[ CAS No. 5471-81-8 ] {[proInfo.proName]}

Name: 5471-81-8|Methyl 4-iodo-3-methylbenzoate|98%
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Quality Control of [ 5471-81-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 5471-81-8 ]

Product Details of [ 5471-81-8 ]

CAS No. :	5471-81-8	MDL No. :	MFCD02683863
Formula :	C₉H₉IO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HCSGWQGKCVQIRM-UHFFFAOYSA-N
M.W :	276.07	Pubchem ID :	231757
Synonyms :

Calculated chemistry of [ 5471-81-8 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	55.4
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.0 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.54
Log Po/w (XLOGP3) :	2.79
Log Po/w (WLOGP) :	2.39
Log Po/w (MLOGP) :	3.11
Log Po/w (SILICOS-IT) :	3.12
Consensus Log Po/w :	2.79

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.55
Solubility :	0.0783 mg/ml ; 0.000284 mol/l
Class :	Soluble
Log S (Ali) :	-3.0
Solubility :	0.277 mg/ml ; 0.001 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.81
Solubility :	0.0428 mg/ml ; 0.000155 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.99

Safety of [ 5471-81-8 ]

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

Application In Synthesis of [ 5471-81-8 ]

* 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 [ 5471-81-8 ]
Downstream synthetic route of [ 5471-81-8 ]

[ 5471-81-8 ] Synthesis Path-Upstream 1~5

1
[ 5471-81-8 ]
[ 75-05-8 ]
[ 25978-68-1 ]

Reference： [1] Synlett, 2012, vol. 23, # 17, p. 2491 - 2496,6

2
[ 67-56-1 ]
[ 52107-87-6 ]
[ 5471-81-8 ]

Reference： [1] Organic Letters, 2006, vol. 8, # 10, p. 2043 - 2045
[2] Organic Letters, 2016, vol. 18, # 17, p. 4166 - 4169
[3] Journal of Organic Chemistry, 2002, vol. 67, # 11, p. 3972 - 3974
[4] Patent: EP2017263, 2009, A1, . Location in patent: Page/Page column 170-171

3
[ 52107-87-6 ]
[ 5471-81-8 ]

Reference： [1] Patent: US6162815, 2000, A,
[2] Patent: US5716624, 1998, A,
[3] Patent: US5723499, 1998, A,

4
[ 18595-14-7 ]
[ 5471-81-8 ]

Reference： [1] Advanced Synthesis and Catalysis, 2010, vol. 352, # 9, p. 1451 - 1454
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420

5
[ 5471-81-8 ]
[ 158429-38-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at -25 - -10℃; for 1.41667 h; Stage #2: With Trimethyl borate In tetrahydrofuran at -20 - 0℃; for 1.05 h; Stage #3: With phosphoric acid; water In tetrahydrofuran at -20 - 20℃;	Boronic Acid 9; A 3 -Liter round bottom flask equipped with a mechanical stirrer, thermocouple, and addition funnel was charged with 100 g of solid 4-iodo-3-methylbenzoic acid methyl ester and 1.0 L of dry THF. The mixture was cooled to -25 °C, and 218 mL of i-PrMgCl (2M in THF) was added dropwise over 25 min while the internal temperature was maintained at <-15 ⁰C. The batch was kept at <-10 °C for 1 hr after the addition of the Grignard reagent. Analysis of a hydrolyzed aliquot showed greater than 97percent deiodination.The batch was then cooled to about -20 °C and quenched with trimethyl borate(77 g). The trimethyl borate reaction is exothermic. The temperature increased to about -4 °C during the addition of the trimethyl borate over 3 min. The resulting solution was aged for 1 h at <0 °C. The batch was then recooled to about -20 °C and further quenched with 1.0 L of IMH₃PO₄. This quench was also exothermic, raising the temperature to 3 °C by the end of the quench. The batch was aged at room temperature overnight.The THF was then removed by distillation at < 45 °C at reduced pressure. The product slurry was allowed to cool to room temperature, and then was filtered. The cake was washed with water (3 X 500 ml) and toluene (2 X 250 mL) and dried under vacuum with nitrogen sweep for 18 h to give the boronic acid 9 (64.3 g, 91percent) as an off-white crystalline solid.

Reference： [1] Patent: WO2008/82567, 2008, A1, . Location in patent: Page/Page column 6
[2] Patent: WO2007/79186, 2007, A2, . Location in patent: Page/Page column 63; 64

[ 5471-81-8 ] Synthesis Path-Downstream 1~88

1
[ 879288-17-2 ]
[ 5471-81-8 ]
[ 879288-19-4 ]

Reference： [1]Organic Letters,2006,vol. 8,p. 581 - 584

2
[ 5471-81-8 ]
[ 430459-53-3 ]
[ 879288-18-3 ]

Yield	Reaction Conditions	Operation in experiment
70%		A 500-mL, oven-dried, one-necked, round-bottom flask, equippedwith a Teflon-coated magnetic stirring bar, was removed from adrying oven, sealed while hot with a rubber septum, purged with dryN2, cooled to r.t., charged with ester 7 (22.6 g, 81.6 mmol, 1.5equiv), and resealed. Anhydrous THF (100 mL) was added by syringeand the flask was submerged in a dry ice-acetone bath at-78 C. The solution was stirred for 10 min, then a 1.3 M solutionof i-PrMgCl·LiCl in THF (62.8 mL, 81.6 mmol, 1.5 equiv; Acros)was added dropwise over 10 min. The dry ice-acetone bath was removedremovedand replaced with an ice bath, and the mixture was stirred for1 h.Meanwhile, a separate, 250-mL, oven-dried, one-necked, roundbottomflask was charged with xanthone 6 (24.0 g, 54.8 mmol, 1.0equiv), sealed with a rubber septum, and purged with dry N2. AnhydrousTHF (100 mL) was added to completely dissolve the xanthone6. After 1 h, the flask containing the aryl Grignard wasresubmerged in the dry ice-acetone bath (-78 C) and the mixturewas stirred for 10 min. The THF solution of 6 was added over 5 minthrough a cannula to the flask containing the aryl Grignard reagentat -78 C. The dry ice-acetone bath was removed and the mixturewas warmed to r.t. and stirred for an additional 12 h. The flask wasthen cooled in an ice-water bath for 5 min before 6 M aq HCl (150mL, 0.9 mol) was added dropwise over 10 min. The resulting slurrywas stirred for 1 h at 4 C, diluted with H2O (300 mL), and stirredfor an additional 30 min. The red-orange precipitate was collectedby vacuum filtration, washed with H2O (3 × 150 mL), and air-driedthoroughly (1.5 h). The resulting yellow-orange pellet was slurriedin 3:1 CH2Cl2-hexanes (150 mL) and the suspension was stirred atr.t. overnight and then at 4 C for 1 h. It was then filtered and thefilter cake was washed with H2O (2 × 300 mL) and air dried to givean orange-red solid; yield: 15.0 g (70%, purity >95%); mp 220-224 C.IR (thin film): 3465, 3000, 1796, 1712, 1213 cm-1.1H NMR (500 MHz, 0.15 M NaOCD3-CD3OD): delta = 8.08 (dt,J = 1.6, 0.7 Hz, 1 H), 8.03 (ddd, J = 7.8, 1.6, 0.8 Hz, 1 H), 7.26 (d,J = 7.8 Hz, 1 H), 6.71 (d, J = 7.4 Hz, 2 H), 6.62 (d, J = 11.4 Hz, 2H), 3.39 (s, 3 H), 2.12 (s, 3 H).13C NMR (126 MHz, 0.15 M NaOCD3-CD3OD): delta = 174.9 (s),172.5 (d, J = 17.4 Hz), 157.5-157.3 (m), 156.2 (s), 155.5 (s), 140.4(s), 136.6 (s), 136.0 (s), 132.5 (s), 128.9 (d, J = 177 Hz), 111.7 (s),111.5 (s), 110.9 (d, J = 8.5 Hz), 106.5 (d, J = 5.5 Hz), 49.9 (s), 19.7(s).HRMS (ESI): m/z [M + H]+ calcd for C22H14O5F2: 397.0884; found:397.0888.

Reference： [1]Organic Letters,2006,vol. 8,p. 581 - 584
[2]Synthesis,2014,vol. 46,p. 158 - 164

3
[ 67-56-1 ]
[ 52107-87-6 ]
[ 5471-81-8 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at 0 - 60℃;	Methanol (120 mL) was added to 4-iodo-3-methylbenzoic acid (3.00 g), and thionyl chloride (4.18 mL) was added dropwise to the mixture under stirring at 0C. After completion of dropwise addition, the reaction mixture was heated to 60C while stirring overnight. The reaction mixture was cooled to room temperature, and concentrated, whereby the title compound (3.16 g) was yielded. 1H-NMR (CDCl3) delta : 2.48(3H,s),3.91(3H,s),7.50(1H,dd,J=8.1,2.2Hz), 7.88-7.90(2H,m). MS(ESI);m/z:277(M+H)+.

Reference： [1]Organic Letters,2006,vol. 8,p. 2043 - 2045
[2]Organic Letters,2016,vol. 18,p. 4166 - 4169
[3]Journal of Organic Chemistry,2002,vol. 67,p. 3972 - 3974
[4]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 170-171

4
N-(2-bromoethyl)pyrrole [ No CAS ]
[ 5471-81-8 ]
10-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-8-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Organic Letters,2006,vol. 8,p. 2043 - 2045

5
[ 5471-81-8 ]
[ 68-12-2 ]
[ 24078-24-8 ]

Yield	Reaction Conditions	Operation in experiment
80%		A solution of <strong>[5471-81-8]methyl 4-iodo-3-methylbenzoate</strong> (21.7 mmol, 6 g) in dry THF (120 mL) was purged with argon. The solution was cooled to -15C, i-PrMgCl (2M in THF, 108.5 mmol, 54.25 mL), and DMF (130.2 mmol, 10 mL) were added and the reaction was stirred for 2h at -15C and then warmed to 25C and allowed to react for an additional hour. The reaction was quenched with aqueous 1N HCl and extracted with EtAcO. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude was purified by flash chromatography on silica gel using an elution of 6% ethylacetate in hexanes to give methyl 4-formyl-3-methylbenzoate (3.08 g. Yield: 80%). [0092] 1H NMR (400 MHz, CDCl3) delta 10.35 (1H, s), 8.00 (1H, d, J=8Hz), 7.99 (1H, s), 7.86 (1H, d, J=8Hz), 3.95 (3H, s), 2.72 (3H, s) [0093] LC-MS: tR = 2.85 [M+H]+ = not ion. (method 3)
80%	With isopropylmagnesium chloride; In tetrahydrofuran; at -15 - 20℃; for 1h;Inert atmosphere;	A solution of <strong>[5471-81-8]methyl 4-iodo-3-methylbenzoate</strong> (21 .7 mmol, 6 g) in dry THF (120 mL) was purged with argon. The solution was cooled to -155C, /-PrMgCI (2M in THF, 108.5 mmol, 54.25 mL), and DMF (130.2 mmol, 10 mL) were added and the reaction was stirred for 2h at -155C and then warmed to 255C and allowed to react for an additional hour. The reaction was quenched with aqueous 1 N HCI and extracted with EtAcO. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude was purified by flash chromatography on silica gel using an elution of 6% ethylacetate in hexanes to give methyl 4-formyl-3-methylbenzoate (3.08 g. Yield: 80%). 1 H NMR (400 MHz, CDCI3) delta 10.35 (1 H, s), 8.00 (1 H, d, J=8Hz), 7.99 (1 H, s), 7.86 (1 H, d, J=8Hz), 3.95 (3H, s), 2.72 (3H, s) LC-MS: tR = 2.85 [M+H]+ = not ion. (method 3)
80%	With isopropylmagnesium chloride; In tetrahydrofuran; at -15 - 25℃; for 3h;Inert atmosphere;	A solution of <strong>[5471-81-8]methyl 4-iodo-3-methylbenzoate</strong> (21 .7 mmol, 6 g) in dry THF (120 mL) was purged with argon. The solution was cooled to -155C, /-PrMgCI (2M in THF, 108.5 mmol, 54.25 mL), and DMF (130.2 mmol, 10 mL) were added and the reaction was stirred for 2 h at -155C and then warmed to 255C and allowed to react for an additional hour. The reaction was quenched with aqueous 1 N HCI and extracted with EtAcO. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude was purified by flash chromatography on silica gel using an elution of 6% ethylacetate in hexanes to give methyl 4-formyl-3-methylbenzoate (3.08g .Yield: 80%). 1 H NMR (400 MHz, CDCI3) delta 10.35 (1 H, s), 8.00 (1 H, d, J=8Hz), 7.99 (1 H, s), 7.86 (1 H, d, J=8Hz), 3.95 (3H, s), 2.72 (3H, s) LC-MS: tR = 2.85 [M+H]+ = not ion (method 3).

80%	With isopropylmagnesium chloride; In tetrahydrofuran; at -15 - 25℃; for 3h;	full text is not avalable from article
70%	With isopropylmagnesium chloride; In tetrahydrofuran; at -15℃; for 2h;	Methyl 4-formyl-3-methylbenzoate (1616-18a). To a solution of methyl 4-iodo-3- methylbenzoate (1.0 g, 3.6 mmol) in THF (24 mL, 0.15 M) at -15C was added isopropylmagnesium chloride (7.2 ml, 14.5 mmol, 4.0 equiv). The reaction mixture was allowed to continue stirring at -15C for 2 hrs before N,N-dimethylformamide (1.4 ml, 18mmol, 5.0 equiv) was added. The mixture was warmed to room temperature over a period of 1 hr. At this time the reaction was quenched with HC1 and extracted with EtOAc (3x). The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated in vacuo.Purification was achieved using flash column chromatography on Si02 (Hexanes/EtOAc:6/1) to yield a white solid (0.45 g, 70 %) which was taken on without further purification.
70%		To a stirred solution of 18-2B (3.2 g, 11.5 mmol; TCI) in THF was treated with isopropyl magnesium chloride (/-PrMgCl) in THF (22.8 mL of 2.0 M in THF, 46 mmol) at -15 C. After 2 hr stirring at the same temperature, dry DMF (4.3 mL, 57.5 mmol) was added and the reaction was allowed to warm to 23 C over 1 hr. After consumption of the starting material (by TLC), the reaction was quenched with aqueous 1M HC1 (60 mL), followed by extracted with EtOAc, dried over Na2S04 and concentrated. The crude compound was purified by flash column chromatography (100-200 silica) using 5% EtOAc in hexanes to afford 18-3B (1.4 g, 7.8 mmol, 70% yield) as an off-white solid. MS (ESI): m z 179.2 (M+l)+.

Reference： [1]Organic Letters,2007,vol. 9,p. 3741 - 3744
[2]Patent: EP2647638,2013,A1 .Location in patent: Paragraph 0091
[3]Patent: WO2013/149996,2013,A1 .Location in patent: Page/Page column 40; 41
[4]Patent: WO2013/149997,2013,A1 .Location in patent: Page/Page column 48; 49
[5]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2016,vol. 55B,p. 854 - 881
[6]Patent: WO2014/25942,2014,A1 .Location in patent: Page/Page column 38
[7]Journal of Medicinal Chemistry,2014,vol. 57,p. 2334 - 2356
[8]Patent: WO2016/154241,2016,A1 .Location in patent: Paragraph 560; 562

6
[ 5471-81-8 ]
[ 879288-18-3 ]

Reference： [1]Organic Letters,2007,vol. 9,p. 3741 - 3744

7
[ 5471-81-8 ]
[ 879288-14-9 ]

Reference： [1]Organic Letters,2007,vol. 9,p. 3741 - 3744

8
[ 5471-81-8 ]
[ 952053-74-6 ]

Reference： [1]Organic Letters,2007,vol. 9,p. 3741 - 3744

9
[ 5471-81-8 ]
N-(4-[(2-amino-9H-purin-6-yl)oxy]methyl}benzyl)-4-(2,7-difluoro-3,6-dihydroxy-xanthen-9H-yl)-3-methylbenzamide [ No CAS ]

Reference： [1]Organic Letters,2007,vol. 9,p. 3741 - 3744

10
[ 5471-81-8 ]
[ 952053-73-5 ]

Reference： [1]Organic Letters,2007,vol. 9,p. 3741 - 3744

11
[ 52107-87-6 ]
[ 5471-81-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In methanol; ethyl acetate;	(b) Synthesis of methyl 3-methyl-4-iodobenzoate 24.4 g (0.093 mol) of 3-methyl-4-iodobenzoic acid and 250 ml of methanol were introduced into a round-bottomed flask and 2.5 ml of concentrated sulfuric acid were added dropwise. The mixture was heated at reflux for 12 hours, the reaction medium evaporated, taken up in ethyl acetate and water, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue was triturated in methanol, filtered and 21.9 g (85%) of the expected methyl ester of melting point 58-9 C. were recovered.
	With sulfuric acid; In methanol; ethyl acetate;	(b) Preparation of methyl 3methyl-4-iodobenzoate 24.4 g (0.093 mol) of 3-methyl-4-iodobenzoic acid and 250 ml of methanol were introduced into a round-bottomed flask and 2.5 ml of concentrated sulfuric acid were added dropwise. Heating was carried out at reflux for twelve hours, the reaction mixture was evaporated and the residue taken up in ethyl acetate and water. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue was triturated in methanol and filtered. 21.9 g (85%) of the expected methyl ester, with a melting point of 58-59 C., were recovered.
	With sulfuric acid; In methanol; ethyl acetate;	(b) Preparation of methyl 3-methyl-4-iodobenzoate 24.4 g (0.093 mol) of 3-methyl-4-iodobenzoic acid and 250 ml of methanol were introduced into a round-bottomed flask and 2.5 ml of concentrated sulfuric acid were added dropwise. The mixture was heated at reflux for twelve hours, the reaction medium evaporated, taken up in ethyl acetate and water, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue was triturated in methanol and filtered; 21.9 g (85%) of the expected methyl ester of melting point 58-59 C. were recovered.

Reference： [1]Patent: US6162815,2000,A
[2]Patent: US5716624,1998,A
[3]Patent: US5723499,1998,A

12
[ 173157-12-5 ]
[ 5471-81-8 ]
methyl 3-methyl-4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(a) Synthesis of methyl 3-methyl-4-(3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)benzoate In a manner similar to Example 1(a), by the reaction of 2.1 g (8.7 mmol) of 3-ethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 2 g (7.2 mmol) of <strong>[5471-81-8]methyl 3-methyl-4-iodobenzoate</strong>, 2.18 g (79%) of the expected methyl ester was obtained in the form of a pale yellow oil.

Reference： [1]Patent: US6162815,2000,A

13
[ 5471-81-8 ]
[ 122284-29-1 ]
methyl 3-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(a) Synthesis of methyl 3-methyl-4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzoate In a manner similar to Example 2(a), by the reaction of 2.55 g (11 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthiol with 3 g (11 mmol) of <strong>[5471-81-8]methyl 3-methyl-4-iodobenzoate</strong>, 1.86 g (43%) of the expected compound in the form of an ethyl ester was obtained as an orange-colored oil.

Reference： [1]Patent: US6162815,2000,A

14
[ 5471-81-8 ]
[ 132392-27-9 ]
3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(c) Synthesis of 3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoic acid In a manner similar to Example 2(a), by the reaction of 2.4 g (11 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthiol with 3 g (11 mmol) of <strong>[5471-81-8]methyl 3-methyl-4-iodobenzoate</strong>, 1.96 g (51%) of 3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylthio)benzoic acid of melting point 195-6 C. was directly obtained.

Reference： [1]Patent: US6162815,2000,A

15
[ 170355-40-5 ]
[ 5471-81-8 ]
methyl 3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(c) Preparation of methyl 3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)benzoate Following the basic procedure of Example 7(f), by reacting 2.8 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthrylboronic acid with 1.84 g (6.7 mmol) of <strong>[5471-81-8]methyl 3-methyl-4-iodobenzoate</strong>, 1.37 g (53%) of methyl 3-methyl-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)benzoate was obtained in the form of a yellow oil.

Reference： [1]Patent: US5723499,1998,A

16
[ 170100-68-2 ]
[ 5471-81-8 ]
methyl 3-methyl-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(c) Synthesis of methyl 3-methyl-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate Following the basic procedure of Example 11(d), by reacting 2.4 g (10 mmol) of alpha-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 2.7 g (10 mmol) of <strong>[5471-81-8]methyl 3-methyl-4-iodobenzoate</strong>, 3.2 g (83%) of the expected ester, with a melting point of 130-131 C., were obtained.

Reference： [1]Patent: US5716624,1998,A

17
[ 5471-81-8 ]
[ 158429-38-0 ]

Yield	Reaction Conditions	Operation in experiment
91%		Boronic Acid 9; A 3 -Liter round bottom flask equipped with a mechanical stirrer, thermocouple, and addition funnel was charged with 100 g of solid 4-iodo-3-methylbenzoic acid methyl ester and 1.0 L of dry THF. The mixture was cooled to -25 °C, and 218 mL of i-PrMgCl (2M in THF) was added dropwise over 25 min while the internal temperature was maintained at <-15 0C. The batch was kept at <-10 °C for 1 hr after the addition of the Grignard reagent. Analysis of a hydrolyzed aliquot showed greater than 97percent deiodination.The batch was then cooled to about -20 °C and quenched with trimethyl borate(77 g). The trimethyl borate reaction is exothermic. The temperature increased to about -4 °C during the addition of the trimethyl borate over 3 min. The resulting solution was aged for 1 h at <0 °C. The batch was then recooled to about -20 °C and further quenched with 1.0 L of IMH3PO4. This quench was also exothermic, raising the temperature to 3 °C by the end of the quench. The batch was aged at room temperature overnight.The THF was then removed by distillation at < 45 °C at reduced pressure. The product slurry was allowed to cool to room temperature, and then was filtered. The cake was washed with water (3 X 500 ml) and toluene (2 X 250 mL) and dried under vacuum with nitrogen sweep for 18 h to give the boronic acid 9 (64.3 g, 91percent) as an off-white crystalline solid.
		A 3 -Liter round bottom flask equipped with a mechanical stirrer, thermocouple, and addition funnel was charged with 100 g of solid 4-iodo-3-methylbenzoic acid methyl ester and 1.0 L of dry THF. The mixture was cooled to -25 0C, and 218 mL of i-PrMgCl (2M in THF) was added dropwise over 25 min while the internal temperature was maintained at <-15 0C. The batch was kept at <-10 0C for 1 hr after the addition of the Grignard reagent. Analysis of a hydrolyzed aliquot showed greater than 97percent deiodination. <n="65"/>The reaction was then cooled to about -20 0C and quenched with trimethyl borate (77 g). The trimethyl' borate reaction is exothermic. The temperature increased to about -4 0C during the addition of the trimethyl borate over a time of about 3 min. The resulting solution was aged for 1 h at <0 0C. The batch was then cooled to about -20 0C and further quenched with 1.0 L of IM H3PO4. This quench was also exothermic, raising the temperature to 3 0C by the end of the quench. The batch was aged at room temperature overnight.The THF was then removed by distillation at < 45 0C under reduced pressure. The product slurry was allowed to cool to room temperature, and then was filtered. The cake was washed with water (3 X 500 ml) and toluene (2 X 250 mL) and then was dried under vacuum with nitrogen sweep for 18 h to give the boronic acid 3 as an off-white crystalline solid.

Reference： [1]Patent: WO2008/82567,2008,A1 .Location in patent: Page/Page column 6
[2]Patent: WO2007/79186,2007,A2 .Location in patent: Page/Page column 63; 64

18
[ 7073-94-1 ]
[ 5471-81-8 ]
[ 1004984-30-8 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 162 - 167

19
[ 1011800-87-5 ]
[ 5471-81-8 ]
[ 1011801-08-3 ]
[ 1011801-06-1 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 1888 - 1897

20
[ 1011801-13-0 ]
[ 5471-81-8 ]
[ 1011801-20-9 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 1888 - 1897

21
[ 1011801-56-1 ]
[ 5471-81-8 ]
[ 1011801-67-4 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 1888 - 1897

22
[ 5471-81-8 ]
[ 119291-22-4 ]
[ 1011801-54-9 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 1888 - 1897

23
[ 680-15-9 ]
[ 5471-81-8 ]
[ 957205-72-0 ]

Yield	Reaction Conditions	Operation in experiment
	copper(l) iodide; In N,N-dimethyl-formamide; at 90℃; for 4h;	DMF (110 mL) was added to <strong>[5471-81-8]4-iodo-3-methylbenzoic acid methyl ester</strong> (3.16 g), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (14.5 mL), and copper(I) iodide (2.18 g), and the mixture was stirred with heating at 90C for 4 hours. The reaction mixture was cooled to room temperature, and saturated brine was added thereto. The mixture was extracted thrice, each with ethyl acetate, and the extracts were combined. The combined extract was washed with saturated brine, and dried over sodium sulfate. Insoluble matter was removed by filtration, and then the filtrate was concentrated. The residue was purified by silica gel column chromatography, whereby the title compound (2.66 g) was yielded. 1H-NMR (CDCl3) delta : 2.56(3H,s), 3.95(3H,s), 7.68(1H,d, J=8.1Hz), 7.93(1H,d,J=8.1Hz),7 .96 (1H, s).

Reference： [1]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 171-172

24
[ 1083171-88-3 ]
[ 5471-81-8 ]
[ 1083171-99-6 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 9164 - 9167

25
[ 1083172-01-3 ]
[ 5471-81-8 ]
[ 1083172-11-5 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 9164 - 9167

26
[ 854778-62-4 ]
[ 5471-81-8 ]
[ 1127737-38-5 ]

Yield	Reaction Conditions	Operation in experiment
	With piperidine;bis-triphenylphosphine-palladium(II) chloride; In toluene; at 20℃; for 3h;	A solution of the above oil, 3-benzyl-8-trifluoromethyl-4-(3-trimethylsilanylethynyl-phenyl)-quinoline (730 mg, 1.6 mmol), <strong>[5471-81-8]methyl 4-iodo-3-methylbenzoate</strong>, (100 mg, 0.4 mmol), PdCl2(PPh3)2 (8.0 mg), and piperidine (63 mg, 0.7 mmol) in toluene (30 mL) is stirred at ambient temperature for 3 h. The reaction mixture is stripped to dryness and the residue taken up in ethyl acetate and washed with 30 mL (1N HCl). The organic layer is dried and concentrated in vacuo to provide after chromatography 8 mg of methyl 4-((3-(3-benzyl-8-(trifluoromethyl)quinolin-4-yl)phenyl)ethynyl)-3-methylbenzoate; MS (ES) m/z 536.2;

Reference： [1]Patent: US2009/69373,2009,A1 .Location in patent: Page/Page column 31

27
[ 5471-81-8 ]
[ 1066-54-2 ]
[ 1057977-05-5 ]

Reference： [1]Chemical Communications,2008,p. 3672 - 3674

28
[ 5471-81-8 ]
[ 294669-33-3 ]
[ 1080564-14-2 ]

Reference： [1]Organic Letters,2008,vol. 10,p. 5219 - 5221

29
[ 1192548-05-2 ]
[ 5471-81-8 ]
[ 1192547-79-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In water; toluene; at 100℃; for 12h;	Step 1. Methyl 3'-fluoro-2-methyl-2'-(trifluoromethyl)biphenyl-4-carboxylate To a mixture solution of 2.0 mL toluene and 0.2 mL water comprising <strong>[5471-81-8]methyl 4-iodo-3-methylbenzoate</strong> (317 mg, manufactured by Wako Pure Chemical Industries, Ltd.), 3-fluoro-2-trifluoromethylphenylboronic acid pinacol ester obtained from the Reference example 31 (500 mg), palladium acetate (51.4 mg, manufactured by Kanto Chemical Co., Inc.), 2-dicyclohexylphosphino-2'-6'-dimethoxybiphenyl (188 mg, manufactured by Aldrich Company) and potassium phosphate (488 mg, manufactured by Wako Pure Chemical Industries, Ltd.) were added, followed by stirring at 100 C. for twelve hours. Upon the completion of stirring, the reaction solution was filtered using Celite, and the filtrate was concentrated under reduced pressure. Thus obtained residues were subjected to flash column chromatography (using 200:1 (v/v) to 100:1 (v/v) hexane/ethyl acetate as an eluent) to obtain the title compound (333 mg). 0.55 (1H, ddd, J=7.68, J=5.13), 7.28-7.20 (1H, m), 7.18 (1H, d, J=7.68), 6.97 (1H, d, J=7.68), 3.94 (3H, s), 2.11 (3H, s).

Reference： [1]Patent: US2009/298894,2009,A1 .Location in patent: Page/Page column 53

30
[ 5471-81-8 ]
[ 1187237-61-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4416 - 4420

31
[ 5471-81-8 ]
[ 98-80-6 ]
[ 892843-59-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4416 - 4420

32
[ 18595-14-7 ]
[ 5471-81-8 ]

Reference： [1]Advanced Synthesis and Catalysis,2010,vol. 352,p. 1451 - 1454
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4416 - 4420

33
[ 5471-81-8 ]
[ 2727-71-1 ]
[ 78-94-4 ]
[ 1238734-99-0 ]

Reference： [1]Advanced Synthesis and Catalysis,2010,vol. 352,p. 1451 - 1454

34
[ 124-38-9 ]
[ 5471-81-8 ]
4-(methoxycarbonyl)-2-methylbenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%		A solution of <strong>[5471-81-8]methyl 4-iodo-3-methylbenzoate</strong> (2.0 g, 7.2 mmol) in THF (30 mL) under ? was cooled to -20 C, a solution of /so-propylmagnesium chloride (2 M in THF, 4 mL, 8.0 mmol) was added dropwise and the suspension stirred at -20 C for 1 hour. CO2 (g) was bubbled through the mixture, and the reaction stirred at room temperature for 1 hour. The solvent was evaporated and water was added, the aqueous layer was washed with DCM (15 mL 3) and the pH adjusted to 3 by addition of 3M HCI. The mixture was extracted with DCM (15 mL 3) and the combined organic layers dried (Na2S04) and concentrated to give the title compound as a white solid (870 mg, 88%). LCMS-C: RT 2.26 min; m/z 195.1 (0878) [M+H]

Reference： [1]Organometallics,2010,vol. 29,p. 4135 - 4138
[2]Patent: WO2016/34673,2016,A1 .Location in patent: Page/Page column 114

35
[ 5471-81-8 ]
[ 1186048-31-6 ]

Reference： [1]CrystEngComm,2012,vol. 14,p. 4137 - 4141

36
[ 5471-81-8 ]
[ 1397691-86-9 ]

Reference： [1]CrystEngComm,2012,vol. 14,p. 4137 - 4141

37
[ 5471-81-8 ]
[ 1397691-87-0 ]

Reference： [1]CrystEngComm,2012,vol. 14,p. 4137 - 4141

38
[ 5471-81-8 ]
[ 31458-18-1 ]

Reference： [1]CrystEngComm,2012,vol. 14,p. 4137 - 4141
[2]Journal of the American Chemical Society,2015,vol. 137,p. 3177 - 3180
[3]Angewandte Chemie - International Edition,2015,vol. 54,p. 14696 - 14700
Angew. Chem.,2015,vol. 127,p. 14909 - 14913,5
[4]Angewandte Chemie - International Edition,2016,vol. 55,p. 10776 - 10780
Angew. Chem.,2016,vol. 128,p. 10934 - 10938,5

39
[ 5471-81-8 ]
[ 75-05-8 ]
[ 25978-68-1 ]

Reference： [1]Synlett,2012,vol. 23,p. 2491 - 2496,6

40
[ 5471-81-8 ]
(+/-)-methyl 4-((4aR,5R,10bR)-3,4,4a,5,6,10b-hexahydro-9-methoxy-2H pyrano[3,2-c]quinolin-5-yl)-3-methylbenzoate [ No CAS ]

Reference： [1]Patent: EP2647638,2013,A1

41
[ 5471-81-8 ]
(+/-)-methyl 4-((4aR,5S,10bR)-3,4,4a,5,6,10b-hexahydro-9-methoxy-2H-pyrano[3,2-c]quinolin-5-yl)-3-methylbenzoate [ No CAS ]

Reference： [1]Patent: EP2647638,2013,A1

42
[ 5471-81-8 ]
[ 1465295-72-0 ]
[ 1465295-73-1 ]

Reference： [1]Patent: EP2647638,2013,A1

43
[ 5471-81-8 ]
rac-methyl 4-((4aR,5R,10bR)-3, 4, 4a, 5, 6,10b-hexahydro-9-methyl-2H-pyrano[3,2-c]quinolin-5-yl)-3-methylbenzoate [ No CAS ]
(+/-)-methyl 4-((4aR,5S,10bR)-3,4,4a,5,6,10b-hexahydro-9-methyl-2H-pyrano[3,2-c]quinolin-5-yl)-3-methylbenzoate [ No CAS ]

Reference： [1]Patent: EP2647638,2013,A1

44
[ 5471-81-8 ]
(+/-)-4-((4aR,5R,10bR)-3,4,4a,5,6,10b-hexahydro-9-methoxy-2H pyrano[3,2-c]quinolin-5-yl)-3-methylbenzoic acid [ No CAS ]

Reference： [1]Patent: EP2647638,2013,A1

45
[ 5471-81-8 ]
(+/-)-4-((4aR,5R,10bR)-3,4,4a,5,6,10b-hexahydro-9-methyl-2H-pyrano[3,2-c]quinolin-5-yl)-3-methylbenzoic acid [ No CAS ]

Reference： [1]Patent: EP2647638,2013,A1

46
[ 5471-81-8 ]
[ 1465295-84-4 ]

Reference： [1]Patent: EP2647638,2013,A1

47
[ 5471-81-8 ]
[ 1465295-72-0 ]