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[ CAS No. 192702-01-5 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}

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3d Animation Molecule Structure of 192702-01-5

Chemical Structure| 192702-01-5

Chemical Structure| 192702-01-5

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Quality Control of [ 192702-01-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 192702-01-5 ]

SDS Specification

Alternatived Products of [ 192702-01-5 ]

Product Details of [ 192702-01-5 ]

CAS No. :	192702-01-5	MDL No. :	MFCD01631551
Formula :	C₇H₅BrClF	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GGTQWWTYUKXFPP-UHFFFAOYSA-N
M.W :	223.47	Pubchem ID :	2757542
Synonyms :

Calculated chemistry of [ 192702-01-5 ]

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 :	0.0 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.34
Log Po/w (XLOGP3) :	3.66
Log Po/w (WLOGP) :	3.64
Log Po/w (MLOGP) :	4.1
Log Po/w (SILICOS-IT) :	3.89
Consensus Log Po/w :	3.53

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.91
Solubility :	0.0275 mg/ml ; 0.000123 mol/l
Class :	Soluble
Log S (Ali) :	-3.35
Solubility :	0.1 mg/ml ; 0.000448 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.56
Solubility :	0.0062 mg/ml ; 0.0000277 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.84

Safety of [ 192702-01-5 ]

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

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.

Upstream synthesis route of [ 192702-01-5 ]
Downstream synthetic route of [ 192702-01-5 ]

[ 192702-01-5 ] Synthesis Path-Upstream 1~5

1
[ 161446-90-8 ]
[ 192702-01-5 ]

Reference： [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, # 24, p. 6842 - 6846
[5] Chemical Biology and Drug Design, 2016, p. 97 - 109

2
[ 34328-61-5 ]
[ 192702-01-5 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6842 - 6846
[2] Chemical Biology and Drug Design, 2016, p. 97 - 109

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

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

4
[ 452-84-6 ]
[ 192702-01-5 ]

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

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

Yield	Reaction Conditions	Operation in experiment
97%	at 25 - 45℃; for 5 h;	[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 25°C. The mixture was stirred for an additional 3 hr at 25°C, and then the reaction was heated to 45°C 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, 97percent) was obtained as an oil. ¹H NMR (500 MHz, CHLOROFORM-d) δ 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).

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

[ 192702-01-5 ] Synthesis Path-Downstream 1~88

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

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

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

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

3
[ 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+]

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

4
[ 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+].

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

5
[ 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

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

6
[ 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

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

7
[ 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+)

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

8
[ 192702-01-5 ]
[ 7731-00-2 ]

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

9
[ 452-84-6 ]
[ 192702-01-5 ]

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

10
[ 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

Reference： [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

11
[ 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)

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

12
[ 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).

Reference： [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

13
[ 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.

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

14
[ 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) +.

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

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

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

16
[ 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).

Reference： [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

17
[ 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%).

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

18
[ 192702-01-5 ]
[ 229640-38-4 ]
C₁₉H₁₇ClFNO₅ [ No CAS ]

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

19
[ 1068150-58-2 ]
[ 192702-01-5 ]
[ 1068150-85-5 ]

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

20
[ 1068150-51-5 ]
[ 192702-01-5 ]
[ 1068150-83-3 ]

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

21
[ 915408-37-6 ]
[ 192702-01-5 ]
[ 915409-45-9 ]

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

22
[ 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).

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

23
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

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

24
[ 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).

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

25
[ 73260-12-5 ]
[ 192702-01-5 ]
[ 1240660-16-5 ]

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

26
[ 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.

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

27
[ 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.

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

28
[ 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+).

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

29
[ 192702-01-5 ]
[ 244194-67-0 ]

Reference： [1]Patent: WO2013/79452,2013,A1

30
[ 192702-01-5 ]
[ 1440519-55-0 ]

Reference： [1]Patent: WO2013/79452,2013,A1

31
[ 192702-01-5 ]
[ 1440519-56-1 ]

Reference： [1]Patent: WO2013/79452,2013,A1

32
[ 192702-01-5 ]
[ 1394003-74-7 ]

Reference： [1]Patent: WO2013/79452,2013,A1

33
[ 192702-01-5 ]
[ 1394003-70-3 ]

Reference： [1]Patent: WO2013/79452,2013,A1

34
[ 7677-24-9 ]
[ 192702-01-5 ]
[ 658-98-0 ]

Yield	Reaction Conditions	Operation in experiment
1.7 g	With tetrabutyl ammonium fluoride; In acetonitrile; for 0.5h;Inert atmosphere; Reflux;	To a solution of 4-bromomethyl-2-chloro-l-fluoro-benzene (3.7 g, 16.5 mmol) in CH3CN (30 mL) was added trimethylsilyl cyanide (2.1 mL) and TBAF (4.8 g, 18.4 mmol). The resulting mixture was heated at reflux for 30 min. After cooling of the mixture to room temperature, it was extracted with EtOAc. The organic layer was washed with brine, dried over anhy. Na2S04, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel flash column chromatography to give the title compound (1.7 g, 60.7%) as an oil.

Reference： [1]Patent: WO2013/79452,2013,A1 .Location in patent: Page/Page column 134

35
[ 1354943-40-0 ]
[ 192702-01-5 ]
[ 1354943-10-4 ]

Yield	Reaction Conditions	Operation in experiment
51%	With sodium azide; copper(ll) sulfate pentahydrate; sodium L-ascorbate; In water; butan-1-ol; at 66℃; for 24h;	General procedure: The mixture of N-hydroxyhept-6-ynamide (141 mg, 1 mmol), benzyl bromide (256 mg, 1.5 mmol), sodium azide (98 mg, 1.5 mmol), copper(II) sulfate pentahydrate (38 mg, 0.13 mmol), sodium ascorbate (60 mg, 0.3 mmol) in wate and tert-butanol (v/v = 1:1, 10ml) was heated to 66 oC, the heterogeneous mixture was stirred vigrously for 24 h. After addition of water (50 ml), the mixture was filtered. The filter cake was dissloved in MeOH (20 ml), the insolubles was filtered, the filtrate was concentrated in vacuo and crystallized in ethyl acetate to give 2 (156 mg, 57%) as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3295 - 3299

36
[ 192702-01-5 ]
4-(azidomethyl)-2-chloro-1-fluorobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With sodium azide; In water; acetone; at 55℃; for 15h;	General procedure: To a solution of bromides 8a-8d or commercially available (8-bromooctyl)benzene (7.0 mmol) inacetone (10 mL) and H2O (2.0 mL) was added sodium azide (1.8 g, 28 mmol) and the mixture wasstirred (55 C, 15 h). The reaction was quenched by the addition of H2O, extracted with Et2O and thecombined organic phase was washed with brine, dried (Na2SO4), concentrated and purified by silicagel chromatography to provide the target azides 9a-9d, and 16.

Reference： [1]Molecules,2019,vol. 24
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6842 - 6846
[3]Chemical Biology and Drug Design,2016,p. 97 - 109

37
[ 192702-01-5 ]
N-((1-(3-chloro-4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-5-nitrofuran-2-carboxamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6842 - 6846

38
[ 34328-61-5 ]
[ 192702-01-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6842 - 6846
[2]Chemical Biology and Drug Design,2016,p. 97 - 109

39
[ 192702-01-5 ]
1-(3-chloro-4-fluorobenzyl)-3-(phenylsulfinyl)-5,6-dihydropyridin-2(1H)-on [ No CAS ]

Reference： [1]Patent: WO2014/18449,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

40
[ 192702-01-5 ]
[ 1080623-42-2 ]

Reference： [1]Patent: WO2014/18449,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

41
[ 192702-01-5 ]
[ 1549803-42-0 ]

Reference： [1]Patent: WO2014/18449,2014,A1

42
[ 192702-01-5 ]
[ 865300-86-3 ]

Reference： [1]Patent: WO2014/18449,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

43
[ 192702-01-5 ]
[ 865300-81-8 ]

Reference： [1]Patent: WO2014/18449,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

44
[ 192702-01-5 ]
[ 1374009-23-0 ]

Reference： [1]Patent: WO2014/18449,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

45
[ 192702-01-5 ]
[ 1549803-93-1 ]

Reference： [1]Patent: WO2014/18449,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

46
[ 192702-01-5 ]
[ 1549802-58-5 ]
[ 1549804-10-5 ]

Reference： [1]Patent: WO2014/18449,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

47
[ 192702-01-5 ]
[ 1549802-41-6 ]

Reference： [1]Patent: WO2014/18449,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

48
[ 192702-01-5 ]
[ 1549804-16-1 ]

Reference： [1]Patent: WO2014/18449,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

49
[ 192702-01-5 ]
(S)-(S)-1-((1R,2R,5S)-8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7'-trioxo-7',8',9',10'-tetrahydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridin]-2'(5'H)-yl)propan-2-yl 2,6-bis((tertbutoxycarbonyl)amino)hexanoate [ No CAS ]

Reference： [1]Patent: WO2014/18449,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

50
[ 192702-01-5 ]
[ 1374009-30-9 ]

Reference： [1]Patent: WO2014/18449,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

51
[ 192702-01-5 ]
(1R,5R)-methyl 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7'-trioxo-2',5',7',8',9',10'-hexahydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3imidazo[5,1-a][2,6]naphthyridine]-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/18449,2014,A1

52
[ 192702-01-5 ]
(1R,5R)-methyl 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-1‘,5',7'-trioxo-2',5',7’,8',9',10'-hexahydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine]-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/18449,2014,A1

53
[ 192702-01-5 ]
[ 1549802-93-8 ]
[ 1549802-99-4 ]

Reference： [1]Patent: WO2014/18449,2014,A1

54
[ 192702-01-5 ]
C₂₄H₂₃ClFN₃O₄S [ No CAS ]

Reference： [1]Patent: WO2014/18449,2014,A1

55
[ 192702-01-5 ]
[ 1549803-11-3 ]

Reference： [1]Patent: WO2014/18449,2014,A1

56
[ 192702-01-5 ]
[ 1080623-41-1 ]

Reference： [1]Patent: WO2014/18449,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

57
[ 192702-01-5 ]
2-(N-methylethylamino)methyl-tanshinone I [ No CAS ]
Br^(1-)*C₂₉H₂₆ClFNO₃⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16.9%	In toluene; at 45℃; for 16h;	Example 3: Synthesis of compound BS-TA-50 To a toluene solution (8 mL) of BS-TA-B03 (100 mg, 0.288 mmol) is added <strong>[192702-01-5]4-(bromomethyl)-2-chloro-1-fluorobenzene</strong> (193 mg, 0.864 mmol). The reaction solution is heated up to 45C and stirred for 16 hours. Once the reaction completes, the resulted solid is filtered, and the residue is washed with toluene (5 mL2) and dichloromethane (10 mL2) to give the compound BS-TA-50 (28.06 mg, yield 16.9%) as a green solid.
16.9%	In toluene; at 45℃; for 16h;	10143] To a toluene solution (8 mE) of BS-TA-B03 (100 mg, 0.288 mmol) is added 4-(bromomethyl)-2-chloro-1 -fluorobenzene (193 mg, 0.864 mmol) The reaction solution is heated up to 45 C. and stirred for 16 hours. Once the reaction completes, the resulted solid is filtered, and the residue is washed with toluene (5 mL2) and dichloromethane (10 mL2) to give the compound ES-TA-SO (28.06 mg, yield 16.9%) as a green solid.10144] LC-MS: retention time: 2.53 mm (100%); m/z: 490 (M-Br);10145] ?H NMR (400 Hz, DM50 d-5) oe 9.187 (d, J=8.8 Hz,1H), 8.492 (d, J=8.8 Hz, 1H), 7.902 (t, 2H), 7.677-7.592 (m,3H), 7.502 (d, J=6.8 Hz, 1H), 4.888 (d, J=14.8 Hz, 1H), 4.752(d, J=14.8 Hz, 1H), 4.664 (s, 2H), 3.435 (m, 1H), 3.320 (m,1H), 3.040 (s, 3H), 2.693 (s, 3H), 2.372 (s, 3H), 1.496 (t, 3H).

Reference： [1]Patent: EP2786990,2014,A1 .Location in patent: Paragraph 0114; 0115; 0116
[2]Patent: US2015/126552,2015,A1 .Location in patent: Paragraph 0142; 0143; 0144; 0145

58
[ 192702-01-5 ]
(Z)-ethyl 5-(1-(3-chloro-4-fluorobenzyl)-1H-pyrazol-3-yl)pent-4-enoate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 86,p. 639 - 652

59
[ 192702-01-5 ]
5-(1-(3-chloro-4-fluorobenzyl)-1H-pyrazol-3-yl)pentanoic acid [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 86,p. 639 - 652

60
[ 192702-01-5 ]
C₁₇H₂₀ClFN₂O₂ [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 86,p. 639 - 652

61
[ 192702-01-5 ]
C₁₅H₁₅Cl₂FN₂O [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 86,p. 639 - 652

62
[ 192702-01-5 ]
5-(1-(3-chloro-4-fluorobenzyl)-1H-pyrazol-3-yl)-N-hydroxypentanamide [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 86,p. 639 - 652

63
[ 3920-50-1 ]
[ 192702-01-5 ]
1-(3-chloro-4-fluorobenzyl)-1H-pyrazole-3-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With potassium carbonate; In acetonitrile; at 20℃;	General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent).

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 86,p. 639 - 652

64
[ 1453851-89-2 ]
[ 192702-01-5 ]
1-(3-chloro-4-fluorobenzyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 1976 - 1991

65
[ 192702-01-5 ]
[ 67503-70-2 ]
3-acetyl-1-[(3-chloro-4-fluorophenyl)methyl]quinolin-4(1H)-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 4610 - 4623

66
[ 1043896-74-7 ]
[ 192702-01-5 ]
3-acetyl-8-chloro-1-[(3-chloro-4-fluorophenyl)methyl]quinolin-4(1H)-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 4610 - 4623

67
[ 192702-01-5 ]
[ 1080623-43-3 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

68
[ 192702-01-5 ]
[ 1549802-99-4 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

69
[ 192702-01-5 ]
(1R,5S)-8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-9',10'-dihydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

70
[ 192702-01-5 ]
(1R,2S,5R)-methyl 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-1',5',7'-trioxo-2',5',7',8',9',10'-hexahydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine]-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

71
[ 192702-01-5 ]
(((1R,2R,5S)-8'-(3-chloro-4-fluorobenzyl)-2'-((S)-2-hydroxypropyl)-1',5',7'-trioxo-2',5',7',8',9',10'-hexahydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridin]-6'-yl)oxy)methyl isopropyl carbonate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

72
[ 192702-01-5 ]
(((1R,2S,5R)-8'-(3-chloro-4-fluorobenzyl)-1-(hydroxymethyl)-2'-methyl-1',5',7'-trioxo-2',5',7',8',9',10'-hexahydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridin]-6'-yl)oxy)methyl isopropyl carbonate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

73
[ 192702-01-5 ]
(((1R,5S)-8'-(3-chloro-4-fluorobenzyl)-1',5',7'-trioxo-2'-((S)-2-(phosphonooxy)-propyl)-2',5',7',8',9',10'-hexahydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridin]-6'-yl)oxy)methyl isopropyl carbonate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

74
[ 192702-01-5 ]
(1R,5S)-8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-9',10'-dihydro-1'Hspiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione [ No CAS ]
C₂₂H₁₉ClFN₃O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8154 - 8165

75
[ 192702-01-5 ]
[ 75-31-0 ]
C₁₀H₁₃ClFN [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2129 - 2132

76
[ 192702-01-5 ]
1-(5-(3-((1-(3-chloro-4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone [ No CAS ]

Reference： [1]Chemical Biology and Drug Design,2016,p. 97 - 109

77
[ 192702-01-5 ]
(E)-3-(3-((1-(3-chloro-4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one [ No CAS ]

Reference： [1]Chemical Biology and Drug Design,2016,p. 97 - 109

78
[ 192702-01-5 ]
2-(2-chloro-5-methylpyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one [ No CAS ]
7-(3-chloro-4-fluorobenzyl)-2-(2-chloro-5-methylpyrimidin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		NaH (68.3 mg, 1.71 mmol) was added to 2-(2-chloro-5-methylpyrimidin-4-yl)-6,7- dihydroimidazo[l,2-a]pyrazin-8(5H)-one (Intermediate 48; 150 mg, 0.57 mmol) in DMF (5 mL) at 25C under nitrogen. The resulting solution was then stirred at 25 C for 30 minutes. 4-(bromomethyl)-2-chloro-l-fluorobenzene (254 mg, 1.14 mmol) was added at 25 C and stirring continue for 2 hours. The reaction mixture was quenched with saturated aqueous NaHC03 (25 mL), the resulting precipitate was collected by filtration, washed with water (50 mL) and dried under vacuum to afford 7-(3-chloro-4-fluorobenzyl)-2-(2- chloro-5-methylpyrimidin-4-yl)-6,7-dihydroimidazo[l,2-a]pyrazin-8(5H)-one (Intermediate 48; 292 mg, >100%) as a yellow solid, which was used without further purification. H NMR (400 MHz, DMSO, 20.1 C) delta 2.64 (3H, s), 3.74 - 3.82 (2H, m), 4.35 - 4.43 (2H, m), 4.70 (2H, s), 7.34 - 7.49 (2H, m), 7.60 (1H, ddd), 8.25 (1H, s), 8.61 (1H, s). m/z (ES+), [M+H]+ = 406

Reference： [1]Patent: WO2017/80979,2017,A1 .Location in patent: Page/Page column 129; 130

79
[ 192702-01-5 ]
C₁₇H₁₅NO₄ [ No CAS ]
C₂₄H₂₀ClFNO₄⁽¹⁺⁾*Br^(1-) [ No CAS ]

Reference： [1]Chemical Biology and Drug Design,2018,vol. 91,p. 756 - 762

80
[ 192702-01-5 ]
C₁₆H₁₃NO₃ [ No CAS ]
C₂₃H₁₈ClFNO₃⁽¹⁺⁾*Br^(1-) [ No CAS ]

Reference： [1]Chemical Biology and Drug Design,2018,vol. 91,p. 756 - 762

81
[ 192702-01-5 ]
2-chloro-5-methoxypyrimidin-4-ol [ No CAS ]
C₁₂H₉Cl₂FN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 8h;	The compound 5 (5 g, 31.1 mmol) was dissolved in dichloromethane (50 mL). DIEA (8.2 mL, 46.7 mmol) was added to the solution. The mixture was stirred until dissolved. Then, <strong>[192702-01-5]3-chloro-4-fluorobenzyl bromide</strong> (5.03 mL, 37.4 mmol) was added to the mixture. The mixture was stirred at room temperature for 8 hours. After the mixture was left standing overnight, the precipitated solids were filtered, and dried to give the compound 13 (3.0 g, yield 32%). 1H-NMR (DMSO-d6) delta: 3.70 (s, 3H), 5.29 (s, 2H), 7.32-7.38 (m, 1H), 7.46 (t, 1H, J = 8.9 Hz), 7.64 (1H, dd, J = 7.0, 1.9 Hz), 7.84 (1H, s)

Reference： [1]Patent: EP3287443,2018,A1 .Location in patent: Paragraph 0594; 0595

82
[ 192702-01-5 ]
[ 81477-94-3 ]
(S)-tert-butyl N-(diphenylmethylene)-(3-chloro-4-fluorophenyl)alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With C37H37N2O(1+)*Br(1-); potassium hydroxide; In chloroform; water; toluene; at -40℃; for 72h;	A 10 mL reactiontube was charged with 2 (30 mg, 0.1 mmol), 3,5-dichlorobenzyl bromide (119 mg, 0.5 mmol, 5 equivalent), catalyst 1f (6 mg, 0.01 mmol, 0.1 equivalent) and toluene and CHCl3 (1.5 mL, 2:1 v/v),and the mixture was cooled to 40 C. After the mixture was stirred for 10 min, 50% aq. KOH (28L, 0.1 mmol, 5 equivalent) was added, and the whole reaction mixture was stirred at 40 C for72 h before being allowed to warm to ambient temperature. The reaction was quenched by addingH2O (2 mL), and the resulting mixture was extracted with EtOAc (3 10 mL). The combined extractswere washed with brine (10 mL) and dried (anhydrous Na2SO4), and the crude product was purifiedby flash column chromatography (eluting with hexane/EtOAc, 50:1) to afford 4a (43 mg, 95% yield)as light yellow liquid. 97% ee; []20D 178.8 (c = 1.0, CH2Cl2); 1H-NMR (400 MHz, CDCl3): 7.57 (s,1H), 7.55 (d, J = 1.4 Hz, 1H), 7.40-7.29 (m, 6H), 7.16 (t, J = 1.7 Hz, 1H), 6.95 (d, J = 1.7 Hz, 2H), 6.76(d, J = 6.1 Hz, 2H), 4.12 (dd, J = 8.9, 4.6 Hz, 1H), 3.19-3.08 (m, 2H), 1.45 (s, 9H); 13C-NMR (100 MHz,CDCl3): 171.1, 170.2, 141.7, 139.2, 136.1, 134.4, 130.3, 128.7, 128.6, 128.3, 128.3, 128.0, 127.6, 126.4, 81.6,66.9, 38.9, 28.0; HRMS (ESI, positive): Calcd. for C26H26Cl2NO2 [M + H]+ 454.1335, found: 454.1333.HPLC analysis: Daicel Chiralcel OD-H, n-hexane/isopropanol = 95:5, flow rate = 0.5 mL/min.

Reference： [1]Molecules,2018,vol. 23

83
[ 192702-01-5 ]
[ 81477-94-3 ]
(R)-tert-butyl N-(diphenylmethylene)-(3-chloro-4-fluorophenyl)alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With C37H37N2O(1+)*Br(1-); potassium hydroxide; In chloroform; water; toluene; at -40℃; for 72h;	A 10 mL reactiontube was charged with 2 (30 mg, 0.1 mmol), 3,5-dichlorobenzyl bromide (119 mg, 0.5 mmol, 5 equivalent), catalyst 1f (6 mg, 0.01 mmol, 0.1 equivalent) and toluene and CHCl3 (1.5 mL, 2:1 v/v),and the mixture was cooled to 40 C. After the mixture was stirred for 10 min, 50% aq. KOH (28L, 0.1 mmol, 5 equivalent) was added, and the whole reaction mixture was stirred at 40 C for72 h before being allowed to warm to ambient temperature. The reaction was quenched by addingH2O (2 mL), and the resulting mixture was extracted with EtOAc (3 10 mL). The combined extractswere washed with brine (10 mL) and dried (anhydrous Na2SO4), and the crude product was purifiedby flash column chromatography (eluting with hexane/EtOAc, 50:1) to afford 4a (43 mg, 95% yield)as light yellow liquid. 97% ee; []20D 178.8 (c = 1.0, CH2Cl2); 1H-NMR (400 MHz, CDCl3): 7.57 (s,1H), 7.55 (d, J = 1.4 Hz, 1H), 7.40-7.29 (m, 6H), 7.16 (t, J = 1.7 Hz, 1H), 6.95 (d, J = 1.7 Hz, 2H), 6.76(d, J = 6.1 Hz, 2H), 4.12 (dd, J = 8.9, 4.6 Hz, 1H), 3.19-3.08 (m, 2H), 1.45 (s, 9H); 13C-NMR (100 MHz,CDCl3): 171.1, 170.2, 141.7, 139.2, 136.1, 134.4, 130.3, 128.7, 128.6, 128.3, 128.3, 128.0, 127.6, 126.4, 81.6,66.9, 38.9, 28.0; HRMS (ESI, positive): Calcd. for C26H26Cl2NO2 [M + H]+ 454.1335, found: 454.1333.HPLC analysis: Daicel Chiralcel OD-H, n-hexane/isopropanol = 95:5, flow rate = 0.5 mL/min.

Reference： [1]Molecules,2018,vol. 23

84
[ 192702-01-5 ]
(6S)-4-amino-2-(3-chloro-4-fluorobenzyl)-10-hydroxy-8-ethyl-6-methyl-7,8-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione [ No CAS ]

Reference： [1]Patent: WO2005/110414,2005,A2

85
[ 192702-01-5 ]
(6S)-2-(3-chloro-4-fluorobenzyl)-8-ethyl-10-hydroxy-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 ]

Reference： [1]Patent: WO2005/110414,2005,A2

86
[ 192702-01-5 ]
N'-[(6S)-2-(3-chloro-4-fluorobenzyl)-10-methoxy-8-ethyl-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazin-4-yl]-N,N-dimethylethanimidamide [ No CAS ]

Reference： [1]Patent: WO2005/110414,2005,A2

87
[ 192702-01-5 ]
[ 865300-50-1 ]

Reference： [1]Patent: WO2006/121831,2006,A2
[2]Patent: WO2008/48538,2008,A1
[3]Patent: US2008/280945,2008,A1

88
[ 192702-01-5 ]
11-(3-chloro-4-fluorobenzyl)-9-hydroxy-2-(2-hydroxyethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione [ No CAS ]

Reference： [1]Patent: WO2006/121831,2006,A2

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

Ghs Hazard Statements

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