192702-01-5|4-(Bromomethyl)-2-chloro-1-fluorobenzene| Ambeed

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Structure of 192702-01-5

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Quality Control of [ 192702-01-5 ] Purity: 98% SDS Specification

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Product Details of [ 192702-01-5 ]

CAS No. :	192702-01-5
Formula :	C₇H₅BrClF
M.W :	223.47
SMILES Code :	FC1=CC=C(CBr)C=C1Cl
MDL No. :	MFCD01631551
Boiling Point :	No data available
InChI Key :	GGTQWWTYUKXFPP-UHFFFAOYSA-N
Pubchem ID :	2757542

Safety of [ 192702-01-5 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H314
Precautionary Statements:	P264-P271-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P403+P233-P501
Class:	8
UN#:	3265
Packing Group:	Ⅱ

Computational Chemistry of [ 192702-01-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	1
Num. H-bond acceptors	1.0
Num. H-bond donors	0.0
Molar Refractivity	44.25
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	0.0 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.34
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	3.66
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.64
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.	4.1
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	3.89
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.53

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.91
Solubility	0.0275 mg/ml ; 0.000123 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.	-3.35
Solubility	0.1 mg/ml ; 0.000448 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	-4.56
Solubility	0.0062 mg/ml ; 0.0000277 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	Low
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	Yes
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.	-5.06 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	1.0
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<2.0
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)	1.84

Application In Synthesis of [ 192702-01-5 ]

* 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 [ 192702-01-5 ]

[ 192702-01-5 ] Synthesis Path-Downstream 1~35

1
[ 1513-25-3 ]
[ 192702-01-5 ]

References: [1]Journal of medicinal chemistry,1967,vol. 10,p. 64 - 66.

2
[ 192702-01-5 ]
[ 1068-90-2 ]
[ 14937-92-9 ]

References: [1]Journal of medicinal chemistry,1967,vol. 10,p. 64 - 66.

3
[ 123-56-8 ]
[ 192702-01-5 ]
1-(3-chloro-4-fluorobenzyl)pyrrolidine-2,5-dione [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 1930 - 1940.

4
[ 186202-57-3 ]
[ 192702-01-5 ]
[ 610779-90-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; for 18h;	Description 16: [(2S)-4-(3-Chloro-4-fluoro-benzvl) morpholin-2-vimethVllcarbamic acid ter-butyl ester A solution of (R)- (2-morpholinylmethyl)-carbamic acid 1, 1-dimethyl ester [CAS 186202-57-3] (0.26g) in dichloromethane (5ml) was treated with triethylamine (0. 167ml) and <strong>[192702-01-5]3-chloro-4-fluorobenzyl bromide</strong> (0.27g). After stirring for 18hrs the mixture was purified by applying directly to an SCX ion exchange cartridge (10g), eluting with methanol followed by 10% 0.880 ammonia/methanol. The basic fraction was evaporated in vacuo to give the title compound (0.37g) as a colourless gum. LC-MS: Rt = 2.46min. Mass Spectrum m/z 359 [MH+]

References: [1]Patent: WO2003/82861,2003,A2 .Location in patent: Page/Page column 44.

5
[ 192702-01-5 ]
[ 123-54-6 ]
[ 1001072-25-8 ]

Yield	Reaction Conditions	Operation in experiment
92%		INTERMEDIATE 7; Synthesis of 3-(3-chloro-4-fluorobenzyl)pentane-2,4-dione; A mixture of pentane-2,4-dione (2.00 g, 10.0 mmol), 4-(bromomethyl)-2-chloro-l- fluorobenzene (2.23 g, 10.0 mmol) and Li2CO3 (1.48 g, 20.0 mmol) was heated in DMF (30 mL) at 75 0C for 1 h. The mixture was then poured on sat NaCl and acidified with sat HCl. Toluene (100 mL) was used to extract the product. The organic phase was washed twice with sat NaCl, dried (Na2SO4), filtered and evaporated to 2.16 g (92%) clear oil, pure as a tautomeric mixture. MS (ESI) m/z 236 [M+H+].

References: [1]Patent: WO2008/3753,2008,A1 .Location in patent: Page/Page column 36.

6
[ 192702-01-5 ]
(6S)-2-(3-chloro-4-fluorobenzyl)-8-ethyl-10-methoxy-N,6-dimethyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a cold (0 C) solution of (6S)-8-ethyl-10-methoxy-N,6-dimethyl-1,9-dioxo- l ,2,6,7,8,9-hexahydropyrazino[ 1 ',2': 1 ,5]pyrrolo[2,3-d]pyridazine-4-carboxamide (1.58 g, 4.73 mmol) in anhydrous DMF (50 mL), a solution of lithium bis (trimethylsilyl)amide mL, 4.97 mmol, 1 M in THF) was added. After stirring at the same temperature for 25 minutes, <strong>[192702-01-5]3-chloro-4-fluorobenzyl bromide</strong> (1.27 g, 5.68 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes and concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1-5% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title compound. ¹H NMR (400 MHz, CDC13) 6 7.46 (dd, J = 6.9, 2.2 Hz, 1H), 7.32 (m, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.03 (br signal, 1H), 5.92 (m, 1H), 5.32 (d, J = 14.1 Hz, 1H), 5.26 (d, J = 14.1 Hz, 1H), 4.14 (s, 3H), 3.97 (dd, J = 13.2, 3.7 Hz, 1H), 3.73 (heptet, J = 7.2 Hz, 1 H), 3.51 (heptet, J = 7.1 Hz, 1H), 3.21 (dd, J = 13.2, 1.7 Hz, 1H), 3.03 (d, J = 5.0 Hz, 3H), 1.42 (d, J = 6.6 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H). ES MS M+1 = 476

References: [1]Patent: WO2005/110414,2005,A2 .Location in patent: Page/Page column 100.

7
[ 192702-01-5 ]
[ 870006-84-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of (65)-4-amino-8-ethyl-1 0-methoxy-6-methyl-7,8- dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.94 g, 3.23 mmol) in anhydrous DMF (32 mL) under an atmosphere of nitrogen, a solution of lithium bis (trimethylsilyl)amide THF (3.87 mL, 1 M, 3.87 mmol) was added. The mixture was stirred at room temperature for 15 minutes and treated with <strong>[192702-01-5]4-fluoro-3-chlorobenzyl bromide</strong> (0.72 g, 3.23 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The residue was partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0-20% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title material. ¹H NMR (400 MHz, DMSO-d6) No. 7.46 (dd, J = 7.2, 2.0 Hz, 1H), 7.37 (t, J = 8.7 Hz, 1H), 7.27 (m, 1H), 5.57 (s, 2H), 5.19 (m, 1H), 5.11 (d, J = 14.7 Hz, 1H), 5.03 (d, J = 14.7 Hz, 1H), 3.91 (s, 3H), 3.89 (m, 1H), 3.65 (heptet, J = 6.4 Hz, 1 H), 3.37 (m), 1.32 (d, J = 6.6 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H). ES MS M+1 = 434

References: [1]Patent: WO2005/110414,2005,A2 .Location in patent: Page/Page column 120.

8
[ 7770-45-8 ]
[ 192702-01-5 ]
[ 925442-48-4 ]

Yield	Reaction Conditions	Operation in experiment
81%		Sodium hydride (97.0 mg, 2.22 mmol) was suspended in N,N-dimethylformamide (10 mL) in a nitrogen atmosphere, and the suspension was cooled to 0C. 4-Hydroxy-1-naphthaldehyde (252 mg, 1.46 mmol) was slowly added, and the mixture was stirred at 0C for 30 minutes. 4-(Bromomethyl)-2-chloro-1-fluorobenzene (480 mg, 2.15 mmol) was further added, and the mixture was stirred at room temperature for three hours. A dilute hydrochloric acid solution (30 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 ml). The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate = 20/1 to 3/1) to give the target compound (371 mg, yield: 81%) as a light yellow solid. 1H-NMR (CDCl3, 500MHz):delta ppm: 5.29 (2H, s), 6.97 (1H, d, J=7.8Hz), 7.22 (1H, t, J=8.5Hz), 7.40 (1H, m), 7.58-7.62 (2H, m), 7.73 (1H, m), 7.92 (1H, d, J=8.3Hz), 8.37 (1H, d, J=8.8Hz), 9.32 (1H, d, J=8.8Hz), 10.23 (1H, s). MS (EI) m/z: 314.0511 (M+)

References: [1]Patent: EP1914229,2008,A1 .Location in patent: Page/Page column 153-154.

9
[ 192702-01-5 ]
[ 7731-00-2 ]

References: [1]Journal of medicinal chemistry,1967,vol. 10,p. 64 - 66.

10
[ 452-84-6 ]
[ 192702-01-5 ]

References: [1]Journal of medicinal chemistry,1967,vol. 10,p. 64 - 66.

11
[ 161446-90-8 ]
[ 192702-01-5 ]

Yield	Reaction Conditions	Operation in experiment
	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃;	[00202] A solution of 3-chloro-4-fluorobenzaldehyde (3 g) in THF (40 ml) was added over 2 minutes to a stirred suspension of sodium borohydride (1.07 g) in methanol (40 ml) at 0 C. The mixture was allowed to warm to room temperature and then quenched with water. The resulting suspension was partitioned between water and diethyl ether and the combined organic extracts were dried and concentrated in vacuo. The residue was dissolved in dichloromethane (90 ml) and triphenylphosphine (4.62 g) and tetrabromomethane (6.64 g) were added at 0 C. The mixture was allowed to warm to room temperature overnight then concentrated in vacuo and the residue purified by column chromatography using iso-hexane as eluent to yield the desired product (3.57 g, 85%). NMR: delta 4.7 (s, 2H), 7.4 (m, 2H), 7.7 (m, 1H).
	With carbon tetrabromide; triphenylphosphine; In dichloromethane; for 3h;	Intermediate 50 (1.25 mmol), triphenylphosphine (1.87 mmol) and carbon tetrabromide (1.87 mmol) were stirred in anhydrous DCM, under nitrogen for 3 hours. The solvent was removed under reduced pressure and the crude material was purified by chromatography on silica gel to give intermediate 51, which was a colourless oil. Intermediate 51 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 400 MHz) (ppm) 4.43 (s, 2H), 7.13 (t, J=8.37 Hz, 1H), 7.26-7.28 (m, 1H), 7.44-7.47 (d, J=6.70 Hz, 1H).
	With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere;	To a solution of (3-chloro-4-fluoro-phenyl)-methanol (4.3 g, 26.8 mmol) in DCM (20 mL) was added PBr3 (1 mL) at 0 C. The resulting mixture was stirred at room temperature for 1 hour before it was quenched with satd. aq. NaHC03 solution. The organic solution was washed with water, brine, dried over anhy. Na2S04 and concentrated in vacuo to give the desired product (3.7 g, 61.9%). It was used directly in the next step, without further purification

References: [1]Patent: US6737435,2004,B1 .Location in patent: Page/Page column 17-18.
[2]Patent: US2009/60866,2009,A1 .Location in patent: Page/Page column 64.
[3]Patent: WO2013/79452,2013,A1 .Location in patent: Page/Page column 133; 134.
[4]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6842 - 6846.
[5]Chemical Biology and Drug Design,2016,p. 97 - 109.

12
[ 865300-47-6 ]
[ 192702-01-5 ]
[ 865300-48-7 ]

Yield	Reaction Conditions	Operation in experiment
		Step 3: 6- (3-chloro-4-fluorobenzyl)-4-hydroxy-N, N, 2-trimethyl-3, 5-oxo-2, 3,5, 6,7, 8- hexahydro-2, 6-naphthyridine-1-carboxamide; A solution of 4-hydroxy-N, N, 2-trimethyl-3,5-dioxo-2, 3,5, 6,7, 8-hexahydro-2,6- naphthyridine-1-carboxamide (0. 018g, 0.068 mmol) in DMF (2 mL) was treated with Cs2C03 (0. 066g, 0.2 mmol) and 3-chloro-4-fluoro benzyl bromide (0. 045g, 0. 2 mmol) and heated to 40 C. The reaction mixture was then cooled to 0 degrees C, a suspension of NaH (95% dispersion in oil, 0. 2 mmol) was added and the reaction was warmed to room temperature. After 1 hr the reaction was partitioned between ice water and EtOAc, the organic layer was dried with brine and Na2SO4, filtered and evaporated to give 6- (3-chloro-4-fluorobenzyl)-4- [ (3-chloro-4-fluorobenzyl) oxy] -N, N, 2-trimethyl-3, 5- dioxo-2, 3,5, 6,7, 8-hexahydro-2, 6-naphthyridine-1-carboxamide (ES MS M+1= 549.9). This material was then dissolved in CH2C12 (3 mL) and treated with 4 drops of a 30% by weight solution of HBr in propionic acid at room temperature. After 20 minutes the solution was concentrated and purified by reverse phase chromatography to give the product. 1HNMR (400 M : Hz, CD30Do o 7.48 (m, 1H), 7.32 (m, 1H), 7.22 (t, J=8. 5 Hz, 1H), 4.76 (d, J=14. 8 Hz, 1H), 4.63 (d, J=14. 8 Hz, 1H), 3.50 (t, J=6. 4 Hz, 2H), 3.44 (s, 3H), 3. 08 (s, 3H), 2.95 (s, 3H), 2.61 (t, J=6. 2 Hz, 2H) ppm. (ES MS M+1= 407. 9)

References: [1]Patent: WO2005/87767,2005,A1 .Location in patent: Page/Page column 42.

13
[ 192702-01-5 ]
[ 865300-49-8 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 12; 6- (3-Chloro-4-fluorobenzyl)-4-hydroxy-N, N, 2-trimethyl-3,5-dioxo-2, 3,5, 6,7, 8-hexahydro-2,6- naphthyridine-1-carboxamide; Step 1 : 1- (3-Chloro-4-fluorobenzyl) piperidin-2-one; Valerolactam (153.3 g, 1.54 mol) was dissolved in NMP (3.5 L) and cooled to 0 C. NaH (67.7g, 1.69 mol, 60% dispersion in oil) was added in portions over 5 minutes keeping the temperature at 0 C. The reaction was stirred for 30 minutes, and 3-chloro-4-fluorobenzylbromide (345.5 g, 1.54 mol) dissolved in 200 mL NMP was added over 30 minutes, again keeping the internal temperature at 0 C. The reaction was aged for 1 hour at 0 C, and allowed to warm to room temperature overnight. LCMS showed the reaction complete. The reaction mixture was quenched with 5L distilled H20, extracted with 3 portions of CH2C12 (2L, 1L, 1L) and the organic layers combined and washed with three 4L portions of water. The organic layer was concentrated and was found to contain NMP. The residual oil was dissolved in EtOAc (4 L), and extracted with three 2L portions of water. The organic layer was concentrated to give the product that solidified upon standing. 1H NMR (400 MHz, CDC13) 8 7.24 (m, 2H), 7.0 (m, 2H), 7.1 (m, 1H), 4.56 (s, 2H), 3.19 (t, J = 4.9, 2H), 2.46 (t, J = 6.4, 2H), 1.8-1. 75 (m, 4H) ppm.
		EXAMPLE 23; 6- (3-Chloro-4-fluorobenzyl)-4-hydroxy-N, N, 2-trimethyl-3,5-dioxo-2, 3,5, 6,7, 8-hexahydro-2,6- naphthyridine-1-carboxamide; Step 1: 1- (3-Chloro-4-fluorobenzyl) piperidin-2-one; Valerolactam (60 g) was dissolved in MTBE (1. 5L) at room temperature. To this solution was added Bu4NS04 (4.9 g) as a phase transfer catalyst. The cloudy solution was stirred at room temperature for 5 minutes. Then, NaOH (50 wt%; 300 mL) was slowly added as to keep the internal temperature below 30C. 3-Chloro-4-fluorobenzyl bromide (108.3 g) was then added slowly to this biphasic mixture, again as to keep the internal temperature under control. The reaction was then aged for 4 hours at room temperature. At this time LC showed the reaction to be complete. Water (500 mL) was then added. After phase cut, the organic layer was washed with brine (300 mL), dried under MgS04 followed by solvent switch to heptane (400 mL). The slurry obtained was stirred at room temperature. for 1 hour and then filtered to afford the title product.
		To a cold (0 0C) solution of valerolactam (153.30 g, 1.54 mol) in anhydrous l-methyl-2- pyrrolidinone (3.5 L), sodium hydride (67.7 g, 1.69 mol, 60% dispersion in oil) was added over a period of 5 minutes. The reaction mixture was stirred for 30 minutes, and a solution of 3-chloro-4- fluorobenzylbromide (345.5 g, 1.54 mol) in l-methyl-2-pyrrolidinone (200 mL) was added over 30 minutes at 0 0C. The reaction mixture was stirred at 0 0C for 1 hour, and was allowed to warm up and stirred at room temperature overnight. The reaction mixture was quenched with distilled water (5 L), and extracted with dichloromethane (three times; 2 L, 1 L, 1 L). The organic extracts were combined, washed with water (3X; 4 L each time). The residual oil was dissolved in ethyl acetate (4 L), and extracted with water (3X; 2 L each time). The organic layer was separated, concentrated under vacuum to give the title product that solidified upon standing. lHNMR (400 MHz, CDCI3) delta 7.24 (m, 2H), 7.0 (m, 2H), 7.1 (m, IH), 4.56 (s, 2H), 3.19 (t, J= 4.9 Hz,2H), 2.46 (t, J= 6.4 Hz, 2H), 1.8-1.75 (m, 4H).

References: [1]Patent: WO2005/87767,2005,A1 .Location in patent: Page/Page column 42-43.
[2]Patent: WO2005/87767,2005,A1 .Location in patent: Page/Page column 64.
[3]Patent: WO2006/121831,2006,A2 .Location in patent: Page/Page column 50-51.

14
[ 192702-01-5 ]
6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		Step 10: 6- (3-chloro-4-fluorobenzyl)-4-hydroxy-N, N, 2-trimethyl-3,5-dioxo-2, 3,5, 6,7, 8- hexahydro-2, 6-naphthyridine-1-carboxamide; 4-Hydroxy-N, N, 2-trimethyl-3,5-dioxo-2, 3,5, 6,7, 8-hexahydro-2, 6-naphthyridine-1- carboxamide (0.43g, 0.0016 mol) was dissolved in lOmL dry DMF and 100mg NaH was added. The mixture was allowed to stir until the bubbles ceased, then 3-chloro-4-fluoro benzyl bromide (0.362g, 0. 0016mole) was added. The reaction was quenched with 30mL of a 10% aq KHS04 solution and diluted with 100mL chloroform. The reaction was further diluted with lOOmL brine and allowed to stir vigorously for 30 minutes. The layers were separated and the aqueous layer was washed with chloroform. The organic fractions were combined and dried over NaSO4, filtered and concentrated under high vacuum to remove the DMF (yield 0. 5g, 75%). HPLC analysis showed 85% purity. The solid product was crystallized first from isopropanol, then from ethanol. 1H NMR (400 MHz, CDC13) 8 2.49-2. 57 (m, 1H), 2.67-2. 74 (m, 1H), 2.9 (s, 3H), 3.1 (s, 3H), 3.34-3. 46 (m, 1H), 3.47 (s, 1H), 3. 48-3. 53 (m, 1H), 4. 48-4. 52 (d, J=15, 1H), 4.79-4. 83 (d, J=15, 1H), 7.11-7. 21 (m, 2H), 7.34-7. 36 (m, 1H), 12.94 (s, 1H). LRMS (M+ 1) 408.2.

References: [1]Patent: WO2005/87767,2005,A1 .Location in patent: Page/Page column 63.

15
[ 192702-01-5 ]
trans tert-butyl [7-(3-chloro-4-fluorobenzyl)-5-hydroxy-4,6-dioxo-2,4,6,7,8,8a-hexahydro-1H-3,7,8b-triazaacenaphthylen-2-yl]methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 15; trans N- [7- (3-Chloro-4-fluorobenzyl)-5-hydroxy-4, 6-dioxo-2,4, 6,7, 8, 8a-hexahydro-lH-3, 7,8b- triazaacenaphthylen-2-yl] -N, N', N'-trimethylethanediamide; Step 1: (+/-) trans tert-Butyl [7-(3-chloro-4-fluorobenzyl-5-hydroxy-4, 6-dioxo-2,4, 6,7, 8, 8a- hexahydro-lH-3, 7,8b-triazaacenaphthylen-2-yl] methylcarbamate (PI); To a suspension of KH (9 equivalents) in THF was added a solution of tert-butyl (5- hydroxy-4, 6-oxo-2, 4,6, 7,8, 8a-hexahydro-lH-3, 7,8b-triazaacenaphthylen-2-yl) methylcarbamate (J8) in THF and the reaction mixture was stirred at room temperature for 10 minutes. 3-Chloro-4-fluorobenzyl bromide (2 equivalents) was added and the resulting suspension was stirred at room temperature for 16 hours. AcOH was added and the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC, using a gradient of H2O (0. 1 % TFA) and MeCN (0. 1 % TFA) as eluants (column : C18) and the product was obtained after lyophilization of the desired fractions. 1H- NMR (400 MHz, d6-DMSO) 8 : 7.57 (1H, br. s), 7.42-7. 39 (2H, m), 5.14-4. 92 (1H, m), 4.77-4. 67 (1H, m), 4.64 (2H, s), 3.71 (1H, dd, J = 11.8, 3.7 Hz), 3.61 (1H, t, J = 10.9 Hz), 2.78 (3H, s), 2.38-2. 27 (1H, m), 2.22-2. 11 (1H, m), 1.39 (6H, s), 1.31 (3H, br. s). MS (ES) C22H24CIFN405 requires: 478, found: 479 (M+H) +.

References: [1]Patent: WO2005/87766,2005,A1 .Location in patent: Page/Page column 66.

16
[ 1028450-05-6 ]
[ 192702-01-5 ]
[ 1028450-15-8 ]

References: [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 3941 - 3958.

17
[ 675-20-7 ]
[ 192702-01-5 ]
[ 865300-49-8 ]

Yield	Reaction Conditions	Operation in experiment
99%		To a 2000 L glass-lined reactor, under the protection of nitrogen, MTBE (633 kg) and valerolactam (34.9 kg, 350 mol) were charged by vacuum. After initiating stirring, a 33% aqueous solution of tetrabutylammonium hydrogen sulfate (8.35 kg) was added. The mixture was cooled to 20-30 C and then a 50% aqueous solution of sodium hydroxide (270 kg) was added to the mixture at a rate of 10-15 L/minute at this temperature. After the addition, the mixture was maintained at the same temperature for 30 minutes followed by the addition of 3- chloro-4-fluoro-benzylbromide (62.9 kg, 280 mol) at a rate of 2-3 kg/minute at 20-30 C. After 5-10 hours, water (283 kg) was added to the reaction mixture at a rate of 30-40 kg/minute at 20- 30 C to quench the reaction. The mixture was stirred for 30 minutes and then the water phase was separated out. The organic phase was washed with 25% aqueous brine solution (226 kg), and the organic phase was dried with anhydrous sodium sulfate (30 kg) under stirring. The dried mixture was filtered by nutsche filter and the filter cake was rinsed with MTBE (50 kg). The combined filtrate was concentrated in vacuo (T< 35 C, P< -0.08 MPa) until the mixture volume remained at about 350-500 L. Petroleum ether was added (138.4 kg) to the mixture and concentrated continuously. After the mixture volume remained at about 350-500 L, another 138 Kg of petroleum ether was added to the mixture and then concentrated in vacuo. The mixture was cooled to 0-5 C, stirred for 2-3 hours, and then filtered. The filter cake was dried by rotary conical dryer below 35 C to provide 67.7 kg of l-(3-chloro-4-fluorobenzyl)piperidin-2-one (99% yield).
		Valerolactam (60 g) was dissolved in MTBE (1.5L) at room temperature. To this solution was added BU4NSO4 (4.9 g) as a phase transfer catalyst. The cloudy solution was stirred at room temperature for 5 minutes. Then, NaOH (50 wt%;300 mL) was slowly added as to keep the internal temperature below 3O0C. 3-Chloro-4-fluorobenzyl bromide (108.3 g) was then added slowly to this biphasic mixture, again as to keep the internal temperature under control. The reaction was then aged for 4 hours at room temperature. At this time LC showed the reaction to be complete. Water (500 mL) was then added. After phase cut, the organic layer was washed with brine (300 mL), dried under MgSO4 followed by solvent switch to heptane (400 mL). The slurry obtained was stirred at room temperature. for 1 hour and then filtered to afford the title product.
		To a cold (O C) solution of valerolactam (153.30 g, 1.54 mol) in mixture of anhydrous l-methyl-2-pyrrolidinone (3.5 L) and THF (350 mL), sodium hydride (67.7 g, 1.69 mol, 60% dispersion in oil) was added over a period of 5 minutes. The reaction mixture was stirred for 30 minutes, and a solution of 3-chloro-4-fluorobenzylbromide (345.5 g, 1.54 mol) in l-methyl-2-pyrrolidinone (200 mL) was added over 30 minutes at 0 C. The reaction mixture was stirred at 0 0C for 1 hour, and was allowed to warm up and stirred at room temperature overnight. The reaction mixture was quenched with distilled water (5 L), and extracted with dichloromethane (three times; 2 L, 1 L, 1 L). The organic extracts were combined, washed with <n="20"/>water (3X; 4 L each time). The residual oil was dissolved in ethyl acetate (4 L), and extracted with water (3X; 2 L each time). The organic layer was separated, concentrated under vacuum to give the title product that solidified upon standing. lH NMR (400 MHz, CDCI3) delta 7.24 (m, 2H), 7.0 (m, 2H), 7.1 (m, IH), 4.56 (s, 2H), 3.19 (t, J=4.9 Hz, 2H), 2.46 (t, J= 6.4 Hz, 2H), 1.8-1.75 (m, 4H).

Step 1: 1-(3-Chloro-4-fluorobenzyl)piperidin-2-one To a cold (0 C.) solution of valerolactam (153.30 g, 1.54 mol) in mixture of anhydrous 1-methyl-2-pyrrolidinone (3.5 L) and THF (350 mL), sodium hydride (67.7 g, 1.69 mol, 60% dispersion in oil) was added over a period of 5 minutes. The reaction mixture was stirred for 30 minutes, and a solution of 3-chloro-4-fluorobenzylbromide (345.5 g, 1.54 mol) in 1-methyl-2-pyrrolidinone (200 mL) was added over 30 minutes at 0 C. The reaction mixture was stirred at 0 C. for 1 hour, and was allowed to warm up and stirred at room temperature overnight. The reaction mixture was quenched with distilled water (5 L), and extracted with dichloromethane (three times; 2 L, 1 L, 1 L). The organic extracts were combined, washed with water (3*; 4 L each time). The residual oil was dissolved in ethyl acetate (4 L), and extracted with water (3*; 2 L each time). The organic layer was separated, concentrated under vacuum to give the title product that solidified upon standing. 1H NMR (400 MHz, CDCl3) delta 7.24 (m, 2H), 7.0 (m, 2H), 7.1 (m, 1H), 4.56 (s, 2H), 3.19 (t, J=4.9 Hz, 2H), 2.46 (t, J=6.4 Hz, 2H), 1.8-1.75 (m, 4H).

References: [1]Patent: WO2014/18449,2014,A1 .Location in patent: Page/Page column 28.
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165.
[3]Patent: WO2006/107478,2006,A2 .Location in patent: Page/Page column 13.
[4]Patent: WO2008/48538,2008,A1 .Location in patent: Page/Page column 18-19.
[5]Patent: US2008/280945,2008,A1 .Location in patent: Page/Page column 8.

18
[ 1056901-33-7 ]
[ 192702-01-5 ]
[ 1056901-34-8 ]

Yield	Reaction Conditions	Operation in experiment
97%		b) 1-[1-tert-Butoxycarbonyl-2-(3-chloro-4-fluoro-phenyl)-1-methyl-ethyl]-1H-pyrrole-2-carboxylic Acid Methyl Ester 1-(1-tert-Butoxycarbonyl-ethyl)-1H-pyrrole-2-carboxylic acid methyl ester (3.2 g, 12.65 mmol) was dissolved in anhydrous tetrahydrofuran (35 mL) and cooled to -78 C. under a nitrogen atmosphere. A 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (25.3 mL, 12.65 mmol) was added dropwise over a period of 30 min. The mixture was stirred at -78 C. for 10 min and then <strong>[192702-01-5]4-bromomethyl-2-chloro-1-fluoro-benzene</strong> (2.28 g, 10.2 mmol) was added dropwise over a period of 2 min. The mixture continued to stir at -78 C. for 12 h and was slowly warmed to 25 C. over a period of 2 h. The mixture was poured into 1.0 M aqueous hydrochloric acid solution (200 mL) and the product was extracted into ethyl acetate (200 mL). The organic phase was washed with saturated aqueous brine solution (50 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 muM, 10% ethyl acetate in hexanes) afforded the desired product, 1-[1-tert-butoxycarbonyl-2-(3-chloro-4-fluoro-phenyl)-1-methyl-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester (3.92 g, 9.9 mmol, 97% yield) as golden oil. 1H NMR (400 MHz, CDCl3) delta: 1.45 (9H, s), 1.59 (3H, s), 3.29 (1H, d, J=14.9 Hz), 3.81-3.85 (4H, m), 6.03 (1H, t, J=3.5 Hz), 6.33-6.37 (1H, m), 6.50 (1H, dd, J1=7.0 Hz, J2=2.4 Hz), 6.53 (1H, t, J=2.4 Hz), 6.86 (1H, t, J=8.8 Hz), 7.16 (1H, dd, J1=3.9 Hz, J2=2.4 Hz). LC-MS (ESI): m/e calcd for C20H23ClFNO4 [M+] 395.13, found [M+H+] (20%), 340.0 [M-tBu+H+] (100%).

References: [1]Patent: US2008/227774,2008,A1 .Location in patent: Page/Page column 26.

19
[ 192702-01-5 ]
[ 229640-38-4 ]
C₁₉H₁₇ClFNO₅ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4360 - 4363.

20
[ 1068150-58-2 ]
[ 192702-01-5 ]
[ 1068150-85-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4581 - 4583.

21
[ 1068150-51-5 ]
[ 192702-01-5 ]
[ 1068150-83-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4581 - 4583.

22
[ 915408-37-6 ]
[ 192702-01-5 ]
[ 915409-45-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2263 - 2265.

23
[ 192702-01-5 ]
[ 76003-29-7 ]
[ 851726-46-0 ]

Yield	Reaction Conditions	Operation in experiment
		To a cold (0 C) suspension of tert-butyl 3-oxopiperazine-1-carboxylate (2.0 g, 9.99 mmol) in DMF (20 mL) under an atmosphere of nitrogen, a solution of lithium bis (trimethylsilyl) amide in THE (10.69 mL, 10.69 mmol) was added and stirred at the temperature for 30 min. The resultant clear red brown solution was treated with <strong>[192702-01-5]3-chloro-4-fluorobenzyl bromide</strong> (2.34 mL, 10.49 mmol), and stirred at 0 C for 2 hours. The product mixture was concentrated under vacuum, and the residue partitioned between water and ethyl acetate. The organic extract was washed successively with 5% aq KHS04, sat. NaHC03, and brine. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0-100% gradient of ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the benzylated product. 'H NMR (400 MHz, CDC13) 8 7.32 (dd, J = 6.7, 1. 8 Hz, 1H), 7. 17-7. 09 (m, 2H), 4.55 (s, 2H), 4.16 (s, 2H), 3.61 (t, J = 5.3 Hz, 2H), 3.27 (t, J = 5.3 Hz, 2H), 1.47 (s, 9H).

References: [1]Patent: WO2005/41664,2005,A1 .Location in patent: Page/Page column 69.

24
methyl (6S)-8-ethyl-10-(methoxy)-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrazine-4-carboxylate [ No CAS ]
[ 192702-01-5 ]
methyl (6S)-2-(3-chloro-4-fluorobenzyl)-8-ethyl-10-methoxy-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrido[3',4':4,5]pyrrolo[1,2-a]pyrazine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a cold (-25 C) solution of methyl (6S)-8-ethyl-10- (methoxy)-6-methyl-1, 9-dioxo- 1, 2,6, 7,8, 9-hexahydropyrido- [3', 4' : 4,5] pyrrolo [1, 2-a] -pyrazine-4-carboxylate (0.29 g, 0.87 mmol) in anhydrous DMF (15 mL) under an atmosphere of nitrogen, a solution of lithium bis (trimethylsilyl) amide in THE (1 M, 0.96 mmol) was added. The reaction mixture was stirred at-25 C for 25 minutes and treated with <strong>[192702-01-5]3-chloro-4-fluorobenzyl bromide</strong> (0.27 g, 1.2 mmol ; passed through activated basic alumina). The reaction mixture was stirred at 0 C for 40 minutes and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HC1. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate-hexane gradient. Collection and concentration of appropriate fractions provided the titled product. 1HNMR (400MHz, CDC13) 6 8. 00 (s, lH), 7.40 (dd, J = 2.4, 6.8, 1H), 7.28-7. 24 (m, 1H), 7.11 (t, J = 8.6 Hz, 1H), 5.15 (d, J = 15.7 Hz, 1H), 5.08 (d, J = 15.7 Hz, 1H), 4.12 (s, 3H), 3.94 (dd, J = 3.8, 13.0 Hz, 1H), 3.88 (s, 3H), 3.71 (m, 1H), 3.52 (m, 1H), 3.19 (dd, J = 1.8, 13.2, 1H),. 1.39 (d, J = 6. 5 Hz, 3H), 1.22 (t, J = 7. 2 Hz, 3H). ES MS M+1 = 476

References: [1]Patent: WO2005/41664,2005,A1 .Location in patent: Page/Page column 136.

25
[ 773837-37-9 ]
[ 192702-01-5 ]
[ 658-98-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	N-benzyl-N,N,N-triethylammonium chloride; In chloroform; water; at 25 - 45℃; for 5h;	[253] Example 3. 2-(3-(3-chloro-4-fluorophenyl)piperidin-3-yl)ethanol (Racemic).; [254] Product 3A: 2-(3-chloro-4-fluorophenyl)acetonitrile.; Into a 3 neck flask equipped with a magnetic stirrer, a condenser, and an addition funnel was placed water (75 mL) then sodium cyanide(13.16 g, 268.49 mmol), then chloroform (100 mL) and the phase transfer catalyst N-benzyl-N,N-diethylethanaminium chloride (3.06 g, 13.42 mmol). The mixture was stirred vigorously as 4-(bromomethyl)-2-chloro-l- fluorobenzene (30 g, 134.25 mmol) was added dropwise as a chloroform solution over 30 min at 25C. The mixture was stirred for an additional 3 hr at 25C, and then the reaction was heated to 45C for an additional 2 hr. The reaction was cooled, separated into layers and the organic layer washed with 0.5 N NaOH then brine. The chloroform layer was dried over Na2SO4, filtered, and concentrated. The aqueous layers were combined and treated with IN NaOH solution and bleach (caution exothermic) before disposal of the cyanide containing waste. The pure 3A (22.05 g, 97%) was obtained as an oil. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 7.39 (dd, /=6.56, 2.29 Hz, IH) 7.21 (dd, /=4.43, 2.29 Hz, IH) 7.17 (d, /=8.55 Hz, IH) 3.71 (s, 2H).

References: [1]Patent: WO2010/71575,2010,A1 .Location in patent: Page/Page column 52.

26
[ 73260-12-5 ]
[ 192702-01-5 ]
[ 1240660-16-5 ]

References: [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 5510 - 5518.

27
[ 192702-01-5 ]
pyrido[3,4-d]pyrimidin-4(3H)-one [ No CAS ]
[ 1202013-24-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;	Step 4: 3-(3-Chloro-4-fluoroben2yl)-5-methoxypyrido[3,4-d]pyrimidin-4(3H)-one A mixture of 5-methoxyIyrido[3,4-d]pyrimidin-4(3H)-one (5 g, 28.2 mmol), 4- (bromomethyl)-2-chloro-l-fluorobenzene (6.31 g, 28.2 mmol), and CS2CO3 (18.4 g, 56.4 mmol) in DMF (50 mL) was stirred at room temperature for 4 hours. The product mixture was filtered and the filtrate was concentrated under vacuum. The residue was diluted with EtOAc (50 mL) and washed subsequently with H2O (40 mL) and brine (40 mL). The organic layer was dried over MgSI¸4, filtered, and concentrated to provide title compound. lH NMR (400 MHz, CDCI3) I' 8.76 (s, IH), 8.35 (s, IH), 8.17 (s, IH), 7.45 (dd, J= 2,7 Hz, IH), 7.29 (m, IH)5 7.12 (t, J- 8.6 Hz5 IH), 5.08 (s, 2H)S 4.11 (s, 3H). ES MS M+l = 520.0.

References: [1]Patent: WO2009/154870,2009,A1 .Location in patent: Page/Page column 46.

28
[ 192702-01-5 ]
[ 24922-01-8 ]
[ 1335027-53-6 ]

Yield	Reaction Conditions	Operation in experiment
63.3%	With N-ethyl-N,N-diisopropylamine; lithium chloride; In tetrahydrofuran; at 80℃; for 18h;	Method VEthyl 2- [(3-chlor o-4-fluoro-phenyl)methyl] -3-cyclobutyl-3-oxo-propanoateLithium chloride (139 mg, 3.28 mmol) was added to 4-(bromomethyl)-2-chloro-l- fluorobenzene (733mg, 3.28 mmol), ethyl 3-cyclobutyl-3-oxopropanoate (558 mg, 3.28 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.143 mL, 6.56 mmol) in THF (12 mL) at 20 C under air. The resulting mixture was stirred at 80 C for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (20 mL) andsaturated brine (20 mL). The organic layer was dried over MgS04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (649 mg, 63.3 %) as a colourless oil. 1H NMR (400.13 MHz, CDC13) delta 1.08-1.16 (3H, m), 1.66-1.77 (1H, m), 1.80-1.92 (2H, m), 1.98-2.04 (2H, m), 2.16-2.26 (1H, m), 2.97-3.08 (2H, m), 3.25-3.34 (1H, m), 3.62 (1H, t), 4.04-4.10 (2H, m), 6.96 (2H, d), 7.14 (1H, d); m/z (ES) (M-H)- = 311.

References: [1]Patent: WO2011/114148,2011,A1 .Location in patent: Page/Page column 82.

29
[ 192702-01-5 ]
[ 57473-33-3 ]
[ 1366126-78-4 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2230 - 2234.

30
[ 192702-01-5 ]
7,8-dimethoxy-3,4-dihydroisoquinolin-1(2H)-one [ No CAS ]
[ 1421423-89-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydride;	Sodium hydride (9.09 mg, 0.379 mmol) and 4-(bromomethyl)-2-chloro-l- fluorobenzene (0.04 mL, 0.32 mmol) was added to the suspension of 7,8-dimethoxy- 3,4-dihydroisoquinolin-l(2H)-one (60 mg, 0.29 mmol) in THF (2 mL) at rt. The reaction mixture was stirred at rt for 1 hour and quenched by pouring into ice. After extracted by ethyl acetate and washed by brine, the organic phase was dried by sodium sulfate. The extraction was filtered and concentrated. The residue was purified by silica gel column. 2-(3-chloro-4-fluorobenzyl)-7,8-dimethoxy-3,4- dihydroisoquinolin- l(2H)-one (82.7 mg) was afforded in 81 % yield. 1H NMR (500 MHz, CDC13) delta 7.39 (dd, J = 7.0, 1.9 Hz, 1H), 7.23 (ddd, J = 7.8, 4.3, 2.0 Hz, 1H), 7.09 (t, J = 8.7 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 4.72 (s, 2H), 3.99 (s, 3H), 3.88 (s, 3H), 3.40 (t, J = 6.3 Hz, 2H), 2.80 (t, J = 6.3 Hz, 2H). 13C NMR (126 MHz, CDC13) delta 162.89, 157.43 (d, J = 248.3 Hz), 153.00, 150.23, 135.01 (d, J = 3.9 Hz), 131.70, 130.02, 127.73 (d, J = 7.2 Hz), 123.49, 122.11, 121.07 (d, J = 17.9 Hz), 116.70 (d, J = 21.1 Hz), 115.46, 61.55, 56.24, 49.13, 45.60, 28.91. ESI-MS m/z: 350.1 (M+H+).

References: [1]Patent: WO2013/16441,2013,A1 .Location in patent: Page/Page column 72-73.

31
[ 192702-01-5 ]
[ 244194-67-0 ]