[ CAS No. 67442-07-3 ] {[proInfo.proName]}

Name: 67442-07-3|2-Chloro-N-methoxy-N-methylacetamide|98%
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Quality Control of [ 67442-07-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 67442-07-3 ]

CAS No. :	67442-07-3	MDL No. :	MFCD00134232
Formula :	C₄H₈ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SCOJKGRNQDKFRP-UHFFFAOYSA-N
M.W :	137.56	Pubchem ID :	2734716
Synonyms :

Calculated chemistry of [ 67442-07-3 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.75
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	30.32
TPSA :	29.54 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.86 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.32
Log Po/w (XLOGP3) :	0.39
Log Po/w (WLOGP) :	0.24
Log Po/w (MLOGP) :	0.42
Log Po/w (SILICOS-IT) :	-0.13
Consensus Log Po/w :	0.45

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.74
Solubility :	25.0 mg/ml ; 0.182 mol/l
Class :	Very soluble
Log S (Ali) :	-0.58
Solubility :	36.5 mg/ml ; 0.265 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.67
Solubility :	29.3 mg/ml ; 0.213 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 67442-07-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302-H312-H332	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 67442-07-3 ]

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

Upstream synthesis route of [ 67442-07-3 ]
Downstream synthetic route of [ 67442-07-3 ]

[ 67442-07-3 ] Synthesis Path-Upstream 1~8

1
[ 6638-79-5 ]
[ 79-04-9 ]
[ 67442-07-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate In tert-butyl methyl ether; water at -5 - 20℃; for 3.5 h;	Example 139 N-methoxy-N-methylchloroacetamide A solution of N,O-dimethylhydroxylamine hydrochloride (200 g, 2.05 mol) and tert-butyl methyl ether (2 L) was added to a cooled (0°C) solution of potassium carbonate (624 g, 4.1 mol) in water (2 L). The mixture was cooled to -5°C and chloroacetyl chloride added such that the temperature remained below 5°C. The vigorously stirred mixture was allowed to warm to room temperature and stirred for an additional 3.5 hours. The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether (3 x 1 L). The combined organic phase was washed with saturated aqueous sodium chloride solution (2 x 1 L), dried (MgSO₄), and concentrated. The residue was dried in vacuo to yield a white solid (257 g, 92percent). Mp 39-40.5°C; ¹H NMR (CDCl₃, 300 MHz) δ 4.24 (s, 2 H), 3.74 (s, 3 H), 3.22 (s, 3 H); MS (CI) 138 (MH⁺); Anal. calcd for C₄H₈ClNO₂: C, 34.92; H, 5.86; N, 10.18. Found: C, 35.06; H, 5.88; N, 10.23.
92%	With potassium carbonate In tert-butyl methyl ether; water	EXAMPLE 139 STR92 N-methoxy-N-methylchloroacetamide A solution of N,O-dimethylhydroxylamine hydrochloride (200 g, 2.05 mol) and tert-butyl methyl ether (2 L) was added to a cooled (0° C.) solution of potassium carbonate (624 g, 4.1 mol) in water (2 L). The mixture was cooled to -5° C. and chloroacetyl chloride added such that the temperature remained below 5° C. The vigorously stirred mixture was allowed to warm to room temperature and stirred for an additional 3.5 hours. The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether (31 L). The combined organic phase was washed with saturated aqueous sodium chloride solution (21 L), dried (MgSO₄), and concentrated. The residue was dried in vacuo to yield a white solid (257 g, 92percent). Mp 39-40.5° C.; ¹ H NMR (CDCl₃, 300 MHz) δ 4.24 (s, 2 H), 3.74 (s, 3 H), 3.22 (s, 3 H); MS (CI) 138 (MH⁺); Anal. calcd for C₄ H₈ ClNO₂: C, 34.92; H, 5.86; N, 10.18. Found: C, 35.06; H, 5.88; N, 10.23.
90%	With potassium carbonate In tert-butyl methyl ether; water at -5 - 0℃; for 2 h;	A 3 L four necked flask equipped with Teflon-blade stirrer, reflux condenser and thermo-pocket was charged with N-methoxymethanamine hydrochloride (345g), water (1 .6 litre) and the resulting reaction mixture was cooled to 0 to -5 °C. Then potassium carbonate (1466 g) was added in lots to the above reaction mixture followed by the addition of methyl tert-butyl ether (1 .4 litre). The chloroacetyl chloride (400 g) was dissolved in tert-butyl methyl ether (0.2 litre) and added dropwise in to the above kept reaction mixture at - 5°C to 0°C and the reaction mixture was stirred for 2 h at 0°C. The reaction mixture was allowed to come to ambient temperature and two phases were separated. The organic layer was dried over sodium sulfate, filtered and evaporated to provide 2-chloro-N-methoxy-N-methyl-acetamide as white solid (440 g, 90percent yield and 98.0percent area purity by HPLC).

Reference： [1] Journal of the American Chemical Society, [2] Journal of the American Chemical Society, 2009, vol. 131, p. 1077 - 1091
[3] European Journal of Organic Chemistry, 2017, vol. 2017, # 27, p. 3917 - 3920
[4] RSC Advances, 2013, vol. 3, # 26, p. 10158 - 10162
[5] Patent: EP1054881, 2008, B1, . Location in patent: Page/Page column 57
[6] Patent: US6051586, 2000, A,
[7] Patent: WO2018/177970, 2018, A1, . Location in patent: Page/Page column 70; 73
[8] Journal of the American Chemical Society, 2010, vol. 132, # 49, p. 17511 - 17515
[9] Journal of the American Chemical Society, 1990, vol. 112, # 19, p. 7001 - 7031
[10] Tetrahedron Letters, 1989, vol. 30, # 29, p. 3779 - 3780
[11] Journal of the American Chemical Society, 2008, vol. 130, # 10, p. 2916 - 2917
[12] Journal of Molecular Structure, 2010, vol. 977, # 1-3, p. 106 - 116
[13] Journal of Organic Chemistry, 2014, vol. 79, # 18, p. 8917 - 8925
[14] Dalton Transactions, 2015, vol. 44, # 45, p. 19464 - 19468
[15] Patent: US2016/83391, 2016, A1, . Location in patent: Paragraph 0595
[16] Angewandte Chemie - International Edition, 2017, vol. 56, # 38, p. 11594 - 11598[17] Angew. Chem., 2017, vol. 129, # 38, p. 11752 - 11756,5

2
[ 79-11-8 ]
[ 1117-97-1 ]
[ 67442-07-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: at 0℃; for 0.166667 h; Stage #2: With phosphorus trichloride In toluene at 20 - 60℃; for 0.5 h;	General procedure: A solution of NHMe(OMe) (0.360 g, 6.0 mmol) and benzoic acid (0.244 g, 2.0 mmol) was stirred in dry toluene (10 mL) at 0 °C for 10 min. A solution of PCl₃ (0.137 g, 1.0 mmol) in dry toluene (2 mL) was then added dropwise to the mixture. The mixture was warmed to r.t. slowly and then stirred at 60 °C for 0.5 h. When the reaction was complete (TLC monitoring), the mixture was cooled to r.t. The mixture was then quenched with sat. NaHCO₃ soln (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (anhyd MgSO₄). The solvent was removed in vacuo.The product was purified by column chromatography (silica gel, petroleum ether–EtOAc, 3:2) to give pure 3a as a colorless oil; yield: 320 mg (97percent).

Reference： [1] Synthesis (Germany), 2014, vol. 46, # 3, p. 320 - 330

3
[ 79-04-9 ]
[ 1117-97-1 ]
[ 67442-07-3 ]

Yield	Reaction Conditions	Operation in experiment
5.1 kg	Stage #1: With potassium carbonate In tert-butyl methyl ether; water at 15 - 20℃; for 0.5 h; Stage #2: at 5 - 20℃;	To a solution of 21.2 kg potassium carbonate K2CO₃ (153.7 mol, 3.0 eq) in 30 L H₂0 was added, Ν,Ο-dimethylhydroxylamine 9 (CAS Reg. No. 1117-97-1) (5.0 kg, 51.3 mol, 1.0 eq) at 15-20 °C. The reaction was stirred at rt for 30min and 30 L methyl tert-butyl ether (TBME) was added. After stirred for 30min, the mixture was cooled to 5°C, and 11.6 kg of 2-Chloroacetyl chloride 8 (CAS Reg. No. 79-04-9 (102.7 mol, 2.0 eq) were added slowly. The reaction was stirred at rt overnight. Organics were separated from aqueous, and aqueous was extracted with TBME (30 L). The combined organics were washed with H₂0 (50 L), brine (50 L) and dried over Na₂S0₄. Filtered and concentrated under vacuum afforded 5.1 kg of 2-chloro-N-methoxy- N-methylacetamide 10 (CAS Reg. No. 67442-07-3) as a white solid.

Reference： [1] Tetrahedron Letters, 1995, vol. 36, # 35, p. 6209 - 6212
[2] Tetrahedron Letters, 1998, vol. 39, # 12, p. 1509 - 1512
[3] Chemical Communications, 2014, vol. 50, # 27, p. 3619 - 3622
[4] Patent: WO2014/140073, 2014, A1, . Location in patent: Page/Page column 10; 25
[5] Patent: WO2014/139882, 2014, A1, . Location in patent: Paragraph 00444-00445
[6] Angewandte Chemie - International Edition, 2015, vol. 54, # 21, p. 6236 - 6240[7] Angew. Chem., 2015, vol. 54, # 21, p. 6334 - 6338

4
[ 1634-04-4 ]
[ 6638-79-5 ]
[ 79-04-9 ]
[ 67442-07-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate In water	EXAMPLE 7 Preparation of N-methoxy-N-methylchloroacetamide (3b). To a cold (0°C), stirred solution of K₂CO₃ (62.4 g, 450 mmol) in H₂O (250 mL) was added, successively, N,O-dimethylhydroxylamine hydrochloride (20 g, 205 mmol) and organic solvent (250 mL, toluene or MTBE). The resulting two phase mixture was cooled to -5°C and chloroacetyl chloride (19.6 ml, 246 mmol) was added over 5 min (solution temperature maintained below 0°C). The vigorously stirred mixture was allowed to warm to 15°C over 30 min, the layers were separated, and the aqueous layer was extracted with organic solvent (3x100 mL, toluene or MTBE). The combined organic extracts were concentrated (MTBE used as solvent) to give the amide 3b (26.8 g, 95percent) as a white solid. Alternatively, the combined organic extracts (toluene used as solvent) were concentrated to 250 mL to effect azeotropic drying (water content 100μg/mL) and the solution of 3b was used directly in reactions with organometallic reagents.

Reference： [1] Patent: EP851850, 2001, B1,

5
[ 6638-79-5 ]
[ 541-88-8 ]
[ 67442-07-3 ]

Reference： [1] Patent: WO2008/21213, 2008, A1, . Location in patent: Page/Page column 148-149

6
[ 1634-04-4 ]
[ 6638-79-5 ]
[ 584-08-7 ]
[ 79-04-9 ]
[ 67442-07-3 ]

Reference： [1] Patent: US5786515, 1998, A,

7
[ 67442-07-3 ]
[ 78191-00-1 ]

Reference： [1] Chemistry - A European Journal, 2005, vol. 11, # 17, p. 4935 - 4952

8
[ 53939-30-3 ]
[ 67442-07-3 ]
[ 136592-00-2 ]

Reference： [1] Organic Process Research and Development, 2010, vol. 14, # 6, p. 1326 - 1336

[ 67442-07-3 ] Synthesis Path-Downstream 1~88

1
[ 67442-07-3 ]
[ 133372-44-8 ]
Isopropylidene Derivative of Methyl 2-(N-Methoxy-N-methylaminocarbonylmethyl)-7,8-exo,exo-dihydroxy-6-exo-(indol-2-yl)-2-azabicyclo<2.2.2>octane-6-endo-carboxylate [ No CAS ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 5673 - 5680

2
[ 67442-07-3 ]
[ 133372-16-4 ]
Methyl 2-(N-Methoxy-N-methylaminocarbonylmethyl)-8,8-dimethoxy-6-exo-(indol-2-yl)-2-azabicyclo<2.2.2>octane-6-endo-carboxylate [ No CAS ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 5673 - 5680

3
[ 6638-79-5 ]
[ 79-04-9 ]
[ 67442-07-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate; In tert-butyl methyl ether; water; at -5 - 20℃; for 3.5h;	Example 139 N-methoxy-N-methylchloroacetamide A solution of N,O-dimethylhydroxylamine hydrochloride (200 g, 2.05 mol) and tert-butyl methyl ether (2 L) was added to a cooled (0°C) solution of potassium carbonate (624 g, 4.1 mol) in water (2 L). The mixture was cooled to -5°C and chloroacetyl chloride added such that the temperature remained below 5°C. The vigorously stirred mixture was allowed to warm to room temperature and stirred for an additional 3.5 hours. The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether (3 x 1 L). The combined organic phase was washed with saturated aqueous sodium chloride solution (2 x 1 L), dried (MgSO4), and concentrated. The residue was dried in vacuo to yield a white solid (257 g, 92percent). Mp 39-40.5°C; 1H NMR (CDCl3, 300 MHz) delta 4.24 (s, 2 H), 3.74 (s, 3 H), 3.22 (s, 3 H); MS (CI) 138 (MH+); Anal. calcd for C4H8ClNO2: C, 34.92; H, 5.86; N, 10.18. Found: C, 35.06; H, 5.88; N, 10.23.
92%	With potassium carbonate; In tert-butyl methyl ether; water;	EXAMPLE 139 STR92 N-methoxy-N-methylchloroacetamide A solution of N,O-dimethylhydroxylamine hydrochloride (200 g, 2.05 mol) and tert-butyl methyl ether (2 L) was added to a cooled (0° C.) solution of potassium carbonate (624 g, 4.1 mol) in water (2 L). The mixture was cooled to -5° C. and chloroacetyl chloride added such that the temperature remained below 5° C. The vigorously stirred mixture was allowed to warm to room temperature and stirred for an additional 3.5 hours. The phases were separated and the aqueous phase was extracted with tert-butyl methyl ether (31 L). The combined organic phase was washed with saturated aqueous sodium chloride solution (21 L), dried (MgSO4), and concentrated. The residue was dried in vacuo to yield a white solid (257 g, 92percent). Mp 39-40.5° C.; 1 H NMR (CDCl3, 300 MHz) delta 4.24 (s, 2 H), 3.74 (s, 3 H), 3.22 (s, 3 H); MS (CI) 138 (MH+); Anal. calcd for C4 H8 ClNO2: C, 34.92; H, 5.86; N, 10.18. Found: C, 35.06; H, 5.88; N, 10.23.
90%	With potassium carbonate; In tert-butyl methyl ether; water; at -5 - 0℃; for 2h;	A 3 L four necked flask equipped with Teflon-blade stirrer, reflux condenser and thermo-pocket was charged with N-methoxymethanamine hydrochloride (345g), water (1 .6 litre) and the resulting reaction mixture was cooled to 0 to -5 °C. Then potassium carbonate (1466 g) was added in lots to the above reaction mixture followed by the addition of methyl tert-butyl ether (1 .4 litre). The chloroacetyl chloride (400 g) was dissolved in tert-butyl methyl ether (0.2 litre) and added dropwise in to the above kept reaction mixture at - 5°C to 0°C and the reaction mixture was stirred for 2 h at 0°C. The reaction mixture was allowed to come to ambient temperature and two phases were separated. The organic layer was dried over sodium sulfate, filtered and evaporated to provide 2-chloro-N-methoxy-N-methyl-acetamide as white solid (440 g, 90percent yield and 98.0percent area purity by HPLC).

With potassium carbonate; In water; at -5 - 20℃; for 2h;

2-Chloro-N-methoxy-N-methylacetamide To a solution of potassium carbonate (93 g, 750 mmol) in H2O (300 mL) was added N,O-dimethylhydroxylamine hydrochloride (30 g, 300 mmol) at 0° C. The mixture was further cooled to -5° C., and 2-chloroacetyl chloride (40.6 g, 360 mmol) was added. The solution was stirred at room temperature for 2 h. The aqueous mixture was extracted with toluene (3*300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give the crude product (35 g, 85percent) as a white solid. LC/MS: m/e=138 (M+H)+.

Reference： [1]Journal of the American Chemical Society,2009,vol. 131,p. 1077 - 1091
[2]European Journal of Organic Chemistry,2017,vol. 2017,p. 3917 - 3920
[3]RSC Advances,2013,vol. 3,p. 10158 - 10162
[4]Patent: EP1054881,2008,B1 .Location in patent: Page/Page column 57
[5]Patent: US6051586,2000,A
[6]Patent: WO2018/177970,2018,A1 .Location in patent: Page/Page column 70; 73
[7]Journal of the American Chemical Society,2010,vol. 132,p. 17511 - 17515
[8]Journal of the American Chemical Society,1990,vol. 112,p. 7001 - 7031
[9]Tetrahedron Letters,1989,vol. 30,p. 3779 - 3780
[10]Journal of the American Chemical Society,2008,vol. 130,p. 2916 - 2917
[11]Journal of Molecular Structure,2010,vol. 977,p. 106 - 116
[12]Journal of Organic Chemistry,2014,vol. 79,p. 8917 - 8925
[13]Dalton Transactions,2015,vol. 44,p. 19464 - 19468
[14]Patent: US2016/83391,2016,A1 .Location in patent: Paragraph 0595
[15]Angewandte Chemie - International Edition,2017,vol. 56,p. 11594 - 11598
Angew. Chem.,2017,vol. 129,p. 11752 - 11756,5

4
[ 67442-07-3 ]
[ 603-35-0 ]
[ 129986-67-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	In acetonitrile; at 80℃; for 20h;	Step 1: N-Methoxy-N-methyl-2-(triphenyl-15-phosphanylidene)acetamide A mixture of (<strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (13.7 g, 0.1 mol) and triphenylphosphane (26.2 g, 0.1 mol) in acetonitrile (200 mL) was heated to 80° C. and held for 20 h. The mixture was cooled and concentrated to remove the solvent below 40° C. The residue was dissolved in dichloromethane (200 mL), followed by 2 N KOH (100 mL). The resulting mixture was stirred at 20° C. for 1 h. Phase separation, the organic layer was washed with brine (200 mL*3), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to afford N-methoxy-N-methyl-2-(triphenyl-15-phosphanylidene) acetamide (36 g, 0.1 mol, 98percent) as a yellow solid. ESI-MS (EI+, m/z): 364.4 [M+H]+.
98%	In acetonitrile; at 80℃; for 20h;	A mixture of (<strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (13.7 g, 0.1 mol) and triphenylphosphane (26.2 g, 0.1 mol) in acetonitrile (200 mL) was heated to 80 °C and held for 20 h. The mixture was cooled and concentrated to remove the solvent below 40 °C. The residue was dissolved in dichloromethane (200 mL), followed by 2 N KOH (100 mL). The resulting mixture was stirred at 20 °C for lh. Phase separation, the organic layer was washed with brine (200 mL*3), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to afford N-methoxy-N-methyl-2-(triphenyl-15-phosphanylidene) acetamide (36 g, 0.1 mol, 98percent) as a yellow solid. ESI-MS (EI, m/z): 364.4 [M+H] .
	In acetonitrile; for 18h;Heating / reflux;	Synthesis of ylide 21. To a solution of N-methoxy-N-methylhydroxylamine hydrochloride (48.52 g, 500 mmol, 1.0 equiv) in CH2Cl2 (1.0 L) at 0°C were added pyridine (80.63 mL, 1.0 mol) and chloroacetic anhydride (85.14 g, 500 mmol, 1.0 equiv). The resulting mixture was stirred for 15 min at 00C, then warm up to 23°C and stirred overnight. The reaction mixture was then poured carefully into sat. NaHCpsi3aq solution (1.0 L) and stirred 1 hour, after which the layers were separated, the aqueous phase was extracted with CHaCl2 (400 mL) and the combined organic layers were washed with IN HCl (200 mL x 2), brine (200 mL x 2), dried over Na2SO4 (10 g) and filtered. Evaporation of the solvents under reduced pressure afforded the corresponding acetamide (N-rnethoxy-N-methyl acetamide-2-chloride) as a green oil which was used in the next step without further purification. To a solution of this acetamide in CH3CN (800 mL) was added Ph3P (107.98 g, 411.7 mmol, 0.82 equiv) and the resulting mixture was refluxed for 18 hours. Then the solvents were removed under vacuum and the resulting viscous oil was dissolved in CH2Cl2 (1.0 L), washed with 2N KOH (400 mL x 2), brine (400 mL) and dried over Na2SO4 (10.0 g). Filtration and evaporation of the solvents under reduced pressure afforded ylide 21 as a thick oil which solidified by standing (146.5 g, 80percent over two steps). This compound was used in the next step without further purification. Rf = 0.85 (Hexane/EtOAc 3/1); 1H NMR (CDCl3, 400 MHz, 25 0C) 57.71-7.65 (m, 6H), 7.55-7.50 (m, 3H), 7.48-7.42 (m, 6H), 3.74 (s, 3H), 3.08 (s, 3H), 1.86 (s, IH); 13C NMR <n="150"/>(CDCl3, 100 MHz, 25 0C) 133.3 (x 3), 133,2 (x 3), 131.9 (x 3), 128.9 (x 3), 128.8 (x 3), 127.9, 61.3, 35.9.

In toluene; at 20℃; for 15h;

Dissolve N-methyl-N'-methoxy-chloroacetamide (132 g, 959 mmol) and triphenylphosphine (239 g, 911mmol) in toluene, stir at room temperature for 15 hours, and wash with 2N aqueous potassium hydroxidesolution ( 1L*2), washed with brine, dried over anhydrous sodium sulfate and evaporated

Reference： [1]Patent: US2017/114080,2017,A1 .Location in patent: Paragraph 0505
[2]Patent: WO2018/200625,2018,A1 .Location in patent: Paragraph 00397; 00398; 00399; 00548; 00549; 00550
[3]Journal of the American Chemical Society,1990,vol. 112,p. 7001 - 7031
[4]European Journal of Organic Chemistry,2017,vol. 2017,p. 3917 - 3920
[5]Patent: WO2008/21213,2008,A1 .Location in patent: Page/Page column 148-149
[6]Patent: CN108658956,2018,A .Location in patent: Paragraph 0165; 0166

5
[ 67442-07-3 ]
[ 122-52-1 ]
[ 124931-12-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	at 100℃; for 18h;	A solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (2.48 g,17.7 mmol) and triethyl phosphite (3.00 mL, 17.7 mmol) was heated to 100 °C for 18 h. The crude product was purified by flash column chromatography (0?2percent MeOH in CH2Cl2) to give 1 as a colorless oil; yield: 3.31 g (13.8 mmol; 78percent); Rf = 0.42 (2percent MeOH in CH2Cl2); HPLC purity (method b): >95percent (210 nm), >95percent (254 nm). IR (ATR): 2985, 2940, 2908, 1659, 1381, 1253, 1050, 1020, 998, 961 cm?1. 1H NMR (400 MHz, CDCl3): delta = 4.26?4.07 (m, 4 H, 2 × OCH2CH3), 3.76(s, 3 H, OCH3), 3.20 (s, 3 H, NCH3), 3.15 (d, J = 22.1 Hz, 2 H, 1-H), 1.33(td, J = 7.1, 0.6 Hz, 6 H, 2 × OCH2CH3). 13C NMR (101 MHz, CDCl3): delta = 166.2 (C-2), 62.7 (2 × OCH2CH3), 61.6(OCH3), 32.3 (NCH3), 30.9 (C-1), 16.5 (2 × OCH2CH3). HRMS (ESI): m/z [M + H]+ calcd for C8H19NO5P+: 240.0995; found: 240.0996.

Reference： [1]Tetrahedron Letters,1992,vol. 33,p. 1957 - 1958
[2]Synthesis,2019,vol. 51,p. 757 - 768
[3]Tetrahedron Letters,1989,vol. 30,p. 3779 - 3780

6
[ 67442-07-3 ]
[ 40248-84-8 ]
[ 853645-32-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 23℃;	Hepta-2,6-dienoic acid methoxy-methyl-amide (2-114): To a solution of 2-chloro-.V-methoxy- //-methylacetamide (6.0 g, 48.8 mmol) in dry DMF (20 mL) at 23 0C was added 3- mercaptophenol (4.44 mL, 48.8 mmol) and K2CO3 (6.7 g, 48.8 mmol). The resulting suspension was stirred at 23 0C overnight. After this period of time, Merrifield resin (24 g, < 2 mmol.g"1, < 48.8 mmol) was added to the mixture followed by K2CO3 (11.4 g, 83.0 mmol) as well as TBAI (catalytic amount), and the suspension was heated up to 50 0C. After 12 hours at this temperature, the resin was filtered and washed several times: HClaq. (50 mL), MeOH (50 mL), CH2Cl2 (50 mL) and Et2O (50 mL). The resin was dried under reduced pressure to constant mass of 29.2 g. The final mass gain (5.2 g, 27.3 mmol) indicated an estimate loading of 0.81 mmol.g"1. Resin 2-49 (10 g, 0.81 mmol.g"1) was suspended in a 1:1 mixture of HFIEVCH2Ch (50 mL). To this suspension, H2O2 (3 mL, 16.0 mmol) was added at 23 0C and the resulting mixture was shaken for 12 h. Resin 2-113 was then filtered, washed using MeOH (50 mL), CH2Cl2 (50 mL) and Et2O (50 mL) and dried under reduced pressure to constant mass before subsequent use. Resin 2-113 (4.0 g, < 0.81 mmol.g"1) was suspended in DMSO (40 mL) followed by the addition of ?BuOK (336 mg, 3.0 mmol). After shaking the reaction for 1 h at room temperature, 5-iodo-l-pentene (588 mg, 3.0 mmol) was added to the suspension and the mixture was shaken for 3 h. The resin was filtered, washed and dried as before. Then, it was suspended in toluene and heated at 80 0C. After 8 h at this temperature, <n="171"/>the resin was filtered and washed several times with more toluene. The combined toluene solutions were evaporated giving pure compound 2-114 as a colourless oil (321 mg, 77 percent) of 95 percent purity judged by NMR. 1H NMR (400 MHz, CDCl3, 25 0C): delta = 6.94 (dt, / = 15.7, 6.7 Hz, IH), 6.39 (d, J = 15.2 Hz, IH), 5.84-5.74 (m, IH), 5.02 (dd, J = 17.4, 1.7 Hz, IH), 4.97 (d, J = 10.1 Hz, IH), 3.67 (s, 3H), 3.21 (s, 3H), 2.34-2.29 (m, 2H), 2.23-2.18 (m, 2H); 13C NMR (100 MHz, CDCl3, 25 0C): 6 = 166.8, 146.7, 137.3, 119.1, 115.3, 61.6, 32.3, 31.7, (one carbon is not detected); LR. (film): Vm3x = 2934, 1681 , 1638, 1378, 1179 cm"1.

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 6999 - 7004
[2]Patent: WO2008/21213,2008,A1 .Location in patent: Page/Page column 96; 169-170

7
[ 109-09-1 ]
[ 67442-07-3 ]
[ 55484-10-1 ]

Reference： [1]Tetrahedron Asymmetry,2006,vol. 17,p. 2154 - 2182

8
[ 109-04-6 ]
[ 67442-07-3 ]
[ 55484-10-1 ]

Reference： [1]Tetrahedron Asymmetry,2006,vol. 17,p. 2154 - 2182
[2]Organic process research and development,2010,vol. 14,p. 1326 - 1336

9
[ 20416-16-4 ]
[ 67442-07-3 ]
[ 908238-76-6 ]

Reference： [1]Organic Letters,2006,vol. 8,p. 3367 - 3370

10
[ 67442-07-3 ]
[ 1666-13-3 ]
[ 867367-67-7 ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 4935 - 4952

11
[ 867367-88-2 ]
[ 67442-07-3 ]
[ 24850-33-7 ]
2,4-Bis-ethoxymethoxy-6-((E)-2-oxo-hexa-3,5-dienyl)-benzoic acid 2-trimethylsilanyl-ethyl ester [ No CAS ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 4935 - 4952

12
[ 867367-88-2 ]
[ 67442-07-3 ]
[ 24850-33-7 ]
[ 378749-88-3 ]
2,4-Dihydroxy-6-((E)-2-oxo-hexa-3,5-dienyl)-benzoic acid (R)-1-methyl-2-((2R,3R)-3-vinyl-oxiranyl)-ethyl ester [ No CAS ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 4935 - 4952

13
[ 67442-07-3 ]
[ 24850-33-7 ]
(E)-N-methoxy-N-methylpenta-2,4-dienamide [ No CAS ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 4935 - 4952

14
[ 67442-07-3 ]
[ 24850-33-7 ]
[ 95091-90-0 ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 4935 - 4952

15
[ 67442-07-3 ]
[ 78191-00-1 ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 4935 - 4952

16
[ 67442-07-3 ]
[ 1066-54-2 ]
[ 18245-82-4 ]

Reference： [1]Journal of Organic Chemistry,2006,vol. 71,p. 5031 - 5034

17
[ 75-18-3 ]
[ 67442-07-3 ]
[(methoxy-methyl-carbamoyl)-methyl]-dimethyl-sulfonium; chloride [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2006,vol. 45,p. 6021 - 6024

18
[ 67442-07-3 ]
[ 2186-92-7 ]
[ 905927-08-4 ]

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 8734 - 8735
[2]Chemistry - A European Journal,2008,vol. 14,p. 1654 - 1665

19
[ 67442-07-3 ]
[ 149-30-4 ]
[ 908863-60-5 ]

Reference： [1]European Journal of Organic Chemistry,2006,p. 2851 - 2855

20
[ 6638-79-5 ]
[ 541-88-8 ]
[ 67442-07-3 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; at 0 - 23℃;	Synthesis of ylide 21. To a solution of N-methoxy-N-methylhydroxylamine hydrochloride (48.52 g, 500 mmol, 1.0 equiv) in CH2Cl2 (1.0 L) at 0°C were added pyridine (80.63 mL, 1.0 mol) and chloroacetic anhydride (85.14 g, 500 mmol, 1.0 equiv). The resulting mixture was stirred for 15 min at 00C, then warm up to 23°C and stirred overnight. The reaction mixture was then poured carefully into sat. NaHCpsi3aq solution (1.0 L) and stirred 1 hour, after which the layers were separated, the aqueous phase was extracted with CHaCl2 (400 mL) and the combined organic layers were washed with IN HCl (200 mL x 2), brine (200 mL x 2), dried over Na2SO4 (10 g) and filtered. Evaporation of the solvents under reduced pressure afforded the corresponding acetamide (N-rnethoxy-N-methyl acetamide-2-chloride) as a green oil which was used in the next step without further purification. To a solution of this acetamide in CH3CN (800 mL) was added Ph3P (107.98 g, 411.7 mmol, 0.82 equiv) and the resulting mixture was refluxed for 18 hours. Then the solvents were removed under vacuum and the resulting viscous oil was dissolved in CH2Cl2 (1.0 L), washed with 2N KOH (400 mL x 2), brine (400 mL) and dried over Na2SO4 (10.0 g). Filtration and evaporation of the solvents under reduced pressure afforded ylide 21 as a thick oil which solidified by standing (146.5 g, 80percent over two steps). This compound was used in the next step without further purification. Rf = 0.85 (Hexane/EtOAc 3/1); 1H NMR (CDCl3, 400 MHz, 25 0C) 57.71-7.65 (m, 6H), 7.55-7.50 (m, 3H), 7.48-7.42 (m, 6H), 3.74 (s, 3H), 3.08 (s, 3H), 1.86 (s, IH); 13C NMR <n="150"/>(CDCl3, 100 MHz, 25 0C) 133.3 (x 3), 133,2 (x 3), 131.9 (x 3), 128.9 (x 3), 128.8 (x 3), 127.9, 61.3, 35.9.

Reference： [1]Patent: WO2008/21213,2008,A1 .Location in patent: Page/Page column 148-149

21
[ 67442-07-3 ]
[ 1007583-17-6 ]
[ 1007583-19-8 ]

Yield	Reaction Conditions	Operation in experiment
22%; 17%		Step 1: 4-Bromo-5-(chloroacetyl)thiophene-2-carbonitrile Butyllithium (2.5 M solution in hexanes; 14.5 mL, 36.3 mmol) was added under nitrogen over approximately 5 min to a solution of 4-bromo-thiophene-2-carbonitrile (5.95 g, 31.6 mmol) in 300 mL of anhydrous tetrahydrofuran at dry ice-acetone temperature. After the addition, the reaction was stirred at dry ice-acetone temperature for 30 min. 2-Chloro-N-methoxy-N-methyl acetamide (4.80 g, 32.7 mmol) in 40 mL of anhydrous tetrahydrofuran was then added dropwise over 30 min. After the addition, the reaction was stirred at dry ice-acetone temperature for 4 h. 6 M HCl (36 mL) was added and the reaction allowed to warm to room temperature. The reaction was concentrated under reduced pressure to remove the tetrahydrofuran. The residue was partitioned between ethyl acetate and water. Saturated sodium chloride was added to aid in the separation of an emulsion. The organic layer was separated, washed with water, saturated sodium chloride, dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified on 800 g of silica gel (230-400 mesh) using a gradient of 30percent methylene chloride in hexane to 60percent methylene chloride in hexane as the eluent. Isolation of the major component gave 4-bromo-5-(chloroacetyl)thiophene-2-carbonitrile (1.81 g, 22percent) as a white solid, mp 126-128° C.; MS (ESI) m/z 262. Isolation of a minor component gave 4-(chloroacetyl)thiophene-2-carbonitrile (1.02 g, 17percent) as a light yellow solid, mp 94-98° C.; MS (ESI) m/z 184.

Reference： [1]Patent: US2008/45556,2008,A1 .Location in patent: Page/Page column 26-27

22
[ 6052-79-5 ]
[ 67442-07-3 ]
[ 945656-70-2 ]

Reference： [1]Organic Letters,2007,vol. 9,p. 2713 - 2716
[2]Journal of the American Chemical Society,2009,vol. 131,p. 1077 - 1091
[3]Journal of the American Chemical Society,2008,vol. 130,p. 2916 - 2917

23
[ 945656-64-4 ]
[ 67442-07-3 ]
[ 945656-65-5 ]

Reference： [1]Organic Letters,2007,vol. 9,p. 2713 - 2716

24
[ 228710-82-5 ]
[ 67442-07-3 ]
[ 228710-83-6 ]

Yield	Reaction Conditions	Operation in experiment
67%	With n-butyllithium; In tetrahydrofuran; hexanes; at -78℃; for 1.2h;	To a solution of bromo pyridine from example 38 (2g, 8. 0mmol) at-78°C, in dry THF (30ml), was added butyllithium (2.5M in hexanes) (3. 5ml 8. 8MMOL), dropwise over 20 minutes. The reaction mixture was stirred for 30 minutes +, HEN <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (1.2g, 8. 8MMOL) in dry THF (20ml) was added dropwise keeping the temperature AT-78°C. Stirring was continued for 30 minutes at this temperature before 1 M HCI (aq) (50ml) was added and the reaction mixture warmed to room temperature. The organic layer was separated and the aqueous layer washed with ethyl acetate (56ml). The organic layers were combined then washed with 3M NAOH (aq) (1 OML) and brine (20ml) before being dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give crude title compound as a brown oil (1.34g, 5. 4mmol, 67percent). 1H NMR (CDCI3, 400MHZ) 6 : 2.20 (s, 6H), 4.68 (s, 2H), 5.92 (s, 2H), 7.32 (d, 1 H), 8.38 (d, 1 H), 9.16 (s, 1 H). LRMS: m/z 249 (M-H+).
67%		To a solution of bromo pyridine from example 38 (2g, delta.Ommol) at -780C, in dry THF (30ml), was added butyllithium (2.5M in hexanes) (3.5ml 8.8mmol), dropwise over 20 minutes. The reaction mixture was stirred for 30 minutes then <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (1.2g, 8.8mmol) in dry THF (20ml) was added dropwise keeping the temperature at -780C. Stirring was continued for 30 minutes at this temperature before 1 M HCI (aq) (50ml) was added and the reaction mixture warmed to room temperature. The organic layer was separated and the aqueous layer washed with ethyl acetate (50ml). The organic layers were combined then washed with 3M NaOH (aq) (10ml) and brine (10ml) before being dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give crude title compound as a brown oil (1.34g, 5.4mmol, 67percent). 1H NMR (CDCI3, 400MHz) delta: 2.20 (s, 6H), 4.68 (s, 2H), 5.92 (s, 2H), 7.32 (d, I H), 8.38 (d, 1 H), 9.16 (s, 1 H). LRMS: m/z 249 (M-H+).
		Example 140 2-Chloro-1-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-3-yl]-ethanone Magnesium turnings (7.26 g, 0.30 mol) were placed in 2 L three neck flask equipped with a dropping funnel and reflux condenser. The system was purged with argon and heated for ten minutes. After cooling the flask to room temperature under argon, tetrahydrofuran (500 mL) and a crystal of iodine were added. A portion of a solution of 5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine (Example 138; 75 g, 0.30 mol) in tetrahydrofuran (200 mL) was added to initiate the reaction. The flask was heated to maintain reflux as the remainder of the solution was added. After three hours the mixture was cooled in an ice-water bath. A solution of N-methoxy-N-methylchloroacetamide (Example 139; 49.3 g, 0.35 mol) in tetrahydrofuran (200 mL) was transferred to the suspension via cannula. The mixture was warmed to ambient temperature. After 18 hours the mixture was quenched with two-thirds saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3x). The combined organic phase was dried (MgSO4) and concentrated to an oil. Silica gel chromatography (75:25 hexane / ethyl acetate) afforded an oil (67 g). The oil was a 7:3 mixture of the title compound and 2-(2,5-dimethyl-pyrrol-1-yl)-pyridine. 1H NMR (CDCl3, 300 MHz; peaks corresponding to the title compound) delta 9.16 (dd, 2.6 Hz, 0.7 Hz, 1 H), 8.40 (dd, 8.5 Hz, 2.6 Hz, 1 H), 7.35 (dd, 8.5 Hz, 0.7 Hz, 1 H), 5.96 (s, 2 H), 4.71 (s, 2 H), 2.21 (s, 6 H); Rf = 0.2 (5:1 hexane / ethyl acetate).

		A solution of 2.5 M n-butyl lithium in hexane (35ml, 87.6mmol) was added to a solution of the bromide from preparation 50 (20.0g, 79.7mmol) in terf-butyl methylether (300ml) at -78°C under nitrogen over a 10 minutes. The reaction was stirred for a further 10 minutes and <strong>[67442-07-3]2-chloro-N-methoxy-N-methyl-acetamide</strong> (12.1g, 87.6mmol) in ferf-butyl methylether (40ml) was added slowly. The reaction was stirred at -78°C for 20 minutes and then 1M hydrochloric acid (200ml) was added. The mixture was allowed to warm to room temperature, stirred for 2 hours and the organic phase separated. The aqueous phase was extracted with te/f-butyl methylether and the combined organic extracts were washed with water (100ml), saturated aqueous sodium chloride (100ml) and 1M sodium hydroxide (100ml). The organic phase was dried (sodium sulfate), concentrated in vacua and the residual oil purified by flash column chromatography on silica gel eluting with pentane:dichloromethane:methanol (75:25:0 changing tp 0:99:1, by volume). Recrystallisation (pentane:dichloromethane) gave the title compound as a yellow solid (11.97g).
		A solution of 2.5 M n-butyl lithium in hexanes (35ml, 87.6mmol) was added to a solution of the bromide from preparation 29 (20.0g, 79.7mmol) in ferf-butyl methylether (300ml) at -78°C under nitrogen over 10 minutes. The reaction was stirred for a further 10 minutes and <strong>[67442-07-3]2-chloro-N-methoxy-N-methyl-acetamide</strong> (12.1g, 87.6mmol) in terf-butyl-methylether (40ml) was added slowly. The reaction was stirred at -78°C for 20 minutes and then 1M hydrochloric acid (200ml) was added. The mixture was allowed to warm to room temperature, stirred for 2 hours and the organic phase separated. The aqueous phase was extracted with fe/f-butyl methylether and the combined organic extracts were washed with water (100ml), saturated aqueous sodium chloride (100ml) and 1M sodium hydroxide (100ml). The organic phase was dried (sodium sulfate), concentrated in vacua and the residual oil purified by flash column chromatography on silica gel eluting with pentane:dichloromethane:methanol (75:25:0 changing to 0:99:1, by volume). The residue was recrystallised from pentane:dichloromethane to give the title compound as a yellow solid.1H NMR (400MHz, CDCI3): 5 = 9.11 (1H, s), 8.34-8.33 (1H, d), 7.32-7.30 (1H,d), 5.91 (2H, s), 4.66 (2H, s), 2.17 (6H, s) ppm.LRMS (electrospray): m/z [M-H]+ 247.

Reference： [1]Organic Process Research and Development,2004,vol. 8,p. 587 - 592
[2]Patent: WO2004/52372,2004,A1 .Location in patent: Page 86
[3]Patent: WO2008/87512,2008,A1 .Location in patent: Page/Page column 52
[4]Patent: EP1054881,2008,B1 .Location in patent: Page/Page column 57
[5]Patent: WO2004/108675,2004,A1 .Location in patent: Page 96
[6]Patent: WO2004/108676,2004,A1 .Location in patent: Page 131-132

25
N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide [ No CAS ]
[ 67442-07-3 ]
N-(4-chlorobenzyl)-2-(hydroxymethyl)-4-{2-[methoxy(methyl)amino]-2-oxoethyl}-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 48h;	[0541] A mixture of N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.288 mmol), potassium carbonate (60 mg, 0.43 mmol) and <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (200 mg) in DMF (1.5 mL) was shaken at room temp. for 48 hrs. The mixture was diluted with water (5 mL), and the resulting solid was collected by filtration. The crude solid was recrystallized from aq. ethanol to afford title compound (90 mg). The title compound is also a compound of formula I. [0542] Physical characteristics are as follows: [0543] 1H NMR (400 MHz, DMSO-d6) delta) 10.45 (1H), 8.73 (1H), 7.37 (4H); 7.26 (1H), 5.91 (1H), 5.47 (2H), 4.74 (2H), 4.54 (2H), 3.86 (3H), 3.16 (3H); HPLC ret time=2.86 min; MS (ES+) m/z 450, 452.

Reference： [1]Patent: US2004/138449,2004,A1 .Location in patent: Page 22

26
C₁₇H₂₃Cl₂N₃O₄S₂Si [ No CAS ]
[ 67442-07-3 ]
[ 808139-27-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 1h;	The product from Example 15 step a) (4 g) was dissolved in dry THF (25 ml) under anatmosphere of nitrogen and treated with a 1 M solution of potassium fert-butoxide in THF(10 ml), added dropwise. After stirring for 30 min the reaction was treated with a saturatedsolution of ammonium chloride ( 20 ml) followed by 2M HC1 (100 ml) and extracted intoethyl acetate ( 200 ml). The ethyl acetate extract was washed with water ( 2 xlOO ml),brine (100 ml), dried (MgSO4) and evaporated to leave a gum (3.5 g). This was dissolvedin dry THF (25 ml) and treated with a 1 M solution of potassium tert-butoxide in THF (5ml) and 2-chloro-JV-methoxy-7V-methyl-acetamide (1 g) added as a solution in THF (5 ml).The mixture was stirred at ambient temperature for 1 hr and partitioned between ethylacetate (200 ml) and 2 M HC1 (100 ml). The ethyl acetate extract was washed with water (2 xlOO ml), brine (100 ml), dried (MgSO4) and evaporated to give the sub-titled compoundas a yellow gum (3.32 g).JH NMR (CDC13) 5 7.98 (1H, dd), 7.94 (1H, s), 7.66 (1H, dd), 7.24 (1H, m), 5.21 (2H, s),4.14 (2H, s), 3.87 (3H, s), 3.79 (2H, t), 3.76 (3H, s), 3.22 (3H, s),0.87 (2H, t), 0.00 (9H, s).

Reference： [1]Patent: WO2004/108692,2004,A1 .Location in patent: Page 45-46

27
[ 67442-07-3 ]
2-chloro-1-quinolin-8-yl-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of n-BuLi (28 mL, 44.0 mmol, 1.6M in hexanes) at -78° C. was added a solution of 8-bromoquinoline (8.5 g, 40.0 mmol) in Et2O (60 mL) over 20 minutes. After stirring for 22 minutes, a solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (5.7 g, 41 mmol) in THF (35 mL) was added over 12 minutes (see Tillyer, R. et al; Synlett 225-226, 1996; and Dolling, U. H. et al; U.S. Pat. No. 5,786,515). After 3 hours the reaction was poured into 11 mL, 4N HCl. The aqueous phase was neutralized to pH 7 using solid NaHCO3 and partitioned with Et2O (2.x.100 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. Purification via SiO2 chromatography (20percent EtOAc/hexanes) afforded the product as a yellow solid (4.2 g). 1H NMR (300 Hz, CDCl3) delta 9.0-8.96 (m, 1H), 8.26-8.19 (m, 2H), 8.04-8.01 (m, 1H), 7.68-7.63 (m, 1H), 7.52-7.48 (m, 1H), 5.37 (s, 2H).
		To a solution of n-BuLi (28 ML, 44.0 mmol, 1.6M in hexanes) at-78 °C was added a solution of 8-bromoquinoline (8.5 g, 40.0 mmol) in ET20 (60 mL) over 20 minutes. After stirring for 22 minutes, a solution of 2-chloro-N-methoxy-N- methylacetamide (5.7 g, 41 mmol) in THF (35 mL) was added over 12 minutes (see Tillyer, R. et al; Synlett 225-226,1996 ; and Dolling, U. H. et al; US 5786515). After 3 hours the reaction was poured into 11 mL, 4N HC1. The aqueous phase was neutralized to pH 7 using solid NAHCO3 and partitioned with ET20 (2 x 100 mL). The combined organic phase was washed with brine (50 mL), dried over NA2SO4 and concentrated in vacuo. Purification via SI02 chromatography (20percent ETOAC/HEXANES) afforded the product as a yellow solid (4.2 g). 1H NMR (300 Hz, CDC13) 8 9.0-8. 96 (m, 1H), 8.26-8. 19 (m, 2H), 8.04-8. 01 (m, 1H), 7.68-7. 63 (m, 1H), 7.52-7. 48 (m, 1H), 5.37 (s, 2H).

Reference： [1]Patent: US2004/254166,2004,A1 .Location in patent: Page 24-25
[2]Patent: WO2004/91613,2004,A2 .Location in patent: Page/Page column 59-60

28
[ 67442-07-3 ]
[ 228710-83-6 ]

Yield	Reaction Conditions	Operation in experiment
78.8%		A solution of 5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine (1.00 Kg 3.98 mol) in TBME (7.5 L) was cooled to -7O0C. n-Butyl lithium (2.5N in hexane; 1.73 L, 4.32 mol) was added drop-wise over 1 hour maintaining the temperature between -74°C and -69°C. The mixture was then stirred at a temperature between -74°C and -69°C for a further 15 minutes. A solution of 2- chloro-Lambda/-methoxy-Lambda/-methylacetamide (0.65 Kg, 4.72 mol) in TBME (3.0 L) was then added drop-wise over 100 minutes maintaining the temperature between -73°C and -67°C. The resulting mixture was then stirred at temperature between -73 and -67°C for a further 100 minutes. 2N HCI (5.0 L) was then added drop-wise over 45 minutes, allowing the temperature to rise from -7O0C to 17°C during the addition. TBME (4.0 L) and water (2.0 L) was added to the resulting suspension and the mixture was stirred before allowing the phases to separate. The organic layer was washed with water (2.0 L), and aqueous NaHCO3 (0.13 Kg in 2.0 L of water) and water (2.0 L) before concentrating in vacuo. IPA (1.50 L) was added to the residue and the mixture was heated to reflux. The mixture was then allowed to cool to room temperature and stirred overnight, before cooling to 8-120C for 1 hour. The product was collected by filtration, washed with IPA (2x0.1 L) and dried at 45°C under vacuum overnight. Yield 78.8percent (0.78 Kg), deltaH (CDCI3, 300 MHz) 2.20 (6H, s), 4.70 (2H1 s), 5.95 (2H, s), 7.35 (1 H, d), 8.40 (1H1 dd), 9.15 (1H1 d) ppm. MS m/z 249 (MH+).
78.8%		2-Chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone A solution of 5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine (1.00 Kg 3.98 mol) in TBME (7.5 L) was cooled to -70° C. n-Butyl lithium (2.5N in hexane; 1.73 L, 4.32 mol) was added drop-wise over 1 hour maintaining the temperature between -74° C. and -69° C. The mixture was then stirred at a temperature between -74° C. and -69° C. for a further 15 minutes. A solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (0.65 Kg, 4.72 mol) in TBME (3.0 L) was then added drop-wise over 100 minutes maintaining the temperature between -73° C. and -67° C. The resulting mixture was then stirred at temperature between -73 and -67° C. for a further 100 minutes. 2N HCl (5.0 L) was then added drop-wise over 45 minutes, allowing the temperature to rise from -70° C. to 17° C. during the addition. TBME (4.0 L) and water (2.0 L) was added to the resulting suspension and the mixture was stirred before allowing the phases to separate. The organic layer was washed with water (2.0 L), and aqueous NaHCO3 (0.13 Kg in 2.0 L of water) and water (2.0 L) before concentrating in vacuo. IPA (1.50 L) was added to the residue and the mixture was heated to reflux. The mixture was then allowed to cool to room temperature and stirred overnight, before cooling to 8-12° C. for 1 hour. The product was collected by filtration, washed with IPA (2*0.1 L) and dried at 45° C. under vacuum overnight. Yield 78.8percent (0.78 Kg), deltaH (CDCl3, 300 MHz) 2.20 (6H, s), 4.70 (2H, s), 5.95 (2H, s), 7.35 (1H, d), 8.40 (1H, dd), 9.15 (1H, d) ppm. MS m/z 249 (MH+).
73%		A solution of 2.5 M n-butyl lithium in hexanes (35 mL, 87.6 mmol) was added to a solution of the bromide from preparation 1 (20.0 g, 79.7 mmol) in tert-butylmethylether (300 mL) at-78°C under nitrogen over 10 minutes. The reaction was stirred for a further 10 minutes and <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (12.1 g, 87.6 mmol) in tert-butylmethylether (40 mL) was added slowly. The reaction was stirred at -78°C for 20 minutes and then 1M hydrochloric acid (200 mL) was added. The mixture was allowed to warm to room temperature, stirred for 2 hours and the organic phase separated. The aqueous phase was extracted with tert-butyl methylether and the combined organic extracts were washed with water (100 mL), saturated aqueous sodium chloride (100 mL) and 1M sodium hydroxide (100 mL). The organic phase was dried (sodium sulfate), concentrated in vacuo and the residual oil purified by flash column chromatography on silica gel eluting with pentane:dichloromethane:methanol (75: 25:0 changing to 0:99:1, by volume). The residue was recrystallised from pentane:dichloromethane to give the title compound as a yellow solid. (14.37g, 73percent) 1H NMR (400MHz, CDC13): No.H 9.11 (1H, s), 8.34-8.33 (1H, d), 7.32-7.30 (1H, d), 5.91 (2H, s), 4.66 (2H, s), 2.17 (6H, s) LRMS (electrospray) : m/z [M-H]+ 247.

Reference： [1]Patent: WO2006/82511,2006,A1 .Location in patent: Page/Page column 6; 37
[2]Patent: US2006/183740,2006,A1 .Location in patent: Page/Page column 15-16
[3]Patent: WO2005/115985,2005,A1 .Location in patent: Page/Page column 68-69

29
[ 67442-07-3 ]
[ 6921-34-2 ]
[ 937-38-2 ]

Yield	Reaction Conditions	Operation in experiment
		Benzylmagnesium chloride (1.0 M in diethyl ether, 50.0 mL) was treated with <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (5.16 g, 37.5 mmol) in tetrahydrofuran (200 mL) at -78° C. drop wise. The reaction was allowed to warm slowly to room temperature overnight and quenched with 1N hydrochloric acid. The layers were separated and the organic phase dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; elution with hexanes) to provide the title. 1H NMR (300 MHz, DMSO-d6) delta 3.87 (s, 2H), 4.62 (s, 2H), 7.25 (m, 5H); MS (DCI/NH3) m/z 186 (M+NH4)+.

Reference： [1]Patent: US2005/176727,2005,A1 .Location in patent: Page/Page column 32

30
[ 5394-13-8 ]
[ 5118-13-8 ]
[ 67442-07-3 ]
ammonium chloride [ No CAS ]
[ 360575-11-7 ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium; In tetrahydrofuran; ethyl acetate; Petroleum ether;	Example 2 To a suspension of magnesium turnings (0.41 g) in tetrahydrofuran (5 ml) under nitrogen were added 1 ml of a solution of 4-bromobenzo[b]thiophene (3.45 g, prepared in a manner similar to that described in Bull. Soc. Chim. Fr., 1966, 11, 3667) in tetrahydrofuran (15 ml) and a crystal of iodine. The mixture was stirred at 50-60° C. and once the reaction had initiated the rest of the bromobenzo[b]thiophene solution was added dropwise at 50-60° C. over 10 minutes. The mixture was stirred for a further 0.5 hour at 50-60° C. then cooled to 0° C. A solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (2.2 g) in tetrahydrofuran (20 ml) was added dropwise at 0-5° C. over 15 minutes and the mixture was stirred at 0-5° C. for 1 hour. Saturated aqueous ammonium chloride solution (25 ml) was added, the mixture was stirred at ambient temperature for 10 minutes, then the aqueous layer was separated and shaken with ethyl acetate (50 ml). The combined organic phases were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 19:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl)-2-chloroethan-1-one (1.15 g) as a pale yellow oil which was used without further purification.

Reference： [1]Patent: US2003/166628,2003,A1

31
[ 360575-41-3 ]
[ 67442-07-3 ]
ammonium chloride [ No CAS ]
[ 360575-42-4 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In tetrahydrofuran;	A solution of 3-bromo-4-methylbenzo[b]thiophene (2 g) in tetrahydrofuran (10 ml) was added dropwise under nitrogen at -70° C. over 10 minutes to a stirred solution of n-butyllithium (2.5M solution in hexanes; 4.58 ml) in ether (30 ml), then the mixture was stirred at -70° C. for 30 minutes. A solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (1.04 g) in tetrahydrofuran (10 ml) was added dropwise at -70 IC over 10 minutes, then the mixture was stirred at -70° C. for 5 hours, allowed to stand at ambient temperature for 18 hours and quenched by the addition of saturated aqueous ammonium chloride solution (40 ml). The organic layer was separated, washed with saturated aqueous sodium chloride solution (40 ml), and dried (MgSO4). The solvents were removed in vacuo to give 2-chloro-1-(4-methylbenzo[b]thiophen-2-yl)ethan-1-one (1.65 g) as a brown oil which was used without further purification.

Reference： [1]Patent: US2003/166628,2003,A1

32
[ 310466-39-8 ]
[ 67442-07-3 ]
ammonium chloride [ No CAS ]
[ 360575-20-8 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In tetrahydrofuran; Petroleum ether;	A solution of 3-bromo-4-fluorobenzo[b]thiophene (0.76 g) in tetrahydrofuran (5 ml) was added dropwise under nitrogen at -60--50° C. over 10 minutes to a stirred solution of n-butyllithium (2.5M solution in hexanes; 1.71 ml) in ether (40 ml), then the mixture was stirred at -50° C. for 30 minutes. A solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (0.39 g) in tetrahydrofuran (10 ml) was added dropwise over 10 minutes, the mixture was stirred at -50° C. for 30 minutes and at 0° C. for 1 hour, then it was quenched by the addition of saturated aqueous ammonium chloride solution (30 ml). The organic layer was separated, washed with saturated aqueous sodium chloride solution (30 ml), dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 10:1 mixture of petroleum ether (b.p. 60-80 C) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-chloro-1-(4-fluorobenzo[b]thiophen-2-yl)ethan-1-one (0.1 g) as a colourless solid which was used without further purification.

Reference： [1]Patent: US2003/166628,2003,A1

33
3-acetoxy-4-fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethylphenyl]-benzamide [ No CAS ]
[ 67442-07-3 ]
4-fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethyl-phenyl]-3-[(N-methoxy-N-methylcarbamoyl)methoxy]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.35 g (92%)	With caesium carbonate; In methanol; diethyl ether; acetone;	(d) To a solution of 0.33 g (0.83 mmol) 3-acetoxy-4-fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethylphenyl]-benzamide, J-1c, in 5 mL acetone and 0.5 mL of methanol was added cesium carbonate (0.54 g, 1.65 mmol) and <strong>[67442-07-3]2-chloro-N-methoxy-N-methyl-acetamide</strong> (0.15 g, 1.07 mmol) and the resulting mixture was stirred for 6 h at 45° C. After cooling to room temperature, the mixture was partitioned between ethyl acetate and sat. brine (220 mL). The organic layer was filtered though a silica gel plug and concentrated. The residue was purified by titurated with diethyl ether (220 mL) to give 0.35 g (92percent) of 4-fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethylphenyl]-3-[(N-methoxy-N-methylcarbamoyl)methoxy]benzamide, J-1d, as a white solid: Rt=11.95 min.; 1H NMR (300 MHz, CDCl3) delta8.34 (d, 1H, J=2.4 Hz), 8.11 (dd, lh, J=8.7 Hz), 7.64-7.54 (m, 3H), 7.42 (d, 1H, J=8.7 Hz), 7.22-7.15 (m, 2H), 6.97 (s, 1H), 502 (s, 2H), 3.72 (s, 3H), 3.06 (s, 3H); MS (ESI): Calculated for C21H18F4N4O4 (M+H+): 467, Found: 467.

Reference： [1]Patent: US2002/103203,2002,A1

34
3-thiobenzoic acid [ No CAS ]
[ 67442-07-3 ]
2-[(3-carboxyphenyl)sulfanyl]-N-methoxy-N-methylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.5 g (96%)	With hydrogenchloride; caesium carbonate; acetic acid; In hexane; ethyl acetate; acetone;	(a) To a solution of 3-thiobenzoic acid (5.0 g, 32.4 mmol) in 150 mL of acetone was added cesium carbonate (22.2 g, 68.1 mmol) and 2-chloro-N -methoxy-N-methylacetamide (4.9 g, 35.7 mmol). After stirring for 1 h, the reaction was quenched with dropwise addition of 1N HCl. The reaction mixture was partitioned between 100 mL of ethyl acetate and 50 mL of 1N HCl, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using 33percent hexane/66percent ethyl acetate/1percent acetic acid to afford 2-[(3-carboxyphenyl)sulfanyl]-N-methoxy-N-methylacetamide, E-1a, as a white solid 8.5 g (96percent). 1H NMR (500 MHz, CDCl3) delta8.15 (t, 1H, J=1.5 Hz), 8.06 (br s, 1H), 7.92 (dt, 1H, J=7.8, 1.2 Hz), 7.68 (dq, 1H, J=6.0, 1.2 Hz), 3.88 (s, 2H), 3.74 (s, 3H), 3.22 (s, 3H).

Reference： [1]Patent: US2002/103203,2002,A1

35
[ 67442-07-3 ]
[ 22948-02-3 ]
2-(3-aminophenylsulfanyl)-N-methoxy-N-methyl-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.57 g (56%)	With sodium carbonate; caesium carbonate; In hexane; ethyl acetate; acetone;	(b) A slurry of 3-mercaptoaniline (1.00 mL, 9.42 mmol), <strong>[67442-07-3]2-chloro-N-methoxy-N-methyl-acetamide</strong> and cesium carbonate (6.12g, 18.84 mmol) in 5 mL of acetone was stirred for 18h. The reaction mixture was partitioned between ethyl acetate (30 mL) and sat. sodium carbonate (2*50 mL) and the organic layer concentrated to dryness to give an amber oil. Purification by chromatography on silica gel using hexane/ethyl acetate (1: 1) afforded 1.57 g (56percent) of 2-(3-aminophenylsulfanyl)-N-methoxy-N-methyl-acetamide, W-1b, as a clear oil. HPLC Rt=5.85 min; 1H NMR (300 MHz, CDCl3) delta7.26 (s, 1H), 7.08 (t, 1H, J=8.1 Hz), 6.84-6.82 (m, 2H), 6.54 (d, 1H, J=8.7 Hz), 3.82 (s, 2H), 3.75 (s, 3H), 3.22 (s, 3H).

Reference： [1]Patent: US2002/103203,2002,A1

36
[ 6137-75-3 ]
[ 67442-07-3 ]
ammonium chloride [ No CAS ]
methyl[6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.03 g (32%)	With n-butyllithium; In tetrahydrofuran; hexane;	To a solution of 2-(3-furyl)-2-propanol (T. M. Bargar et al., J. Med. Chem., 1986, 29, 315., 2.0 g, 15.85 mmol) in THF (100 ml) was added a solution of n-butyllithium in hexane (1.55M, 30.7 ml, 47.55 mmol) at -78° C. After stirring for 1 h, <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (6.54 g, 47.55 mmol) was added at 0° C. Saturated aqueous ammonium chloride (100 ml) was added to the mixture and the organic layer was separated. The organic layer was washed with water (100 ml*2) and brine (50 ml) and dried (MgSO4). After removal of the solvent, the residue was purified by flash chromatography eluding with ethyl acetate/hexane (1:4) to afford 1.03 g (32percent) of the title compound as an oil. 1H-NMR (CDCl3) delta: 7.52 (1H, d, J=1.8 Hz), 6.56 (1H, d, J=1.8 Hz), 5.51 (1H, s), 4.74 (2H, s), 1.56 (6H, s).

Reference： [1]Patent: US6608070,2003,B1

37
[ 228710-82-5 ]
[ 67442-07-3 ]
ammonium chloride [ No CAS ]
[ 228710-83-6 ]

Yield	Reaction Conditions	Operation in experiment
	With iodine; magnesium; In tetrahydrofuran;	EXAMPLE 140 STR93 2-Chloro-1-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-3-yl]-ethanone Magnesium turnings (7.26 g, 0.30 mol) were placed in 2 L three neck flask equipped with a dropping funnel and reflux condenser. The system was purged with argon and heated for ten minutes. After cooling the flask to room temperature under argon, tetrahydrofuran (500 mL) and a crystal of iodine were added. A portion of a solution of 5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine (Example 138; 75 g, 0.30 mol) in tetrahydrofuran (200 mL) was added to initiate the reaction. The flask was heated to maintain reflux as the remainder of the solution was added. After three hours the mixture was cooled in an ice-water bath. A solution of N-methoxy-N-methylchloroacetamide (Example 139; 49.3 g, 0.35 mol) in tetrahydrofuran (200 mL) was transferred to the suspension via cannula. The mixture was warmed to ambient temperature. After 18 hours the mixture was quenched with two-thirds saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3*). The combined organic phase was dried (MgSO4) and concentrated to an oil. Silica gel chromatography (75:25 hexane/ethyl acetate) afforded an oil (67 g). The oil was a 7:3 mixture of the title compound and 2-(2,5-dimethyl-pyrrol-1-yl)-pyridine. 1 H NMR (CDCl3, 300 MHz; peaks corresponding to the title compound) delta 9.16 (dd, 2.6 Hz, 0.7 Hz, 1 H), 8.40 (dd, 8.5 Hz, 2.6 Hz, 1 H), 7.35 (dd, 8.5 Hz, 0.7 Hz, 1 H), 5.96 (s, 2 H), 4.71 (s, 2 H), 2.21 (s, 6 H); Rf =0.2 (5:1 hexane/ethyl acetate).

Reference： [1]Patent: US6051586,2000,A

38
[ 1634-04-4 ]
[ 6638-79-5 ]
[ 584-08-7 ]
[ 79-04-9 ]
[ 67442-07-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	In water;	EXAMPLE 7 Preparation of N-methoxy-N-methylchloroacetamide (3b). To a cold (0° C.), stirred solution of K2 CO3 (62.4 g, 450 mmol) in H2 O (250 mL) was added, successively, N,O-dimethylhydroxylamine hydrochloride (20 g, 205 mmol) and organic solvent (250 mL, toluene or MTBE). The resulting two phase mixture was cooled to -5° C. and chloroacetyl chloride (19.6 ml, 246 mmol) was added over 5 min (solution temperature maintained below 0° C.). The vigorously stirred mixture was allowed to warm to 15° C. over 30 min, the layers were separated, and the aqueous layer was extracted with organic solvent (3*100 mL, toluene or MTBE). The combined organic extracts were concentrated (MTBE used as solvent) to give the amide 3b (26.8 g, 95percent) as a white solid. Alternatively, the combined organic extracts (toluene used as solvent) were concentrated to 250 mL to effect azeotropic drying (water content 100 mug/mL) and the solution of 3b was used directly in reactions with organometallic reagents.

Reference： [1]Patent: US5786515,1998,A

39
[ 1634-04-4 ]
[ 6638-79-5 ]
[ 79-04-9 ]
[ 67442-07-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; In water;	EXAMPLE 7 Preparation of N-methoxy-N-methylchloroacetamide (3b). To a cold (0°C), stirred solution of K2CO3 (62.4 g, 450 mmol) in H2O (250 mL) was added, successively, N,O-dimethylhydroxylamine hydrochloride (20 g, 205 mmol) and organic solvent (250 mL, toluene or MTBE). The resulting two phase mixture was cooled to -5°C and chloroacetyl chloride (19.6 ml, 246 mmol) was added over 5 min (solution temperature maintained below 0°C). The vigorously stirred mixture was allowed to warm to 15°C over 30 min, the layers were separated, and the aqueous layer was extracted with organic solvent (3x100 mL, toluene or MTBE). The combined organic extracts were concentrated (MTBE used as solvent) to give the amide 3b (26.8 g, 95percent) as a white solid. Alternatively, the combined organic extracts (toluene used as solvent) were concentrated to 250 mL to effect azeotropic drying (water content 100mug/mL) and the solution of 3b was used directly in reactions with organometallic reagents.

Reference： [1]Patent: EP851850,2001,B1

40
[ 67442-07-3 ]
ammonium chloride [ No CAS ]
[ 153498-16-9 ]
[6-CHLORO-3-(1H-1,2,3,4-TETRAZOL-5-YLMETHYL)-1H-INDOL-2-YL](3-METHOXYMETHYL-2-FURYL) METHANONE [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.43 g (37%)	With n-butyllithium; In tetrahydrofuran; hexane;	*2-Chloroacetyl-3-(methoxymethyl)furan To a solution of 3-(methoxymethyl)furan (N.Greeves et al., Synthesis, 1993, 1109, 2.33 g, 20.78 mmol) in THF (50 ml) was added 1.55M n-butyl lithium in hexane (16.1 ml, 24.94 mmol) at -78°C and the mixture was stirred at that temperature for 2h. The resulting mixture was warmed slowly to 0°C and <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (5.72 g, 41.56 mmol) was added. The mixture was quenched with saturated aqueous ammonium chloride (50 ml) and the organic layer was separated. The organic layer was washed with water (50 ml x 2), brine (50 ml), dried (MgSO4), and concentrated. The residue was purified by flash chromatography eluding with ethyl acetate/hexane (1:4) to afford 1.43 g (37percent) of the title compound as an oil. 1H-NMR (CDCl3) delta: 7.52 (1H, d, J=1.8Hz), 6.74 (1H, d, J=1.8Hz), 4.73 (2H, s), 4.62 (2H, s), 3.44 (3H, s).

Reference： [1]Patent: EP1065206,2001,A1

41
[ 2759-28-6 ]
[ 67442-07-3 ]
[ 256352-19-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate; In tetrahydrofuran; at 60℃; for 18h;	A mixture of 1-benzyl-piperazine (1.0 g, 5.67 mmol), 2-chloro-LambdaA-methylacetamide (671.2 mg, 6.24 mmol, 1.1 eq.), and potassium carbonate (941 mg, 6.81 mmol, 1.2 eq.) in anhydrous THF (23 mL) was stirred at 60 0C under N2 for 18 h. The mixture was cooled to rt and poured into EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC(Biotage.(R)., gradient elution 1:4:5 v/v MeOH:Acetone:DCM) to give 1.16 g (83percent) of the product as a white solid. 1H-NMR (300 MHz, DMSO-alphafe) .delta 7.62 to 7.56 (broad d, 1H),7.33 to 7.20 (m, 5H), 3.45 (s, 2H), 2.85 (s, 2H), 2.58 (d, 3H), 2.44 to 2.33 (broad s, 8H);ES-MS m/z 248.2 [M+H]+, RT (min) 0.33.

Reference： [1]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 103

42
[ 629-05-0 ]
[ 67442-07-3 ]
1-chloro-dec-3-yn-2-one [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 4499 - 4507

43
[ 67442-07-3 ]
[ 88158-68-3 ]
[ 1160482-41-6 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 4499 - 4507

44
[ 67442-07-3 ]
[ 4039-83-2 ]
[ 1160482-43-8 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 4499 - 4507

45
[ 67442-07-3 ]
[ 536-74-3 ]
[ 176648-09-2 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 4499 - 4507
[2]Dalton Transactions,2015,vol. 44,p. 19464 - 19468

46
[ 75-77-4 ]
[ 67442-07-3 ]
[ 508191-77-3 ]
[ 1186220-88-1 ]

Reference： [1]Synthetic Communications,2009,vol. 39,p. 2852 - 2858

47
[ 67442-07-3 ]
[ 1184949-73-2 ]
[ 1184949-75-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	With isopropylmagnesium chloride;lithium chloride; In tetrahydrofuran; at -20 - 5℃;	To a solution of 1-(7-iodo-3-methyl-3,4-dihydro-1/-/-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (preparation 19c, 860 mg, 2.33 mmol) in anhydrous THF (20 mL) is added at -200C a solution of isopropylmagnesium chloride and lithium chloride ("Turbo Grignard", 1.79 mL of 14percent solution in THF). After 10 min, the Grignard solution is added to a solution of 2-chloro-N- methoxy-N-methylacetamid (320 mg, 2.33 mmol) in THF (20 mL), keeping the temperature below 00C. After stirring for 30 min (temperature increases to 5°C), the reaction mixture is poured into pH 7 buffer and extracted with tert-butylmethylether. The organic layer is washed with water, dried over MgSO4 and concentrated in vacuo. Yield: 550 mg (74 percent of theory); Rf value: 0.29 (silica gel, 30percent ethyl acetate in hexanes).

Reference： [1]Patent: WO2009/103478,2009,A1 .Location in patent: Page/Page column 59

48
C₁₂H₁₅Cl₂NO₃S [ No CAS ]
[ 67442-07-3 ]
2-(2,4-dichloro-5-(piperidine-1-sulphonyl)benzyloxy)-N-methoxy-N-methylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		To an ice-cold suspension of NaH (185 mg of a 60percent dispersion in mineral oil, 4.62 mmol) in anhydrous THF (10 ML) was added a solution of (2, 4-DICHLORO-5-(PIPERIDINE-1- sulphonyl) phenyl) methanol (1.0 g, 3.08 mmol) in anhydrous THF (10 mL). After 1 hour a solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (635 mg, 4.62 mmol) in anhydrous THF (10 mL) was added. The reaction was allowed to slowly warm to room temperature. After 2 hours the reaction was quenched with saturated NH4C1 and poured into water. This was extracted with EtOAc. The organic phase was washed with brine, dried (NA2SO4), filtered, and concentrated. Column chromatography (45percent ETOAC/HEXANES) provided 2- (2, 4-dichloro-5- (piperidine-l-sulphonyl) benzyloxy)-N- methoxy-N-methylacetamide (1.31 g, 72percent) as a colourless solid 1H NMR (CDC13) 8 : 8. 15 (s, 1H), 7.45 (s, 1H) 9 4. 68 (s, 2H), 4.36 (s, 2H), 3.64 (s, 3H), 3.14-3. 20 (m, 4H), 3.14 (s, 3H), 1.46-1. 55 (m, 6H).

Reference： [1]Patent: WO2004/92135,2004,A2 .Location in patent: Page 56-57

49
[ 67442-07-3 ]
[ 1110767-07-1 ]
[ 1110767-09-3 ]

Yield	Reaction Conditions	Operation in experiment
		To a THF solution of (RS)-1-bromo-2-mehyloxy-3-(1-methyloxyheptyl)benzene (2, 6.3 g, 20 mmol) obtained in the second step was added dropwise 2M isopropylmagnesium chloride (20 mL). 2-Chloro-N-methyloxy-N-methylacetamide (5.5 g) was added thereto, and the mixture was stirred at room temperature. To the reaction solution was added aqueous hydrochloride acid solution, followed by extraction with ethyl acetate. After the solvent was distilled off, the residue was purified by silica gel chromatography to obtain 2.80 g of a compound (3). NMR (CDCl3) delta ppm: 7.58 - 7.61 (m, 1H), 7.51 - 7.54 (m, 1H), 7.22 - 7.27 (m, 1H), 4.72 (dd, 2H, J = 20.8 Hz, 15.9 Hz), 4.54 (dd, 1H, J = 8.1 Hz, 4.8 Hz), 3.78 (s, 3H), 3.22 (s, 3H), 1.14 - 1.77 (m, 10H), 0.84 - 0.90 ( m, 3H)

Reference： [1]Patent: EP2184279,2010,A1 .Location in patent: Page/Page column 15

50
[ 67442-07-3 ]
[ 1110767-81-1 ]
[ 1110767-83-3 ]

Yield	Reaction Conditions	Operation in experiment
		To a THF solution of (S)-1-bromo-2-methyloxy-3-(1-methyloxyheptyl)benzene (9, 12.5 g) obatined in the second step was added dropwise a 2M isopropyl magnesium chloride THF solution (44 mL) under ice-cooling. After the reaction solution was stirred at 45°C for 3 hours, N-methyloxy-N-methyl-2-chloroacetamide(10, 3.5 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and purified by silica gel chromatography to obtain (S)-2-chloro-1-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)ethanone (11). NMR (CDCl3) delta ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 - 1.82 (10H, m), 3.22 (3H, s), 3.78 (3H, s), 4.53 (1H, m), 4.73 (2H, m), 7.24 (1H, t, J = 7.6Hz), 7.52 (1H, dd, J = 7.6 Hz, J = 1.8 Hz), 7.60 (1H, dd, J = 7.7 Hz, J = 1.8Hz)

Reference： [1]Patent: EP2184279,2010,A1 .Location in patent: Page/Page column 23

51
[ 41404-58-4 ]
[ 67442-07-3 ]
[ 1104606-44-1 ]

Yield	Reaction Conditions	Operation in experiment
		Step A: 2-Chloroacetyl-5-fluoropyridine. 2-Bromo-5-fluoropyridine (50.0 g, 284 mmol) in 200 mL of THF was added drop-wise over 25 min to isopropylmagnesium chloride (2 M in THF, 284 mL, 568 mmol) at RT, and the mixture was stirred for 2 hours at room temperature. A solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> in 150 mL of THF was added dropwise over 30 minutes to the reaction mixture at RT. The mixture was stirred at RT overnight. The mixture was then poured into 2000 g of ice with 500 mL of 2 N HCl. The mixture was extracted into ether, washed with brine, dried over anhydrous sodium sulfate and concentrated to a residue, which was dissolved in 1 L of warm hexane and treated with several grams of silica gel to remove colored impurities. The mixture was then filtered. The filtrate was concentrated and chilled at ice temperature for 30 minutes. The resulting solid was isolated by filtration to give 2-chloroacetyl-5-fluoropyridine. 1H NMR (500 MHz, CDCl3): delta 8.53 (d, 1H), 8.19 (dd, 1H), 7.60 (td, 1H), 5.09 (s, 2H).
		Example 50a2-Chloro-1-(5-fluoro-2-pyridyl)ethanone2-Bromo-5-fluoropyridine (3.88 g, 22 mmol) dissolved in toluene (10 mL) was added slowly to a solution of isopropylmagnesium chloride (13.2 mL, 26.4 mmol, 2M in THF) in toluene (30 mL) at room temperature.The reaction mixture was stirred for 3.5 hours at room temperature, cooled to 0° C. and a solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methyl-acetamide</strong> (3.64 g, 26.4 mmol) in toluene (10 mL) was added slowly.The reaction mixture was stirred for 2.5 hours at 0° C., quenched with saturated ammonium chloride, diluted with ethyl acetate and saturated sodium bicarbonate and extracted with ethyl acetate (2*100 mL).The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 3.75 g (98percent) of the title compound which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) delta ppm 5.07 (s, 2H), 7.56 (td, 1H), 8.17 (dd, 1H), 8.50 (d, 1H).
		Step A: 2-ChIoroacetyl-5-fluoropyridine.2-Bromo-5-fluoropyridine (50.0 g, 284 mmol) in 200 mL of THF was added dropwise over 25 min to isopropylmagnesium chloride (2 M in THF, 284 mL, 568 mmol) at RT, and the mixture was stirred for 2 hours at room temperature. A solution of 2-chloro-N-methoxy-N- methylacetamide (43.0 g, 313 mmol) in 150 mL of THF was added dropwise over 30 minutes to the reaction mixture at RT. The mixture was stirred at RT overnight. The mixture was then poured into 2000 g of ice with 500 mL of 2 N HCl. The mixture was extracted into ether, washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was dissolved in 1 L of warm hexane and treated with several grams of silica gel to remove colored impurities. The resulting mixture was then filtered, and the filtrate was concentrated and chilled in an ice bath for 30 minutes. The resulting solid was isolated by filtration to give 2-chloroacetyl- 5-fluoropyridine. 1HNMR (500 MHz, CDCI3): 6 8.53 (d, 1 H), 8.19 (dd, 1 H), 7.60 (td, 1 H), 5.09 (s, 2 H).

Reference： [1]Patent: US2010/184799,2010,A1 .Location in patent: Page/Page column 25
[2]Patent: US2012/122843,2012,A1 .Location in patent: Page/Page column 50-51
[3]Patent: WO2011/88025,2011,A1 .Location in patent: Page/Page column 48-49
[4]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 513 - 517

52
[ 67442-07-3 ]
[ 7368-78-7 ]
[ 1243253-49-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 17h;	A mixture of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (2.7 g, 19.63 mmol), 4-bromo-2-methoxyphenol (3.98 g, 19.63 mmol), and potassium carbonate (5.43 g, 39.3 mmol) in DMF (20 mL) was heated at 600C for lhour and stirred at RT overnight (16 hours). The reaction mixture was diluted with CH2CI2, washed with sat NaHCO3, brine and dried (Na2SO4). After concentration, the crude product was purified by ISCO flash chromatography (silica gel/ hexanes-ethyl acetate 100:0 to 0: 100 gradient) to afford 2-(4-bromo-2-methoxyphenoxy)-N-methoxy-N- methylacetamide 16A (4.86 g, 15.98 mmol, 81 percent yield) as a yellow solid. 1H NMR (400 MHz, chloroform-^/) delta 6.97 - 7.04 (2 H, m), 6.76 (1 H, d, J=8.03 Hz), 4.86 (2 H, s), 3.87 (3 H, s), 3.75 (3 H, s), 3.23 (3 H, s).

Reference： [1]Patent: WO2010/104818,2010,A1 .Location in patent: Page/Page column 88; 89

53
[ 67442-07-3 ]
3-(4-bromophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole [ No CAS ]
2-chloro-1-[4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 3-(4-bromo-phenyl)-1-methyl-5-trifluoromethyl-1 H-pyrazole (1.50 g, 4.92 mmol) in MTBE (75 mL) at -78 0C was added t-BuLi (6.65 mL of a 1.7 M soln in pe?tane, 11.3 mmol) over 2 mi?. After 5 min a solution of 2-chloro-N-methoxy-N- methyiacetamide (1.56 g, 11.3 mmol) in MTBE (15 mL) was added quickly via cannula. After5 min 1 M aq HCI (20 mL) was added, and the reaction mixture was warmed to rt over 1 h.EtOAc was added followed by 1 M aq NaOH to basify to pH 10. The mixture was extracted with EtOAc (2x). The combined extracts were washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude solid was purified by chromatography (loaded with hexanes; eluted with a gradient of 5-20% EtOAc in hexa?es) to provide 950 mg of 2-chloro-1-[4-(1-methyl-5-trfluoromethyl-1H-pyrazol-3-yl)-phenyl]-etha?o?e as a white solid. MS: (M+)303, 305. 1H NMR (400 MHz, CDCI3): delta 8,01 (d, 2, J = 8.7), 7.90 (d, 2, J = 87), 6.98 (s, 1), 4.73 (s, 2), 4.06 (s, 3).

Reference： [1]Patent: WO2007/34278,2007,A2 .Location in patent: Page/Page column 54

54
[ 937046-98-5 ]
[ 67442-07-3 ]
[ 937047-12-6 ]

Yield	Reaction Conditions	Operation in experiment
84%		A 1 L, 3-neck RB flask was fitted with a mechanical stirrer, a nitrogen inlet, thermocouple and thermocontroller, and a water cooling bath. In the flask 7-bromopyrrolo[2,1- f][1 ,2,4]triazin-4-amine (175 g, 352mmol) was suspended in tetrahydrofuran (100 ml_) and treated with chlorotrimethylsilane (7.65g, 70.4 mmol). The mixture was allowed to stir 3 h at rt. A solution of isopropylmagnesium bromide in THF (2M, 70.4 mL, 141 mmol) was added slowly over 20 min taking care that the internal temperature never rose above 40 0C. After 1 h a sample quenched in MeOH and analyzed by RP-HPLC indicated that the metallation was > 90percent complete. The water bath was replaced with an ice-acetone bath and stirring was continued until the internal temperature fell to -10 0C. 2-Chloro-N- methoxy-N-methylacetamide (7.3 g, 53 mmol) was added as a solid, and the reaction allowed to warm to rt over 30 min. The reaction was quenched with MeOH and diluted with EtOAc (200 mL) and 500 mL of citrate buffer (pH 4). The mixture was stirred for 15 min, during which time a thick tan precipitate formed. This was filtered off to provide the desired compound as a tan solid (2g, 27percent). The organic layer was separated, dried with sodium sulfate and filtered through a silica plug. Removal of the solvent in vacuo and trituration of the residue with EtOAc gave a second batch of the desired product (4.3 g, 58percent). The 2 batches were combined to provide the desired product as a tan powder (6.25 g, 84percent). 1H-NMR (DMSO): delta 7.88 (bs, 1 H), 7.80 (s, 1 H), 7.08 (d, 1 H, J = 5 Hz), 6.70 (d, 1H, J = 5 Hz), 4.82 (s, 2H), 3.06 (bs, 1); MS: LC/MS (+esi): m/z=211.2 [MH]+ ;LC/MS rt = 1.69 min.
76%		To a stirred suspension of Intermediate B (3.00 g, 14.08 mmol) in THF (50 ml_) was added chlorotrimethylsilane (3.57 mL, 28.16 mmol). The mixture was stirred at rt for 3 h. The mixture was placed in a water ice bath and 2-propylmagnesium chloride (2M in THF; 29.6 mL, 59.14 mmol) was added dropwise. The suspension immediately went into solution. The ice bath was removed and the mixture was stirred at rt for 3 h. The mixture was placed in an ice bath and 2- chloro-AA-methoxy-AA-methylacetamide (2.91 g, 21.12 mmol) was added in one portion. The ice bath was once again removed and the reaction was stirred at rt for 16 h. The reaction was poured over a mixture of ice and saturated, aqueous ammonium chloride (250 mL). The mixture was allowed to warm to rt and EtOAc (200 mL) was added. The undissolved solid was collected by filtration to afford 636 mg (21percent) of the desired product. The layers of the filtrate were separated and and the aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude solid was triturated with EtOAc to provide an additional 1.62 g (55percent) of the desired product, for a combined yield of 2.26 g (76percent). ES-MS m/z 211.47 [M+H]+, HPLC RT (min) 1.67.

Reference： [1]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 84-85
[2]Patent: WO2007/56170,2007,A2 .Location in patent: Page/Page column 116-117

55
[ 67442-07-3 ]
[ 209971-03-9 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 17511 - 17515
[2]Advanced Synthesis and Catalysis,2011,vol. 353,p. 3467 - 3472

56
[ 67442-07-3 ]
[ 13125-66-1 ]
[ 41055-93-0 ]

Reference： [1]Organic and Biomolecular Chemistry,2011,vol. 9,p. 57 - 61

57
[ 109-04-6 ]
[ 67442-07-3 ]
C₁₄H₁₁ClN₂O₂ [ No CAS ]
[ 55484-10-1 ]

Reference： [1]Organic process research and development,2010,vol. 14,p. 1326 - 1336

58
[ 53939-30-3 ]
[ 67442-07-3 ]
[ 136592-00-2 ]

Reference： [1]Organic process research and development,2010,vol. 14,p. 1326 - 1336

59
[ 1019639-01-0 ]
[ 67442-07-3 ]
3,4,5-tris(octadecyloxy)benzyl 2-(methoxy(methyl)carbamoyl)cyclopropanecarboxylate [ No CAS ]

Reference： [1]Chemistry Letters,2011,vol. 40,p. 1077 - 1078

60
[ 67442-07-3 ]
[ 61099-40-9 ]
[ 1352303-76-4 ]

Yield	Reaction Conditions	Operation in experiment
88%		To a solution of N-chloro-N-methylacetamide (495 mg, 3.60 mmol) in THF (3.5 mL) at -78 °C was added dropwise LHMDS (freshly prepared from hexamethyldisilyl amine, 820 muL, 3.9 mmol and n-BuLi (a 2.6 M solution in hexane, 1.7 mL, 4.5 mmol)) under argon. The reaction mixture was stirred for an additional 20 min at -78 °C. A solution of 22 (685 mg, 3.0 mmol) in THF (4.5 mL) was added to the mixture via cannula. The reaction mixture was warmed to room temperature, stirred for 17 h, then quenched with saturated NH4Cl, and extracted with AcOEt (.x.3). The combined organic layers were dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with hexane/AcOEt=15/1, 10/1, 6/1 then 3/1) to give 18e (847 mg, 88percent, based on recovered starting material) as pale yellow oil. Rf 0.44 (hexane/AcOEt 2/1); FTIR (neat) 2937, 1680, 1464, 1379, 1309, 1250, 1184, 1082, 993, 928, 823, 754 cm-1; 1H NMR (400 MHz, CDCl3) delta 3.74, 3.73 (each s, 3H), 3.64, 3.62 (each br s, 1H), 3.24, 3.22 (each s, 3H), 3.17 (s, 3H), 1.71-1.52 (m, 4H), 1.50-1.35 (m, 3H), 1.43, 1.31 (each s, 3H), 1.33-1.21 (m, 4H), 1.19-1.05 (m, 2H), 1.13 (s, 3H), 1.13 (s, 3H), 0.87, 0.85, 0.84 (each d, J=6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) delta 168.6, 74.5, 74.5, 62.4, 62.2, 61.5, 60.1, 59.2, 59.2, 49.0, 40.1, 40.1, 38.1, 37.5, 37.5, 37.4, 36.9, 36.8, 32.6, 32.6, 32.6, 32.5, 24.9, 22.8, 22.8, 22.5, 22.4, 21.4, 21.2, 19.5, 19.4, 19.4, 19.3, 16.4; HRMS (CI) m/z [M+H]+ calcd for [C18H35NO4+H]+ 330.2644, found 330.2638.

Reference： [1]Tetrahedron,2012,vol. 68,p. 106 - 113

61
[ 67442-07-3 ]
[ 1369596-00-8 ]
[ 1369594-60-4 ]

Yield	Reaction Conditions	Operation in experiment
35%		To a solution of Compound Int-24a(1.48 g, 3.76 mmol) in 11 mL THF at -78 °C was added n-BuLi (2.5 M in hexane, 1.66 mL, 4.14 mmol). The reaction was allowed to stir at -78 °C for 30 minutes, then 2-chloro-N-methoxy-N- methylacetamide(l .l g, 7.52 mmol) in 2 mL of THF was added at -78 °C . The reaction was allowed to stir for 1 hour at -78 °C, then was quenched with saturated aqueousNH4CI. The resulting solution was extracted with EtOAc and the organic extract was washed with brine solution, dried (Na2S04), filtered and concentrated in vacuo. The resulting residue was purified using an ISCO 80 g column (hexane to 50percent EtOAc-hexane, gradient) to provide Compound Int-24b, 503 mg (35percent). LRMS: (M+H)+ = 390
35%		To a solution of Compound Int-24a(1.48 g, 3.76 mmol) in 11 mL THF at - 78 °C was added n-BuLi (2.5 M in hexane, 1.66 mL, 4.14 mmol). The reaction was allowed to stir at -78 °C for 30 minutes, then <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong>(l . l g, 7.52 mmol) in 2 mL of THF was added at -78 °C . The reaction was allowed to stir for 1 hour at - 78 °C, then was quenched with saturated aqueous H4C1. The resulting solution was extracted with EtOAc and the organic extract was washed with brine solution, dried (Na2S04), filtered and concentrated in vacuo. The resulting residue was purified using an ISCO 80 g column (hexane to 50percent EtOAc-hexane, gradient) to provide Compound Int-24b, 503 mg (35percent). LRMS: (M+H)+ = 390.

Reference： [1]Patent: WO2012/41014,2012,A1 .Location in patent: Page/Page column 141
[2]Patent: WO2012/40923,2012,A1 .Location in patent: Page/Page column 119-120

62
[ 67442-07-3 ]
[ 1378382-90-1 ]
[ 1378382-92-3 ]

Yield	Reaction Conditions	Operation in experiment
67%		To a solution of (2-bromo-5-iodobenzyloxy)-(teri-butyl)dimethylsilane (8.7 g, 20.3 mmol) in tetrahydrofuran (135 mL) under argon at -20 °C was added z-propylmagnesium chloride - lithium chloride solution (1.3M in THF, 16.4 mL, 21.3 mmol). After stirring at this temperature for thirty minutes, a solution of 2-chloro-N-methoxy-N-methyl acetamide (3.4 g, 24.3 mmol) in tetrahydrofuran (5 mL) was added to the reaction via cannula. The reaction was stirred at -20 °C for one hour and then warmed to room temperature. After one hour at room temperature the reaction was diluted with ethyl acetate and the organics were washed with saturated aqueous NH4CI solution, water and brine. The organic layer was dried (MgS04) and concentrated, and the resulting residue was purified by flash chromatography to yield l -(4-bromo-3-((tert- butyldimethylsilyloxy)methyl)phenyl)-2-chloroethanone (5.1 g, 67percent).

Reference： [1]Patent: WO2012/68234,2012,A2 .Location in patent: Page/Page column 583; 584

63
[ 67442-07-3 ]
[ 1378382-83-2 ]
[ 1378382-86-5 ]

Yield	Reaction Conditions	Operation in experiment
75%		To a solution of (6- bromonaphthalen-l-yloxy)triisopropylsilane (10.4 g, 27.5 mmol) in tetrahydrofuran (180 mL) under argon at -78 °C was added ra-butyllithium (2.5M in hexanes, 11.5 mL, 28.7 mmol). After stirring at this temperature for one hour, a solution of 2-chloro-N-methoxy-N-methyl acetamide (7.6 g, 55.2 mmol) in tetrahydrofuran (10 mL) was added to the reaction via cannula. The dry ice bath was removed and the reaction was allowed to warm to room temperature. After one hour at room temperature the reaction was diluted with ethyl acetate and the organics were washed with saturated aqueous NH4C1 solution, water and brine. The organic layer was dried (MgS04) and concentrated, and the resulting residue was purified by flash chromatography to yield 2-chloro-l -(5-(triisopropylsilyloxy)-naphthalen-2-yl)ethanone (7.8 g, 75percent) as a pale yellow oil.

Reference： [1]Patent: WO2012/68234,2012,A2 .Location in patent: Page/Page column 582; 583

64
[ 67442-07-3 ]
[ 1414360-77-2 ]
[ 663925-96-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 10l-(4-teri-butoxy-2-isopropoxy-l,3-benzothiazol-7- l)-2-chloro-ethanoneA solution of n-butyllithium in hexanes (1.6 M, 0.41 mL, 0.65 mmoles) was added dropwise to a pre-cooled (-50 °C) solution of 7-bromo-4-tert-butoxy-2-isopropoxy-l,3-benzothiazole XVII (225 mg, 0.59 mmoles) in methyl tert-butyl ether (2.5 mL) maintaining a temperature below -45 °C. The mixture was allowed to warm to -20 °C and left to stir for 30 minutes. A solution of 2-chloro-N-methoxy-N-methyl acetamide (122 mg, 0.89 mmoles) in methyl tert- butyl ether (2.5 mL) was then added dropwise maintaining a temperature below -15 °C and the mixture allowed to stir for 20 minutes. The reaction was then quenched by the addition of saturated ammonium chloride solution (2.0 mL) and water (10.0 mL). The aqueous phase was extracted with methyl fert-butyl ether (2 x 10 mL) and the combined organic phases were dried (MgSC^), filtered and evaporated to give a pale orange solid. Purification by flash chromatography (isohexane/EtOAc, 95/5 to 90/10) gave title compound XVI as a beige solid (120 mg, 0.35 mmoles).1H NMR (500 MHz, CDC13) delta 7.75 (d, J= 8.5 Hz, 1H), 7.11 (d, J= 8.5 Hz, 1H), 5.46 (hept, J= 6.2 Hz, 1H), 4.79 (s, 2H), 1.50 (s, 9H), 1.47 (d, J= 6.2 Hz, 6H).

Reference： [1]Patent: WO2012/156693,2012,A1 .Location in patent: Page/Page column 42-43; 52-53; 56

65
[ 67442-07-3 ]
[ 3761-92-0 ]
[ 63988-10-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	In tetrahydrofuran; diethyl ether; at 0 - 20℃; for 3h;	1 -Chloro-2-octanone (2a): A solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (10.00 g, 72.7 mmol) in 300 mL of dry THF at 0°C was treated with 46 mL of hexylmagnesium bromide (2.0 M in diethyl ether). The mixture was allowed to slowly warm to room temperature and stir for 3 hours before being quenched with a 5percent HCI solution. The reaction mixture was diluted with diethyl ether (300 mL) and the organic layer was washed once with saturated sodium bicarbonate (200 mL) and twotimes with brine (200 mL each). The organic layer was dried over MgSO4 and concentrated under vacuum to give 10.86 g (92percent) of the title compound, of the title compound, a yellow liquid that required no further purification. 1H NMR (CDCI3, 400 MHz): 4.07 (5, 2H), 2.58 (t, J= 7.4 Hz, 2H), 1.61 (m, 2H), 1.28 (m, 6H), 0.88 (t, J= 6.9 Hz, 3H). 130 NMR (ODd3, 100 MHz): 203.0, 48.3, 39.9, 31.6, 28.9, 23.7, 22.6, 14.1. HRMS-EI: calc.163.0890, found 163.0892, A = 1.2 ppm.

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 951 - 954
[2]Patent: WO2014/67016,2014,A1 .Location in patent: Page/Page column 10; 11

66
[ 67442-07-3 ]
[ 15890-72-9 ]
[ 56354-96-2 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 951 - 954

67
[ 67442-07-3 ]
2-ethylhexylmagnesium bromide [ No CAS ]
[ 1417444-64-4 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 951 - 954

68
[ 889362-84-9 ]
[ 67442-07-3 ]
[ 1426954-84-8 ]

Yield	Reaction Conditions	Operation in experiment
17.9%		Under a nitrogen atmosphere, a solution of ferf-butyllithium (481 ml, 737.6 mmol, 1.6 M) was added dropwise to a solution of (3-tert-Butoxy-5-fluoro-phenyl)-thiocarbamic acid O-isopropyl ester (200 g, 700.83 mmol) in 2-Me-THF (1600 ml) at temperature below -65 °C. The reaction temperature was warmed to -35°C, and a second portion of ferf-butyllithium (388 ml, 737.6 mmol, 1 .9 M) was added slowly while keeping the temperature below -35 °C. The reaction mixture was then stirred at this temperature for 3 h and cooled down to -70 °C. A solution of /V-methyl-N-methoxy chloroacetamide (96.4 g, 700.83 mmol) in 2-MeTHF (300 ml) was added to the reaction mixture while keeping the temperature below -70 °C. The mixture was then warmed to -30 °C and stirred for 45 minutes. The cold reaction mixture was quenched by dropwise addition of 30percent HCI in isopropanol (240 g) followed by the addition of 1500 ml water. The organic layer was washed sequentially with 1000 ml water, 1500 ml saturated aqueous NaHC03 and 1500 ml brine. After concentration, the resulting light brown residue was added to isopropanol (135 ml). The mixture was warmed to 50 °C and cooled down slowly to 25 °C. n-heptane (135 ml) was added dropwise to the solution and the mixture was stirred overnight. The slurry was filtered and the filter cake was washed with n- heptane (40 ml) followed by another portion of n-heptane (20 ml). The cake was dried under vacuum to yield 1-(5-fert-butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanone as off- white powder (42.8 g, 17.9percent yield). 1H NMR (400 MHz, CDCI3): 7.60 (d, J = 2.0 Hz, 1 H), 7.45 (d, J = 2.0 Hz, 1 H), 5.40 (heptet, J = 6.3 Hz, 1 H), 4.77 (s, 2H), 1 .47 (d, J = 6.3 Hz, 6H), 1.40 (s, 9H). LCMS: [M+H]+ = 342.1 , RT = 7.29 min.
17.9%		Under a nitrogen atmosphere, a solution of ferf-butyllithium (481 ml, 737.6 mmol, 1.6 M) was added dropwise to a solution of (3-tert-Butoxy-5-fluoro-phenyl)-thiocarbamic acid O-isopropyl ester (200 g, 700.83 mmol) in 2-Me-THF (1600 ml) at temperature below -65 °C. The reaction temperature was warmed to -35°C, and a second portion of ferf-butyllithium (388 ml, 737.6 mmol, 1 .9 M) was added slowly while keeping the temperature below -35 °C. The reaction mixture was then stirred at this temperature for 3 h and cooled down to -70 °C. A solution of /V-methyl-N-methoxy chloroacetamide (96.4 g, 700.83 mmol) in 2-MeTHF (300 ml) was added to the reaction mixture while keeping the temperature below -70 °C. The mixture was then warmed to -30 °C and stirred for 45 minutes. The cold reaction mixture was quenched by dropwise addition of 30percent HCI in isopropanol (240 g) followed by the addition of 1500 ml water. The organic layer was washed sequentially with 1000 ml water, 1500 ml saturated aqueous NaHC03 and 1500 ml brine. After concentration, the resulting light brown residue was added to isopropanol (135 ml). The mixture was warmed to 50 °C and cooled down slowly to 25 °C. n-heptane (135 ml) was added dropwise to the solution and the mixture was stirred overnight. The slurry was filtered and the filter cake was washed with n- heptane (40 ml) followed by another portion of n-heptane (20 ml). The cake was dried under vacuum to yield 1-(5-fert-butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanone as off- white powder (42.8 g, 17.9percent yield). 1H NMR (400 MHz, CDCI3): 7.60 (d, J = 2.0 Hz, 1 H), 7.45 (d, J = 2.0 Hz, 1 H), 5.40 (heptet, J = 6.3 Hz, 1 H), 4.77 (s, 2H), 1 .47 (d, J = 6.3 Hz, 6H), 1.40 (s, 9H). LCMS: [M+H]+ = 342.1 , RT = 7.29 min.
17.9%	With tert.-butyl lithium; In 2-methyltetrahydrofuran; at -70 - -30℃; for 3.75h;	c) 1-(5-tert-Butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanone Under a nitrogen atmosphere, a solution of ferf-butyllithium (481 ml, 737.6 mmol, 1.6 M) was added dropwise to a solution of (3-fert-Butoxy-5-fluoro-phenyl)-thiocarbamic acid O-isopropyl ester (200 g, 700.83 mmol) in 2-Me-THF (1600 ml) at temperature below -65 °C. The reaction temperature was warmed to -35°C, and a second portion of ferf-butyllithium (388 ml, 737.6 mmol, 1 .9 M) was added slowly while keeping the temperature below -35 °C. The reaction mixture was then stirred at this temperature for 3 h and cooled down to -70 °C. A solution of /V-methyl-N-methoxy chloroacetamide (96.4 g, 700.83 mmol) in 2-MeTHF (300 ml) was added to the reaction mixture while keeping the temperature below -70 °C. The mixture was then warmed to -30 °C and stirred for 45 minutes. The cold reaction mixture was quenched by dropwise addition of 30percent HCI in isopropanol (240 g) followed by the addition of 1500 ml water. The organic layer was washed sequentially with 1000 ml water, 1500 ml saturated aqueous NaHC03 and 1500 ml brine. After concentration, the resulting light brown residue was added to isopropanol (135 ml). The mixture was warmed to 50 °C and cooled down slowly to 25 °C. n-heptane (135 ml) was added dropwise to the solution and the mixture was stirred overnight. The slurry was filtered and the filter cake was washed with n- heptane (40 ml) followed by another portion of n-heptane (20 ml). The cake was dried under vacuum to yield 1 -(5-ferf-butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanone as off- white powder (42.8 g, 17.9percent yield). 1 H NMR (400 MHz, CDCI3): 7.60 (d, J = 2.0 Hz, 1 H), 7.45 (d, J = 2.0 Hz, 1 H), 5.40 (heptet, J = 6.3 Hz, 1 H), 4.77 (s, 2H), 1.47 (d, J = 6.3 Hz, 6H), 1 .40 (s, 9H). LCMS: [M+H]+ = 342.1 , RT = 7.29 min

Reference： [1]Patent: WO2013/35047,2013,A1 .Location in patent: Page/Page column 46; 47
[2]Patent: US2013/245080,2013,A1 .Location in patent: Paragraph 0252-0254
[3]Patent: WO2014/33654,2014,A1 .Location in patent: Page/Page column 44-45

69
[ 624-28-2 ]
[ 67442-07-3 ]
[ 1260759-84-9 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 2642 - 2650

70
[ 67442-07-3 ]
[ 6380-21-8 ]
[ 1448663-01-1 ]
[ 1448663-02-2 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To the solution of 2-propenylphenol (1), (1 equiv, mixture of E and Z isomers) in DMF (C=0.5 M) solid K2CO3 (2equiv) was added, and the resulting mixture was stirred at room temperature for 15 min. Next, the appropriate alkylating reagent 2a or 2b (1.2 equiv) was added and the reaction mixture was heated at 50 °C for 20 h with vigorous stirring. After that time, solvent was removed under vacuum and water was added to the residue. The aqueous phase was extracted with EtOAc and the organic layer was washed with brine and dried over MgSO4. Crude products were purified by column chromatography using mixture of EtOAc/c-hexane as eluent.

Reference： [1]Tetrahedron,2013,vol. 69,p. 7408 - 7415

71
[ 67442-07-3 ]
[ 111373-03-6 ]
2-{4-[2-(N-methoxy-N-methylamino)-2-oxoethyl]piperazin-1-yl}benzonitrile [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2013,p. 4918 - 4932

72
[ 67442-07-3 ]
2-bromo-9,9-difluoro-7-iodo-9H-fluorene [ No CAS ]
1-(7-bromo-9,9-difluoro-9-hydrofluoren-2-yl)-2-chloroethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		Under nitrogen protection, 1340.5g of intermediate was taken, dissolved in 200mL anhydrous THF, the reaction system was cooled to -15°, and 13g of THF solution of 13g isopropylmagnesium chloride was added dropwise. During the dropwise addition, the reaction temperature was controlled at -5°. After the completion of the dropwise addition, the reaction was continued for 1 h, and then 60 g of a solution of 15 g of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> in THF was added dropwise thereto, and the reaction temperature was controlled not to exceed -5° during the dropwise addition. After the end of the addition, the temperature of the system was raised to -5-0 °, and after the reaction was completed, the reaction was quenched by the addition of 2N hydrochloric acid at 0 °, and ethyl acetate (200 mL) was added, and the mixture was separated. , filtration, solvent recovery under reduced pressure, residue,With methanol:Water = 10:1 recrystallized to give a white solid, 27 g, yield 76percent.
74%		1L three bottles, 20g2- iodine-bromo-7-fluoro-9,9-fluorene And 500mL THF (reaction solvent), dissolve clear. Temperature of the system was cooled to -10 deg.] C, was added dropwise 36.5g 18wt% of isopropylmagnesium chloride in tetrahydrofuran was incubated for 1 hour. Then added dropwise 48.3g 20wt% of the active acid amide (<strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong>) in toluene. Incubated for 1 hour. End of the reaction, with 35g 15% hydrochloric acid quenched stratification. Toluene and the combined organic phases. Removing solvent to give crude product was recrystallized from toluene to give 1- (7-bromo-9,9-difluoro-9H-fluoren-2-yl) -2-chloroethanone13g, yield 74%.
70.8%		C. Synthesis of Intermediate 22 [0210] A 3-neck flask was charged with 21 (100 g) and THF (800 mL). The solution was degassed three times by slowly applying vacuum, followed by breaking vacuum with nitrogen. The solution was cooled to -10 C. internal temperature. A solution of 2N i-PrMgCl solution in THF (125 g, 1.04 mole equiv) was added slowly while maintaining internal temperature at -10 C. to 0 C. The resulting mixture was then stirred for 30 minutes at -10 C. until reaction was complete. 2-Chloro-N-methoxy-N-methylacetamide (40.6 g, 1.20 mole equiv) was dissolved in MTBE (122 g, 1.22 wt equiv) and filtered through a 1 mum filter. The MTBE solution of the acetamide was then added slowly to the flask maintaining internal temperature at -10 C. to 0 C. Upon completion of the addition, the internal temperature was adjusted to 0 C. and agitated for 2 hours. After the reaction is complete, 1N HCl (750 g) was added slowly so that the internal temperature did not exceed 20 C. If necessary, the internal temperature was adjusted to 20 C. The layers were separated and the aqueous layer was extracted with MTBE (410 g). The organic layers were combined and dried over MgSO4. The MgSO4 was filtered off and rinsed with THF (200 g). The filtrate and rinse were concentrated under vacuum 10 volumes (1000 mL). Isopropanol (785 g) was added and small amounts of crystals began to form. This slurry was again concentrated under vacuum to 10 volumes (1000 mL). Isopropanol (785 g) was once again added and the slurry was concentrated under vacuum to 10 volumes (1000 mL). The internal temperature was adjusted to 20-25 C. and agitated for ca. 30 minutes. The slurry was filtered and rinsed with isopropanol (100 g) then dried under vacuum to provide 62.28 g (70.8%, 98% purity by HPLC) of the product 22 as an off-white to pale yellow solid. 1H NMR (400 MHz, CDCl3, delta): 8.19 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.82 (s, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.52 (d, J=7.8 Hz, 1H), 4.71 (s, 2H). 19F NMR (376 MHz, CDCl3) delta -111.4 (s, 2F).

70.8%		C. Synthesis of Intermediate 22 [0244] A 3-neck flask was charged with 21 (100 g) and THF (800 mL). The solution was degassed three times by slowly applying vacuum, followed by breaking vacuum with nitrogen. The solution was cooled to -10 C. internal temperature. A solution of 2N i-PrMgCl solution in THF (125 g, 1.04 mole equiv) was added slowly while maintaining internal temperature at -10 C. to 0 C. The resulting mixture was then stirred for 30 minutes at -10 C. until reaction was complete. 2-Chloro-N-methoxy-N-methylacetamide (40.6 g, 1.20 mole equiv) was dissolved in MTBE (122 g, 1.22 wt equiv) and filtered through a 1 mum filter. The MTBE solution of the acetamide was then added slowly to the flask maintaining internal temperature at -10 C. to 0 C. Upon completion of the addition, the internal temperature was adjusted to 0 C. and agitated for 2 hours. After the reaction is complete, 1N HCl (750 g) was added slowly so that the internal temperature did not exceed 20 C. If necessary, the internal temperature was adjusted to 20 C. The layers were separated and the aqueous layer was extracted with MTBE (410 g). The organic layers were combined and dried over MgSO4. The MgSO4 was filtered off and rinsed with THF (200 g). The filtrate and rinse were concentrated under vacuum 10 volumes (1000 mL). Isopropanol (785 g) was added and small amounts of crystals began to form. This slurry was again concentrated under vacuum to 10 volumes (1000 mL). Isopropanol (785 g) was once again added and the slurry was concentrated under vacuum to 10 volumes (1000 mL). The internal temperature was adjusted to 20-25 C. and agitated for ca. 30 minutes. The slurry was filtered and rinsed with isopropanol (100 g) then dried under vacuum to provide 62.28 g (70.8%, 98% purity by HPLC) of the product 22 as an off-white to pale yellow solid. 1H NMR (400 MHz, CDCl3, delta): 8.19 (s, 1H), 8.12 (d, J=7.8 Hz, 1H), 7.82 (s, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.52 (d, J=7.8 Hz, 1H), 4.71 (s, 2H). 19F NMR (376 MHz, CDCl3) delta -111.4 (s, 2F).
1.51 g		2 1.96 g of compound 2 and 6.66 g of N-fluorobisulfonamide were added to 40 mL of nitrogen Water tetrahydrofuran, the ice salt bath was cooled for 30 minutes, and then a solution of potassium tris Of tetrahydrofuran solution), dropping the natural temperature of 3h. The reaction solution was cooled in an ice bath and 0.1 mL of methanol was added dropwise Grade), adding n-hexane 40 mL to dilute the reaction solution. The above suspension was stirred for 30 minutes and then filtered, and the filter cake was oil Ether (50 mL x 3), the filtrate was collected and the column chromatography (petroleum ether) gave 3 m of a white solid (2.57 g).
		into the reactor add LD-I and tetrahydrofuran; Replace nitrogen 3 times, under nitrogen protection, cool the solution at-12 C, slowly add 2N iso-propylmagnesium chloride THF solution, the resulting reaction solution is stirred at -12C for 1h, until the reaction is complete, dissolve 2-chloro-N-methoxyl-N-methylacetamide into methyl tert-butyl ether, after that slowly add 2-chloro-N-methoxyl-N-methylacetamide solution into the reactor, while dropping, keep the internal temperature at -10C, adjust the internal temperature at 0C and continue stirring for 2 hours, after the reaction is completed, 1N hydrochloric acid is added and the layers are separated, and extracting the aqueous layer with methyl tert-butyl ether, combining organic layers, concentrate under reduced pressure at 10 volumes, adjust the temperature at 20 C, and stir for 1.5h, centrifuge, and wash the filter cake with isopropyl alcohol, dried, and obtained solid product LD-J.
		Preparation steps: the reactor was added LD-I and tetrahydrofuran; nitrogen three times, under nitrogen protection, the solution was cooled to -12 C, 2N isopropyl magnesium chloride in THF was slowly added, the resulting reaction was -12 C Stirred for 1 h until the reaction was complete. Dissolve <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> in methyl tert-butyl ether, then add 2-chloro-N-methoxy-N- dimethylacetamide solution was slowly added to the reaction vessel, was added dropwise while maintaining the internal temperature at -10 C, dropwise, the inner portion temperature was adjusted to 0 C, stirring was continued for 2h, after completion of the reaction, 1N hydrochloric acid, layered, and The aqueous layer was extracted with methyl tert-butyl ether, the organic layers were combined, concentrated under reduced pressure to 10 volumes, the temperature was adjusted to 20 C, and stirred for 1.5 hours, centrifuged, and the filter cake was washed with isopropanol and dried to give a solid product. LD-J.

Reference： [1]Patent: CN109678686,2019,A .Location in patent: Paragraph 0077-0079
[2]Patent: CN105237384,2016,A .Location in patent: Paragraph 0161; 0162
[3]Patent: US2013/324740,2013,A1 .Location in patent: Paragraph 0209; 0210
[4]Patent: US2013/324496,2013,A1 .Location in patent: Paragraph 0243-0244
[5]Journal of Medicinal Chemistry,2014,vol. 57,p. 2033 - 2046
[6]Patent: CN106117187,2016,A .Location in patent: Paragraph 0062; 0064
[7]Patent: CN107879908,2018,A .Location in patent: Paragraph 0044-0047; 0069; 0090
[8]Patent: CN107954990,2018,A .Location in patent: Paragraph 0113; 0115; 0116; 0186; 0255

73
[ 67442-07-3 ]
[ 824-79-3 ]
N-methoxy-N-methyl-2-(p-toluenesulfonyl)acetamide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 10978 - 10985

74
[ 67442-07-3 ]
[ 52107-66-1 ]
3-(2-chloroacetyl)-2-methylbenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In tetrahydrofuran; hexane; at -78℃; for 0.25h;	Step A: 3-(2-Chloroacetyl)-2-methylbenzonitrile; To a solution of 3-iodo-2-methylbenzonitrile (7.71 g, 31.7 mmol) and 2-chloro-N-methoxy-Nmethylacetamide(6.55 g, 47.6 mmol) in THF (100 mL) at -78 °C was added n-butylithium (2.5Min hexanes, 14.0 mL, 34.9 mmol) dropwise. After complete addition, the mixture was stirred15 min. at -78 °C, then quenched with the dropwise addition of 1 N HCl. The mixture was partitioned between EtOAc/water and the layers separated. The aqueous was extracted withEtOAc (2x) and the combined organic layers were washed with brine, dried (magnesium sulfate),filtered and concentrated. Recrystallization of the resulting residue from hexanes provided 3-(2-chloroacetyl)-2-methylbenzonitrile: 1H NMR (500 MHz, CDCh), 8 7.76 (m, 2H), 7.41 (m, 1H),4.55 (s, 2H), 2.68 (s, 3H).
	In tetrahydrofuran; hexane; at -78℃; for 0.25h;	To a solution of 3-iodo-2-methylbenzonitrile (7.71 g, 31.7 mmol) and <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (6.55g, 47.6 mmol) in THF (100 mL) at -78 °C was added n-butylithium (2.5 M in hexanes, 14.0 mL, 34.9 mmol) dropwise.After complete addition, the mixture was stirred 15 min. at -78 °C, then quenched with the dropwise addition of 1 NHCl. The mixture was partitioned between EtOAc/water and the layers separated. The aqueous was extracted withEtOAc (2x) and the combined organic layers were washed with brine, dried (magnesium sulfate), filtered and concentrated.Recrystallization of the resulting residue from hexanes provided 3-(2-chloroacetyl)-2-methylbenzonitrile:1H NMR (500 MHz, CDCl3), delta 7.76 (m, 2H), 7.41 (m, 1H), 4.55 (s, 2H), 2.68 (s, 3H).

Reference： [1]Patent: WO2013/28474,2013,A1 .Location in patent: Page/Page column 73; 74
[2]Patent: EP2744499,2016,B1 .Location in patent: Paragraph 0173

75
[ 530-48-3 ]
[ 67442-07-3 ]
[ 1570275-36-3 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 3619 - 3622

76
[ 67442-07-3 ]
[ 105-13-5 ]
[ 191731-32-5 ]

Yield	Reaction Conditions	Operation in experiment
9.85%	In tetrahydrofuran; ethyl acetate;	Step 1. N-methoxy-2-((4-methoxybenzyl)oxy)-N-methylacetamide To a suspension of sodium hydride (1.86 g, 46.5 mmol) in THF (80 ml) at 0° C. was added (4-methoxyphenyl)methyl alcohol (5.80 mL, 46.7 mmol) over 5 min. The reaction mixture was warmed to RT for 1 h, then cooled to 0° C. and a solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (6.50 g, 47.3 mmol) in THF (20 mL) was added. The reaction mixture was warmed to room temperature and stirred for 72 hr then quenched with NH4Cl and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (2) and the combined organic extracts were washed with brine (1), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (120 g, 30percent to 80percent EtOAc in hexanes) gave N-methoxy-2-((4-methoxybenzyl)oxy)-N-methylacetamide (1.10 g, 4.60 mmol, 9.85percent yield) as a yellow oil. ESI (M+Na) 262.1.

Reference： [1]Patent: US2014/107109,2014,A1 .Location in patent: Page/Page column

77
[ 79-11-8 ]
[ 1117-97-1 ]
[ 67442-07-3 ]

Yield	Reaction Conditions	Operation in experiment
94%		General procedure: A solution of NHMe(OMe) (0.360 g, 6.0 mmol) and benzoic acid (0.244 g, 2.0 mmol) was stirred in dry toluene (10 mL) at 0 °C for 10 min. A solution of PCl3 (0.137 g, 1.0 mmol) in dry toluene (2 mL) was then added dropwise to the mixture. The mixture was warmed to r.t. slowly and then stirred at 60 °C for 0.5 h. When the reaction was complete (TLC monitoring), the mixture was cooled to r.t. The mixture was then quenched with sat. NaHCO3 soln (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (anhyd MgSO4). The solvent was removed in vacuo.The product was purified by column chromatography (silica gel, petroleum ether?EtOAc, 3:2) to give pure 3a as a colorless oil; yield: 320 mg (97percent).

Reference： [1]Synthesis,2014,vol. 46,p. 320 - 330

78
[ 663925-82-4 ]
[ 67442-07-3 ]
[ 663925-96-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4341 - 4347

79
[ 67442-07-3 ]
[ 1401305-30-3 ]
2-chloro-1-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a 10L four necked flask was charged l-Isopropyl-3-methyl-lH-l,2,4-triazole 7 (400 g) in THF (2.5 L). The resulting solution was cooled to -40 C and 2.5 M n-butyllithium BuLi in n- hexanes (1.41 L) was added while keeping the internal temp, below -20C. The resulting yellow suspension was stirred at -40C for 1 hour before being transferred. To a 20L flask was charged <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> 10 (485 g) in THF (4 L). The resulting solution was cooled to -40 C at which point a white suspension was obtained, and to this was added the solution of lithiated triazole 7 keeping the internal temp, below -20C. At this point a yellow orange solution was obtained which was stirred at - 30C for lhour. Propionic acid (520 mL) was added keeping the internal temp, below -20C. The resulting off-white to yellowish suspension was warmed to -5 C over 30 minutes. Citric acid (200 g) in water (0.8 L) was added and after stirring for 5 minutes a clear biphasic mixture was obtained. At this point stirring was stopped and the bottom aqueous layer was removed. The organic phase was washed with 20w% K3PO4 solution (1 L), 20w% K2HP04 solution (2 L), and 20w% NaCl solution (1 L). The organics was reduced to ca 4L via distillation under vacuum to afford 2-chloro-l-(l-isopropyl-3- methyl-lH-l,2,4-triazol-5-yl)ethanone 13 as a dark amber liquid which was used "as is" in the next step.

Reference： [1]Patent: WO2014/140073,2014,A1 .Location in patent: Page/Page column 11; 26
[2]Organic Process Research and Development,2019,vol. 23,p. 775 - 782

80
[ 67442-07-3 ]
[ 1172111-81-7 ]
tert-butyl (2S,3S)-3-(2-(methoxy(methyl)amino)-2-oxoethoxy)-2-(naphthalen-2-yl)-3-phenylpropyl(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		Compound No. 8a (300 mg, 0.77 mmol) in DMF was treated with NaH (92 mg, 2.30 mmol) at 0°C for 20 minutes. <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (158 mg, 1.15 mmol) in DMF was added at 0°C slowly into the stirring solution. The resulting mixture was warmed to room temperature and stirred for 15 hours at room temperature before LCMS indicated the reaction was complete. The reaction was diluted with 100 mL of ethyl acetate, washed with plenty of water and brine, dried with sodium sulfate ,filtered, and concentrated under reduced pressure. ISCO purification eluting with 0-80percent ethyl acetate in hexane afforded 350 mg (95percent) of a clean product. Both LCMS and NMR data matched the proposed structure.

Reference： [1]Patent: WO2014/159251,2014,A2 .Location in patent: Page/Page column 194

81
[ 1878-66-6 ]
[ 67442-07-3 ]
[ 33107-83-4 ]