188187-03-3|Methyl 2-(bromomethyl)-3-chlorobenzoate| Ambeed

HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Structure of 188187-03-3

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 188187-03-3 ] Purity: 97% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 188187-03-3 ]

CAS No. :	188187-03-3
Formula :	C₉H₈BrClO₂
M.W :	263.52
SMILES Code :	COC(C1=C(C(=CC=C1)Cl)CBr)=O
MDL No. :	MFCD04114322
InChI Key :	BZXFVKQUKUJTIM-UHFFFAOYSA-N
Pubchem ID :	11032726

Safety of [ 188187-03-3 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H302-H314
Precautionary Statements:	P261-P280-P305+P351+P338-P310
Class:	8
UN#:	3261
Packing Group:	Ⅱ

Computational Chemistry of [ 188187-03-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.22
Num. rotatable bonds	3
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	55.57
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	26.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.4
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.96
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.87
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	3.25
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.36
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.97

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.48
Solubility	0.0868 mg/ml ; 0.00033 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.18
Solubility	0.176 mg/ml ; 0.000668 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.35
Solubility	0.0118 mg/ml ; 0.0000448 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.81 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.04

Application In Synthesis of [ 188187-03-3 ]

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

Downstream synthetic route of [ 188187-03-3 ]

[ 188187-03-3 ] Synthesis Path-Downstream 1~36

1
[ 188187-03-3 ]
trans-1-ethyl-3-[9-(6-hydroxymethyl-2-styryl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl]-urea [ No CAS ]
3-Chloro-2-{6-[6-(3-ethyl-ureido)-purin-9-yl]-2-trans-styryl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxymethyl}-benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium acetate; In tetrahydrofuran; acetonitrile;	3-Chloro-2-{6-[6-(3-ethyl-ureido)-purin-9-yl]-2-trans-styryl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxymethyl}-benzoic acid 1-Ethyl-3-[9-(6-hydroxymethyl-2-trans-styryl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl]-urea (0.200 g, 0.44 mmol) was suspended in tetrahydrofuran (5 mL) and sodium hydride (60% w/w in oil, 0.106 g, 2.65 mmol) added. Once the bubbling ceased, added <strong>[188187-03-3]methyl-2-bromomethyl-3-chloro-benzoate</strong> (0.233 g, 0.88 mmol) and stirred the reaction mixture overnight at room temperature. Mass spectral analysis indicated that the reaction was complete and that the product was the title compound, arising from in situ hydrolysis of the methyl ester. The pH was lowered to 5 with acetic acid, and the mixture partitioned between ethyl acetate (40 mL) and 50% saturated sodium chloride (50 mL). The layers were separated and the ethyl acetate layer concentrated to dryness. The residue was reconstituted in in aqueous acetonitrile and the product purified on preparative HPLC (C18 column, gradient from 0.05 M ammonium acetate (pH 6.5) to acetonitrile over 20 minutes). The solvent was removed from the fraction containing the product, giving the title compound after overnight lyophilization (0.194 g, 70%) MW calculated for C30H29ClN6O7 (MH-) 620.0 found 619.6 by LCMS. 1H-NMR (300 MHz, CDCl3). 1.29 (t 3H), 3.42 (q, 2H), 3.77 (dd, 1H), 3.97 (dd, 1H), 4.70 (s, 1H), 4.90 (d, 1H), 5.05 (d, 1H), 5.19 (d, 1H), 5.60 (dd, 1H), 5.86 (d, 1H), 6.18 (dd, 1H), 6.28 (d, 1H), 6.83 (d, 1H), 7.36 (m, 7H), 7.89 (d, 1H), 8.52 (s, 1H), 8.57 (s, 1H), 9.33 (s, 1H), 9.56 (t, 1H).

References: [1]Patent: US2005/267134,2005,A1 .

2
[ 7499-08-3 ]
[ 45514-47-4 ]
[ 188187-03-3 ]

Yield	Reaction Conditions	Operation in experiment
82%	With benzyl hydroperoxide; for 18h;Heating / reflux;	s) 2-Chloro-6-methyl carboxylate benzylbromide To a solution of methyl 3-chloro-2-methylbenzoate (1.30 g, 7.04 mmol) in benzene (20 mL) was added NBS (1.50 g. 8.45 mmol) and benzoyl peroxide (0.20 g, 0.83 mmol). After stirring at reflux for 18 h, the mixture was poured into water, and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash column chromatography (1:1 ether/hexane) of the residue gave 1.87 g (82%) of the title compound as a dark oil: 1H NMR (250 MHz CDCl3) d 7.72 (d, 1H), 7.55 (d, 1H), 7.21 (t, 1H), 5.09 (s, 2H), 3.92 (s, 3H).

References: [1]Patent: US6353116,2002,B1 .Location in patent: Page column 24.

3
[ 188187-03-3 ]
Ethyl (E)-3-[1-n-butyl-5-(4-chloro-2-hydroxyphenyl)-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate [ No CAS ]
Ethyl (E)-[1-n-butyl-5-[2-(2-methoxycarbonyl)-6-chlorophenylmethoxy-4-chloro-phenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 4h;Stirred;	t) Ethyl (E)-[1-n-butyl-5-[2-(2-methoxycarbonyl)phenylmethoxy-4-chloro-phenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate To a solution of the ethyl (E)-[1-n-butyl-5-(2-hydroxy-4-chlorophenyl)-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate (0.20 g, 0.39 mmol) and methyl 2-bromomethyl-3-chlorobenzoate (0.13 g, 0.47 mmol) in DMF (5 mL) was added sodium hydride (0.02 g, 0.59 mmol) at 0 C. The mixture was stirred at room temperature for 4 h. After an aqueous work up, extracting with ethyl acetate (3×15 mL), the combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash column chromatography (1:1 ethyl acetate/hexane) of the residue afforded the title compound as an oil (0.22 g, 80%). 1H NMR (250 MHz, CDCl3) d 7.78 (d, 1H), 7.55 (d, 1H), 7.48 (s, 1H), 7.32 (m, 2H), 7.12 (d, 2H), 6.75 (s, 1H), 6.45 (s, 1H), 5.55 (dd, J=10, 27.5 Hz, 2H),4.49 (t, 2H), 4.10 (q, 2H), 3.83 (s, 3H) 3.77 (t, 2H), 3.65 (s, 3H), 3.15 (t, 2H), 1.52 (quintet, 2H), 1.20 (t, 3H), 1.05 (sextet, 2H), 0.75 (t, 3H).

References: [1]Patent: US6353116,2002,B1 .Location in patent: Page column 24.

4
[ 99586-84-2 ]
[ 188187-03-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 90℃; for 3.45h;	A suspension of methyl 3-chloro-2-methylbenzoate obtained in Example 10b (1 g, 5.42 mmol), carbon tetrachloride (13.3 ml), N-bromosuccinimide (1.06 g, 5.96 mmol) and benzoyl peroxide (3.5 mg, 0.0108 mmol) was heated in a 90 C. oil bath under a nitrogen stream. After three hours and 45 minutes, heating was completed, and the mixture was diluted with water, ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (1.43 g, yield: 100%). 1H-NMR (400 MHz, CDCl3) delta ppm; 4.00 (3H, s), 5.12 (2H, s), 7.32 (1H, t, J=8 Hz), 7.58 (1H, dd, J=2, 8 Hz), 7.86 (1H, dd, J=2, 8 Hz).
100%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 90℃; for 3.75h;Inert atmosphere;	(Example 10c) Methyl 2-(bromomethyl)-3-chlorobenzoate A suspension of methyl 3-chloro-2-methylbenzoate obtained in Example 10b (1 g, 5.42 mmol), carbon tetrachloride (13.3 ml), N-bromosuccinimide (1.06 g, 5.96 mmol) and benzoyl peroxide (3.5 mg, 0.0108 mmol) was heated in a 90C oil bath under a nitrogen stream. After three hours and 45 minutes, heating was completed, and the mixture was diluted with water, ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (1.43 g, yield: 100%). 1H-NMR (400 MHz, CDCl3) delta ppm; 4.00 (3H, s), 5.12 (2H, s), 7.32 (1H, t, J=8 Hz), 7.58 (1H, dd, J=2, 8 Hz), 7.86 (1H, dd, J=2, 8 Hz).
1.87 g (82%)	With N-Bromosuccinimide; dibenzoyl peroxide; In benzene;	s 2-Chloro-6-methyl carboxylate benzylbromide To a solution of methyl 3-chloro-2-methylbenzoate (1.30 g, 7.04 mmol) in benzene (20 mL) was added NBS (1.50 g, 8.45 mmol) and benzoyl peroxide (0.20 g, 0.83 mmol). After stirring at reflux for 18 h, the mixture was poured into water, and the resulting mixture was extracted with ethyl acetate (3*50 mL). The combined organic extracts were washed with brine and dried (Na2 SO4). After removing the solvent under reduced pressure, flash column chromatography (1:1 ether/hexane) of the residue gave 1.87 g (82%) of the title compound as a dark oil: 1 H NMR (250 MHz, CDCl3) d 7.72 (d, 1H), 7.55 (d, 1H), 7.21 (t, 1H), 5.09 (s, 2H), 3.92 (s, 3H.

	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 85℃; for 16h;Irradiation;	A. To a suspension of 3-chloro-2-methylbenzoic acid methyl ester (5.62 g, 30.4 MMOL), and N-bromosuccinimide (5.94 g, 33.4 MMOL) in carbon TETRACHLORIDE (200 mL) was added benzoyl peroxide (800 mg, 3.30 MMOL). The resulting suspension was immersed in an oil bath held at 85C, and illuminated with a 300W halogen worklight. After stirring for 16 hours with heat and illumination the reaction mixture was allowed to cool to ambient temperature, filtered to remove the insoluble succinimide, and concentrated under reduced pressure to afford 2- bromomethyl-3-chlorobenzoic acid methyl ester as a yellow semi-solid. This crude material was carried on to the next step without purification.
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Heating / reflux;	Example 28 1 - [ (5-CHLORO-1, 2,3, 4-tetrahydroisoquinolin-3-yl) METHYL]-1-METHYL-1, 2- dihydrospiro [indole-3, 4'-piperidine] (A) 5-CHLORO-L-OXO-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid To a stirred suspension of 3-chloro-2-methylbenzoic acid (10.00 g, 58.6 mmol) in methanol (100 mL) was added dropwise thionyl chloride (8.5 mL, 117.2 mmol) at 0 C. The reaction mixture was refluxed for 2 h. After cooling down to room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (300 ML), washed with 1N NaOH solution (100 mL), water (100 mL) and brine (100 ML), dried (NA2S04), filtered, and concentrated to give 10.86 g of methyl ester as colorless oil. A mixture of this ester (10.80 g, 58.5 mmol), N-bromosuccinimide (10.45 g, 64.4 mmol), and benzoyl peroxide (0.71 g, 2.9 mmol) in carbon tetrachloride (70 mL) was refluxed for 3 h. After cooling down to room temperature, the reaction mixture was filtered and the filtrate wad concentrated to give 16.30 g of methyl 3-chloro-2-bromomethylbenzoate as a colorless oil. To a stirred suspension of NaH (2.45 g, 61.3 mmol) in DMF (50 mL) was added dropwise a solution of diethyl acetamidomalonate (12.10 g, 55.7 mmol) in DMF (50 mL) at room temperature. After 15 min stirreing, a solution of methyl 3-chloro-2- bromomethylbenzoate (16.3 g, 58. 5 mmol) in DMF (50 mL) at room temperature. After 18 h stirring, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate (800 ML), washed with water (200 mL x 2) and brine (200 mL), dried (NA2S04), filtered, and concentrated to give 21.5 g of yellow solid, which was purified by silica gel column chromatography (hexane/ethyl acetate: 2/1 to 111) to afford 14.33 g (64.3 %) of coupling product as a white solid. A mixture of this solid (13.90 g, 34.7 mmol) and 47 % HBr (160 mL) was refluxed for 24 h. After cooling down to room temperature, the solid formed was collected by filtration and dried togive 6.16 g (78.6 %) of title compound as a cream color solid. LHNMR (300MHZ, DMSO-D6) O8. 26 (1H, d, J = 4. 0 HZ), 7.85 (1H, dd, J = 1.1, 7.7 Hz), 7.64 (1H, dd, J = 1. 3, 8. 1 HZ), 7.39 (1H, dd, J = 7. 9,7. 9 HZ), 4.34-4. 28 (1H, m), 3.42-3. 36 (1H, overlapped with water peak at 3.36 ppm), 3.26 (1H, dd, J = 6.8, 16.9 Hz).
	With N-Bromosuccinimide; dibenzoyl peroxide; In chloroform; at 20℃; for 16h;Heating / reflux;	To compound 1190 (4.42 g, 0.0239 mol) dissolved in CCl4 (100 mL) was added n-bromosuccinimide (5.11 g, 0.287 mol) and benzoyl peroxide (0.58 g, 0.00239 mol). The reaction mixture was heated at reflux for 16 h then cooled to room temperature. The solid was removed by filtration and washed with CH2CI2. The filtrate was concentrated to give 7.80 g of the product 1193 with succinimide as a yellow oil and solid mixture
	With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; at 80℃; for 12h;	General procedure: A mixture of methyl 3-bromo-2-methylbenzoate (500 mg, 3.3 mmol), NBS (770.4 mg, 4.3 mmol), and di-benzoyl peroxide (BPO, 80.7 mg, 0.3 mmol) in 1,2-dichloroethane (10 mL) was heated at 80 C for 12 h. The reaction mixture was cooled to room temperature, and the precipitated solid was removed by filtration and washed with ethers (10 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 2 N NaHCO3 (15 mL) and ethers (15 mL). The organic layer was separated, dried over NaSO4, filtered and concentrated to give a crude product (683.2 mg, 89.6%), which was used in the next step reaction without further purification.

References: [1]Patent: US2013/65925,2013,A1 .Location in patent: Paragraph 0338; 0339.
[2]Patent: EP2757103,2014,A1 .Location in patent: Paragraph 0215.
[3]Patent: US5958968,1999,A .
[4]Patent: WO2004/58717,2004,A1 .Location in patent: Page 77.
[5]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365.
[6]Patent: WO2005/16913,2005,A1 .Location in patent: Page/Page column 68-69.
[7]Patent: WO2005/121130,2005,A2 .Location in patent: Page/Page column 560.
[8]European Journal of Medicinal Chemistry,2019,vol. 180,p. 509 - 523.

5
[ 188187-03-3 ]
3-chloro-2-cyanomethylbenzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium cyanide; In DMF (N,N-dimethyl-formamide); at 20 - 55℃; for 17.5h;	A. To a solution of crude <strong>[188187-03-3]2-bromomethyl-3-chlorobenzoic acid methyl ester</strong> (30.4 MMOL) in DMF (60 mL), was added finely powdered sodium cyanide (2.22 g, 45 MMOL). The reaction mixture turned brown rapidly, and became warm. The dark suspension was then immersed in an oil bath held at 55C. The reaction mixture was allowed to stir at 55C for 1.5 hours, at which time heating was discontinued, and the reaction was allowed to cool to ambient temperature. After stirring at ambient temperature for 16 hours, the reaction was diluted with ether (300 mL) and water (200 mL). The layers were separated, the aqueous was extracted with ether (3 x 75 mL), and the combined organic extracts were washed with water (3 x 50 mL). The organic layer was then washed with brine (100 mL), dried over NA2SO4, filtered, and concentrated under reduced pressure to afford a yellow oil. The crude oil was purified by flash chromatography eluting with a gradient from 0% to 16% ethyl acetate/hexane to afford 3-CHLORO-2-CYANOMETHYLBENZOIC acid methyl ester (3.9 g, 65 % yield over two steps) as a white solid : 1H-NMR (400 MHz, CDCI3) : 5 7.96 (1H, dd, J = 8.1 Hz, 1.3 Hz), 7.65 (1H, dd, J = 8.1, 1.3), 7.4 (1H, t, J = 7.9 Hz), 4.35 (2H, s), 3.97 (3H, s) ppm.

References: [1]Patent: WO2004/58717,2004,A1 .Location in patent: Page 77-78.

6
[ 188187-03-3 ]
[ 871723-37-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With ammonia; In methanol; at 20℃; for 7h;Heating / reflux;	Compound 1193 (6.31 g, 0.0239 mol) was dissolved in 7 N NH3 in MeOH (50 mL) and stirred at room temperature for 3 h then heated at reflux for 4 h. The reaction mixture was cooled to room temperature and concentrated. The residue was suspended in CH2Cl2 (150 mL), and the solid was removed by filtration and washed with CH2Cl2. The filtrate was concentrated, and the crude product was purified by silica gel flash chromatography (eluant: 5% MeOH-CH2CI2 to 10% MeOH-CH2Cl2) to give 3.68 g (92%) of the product 1196 as a white solid. MS for M+1: 168.

References: [1]Patent: WO2005/121130,2005,A2 .Location in patent: Page/Page column 561.

7
[ 188187-03-3 ]
[ 188187-01-1 ]
[ 188187-07-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	In N,N-dimethyl-formamide;	t Ethyl (E)-[1-n-butyl-5-[2-(2-methoxycarbonyl)phenylmethoxy-4-chloro-phenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate To a solution of the ethyl (E)-[1-n-butyl-5-(2-hydroxy-4-chlorophenyl)-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate (0.20 g, 0.39 mmol) and methyl 2-bromomethyl-3-chlorobenzoate (0.13 g, 0.47 mmol) in DMF (5 mL) was added sodium hydride (0.02 g, 0.59 mmol) at 0 C. The mixture was stirred at room temperature for 4 h. After an aqueous work up, extracting with ethyl acetate (3*15 mL), the combined organic extracts were washed with brine and dried (Na2 SO4). After removing the solvent under reduced pressure, flash column chromatography (1:1 ethyl acetate/hexane) of the residue afforded the title compound as an oil (0.22 g, 80%). 1 H NMR (250 MHz, CDCl3) d 7.78 (d, 1H), 7.55 (d, 1H), 7.48 (s, 1H), 7.32 (m, 2H), 7.12 (d, 2H), 6.75 (s, 1H), 6.45 (s, 1H), 5.55 (dd, J=10, 27.5 Hz, 2H), 4.49 (t, 2H), 4.10 (q, 2H), 3.83 (s, 3H) 3.77 (t, 2H), 3.65 (s, 3H), 3.15 (t, 2H), 1.52 (quintet, 2H), 1.20 (t, 3H), 1.05 (sextet, 2H), 0.75 (t, 3H).

References: [1]Patent: US5958968,1999,A .

8
[ 188187-03-3 ]
[ 944256-20-6 ]
[ 1184872-03-4 ]

References: [1]Tetrahedron Letters,2009,vol. 50,p. 4958 - 4961.

9
[ 188187-03-3 ]
[ 1068-90-2 ]
[ 845552-89-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 28 1 - [ (5-CHLORO-1, 2,3, 4-tetrahydroisoquinolin-3-yl) METHYL]-1-METHYL-1, 2- dihydrospiro [indole-3, 4'-piperidine] (A) 5-CHLORO-L-OXO-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid To a stirred suspension of 3-chloro-2-methylbenzoic acid (10.00 g, 58.6 mmol) in methanol (100 mL) was added dropwise thionyl chloride (8.5 mL, 117.2 mmol) at 0 C. The reaction mixture was refluxed for 2 h. After cooling down to room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (300 ML), washed with 1N NaOH solution (100 mL), water (100 mL) and brine (100 ML), dried (NA2S04), filtered, and concentrated to give 10.86 g of methyl ester as colorless oil. A mixture of this ester (10.80 g, 58.5 mmol), N-bromosuccinimide (10.45 g, 64.4 mmol), and benzoyl peroxide (0.71 g, 2.9 mmol) in carbon tetrachloride (70 mL) was refluxed for 3 h. After cooling down to room temperature, the reaction mixture was filtered and the filtrate wad concentrated to give 16.30 g of <strong>[188187-03-3]methyl 3-chloro-2-bromomethylbenzoate</strong> as a colorless oil. To a stirred suspension of NaH (2.45 g, 61.3 mmol) in DMF (50 mL) was added dropwise a solution of diethyl acetamidomalonate (12.10 g, 55.7 mmol) in DMF (50 mL) at room temperature. After 15 min stirreing, a solution of methyl 3-chloro-2- bromomethylbenzoate (16.3 g, 58. 5 mmol) in DMF (50 mL) at room temperature. After 18 h stirring, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate (800 ML), washed with water (200 mL x 2) and brine (200 mL), dried (NA2S04), filtered, and concentrated to give 21.5 g of yellow solid, which was purified by silica gel column chromatography (hexane/ethyl acetate: 2/1 to 111) to afford 14.33 g (64.3 %) of coupling product as a white solid. A mixture of this solid (13.90 g, 34.7 mmol) and 47 % HBr (160 mL) was refluxed for 24 h. After cooling down to room temperature, the solid formed was collected by filtration and dried togive 6.16 g (78.6 %) of title compound as a cream color solid. LHNMR (300MHZ, DMSO-D6) O8. 26 (1H, d, J = 4. 0 HZ), 7.85 (1H, dd, J = 1.1, 7.7 Hz), 7.64 (1H, dd, J = 1. 3, 8. 1 HZ), 7.39 (1H, dd, J = 7. 9,7. 9 HZ), 4.34-4. 28 (1H, m), 3.42-3. 36 (1H, overlapped with water peak at 3.36 ppm), 3.26 (1H, dd, J = 6.8, 16.9 Hz).

References: [1]Patent: WO2005/16913,2005,A1 .Location in patent: Page/Page column 68-69.

10
[ 188187-03-3 ]
[ 24666-56-6 ]
[ 1198299-48-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365.

11
[ 7499-08-3 ]
[ 188187-03-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365.
[2]Patent: US2013/65925,2013,A1 .
[3]Patent: EP2757103,2014,A1 .
[4]Patent: WO2005/16913,2005,A1 .
[5]Patent: WO2005/121130,2005,A2 .

12
[ 188187-03-3 ]
[ 1379313-10-6 ]

Yield	Reaction Conditions	Operation in experiment
98.3%	With diisobutylaluminium hydride; In hexane; dichloromethane; at -78℃; for 1h;Inert atmosphere;	Dichloromethane (10 ml) was added to <strong>[188187-03-3]methyl 2-(bromomethyl)-3-chlorobenzoate</strong> obtained in Example 10c (500 mg, 1.9 mmol), a 1.04 M diisobutylaluminum hydride/n-hexane solution (4.57 ml, 4.75 mmol) was added at -78 C., followed by stirring for one hour under a nitrogen atmosphere. A saturated aqueous Rochelle salt solution and tert-butyl methyl ether were added, followed by extraction with tert-butyl methyl ether. The organic layer was washed with brine, dried over magnesium sulfate and then allowed to pass through a silica gel pad. The eluate was concentrated to give the title compound (440 mg, yield 98.3%). 1H-NMR (400 MHz, CDCl3) delta ppm; 1.82 (1H, t, J=6 Hz), 4.78 (2H, s), 4.85 (2H, d, J=5 Hz), 7.25-7.28 (1H, m), 7.31-7.40 (2H, m).
98.3%	With diisobutylaluminium hydride; In hexane; dichloromethane; at -78℃; for 1h;Inert atmosphere;	(Example 10d) [2-(Bromomethyl)-3-chlorophenyl]methanol Dichloromethane (10 ml) was added to <strong>[188187-03-3]methyl 2-(bromomethyl)-3-chlorobenzoate</strong> obtained in Example 10c (500 mg, 1.9 mmol), a 1.04 M diisobutylaluminum hydride/n-hexane solution (4.57 ml, 4.75 mmol) was added at -78C, followed by stirring for one hour under a nitrogen atmosphere. A saturated aqueous Rochelle salt solution and tert-butyl methyl ether were added, followed by extraction with tert-butyl methyl ether. The organic layer was washed with brine, dried over magnesium sulfate and then allowed to pass through a silica gel pad. The eluate was concentrated to give the title compound (440 mg, yield 98.3%). 1H-NMR (400 MHz, CDCl3) delta ppm; 1.82 (1H, t, J=6 Hz), 4.78 (2H, s), 4.85 (2H, d, J=5 Hz), 7.25-7.28 (1H, m), 7.31-7.40 (2H, m).

References: [1]Patent: US2013/65925,2013,A1 .Location in patent: Paragraph 0340; 0341.
[2]Patent: EP2757103,2014,A1 .Location in patent: Paragraph 0216.

13
[ 188187-03-3 ]
[ 1379323-52-0 ]

References: [1]Patent: US2013/65925,2013,A1 .
[2]Patent: EP2757103,2014,A1 .

14
[ 188187-03-3 ]
[ 1427058-75-0 ]

References: [1]Patent: US2013/65925,2013,A1 .
[2]Patent: EP2757103,2014,A1 .

15
[ 188187-03-3 ]
[ 1427309-42-9 ]

References: [1]Patent: US2013/65925,2013,A1 .
[2]Patent: EP2757103,2014,A1 .

16
[ 188187-03-3 ]
[ 1427058-40-9 ]

References: [1]Patent: US2013/65925,2013,A1 .
[2]Patent: EP2757103,2014,A1 .

17
[ 188187-03-3 ]
[ 1427309-44-1 ]

References: [1]Patent: US2013/65925,2013,A1 .
[2]Patent: EP2757103,2014,A1 .

18
[ 188187-03-3 ]
C₂₅H₃₆ClF₂N₃O₃ [ No CAS ]

References: [1]Patent: US2013/65925,2013,A1 .

19
[ 188187-03-3 ]
[ 1449754-12-4 ]

References: [1]Patent: EP2757103,2014,A1 .

20
[ 188187-03-3 ]
C₁₄H₁₁ClN₂O [ No CAS ]