. This shows clearly that the polymolybdate used was reduced. By means of GC-MS analysis, 0.56 mg of lignin-based products (principally vanillin) was quantified.The yield of lignin-based products could be increased by approx. 30% by in situ extraction (cf. experiment 01 with experiment O2). To this end, a second liquid phase (chloroform) was added to the reaction mixture. This has a higher solubility for the desired degradation products and can therefore withdraw any products formed from the actual reaction medium (aqueous POM solution) before possible further reactions destroy the products formed again.The degradation of lignin with 0.05 molar H3PMo12O40 solution under oxygen (experiment 06) likewise increased the yield compared to the degradation under inert gas (experiment 01). After the experiment under oxygen, in contrast to the experiment under inert gas, only slight discoloration of the solution to yellow-greenish was detected, i.e. the polyoxomolybdate was reduced only very slightly, if at all. This leads to the suspicion that the POM is reoxidizable under the conditions used and, in this case, oxygen is consumed by the POM during the degradation of lignin.Experiment 07 shows that various lignin types can be used and that the yield of chemicals here is within the same order of magnitude. According to the manufacturer, the lignin from Aldrich (batch No. 09724CE) is a softwood lignin (principally from spruce wood), which was obtained in the Kraft process. The lignin from the Granit process was, in contrast, obtained from plants utilized in agriculture and therefore has a different chemical structure.In experiment 05, the POM used was the sodium salt Na3PMo12O40 corresponding to H3PMo12O40. The yield of chemicals is noticeably higher in this experiment. It is therefore found that changes in the POM system used which are slight from a chemical point of view can affect the yield of desired products. The use of a very substantially optimal POM system is therefore of crucial significance for the attainment of high yields.The positive effect of the free-radical scavenger with regard to the yield of chemicals was demonstrated in experiments 03 and 04 compared to experiment 01 and the blank sample. In experiments 03 and 04, ethanol and methanol were used as free-radical scavengers. Using the free-radical scavengers, the yield was enhanced from 0.56 mg to 1.17 mg in the case of ethanol and to 2.38 mg in the case of methanol.In the case of the blank sample without POM, no lignin-based products were detectable.FIG. 1 shows the corresponding GC-MS chromatograms and illustrates that not only are the amounts of vanillin and 4-hydroxyacetyl-2-methoxyphenol produced greater when the free-radical scavengers are used, but novel components are also prepared in amounts comparable to vanillin.The formation of vanillic acid methyl ester in experiment 04 shows that methanol is incorporated into the product (see equation 11).Using ethanol as the free-radical scavenger, in contrast, vanillic acid ethyl ester is formed (see equation 12).In addition, experiments were carried out to verify the mechanism indicated in equations 11 and 12. With deuterated methanol CD3OD, it was possible to show clearly that a methanol radical is incorporated into the vanillic acid methyl ester product. The molecular weight of vanillic acid methyl ester produced in reactions of lignin in the presence of undeuterated methanol was determined by means of GC-MS analysis to be 182 g/mol. Using deuterated methanol, the molecular weight was determined to be 185 g/mol. In addition, it was checked whether the formation of the vanillic acid methyl ester is also possible from vanillin, for example via the reaction route of vanillin vanillic acid vanillic acid methyl ester. The treatment of vanillin in 0.05 molar H3PMo12O40 solution under nitrogen in the presence of methanol gave no products whatsoever. It can consequently be assumed that the acyl radical shown in equations 11 and 12 results from the scission of the Cα-Cβ bond in the lignin.The formation of the CH3O. radical from methanol was also considered in more detail. The homolytic scission of the O-H bond in methanol is thermodynamically improbable owing to the high bond energy of 104 kcal/mol. It was, however, found that methanol in aqueous H3PMo12O40 solution under nitrogen is converted partly to dimethyl ether. The homolytic scission of the C-O bond in dimethyl ether is possible owing to the relatively low bond energy of 84 kcal/mol. It is consequently possible that methanol can form free radicals via acid-catalyzed ether formation and is thus considered to be a free-radical scavenger in the context of this invention. The direct addition of dimethyl ether as a free-radical scavenger for conversion of lignin in aqueous H3PMo12O40 solution under nitrogen and in the absence of methanol results in the production of a small amount of vanillic acid methyl ester. It was thus shown that dimethyl ether is directly active as a free-radical scavenger, and the homolytic scission of dimethyl ether and the associated formation of vanillic acid methyl ester is possible. In order to be able to compare the results of the degradation of lignin by means of POM and free-radical scavengers with the prior art, the method used by Wu et al. (benchmark) was applied to the lignin from Aldrich used in our examples.A comparison of the results revealed that the yield of lignin-based chemicals using the softwood lignin is very much lower compared to Wu et al. (one factor of ten). The reason for this may be the use of a very different lignin type. The lignin from Sigma-Aldrich used in our study is, according to the manufacturer, a typical softwood lignin which was isolated from spruce wood by means of the Kraft process. Wu et al. used, in contrast, a self-produced lignin type produced from hardwood by means of steam digestion. It is known that hardwood lignin has a very much higher proportion of syringyl units (50%). The comparatively high proportion of syringyl units is also reflected in the results of Wu et al. in the considerable amount of syringaldehyde produced (7.8% by weight). Softwood lignin (from the spruce) possesses, in contrast, a very great proportion of guaiacyl units (90%). This corresponds with our results, in which only traces of syringaldehyde were formed. It is additionally known that the degradation of hardwood lignin proceeds very much more easily and rapidly than the degradation of softwood lignin. In addition, the hardwood lignin produced by Wu et al. was not characterized fully. The composition of the acid-insoluble lignin is reported by Wu et al. as: Klason lignin=84.7%; acid-soluble lignin=3.0% and others (unknown)=12.3%.An economically viable process requires a reliable and inexpensive lignin source. It therefore appears to be advisable to use softwood lignin, which is obtainable in large amounts, as a starting material for chemical production. As already indicated, softwood lignin is obtained as a waste product in papermaking (for example in the Kraft or sulfite process). The method of Wu et al. is therefore applied below to the lignin available to us as a benchmark.A comparison of experiment 10 in which lignin was converted under oxygen in the presence of POM and free-radical scavenger with the prior art method (experiment 12) shows that a higher product yield is achieved with the inventive method. The chemicals produced are principally vanillin (16.5 mg) and vanillic acid methyl ester (13.5 mg).In experiment 11, poplar lignin was used. The product yield is likewise in the region of 3.5% by weight. The main products here are, however, vanillin (5.0 mg), vanillic acid methyl ester (6.2 mg), syringaldehyde (8.2 mg) and syringic acid methyl ester (12.2 mg), corresponding to the chemical structure of poplar lignin with a relatively high proportion of syringyl units.It should be noted that the examples adduced in this document represent the first test series. The achievement of the comparatively higher yields is therefore particularly promising, since the inventive method has not yet been optimized. In view of the numerous possible combinations of POM, free-radical scavengers and ultimately also lignin types, there is still a very large amount of room for improvement of the yields. In addition, some reaction technology solutions, for example in situ extraction, are still available. The potential becomes clear in a comparison of experiments 06 and 10, among others. Here, the yield of chemicals was increased by a factor of 30 solely through the use of an aqueous methanol solution. One advantage of the invention presented here also lies in the possibility of preparing different chemicals depending on the free-radical scavenger. For instance, vanillic acid methyl ester is formed in the case of use of methanol, and vanillic acid ethyl ester in the case of use of ethanol. It consequently appears possible, through suitable combinations of POM and free-radical scavenger, to be able to crucially influence not just the yield but also the selectivity for a target product. TABLE 1 Results for production of chemicals from lignin by means of POM and free-radical scavenger compared to conventional methods. Products Experi- Catalytic Lignin [mg] % by ment system Medium Gas type GC-MSwt.) 01H3PMo12O40 H2ON2 Aldrich 0.56 0.06 (9.13 g) (100 ml) (10 bar) (1 g) 02H3PMo12O40 H2ON2 Aldrich 0.74 0.08 (9.13 g) (100 ml) (10 bar) (1 g) CHCl3 (30 ml) 03H3PMo12O40 H2ON2 Aldrich 1.17 0.13 (9.13 g) (60 ml) (10 bar) (1 g) C2H5OH (40 ml) 04H3PMo12O40 H2ON2 Aldrich 2.38 0.26 (9.13 g) (60 ml) (10 bar) (1 g) CH3OH (40 ml) 05Na3PMo12O40 H2OO2 Aldrich 1.47 0.16 (9.45 g) (100 ml) (5.1 bar) (1 g) 06H3PMo12O40 H2OO2 Aldrich 0.97 0.11 (9.13 g) (100 ml) (5.1 bar) (1 g) 07H3PMo12O40 H2OO2 Granit 0.59 0.06 (9.13 g) (100 ml) (5.1 bar) (1 g) 08H3PMo12O40 H2OO2 Aldrich 9.5 1.04 (9.13 g) (60 ml) (5.1 bar) (1 g) CH3OH (40 ml) 09H3PMo12O40 H2OO2 Aldrich 25.63 2.79 (9.13 g) (40 ml) (5.1 bar) (1 g) CH3OH (60 ml) 10H3PMo12O40 H2OO2 Aldrich 32.73 3.57 (9.13 g) (20 ml) (5.1 bar) (1 g) CH3OH (80 ml) 11H3PMo12O40 H2OO2 Poplar 34.22 3.64 (9.13 g) (20 ml) (5.1 bar) (1 g) CH3OH (80 ml) 12CuSO4/FeCl3 H2OO2 Aldrich 145 1.58 (0.5 g/0.05 g) (100 ml) (13.2 bar) (10 g) NaOH (12 g) Wu et al.CuSO4/FeCl3 H2OO2 Hardwood 12.9 (0.5 g/0.05 g) (100 ml) (13.8 bar) (10 g) NaOH (14.7 g) Blank noneH2ON2 Aldrich 0 0 sample (60 ml) (10 bar) (1 g) C2H5OH (40 ml) )Based on dry lignin

Reference： [1]Current Patent Assignee: EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - US2010/121110, 2010, A1 Location in patent: Page/Page column 5-8

46
[ 3943-74-6 ]
[ 6940-76-7 ]
[ 111627-40-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In acetonitrile; at 80℃; for 3h;	To a 2-L round-bottom flask was added methyl 4-hydroxy-3-methoxybenzoate (100 g, 548.93 mmol, 1.00 eq.), 1-chloro-3-iodopropane (224 g, 1.10 mol, 2.0 eq.), K2C03 (22.7 g, 3.00 eq.) followed by MeCN (1 L). The resulting mixture was allowed to stir at 80 °C for 3 h. The mixture wascooled to rt, the solids were filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure to afford methyl 4-(3-chloropropoxy)-3-methoxybenzoate as a white solid (12890percent).
	With potassium carbonate; In acetonitrile; at 80℃; for 3h;	To a 2-L round-bottom flask was added methyl 4-hydroxy-3-methoxybenzoate (100 g, 548.93mmol, 1.00 eq.), i-chloro-3-iodopropane (224 g, 1.10 mol, 2.0 eq.), K2C03 (22.7 ,3. 00 eq.)followed by CH3CN (1 L). The resulting mixture was allowed to stir at 80 C for 3 h. The reaction mixture was cooled to 11, the solids were filtered off and washed with EtOAc. The filtrate wasconcentrated under reduced pressure to afford the desired crude product of methyl 4-(3 chloropropoxy)-3-inethoxybenzoate as a white solid (128 g, 90%).

Reference： [1]Patent: WO2019/36384,2019,A1 .Location in patent: Page/Page column 144; 145
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 6139 - 6150
[3]Journal of Medicinal Chemistry,2013,vol. 56,p. 8931 - 8942
[4]ChemMedChem,2014,vol. 9,p. 549 - 553
[5]Patent: WO2017/142947,2017,A1 .Location in patent: Page/Page column 42

47
[ 3943-74-6 ]
[ 21742-00-7 ]
[ 1354549-28-2 ]

Reference： [1]ACS Chemical Biology,2012,vol. 7,p. 552 - 562

48
[ 3943-74-6 ]
[ 124-63-0 ]
3-methoxy-4-[(methyl-sulfonyl)oxy]-benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate In acetonitrile at 20℃; for 3h; Inert atmosphere;
71%	With potassium carbonate In acetonitrile at 0 - 20℃; for 3h; Inert atmosphere;	1 Synthesis of methyl 3-methoxy-4-[(methylsulfonyl)oxy] -benzoate (Compound 9) Under an argon atmosphere, methyl vanillate (1.0 g, 5.49 mmol)And acetonitrile (30 ml) were added to potassium carbonate (1.13 g, 8.24 mmol), and the mixture was cooled to 0 ° C.Therein, methanesulfonyl chloride (0.51 ml, 6.59 mmol)Was added dropwise. The reaction solution was warmed to room temperature and stirred for 3 hours.The reaction solution was suction filtered through celite, and the solvent was distilled off under reduced pressure.Ethyl acetate (30 ml) and 1 N HCl aqueous solution (30 ml) were added to the residue,And extracted. Further, the aqueous layer was extracted twice with ethyl acetate (20 ml).The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography(Hexane: ethyl acetate = 3: 1). The obtained solid was washed with water. Recrystallization with ethyl acetate and hexane, to give Methyl 3-methoxy-4 - [(methylsulfonyl) oxy] -benzoate(1.01 g, 71%) as a white solid.

Reference： [1]Location in patent: experimental part Yanagita, Hiroshi; Yamamoto, Norio; Fuji, Hideyoshi; Liu, Xinli; Ogata, Masakazu; Yokota, Mizuho; Takaku, Hiroshi; Hasegawa, Hideki; Odagiri, Takato; Tashiro, Masato; Hoshino, Tyuji [ACS Chemical Biology, 2012, vol. 7, # 3, p. 552 - 562]
[2]Current Patent Assignee: CHIBA UNIVERSITY; JUNTENDO UNIVERSITY - JP5765650, 2015, B2 Location in patent: Paragraph 0068

49
[ 3943-74-6 ]
[ 653-35-0 ]
[ 1354549-26-0 ]

Reference： [1]ACS Chemical Biology,2012,vol. 7,p. 552 - 562

50
[ 3943-74-6 ]
[ 329710-76-1 ]
[ 1346498-24-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.666667h; Inert atmosphere; Stage #2: 2-(trifluoromethoxy)ethyl trifluoromethanesulphonate In N,N-dimethyl-formamide; mineral oil at 0 - 40℃; for 0.666667h;	1 Step 1: methyl 3-methoxy-4-[2-(trifluoromethoxy)ethoxyj benzoate [00327j Step 1: methyl 3-methoxy-4-[2-(trifluoromethoxy)ethoxyj benzoate [00328j A 100 mL RB flask was fitted with a teflon stirrer bar, a magnetic stirrer, a cooling bath and a nitrogen inlet/outlet. The vessel was charged under a nitrogen atmosphere with 60% sodium hydride (1.1 g, 26.7 mmol) in mineraloil and cooled to 0 °C with an ice bath. The vessel was then charged with N,Ndimethylformamide (35 ml) via syringe and stirring was commenced. The vessel was then charged with methyl 4-hydroxy-3-methoxy-benzoate (4.9 g, 26.7 mmol) as a solid in 4 equal portions over 20 mm resulting in slight foaming. The reaction mixture was stirred for 20 mm and then treated with 2-(trifluoromethoxy)ethyltrifluoromethanesulfonate (14.0 g, 26.7 mmol) neat via canula over 10 mm. The cooling bath was removed and the reaction mixture was continued to stir and allowed to warm to rt. The reaction mixture was heated to 40 °C for 30 mm, After cooling to rt the reaction mixture was poured onto crushed ice (150 g). The mixture was diluted with water (150 ml) and then transferred to a separatory funnel and partitioned withethyl acetate (250 ml). The organic was removed and the aqueous layer was extracted0with ethyl acetate (2 x 100 ml). The combined organics were washed with 0.1 M NaOH aqueous solution (2 x 150 ml), saturated aqueous sodium chloride (4 x 150 ml), dried over sodium sulfate (250 g), and filtered through a glass fit Buchner funnel. The filtrate was concentrated under reduced pressure. Purification by flash colunmchromatography (Si02-220 g, 0-20 % ethyl acetate-hexanes) afforded methyl 3- methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoate (7.5 g, 95%). ‘H NMR (400 MHz, CDC13) ö 7.68 (dd, J = 8.4, 2.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.41 - 4.29 (m, J = 8.3, 5.3, 2.7 Hz, 4H), 3.94 (s, 3H), 3.92 (s, 3H).
	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With sodium hydride In N,N-dimethyl-formamide Inert atmosphere; Stage #2: 2-(trifluoromethoxy)ethyl trifluoromethanesulphonate In N,N-dimethyl-formamide at 20 - 50℃; for 4h;	1 3-Methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoic acid Step 1 To sodium hydride (200 mg, 5.0 mmol) in DMF (6 mL) under N2 was added methyl 4-hydroxy-3-methoxy-benzoate (920 mg, 5.0 mmol) and the mixture was stirred for 10 min. 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (1.2 g, 4.6 mmol) was then added dropwise and the solution was stirred at room temperature for 2 h, then at 50° C. for 2 h. The mixture was concentrated to a solid, and the residue was taken up in 50 mL of CH2Cl2 before it was washed with brine (20 mL), dried over MgSO4 and purified by column chromatography (0-25% EtOAc/hexane) to give methyl 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoate as a white solid. ESI-MS m/z calc. 294.1. found 295.3 (M+1)+; Retention time: 1.63 minutes (3 min run).

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2015/6280, 2015, A1 Location in patent: Paragraph 00327; 00328
[2]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2012/196869, 2012, A1 Location in patent: Paragraph 0353; 0354; 0355

51
[ 3943-74-6 ]
[ 162012-72-8 ]

Reference： [1]Patent: US2014/235634,2014,A1
[2]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 6796 - 6805
[3]Patent: US2007/149523,2007,A1

Yield	Reaction Conditions	Operation in experiment
		General procedure: FIGURES 8A-8C are illustrations of the hydroxylation of arenes mediated by 4,5-dichlorophthaloyl peroxide. To examine the scope of the hydroxylation reaction mediated by 4,5-dichlorophthaloyl peroxide (2), two general sets of reaction conditions were developed. The oxidations are carried out using either 1.3 equivalents of 4,5-dichlorophthaloyl peroxide (2) at 50 C or 2.5 equivalents heated to 75 C. Operationally the reaction proceeds without the need for special exclusion of air and the use of commercial grade HFIP is sufficient. Thermogravimetric analysis indicates that 4,5-dichlorophthaloyl peroxide has a point of decomposition at 135 C. Therefore, all reactions reported are conducted at or below 75 C. While we have not encountered exothermic reactions, appropriate precautions must be used similar to those for all experiments using peroxides. Isolated yields are given below each entry. The yield in parentheses refers to the starting material recovered. The minor regioisomeric positions are labeled with the respective carbon atom number and, after the major isomer, listed sequentially. Reaction conducted at 0C. Prior to the addition of 4,5-dichlorophthaloyl peroxide (2) p-toluenesulfonic acid monohydrate (1.0 equiv.) was added to the solution of 3(y).

53
[ 3943-74-6 ]
[ 380844-49-5 ]

Reference： [1]Heterocycles,2014,vol. 89,p. 2806 - 2813

54
[ 3943-74-6 ]
[ 1132843-09-4 ]
C₁₄H₁₆F₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 7.5h;	1 Step 1: methyl 3-chloro-4-((3,3-difluorocyclobutyl)methoxy)benzoate [00402j Step 1: methyl 3-chloro-4-((3,3-difluorocyclobutyl)methoxy)benzoate [004031 A 1 L flask equipped with a nitrogen inlet, a condenser and a magnetic stirbar was charged with (3,3-difluorocyclobutyl)methyl methanesulfonate (19.7 g, 88.6 mmol) and anhydrous DMF (400 mL). The mixture was treated withmethyl 4-hydroxy-3-methoxy-benzoate (16.1 g, 88.5 mmol) and powdered K2C03 (24.5 g, 177.1 mmol). The reaction mixture was heated at 80 °C for 30 mm. Once the bath reached this temperature, the reaction mixture turned into a very thick gel that rendered magnetic stirring almost inoperative. The reaction mixture requiredintermittent manual stirring of the gel with a spatula for 3 h. Progressively, efficient stirring was restored and the reaction was stirred for an additionaly 4 h. The reactionmixture was cooled down to rt overnight and poured into ice-cold water under stirring (divided into 2 x 1.4 L). The resulting suspensions were stirred at rt for 4 h and were filtered on the same buchner filter. The combined white solid was washed with water (2 x 200 mL) and partially dried by suction. The wet solid was dissolved in DCM (200 mL) and the residual water was separated by decantation. The organic layer was driedover sodium sulfate, filtered, and the solvents concentrated under reduced pressure toafford a crude pink solid. Purification by flash chromatography on silica gel (330 gcolumn ) using a gradient of AcOEt (0 to 70% over 30 mm) in hexanes providedmethyl 3-chloro-4-((3,3-difluorocyclobutyl)methoxy)benzoate (22 g, 88% yield) as awhite solid. ESI-MS mlz calc. 286.0, found 287.0 (M+1); Retention time: 1.57 mm (3minrun).

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2015/6280, 2015, A1 Location in patent: Paragraph 00402; 00403

55
[ 3943-74-6 ]
[ 40557-20-8 ]
C₁₃H₁₅NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With caesium carbonate In dichloromethane at 20℃; for 5h;	64 EXAMPLE 64 Preparation of 2-10 [0417\| Compound 2-12 (4.86 g, 26.7 mmol) was added to a stirring suspension of cesium carbonate (1 5.4 g, 47.5 mmol) in DCM ( 120 mL). A solution of 2-11 (3.13 g. 19.0 mmol) in DCM (20 mL) was added. The mixture was stirred at r.t. for 5 h. The mixturew was filtered through a pad of Celite, washed thoroughly with DCM and concentrated. The residue was dissolved in EtOAc. The organic portion was washed with water and brine, dried with Na2S04, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane: EtOAc 100:0 to 0: 100) afforded 2-13 as a white solid (4.50 g. 89%). UPLC/MS(ES+): m/z 266.15 [M+H]+.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2015/26792, 2015, A1 Location in patent: Paragraph 0417

56
[ 453-20-3 ]
[ 3943-74-6 ]
methyl vanillate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.6%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; for 2h;	100 EXAMPLE 100 Preparation of Compound 235 10492] To a solution of 235-1 ( 1.82 g, 10.0 mmol), tetrahydrofuran-3-ol (880 mg, 10.0 mmol) and PPh3 (2.62 g, 10.0 mmol) in THF (30 mL) at 0 °C was added DIAD (2.02 g, 10.0 mmol) dropwise. The mixture was stirred at 0 °C for 2 h, and the reaction was then quenched with sat. NaHC03 solution. The aqueous layer was extracted by DCM (3x). The combined organic layers were dried over MgSC>4, filtered and concentrated at low pressure. The residue was purified by flash column chromatography on silica gel to give 235-2 (2.4 g, 89.6%).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2015/26792, 2015, A1 Location in patent: Paragraph 0492

57
[ 108-05-4 ]
[ 3943-74-6 ]
methyl 3-methoxy-4-(vinyloxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With bis(1,5-cyclooctadiene)iridium(I) tetrafluoroborate; anhydrous Sodium acetate In 2-methyltetrahydrofuran at 100℃; for 5h; Schlenk technique; Inert atmosphere; Sealed tube;
58%	With bis(1,5-cyclooctadiene)diiridium(I) dichloride; anhydrous sodium carbonate In toluene at 110℃; for 3h; Inert atmosphere;
55%	With di-μ-chlorobis[(1,2,5,6-η)-1,5-cyclooctadiene]diiridium; anhydrous sodium carbonate In toluene at 110℃; for 1.5h; Inert atmosphere;	173 EXAMPLE 173 Preparation of Compound 369 [0688] Methyl vanillate (0.25g, 1 .4 mmol) and vinyl acetate (0.25 mL, 2.7 mmol) were added to [IrCl(cod)]? (9 mg. 0.014) and sodium carbonate (52 mg. 0.49 mmol) in toluene ( 1 mL). The mixture was flushed with Ar and stirred at 1 10 °C for 1 .5 h and then diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 369-1 (0.159 g, 55%). NMR (400 MHz, CDC13): δ 7.61 (dd. J = 1 .6. 8.0, 1 H), 7.0 (d. J = 8.4, 1 H), 6.63 (dd. J = 6.0, 14. 1 H), 4.87 (dd, J = 2.4. 14, 1 H). 4.55 (dd, J = 2.0, 6.0. 1 H), 2.92 (s. 2H), 3.91 (s, 3H).

Reference： [1]Spiegelberg, Brian; Jiao, Haijun; Grauke, Reni; Kubis, Christoph; Spannenberg, Anke; Brandt, Adrian; Taden, Andreas; Beck, Horst; Tin, Sergey; de Vries, Johannes G. [Advanced Synthesis and Catalysis, 2022, vol. 364, # 7, p. 1251 - 1263]
[2]Reed, Carson W.; McGowan, Kevin M.; Spearing, Paul K.; Stansley, Branden J.; Roenfanz, Hanna F.; Engers, Darren W.; Rodriguez, Alice L.; Engelberg, Eileen M.; Luscombe, Vincent B.; Loch, Matthew T.; Remke, Daniel H.; Rook, Jerri M.; Blobaum, Anna L.; Conn, P. Jeffrey; Niswender, Colleen M.; Lindsley, Craig W. [ACS Medicinal Chemistry Letters, 2017, vol. 8, # 12, p. 1326 - 1330]
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2015/26792, 2015, A1 Location in patent: Paragraph 0688

58
[ 3943-74-6 ]
[ 15448-47-2 ]
C₁₂H₁₆O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h;	114 EXAMPLE 114 Preparation of Compounds 255, 256 and 398 [0526] To a solution of 255-1 (5 g, 27 mmol) and (R)-2-methyloxirane (4.7 g, 82 mmol) in DMF ( 100 mL) was added K2C03 (7.4 g, 54 mmol). The mixture was stirred at 80 °C for 3 h. The reaction was quenched with water and extracted by ΕΛ (3 x 50 mL). The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated at low pressure. The residue was purified by column chromatography on silica gel to give 255-2 (6.5 g, 95%).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2015/26792, 2015, A1 Location in patent: Paragraph 0526

59
[ 3943-74-6 ]
[ 100058-61-5 ]
C₂₀H₂₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.7%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 50℃; for 3.08333h;Inert atmosphere;	[0635] A solution of 323-2 (2.0 g, 1 1 .2 mmol), methyl 4-hydroxy-3- methoxybenzoate (2.1 g, 1 1 .5 mmol) and PP1 (4.5 g, 17.3 mmol) was stirred in dry THT (40 mL) at 0 C under a N2 atmosphere. D1AD (3.5 g. 1 7.5 mmol) added dropwise over a period of 5 mins. and the solution was allowed to stir at 50C for 3 h. After disappearance of the starting material, the solvent was evaporated under reduced pressure. The residue was purified on by column chromatography on silica gel (PE:EA 10: 1 ) to give 323-3 as a white solid (2.8 g. 73.7%): -NMR (CDC13, 400 MHz). delta = 7.62-7.60 (dd. J = 1 .6 Hz, J = 10.0 Hz, 1 H), 7.53 (s, 1 H). 7.34-7.25 (m, 5H), 6.66 (d, J= 8.4 Hz, 1 H). 4.96-4.93 (m, 1 H), 4.44 (s. 2H). 4.36-4.32 (m, 1H), 3.93 (s. 3H), 3.87 (s. 3H),2.59-2.54 (m, 4H).

Reference： [1]Patent: WO2015/26792,2015,A1 .Location in patent: Paragraph 0635

60
[ 75-30-9 ]
[ 3943-74-6 ]
[ 3535-27-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium hydride; In N,N-dimethyl-formamide; at 65.0℃; for 1.0h;	[0705] NaH (0.13 g. 3.1 mmol) was added to a solution of methyl vanillate (0.44 g, 2.4 mmol) and 2-iodopropane ( 1 .2 mL. 12 mmol) in DMF (3.0 mL). and the mixture was heated at 65 C for 1 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 378-1 (0.50 g, 93%). NMR (400 MHz, CDC ): delta 7.65 (dd, J = 1.95, 8.6, 1H), 7.55 (d, J = 1.96, 1H), 6.90 (d, J = 8.6, lH), 4.61 -4.66 (m, 1H), 3.91 (s, 3H), 3.58 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H).

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 1326 - 1330
[2]Patent: WO2015/26792,2015,A1 .Location in patent: Paragraph 0705

61
[ 5368-81-0 ]
[ 3943-74-6 ]
[ 6342-70-7 ]
[ 2905-82-0 ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 8084 - 8095

62
[ 3943-74-6 ]
[ 6938-66-5 ]
C₃₁H₅₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%		To methyl vanillate (4.6 g) and potassium carbonate (17.3 g), 1,3-dimethyl-2-imidazolidinone (80 mL) wasadded, then the mixture was stirred at 80C for 30 minutes and then was cooled to 70C. <strong>[6938-66-5]1-Bromodocosane</strong> (10.7 g)was added thereto, and the mixture was stirred at 70C for 15 hours. Water (300 mL) was added to the reaction liquid,the solution was stirred, then the precipitate was collected by suction filtration and washed with water and acetonitrileto obtain the compound represented by E38 (12.1 g, percent yield: 99%). 1H NMR (500 MHz, CDCl3) delta 7.65 (1 H, dd J = 8.5, 1.9 Hz), 7.54 (1 H, d J = 1.9 Hz), 6.87 (1 H, d J = 8.5 Hz),4.06 (2 H, t J = 6.9 Hz), 3.89 (3 H, s), 3.9 (3 H, s), 1.86 (2 H, m), 1.46 (2 H, m), 1.21-1.39 (36 H, br), 0.88 (3 H,t J = 7.0 Hz).

Reference： [1]Patent: EP2921499,2015,A1 .Location in patent: Paragraph 0211; 0212; 0213

63
[ 3943-74-6 ]
[ 536-60-7 ]
C₁₉H₂₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With di-tert-butyl-diazodicarboxylate In dichloromethane at 20℃; for 3h;	A148.a a- Synthesis of Int. 291 a- Synthesis of Int. 291: Under N2, to a suspension of methyl vanillate (2.0 g, 11 mmol), 4-isopropylbenzyl alcohol (1.7 mL, 11 mmol), PP supp. (3.4 g, 11 mmol) in dry DCM (48 mL) was added DBAD (2.5 g, 11 mmol) and the r.m. was stirred at r.t. for 3 h. The mixture was filtrated throught a Celite pad, evaporated in vacuo to give a colorless oil. This oil was purified by prep. LC (irregular SiOH 30 μιη, 120g Interchim, mobile phase gradient: heptane/EtOAc, from 90/10 to 80/20). The pure fractions were collected and solvent evaporated to give 2.22 g of

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2015/144799, 2015, A1 Location in patent: Page/Page column 251

64
[ 3943-74-6 ]
[ 1486-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / acetone 2: methanol; potassium hydroxide
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 1 h / 170 °C / Microwave irradiation; Sealed tube 2: lithium hydroxide; water / tetrahydrofuran
	Multi-step reaction with 2 steps 1: potassium iodide; potassium carbonate / acetone / Inert atmosphere; Reflux 2: sodium hydroxide / ethanol / 2 h / Inert atmosphere; Reflux

Reference： [1]Orlowska, Ewelina; Roller, Alexander; Wiesinger, Hubert; Pignitter, Marc; Jirsa, Franz; Krachler, Regina; Kandioller, Wolfgang; Keppler, Bernhard K. [RSC Advances, 2016, vol. 6, # 46, p. 40238 - 40249]
[2]Reed, Carson W.; Yohn, Samantha E.; Washecheck, Jordan P.; Roenfanz, Hanna F.; Quitalig, Marc C.; Luscombe, Vincent B.; Jenkins, Matthew T.; Rodriguez, Alice L.; Engers, Darren W.; Blobaum, Anna L.; Conn, P. Jeffrey; Niswender, Colleen M.; Lindsley, Craig W. [Journal of Medicinal Chemistry, 2019, vol. 62, # 3, p. 1690 - 1695]
[3]Ruyet, Louise; Poisson, Thomas; Besset, Tatiana [European Journal of Organic Chemistry, 2021, vol. 2021, # 23, p. 3407 - 3410]

65
[ 3943-74-6 ]
[ 109-64-8 ]
[ 130107-96-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1h; Stage #2: 1,3-dibromo-propane In N,N-dimethyl-formamide at 100℃; for 11h;	2 A. General procedure for synthesis of aromatic diesters (2) General procedure: A. General procedure for synthesis of aromatic diesters (2) Into a 250 mL two-necked round bottom flask equipped with a reflux condenser were placed, methyl vanillate/syringate (80 mmol), anhydrous potassium carbonate (44.2 g, 320 mmol) and dry N, N-dimethylformamide (150 mL). The reaction mixture was heated at 100 °C for 1 h and then 1,3-dibromopropane (8.04 g, 40 mmol) was added dropwise. The heating was continued at 100 °C for 11 h. After completion of reaction (TLC), the reaction mixture was poured into ice cold water (500 mL). The solid product was collected by filtration and the solid was dissolved in dichloromethane (300 mL). The dichloromethane solution was washed with water (2x100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in a vacuo. The crude product was purified by silica gel column chromatography. a) Synthesis of dimethyl 4,4'-(propane-l,3-diylbis(oxy))bis(3-methoxybenzoate)Yield: 80 %; M.P.-158 °C;XH NMR (200 MHz, CDC13, δ/ppm): 2.35-2.48 (m, 2H), 3.90 (s, 6H), 4.30 (t, 2H), 6.94 (d, 2H), 7.54 (d, 2H), 7.64 (dd, 2H).13C NMR (50 MHz, CDC13,δ/ppm): 28.9, 52.0, 56.0, 65.4, 111.5, 112.3, 122.8, 123.4, 148.9, 152.2, 166.8
80%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1h; Inert atmosphere; Stage #2: 1,3-dibromo-propane In N,N-dimethyl-formamide at 100℃; Inert atmosphere;
17.7%	With potassium carbonate In dimethyl sulfoxide at 20℃; for 16h;	4 A suspension of methyl 4-hydroxy-3-methoxybenzoate 14 (18 g, 99 mmol), K2C03 (20.48 g, 148 mmol) and 1,3-dibromopropane 15 (5.04 ml, 49.4 mmol) in DMSO (300 mL) was stirred at RT for 16 hours. To the reaction mixture was added water, and the resultingsolution stirred at RT for 20 mm. The resulting precipitate was filtered, washed with water and dried under vacuum. The resulting white solid was triturated with EtOAc/DCM and filtered to give compound 16 (10.45 g, 52.4%) and a dark brown filtrate. The filtrate was purified by ISCO (0 % - 50 % of EtOAC/DCM in 15 minutes, 120 g column) to provide additional compound 16 (3.55 g, 17.7%). LCMS (M+H) = 405; ‘H NIVIR (4001V11{z, DMSO-d6) ö 7.58(dd, J=8.4, 2.0 Hz, 2H), 7.46 (d, J=2.0 Hz, 2H), 7.12 (d, J=8.6 Hz, 2H), 4.22 (t, J=6.2 Hz, 4H),3.83 (s, 6H), 3.81 (s, 6H), 2.24 (t, J=6.2 Hz, 2H);.

With potassium carbonate In dimethyl sulfoxide at 20℃; for 16h;

A suspension of methyl 4-hydroxy-3-methoxybenzoate (10) (18 g, 99 mmol), K2CO3(20.48 g, 148 mmol) and 1,3-dibromopropane (5.04 ml, 49.4 mmol) in DMSO (300 mL) wasstirred at rt for 16 h. Water was added, and the resulting solution was stirred at rt for 20 min.The resulting precipitate was filtered, washed with water and dried under vacuum. The resultingwhite solid was triturated with EtOAc-CH2Cl2 and filtered to give S7 (10.45 g, 52%). Thefiltrate was purified by flash chromatography (120 g silica gel; linear gradient 0-50% EtOAc-CH2Cl2) to provide additional S7 (3.55 g, 18%).

Reference： [1]Current Patent Assignee: COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH (IN) - WO2016/103283, 2016, A1 Location in patent: Page/Page column 8; 9
[2]Kuhire, Sachin S.; Sharma, Pragati; Chakrabarty, Suman; Wadgaonkar, Prakash P. [Journal of Polymer Science, Part A: Polymer Chemistry, 2017, vol. 55, # 21, p. 3636 - 3645]
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2016/209951, 2016, A1 Location in patent: Paragraph 00167-00168
[4]Donnell, Andrew F.; Zhang, Yong; Stang, Erik M.; Wei, Donna D.; Tebben, Andrew J.; Perez, Heidi L.; Schroeder, Gretchen M.; Pan, Chin; Rao, Chetana; Borzilleri, Robert M.; Vite, Gregory D.; Gangwar, Sanjeev [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 23, p. 5267 - 5271]

66
[ 3943-74-6 ]
[ 936643-80-0 ]
methyl 3-methoxy-4-(pyrimidin-2-ylmethoxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;	A solution of methyl 4-hydroxy-3-methoxybenzoate (0.778 g, 4.3 mmol, 1 eq.), 2- chloromethylpyrimidine hydrochloride (0.775 g, 4.7 mmol, 1.1 eq.) and potassium carbonate (1.77 g, 12.8 mmol, 3 eq.) in N,N-dimethylformamide (8 mL) was stirred at 100 C overnight. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, 2M aqueous sodium hydroxide and brine. The solvent was removed in vacuo to afford methyl 3-methoxy-4- (pynmidin-2-ylmethoxy)benzoate (0.295 g, 25% yield). NMR (400 MHz, CDC13) 8.78 (2H, d, J=4.9 Hz), 7.62 - 7.57 (2H, m), 7.24 (1H, t, J=4.9 Hz), 6.88 (1H, d, J=8.3 Hz), 5.42 (2H, s), 3.95 (3H, s), 3.88 (3H, s).

Reference： [1]Patent: WO2016/98005,2016,A1 .Location in patent: Page/Page column 90; 91

67
[ 3943-74-6 ]
[ 34469-09-5 ]
(R)-methyl 4-(2-(dimethylamino)-1-phenylethoxy)-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With triphenylphosphine; diethylazodicarboxylate In dichloromethane at 31 - 40℃; for 23.5h;	6.b b) (R)-methyl 4-(2-(dimethylamino)-l-phenylethoxy)-3-methoxybenzoate (Compound of Formula I -IV , Scheme 1) To a stirred solution of (i?)-2-(dimethylamino)-l -phenylethanol (5.1 g, 30.9 mmol, 1 eq.), methyl vanillate (6.2 g, 34 mmol, 1.1 eq.) and triphenyl phosphine (12.1 g, 46.3 mmol, 1.5eq.) in dichloromethane (150 mL) at 31°C was added diethylazodicarboxylate (7.6 mL, 46.3 mmol, 1.5 eq.) dropwise over a period of 30 minutes at such a rate so as to maintain the temperature between 33-40 °C. The resulting mixture was then stirred at room temperature for 23 hours. The solvent removed in vacuo. The crude product was dissolved in methanol (100 mL) divided into two portions and each portion loaded onto a Biotage SCX-2 cartidge (70 g). The cartridges were washed through with methanol (250 mL) and the product eluted with ammonia in methanol (3.5 M), evaporation in vacuo yielded (R)-4- (2-(dimethylamino)-l-phenylethoxy)-3-methoxybenzoic acid as a yellow liquid (9.21 g, 91 % yield). NMR (400 MHz, CDC13) 7.51 (IH, d, J=2.0 Hz), 7.44 (IH, dd, J=2.0, 8.6 Hz), 7.37 - 7.28 (4H, m), 7.28 - 7.21 (IH, m), 6.69 (IH, d, J=8.3 Hz), 5.38 (IH, dd, J=3.5, 8.3 Hz), 3.92 (3H, s), 3.84 (3H, s), 3.05 (IH, dd, J=8.5, 13.5 Hz), 2.65 (IH, dd, J=3.5, 13.6 Hz), 2.38 (6H, s).

Reference： [1]Current Patent Assignee: CALLIDITAS THERAPEUTICS AB - WO2016/98005, 2016, A1 Location in patent: Page/Page column 69

68
[ 50-00-0 ]
[ 3943-74-6 ]
[ 2549-14-6 ]
(R)-methyl 4-(2-(dimethylamino)-1-phenylethoxy)-3-methoxybenzoate [ No CAS ]
(S)-methyl 3-methoxy-4-(2-(methylamino)-1-phenylethoxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of (i?)-2-amino-l -phenylethanol (0.627 g, 4.5 mmol, 1 eq), formic acid (4 mL) and formaldehyde (37 wt % in water, 8 mL) was stirred at 95C overnight. 2M Hydrochloric acid (5 mL) was added and the reaction washed twice with diethyl ether. The aqueous solution was cooled in an ice bath and basified to pH 14 with sodium hydroxide. The mixture was extracted with dichloromethane (x3), the combined extracts dried with magnesium sulfate and evaporated in vacuo to afford a mixture of (i?)-2-(methylamino)-l- phenylethanol and (i?)-2-(dimethylamino)-l-phenylethanol. To a stirred solution of (i?)-2-(methylamino)-l-phenylethanol and (i?)-2-(dimethylamino)- 1 -phenylethanol (0.405 g, 2.45 mmol, 1.5 eq.), methyl 4-hydroxy-3-methoxybenzoate (0.3 g, 1.6 mmol, 1.0 eq.) and triphenyl phosphine (0.65 g, 2.45 mmol, 1.5 eq.) in dichloromethane (8 mL) cooled in an ice bath was added diethylazodicarboxylate (400 muL , 2.45 mmol, 1.5 eq.) dropwise over a period of 20 minutes. The organic solution was loaded onto a Biotage SCX-2 cartidge (20 g). The cartridge was washed through with methanol (120 mL) and the product eluted with ammonia in methanol (3.5 M, lOOmL), evaporation in vacuo yielded a mixture of (S)-methyl 3-methoxy-4-(2-(methylamino)-l- phenylethoxy)benzoate and (i?)-methyl 4-(2-(dimethylamino)-l -phenylethoxy)-3- methoxybenzoate (0.65 g). The mixture was dissolved in dichloromethane (7 mL) and triethylamine (450 muL, 3.5 mmol, 3eq.) and cooled in an ice bath. Di-ieri-butyl dicarbonate (0.24 g, l .lmmol, 1.1 eq.) was added and the ice bath removed and the resultant mixture stirred at ambient temperature for 1 hour. The crude mixture was purified by silica gel column chromatography using 20-100 % ethyl acetate in iso- exane gradient to afford (S)- methyl 4-(2-((ieri-butoxycarbonyl)(methyl)amino)-l -phenylethoxy)-3-methoxybenzoate as a clear oil (0.1 g, 23% yield). NMR (400 MHz, CDC13) 7.53 (1H, d, J=2.0 Hz), 7.48 - 7.38 (2H, m), 7.36 - 7.27 (4H, m), 6.69 (0.5H, d, J=8.6 Hz), 6.63 (0.5H, d, J=8.6 Hz), 5.52 (0.5H, dd, J=3.4, 8.0 Hz), 5.35 (0.5H, dd, J=4.4, 7.5 Hz), 3.93 (3H, s), 3.85 (3H, s), 3.80 - 3.76 (1H, m), 3.59 - 3.43 (1H, m), 1.87 - 1.83 (3H, m), 1.43 (9H, s) rotamenc forms observed in NMR.

Reference： [1]Patent: WO2016/98005,2016,A1 .Location in patent: Page/Page column 83; 84

69
[ 50-00-0 ]
[ 3943-74-6 ]
[ 24424-99-5 ]
[ 2549-14-6 ]
(S)-methyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)-1-phenylethoxy)-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%		A mixture of (i?)-2-amino-l -phenylethanol (0.627 g, 4.5 mmol, 1 eq), formic acid (4 mL) and formaldehyde (37 wt % in water, 8 mL) was stirred at 95C overnight. 2M Hydrochloric acid (5 mL) was added and the reaction washed twice with diethyl ether. The aqueous solution was cooled in an ice bath and basified to pH 14 with sodium hydroxide. The mixture was extracted with dichloromethane (x3), the combined extracts dried with magnesium sulfate and evaporated in vacuo to afford a mixture of (i?)-2-(methylamino)-l- phenylethanol and (i?)-2-(dimethylamino)-l-phenylethanol. To a stirred solution of (i?)-2-(methylamino)-l-phenylethanol and (i?)-2-(dimethylamino)- 1 -phenylethanol (0.405 g, 2.45 mmol, 1.5 eq.), methyl 4-hydroxy-3-methoxybenzoate (0.3 g, 1.6 mmol, 1.0 eq.) and triphenyl phosphine (0.65 g, 2.45 mmol, 1.5 eq.) in dichloromethane (8 mL) cooled in an ice bath was added diethylazodicarboxylate (400 muL , 2.45 mmol, 1.5 eq.) dropwise over a period of 20 minutes. The organic solution was loaded onto a Biotage SCX-2 cartidge (20 g). The cartridge was washed through with methanol (120 mL) and the product eluted with ammonia in methanol (3.5 M, lOOmL), evaporation in vacuo yielded a mixture of (S)-methyl 3-methoxy-4-(2-(methylamino)-l- phenylethoxy)benzoate and (i?)-methyl 4-(2-(dimethylamino)-l -phenylethoxy)-3- methoxybenzoate (0.65 g). The mixture was dissolved in dichloromethane (7 mL) and triethylamine (450 muL, 3.5 mmol, 3eq.) and cooled in an ice bath. Di-ieri-butyl dicarbonate (0.24 g, l .lmmol, 1.1 eq.) was added and the ice bath removed and the resultant mixture stirred at ambient temperature for 1 hour. The crude mixture was purified by silica gel column chromatography using 20-100 % ethyl acetate in iso- exane gradient to afford (S)- methyl 4-(2-((ieri-butoxycarbonyl)(methyl)amino)-l -phenylethoxy)-3-methoxybenzoate as a clear oil (0.1 g, 23% yield). NMR (400 MHz, CDC13) 7.53 (1H, d, J=2.0 Hz), 7.48 - 7.38 (2H, m), 7.36 - 7.27 (4H, m), 6.69 (0.5H, d, J=8.6 Hz), 6.63 (0.5H, d, J=8.6 Hz), 5.52 (0.5H, dd, J=3.4, 8.0 Hz), 5.35 (0.5H, dd, J=4.4, 7.5 Hz), 3.93 (3H, s), 3.85 (3H, s), 3.80 - 3.76 (1H, m), 3.59 - 3.43 (1H, m), 1.87 - 1.83 (3H, m), 1.43 (9H, s) rotamenc forms observed in NMR.

Reference： [1]Patent: WO2016/98005,2016,A1 .Location in patent: Page/Page column 83; 84

70
[ 3943-74-6 ]
[ 178215-45-7 ]
C₁₆H₂₀O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate In acetone at 60℃; for 1.5h;	A mixture of methyl vanillate (402.2 mg, 2.21 mmol), EC2153 (502.9 mg, 2.43 mmol), andK2C03 (0.6 g, 4.42 mmol) in anhydrous acetone (8.84 mL) was heated with stirring at 60°C for1.5 hr. The reaction was cooled to ambient temperature, the solid was filtered out, andconcentrated under reduced pressure to give a residue, which was purified by CombiFlash in 0-25% EtOAc/p-ether to give 678.8 mg of EC2314 (yield 99%). LCMS: [M+H] mlz =309. ‘HNMR (500 MHz, CDC13) 5 7.64 (dd,J = 8.80, 1.96 Hz, 1H), 7.53 (d, I = 1.96 Hz, 1H), 5.90 (m,1H), 5.32 (dd, I = 17.60, 1.95 Hz, 1H), 5.23 (dd, I = 10.27, 0.98 Hz, 1H), 4.59 (dd, I = 5.87,

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2016/148674, 2016, A1 Location in patent: Page/Page column 129; 130

71
[ 3943-74-6 ]
[ 6940-76-7 ]
[ 214470-57-2 ]

Reference： [1]ChemMedChem,2016,vol. 11,p. 2327 - 2338

72
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[ 5544-60-5 ]
methyl 3-methoxy-4-(4-hydroxybenzyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate; In acetonitrile; for 12h;	Methyl vanillinate (1.0 g, 5.49 mmol) and potassium carbonate(1.13 g, 8.24 mmol) was added acetonitrile (30 ml).4-Benzyloxybenzyl bromide (1.83 g, 6.59 mmol) was added and stirred for 12 h. The reaction solution was suction filtered through celite, and the solvent was distilled off under reduced pressure.Ethyl acetate (30 ml) and 1 N HCl aqueous solution (30 ml) were added to the residue,and extracted. Further, the aqueous layer was extracted twice with ethyl acetate (20 ml).The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography(Hexane: ethyl acetate = 3: 1). The obtained solid was washed with waterRecrystallization with ethyl acetate and hexane, to give methyl 3-methoxy-4- (4-hydroxybenzyl)benzoate(1.68 g, 83%) as a white solid.

Reference： [1]Patent: JP5765650,2015,B2 .Location in patent: Paragraph 0070

73
[ 3943-74-6 ]
[ 60771-18-8 ]

Reference： [1]MedChemComm,2017,vol. 8,p. 1069 - 1092

74
[ 19748-66-4 ]
[ 3943-74-6 ]
methyl 3-methoxy-4-(3-pyrrolidin-1-ylpropoxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 30h;	To a solution of commercially available methyl 4-hydroxy-3-methoxy-benzoate (1-12a, 146 g, 800 mmol) in THF (4 L) was added DIAD (323 g, 1 .60 mol), 3- pyrrolidin-1 -ylpropan-1 -ol (R-01 a, 103 g, 800 mmol) and PPh3 (419 g, 1 .60 mol) at 0 °C and the solution was stirred at room temperature for 30 hours. Then, the reaction mixture was concentrated and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product which was purified by column chromatography to give intermediate 1-13a (176 g, 75percent). ESI-MS (M+1 ): 294.0 calc.for C16H23NO4: 293.2.

Reference： [1]Patent: WO2017/85053,2017,A1 .Location in patent: Page/Page column 72; 73

75
[ 3943-74-6 ]
[ 99-50-3 ]
[ 2150-43-8 ]

Yield	Reaction Conditions	Operation in experiment
1: 72% 2: 14%	With aluminium(III) iodide; ethyl acetate; diisopropyl-carbodiimide In acetonitrile at 80℃; for 5h;
1: 31% 2: 64%	With aluminium(III) iodide; diisopropyl-carbodiimide In acetonitrile at 40℃; for 18h; Overall yield = 89 %; Overall yield = 0.684 g;	30 Example 29 (methyl vanillate demethylation) To a 100 ml eggplant flask were added aluminum triiodide (2.247 g), Acetonitrile (40 ml) DIC (0.378 g) and vanillic acid methyl ester (0.909 g), heated to 40 ° C, After stirring for 18 hours, the mixture was stirred, cooled to room temperature and then acidified with 2 mol / L dilute hydrochloric acid (10 ml) And extracted with ethyl acetate (50 ml X). The combined organic phases were washed first with a saturated aqueous solution of sodium thiosulfate (10 ml), washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated Instrument evaporated, The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 3: 7, volume ratio) 0.260 g of methyl catecholate (white solid, 31% yield) and unreacted starting material (2 mg) were obtained. The polarity of the eluent was increased to ethyl acetate / petroleum ether = 1: 1 (volume ratio) To give 0.496 g of protocatechuic acid (white solid, 64% yield)

Reference： [1]Tian, Juan; Yi, Cuicui; Fang, Huasheng; Sang, Dayong; He, Zhoujun; Wang, Jiahui; Gan, Yongjiang; An, Qing [Tetrahedron Letters, 2017, vol. 58, # 36, p. 3522 - 3524]
[2]Current Patent Assignee: JINGCHU UNIVERSITY OF TECHNOLOGY - CN106866377, 2017, A Location in patent: Paragraph 0125-0127

76
[ 111-24-0 ]
[ 3943-74-6 ]
[ 145325-42-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 3h; Inert atmosphere;	I: To a solution of methyl vanillate (6.84 g, 37.5 mmol) dissolved in dry DMF (30 mL), was added 1,5-dibromopentane (2.44 mL, 17.9 mmol) and K2CO3 (19.7 g, 142 mmol). The reaction mixture was heatedto 75 °C under Ar for 3 h. The reaction was cooled to r.t. and the solid was filtered out. The filtrate wasdiluted with ether (200 mL), and the resulting organic phase was washed with 10% aq. NH4Cl solution 3times, with white precipitate formation in the organic layer. Dichloromethane was added to the organic layer to dissolve white precipitate, then washed again with 10% aq. NH4Cl solution to remove residualDMF. Organic layer was dried over anhydrous sodium sulfate. After filtration, the solution wasevaporated under high vacuum. 7.92 g, (95% purity) of I was obtained in quantitative yields and usedwithout further purification.
7.92 g	With potassium carbonate In N,N-dimethyl-formamide for 3h; Inert atmosphere;

Reference： [1]Felten, Albert; Hahn, Spencer J.; Klein, Hanna F.; Kleindl, Paul J.; Leamon, Christopher P.; Nicoson, Jeff; Parham, Garth L.; Qi, Longwu; Reddy, Joe; Reno, Dan; Santhapuram, Hari Krishna R.; Vaughn, Jeremy F.; Vlahov, Iontcho R.; Wang, Kevin; You, Fei; Zou, Ning [Bioorganic and medicinal chemistry letters, 2020]
[2]Vlahov, Iontcho R.; Qi, Longwu; Kleindl, Paul J.; Santhapuram, Hari K.; Felten, Albert; Parham, Garth L.; Wang, Kevin; You, Fei; Vaughn, Jeremy F.; Hahn, Spencer J.; Klein, Hanna F.; Vetzel, Marilynn; Reddy, Joseph A.; Nelson, Melissa; Nicoson, Jeff; Leamon, Christopher P. [Bioconjugate Chemistry, 2017, vol. 28, # 12, p. 2921 - 2931]

77
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[ 108549-23-1 ]
methyl 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With 1H-tetrazole; dihydrogen peroxide In dichloromethane; water at 0 - 20℃; for 1h;	434.434A 434A: To a mixture of methyl vanillate (250 mg, 1.372 mmol) in DCM (2745 μ) was added dibenzyl N,N-diisopropylphosphoramidite (677 μ, 2.058 mmol) followed by tetrazole (0.45 M in acetonitrile) (4574 μ, 2.058 mmol). The resulting mixture was stirred at rt 1 h. TLC indicated the starting material had been consumed. The reaction mixture was cooled to 0 °C and hydrogen peroxide (35% in water) (1180 μ, 13.72 mmol) was added. The mixture was allowed to come to rt and stir for 1 h. TLC indicated the product of step 1 had been consumed. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over MgS04, filtered and concentrated in vacuo. Purification by flash chromatography (silica, 24g, 0-75% EtOAc/Hexanes) gave methyl 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate (594 mg, 1.343 mmol, 98 % yield). MSESI m/z 443.1 (M+H) 1H NMR (400MHz, DMSO-d6) δ 7.63-7.54 (m, 2H), 7.40-7.37 (m, 10H), 7.35-7.31 (m, 1H), 5.22-5.20 (m, 2H), 5.19 (s, 2H), 3.87 (s, 3H), 3.86-3.85 (m, 3H).
97%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane; acetonitrile at 20℃; for 8h; Stage #2: With dihydrogen peroxide In dichloromethane; acetonitrile at 20℃; for 2h;	2.2A 2 A: Methyl 4-((/>A(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate To a stirred solution of methyl 4-hydroxy-3-methoxybenzoate (3.000 g, 16.47 mmol) in dry dichloromethane (30 mL), was added dibenzyl N,N- diisopropylphosphoramidite (8.30 mL, 24.70 mmol), and liTtetrazole (0.4 M in acetonitrile, 73.0 mL, 24.70 mmol). The mixture was stirred at room temperature for 8 h and cooled to 0 °C. H2O2 (5.05 mL, 165 mmol) was added. The mixture was stirred at room temperature for 2 h, diluted with water and extracted with dichloromethane (3 xlOO mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum at ~30 °C to give colorless oil. The crude product was purified by ISCO (silica gel 60-120 mesh; 30% ethyl acetate in hexane as eluent) to give methyl 4-((/>A(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate (8.200 g, 15.94 mmol, 97%) as a colorless oil. NMK (400 MHz, chloroform-tf) d ppm = 7.59 - 7.56 (m, 2H), 7.37 - 7.33 (m, 10H), 7.27 (dd, J=8.3, 1.1 Hz, 1H), 5.17 (d, =8.3 Hz, 4H), 3.91 (s, 3H), 3.84 (s, 3H). LC-MS (ES): m/z= 443 [M+H]+.
97%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane; acetonitrile at 20℃; for 8h; Stage #2: With dihydrogen peroxide In dichloromethane; acetonitrile at 0 - 20℃; for 2h;	5.1 Step 1 (0215) Methyl 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate To a solution of methyl 4-hydroxy-3-methoxybenzoate (3.000 g, 16.47 mmol) in dichloromethane (30 mL), was added dibenzyl-/V,/V-diisopropylphosphoramidite (8.30 mL, 24.70 mmol) followed by 1H-tetrazole (73.0 mL, 24.70 mmol) (0.45 M in acetonitrile) and the mixture was stirred at room temperature for 8 h. The reaction was cooled at 0 °C. H2O2 (5.05 mL, 165 mmol) was added. After being stirred at room temperature for 2 h, the reaction mixture was concentrated to remove acetonitrile and the remaining aqueous layer was diluted with water, and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by ISCO [silica gel 60- 120 mesh, column size 80 g, ethyl acetate in hexane as eluent]. The product was eluted at 30% ethyl acetate in hexane to get the title compound (8.200 g, 15.94 mmol, 97% yield) as a colourless oil. 1H NMR (400 MHz, CDCl3) d 3.84 (s, 3H), 3.91 (s, 3H), 5.16 (s, 2H), 5.18 (s, 2H), 7.25 (d, J= 8.00 Hz, 1H), 7.31-7.37 (m, 10H), 7.57 (d, J= 9.20 Hz, 2H).; LC-MS (ES): m/z = 443.2 [M+H]+

Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester; Dibenzyl N,N-diisopropylphosphoramidite With 1H-tetrazole In dichloromethane; acetonitrile at 20℃; for 8h; Stage #2: With dihydrogen peroxide In dichloromethane; acetonitrile at 0 - 20℃; for 2h;

429A 429A: Methyl 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate: To a solution of methyl 4-hydroxy-3-methoxybenzoate (5.00 g, 27.4 mmol) in dichloromethane (50 mL)was added dibenzyl N,N-diisopropylphosphoramidite (13.83 mL, 41.2 mmol) followed by 1H-tetrazole (0.45 M in acetonitrile) (122 mL, 41.2 mmol) and the mixture stirred at rt for 8 h. The reaction was cooled at 0 °C and H202 (8.41 mL, 274 mmol) was added. The mixture was then stirred at rt for 2 h. The reaction was concentrated to remove the acetonitrile and the obtained aqueous layer was diluted and extracted with ethyl acetate (3x 100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to get a colorless oil. The cmde material was purified by silica gel chromatography, eluting with ethyl acetate in hexane. The product was eluted at 30% ethyl acetate in hexane to give methyl 4- ((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoate (10. 600 g, 20.61 mmol, 75 %yield) as a colorless oil. MS ESI m/z 443.2 (M+H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2019/89442, 2019, A1 Location in patent: Page/Page column 232
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2019/136112, 2019, A1 Location in patent: Page/Page column 47; 48
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2021/11513, 2021, A1 Location in patent: Page/Page column 43-44
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2018/148626, 2018, A1 Location in patent: Page/Page column 413

78
[ 3943-74-6 ]
[ 71999-74-1 ]
[ 1569084-51-0 ]

Reference： [1]Journal of Polymer Science, Part A: Polymer Chemistry,2018,vol. 56,p. 2154 - 2160

79
[ 3943-74-6 ]
[ 93489-14-6 ]

Reference： [1]Patent: US6384080,2002,B1

80
[ 3943-74-6 ]
[ 60758-86-3 ]

Reference： [1]Patent: US6384080,2002,B1
[2]Patent: US6384080,2002,B1
[3]Patent: US6384080,2002,B1
[4]Patent: US6384080,2002,B1

81
[ 3943-74-6 ]
[ 108439-67-4 ]

Reference： [1]Patent: US6384080,2002,B1
[2]Patent: US6384080,2002,B1
[3]Patent: US6384080,2002,B1
[4]Patent: US6384080,2002,B1
[5]Patent: US6384080,2002,B1

82
[ 3943-74-6 ]
[ 1809-10-5 ]
methyl 3-methoxy-4-(pentan-3-yloxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium hydride; sodium iodide In mineral oil at 65℃;
37%	With sodium hydride; sodium iodide In N,N-dimethyl-formamide; mineral oil at 65℃; for 4h;	methyl 4-(sec-butoxy)-3-methoxybenzoate General procedure: The title compound was synthesized by the method described previously with slight modifications151. To a DM F solution of methyl 4-hydroxy-3-methoxybenzoate (440 mg, 2.4 mmol, 1 equiv) was slowly added sodium hydride (60 % dispersion in mineral oil, 150 mg, 3.75 mmol, 1 .56 equiv) followed by 2-iodobutane (1 .4 mL, 12 mmol, 5 equiv). The solution was heated to 65°C and stirred 4 h. After cooling to rt, aqueous saturated LiCI was added and extracted with ethyl acetate. The organic layer was combined and washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography (Hexane: ethyl acetate = 5:1) gave the title compound as a white powder (200 mg, 35 %).1H NMR (500 MHz, CDCIs) δ 7.64 (dd, J = 8.5, 2.0 Hz, 1 H), 7.55 (d, J = 2.0 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 4.42 - 4.35 (m, 1 H), 3.90 - 3.88 (m, 6H), 1.89 - 1.77 (m, 1 H), 1.74 - 1.60 (m, 1 H), 1.35 (d, J = 6.1 Hz, 3H), 0.99 (t, J = 7.5 Hz, 3H).13C NMR (126 MHz, DMSO)5166.9, 151.9, 149.7, 123.4, 122.4, 113.4, 112.8, 76.5, 56.1, 51.9, 29.1, 19.2, 9.8.

Reference： [1]Kitamura, Seiya; Owensby, Anna; Wall, Daniel; Wolan, Dennis W. [Cell Chemical Biology, 2018, vol. 25, # 3, p. 301 - 12,308]
[2]Current Patent Assignee: SCRIPPS RESEARCH - WO2019/10165, 2019, A1 Location in patent: Page/Page column 36-38

83
[ 3943-74-6 ]
[ 4163-60-4 ]
(2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(2-methoxy-4-(methoxycarbonyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester; β-D-galactose peracetate With triethylamine In dichloromethane for 1h; Inert atmosphere; Molecular sieve; Stage #2: With boron trifluoride diethyl etherate In dichloromethane at 0℃; for 8h; Inert atmosphere; Molecular sieve;	4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)vanillic acid methyl ester (6) A mixture of methyl ester 5 (2.73 g, 15.0 mmol), 1,2,3,4,6-penta-O-acetyl-β-D-galactopyranoside 1 (2.90 g, 7.5 mmol), triethylamine (1.0 mL, 7.0 mmol) and freshly activated molecular sieves (4 Å) in dry CH2Cl2 (40 mL) were stirred under argon for 1 h . BF3·OEt2 (2.5 mL, 20.0 mmol) was added and the reaction mixture was kept for 8 h at 0°C and monitored by TLC. After completion, the mixture was diluted with CH2Cl2 (30 mL) and washed with water (10 mL), saturated aqueous NaHCO3 (10 mL) and water (3×10 mL). The organic phase was separated, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane gradient elution) to afford the title compound (3.0 g, 80% yield) as white crystals.

Reference： [1]Al Bujuq, Nader; Arar, Sharif; Khalil, Raida [Natural Product Research, 2017, p. 1 - 7]

84
[ 3943-74-6 ]
benzyl halide [ No CAS ]
[ 56441-97-5 ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 1690 - 1695

85
[ 3943-74-6 ]
[ 2895-21-8 ]
4-[2-(isopropylamino)-2-oxoethoxy]-3-methoxybenzoic acid [ No CAS ]

Reference： [1]Patent: WO2019/145729,2019,A1

86
[ 3943-74-6 ]
[ 2895-21-8 ]
methyl 4-[2-(isopropylamino)-2-oxoethoxy]-3-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 18h;Inert atmosphere;	To a stirred solution of methyl vanillate (228 mg, 1.50 mmol) and potassium carbonate (829 mg, 6.00 mmol) in DMF (10 mL) at r.t. under N2 was added <strong>[2895-21-8]2-chloro-N-isopropylacetamide</strong> (274 mg, 2.00 mmol) in a single portion and the reaction heated at 80 C for 18 h. The solvents were removed under reduced pressure and the residue partitioned between EtOAc (20 mL) and H2O (20 mL). The layers were separated and the aqueous layer extracted with further EtOAc (2 x 15 mL). The combined organics were washed with H2O (20 mL) and brine (20 mL), dried (phase separator) and concentrated. The crude product was purified by flash column chromatography (SiO2, eluting with 30-80% EtOAc in Pet. Ether) giving methyl 4-[2- (isopropylamino)-2-oxoethoxy]-3-methoxybenzoate (278 mg, 0.99 mmol, 66% yield) as an off-white solid. LC-MS (ES+, Method C): 2.22 min, m/z 282.1 [M+H]+.1H NMR (500 MHz, CDCl3): delta 7.66 (dd, J = 8.5, 2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.68 (s, 1H), 4.54 (s, 2H), 4.15 (dp, J = 8.0, 6.5 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 1.19 (s, 3H), 1.18 (s, 3H)

Reference： [1]Patent: WO2019/145729,2019,A1 .Location in patent: Page/Page column 92

87
[ 771430-70-7 ]
[ 3943-74-6 ]
4,4'-((2-(prop-2-yn-1-yl)propane-1,3-diyl)bis(oxy))bis(3-methoxybenzoic acid methyl ester) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 4-hydroxy-3-methoxybenzoic acid methyl ester With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0℃; for 0.583333h; Inert atmosphere; Stage #2: 2-(prop-2-yn-1-yl)propane-1,3-diol In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;	6.A 4,4'-((2-(Prop-2-yn-l-yl)propane-l,3-diyl)bis(oxy))bis(3-methoxybenzoic acid methyl ester) (26) Method A. Under argon, at 0 °C, to a solution of (10) (900 mg, 4.9 mmol) and triphenylphosphine (3.24 g, 12.4 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise diethyl azodicarboxylate (1.95 mL, 9.9 mmol) over 5 min. After addition, the resulting mixture was vigorously stirred at 0 °C for 30 min and a solution of 2-(prop-2-ynyl)propane-l,3-diol (170 mg, 2.4 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise. The reaction mixture was stirred at 0 °C for an additional 1 hr and concentrated under reduced pressure. The crude residue was purified by column chromatography, eluent petroleum ether-EtOAc (3:1) to afford the 4,4'-((2-(Prop-2-yn-l- yl)propane-l,3-diyl)bis(oxy))bis(3-methoxybenzoic acid methyl ester) (26) (1 g, quantitative) as a white crystal. NMR (400 MHz, CDC13) d 7.63 (d, J =8.2 Hz, 2H), 7.53 (s, 2H), 6.95 (d, J =8.2 Hz, 2H), 4.26 (m, 4H), 3.88 (s, 6H), 3.87 (s, 6H), 2.69 (sept, J =5.6 Hz, 1H), 2.62 (dd, J =5.6 and 2.7 Hz, 2H) and 2.02 {t, J =2.1 Hz, 1H); 13C NMR (100 MHz, CDC13) d 166.9, 152.3, 149.1, 123.5, 123.0, 112.5, 112.1, 81.3, 70.6, 68.1, 56.1, 52.1, 37.9 and 18.1. LCMS C24H2608 Rt = 7.131 min, ESI+ m/z = 411.0 (M-OMe).

Reference： [1]Current Patent Assignee: PAOLI CALMETTES INSTITUTE; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; AIX-MARSEILLE UNIVERSITY - WO2021/74392, 2021, A1 Location in patent: Page/Page column 44; 45-46

88
[ 67-56-1 ]
[ 498-00-0 ]
[ 3943-74-6 ]

Yield	Reaction Conditions	Operation in experiment
84 %Chromat.	With potassium carbonate at 55℃; for 24h;	S6. Procedure for the synthesis of esters General procedure: A magnetic stir bar and the alcohol substrate were transferred to 20 mL glass tube and then 2 mL of MeOH oralcohol was added. Then, 35 mg catalyst and 10 mol% of K2CO3 were added. The glass tube containingreaction mixture was fitted with septum and connected to a balloon containing one bar air. Then the glass tubewas placed into a preheated aluminum block at 60°C. Temperature inside the reaction tube was measured tobe 55 oC and this temperature has been taken as the reaction temperature. After completion of the reaction,the glass tube was cooled down to room temperature. Af terwards, the catalyst was f iltered-off and washedwith methanol. The solvent from the filtrate containing the reaction products was removed in vacuum and thecorresponding ester was purified by column chromatography. Products were analyzed by GC-MS and NMRspectroscopy analysis. In the case of yields determined the by GC, 100 μL n-hexadecane was added to thereaction vial containing the products and diluted with ethyl acetate. Then catalyst was f iltered through a plugof silica and the filtrate containing product was analyzed by GC.

Reference： [1]Bartling, Stephan; Beller, Matthias; Chandrashekhar, Vishwas G.; Jagadeesh, Rajenahally V.; Rabeah, Jabor; Rockstroh, Nils; Senthamarai, Thirusangumurugan [Chem, 2022, vol. 8, # 2, p. 508 - 531]

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[ CAS No. 3943-74-6 ] {[proInfo.proName]}

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[ 3943-74-6 ] Synthesis Path-Upstream 1~21

[ 3943-74-6 ] Synthesis Path-Downstream 1~88

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[ CAS No. 3943-74-6 ] {[proInfo.proName]}

Quality Control of [ 3943-74-6 ]

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Application In Synthesis of [ 3943-74-6 ]

[ 3943-74-6 ] Synthesis Path-Upstream 1~21

[ 3943-74-6 ] Synthesis Path-Downstream 1~88

Pharmaceutical Intermediates of [ 3943-74-6 ]

Bosutinib Intermediates

Vandetanib Related Intermediates

Related Functional Groups of [ 3943-74-6 ]

Aryls

Ethers

Esters

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Pharmaceutical Intermediates of
[ 3943-74-6 ]

Related Functional Groups of
[ 3943-74-6 ]