[ CAS No. 18179-39-0 ]

Name: 18179-39-0|Methyl 2-hydroxy-4-iodobenzoate|97%
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Quality Control of [ 18179-39-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 18179-39-0 ]

Product Details of [ 18179-39-0 ]

CAS No. :	18179-39-0	MDL No. :	MFCD06797864
Formula :	C₈H₇IO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WUFUURSWOJROKY-UHFFFAOYSA-N
M.W :	278.04	Pubchem ID :	11380407
Synonyms :

Calculated chemistry of [ 18179-39-0 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	52.46
TPSA :	46.53 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) :	-5.72 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.06
Log Po/w (XLOGP3) :	3.2
Log Po/w (WLOGP) :	1.78
Log Po/w (MLOGP) :	2.21
Log Po/w (SILICOS-IT) :	2.18
Consensus Log Po/w :	2.29

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.82
Solubility :	0.0423 mg/ml ; 0.000152 mol/l
Class :	Soluble
Log S (Ali) :	-3.85
Solubility :	0.0394 mg/ml ; 0.000142 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.85
Solubility :	0.395 mg/ml ; 0.00142 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.89

Safety of [ 18179-39-0 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 18179-39-0 ]

* 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 [ 18179-39-0 ]
Downstream synthetic route of [ 18179-39-0 ]

[ 18179-39-0 ] Synthesis Path-Upstream 1~9

1
[ 16870-28-3 ]
[ 74-88-4 ]
[ 18179-39-0 ]

Yield	Reaction Conditions	Operation in experiment
76.5%	Stage #1: With sodium hydrogencarbonate In N,N-dimethyl-formamide for 0.0833333 h; Stage #2: at 40℃; for 5 h;	4-Iodosalicylic acid 60 (7.3 g, 27.65 mmol) was dissolved in 41 ml DMF and NaHCO₃ (2.78 g, 33.18 mmol) were added (evolution of CO₂) and the mixture stirred for 5 min. MeI (2.66 ml, 5.85 g, 41.47 mmol, 1.5 eq) was added and the reaction mixture was heated to 40° C. for 5 h while stirring (monitored by TLC). Upon reaction completion, the mixture was diluted with 170 ml H₂O and 170 ml EA. The organic layer was subsequently washed with 170 ml of 5percent NaHCO₃, 170 ml 5percent NaCl and was dried over Na₂SO₄. The solvent was evaporated to give ˜9 g of crude oily product (black color), which was purified by column chromatography: SiO₂ (100 g), Hexane, Hexane:EA 100:2. 5.86 g, Yield: 76.5percent.

Reference： [1] Patent: US2016/2269, 2016, A1, . Location in patent: Paragraph 0253; 0254

2
[ 67-56-1 ]
[ 16870-28-3 ]
[ 18179-39-0 ]

Yield	Reaction Conditions	Operation in experiment
50%	for 10 h; Reflux	Synthesis of Compound 3 10.0 g (37.8 mmol) of Compound 2 was taken in 200.0 ml dry methanol. To this 11.5 ml (151.0 mmol) of SOCl₂was added drop wise. Then the reaction mixture was refluxed for 10 h. After completion of reaction, the reaction mixture was cooled to room temperature and methanol was evaporated to dryness under vacuum to obtain 12.0 g crude product which was further purified by washing with minimum amount of methanol to obtain 5.2 g of Compound 3. Yield: 50.0percent Analysis: ¹H NMR (300 MHz, CDCl₃): δ 10.8 (s, 1H); 7.49 (d, 1H); 7.40 (d, 1H); 7.24 (dd, 1H); 3.9 (s, 3H). MS (m/z): 277 (M⁺−H)
50%	for 10 h; Reflux	Synthesis of Compound 3 10.0 g (37.8 mmol) of Compound 2 was taken in 200.0 ml dry methanol. To this 11.5 ml (151.0 mmol) of SOCl₂was added drop wise. Then the reaction mixture was refluxed for 10 h. After completion of reaction, the reaction mixture was cooled to room temperature and methanol was evaporated to dryness under vacuum to obtain 12.0 g crude product which was further purified by washing with minimum amount of methanol to obtain 5.2 g of Compound 3. Yield: 50.0percent Analysis: ¹H NMR (300 MHz, CDCl₃): δ 10.8 (s, 1H); 7.49 (d, 1H); 7.40 (d, 1H); 7.24 (dd, 1H); 3.9 (s, 3H). MS (m/z): 277 (M⁺−H)

Reference： [1] Patent: US2014/81044, 2014, A1, . Location in patent: Paragraph 0150-0153
[2] Patent: WO2014/45135, 2014, A1, . Location in patent: Page/Page column 16-17
[3] Patent: WO2007/77961, 2007, A2, . Location in patent: Page/Page column 320
[4] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 18, p. 6567 - 6582

3
[ 16870-28-3 ]
[ 18107-18-1 ]
[ 18179-39-0 ]

Reference： [1] Patent: US2008/194668, 2008, A1, . Location in patent: Page/Page column 7

4
[ 4136-97-4 ]
[ 18179-39-0 ]

Reference： [1] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 12, p. 3860 - 3863

5
[ 65-49-6 ]
[ 18107-18-1 ]
[ 18179-39-0 ]

Reference： [1] Patent: WO2007/37187, 2007, A1, . Location in patent: Page/Page column 132

6
[ 65-49-6 ]
[ 18179-39-0 ]

Reference： [1] Patent: US2014/81044, 2014, A1,
[2] Patent: WO2014/45135, 2014, A1,
[3] Patent: US2016/2269, 2016, A1,

7
[ 67-56-1 ]
[ 813-78-5 ]
[ 18179-39-0 ]

Reference： [1] Journal of the American Chemical Society, 2009, vol. 131, p. 368 - 377

8
[ 124-41-4 ]
[ 512-56-1 ]
[ 18179-39-0 ]

Reference： [1] Journal of the American Chemical Society, 2009, vol. 131, # 38, p. 13738 - 13748

9
[ 18179-39-0 ]
[ 38170-02-4 ]

Reference： [1] Journal of Pharmacy and Pharmacology, 2016, vol. 68, # 2, p. 233 - 244

[ 18179-39-0 ] Synthesis Path-Downstream 1~68

1
[ 18179-39-0 ]
[ 65427-16-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine
	With sodium hydroxide; hydroxylamine hydrochloride In n-heptane; ethyl acetate	26.a N-Hydroxy-2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide. (a) N-Hydroxy-2-hydroxy-4-iodobenzamide. 23.3 g (84 mmol) of methyl 2-hydroxy-4-iodobenzoate and 360 ml of sodium hydroxide solution (1 N) are introduced into a three-necked flask under a stream of nitrogen. 8 g (113 mmol) of hydroxylamine hydrochloride are added and the mixture is stirred at room temperature for two hours. The reaction medium is adjusted to pH 7-8 with concentrated hydrochloric acid and the solid is filtered off. The solid is dissolved in ethyl acetate and washed with water, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue is triturated from heptane, filtered and dried. 17.6 g (71.5%) of the expected product are collected, with a melting point of 195-6° C.
	With hydroxylamine In 1,4-dioxane	26-1 Isomer B: 6-iodo-3-methoxybenzo[d]isoxazole To a solution of methyl 2-hydroxy-4-iodobenzoate (7.75 g; commercially available product) in 1,4-dioxane (200 mL), hydroxylamine (50 mL) was added at room temperature. The resultant was stirred at room temperature for 3 days, water and ethyl acetate were added to the resultant reaction solution, and the organic layer and the aqueous layer were separated. The aqueous layer was prepared to be acidic by using concentrated hydrochloric acid. The resultant was extracted with ethyl acetate, washed with saturated saline, and dried over sodium sulfate. The resultant was filtered, the thus obtained filtrate was concentrated under reduced pressure to obtain a crude product containing N,2-dihydroxy-4-iodobenzamide (11.8 g).

Reference： [1]Current Patent Assignee: BAYER AG - DE855866, 1950, C
[2]Current Patent Assignee: Eqt Partners AB; Galderma (in: EQT Partners) - US6046220, 2000, A
[3]Current Patent Assignee: KYORIN HOLDINGS, INC. - EP3922247, 2021, A1 Location in patent: Paragraph 0405-0407

2
[ 18179-39-0 ]
[ 74-88-4 ]
[ 89942-34-7 ]

Reference： [1]Chemical and pharmaceutical bulletin,1962,vol. 10,p. 1137 - 1141

3
[ 217818-87-6 ]
[ 18179-39-0 ]
methyl 2-hydroxy-4-[3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With triethylamine;copper(l) iodide; bis(triphenylphosphine)palladium(II) dichloride; at 20℃; for 8h;Nitrogen sparging; Argon gasification;	(d) methyl 2-hydroxy-4-[3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate 1.18 g (5.9 mmol) of 3-(4,4-dimethylchroman-8-yl)-1-propyne, 1.60 g (5.9 mmol) of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> and 60 ml of triethylamine are introduced into a three-necked flask under argon.. The reaction mixture is degassed by sparging with nitrogen, 332 mg (0.46 mmol) of bis(triphenylphosphine)palladium(II) chloride and 134 mg of copper iodide are introduced and the mixture is stirred at room temperature for eight hours.. The reaction mixture is evaporated to dryness, the residue is taken up in ethyl acetate and hydrochloric acid (1N), and the organic phase is separated by settling, dried over magnesium sulphate and evaporated.. The residue is purified by chromatography on a silica column eluted with heptane.. After evaporating the solvents, an oil, which slowly crystallizes, is obtained and is recrystallized from heptane. 1.00 g (50%) of methyl 2-hydroxy-4-[3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate is collected in the form of a white solid with a melting point of 92-93 C. 1H NMR (CDCl3) delta1.34 (s, 6H), 1.84 (t, 2H, J=5.4 Hz), 3.75 (s, 2H), 3.94 (s, 3H), 4.23 (t, 2H, J=5.4 Hz), 6.89 (t, 1H, J=7.6 Hz), 6.95 (dd, 1H, J=8.2/1.5 Hz), 7.06 (d, 1H, J=1.4 Hz), 7.20 (d, 1H, J=6.3 Hz), 7.35 (d, 1H, J=7.4 Hz), 7.75 (d, 1H, J=8.2 Hz), 10.73 (s, 1H).

Reference： [1]Patent: US6346546,2002,B1 .Location in patent: Page column 15

4
[ 217818-89-8 ]
[ 18179-39-0 ]
[ 217818-09-2 ]

Yield	Reaction Conditions	Operation in experiment
56%	With triethylamine;copper(l) iodide; bis(triphenylphosphine)palladium(II) dichloride; at 20℃; for 4.5h;Nitrogen gasification;	3.00 g (13.9 mmol) of alpha-ethynyl-4,4-dimethylchroman-8-methanol, 3.90 g (13.9 mmol) of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> and 100 ml of triethylamine are introduced into a three-necked flask. The reaction mixture is degassed with nitrogen for 30 minutes and then 780 mg (1.1 mmol) of bis(triphenylphosphine)palladium(II) chloride and 320 mg (1.7 mmol) of copper iodide are successively added. The reaction mixture is stirred at room temperature for 4 hours and is evaporated to dryness and the residue obtained is taken up in water and ethyl ether. The organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture composed of 50% ethyl acetate and 50% heptane. 2.85 g (56%) of methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate are collected in the form of a white solid with a melting point of 122-123 C. 1H NMR (CDCl3) delta1.36 (s, 6H), 1.87 to 1.90 (m, 2H), 3.18 (d, 1H, J=6.4 Hz), 3.95 (s, 3H), 4.31 (t, 2H, J=5.3 Hz), 5.86 (d, 1H, J=6.4 Hz), 6.89 to 7.00 (m, 2H), 7.09 (s, 1H), 7.29 (d, 1H, J=7.9 Hz), 7.40 (d, 1H, J=7.4 Hz), 7.77 (d, 1H, J=8.2 Hz).

Reference： [1]Patent: US6346546,2002,B1 .Location in patent: Page column 17

5
[ 217818-92-3 ]
[ 18179-39-0 ]
methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-ynyl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine;copper(l) iodide; bis(triphenylphosphine)palladium(II) dichloride; for 8h;Nitrogen sparging;	d) methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-ynyl]benzoate 670 mg (3.1 mmol) of 3-(4,4-dimethylthiochroman-8-yl)prop-1-yne, 860 mg (3.1 mmol) of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> and 33 ml of triethylamine are introduced into a three-necked flask under argon. The reaction mixture is degassed by sparging with nitrogen, 174 mg (0.25 mmol) of bis(triphenylphosphine)palladium(II) chloride and 71 mg of copper iodide are introduced and the reaction mixture is stirred at room temperature for eight. hours. The reaction mixture is evaporated to dryness, the residue is taken up in ethyl acetate and hydrochloric acid (1N) and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica column eluted with a mixture composed of 99% heptane and 1% ethyl acetate. After evaporating the solvents, 1.50 g (75%) of methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-yn-yl]benzoate are collected in the form of a yellow oil. 1H NMR (CDCl3) delta1.35 (s, 6H), 1.97 (t, 2H, J=6.0 Hz), 3.06 (t, 2H, J=6.1 Hz), 3.76 (s, 2H), 3.94 (s, 3H), 6.96 (dd, 1H, J=8.2/1.5 Hz), 7.04 to 7.10 (m, 2H), 7.33 (d, 1H, J=6.9 Hz), 7.41 (d, 1H, J=7.4 Hz), 7.75 (d, 1H, J=8.2 Hz).

Reference： [1]Patent: US6346546,2002,B1 .Location in patent: Page column 18

6
[ 18179-39-0 ]
[ 1066-54-2 ]
[ 216443-97-9 ]

Yield	Reaction Conditions	Operation in experiment
89%		EXAMPLE 5: 4- (8, 8-Dimethyl-5-p-tolyl-7, 8-dihydro-2- naphthylselanylethynyl) -2-methoxybenzoic acid a. METHYL 4-ETHYNYL-2-HYDROXYBENZOATE 5.5 g (20 mmol) of <strong>[18179-39-0]methyl 4-iodosalicylate</strong> and 2.3 g (24 mmol) of trimethylsilylacetylene are dissolved'in 50 ml of triethylamine, and 0.7 g (1 mmol) of trans-dichlorobis (triphenylphosphine) palladium and 0.28 g (2 mmol) of copper iodide are then added. The reaction medium is stirred for 24 hours, treated with ammonium chloride solution and extracted with ethyl ether. The residue obtained is purified by chromatography (eluent: 8/2 heptane/dichloromethane). The yellow oil obtained (5.1 g; yield = 100%) is dissolved in 100 ml of tetrahydrofuran, and 22 ml (22 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran are added. The medium is stirred for one hour, acidified with 1N hydrochloric acid solution and then extracted with ethyl acetate. A beige-coloured solid is obtained (3.1 g; yield = 89% ; m. P. = 85C).

Reference： [1]Patent: WO2004/46096,2004,A2 .Location in patent: Page 31-32

7
[ 18179-39-0 ]
[ 16870-28-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydroxide; water; In tetrahydrofuran; methanol; at 40℃;	40 g (1 mol) of sodium hydroxide are added to 55.6 g (0.2 mol) of methyl 4-iodosalicylate in 600 ml of THF, 10 ml of methanol and 10 ml of water. The solution is heated at 40 C. overnight. It is then evaporated. The residue is taken up in water. It is acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed several times with water, dried over magnesium sulphate and concentrated. The product is triturated in a dichloromethane-hexane mixture and then filtered. [00486] Orange-coloured powder. m=48.53 g. Y=92%. 1H NMR (CDCl3): 7.20-7.24 (1H, dd, J=6.8 Hz, J'=1.5 Hz), 7.36-7.37 (1H, d, J=1.5 Hz), 7.52-7.56 (1H, d, J=8.3 Hz), 11.29 (1H, s).

Reference： [1]Patent: US6689922,2004,B1 .Location in patent: Page column 30

8
[ 4282-40-0 ]
[ 18179-39-0 ]
[ 854028-39-0 ]

Yield	Reaction Conditions	Operation in experiment
100%		EXAMPLE 1:; Ethyl (4-14- [5- (4-tert-butylphenyl)-4-methyl-4H- [1,2, 4]-triazol-3-ylsulphanyl]-2-heptyloxybenzylamino}- phenyl) acetate; Step a: Methyl 2-heptyloxy-4-iodobenzoate; A mixture of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (25 g, 90 mmol), caesium carbonate (35.2 g, 108 mmol) and n-heptyl iodide (19.2 ml, 117 mmol), in 500 ml of dimethylformamide (DMF) is stirred for 10 hours at room temperature. The solution is neutralized by addition of 2N hydrochloric acid solution. The desired product is extracted by addition of ethyl acetate. The organic phase is washed with water, dried with magnesium sulphate and concentrated using a rotary evaporator. After evaporation of the solvent, 33.84 g (100%) of the expected compound are recovered in the form of a brown oil.; Methyl 2-heptyloxy-4-iodobenzoate A suspension of caesium carbonate (35.2 g, 108 mmol), <strong>[18179-39-0]methyl 4-iodo-2-hydroxybenzoate</strong> (25 g, 90 mmol), iodoheptane (19.2 ml, 117 mmol) in DMF (500 ml) is stirred for 10 hours at room temperature. The organic phase is acidified at room temperature with a 2N hydrochloric acid solution to pH 5. The desired product is extracted by addition of ethyl acetate. The organic phase is washed with water, dried with magnesium sulphate and concentrated using a rotary evaporator. After evaporation of the remainder of the iodoheptane by placing the oil obtained under vacuum produced by a rotary vane pump, 33.8 g (100%) of the expected compound are recovered in the form of a brown oil.

Reference： [1]Patent: WO2005/58844,2005,A2 .Location in patent: Page/Page column 29; 34-35

9
[ 18179-39-0 ]
[ 103-63-9 ]
[ 854028-45-8 ]

Yield	Reaction Conditions	Operation in experiment
		Methyl 4-iodo-2-phenethyloxybenzoate; A suspension of caesium carbonate (35.2 g, 108 mmol), <strong>[18179-39-0]methyl 4-iodo-2-hydroxybenzoate</strong> (25 g, 90 mmol), phenethyl bromide (16 ml, 117 mmol) in DMF (500 ml) is stirred for 10 hours at room temperature. Caesium carbonate (20 g, 61.4 mmol) and phenethyl bromide (8.5 ml, 61.4 mmol) are added to the suspension. The organic phase is acidified at room temperature with a 2N hydrochloric acid solution to pH 5. The desired product is extracted by addition of ethyl ether. The organic phase is washed with water, dried with magnesium sulphate and concentrated using a rotary evaporator.

Reference： [1]Patent: WO2005/58844,2005,A2 .Location in patent: Page/Page column 35-36

10
[ 18179-39-0 ]
[ 166386-81-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; lithium borohydride In tetrahydrofuran	7.3 Step 3 Step 3 2-Hydroxy-4-iodo-benzylalcohol Methyl-2-hydroxy-4-iodo-benzoate from Step 2 (17.8 g, 64 mmol) was dissolved in THF. LiBH4 (3.07 g, 144 mmol) was added portionwise. The reaction mixture was heated at 50° for 16 hours. The reaction mixture was quenched carefully with 1N HCl and then extracted with EtOAc (3*). The organic layers were combined, washed with brine, dried (MgSO4) filtered and concentrated to yield the title compound as a white solid. 1 H NMR (400 MHz, CD3 OD) δ 7.15 (m, 2H); 7.0 (d, 1H); 4.6 (s, 2H).
	With lithium aluminium tetrahydride In tetrahydrofuran

Reference： [1]Current Patent Assignee: MERCK & CO INC - US5939439, 1999, A
[2]Martínez, Mario D.; Luna, Lorena; Tesio, Alvaro Y.; Feresin, Gabriela E.; Durán, Fernando J.; Burton, Gerardo [Journal of Pharmacy and Pharmacology, 2016, vol. 68, # 2, p. 233 - 244]

11
[ 217818-87-6 ]
[ 18179-39-0 ]
[ 7681-65-4 ]
methyl 2-hydroxy-4-[3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With nitrogen; triethylamine;bis(triphenylphosphine)palladium(II)-chloride; In ethyl acetate;	(d) methyl 2-hydroxy-4-[3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate 1.18 g (5.9 mmol) of 3-(4,4-dimethylchroman-8-yl)-1-propyne, 1.60 g (5.9 mmol) of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> and 60 ml of triethylamine are introduced into a three-necked flask under argon. The reaction mixture is degassed by sparging with nitrogen, 332 mg (0.46 mmol) of bis(triphenylphosphine)palladium(II) chloride and 134 mg of copper iodide are introduced and the mixture is stirred at room temperature for eight hours. The reaction mixture is evaporated to dryness, the residue is taken up in ethyl acetate and hydrochloric acid (1N), and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica column eluted with heptane. After evaporating the solvents, an oil, which slowly crystallizes, is obtained and is recrystallized from heptane. 1.00 g (50%) of methyl 2-hydroxy-4-[3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate is collected in the form of a white solid with a melting point of 92-93 C.

Reference： [1]Patent: US6103762,2000,A

12
[ 217818-89-8 ]
[ 18179-39-0 ]
[ 7681-65-4 ]
[ 217818-09-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;bis(triphenylphosphine)palladium(II)-chloride; In water;	(c) methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate 3.00 g (13.9 mmol) of alpha-ethynyl-4,4-dimethylchroman-8-methanol, 3.90 g (13.9 mmol) of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> and 100 ml of triethylamine are introduced into a three-necked flask. The reaction mixture is degassed with nitrogen for 30 minutes and then 780 mg (1.1 mmol) of bis(triphenylphosphine)palladium(II) chloride and 320 mg (1.7 mmol) of copper iodide are successively added. The reaction mixture is stirred at room temperature for 4 hours and is evaporated to dryness and the residue obtained is taken up in water and ethyl ether. The organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture composed of 50% ethyl acetate and 50% heptane. 2.85 g (56%) of methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate are collected in the form of a white solid with a melting point of 122-123 C.

Reference： [1]Patent: US6103762,2000,A

13
[ 217818-92-3 ]
[ 18179-39-0 ]
[ 7681-65-4 ]
methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-ynyl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With nitrogen; triethylamine;bis(triphenylphosphine)palladium(II)-chloride; In ethyl acetate;	(d) methyl 2-hydroxy-4-[3-(4,4-dimethylthiochroman-8-yl)prop-1-ynyl]benzoate 670 mg (3.1 mmol) of 3-(4,4-dimethylthiochroman-8-yl)prop-1-yne, 860 mg (3.1 mmol) of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> and 33 ml of triethylamine are introduced into a three-necked flask under argon. The reaction mixture is degassed by sparging with nitrogen, 174 mg (0.25 mmol) of bis(triphenylphosphine)palladium(II) chloride and 71 mg of copper iodide are introduced and the reaction mixture is stirred at room temperature for eight hours. The reaction mixture is evaporated to dryness, the residue is taken up in ethyl acetate and hydrochloric acid (1N) and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica column eluted with a mixture composed of 99% heptane and 1% ethyl acetate.

Reference： [1]Patent: US6103762,2000,A

14
[ 18179-39-0 ]
[ 74-88-4 ]
[ 148490-97-5 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide;	(a) Preparation of methyl 4-iodo-2-methoxybenzoate 238 mg (7.9 mmol) of sodium hydride (80% in oil) and 20 ml of DMF were introduced into a three-necked flask, a solution of 2 g (7.2 mmol) of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> in 50 ml of DMF was added dropwise and stirring was carried out until gas evolution had ceased. 540 mul (8.6 mmol) of iodomethane were then added and stirring was carried out at room temperature for two hours. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. 2.1 g (100%) of methyl 4-iodo-2-methoxybenzoate were recovered.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6855 - 6861
[2]ACS Chemical Biology,2013,vol. 8,p. 2209 - 2216
[3]Patent: US5716624,1998,A
[4]Chemical Communications,2012,vol. 48,p. 9370 - 9372

15
[ 18179-39-0 ]
[ 1066-54-2 ]
[ 170100-60-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	Methyl 2-hydroxy-4-iodobenzoate (1.00 g, 3.60 mmol)Dissolved in 10mL of N, N-dimethylformamide solution,Triphenylphosphine palladium dichloride (50 mg, 0.07 mmol) was added sequentially under nitrogen.Cuprous iodide (27 mg, 0.14 mmol), triethylamine (0.53 g, 5.40 mmol)And trimethylsilyne (0.53 g, 5.40 mmol).Stir at room temperature overnight.Quenched with water, extracted with ethyl acetate and dried.The crude product was purified by column chromatography using petroleum ether to give compound 9A.Red oily liquid (0.79 g, 89% yield).
		(a) Preparation of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate Following the basic procedure of Example 1(a), by reacting 34 g (122 mmol) of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> with 34 ml (244 mmol) of trimethylsilylacetylene, 25.9 g (85%) of the expected compound were obtained in the form of a brown oil.
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; for 24h;	General procedure: Methyl 4-ethynylsalicylate was synthesized by modifying a literature procedure [36]. Thirty-six mmol (10.01g, 1 equiv.) of 9 <strong>[18179-39-0]methyl 4-iodosalicylate</strong> was dissolved in 180mL of 10 triethylamine to form a clear and brown solution. Then, 43.2mmol (6.15mL, 1.2 equiv.) of 11 trimethylsilylacetylene was added and stirred. Next, 1.8mmol (1.2763g, 0.05 equiv.) of 12 palladium(II) bis(triphenylphosphine)dichloride and 3.6mmol (0.6855g, 0.1 equiv.) of 13 copper(I) iodide was added and stirred for 24h to form a cloudy brown-green solution. The reaction was quenched by adding 145mL of 1M 14 aqueous ammonium chloride and stirring for about a half hour. This solution was extracted using two 100mL portions of ethyl acetate, then another three 50mL portions, and dried over sodium sulfate and gravity filtered. The filtrate was evaporated on a flash evaporator to give a brown-red oil. The residue was dissolved in 10mL of 15 dichloromethane and purified using a silica gel column with an increasing gradient of dichloromethane in hexanes to yield a yellow oil. The purified intermediate was dissolved in 45mL of 16 tetrahydrofuran and treated with 45mL of 1M 17 tetrabutylammonium fluoride in tetrahydrofuran for 2h. The resulting honey-colored mixture was acidified to pH1 using 1M 18 aqueous hydrochloric acid, then mixed with 50mL of distilled water. The mixture was extracted with four portions of ethyl acetate, dried over sodium sulfate and gravity filtered. The filtrate was evaporated on a flash evaporator to yield

Reference： [1]Patent: CN104045552,2019,B .Location in patent: Paragraph 0158; 0159; 0160; 0161
[2]Patent: US5716624,1998,A
[3]Journal of Inorganic Biochemistry,2019,vol. 192,p. 119 - 125

16
[ 932372-87-7 ]
[ 18179-39-0 ]
C₂₁H₂₆N₂O₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With caesium carbonate In toluene at 100℃; for 12h;

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - WO2007/37187, 2007, A1 Location in patent: Page/Page column 132

17
[ 18179-39-0 ]
[ 16420-13-6 ]
methyl 2-[(dimethylamino)carbonothioyl]oxy}-4-iodobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20 - 60℃; for 3h;	To a mixture of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (11.00 g) and 1, 8-diazabicyclo [5, 4, 0] undec-7-ene (12.2 g) in DMF (50 mL) was added N, N-dimethylthiocarbamoyl chloride (7.42 g) . The mixture was stirred at room temperature for 14 hr and at 600C for 3 hr, poured into water and extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel using ethyl acetate as an eluent, and the product was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as crystals (8.80 g) . 1H-NMR (300 MHz, CDCl3) delta: 3.38 (s, 3H), 3.46 (s, 3H), 3.83 (s, 3H), 7.50 (d, J = 0.9 Hz, IH), 7.64 - 7.71 (m, 2H).

Reference： [1]Patent: WO2007/77961,2007,A2 .Location in patent: Page/Page column 321

18
[ 67-56-1 ]
[ 16870-28-3 ]
[ 18179-39-0 ]

Yield	Reaction Conditions	Operation in experiment
50%	With thionyl chloride; for 10h;Reflux;	Synthesis of Compound 3 10.0 g (37.8 mmol) of Compound 2 was taken in 200.0 ml dry methanol. To this 11.5 ml (151.0 mmol) of SOCl2 was added drop wise. Then the reaction mixture was refluxed for 10 h. After completion of reaction, the reaction mixture was cooled to room temperature and methanol was evaporated to dryness under vacuum to obtain 12.0 g crude product which was further purified by washing with minimum amount of methanol to obtain 5.2 g of Compound 3. Yield: 50.0% Analysis: 1H NMR (300 MHz, CDCl3): delta 10.8 (s, 1H); 7.49 (d, 1H); 7.40 (d, 1H); 7.24 (dd, 1H); 3.9 (s, 3H). MS (m/z): 277 (M+-H)
50%	With thionyl chloride; for 10h;Reflux;	Synthesis of Compound 3 10.0 g (37.8 mmol) of Compound 2 was taken in 200.0 ml dry methanol. To this 11.5 ml (151.0 mmol) of SOCl2 was added drop wise. Then the reaction mixture was refluxed for 10 h. After completion of reaction, the reaction mixture was cooled to room temperature and methanol was evaporated to dryness under vacuum to obtain 12.0 g crude product which was further purified by washing with minimum amount of methanol to obtain 5.2 g of Compound 3. Yield: 50.0% Analysis: 1H NMR (300 MHz, CDCl3): delta 10.8 (s, 1H); 7.49 (d, 1H); 7.40 (d, 1H); 7.24 (dd, 1H); 3.9 (s, 3H). MS (m/z): 277 (M+-H)
	With thionyl chloride; for 14h;Heating / reflux;	To a solution of <strong>[16870-28-3]2-hydroxy-4-iodobenzoic acid</strong> (35.0 g) in methanol (700 mL) was added dropwise thionyl chloride (40 mL) . The mixture was refluxed for 14 hr and concentrated. The residue was chromatographed on silica gel using n-hexane/ethyl acetate as an eluent to give the title compound as crystals (34.2 g) . mp. 690C (ethyl acetate/n-hexane) . 1H-NMR (300 MHz, CDCl3) delta: 3.94 (s, 3H) , 7.23 (dd, J = 8.4,1.8 Hz, IH) , 7.40 (d, J = 1.8 Hz, IH) , 7.50 (d, J = 8.4 Hz,IH) , 10.74 (s, IH) .

Reference： [1]Crystal Growth and Design,2019,vol. 19,p. 1954 - 1964
[2]Patent: US2014/81044,2014,A1 .Location in patent: Paragraph 0150-0153
[3]Patent: WO2014/45135,2014,A1 .Location in patent: Page/Page column 16-17
[4]Patent: WO2007/77961,2007,A2 .Location in patent: Page/Page column 320
[5]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 6567 - 6582

19
[ 16870-28-3 ]
[ 18107-18-1 ]
[ 18179-39-0 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; methanol; diethyl ether; at 20℃; for 2.5h;	A solution of <strong>[16870-28-3]2-hydroxy-4-iodo-benzoic acid</strong> (4.0 g, 0.015 mol) in THF (25 ml) and MeOH (25 ml) is treated by the dropwise addition of (trimethylsilyl)-diazomethane (2.0M in Et2O, 15 ml) and stirred at room temperature for 2.5 hours. Volatiles are removed in vacuo and the crude residue diluted into EtOAc. The organic phase is sequentially washed with saturated aqueous NaHCO3 (3×), saturated aqueous NaCl (1×), and H2O (1×). The organic phase is dried over MgSO4, filtered, and concentrated. The crude product is purified with silica gel column chromatography (0-80% ethyl acetate in hexanes gradient) to afford <strong>[16870-28-3]2-hydroxy-4-iodo-benzoic acid</strong> methyl ester: ESMS m/z 279.0 (M+H+).

Reference： [1]Patent: US2008/194668,2008,A1 .Location in patent: Page/Page column 7

20
[ 6336-45-4 ]
[ 18179-39-0 ]
[ 71534-96-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In tetrahydrofuran; water; for 2.08333h;Inert atmosphere; Reflux;	B: To a solution of methyl hydroxy-4-iodobenzoate (1.0 mmol) in THF:H20 (4:1,0.13 M) was added dibutyl vinylboronate (1.5 equiv), sodium carbonate (7.0 equiv) and 5mol% dichloro-bis(triphenylphosphine)palladium. The reaction mixture was purged with N2 (g) for 5 mm before being refluxed for 2 hrs. The resulting mixture was concentrated in vacuo, diluted with EtOAc and washed with water and brine. The combined organiclayers were dried over MgSO4, filtered and concentrated in vacuo. Purification was achieved using flash column chromatography on Si02 (Hexanes/EtOAc: 6/1) to yield the product; Methyl 2-hydroxy-4-vinylbenzoate (1616-07a). Compound 1616-07a was prepared via Procedure B from <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (1.0 g, 3.6 mmol) to yield a clear oil (0.51 g, 80%).
	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; water; for 2h;Heating / reflux;	A solution of 2-hydroxy-4-iodo-benzoic acid methyl ester (8.01 g, 0.0288 mol) in THF (184 ml) and H2O (46 ml) is treated with vinyl-boronic acid di-butyl ester (9.53 ml, 0.0432 mol, 1.5 eq.), NaCO3 (21.37 g, 0.201 mol, 7 eq.), and dichloro-bis(triphenyl-phosphine)palladium (1.01 g, 1.44 mmol, 5 mol %). The solution is purged with N2 (g) for 5 minutes and then heated to reflux for 2 hour. The reaction is concentrated in vacuo, diluted with EtOAc, and sequentially washed with H2O and saturated aqueous NaCl. The organic phase is dried over MgSO4, filtered, and concentrated. The crude product is purified with silica gel column chromatography (5% ethyl acetate in hexanes) to afford 2-hydroxy-4-vinyl-benzoic acid methyl ester: ESMS m/z 179.1 (M+H+).

Reference： [1]Patent: WO2014/25942,2014,A1 .Location in patent: Page/Page column 26; 27; 32
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 2334 - 2356
[3]Patent: US2008/194668,2008,A1 .Location in patent: Page/Page column 7

21
[ 18179-39-0 ]
[ 813-77-4 ]
C₁₀H₁₂IO₆P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methyl 4-iodosalicylate With sodium hydride In tetrahydrofuran; mineral oil Stage #2: Dimethyl chlorophosphate In tetrahydrofuran; mineral oil at 20℃; for 2h;
	Stage #1: methyl 4-iodosalicylate With sodium hydride In tetrahydrofuran; mineral oil for 0.0833333h; Stage #2: Dimethyl chlorophosphate In tetrahydrofuran; mineral oil at 20℃; for 2h;

Reference： [1]Edwards, David R.; Neverov, Alexei A.; Brown, R. Stan [Journal of the American Chemical Society, 2009, vol. 131, p. 368 - 377]
[2]Edwards, David R.; Liu, C. Tony; Garrett, Graham E.; Neverov, Alexei A.; Brown, R. Stan [Journal of the American Chemical Society, 2009, vol. 131, # 38, p. 13738 - 13748]

22
[ 18179-39-0 ]
[ 100-39-0 ]
[ 854028-46-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In acetonitrile; at 80℃;Inert atmosphere;	Solid K2CO3 (76.1 g, 0.55 mol) was added to a solution of <strong>[18179-39-0]methyl 4-iodosalicylate</strong> (1) (76.5 g, 0.28 mol) in MeCN (550 mL) at RT. Benzyl bromide (32.7 mL, 0.28 mol) was added via syringe, and the resulting reaction mixture was warmed to 80 C. and stirred overnight. The reaction mixture was then cooled to RT and filtered subsequently to remove insoluble salts, which were washed further with EtOAc. The filtrate was concentrated in vacuo, before re-dissolving the residue in fresh EtOAc and filtering a second time. The filtrate was concentrated in vacuo to provide an oil which solidified upon standing to yield 2 (99%, 100.5 g) as a beige solid that required no further purification. 1H NMR (500 MHz, CDCl3, 25 C.): delta=7.54 (d, J=8.0 Hz, 1H), 7.49 (d, J=7.5 Hz, 2H), 7.43-7.35 (m, 4H), 7.33 (t, J=7.5 Hz, 1H), 5.15 (s, 2H), 3.89 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3, 25 C.): delta=166.3, 158.4, 136.2, 133.1, 130.1, 128.8, 128.1, 127.0, 123.3, 120.3, 100.0, 71.0, 52.3 ppm. HRMS (ESI) calculated for C15H14IO3: m/z=367.9909 ([M+H]+). Found m/z=367.9893.
99%	With potassium carbonate; In acetonitrile; at 80℃;	Methyl 2-(Benzyloxy)-4-iodobenzoate (2): Solid K2CO3 (76.1 g, 0.55 mol) was added to a solution of <strong>[18179-39-0]methyl 4-iodosalicylate</strong> (1) (76.5 g, 0.28 mol) in MeCN (550 mL) at rt. Benzyl bromide (32.7 mL, 0.28 mol) was added via a syringe, and the resulting reaction mixture was warmed to 80 C. and stirred overnight. The reaction mixture was then cooled to rt and filtered subsequently to remove insoluble salts, which were washed further with EtOAc. The filtrate was concentrated in vacuo, before redissolving the residue in fresh EtOAc and filtering it a second time. The filtrate was concentrated in vacuo to provide an oil which solidified upon standing to yield 2 (100.5 g, 99%) as a beige solid which required no further purification. 1H NMR (500 MHz, CDCl3, 25 C.) delta=7.54 (d, J=8.0 Hz, 1H), 7.49 (d, J=7.5 Hz, 2H), 7.43-7.35 (m, 4H), 7.33 (t, J=7.5 Hz, 1H), 5.15 (s, 2H), 3.89 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3, 25 C.) delta=166.3, 158.4, 136.2, 133.1, 130.1, 128.8, 128.1, 127.0, 123.3, 120.3, 100.0, 71.0, 52.3 ppm. HRMS (ESI) Calcd for C15H14IO3: m/z=367.9909 ([M+H]+); Found m/z=367.9893.
99.9%	With potassium carbonate; In acetonitrile; at 80℃; for 4h;	Synthesis of Compound 4 5.2 g (18.7 mmol) of Compound 3 and 16.0 g (37.4 mmol) of K2CO3 were taken in 40.0 ml acetonitrile. To this 2.4 ml (19.6 mmol) of benzyl bromide was added drop wise at RT. Then the reaction mixture was heated to 80 C. for 4 h. After completion of reaction, the reaction mixture was cooled to room temperature and filtered. The solid residue remained was repeatedly washed with ethyl acetate. Finally the filtrate was evaporated to dryness under vacuum to obtain 7.0 g of Compound 4 as dark brown oily liquid which solidifies on standing at room temperature. Yield: 99.9% Analysis: 1H NMR (300 MHz, CDCl3): delta 7.47-7.41 (m, 3H); 7.39-7.31 (m, 5H); 5.1 (s, 2H); 3.9 (s, 3H). MS (m/z): 367 (M+-H)

99.9%	With potassium carbonate; In acetonitrile; at 80℃; for 4h;	Synthesis of Compound 4 5.2 g (18.7 mmol) of Compound 3 and 16.0 g (37.4 mmol) of K2CO3 were taken in 40.0 ml acetonitrile. To this 2.4 ml (19.6 mmol) of benzyl bromide was added drop wise at RT. Then the reaction mixture was heated to 80 C. for 4 h. After completion of reaction, the reaction mixture was cooled to room temperature and filtered. The solid residue remained was repeatedly washed with ethyl acetate. Finally the filtrate was evaporated to dryness under vacuum to obtain 7.0 g of Compound 4 as dark brown oily liquid which solidifies on standing at room temperature. Yield: 99.9% Analysis: 1H NMR (300 MHz, CDCl3): delta 7.47-7.41 (m, 3H); 7.39-7.31 (m, 5H); 5.1 (s, 2H); 3.9 (s, 3H). MS (m/z): 367 (M+-H)
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72h;	(i) Methyl 2-(benzyloxy)-4-iodobenzoate <n="144"/>A mixture of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (22.8g), benzyl bromide (10.3ml) and K2CO3 (22.67g) in DMF (200ml) was stirred at rt for 72h. The mixture was partitioned between diethyl ether and water, the organics separated washed with water, dried and evaporated under reduced pressure to give a white solid, 29.5g. 1U NMR CDCl3 : delta 7.54-7.30 (m, 8H) , 5.14 (s, 2H) , 3.88 (s, 3H) LC-MS m/z 369 APCI +
	With potassium carbonate; In ISOPROPYLAMIDE; at 80℃; for 1h;	Reference Example 7a; Potassium carbonate (1.9 g) and benzyl bromide (1.2 mL) were sequentially added to an N,N-dimethylacetamide (20 mL) solution of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (2.5 g), followed by stirring at 80 C. for 1 hour. The reaction mixture was cooled to room temperature, and then 1 mol/L hydrochloric acid and ethyl acetate were added thereto. The organic layer was separated, washed with 1 mol/L hydrochloric acid and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-80% hexane/ethyl acetate] to obtain 3.3 g of methyl 2-(benzyloxy)-4-iodobenzoate as a yellow oily substance.1H-NMR (CDCl3) delta: 3.88 (3H, s), 5.15 (2H, s), 7.30-7.43 (5H, m), 7.47-7.51 (2H, m), 7.53 (1H, d, J=8.1 Hz).
	With potassium carbonate; In N,N-dimethyl acetamide; at 80℃; for 1h;	Reference Example 7a [Show Image] Potassium carbonate (1.9 g) and benzyl bromide (1.2 mL) were sequentially added to an N,N-dimethylacetamide (20 mL) solution of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (2.5 g), followed by stirring at 80C for 1 hour. The reaction mixture was cooled to room temperature, and then 1 mol/L hydrochloric acid and ethyl acetate were added thereto. The organic layer was separated, washed with 1 mol/L hydrochloric acid and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-80% hexane/ethyl acetate] to obtain 3.3 g of methyl 2-(benzyloxy)-4-iodobenzoate as a yellow oily substance. 1H-NMR (CDCl3) delta: 3.88 (3H, s), 5.15 (2H, s), 7.30-7.43 (5H, m), 7.47-7.51 (2H, m), 7.53 (1H, d, J=8.1 Hz).

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 15632 - 15649
[2]Patent: US2013/96210,2013,A1 .Location in patent: Paragraph 0212; 0224
[3]Patent: US2013/122297,2013,A1 .Location in patent: Paragraph 0049
[4]Patent: US2014/81044,2014,A1 .Location in patent: Paragraph 0154-0157
[5]Patent: WO2014/45135,2014,A1 .Location in patent: Page/Page column 17
[6]Journal of the American Chemical Society,2017,vol. 139,p. 10601 - 10604
[7]Patent: WO2009/67081,2009,A1 .Location in patent: Page/Page column 142-143
[8]Patent: US2011/275797,2011,A1 .Location in patent: Page/Page column 26
[9]Patent: EP2385036,2011,A1 .Location in patent: Page/Page column 38-39
[10]Crystal Growth and Design,2016,vol. 16,p. 5852 - 5858
[11]Journal of the American Chemical Society,2020,vol. 142,p. 3002 - 3012

23
[ 18179-39-0 ]
[ 107-30-2 ]
[ 51985-45-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 6567 - 6582
[2]Angewandte Chemie - International Edition,2019,vol. 58,p. 12862 - 12867
Angew. Chem.,2019,vol. 131,p. 12994 - 12999,6
[3]Crystal Growth and Design,2019,vol. 19,p. 1954 - 1964

24
[ 18179-39-0 ]
[ 75-03-6 ]
[ 1246765-31-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;	Preparation 18: methyl 2-ethoxy-4-(4,4,5,5-tetramethyl-1, 3, 2-dioxaborolan-2- yl)benzoate; Step 1 : Methyl 2-ethoxy-4-iodobenzoate; Methyl 4-iodosalicylate (5.0Og, 18.0mmol) was dissolved in N,N-dimethylformamide (55mL) and cooled to 00C. Cesium carbonate (11.7 g, 36.0 mmol) and ethyl iodide (1.91 ml_, 23.9 mmol) were added. The reaction was slowly warmed to room temperature while stirring for 16 h. The reaction was diluted with ethyl acetate and washed with water. The organic layer was washed with brine and dried over magnesium sulfate, filtered, and concentrated. The residue was purified by purified by silica gel column chromatography eluting with a gradient of 0%-20% ethyl acetate/ heptane to obtain the title compound as a colorless oil. (5.40 g, 98%). 1H NMR (400 MHz, DMSO-Of6) delta ppm 7.47 (s, 1 H), 7.38 (s, 2H), 4.10 (q, 2H), 3.76 (s, 3H), 1.30 (t, 3H).
6 g	With potassium carbonate; In acetone; at 60℃; for 48h;	A mixture of Compound I (5.0 g), acetone (45 mL), potassium carbonate (12.4 g) and ethyl iodide (7.2 mL) was stirred at 60C for 2 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 10/0 to 9/1) to give Compound II (6.0 g).
16.5 g	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 1h;Inert atmosphere;	Iodoethane (6.47 mL) was added to a mixture of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (15 g), potassium carbonate (14.9 g), and DMF (100 mL), and the resultant mixture was stirred at 70 C. for 1 hour in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (16.5 g). 1H NMR (300 MHz, CDCl3) delta 1.46 (3H, t, J=7.0 Hz), 3.87 (3H, s), 4.09 (2H, q, J=6.9 Hz), 7.28-7.35 (2H, m), 7.48 (1H, d, J=8.1 Hz).

Reference： [1]ACS Chemical Biology,2013,vol. 8,p. 2209 - 2216
[2]Patent: WO2010/116282,2010,A1 .Location in patent: Page/Page column 58
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 4273 - 4288
[4]Patent: EP2612848,2013,A1 .Location in patent: Paragraph 0468; 0469; 0470
[5]Patent: US2015/99777,2015,A1 .Location in patent: Paragraph 0545; 0546; 0547; 0618; 0619; 0620; 0809; 0810

25
[ 18179-39-0 ]
[ 1312685-16-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-chloro-succinimide; In acetic acid; at 100℃; for 1h;	A solution of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (50 g, 0.18 mol) [Aldrich, 652636] in acetic acid (360 mL) was treated with N-chlorosuccinimide (29 g, 0.22 mol) and heated at 100 C for 1 hour. The reaction mixture was cooled until the internal temperature was 19 C and then the solid that precipitated was filtered, washed with cold acetic acid, and air dried. The solid was diluted with toluene and concentrated (2 x 200 mL) to remove residual acetic acid to give 34.8 g of the desired product. The filtrate was concentrated, and the residue was purified by flash column chromatography using ethyl acetate in hexanes (0% - 20%) to give an additional 8.6 g of desired product (total yield = 43 g, 77%). LCMS for CgHyClIC^ (M+H)+: m/z = 312.9; Found: 313.0.
77%	With N-chloro-succinimide; acetic acid; at 100℃; for 1h;	Example 1. 4-Amino-6-({l-[5-chloro-8-(3-fluorophenyI)cinnolin-7-yl]ethyl}amino)- pyrimidine-5-carbonitrile; Step A: Methyl 5-chloro-2-hydroxy-4-iodobenzoateA solution of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (50 g, 0.18 mol) [Aldrich, 652636] in acetic acid (360 mL) was treated with N-chlorosuccinimide (29 g, 0.22 mol) and heated at 100 C for 1 hour. The reaction mixture was cooled until the internal temperature was 19 C and then the solid that precipitated was filtered, washed with cold acetic acid, and air dried. The solid was diluted with toluene and concentrated (2 x 200 mL) to remove residual acetic acid to give 34.8 g of the desired product. The filtrate was concentrated, and the residue was purified by flash column chromatography using ethyl acetate in hexanes (0% - 20%) to give an additional 8.6 g of desired product (total yield = 43 g, 77%). LCMS for C8H7C1IC>3(M+H)+: m/z = 312.9; Found: 313.0.

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1554 - 1560
[2]Patent: WO2011/75630,2011,A1 .Location in patent: Page/Page column 95-96
[3]Patent: WO2012/125629,2012,A1 .Location in patent: Page/Page column 30-31

26
[ 18179-39-0 ]
[ 79887-14-2 ]
[ 1224717-23-0 ]

Yield	Reaction Conditions	Operation in experiment
51%	With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; at 20℃; for 0.25h;	Reference Example 47 methyl 4-[(4-ethoxyphenyl)ethynyl]-2-(methoxymethoxy)benzoate To a solution of methyl 2-hydroxy-4-iodobenzoate (1.00 g, 3.60 mmol) and <strong>[79887-14-2]1-ethoxy-4-ethynylbenzene</strong> (789 mg, 5.40 mmol) and copper(I) iodide (68.6 mg, 0.360 mmol) in triethylamine (9 mL) was added bis(triphenylphosphine)palladium(II) chloride (253 mg, 0.360 mmol), and the mixture was stirred under an argon stream at room temperature for 15 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in DMF (10 mL). Potassium carbonate (2.59 g, 18.8 mmol) and chloromethyl methyl ether (1.07 mL, 14.0 mmol) were added thereto, and the mixture was stirred at room temperature for 20 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 1:1) to give the title compound (623 mg, yield 51%) as a yellow solid. 1H NMR (CDCl3) delta 1.43 (t, J=7.0 Hz, 3H), 3.54 (s, 3H), 3.89 (s, 3H), 4.05 (q, J = 7.0 Hz, 2H), 5.28 (s, 2H), 6.87 (d, J = 8.9 Hz, 2H), 7.17 (dd, J = 8.0, 1.4 Hz, 1H), 7.33 (d, J = 1.4 Hz, 1H), 7.47 (d, J = 8.9 Hz, 2H), 7.76 (d, J = 8.0 Hz, 1H).

Reference： [1]Patent: EP2351743,2011,A1 .Location in patent: Page/Page column 129-130

27
[ 27329-70-0 ]
[ 18179-39-0 ]
[ 1277116-14-9 ]

Yield	Reaction Conditions	Operation in experiment
96%		Methyl-4-iodosalycilate 3 (1.00mmol) and 5-formyl-2- furan boronic acid 4 were dissolved in 10 mL of DMF and 15 mL ofEtOH. The reaction mixture was stirred for 10 minutes under N2, then Pd(PPh3)2 Cl2 (0.10mmol) was added and finally Na2CO3 2M (6.00 mmol). The reaction mixture (light-orange)was stirred under N2 at room temperature. After 1h the reaction went to completion (monitoringwith TLC) and was quenched with H2O and 2N HCl, then EtOAc was added, and the mixture was stirred until the two layers became clear. The aqueous layer was extracted threetimes with EtOAc, then the organic phase were washed several times with H2O and brine,dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product waspurified by flash chromatography using PE/EtOAc = 4:1 as eluent to yield the wishes product5 as a light orange solid (yield: 96%); mp = 150C (decomposition); 1H NMR (CDCl3, 400MHz): delta = 10.84 (s, 1H), 9.69 (s, 1H), 7.91-7.88 (d, 1H, J = 12 Hz), 7.40-7.39 (d, 1H, J = 4 Hz),7.35-7.32 (m, 3H), 6.94-6.93 (d, 1H, J = 4Hz), 3.97 (s, 3H); 13C (CDCl3, 100 MHz): delta= 177.47,161.69, 157.37, 152.53, 135.17, 130.58,122.56, 115.74, 113.73, 112.82, 109.84, 52.40, 29.59; MS(ES): m/z 245.0 [M-H]- ; Anal. (C13H10O5) C, H, N.
96%		General procedure: Methyl-4-iodosalycilate 1 or 4-Chloro-3-iodobenzotrifluoride 2 (1.00 mmol) and 5-formyl-2-furan boronic acid 3 were dissolved in 10 mL of DMF and 15 mL of EtOH. The reaction mixture was stirred for 10 min under N2, then Pd(PPh3)2Cl2 (0.10 mmol) was added and finally Na2CO3 2M (6.00 mmol). The reaction mixture (light-orange) was stirred under N2 at room temperature. After 1h the reaction went to completion and was quenched with H2O and 2N HCl; then EtOAc was added and the mixture was stirred until the two layers became clear. The aqueous layer was extracted three times with EtOAc, then the organic phase was washed several times with H2O and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. 5-(2-chloro-5-(trifluoromethyl)phenyl)furan-2-carbaldehyde (4). The crude product was purified by flash chromatography using PE/EtOAc = 4:1 as eluent to yield the wished product 4 as a brown solid (yield: 20%).
64%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	General procedure: The corresponding iodobenzenederivative 14a or 14b (1.80 mmol) and 5-formyl furan-2-ylboronicacid 15 (2.34 mmol) were dissolvedin 10 mL DMF and 15 mL EtOH. The reaction mixture was stirred for 10 min underN2, then Pd(PPh3)2Cl2 (0.18 mmol)and a solution of Na2CO3 (2M, 10.8 mmol) were added to thereaction mixture, and the light-orange suspension was stirred under N2at room temperature. After 1 h the reaction went to completion (TLC) and wasquenched with 1M HCl, then EtOAc (10 mL) was added, and the mixture was stirreduntil the two layers became clear. The combined organic layers were washed withH2O and brine, dried over Na2SO4, filtered,and evaporated under reduced pressure. The crude product was purified by flashchromatography using PE/EtOAc as eluent to yield the desired product as a solid(yields: 8 (64%), 13 (87%)).

Reference： [1]ChemMedChem,2011,vol. 6,p. 343 - 352
[2]Antimicrobial Agents and Chemotherapy,2014,vol. 58,p. 3043 - 3052
[3]PLoS ONE,2018,vol. 13
[4]PLoS ONE,2018,vol. 13
[5]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 2502 - 2505

28
[ 18179-39-0 ]
[ 105-36-2 ]
[ 1315688-26-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; potassium iodide In acetone at 50℃; for 5h;

Reference： [1]Location in patent: scheme or table Sundar, Babu G.; Bailey, Thomas R.; Dunn, Derek D.; Bacon, Edward R.; Salvino, Joseph M.; Morton, George C.; Aimone, Lisa D.; Zeqi, Huang; Mathiasen, Joanne R.; Dicamillo, Amy; Huffman, Mark J.; McKenna, Beth A.; Kopec, Karla; Lu, Lily D.; Brown, Rebecca; Qian, Jie; Angeles, Thelma; Connors, Thomas; Spais, Chrysanthe; Holskin, Beverly; Galinis, Deborah; Duzic, Emir; Schaffhauser, Herve; Rosse, Gerard C. [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 120 - 123]

29
[ 18179-39-0 ]
[ 1382734-75-9 ]

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 15632 - 15649
[2]Chemistry - A European Journal,2012,vol. 18,p. 15632 - 15649
[3]Patent: US2013/96210,2013,A1
[4]Patent: US2013/96210,2013,A1
[5]Patent: US2013/122297,2013,A1
[6]Journal of the American Chemical Society,2017,vol. 139,p. 10601 - 10604
[7]Journal of the American Chemical Society,2017,vol. 139,p. 10601 - 10604
[8]Journal of the American Chemical Society,2020,vol. 142,p. 3002 - 3012
[9]Journal of the American Chemical Society,2020,vol. 142,p. 3002 - 3012

30
[ 18179-39-0 ]
[ 861533-46-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / acetonitrile / 80 °C / Inert atmosphere 2: cesium fluoride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / Inert atmosphere; Reflux 3: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / Inert atmosphere 4: sodium hydroxide; water / tetrahydrofuran / 50 °C
	Multi-step reaction with 5 steps 1: potassium carbonate / acetonitrile / 80 °C / Inert atmosphere 2: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 16 h / Inert atmosphere; Reflux 3: cesium fluoride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / Inert atmosphere; Reflux 4: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / Inert atmosphere 5: sodium hydroxide; water / tetrahydrofuran / 50 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 80 °C / Inert atmosphere 2.1: cesium fluoride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 3.1: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; ethyl acetate / 24 h / 50 °C / Sealed tube; Inert atmosphere 4.1: sodium hydroxide / water; tetrahydrofuran / 24 h / 50 °C / Inert atmosphere 4.2: pH <2 / Inert atmosphere

	Multi-step reaction with 5 steps 1.1: potassium carbonate / acetonitrile / 80 °C / Inert atmosphere 2.1: bis-triphenylphosphine-palladium(II) chloride; potassium acetate / 1,4-dioxane / 16 h / 130 °C / Inert atmosphere 3.1: cesium fluoride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 24 h / 90 °C / Inert atmosphere 4.1: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; ethyl acetate / 24 h / 50 °C / Sealed tube; Inert atmosphere 5.1: sodium hydroxide / water; tetrahydrofuran / 24 h / 50 °C / Inert atmosphere 5.2: pH <2 / Inert atmosphere
	Multi-step reaction with 4 steps 1: potassium carbonate / acetonitrile / 80 °C 2: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 16 h / 130 °C / Reflux; Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; cesium fluoride / water; 1,4-dioxane 4: palladium on activated charcoal; hydrogen / ethyl acetate; tetrahydrofuran / Reflux
	Multi-step reaction with 3 steps 1.1: potassium carbonate / acetonitrile / 80 °C 2.1: cesium fluoride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 14 h / 90 °C / Reflux 3.1: palladium on activated charcoal; hydrogen / ethyl acetate; ethanol / 24 h / 50 °C 3.2: 50 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 80 °C 2.1: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 16 h / Reflux 3.1: cesium fluoride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 14 h / 90 °C / Reflux 4.1: palladium on activated charcoal; hydrogen / ethyl acetate; ethanol / 24 h / 50 °C 4.2: 50 °C
	Multi-step reaction with 3 steps 1: sulfuric acid / 80 °C 2: copper / N,N-dimethyl-formamide / 10 h / 155 °C / Inert atmosphere 3: sodium hydroxide / tetrahydrofuran / Reflux
	Multi-step reaction with 3 steps 1.1: potassium carbonate / acetonitrile 2.1: cesium fluoride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 90 °C 3.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; ethyl acetate 3.2: 50 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile 2.1: potassium acetate; bis-triphenylphosphine-palladium(II) chloride 3.1: cesium fluoride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 90 °C 4.1: palladium on activated charcoal; hydrogen / tetrahydrofuran; ethyl acetate 4.2: 50 °C

Reference： [1]Grunder, Sergio; Valente, Cory; Whalley, Adam C.; Sampath, Srinivasan; Portmann, Jürg; Botros, Youssry Y.; Stoddart, J. Fraser [Chemistry - A European Journal, 2012, vol. 18, # 49, p. 15632 - 15649]
[2]Grunder, Sergio; Valente, Cory; Whalley, Adam C.; Sampath, Srinivasan; Portmann, Jürg; Botros, Youssry Y.; Stoddart, J. Fraser [Chemistry - A European Journal, 2012, vol. 18, # 49, p. 15632 - 15649]
[3]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - US2013/96210, 2013, A1
[4]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - US2013/96210, 2013, A1
[5]Current Patent Assignee: NORTHWESTERN UNIVERSITY (ILLINOIS) - US2013/122297, 2013, A1
[6]Zheng, Jian; Vemuri, Rama S.; Estevez, Luis; Koech, Phillip K.; Varga, Tamas; Camaioni, Donald M.; Blake, Thomas A.; McGrail, B. Peter; Motkuri, Radha Kishan [Journal of the American Chemical Society, 2017, vol. 139, # 31, p. 10601 - 10604]
[7]Zheng, Jian; Vemuri, Rama S.; Estevez, Luis; Koech, Phillip K.; Varga, Tamas; Camaioni, Donald M.; Blake, Thomas A.; McGrail, B. Peter; Motkuri, Radha Kishan [Journal of the American Chemical Society, 2017, vol. 139, # 31, p. 10601 - 10604]
[8]Zhu, Neng-Xiu; Wei, Zhang-Wen; Chen, Cheng-Xia; Wang, Dawei; Cao, Chen-Chen; Qiu, Qian-Feng; Jiang, Ji-Jun; Wang, Hai-Ping; Su, Cheng-Yong [Angewandte Chemie - International Edition, 2019, vol. 58, # 47, p. 17033 - 17040][Angew. Chem., 2019, vol. 131, p. 17189 - 17196,8]
[9]Barpaga, Dushyant; Bhattacharya, Papri; Brown, Craig M.; Fan, Yanzhong; Jenks, Jeromy J.; Maurin, Guillaume; McGrail, B. Peter; Motkuri, Radha Kishan; Shetty, Manish; Su, Cheng-Yong; Trump, Benjamin A.; Zheng, Jian [Journal of the American Chemical Society, 2020, vol. 142, # 6, p. 3002 - 3012]
[10]Barpaga, Dushyant; Bhattacharya, Papri; Brown, Craig M.; Fan, Yanzhong; Jenks, Jeromy J.; Maurin, Guillaume; McGrail, B. Peter; Motkuri, Radha Kishan; Shetty, Manish; Su, Cheng-Yong; Trump, Benjamin A.; Zheng, Jian [Journal of the American Chemical Society, 2020, vol. 142, # 6, p. 3002 - 3012]

31
[ 18179-39-0 ]
[ 1073355-16-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 80 °C / Inert atmosphere 2: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 16 h / Inert atmosphere; Reflux
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 80 °C / Inert atmosphere 2: bis-triphenylphosphine-palladium(II) chloride; potassium acetate / 1,4-dioxane / 16 h / 130 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 80 °C 2: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 16 h / 130 °C / Reflux; Inert atmosphere

	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 80 °C 2: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 16 h / Reflux
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile 2: potassium acetate; bis-triphenylphosphine-palladium(II) chloride

Reference： [1]Grunder, Sergio; Valente, Cory; Whalley, Adam C.; Sampath, Srinivasan; Portmann, Jürg; Botros, Youssry Y.; Stoddart, J. Fraser [Chemistry - A European Journal, 2012, vol. 18, # 49, p. 15632 - 15649]
[2]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - US2013/96210, 2013, A1
[3]Current Patent Assignee: NORTHWESTERN UNIVERSITY (ILLINOIS) - US2013/122297, 2013, A1
[4]Zheng, Jian; Vemuri, Rama S.; Estevez, Luis; Koech, Phillip K.; Varga, Tamas; Camaioni, Donald M.; Blake, Thomas A.; McGrail, B. Peter; Motkuri, Radha Kishan [Journal of the American Chemical Society, 2017, vol. 139, # 31, p. 10601 - 10604]
[5]Barpaga, Dushyant; Bhattacharya, Papri; Brown, Craig M.; Fan, Yanzhong; Jenks, Jeromy J.; Maurin, Guillaume; McGrail, B. Peter; Motkuri, Radha Kishan; Shetty, Manish; Su, Cheng-Yong; Trump, Benjamin A.; Zheng, Jian [Journal of the American Chemical Society, 2020, vol. 142, # 6, p. 3002 - 3012]

32
[ 109-86-4 ]
[ 18179-39-0 ]
[ 1361938-49-9 ]

Yield	Reaction Conditions	Operation in experiment
1.2 g	With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 20℃;	To a mixture of Compound I (1.0 g), toluene (12 mL), 2-methoxyethanol (312 muL) and triphenylphosphine (1.42 g) was added DIAD (1.1 mL), and the mxitue was stirred at room temperature overnight. The reaction mixture was dried under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 9/1 to 7/3) to give Compound II (1.20 g).

Reference： [1]Patent: EP2612848,2013,A1 .Location in patent: Paragraph 0460; 0461; 0462

33
[ 75-30-9 ]
[ 18179-39-0 ]
[ 1160240-38-9 ]

Yield	Reaction Conditions	Operation in experiment
5.78 g	With potassium carbonate; In acetone; at 60℃; for 48h;	A mixture of Compound I (5.0 g), acetone (45 mL), potassium carbonate (12.4 g) and isopropyl iodide (9.0 mL) was stirred at 60C for 2 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 10/0 to 9/1) to give Compound II (5.78 g).
7.92 g	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 48h;Inert atmosphere;	[1411] 2-Iodopropane (6.42 g) was added to a mixture of methyl 2- hydroxy-4-iodobenzoate (7.00 g), potassium carbonate (6.96 g) and DMF (100 mL) at room temperature, and the resultant was stirred for 2 days at 70C in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and extraction thereof was performed using ethyl acetate. The obtained organic layer was sequentially washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the title compound (7.92 g). 1H NMR (300 MHz, CDC13) delta 1.37 (6H, d, J = 6.0 Hz), 3.86 (3H, s), 4.49-4.63 (1H, m), 7.28-7.33 (2ft m), 7.46 (lft d, J = 8.5 Hz).
7.92 g	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 48h;Inert atmosphere;	2-Iodopropane (6.42 g) was added at room temperature to a mixture of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (7.00 g), potassium carbonate (6.96 g), and DMF (100 mL), and the resultant mixture was stirred at 70 C for 2 days in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.92 g) 1H NMR (300 MHz, CDCl3) delta 1.37 (6H, d, J=6.0 Hz), 3.86 (3H, s), 4.49-4.63 (1H, m), 7.28-7.33 (2H, m), 7.46 (1H, d, J=8.5 Hz).

7.92 g

With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 70℃; for 48h;Inert atmosphere;

2-Iodopropane (6.42 g) was added at room temperature to a mixture of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (7.00 g), potassium carbonate (6.96 g), and DMF (100 mL), and the resultant mixture was stirred at 70 C. for 2 days in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.92 g). 1H NMR (300 MHz, CDCl3) delta 1.37 (6H, d, J=6.0 Hz), 3.86 (3H, s), 4.49-4.63 (1H, m), 7.28-7.33 (2H, m), 7.46 (1H, d, J=8.5 Hz).

Reference： [1]Patent: EP2612848,2013,A1 .Location in patent: Paragraph 0476; 0477; 0478
[2]Patent: WO2014/142363,2014,A1 .Location in patent: Paragraph 1411
[3]Patent: US2015/119412,2015,A1 .Location in patent: Paragraph 0356; 0357
[4]Patent: US2015/99777,2015,A1 .Location in patent: Paragraph 0487; 0488; 0489

34
[ 18179-39-0 ]
[ 42137-51-9 ]

Reference： [1]Patent: US2014/73629,2014,A1
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 2334 - 2356

35
[ 18179-39-0 ]
2,4,6-trivinylcyclotriboroxane*pyridine complex [ No CAS ]
[ 71534-96-8 ]
[ 71534-98-0 ]

Yield	Reaction Conditions	Operation in experiment
1: 3.7 g 2: 0.3 g	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,2-dimethoxyethane; water at 20℃; for 20h; Inert atmosphere; Reflux;	26 A round-bottom flask is charged with 2-Hydroxy-4-iodo-benzoic acid methyl ester, 26-01 (12.0 g, 43.2 mmol), 2,4,6-Trivinyl-cyclotriboroxane-pyridine complex (11.4 g, 47.5 mmol), tetrakis(triphenylphosphine) palladium (2.49 g, 2.16 mmol), 2.0 M aqueous solution of sodium carbonate (25.9 mL, 51.7 mmol), and 1,2-dimethoxyethane (50 mL), deoxygenated by alternating between vacuum and argon (3×), and refluxed under argon pressure for 3 h, and then stirred 18 h at ambient temperature. Volatiles are stripped in vacuo, the residue is suspended in 1N HCl (800 mL) and extracted with EtOAc (600 mL, 300 mL, and then 300 mL). The combined organic extracts are washed brine, dried over NaSO4, and purified by chromatography (silica gel, 5-30% EtOAc in heptane) to afford 2-Hydroxy-4-vinyl-benzoic acid, 26-02 (3.70 g) and 2-Hydroxy-4-vinyl-benzoic acid methyl ester (0.300 g).

Reference： [1]Current Patent Assignee: CORTEVA INC; C.H. Boehringer Sohn AG & Co. KG; F.LLI GANCIA & C. SPA - US2014/73629, 2014, A1 Location in patent: Paragraph 0279

36
[ 18179-39-0 ]
[ 73183-34-3 ]
[ 1073371-99-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With trans-bis(triphenylphosphine)palladium dichloride; potassium acetate; In 1,4-dioxane; at 120℃; for 16h;Inert atmosphere;	Scheme 2: Synthetic path for 3-hydroxy-(methoxycarbonyl) phenylboronic acid pinacol ester (2):Dioxane (450 mL) was added to a flask containing iodide 1 (25.0 g, 90.0 mmol) , bis (pinacolato) diboron (25.1 g, 98.8 mmol) , KOAc (29.1 g, 297 mmol), and PdCl2(PPh3)2 (1.26 g, 1.80 mmol) . The resulting suspension was deoxygenated by nitrogen bubbling at room temperature for 30 min, then immersed in oil bath preheated to 120 C, and stirred at reflux for 16 h. After cooled down to room temperature, the mixture was filtered to remove the insoluble material using AcOEt to rinse the filter cake. The filtrate was evaporated to give brown oil which solidified slowly at room temperature. The crude product was purified by flash silica gel column chromatography (hexanes/AcOEt, 10:1) followed by recrystallization from hot hexanes to provide compound 2 as colorless crystals (20.3 g, 73.1 mmol, 81%). 1H NMR (400 MHz, CDCl3), [ppm] : 1.34 (s, 12H) , 3.94 (s, 3H) , 7.27 (d, J = 8.1 Hz, 1H) , 7.41 (s, 1H) , 7.80 (d, J = 7.9 Hz, 1H) , 10.6 (s, 1H) ; 13C{1H} NMR (100 MHz, CDCl3) , [ppm] : 24.8, 52.3, 84.2, 114.2, 123.8, 124.7, 128.9, 160.7, 170.5; (Carbon directly bonded to boron was not observed) . IR (ATR) , v_max [cm-1] : 3177 (br) , 2982 (w) , 1676 (m) , 1619 (w), 1557 (w) , 1502 (w) , 1438 (w) , 1371 (sh) , 1359 (s) , 1329 (s), 1282 (m) , 1220 (m) , 1192 (m) , 1159 (sh) , 1136 (s), 1099 (s)961 (w) , 920 (m) , 850 (m) , 821 (w) , 788 (s) , 712 (s) , 638 (m) , 663 (m) , 562 (m), 547 (m) , 500 (w) , 467 (w) .

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 8863 - 8866
[2]Patent: WO2015/195179,2015,A2 .Location in patent: Paragraph 00155; 00156

37
[ 18179-39-0 ]
[ 536-90-3 ]
[ 1644060-64-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; caesium carbonate In toluene at 100℃; for 15.25h; Inert atmosphere;

Reference： [1]Schuster, Christian; Boerger, Carsten; Julich-Gruner, Konstanze K.; Hesse, Ronny; Jaeger, Anne; Kaufmann, Gyoerley; Schmidt, Arndt W.; Knoelker, Hans-Joachim [European Journal of Organic Chemistry, 2014, vol. 2014, # 22, p. 4741 - 4752]

38
[ 18179-39-0 ]
[ 26690-80-2 ]
2-(2-((tert-butoxycarbonyl)amino)ethoxy)-4-iodobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran;Inert atmosphere;	To a solution of 300 mg (1.76 mmol, 1.0 eq) of Methyl 4-fluoro-2-hydroxybenzoate, 196 muL (1.76 mmol, 1.0 eq) boc-ethanolamine and 578 mg (2.20 mmol, 1.25 eq) triphenyl phosphine in 10 mL of dry THF was added 578 mg (2.20 mmol, 1.25 eq) of DIAD and the reaction mixture was left stirring overnight under nitrogen atmosphere. The reaction mixture was evaporated and without further processing was loaded on a silica column. The product was eluted 7:2 He:EtOAc (TLC Rf:0.45).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 4099 - 4108

39
[ 18179-39-0 ]
[ 1765-93-1 ]
[ 873784-26-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium phosphate; palladium diacetate; In water; toluene; at 90℃;	Palladium (II) acetate (1.25 g, 5.57 mmol) was added to a mixture of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (15.5 g, 55.8 mmol), 4-fluorophenylboronic acid (15.6 g, 111.5 mmol), tricyclohexylphosphine (19.8 ml, 11.2 mmol) and K3PO4 (35.5 g, 167.2 mmol) in toluene (150 ml) and water (75 ml) at room temperature. The mixture was stirred at 90 C for overnight. The mixture was separated and aqueous layer was acidified with 2M HCl. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was passed through NH silica gel pad, and concentrated in vacuo. The residue was slurried in MeOH to give the title compound (13.7 g, 100%) as yellow solids. 1H NMR (300 MHz, DMSO-d6) delta 3.74-4.07 (3H, m), 7.19-7.38 (4H, m), 7.65-7.92 (3H, m), 10.60 (1H, brs).
16.4 g	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 90℃; for 1.5h;Inert atmosphere;	[0806] Palladium acetate (1.45 g) was added to a mixture of methyl 2- hydroxy-4-iodobenzoate (18.0 g), tripotassium phosphate (41.2 g), (4-fluorophenyl)boronic acid (18.1 g), tricyclohexylphosphine (20% toluene solution, 23.0 mL), toluene (200 mL) and water (100 mL), and the resultant was stirred for 1.5 hours at 90C in an argon atmosphere. The reaction mixture was cooled to room temperature, and the organic layer was separated. After the aqueous layer was acidified with 2 M hydrochloric acid, extraction thereof was performed using ethyl acetate. The collected organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then distilled off under reduced pressure. The obtained residue was crystallized (methanol), thereby obtaining the title compound (16.4 g). 1H NMR (300 MHz, DMSO-d^ delta 3.92 (3H, s), 7.23-7.36 (4H, m), 7.73-7.82 (2H, m), 7.86 (1H, d, J = 8.9 Hz), 10.60 (1H, brs).

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 4683 - 4696
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 4153 - 4162
[3]Journal of Organic Chemistry,2016,vol. 81,p. 9046 - 9074
[4]Patent: WO2014/142363,2014,A1 .Location in patent: Paragraph 0806

40
[ 18179-39-0 ]
[ 144025-03-6 ]
C₁₄H₁₀F₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; In water; toluene; at 100℃; for 2h;	[1477] A mixture of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (22.0 g), (2,4-difluorophenyl)boronic acid (25.0 g), dicyclohexyl (2 6'-dimethoxybiphenyl-2-yl)phosphine (4.87 g), 2 M aqueous sodium carbonate solution (119 mL), tris(c benzyUdeneacetone)dipaUadium(0) (5.07 g) and toluene (150 mL) was stirred 2 hours at 100C. The reaction mixture was poured into water at room temperature, it was filtered using celite, and then the filtrate was extracted using ethyl acetate. The obtained organic layer was washed with a saturated saline solution, it was passed through a short column of a silica gel (NH), and the solvent was distilled off under reduced pressure, benzylbromide (10.4 mL) was added to a mixture of the obtained residue, potassium carbonate (21.9 g) and DMF (100 mL), the resultant was stirred for 1 hour at 70C in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and extraction thereof was performed using ethyl acetate. The obtained organic layer was sequentially washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the title compound (30.5 g). 1H NMR (300 MHz, CDC13) delta 3.92 (3H, s), 5.22 (2H, s), 6.85-7.02 (2H, m), 7.09-7.19 (2H, m), 7.28-7.45 (3H, m), 7.47-7.56 (2H, m), 7.62 (1H, dd, J = 6.8, 2.9 Hz), 7.90 (1H, d, J = 8.0 Hz).
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; In water; toluene; at 100℃; for 2h;	A mixture of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (22 g), 2,4-difluorophenylboronic acid (25 g), a 2 M aqueous sodium carbonate solution (119 mL), tris(dibenzylideneacetone)dipalladium(0) (5.07 g), and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (4.87 g) in toluene (150 mL) was stirred at 100 C for 2 hours. The reaction mixture was poured to water, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and passed through a basic silica gel, and the solvent was distilled off under reduced pressure. Benzyl bromide (10.4 mL) was added at room temperature to a mixture of the obtained residue, potassium carbonate (21.9 g), and DMF (100 mL), and the mixture was stirred at 70 C for 1 hour in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (30.5 g)

Reference： [1]Patent: WO2014/142363,2014,A1 .Location in patent: Paragraph 1474
[2]Patent: US2015/119412,2015,A1 .Location in patent: Paragraph 0372

41
[ 2162-31-4 ]
[ 18179-39-0 ]
4-iodo-2-[2-(tetrahydropyran-2-yloxy)ethoxy]benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃;Inert atmosphere;	a. 4-Iodo-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoic acid methyl ester (Intermediate 55a) To a solution of 4-Iodo-methyl salicylate (2.00 g, 7.20 mmol) and triphenylphosphine (3.77 g, 14.4 mmol) in THF (20 mL), under Argon atmosphere, was added 2-(tetrahydro-pyran-2-yloxy)-ethanol (1.54 mL, 10.8 mmol) followed by dropwise addition of DEAD (2.84 mL, 14.4 mmol). The reaction was stirred at RT overnight. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic phase was washed with brine and dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by FCC, eluting with 0-20% EtOAc in DCM, to give the title compound as a colourless oil (2.64 g, 90%). 1H NMR (300 MHz, CDCl3): 1.48-1.67 (4H, m), 1.68-1.90 (2H, m), 3.5-3.59 (1H, m), 3.75-3.94 (5H, m), 3.96-4.13 (1H, m), 4.14-4.27 (2H, m), 4.75 (1H, t), 7.33 (1H, dd, J=8.23, 1.45 Hz), 7.40 (1H, d, J=1.5 Hz), 7.47 (1H, d, J=8.3 Hz).
90%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃;Inert atmosphere;	To a solution of 4-Iodo-methyl salicylate (2.00 g, 7.20 mmol) and triphenylphosphine (3.77 g, 14.4 mmol) in THF (20 mL), under Argon atmosphere, was added 2-(tetrahydro- pyran-2-yloxy)-ethanol (1.54 mL, 10.8 mmol) followed by dropwise addition of DEAD (2.84 mL, 14.4 mmol). The reaction was stirred at RT overnight. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic phase was washed with brine and dried over Na2S04 and evaporated under reduced pressure. The residue was purified by FCC, eluting with 0-20% EtOAc in DCM, to give the title compound as a colourless oil (2.64 g, 90%). XH MR (300 MHz, CDC13): 1.48-1.67 (4H, m), 1.68-1.90 (2H, m), 3.5-3.59 (1H, m), 3.75-3.94 (5H, m), 3.96-4.13 (1H, m), 4.14-4.27 (2H, m), 4.75 (1H, t), 7.33 (1H, dd, J = 8.23, 1.45 Hz), 7.40 (1H, d, J = 1.5 Hz), 7.47 (1H, d, J = 8.3 Hz).

Reference： [1]Patent: US2014/364412,2014,A1 .Location in patent: Paragraph 0640; 0641
[2]Patent: WO2014/195402,2014,A1 .Location in patent: Page/Page column 198-199

42
[ 13154-24-0 ]
[ 18179-39-0 ]
5-iodo-2-(triisopropylsilanyloxy)benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18h;	A solution of methyl 5-iodosalicylate (2.00 g, 7.20 mmol) in DMF (20 mL) was treated with imidazole (1.22 g, 18.0 mmol) then chlorotriisopropylsilane (1.85 mL, 8.60 mmol). The mixture was stirred at RT for 18 h. The mixture was evaporated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (2 x ). The combined organic layers were washed with a 10% aqueous citric acid solution, IN aqueous NaOH solution and brine, dried (Na2S04), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% EtOAc in cyclohexane, to give the title compound as a colourless oil (2.88 g, 92%>). LCMS (Method 3): Rt 5.72 min, m/z 435 [MH+].

Reference： [1]Patent: WO2014/195402,2014,A1 .Location in patent: Page/Page column 211

43
[ 18179-39-0 ]
[ 75-26-3 ]
[ 1160240-38-9 ]

Yield	Reaction Conditions	Operation in experiment
14.0 g	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;	2-Bromopropane (6.49 mL) was added to a DMF (70 mL) suspension of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (12.8 g) and potassium carbonate (12.7 g), and the mixture was stirred at 60 C for 2 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to obtain the title compound (14.0 g). 1H NMR (300 MHz, CDCl3) delta 1.37 (6H, d, J=6.0 Hz), 3.86 (3H, s), 4.41-4.67 (1H, m), 7.29-7.35 (2H, m), 7.46 (1H, d, J=8.6 Hz).
14 g	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;	2-Bromopropane (6.49 mL) was added to a DMF (70 mL) suspension of <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (12.8 g) and potassium carbonate (12.7 g), and the mixture was stirred at 60 C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to obtain the title compound (14.0 g). 1H NMR (300 MHz, CDCl3) delta 1.37 (6H, d, J=6.0 Hz), 3.86 (3H, s), 4.41-4.67 (1H, m), 7.29-7.35 (2H, m), 7.46 (1H, d, J=8.6 Hz).

Reference： [1]Patent: US2015/119412,2015,A1 .Location in patent: Paragraph 0342; 0343
[2]Patent: US2015/99777,2015,A1 .Location in patent: Paragraph 0372; 0373; 0374

44
[ 18179-39-0 ]
[ 1765-93-1 ]
[ 75-03-6 ]
methyl 3-ethoxy-4'-fluorobiphenyl-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.92 g	Stage #1: methyl 4-iodosalicylate; 4-fluoroboronic acid With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 90℃; for 1.5h; Inert atmosphere; Stage #2: ethyl iodide With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 1h;	2.A A) Methyl 3-ethoxy-4'-fluorobiphenyl-4-carboxylate Palladium acetate (0.484 g) was added to a mixture of methyl 2-hydroxy-4-iodobenzoate (6.00 g), tripotassium phosphate (13.7 g), (4-fluorophenyl)boronic acid (6.04 g), tricyclohexylphosphine (20% toluene solution, 7.66 mL), toluene (30 mL), and water (15 mL), and the resultant mixture was stirred at 90° C. for 1.5 hours in an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and then, the organic layer was separated. The aqueous layer was subjected to extraction with ethyl acetate. Combined organic layers were washed with saturated saline, then dried over anhydrous magnesium sulfate, and then passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. Iodoethane (2.59 mL) was added to a DMF (50 mL) suspension of the obtained residue and potassium carbonate (4.47 g), and the mixture was stirred at 80° C. for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.92 g). 1H NMR (300 MHz, CDCl3) δ 1.50 (3H, t, J=7.0 Hz), 3.91 (3H, s), 4.19 (2H, q, J=7.1 Hz), 7.04-7.21 (4H, m), 7.46-7.63 (2H, m), 7.86 (1H, d, J=8.0 Hz).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2015/99777, 2015, A1 Location in patent: Paragraph 0312; 0313; 0314

45
[ 18179-39-0 ]
[ 100-39-0 ]
[ 144025-03-6 ]
methyl 3-(benzyloxy)-2',4'-difluorobiphenyl-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30.5 g	Stage #1: methyl 4-iodosalicylate; 2,4-difluorophenylboronic acid With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium carbonate In water; toluene at 100℃; for 2h; Stage #2: benzyl bromide With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 1h; Inert atmosphere;	66.A A) Methyl 3-(benzyloxy)-2',4'-difluorobiphenyl-4-carboxylate A mixture of methyl 2-hydroxy-4-iodobenzoate (22 g), (2,4-difluorophenyl)boronic acid (25 g), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (4.87 g), a 2 M aqueous sodium carbonate solution (119 mL), tris(dibenzylideneacetone)dipalladium(0) (5.07 g), and toluene (150 mL) was stirred at 100° C. for 2 hours. The reaction mixture was poured to water at room temperature, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. Benzyl bromide (10.4 mL) was added to a mixture of the obtained residue, potassium carbonate (21.9 g), and DMF (100 mL), and the resultant mixture was stirred at 70° C. for 1 hour in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (30.5 g). 1H NMR (300 MHz, CDCl3) δ 3.92 (3H, s), 5.22 (2H, s), 6.85-7.02 (2H, m), 7.09-7.19 (2H, m), 7.28-7.45 (3H, m), 7.47-7.56 (2H, m), 7.62 (1H, dd, J=6.8, 2.9 Hz), 7.90 (1H, d, J=8.0 Hz).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2015/99777, 2015, A1 Location in patent: Paragraph 0699; 0700

46
[ 18179-39-0 ]
[ 103057-44-9 ]
tert-butyl 3-(5-iodo-2-(methoxycarbonyl)phenoxy)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 12h;

Reference： [1]Deng, Hongfeng; Zhou, Jingye; Sundersingh, Flora S.; Summerfield, Jennifer; Somers, Don; Messer, Jeffrey A.; Satz, Alexander L.; Ancellin, Nicolas; Arico-Muendel, Christopher C.; Bedard, Katie L.; Beljean, Arthur; Belyanskaya, Svetlana L.; Bingham, Ryan; Smith, Sarah E.; Boursier, Eric; Carter, Paul; Centrella, Paolo A.; Clark, Matthew A.; Chung, Chun-Wa; Davie, Christopher P.; Delorey, Jennifer L.; Ding, Yun; Franklin, G. Joseph; Grady, LaShadric C.; Herry, Kenny; Hobbs, Clare; Kollmann, Christopher S.; Morgan, Barry A.; Kaushansky, Laura J.; Zhou, Quan [ACS Medicinal Chemistry Letters, 2015, vol. 6, # 8, p. 919 - 924]

47
[ 16870-28-3 ]
[ 74-88-4 ]
[ 18179-39-0 ]

Yield	Reaction Conditions	Operation in experiment
76.5%		4-Iodosalicylic acid 60 (7.3 g, 27.65 mmol) was dissolved in 41 ml DMF and NaHCO3 (2.78 g, 33.18 mmol) were added (evolution of CO2) and the mixture stirred for 5 min. MeI (2.66 ml, 5.85 g, 41.47 mmol, 1.5 eq) was added and the reaction mixture was heated to 40 C. for 5 h while stirring (monitored by TLC). Upon reaction completion, the mixture was diluted with 170 ml H2O and 170 ml EA. The organic layer was subsequently washed with 170 ml of 5% NaHCO3, 170 ml 5% NaCl and was dried over Na2SO4. The solvent was evaporated to give ?9 g of crude oily product (black color), which was purified by column chromatography: SiO2 (100 g), Hexane, Hexane:EA 100:2. 5.86 g, Yield: 76.5%.

Reference： [1]Patent: US2016/2269,2016,A1 .Location in patent: Paragraph 0253; 0254

48
[ 18179-39-0 ]
[ 115-19-5 ]
methyl 2-hydroxy-4-(3-hydroxy-3-methylbut-1-ynyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With copper(l) iodide; bis(triphenylphosphine)palladium(II) dichloride; triethylamine; triphenylphosphine for 24h; Inert atmosphere; Reflux;	11 Synthesis of 4-(3′-hydroxy-4-carboxymethyl)phenyl-3-butyne-2-methy-2-ol (78): A solution of methyl 4-iodosalicylate 76 (5.8 g, 20.8 mmol) and 2-methyl-3-butyn-2-ol 77 (2.44 ml, 2.12 g, 25.2 mmol) in NEt3 (58 ml) was prepared under N2. CuI (22 mg), PPh3 (44 mg) and Pd(PPh3)Cl2 (22 mg) were added. The mixture was stirred under reflux for 24 h. NEt3.HI was precipitated. The reaction mixture was cooled and 450 ml of EA and 170 ml water were added. The organic solution was separated from green water and dried over Na2SO4. The yellow organic solution was evaporated to obtain yellow oily residue, which was purified by column chromatography: SiO2(80 g), Hexane:EA 20:1→2:1 to obtain 3.55 g of solid yellow product. Yield: 73%.

Reference： [1]Current Patent Assignee: WEIZMANN INSTITUTE OF SCIENCE - US2016/2269, 2016, A1 Location in patent: Paragraph 0253; 0255

49
[ 18179-39-0 ]
[ 536-74-3 ]
methyl 2-hydroxy-4-(phenylethynyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.26%	With copper(l) iodide; bis(triphenylphosphine)palladium(II) dichloride; triethylamine; triphenylphosphine; at 80 - 90℃; for 0.5h;Inert atmosphere;	A solution of <strong>[18179-39-0]methyl 4-iodosalicylate</strong> 76 (0.834 g, 3 mmol) and ethynylbenzen 109 (0.395 ml, 0.368 g, 3.6 mmol) in NEt3 (9 ml) was prepared under N2. CuI (3 mg), PPh3 (6 mg) and Pd(PPh3)Cl2 (3 mg) were added. The mixture was stirred under at 80-90 for 0.5 h. NEt3.HI was precipitated. The reaction mixture was cooled and 70 ml of EA and 250 ml water were added. The organic solution was separated washed with 12 ml of water and dried over Na2SO4. The organic solution was evaporated to obtain 1.1 g of light brown solid product, which was purified by column chromatography: SiO2(20 g), Hexane; Hexane:CHCl3 (20:1), Hexane:CHCl3 (4:1), to obtain 0.707 g of solid colorless product. Yield: 94.26%.

Reference： [1]Patent: US2016/2269,2016,A1 .Location in patent: Paragraph 0283; 0284

50
[ 18179-39-0 ]
[ 380600-93-1 ]
C₄₉H₅₄O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In tetrahydrofuran; at 60℃; for 5h;Inert atmosphere;	A mixture of 9,9-dioctyl-2,7-diethynylfluorene [21] (0.20 g,0.46 mmol), PdCl2(PPh3)2 (64 mg, 0.09 mmol), CuI (35 mg, 0.18 mmol), PPh3 (48 mg, 0.18 mmol) and <strong>[18179-39-0]methyl 4-iodosalicylate</strong> (0.28 g, 1.0 mmol) in THF (10 mL) andtriethylamine (10 mL) was added and the mixture was stirredat 60 C for 5 h. The reaction mixture was extracted withCH2Cl2 (2 × 20 mL). The combined organic phase waswashed with water (2 × 25 mL) and dried over anhydrousNa2SO4. The solvent was evaporated and the crude productwas purified by a silica gel column chromatography using hexaneas an eluent to afford methyl ester of 2 as yellow oil. Asolution of this ester in THF (10 mL) was added an aqueoussaturatedKOHsolution (0.3mL). After the mixture was heatedto 70 C for 24 h, the volatile solvents were evaporated and theresidue was dissolved in water (20 mL). The aqueous layer wasacidified by an addition of 6 N HCl and the resulting suspensionwas centrifuged. The precipitates were collected andwashed with a copious amount of water to afford 2 as an offwhitesolid in 62%overall yield.

Reference： [1]Journal of Fluorescence,2016,vol. 26,p. 745 - 752

51
[ 18179-39-0 ]
[ 38170-02-4 ]

Reference： [1]Journal of Pharmacy and Pharmacology,2016,vol. 68,p. 233 - 244

52
[ 18179-39-0 ]
copper(l) cyanide [ No CAS ]
methyl 4-cyano-2-hydroxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	In N,N-dimethyl-formamide at 140℃; for 2h; Inert atmosphere;
420 mg	In N,N-dimethyl-formamide at 140℃; for 2h;	107.1 Step 1: Methyl 4-cyano-2-hydroxybenzoate Methyl 2-hydroxy-4-iodobenzoate (1 g, 3.60 mmol) was dissolved in DMF (9 mL) and CuCN (773.33 mg, 8.63 mmol, 1.89 mL) was added. The reaction was heated to reflux at 140 °C for 2 hrs. The reaction was cooled to r.t. and dissolved in neat H2O (50 mL). The resulting mixture was diluted with EtOAc (80 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was separated, washed with H2O (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (420 mg) as a yellow solid which was used without further purification.1H NMR (400MHz, DMSO-d6) d 10.75 (s, 1H), 7.84 (d, J=8 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J=8 Hz, 1H), 3.88 (s, 3H).

Reference： [1]Kennedy, Andrew J.; Bruce, Alexandra M.; Gineste, Catherine; Ballard, T. Eric; Olekhnovich, Igor N.; Macdonald, Timothy L.; Hoffman, Paul S. [Antimicrobial Agents and Chemotherapy, 2016, vol. 60, # 7, p. 3980 - 3987]
[2]Current Patent Assignee: E SCAPE BIO - WO2021/7477, 2021, A1 Location in patent: Page/Page column 250; 251

53
[ 18179-39-0 ]
3-[2-chloro-6-(trifluoromethyl)phenyl]methyl}-1H-indole [ No CAS ]
4-[3-[[2-chloro-6-(trifluoromethyl)phenyl]methyl]indol-1-yl]-2-hydroxy-benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6%	With copper(l) iodide; 2-methyl-8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 95℃; for 48h;Inert atmosphere;	Step 33-(2-chloro-6-(trifluoromethyl)benzyl)-1H-indole (0.048 g, 0.15 mmol), <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (0.052 g, 0.19 mmol), 2-methylquinolin-8-ol (1.234 mg, 7.75pmol), copper(l) iodide (4.43 mg, 0.02 mmol) were mixed as solids and diluted inDMSO (1 mL). potassium carbonate (0.075 g, 0.54 mmol) was added and themixture was degassed by bubbling nitrogen for 15 mins. The mixture was stirred at 95 Cfor2 days.Some water (0.5 mL) was added and the mixture was stirred 10 mins and thenpartitioned between 4 M HCI (2 mL) and ethyl acetate (7 ml). The layers wereseparated and the organic layer was washed with 50% saturated brine (3x1 mL). The organic layer was passed through a phase separator and concentrated under reduced pressure. The residue was dissolved in DMSO (1 mL), filtered and purified by reverse phase HPLC to give the product (0.0044 g, 6%).IH NMR (600 MHz, DMSO) 64.34(s, 2H), 6.84 (5, 1H), 6.96 (d, 1H), 6.99-7.02 (m,1H), 7.19- 7.23 (m, 1H), 7.26 - 7.3 (m, 1H), 7.58 (t, 1H), 7.68 (d, 1H), 7.72 (d, 1H),7.81 - 7.84 (m, 1H), 7.84-7.88 (m, 2H).Expected Number of Hs: 15Assigned Hs: 13.

Reference： [1]Patent: WO2016/63080,2016,A1 .Location in patent: Page/Page column 33

54
[ 18179-39-0 ]
[ 100-44-7 ]
[ 854028-46-9 ]

Reference： [1]Journal of Materials Chemistry C,2017,vol. 5,p. 9972 - 9978

55
[ 13220-46-7 ]
[ 18179-39-0 ]
methyl 4-(4-methylindolin-2-on)ylsalicylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23.5%	With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate; In 1,4-dioxane; at 125℃; for 2h;Microwave irradiation;	Step 1: synthesis of methyl 4-(4-methylindolin-2-on)ylsalicylate (1-2) (0094) (0095) 4-Methylindol-2-one (147 mg, 1 mmol) and methyl 4-iodosalicylate (306 mg, 1.1 mmol) were dissolved in 2 mL dioxane, followed by adding cuprous iodide (38 mg, 0.2 mmol), 1,10-phenanthroline (54 mg, 0.3 mmol) and potassium carbonate (415 mg, 3 mmol). The mixture was heated by microwave at 125C to react for 120 min. The mixture was cooled to room temperature, diluted with 20 mL ethyl acetate, filtered, and evaporated under reduced pressure to remove the solvent. The residue was separated by column chromatography (silica gel 200-300 mesh, eluent: n-hexane/ethyl acetate = 4/1) to give 70 mg methyl 4-(4-methylindolin-2-on)-ylsalicylate as a yellow solid with a yield of 23.5%.

Reference： [1]Patent: EP3252038,2017,A1 .Location in patent: Paragraph 0094-0095

56
[ 18179-39-0 ]
[ 100-51-6 ]
[ 854028-46-9 ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 24h;Cooling with ice;	In <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong>(2 equiv., 0.6 mmol) in stirred THF solution (4 ml) was added 1 equivalent of benzyl alcohol (0.3 mmol) and 1.5 equivalents of triphenylphosphinePPh3 (0.45 mmol) and allowed to dissolve.The reaction mixture was cooled in an ice bath, 1.5 equivalents of diisopropyl azodicarboxylate DIAD (0.45 mmol) was added dropwise thereto.The reaction was then allowed to return to room temperature and stirring was continued for 24 hours.The solvent was removed under reduced pressure.Purification by silica gel flash column chromatography using a 0-20% EtOAc / hexanes gradient.The fractions containing the desired product (02a) were confirmed by LCMS,And the solvent removed under reduced pressure to give compound 02a.

Reference： [1]Patent: CN107530302,2018,A .Location in patent: Paragraph 0194; 0196; 0198; 0199

57
[ 110-52-1 ]
[ 18179-39-0 ]
methyl 2-(4-bromobutoxy)-4-iodobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; In acetone; at 90℃; under 7757.43 Torr; for 0.75h;Microwave irradiation; Sealed tube;	General procedure: Method A: To a suspension of the appropriate phenol (15 mmol) in acetone (15 mL), K2CO3 (30mmol) and 1,4-dibromobutane (30 mmol) were added. The mixture and a magnetic bar were sealedin Pyrex test tubes (ca. 10 mL) and heated at 90 C under microwaves irradiation for 45 min (run time2 min, microwave max power 150 W, max pressure 150 Psi). After cooling, the inorganic materialwas removed by filtration and the solvent was evaporated in vacuum to give a residue which waspurified by flash chromatography using mixtures of cyclohexane/ethyl acetate. By use of thisprocedure, the following compounds were prepared.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 158,p. 937 - 950

58
[ 18179-39-0 ]
2-hydroxy-4-iodobenzohydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With hydrazine hydrate; In ethanol; under 760.051 Torr; for 5h;Reflux;	General procedure: Various benzohydrazides 5-7 and 9-13 were obtained accordingto known procedures [40,65] except for benzohydrazides 4and 8 which were commercially available. A solution of the methylbenzoate (1 equiv) in ethanol was added dropwise to 65% hydrazinemonohydrate (5 equiv). The reaction mixture was then heatedunder reflux and stirred overnight. The reaction progress was followedup by TLC. Crude product was collected by filtration aftercooling of the reaction medium and finally washed with coldethanol unless specified otherwise. The desired benzohydrazides were used without any further purification.The analysis of spectral data (1H and 13C NMR), the yields, HRMS,Mp and Rf of these precursors are presented in SupplementaryInformation.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 159,p. 324 - 338

59
[ 18179-39-0 ]
6-ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene [ No CAS ]
methyl 4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)-2-hydroxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 8h;Inert atmosphere;	Embodiment 39 methyl 4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)-2-hydroxybenzoate 6-Ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (116mg, 0.45mmol) and <strong>[18179-39-0]methyl 2-hydroxy-4-iodobenzoate</strong> (250mmuL 0.9mmol) was added to a flask, followed by addition of Pd(PPh3)2Cl2 (9.5mg, 0.0135mmol) and CuI (5.1mg, 0.027mmol). After the flask was purged with argon for 3 times to remove oxygen, 3mL dry DMF and 0.2mL dry Et3N were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA = 500:1) to give WYC-301 (155mg, 79%). 1H NMR (500 MHz, CDCl3) delta 10.75 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.43 (dd, J = 7.7, 7.1 Hz, 7H), 7.37 (dd, J = 9.3, 3.7 Hz, 4H), 7.21 (d, J = 1.3 Hz, 1H), 7.09 (d, J = 1.2 Hz, 1H), 6.97 (dd, J = 8.2, 1.2 Hz, 1H), 6.02 (t, J = 4.6 Hz, 1H), 3.94 (s, 3H), 2.37 (d, J = 4.7 Hz, 2H), 1.36 (s, 6H). 13C NMR (126 MHz, CDCl3) delta 170.27, 161.31, 146.42, 140.63, 138.99, 134.24, 131.17, 130.83, 129.82, 129.20, 128.80, 128.54, 127.41, 127.38, 124.18, 122.47, 120.36, 120.07, 111.98, 92.99, 87.93, 52.47, 38.85, 33.94, 28.19. ESI(+)-MS: 409.3 [M+1]+.

Reference： [1]Patent: EP3428155,2019,A1 .Location in patent: Paragraph 0146; 0147

60
[ 118292-06-1 ]
[ 18179-39-0 ]
methyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-hydroxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; isopropylamine; In N,N-dimethyl-formamide; at 20℃; for 8h;Inert atmosphere;	Embodiment 1 methyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-hydroxybenzoate Commercially available 6-ethynyl-4,4-dimethylbenzothiopyran (202.8mg, 1mmol) and methyl 2-hydroxy-4-iodobenzoate (292. 1mg, 1mmol) used as raw material were added to a flask, followed by addition of Pd(PPh3)2Cl2 (14mg, 0.02mmol) and CuI (7.6mg, 0.04mmol). After the flask was purged with argon for 3 times to remove oxygen, 2mL dry DMF and 0.2mL dry iPr2NH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc = 100:1 to 20:1) to give WYC-101 (296mg, 81%). 1H NMR (400 MHz, CDCl3) delta 7.79 (d, 1H), 7.53 (d, 1H), 7.18-7.20 (dd, 1H), 7.12 (d, 1H), 7.06-7.07 (d, 1H), 7.00-7.02 (dd, 1H), 3.95 (s, 3H), 3.03-3.06 (m, 2H), 1.94-1.97 (m, 1H), 1.34 (s, 6H); 13C NMR (101 MHz, CDCl3) delta 170.09, 161.38, 161.12, 153.37, 142.25, 134.10, 130.91, 130.00, 129.85, 129.24, 126.73, 122.45, 120.25, 117.90, 111.95, 93.23, 88.03, 77.48, 77.16, 76.84, 52.52, 37.27, 32.54, 29.99, 23.43; ESI(+)-MS: 353.3 [M+1]+.

Reference： [1]Patent: EP3428155,2019,A1 .Location in patent: Paragraph 0065; 0066

61
[ 18179-39-0 ]
[ 119362-54-8 ]
methyl 2-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; for 8h;Inert atmosphere;	Embodiment 79 methyl 2-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoate 6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (50mg, 0.205mmol) and Compound c (75.3mg, 0.271mmol) were added to a flask, followed by addition of Pd(PPh3)2Cl2 (14mg, 0.02mmol) and CuI (5.6mg, 0.03mmol). After the flask was purged with argon for 3 times to remove oxygen, 2mL dry DMF and 0.14mL dry Et3N were added via syringe. Then the reaction was continued at 70C for 8 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE) to give the product (45.2mg, 61%). 1H NMR (400 MHz, CDCl3) delta 10.76 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.48 (s, 1H), 7.29 (d, J = 0.8 Hz, 2H), 7.13 (d, J = 1.4 Hz, 1H), 7.03 (dd, J = 8.2, 1.5 Hz, 1H), 3.96 (s, 3H), 1.69 (s, 4H), 1.30 (s, 6H), 1.28 (s, 6H). ESI(+)-MS: 363.3 [M+1]+.

Reference： [1]Patent: EP3428155,2019,A1 .Location in patent: Paragraph 00226; 0227

62
[ 18179-39-0 ]
[ 54663-78-4 ]
methyl 2-hydroxy-4-(thiophen-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 50 - 120℃; for 12h;Inert atmosphere;	In a two-necked, oven-dried 50mL round-bottom flask, Methyl 4-iodosalicylate (1) (0.10g, 0.36mmol) and 2-(tributylstannyl)thiophene (0.15g, 0.39mmol) were dissolved in 7mL of anhydrous DMF and heated to 50C under nitrogen gas (N2) for 30min. Bis(triphenylphosphine)palladium(II) dichloride (0.005g, 7.2×10-6mol) was then added, and the reaction mixture was further stirred and heated to 120C for 12h. The reaction mixture was allowed to cool down to room temperature, and the solvent was evaporated under vacuo. The compound was purified by column chromatography using DCM and hexane mixture as an eluent. (98% yield) IR (neat): numax3159, 3097, 2959, 2864, 1659, 1620, 1558, 1535, 1493, 1443, 1335, 1292, 1257, 1203, 1188, 1157, 1099, 1065, 1003, 960, 872, 845, 822, 775, 744, 721, 694, 544cm-1. 1H NMR (400MHz, chloroform-d) delta ppm 3.97 (s, 3H) 7.10-7.18 (m, 2H) 7.25 (s, 1H) 7.37 (d, J=5.12Hz, 1H) 7.43 (d, J=3.17Hz, 1H) 7.83 (d, J=8.29Hz, 1H) 10.83 (s, 1H) (Supporting Information, Fig. S3). 13C NMR (126MHz, chloroform-d) delta ppm 170.4, 162.0, 142.8, 141.4, 130.6 128.3, 126.7, 125.0, 116.9, 114.1, 111.2, 52.4 (Supporting Information, Fig. S4). GC-MS m/z (rel. intensity) 233(M+, 100), 176 (78), 146 (49), 108 (44), 97 (71).
	With bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide;Heating;	To a round flask was added 7 mL of N,N-dimethylformamide (N,N-imethylformamide), The starting material <strong>[18179-39-0]methyl 4-iodo-2-hydroxybenzoate</strong> (Methyl 4-iodo-2-hydroxybenzoate) 0.1000 g (0.3596 mmol), 0.1476 g (0.3956 mmol) of 2-(tributylstannyl)thiophene (2-(tributylstannyl)thiophene), bis(triphenylphosphine)palladium(II) dichloride (bis(triphenylphosphine)palladium(II) dichloride, Pd2Cl2(PPh3)2) 0.0050 g (7.1929 x 10-6 mol) are added. After the reaction mixture was stirred at 60 C until it was dissolved in a transparent state, the temperature was gradually raised to 120 C and stirred while refluxing for 10 hours. The temperature of the reaction mixture is then lowered to room temperature and the solvent is removed using a rotary evaporator. Compound 1 was then isolated using column chromatography (eluent: dichloromethane / Hexane = 1/49, vol / vol). The reaction scheme of the synthesis process according to Example 1 of the present invention is shown in FIG. 3

Reference： [1]Inorganica Chimica Acta,2019,vol. 495
[2]Patent: KR101931033,2018,B1 .Location in patent: Paragraph 0112-0114

63
[ 18179-39-0 ]
[ 17997-47-6 ]
methyl 2-hydroxy-4-(pyridin-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 1h;Microwave irradiation;	In a microwave vial, <strong>[18179-39-0]methyl 4-iodosalicylate</strong> (1) (0.2g, 0.72mmol), 2-(tributylstannyl)pyridine (0.34g, 0.94mmol) and tetrakis(triphenylphosphine) palladium(0) (0.016g, 0.014mmol) were dissolved in 5mL of anhydrous N,N-dimethylformamide (DMF), and the mixture was combined in a microwave reactor for 1h (110C, ~20W). The solvent was evaporated under vacuo, and the reaction mixture was purified by column chromatography using dichloromethane (DCM) and hexane mixture as an eluent. (21% yield) IR (neat): numax 3101, 3063, 2955, 2928, 2854, 1666, 1620, 1562, 1504, 1470, 1439, 1377, 1342, 1277, 1227, 1200, 1157, 1099, 1038, 991, 960, 906, 876, 795, 768, 729, 698, 621cm-1.1H NMR (400MHz, chloroform-d) delta ppm 7.17-7.26 (m, 2H) 7.50-7.54 (m, 2H) 7.67-7.75 (m, 2H) 7.86 (d, J=8.29Hz, 1H) 8.65 (d, J=4.15Hz, 1H) 10.72 (s, 1H) (Supporting Information, Fig. S1). 13C NMR (126MHz, chloroform-d) delta ppm 170.4, 161.8, 155.8, 149.8, 146.3, 136.9, 130.3, 123.1, 121.1, 117.8, 115.7, 112.4, 52.3 (Supporting Information, Fig. S2). GC-MS m/z (rel. intensity) 228 (M+, 100), 190 (56), 149 (28), 105 (40) (See Scheme 1 ).
	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide;Microwave irradiation; Heating;	In a microwave tube, 4 to 6 mL of N,N-dimethylformamide (N,N-dimethylformamide) was used as a solvent and 0.1000 g (0.3596 mmol) of <strong>[18179-39-0]methyl 4-iodo-2-hydroxybenzoate</strong> (Methyl 4-iodo-2-hydroxybenzoate) as the first monomer, 0.1721 g (0.4675 mmol) of 2-(tributylstannyl)pyridine (2-(tributylstannyl)pyridine), 0.0083 g (7.1929 x 10-6 mol) of tetrakis(triphenylphosphine)palladium(0) (tetrakis(triphenylphosphine)palladium(0), Pd(PPh3)4) are added. The microwave is irradiated using a microwave irradiation apparatus (Discover system, CEM). At this time, the microwave irradiation condition was such that the temperature was raised to 110 C over 20 minutes by irradiating microwaves of about 20w, and then the reaction was maintained at 110 C for 40 minutes. The temperature of the reaction mixture is then lowered to room temperature and the solvent is removed using a rotary evaporator. The resulting organic mixture was then subjected to column chromatography(Eluent: dichloromethane 100%). The reaction scheme for the synthesis of Compound 3 according to Example 3 is shown in FIG.19

Reference： [1]Inorganica Chimica Acta,2019,vol. 495
[2]Patent: KR101931033,2018,B1 .Location in patent: Paragraph 0136-0138

64
[ 423-39-2 ]
[ 18179-39-0 ]
[ 768-60-5 ]
methyl 2-hydroxy-4-((1E)-3,3,4,4,5,5,6,6,6-nonafluoro-1-(4-methoxyphenyl)hex-1-en-1-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: 1-iodo-2,2,3,3,4,4,5,5,5-nonafluorobutane; methyl 4-iodosalicylate; 4-methoxyphenylacetylen With methanesulfonic acid(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); methanesulfonato[2,2'-bis(diphenylphosphino)-1,1'-binapthyl](2'-amino-1,1'-biphenyl-2-yl)palladium (II); water; caesium carbonate; bis(pinacol)diborane In 1,2-dichloro-ethane at 70℃; for 4h; Glovebox; Sealed tube; Inert atmosphere; Stage #2: In 1,2-dichloro-ethane at 120℃; for 6h; Glovebox; Sealed tube; Inert atmosphere;

Reference： [1]Domański, Sylwester; Gatlik, Beata; Chaładaj, Wojciech [Organic Letters, 2019, vol. 21, # 13, p. 5021 - 5025]

65
[ 18179-39-0 ]
[ 116886-71-6 ]
methyl 2-hydroxy-4-(selenophen-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 50 - 120℃; for 12h;Inert atmosphere;	In a two-necked, oven-dried 25mL round-bottom flask, Methyl 4-iodosalicylate (1) (0.10g, 0.36mmol) and 2-(tributylstannyl)selenophene (0.12g, 0.39mmol) were dissolved in 7mL of anhydrous DMF and heated to 50C under nitrogen gas (N2) for 30min. Bis(triphenylphosphine)palladium(II) dichloride (0.005g, 7.2×10-6mol) was then added, and the reaction mixture was further stirred and heated to 120C for 12h. The reaction mixture was allowed to cool down to room temperature, and the solvent was evaporated under vacuo. The compound was purified by column chromatography using DCM and hexane mixture as an eluent. (93% yield) IR (neat): numax 3163, 3097, 2959, 2924, 2854, 1663, 1616, 1558, 1539, 1493, 1443, 1335, 1288, 1261, 1207, 1188, 1153, 1099, 1049, 991, 960, 888, 856, 822, 775, 744, 706, 687, 652, 544cm-1. 1H NMR (400MHz, chloroform-d) delta ppm 3.86 (s, 3H) 6.99 (d, J=8.29Hz, 1H) 7.09 (s, 1H) 7.25 (d, J=3.66Hz, 1H) 7.49 (d, J=2.44Hz, 1H) 7.71 (d, J=8.29Hz, 1H) 7.94 (d, J=5.12Hz, 1H) 10.74 (s, 1H) (Supporting Information, Fig. S5). 13C NMR (126MHz, chloroform-d) delta ppm 170.2, 161.7, 148.9, 143.1, 131.9, 130.7, 130.4, 127.1, 117.2, 114.3, 111.1, 52.2 (Supporting Information, Fig. S6). GC-MS m/z (rel. intensity) 282 (M+, 100), 222 (39), 194 (48), 115 (28), 102 (27).

Reference： [1]Inorganica Chimica Acta,2019,vol. 495

66
[ 18179-39-0 ]
[ 106-94-5 ]
[ 854028-44-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide In acetone for 48h; Reflux; Inert atmosphere;
	With potassium carbonate; potassium iodide In acetone for 48h; Reflux; Inert atmosphere;	Methyl 2-propoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate: To a mixture of methyl 2-hydroxy-4-iodobenzoate (2.78 g, 10 mmol), K2CO3 (5.6 g, 40 mmol), and KI (100 mg, 0.6 mmol) in acetone (150 mL) was added with 1-propylbromide (2 mL, 22 mmol) dropwisely. The mixture was refluxed with stirring under N2 atmosphere for 2 days and hot filtered through a Celite bed. The filtrate was evaporated and purified via flash chromatography (hexane/ethyl acetate= 5:1) to give a colorless oil. The oil was then added to a mixture of bis(pinacolato)diboron (2.67 g, 10.5 mmol), potassium acetate (2.94 g, 30 mmol), PdCl2(PPh3)2 (105 mg, 0.15 mmol) in 1,4-dioxane (50 mL) under N2 atmosphere. The mixture was heated at 100 °C for 18 h. The mixture was diluted with ethyl acetate and water. The organic layer was separated, dried over Na2SO4 and evaporated via vacuum. The residue was purified by flash chromatography (hexane/ethyl=5:1) to give a colorless oil (2.59 g, 81%). 1H NMR (500 MHz, CDCl3) d 7.73 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.36 (s, 1H), 4.05 (t, J = 6.4 Hz, 2H), 3.88 (s, 3H), 1.89- 1.80 (m, 2H), 1.35 (s, 12H), 1.06 (t, J = 7.4 Hz, 3H).

Reference： [1]Chee, See Wee; Choi, Hwa Seob; Li, Xing; Loh, Kian Ping; Mirsaidov, Utkur; Qiao, Jingsi; Quek, Su Ying; Xu, Hai-Sen; Yu, Wei; Zhao, Xiaoxu [Journal of the American Chemical Society, 2020, vol. 142, # 10, p. 4932 - 4943]
[2]Current Patent Assignee: NATIONAL UNIVERSITY OF SINGAPORE - WO2020/214095, 2020, A1 Location in patent: Page/Page column 73; 74

67
[ 18179-39-0 ]
[ 164461-18-1 ]
C₂₄H₁₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; at 70℃; for 2h;Inert atmosphere;	1-Pyreneboronic acid (0.22 g, 0.90 mmol), <strong>[18179-39-0]methyl 4-iodosalicylate</strong>(0.20 g, 0.72 mmol), and K2CO3 (1.12 g, 8.10 mmol) were first dissolvedin THF (25 mL) and water (9 mL). The solution was then degassedunder a N2 atmosphere for 20 min. Pd(PPh3)4 (0.05 g, 0.04 mmol) wasthen added, and the mixture was stirred at 70 C for 2 h under a N2atmosphere. Once the reaction mixture had cooled, it was diluted withwater (20 mL) and washed with DCM (3×30 mL). The organic extractswere combined, MgSO4 was added to dry the mixture, and the mixturewas filtered. The solvent was evaporated from the filtrate, and the crudeproduct was purified using silica gel column chromatography withgradient elution; the mobile phase was changed from pure hexane tohexane/DCM 4:1 (v/v), affording Compound 1 as a yellow solid(0.2176 g, 85% yield, mp: 156-158 C). 1H-NMR (400 MHz, CDCl3): delta(ppm) 10.93 (s, 1 H), 8.23-8.17 (m, 4 H), 8.11 (s, 1 H), 8.10 (s, 1 H),8.06-8.00 (m, 3 H), 7.97 (d, J =7.6 Hz, 1 H), 7.29 (d, J =1.6 Hz, 1 H),7.18 (dd, J=8 and 1.6 Hz, 1 H), 4.03 (s, 3 H). 13C-NMR (100 MHz,CDCl3): delta (ppm) 170.6, 161.5, 149.1, 136.1, 131.4, 131.1, 130.9, 129.8,128.2, 127.9, 127.8, 127.4, 127.1, 126.2, 125.4, 125.1, 124.9, 124.8,124.8, 124.7, 121.9, 119.5, 111.3, 52.4. HRMS-ESI m/z calcd forC24H16NaO3: 375.0992 [M+Na]+, found: 375.0991.

Reference： [1]Journal of Photochemistry and Photobiology A: Chemistry,2020,vol. 397

68
[ 18179-39-0 ]
(5-formylthiophen-2-yl)boronic acid [ No CAS ]
4-(5-formylthiophen-2-yl)-2-hydroxybenzoate methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In ethanol; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;	4.1.2 General procedure for the synthesis of compounds 7a-e General procedure: Methyl-4-iodosalycilate 5a-e (1.00mmol) and 5-formyl-2-furan boronic acid 6a, b (1.30mmol) were dissolved in EtOH (10mL) and DMF (5mL) mL. The reaction mixture was stirred for 10min under Argon at room temperature, then Pd(PPh3)2Cl2 (0.1mmol) and a 2M solution of Na2CO3 (4mL) were added. After 1h, to the resultant orange suspension was added H2O (20mL) and 2N HCl till pH=4-5 and then extracted with EtOAc (3×20mL). When necessary, the mixture was stirred until organic and aqueous layers become clear. The combined organic layers were washed with brine (2×10mL), dried over Na2SO4, filtered, and evaporated to give a crude product that was purified by flash chromatography with the opportune eluent to yield the desired product 7a-e as brown-orange solids.

Reference： [1]Gentili, Valentina; Turrin, Giulia; Marchetti, Paolo; Rizzo, Sabrina; Schiuma, Giovanna; Beltrami, Silvia; Cristofori, Virginia; Illuminati, Davide; Compagnin, Greta; Trapella, Claudio; Rizzo, Roberta; Bortolotti, Daria; Fantinati, Anna [Bioorganic Chemistry, 2022, vol. 119]

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 18179-39-0 ]

Quality Control of [ 18179-39-0 ]

Related Doc. of [ 18179-39-0 ]

Product Details of [ 18179-39-0 ]

Calculated chemistry of [ 18179-39-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 18179-39-0 ]

Application In Synthesis of [ 18179-39-0 ]

[ 18179-39-0 ] Synthesis Path-Upstream 1~9

[ 18179-39-0 ] Synthesis Path-Downstream 1~68

Related Functional Groups of [ 18179-39-0 ]

Aryls

Esters

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 18179-39-0 ]