[ CAS No. 2945-08-6 ] {[proInfo.proName]}

Name: 2945-08-6|Methyl 2-(4-nitrophenyl)acetate|98%
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Product Details of [ 2945-08-6 ]

CAS No. :	2945-08-6	MDL No. :	MFCD00024802
Formula :	C₉H₉NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PQRGTRBYCFLHKY-UHFFFAOYSA-N
M.W :	195.17	Pubchem ID :	270191
Synonyms :

Calculated chemistry of [ 2945-08-6 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	51.13
TPSA :	72.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.27 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.69
Log Po/w (XLOGP3) :	1.72
Log Po/w (WLOGP) :	1.31
Log Po/w (MLOGP) :	0.89
Log Po/w (SILICOS-IT) :	-0.1
Consensus Log Po/w :	1.1

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.19
Solubility :	1.27 mg/ml ; 0.0065 mol/l
Class :	Soluble
Log S (Ali) :	-2.85
Solubility :	0.275 mg/ml ; 0.00141 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.26
Solubility :	1.07 mg/ml ; 0.00546 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.69

Safety of [ 2945-08-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 2945-08-6 ]

* 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 [ 2945-08-6 ]
Downstream synthetic route of [ 2945-08-6 ]

[ 2945-08-6 ] Synthesis Path-Upstream 1~8

1
[ 2945-08-6 ]
[ 19733-56-3 ]

Reference： [1] Patent: CN106883166, 2017, A,

2
[ 2945-08-6 ]
[ 100-27-6 ]

Reference： [1] Chemistry - A European Journal, 2011, vol. 17, # 27, p. 7414 - 7417
[2] Synthesis, 2011, # 18, p. 2935 - 2940
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134

3
[ 101-41-7 ]
[ 2945-08-6 ]
[ 10268-12-9 ]
[ 30095-98-8 ]

Reference： [1] Bulletin of the Chemical Society of Japan, 1995, vol. 68, # 4, p. 1155 - 1161
[2] Journal of Organic Chemistry, 1998, vol. 63, # 4, p. 952 - 958
[3] Journal of Organic Chemistry, 1996, vol. 61, # 17, p. 5944 - 5947
[4] Tetrahedron Letters, 2001, vol. 42, # 7, p. 1387 - 1389
[5] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 8088 - 8094

4
[ 2916-76-9 ]
[ 98-95-3 ]
[ 2945-08-6 ]
[ 30095-98-8 ]

Reference： [1] Journal of Organic Chemistry, 1984, vol. 49, # 23, p. 4571 - 4572
[2] Journal of Organic Chemistry, 1984, vol. 49, # 23, p. 4571 - 4572
[3] Journal of the American Chemical Society, 1985, vol. 107, # 19, p. 5473 - 5483

5
[ 101-41-7 ]
[ 2945-08-6 ]
[ 30095-98-8 ]

Reference： [1] Phosphorus, Sulfur and Silicon and the Related Elements, 2004, vol. 179, # 2, p. 221 - 226
[2] Tetrahedron Letters, 2005, vol. 46, # 48, p. 8307 - 8310

6
[ 2945-08-6 ]
[ 39552-81-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 22, p. 8092 - 8105
[2] Chemical Communications, 2000, # 5, p. 401 - 402
[3] Synthetic Communications, 2010, vol. 40, # 5, p. 661 - 665
[4] Advanced Synthesis and Catalysis, 2012, vol. 354, # 10, p. 1879 - 1884
[5] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 19, p. 2759 - 2770

7
[ 2945-08-6 ]
[ 18600-42-5 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1914, vol. <2> 89, p. 500,512[2] Journal fuer Praktische Chemie (Leipzig), 1915, vol. <2> 91, p. 7

8
[ 2945-08-6 ]
[ 890839-11-9 ]

Reference： [1] Green Chemistry, 2017, vol. 19, # 20, p. 4798 - 4803

[ 2945-08-6 ] Synthesis Path-Downstream 1~40

1
[ 67-56-1 ]
[ 104-03-0 ]
[ 2945-08-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; for 12h;Reflux;	Compound 9-1 was refluxed in a solution of HCl in MeOH (500 ml) for 12 h, and then the resulting solution was concentrated to give compound 9-2 (brown solid, 53 g, Yield 100%). 1H NMR (400 MHz, CDCl3): delta ppm 8.21 (d, J=8 Hz, 2H), 7.48 (d, J=8 Hz, 2H), 3.77 (s, 2H), 3.75 (s, 3H).
98%	With thionyl chloride; at 0 - 23℃; for 2.16667h;	Step 1 : To a stirred MeOH (100 mL) solution of 2-(4-nitrophenyl)acetic acid (10.0 g, 55.202 mmol, 1 .0 eq) SOCl2 (6.7 mL, 1 10.045 mmol, 2.0 eq) was added at 0C for 10 min and the mixture was stirred at RT for 2 h, then excess of SOCl2 was removed under vacuum and the residue was dissolved in EtOAC (50 mL), washed with water, sat. (aq) NaHCO3, dried (Na2SO4) and the solvent was evaporated to get methyl 2-(4-nitrophenyl)acetate (10.5g, 98%, solid; TLC system: EtOAc/PE (3:7), Rf: 0.60).
97%	With sulfuric acid; for 18h;Inert atmosphere; Reflux;	(a) Synthesis of (4-nitro-phenyl)-acetic acid methyl ester To 4-nitrophenyl acetic acid (50.12 g, 276 mmol) dissolved in methanol (300 mL) was added concentrated sulfuric acid (8 mL). The reaction mixture was stirred at reflux for 18 h under nitrogen atmosphere. The methanol was removed in vacuo and the resulting residue was diluted with H2O. The reaction mixture was extracted two times with CH2Cl2, and then washed with 0.5% NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated by rotary evaporation. The resulting solid was dried under vacuum for about 10-19 h. The title compound as pale yellow solid was used as such with no further purification (52.2 g, 97% yield).1H NMR (300 MHz, CDCl3, TMS): delta 3.72 (s, 3H), 3.74 (s, 2H), 7.43 to 7.48 (m, 2H), 8.17-8.21 (m, 2H).LC-MSD (ES+): (m/z) 196 [(M+H)+, 100].

97%	With sulfuric acid; for 3h;Reflux;	A single-neck RBFequipped with a magnetic stirrer and a reflux condenser was charged sequentiallywith 4-nitrophenyl acetic acid (1, 60.88 g, 336.08 mmol), MeOH (360 mL) and concentrated sulfuricacid (2.5 mL). The solution was heated to reflux for 3 h. After evaporation invacuo, the resulting residue was dissolved in ether (350 mL). The ether solution was then washed withsaturated sodium bicarbonate solution (50 mL x 2) and brine (50 mL x 2), driedover magnesium sulfate and filtered. The filtrate was concentrated under vacuumto afford white crystals as compound 2(63.80 g, 97%).
97%	With sulfuric acid; for 12h;Reflux;	S1. Add 626 g of methanol to a 1000 mL four-necked flask with a reflux condenser, and slowly add 67.5 g of concentrated sulfuric acid.And 414 g of p-nitrophenylacetic acid was heated to reflux for 12 h.S2. The above reaction solution was cooled to room temperature, poured into a 2000 mL beaker containing 72.2 g of sodium carbonate and 672 g of water, drained, washed with water until the wash was neutral.After draining and drying, methyl p-nitrophenylacetate (434 g, yield 97%, mp: 53-54 C) was obtained.
96%	With sulfuric acid; for 16h;Heating / reflux;	Methyl 2-(4-Nitrophenyl)acetate (1); A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 4-nitrophenylacetic acid (14.1 g, 77.5 mmol), anhydrous methanol (130 mL) and concentrated sulfuric acid (12.0 mL, 216 mmol), and the reaction mixture was heated at reflux for 16 h. After this time, the reaction was concentrated to dryness under reduced pressure. The resulting residue was partitioned between water (500 mL) and diethyl ether (200 mL) and the layers separated. The aqueous phase was extracted with diethyl ether (100 mL). The combined organic phases were washed with saturated aqueous sodium carbonate and dried over magnesium sulfate, and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure and dried to a constant weight under vacuum to afford a 96% yield of 1 (14.6 g) as a white solid: mp 45-46 C.; 1H NMR (500 MHz, CDCl3) delta 8.19 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 3.75 (s, 2H), 3.73 (s, 3H). Reference: Tetrahedron 2002, 58, 10113.
96%	With sulfuric acid; for 16h;Reflux;	A l-L single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2-(4-nitrophenyl)acetic acid (If) (14.1 g, 77.5 mmol), anhydrous methanol (130 mL) and concentrated sulfuric acid (12.0 mL, 216 mmol), and the reaction mixture was heated at reflux for 16 h. After this time, the reaction was concentrated to dryness under reduced pressure. The resulting residue was partitioned between water (500 mL) and diethyl ether (200 mL) and the layers separated. The aqueous phase was extracted with diethyl ether (100 mL). The combined organic phases were washed with saturated aqueous sodium carbonate and dried over magnesium sulfate, and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure and dried to a constant weight under <n="68"/>vacuum to afford a 96% yield of Ig (14.6 g) as a white solid: mp 45-46 0C; 1H NMR (500 MHz, CDCl3) 58.19 (d, 2H, J = 8.5 Hz), 7.46 (d, 2H, J = 8.5 Hz), 3.75 (s, 2H), 3.73 (s, 3H). Reference: Tetrahedron 2002, 58, 10113.
91%	With sulfuric acid; for 5h;Reflux;	To a solution of 4-nitrobenzene acetic acid (9.0?g, 50?mmol) in absolute methanol (60?mL), concentrated sulfuric acid (1?mL) was added. The reaction mixture was refluxed for 5?h. After the completion of the reaction, the residue was concentrated under vacuum, poured into deionized water (20?mL) and then extracted with ethyl acetate (3?*?10?mL). The organic layers were combined and washed with saturated aqueous NaCl (10?mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane (1:8, v:v) as an eluent to afford 4 as yellow solid. Yield: 8.9?g (91%, 45.5?mmol). 1H NMR (400?MHz, CDCl3) delta [ppm]?=?8.21 (d, 3J(H,H)?=?8.8?Hz, 2H), 7.48 (d, 3J(H,H)?=?8.8?Hz, 2H), 3.76 (s, 2H), 3.75 (s, 3H). 13C NMR (100?MHz, CDCl3) delta [ppm]?=?170.6, 147.2, 141.3, 130.3, 123.8, 52.4, 40.8. GC-MS (M)+ calculated for C9H9NO4 195.05, found 195.0.
	With sulfuric acid; for 3h;Reflux;	Concentrated sulfuric acid (1 mL) was added to a solution of 4-nitrophenylacetic acid (10.0 g, 55.2 mmol) in anhydrous MeOH and heated under reflux for 3 hours. After evaporation of solvent under reduced pressure the mixture was dissolved in ethyl acetate and washed sequentially with 5% sodium bicarbonate, water, and brine. The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was solidified on standing at a temperature in the range of 15 C. to 40 C. to afford the title compound as a white solid.1HNMR (CDCl3, 300 MHz): delta 8.40 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 2H), 3.52 (s, 2H), 3.42 (s, 3H).LC-MSD (ES+): (m/z) 196 [(M+H)+, 100].
	With sulfuric acid; for 2h;Reflux;	Example 101 Preparation of methyl 2-(4-nitrophenyl)acetate U [0385] A solution of 2-(4-nitrophenyl)acetic acid (10.0 g, 55.2 mmol) in methanol (50 mL) was treated with 18 M sulfuric acid (5 rriL) and the mixture stirred at reflux for 2 hours. After this time, the reaction was slowly cooled to 5C, let stand for 30 minutes and the resulting suspension filtered. The filter cake was washed with methanol and dried to a constant weight under vacuum to afford methyl 2-(4-nitrophenyl)acetate as an off-white solid: *H NMR (300 MHz, DMSO-i): delta 8.19 (d, 2H), 7.57 (d, 2H), 3.90 (s, 2H), 3.64 (s, 3H).
	With thionyl chloride; for 3h;Reflux;	General procedure: To a mixture of LiAlH4 (15 mmol) in anhydrous THF (25 mL) in an ice-bath was added dropwise a solution of phenylacetic acids (15 mmol) in THF (8 mL). This mixture was stirred at room temperature for 30 min, and then heated to reflux for 4 h. After it was cooled to room temperature, water (0.5 mL) was added, and then NaOH (15%, 0.5 mL) and water (1.5 mL) were added in sequence. After stirring for another 30 min, the mixture was filtered, dried over anhydrous Na2SO4 and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 50-85% yield by column chromatography. Alternative method: To a solution of phenylacetic acids (15 mmol) in MeOH (30 mL) was added SOCl2 (30 mmol). This mixture was heated to reflux for 3 h before evaporation. The residue was dissolved in DCM (30 mL), washed with aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated to give 100% yield of crude methyl phenylacetates which were used to next step without further purification. To a solution of the methyl phenylacetates in THF (30 mL) was added NaBH4 (60 mmol). When the mixture was heated to gently reflux, MeOH (1.0 mL) was added dropwise from a syringe over 5 min. After refluxing for another 6 h, the mixture was cooled to room temperature and poured into 30 mL ice water, and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 70-85% yield by column chromatography.
	With sulfuric acid; for 2h;Reflux;	20 g (0.11 mol)Nitrobenzoic acid was dissolved in 300ml of methanol, 2ml of concentrated sulfuric acid was added,Plus warming to reflux, the reaction 2 hours. A portion of the solvent was distilled off under reduced pressure,The residue was added with saturated aqueous sodium bicarbonate to adjust the pH to 7-8, 200 ml of water was added and extracted with ethyl acetate (100 ml × 3). The combined organic phases were washed with brine (100 ml × 2), dried over anhydrous sodium sulfate, Concentration under reduced pressure gave 21.2 g of pale yellow needles. The crude product is used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 2843 - 2866
[2]Patent: US2017/313683,2017,A1 .Location in patent: Paragraph 0359-0360
[3]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 8092 - 8105
[4]Patent: WO2013/68461,2013,A1 .Location in patent: Page/Page column 144
[5]Journal of Medicinal Chemistry,2013,vol. 56,p. 5213 - 5217
[6]Chemical Communications,2000,p. 401 - 402
[7]Patent: US2010/144722,2010,A1 .Location in patent: Page/Page column 18
[8]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 1333 - 1337
[9]Patent: CN109096134,2018,A .Location in patent: Paragraph 0056; 0057; 0058; 0059
[10]Tetrahedron Asymmetry,2003,vol. 14,p. 3503 - 3515
[11]Patent: US2009/82330,2009,A1 .Location in patent: Page/Page column 21-22
[12]Green Chemistry,2017,vol. 19,p. 4798 - 4803
[13]Patent: WO2009/137596,2009,A1 .Location in patent: Page/Page column 62; 65-66
[14]Tetrahedron,2002,vol. 58,p. 10113 - 10126
[15]Chemical Communications,2012,vol. 48,p. 5184 - 5186
[16]Chemical Communications,2004,p. 1512 - 1513
[17]Advanced Synthesis and Catalysis,2017,vol. 359,p. 1990 - 1995
[18]Organic and Biomolecular Chemistry,2014,vol. 12,p. 5629 - 5633
[19]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3939 - 3946
[20]Chemische Berichte,1879,vol. 12,p. 1764
[21]Journal of the American Chemical Society,1938,vol. 60,p. 2338
[22]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1893 - 1895
[23]Patent: US2010/144731,2010,A1 .Location in patent: Page/Page column 18
[24]Organic Letters,2011,vol. 13,p. 4240 - 4243
[25]Synthesis,2011,p. 2935 - 2940
[26]Patent: WO2013/188856,2013,A1 .Location in patent: Paragraph 0385
[27]Advanced Synthesis and Catalysis,2015,vol. 357,p. 2479 - 2484
[28]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 131 - 134
[29]Patent: CN106883166,2017,A .Location in patent: Paragraph 0028; 0029

2
[ 2945-08-6 ]
[ 22812-58-4 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-acetamidobenzenesulfonyl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 20℃; for 24h;Inert atmosphere;	General procedure: Diazo esters that are substituted at the alpha-carbon atom were prepared according to the literatures from Aouad,5 arylacetate (1 equiv.) and p-ABSA (1.2 equiv.) were dissolved in CH3CN and cooled to 0 C under nitrogen atmosphere. Then DBU (1.5 equiv.) was added dropwise with stirring. The mixture was stirred for 24 h at room temperature. After that the solvent was evaporated, and the residue was extracted thrice with CH2Cl2 and 10% NH4Cl aqueous solution. The organic layer was further washed with brine, and then dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. Finally the residue was purified by flash chromatography on silica gel (petroleum ether / EtOAc 50:1).

Reference： [1]Organic Letters,2010,vol. 12,p. 604 - 607
[2]Journal of the American Chemical Society,2005,vol. 127,p. 3714 - 3715
[3]Green Chemistry,2018,vol. 20,p. 4547 - 4556
[4]Chemical Communications,2019,vol. 55,p. 5239 - 5242
[5]Organometallics,2013,vol. 32,p. 473 - 479
[6]Journal of Organic Chemistry,1970,vol. 35,p. 862 - 864
[7]Chemische Berichte,1970,vol. 103,p. 3093 - 3103
[8]Tetrahedron Letters,2005,vol. 46,p. 3927 - 3929
[9]Journal of Organic Chemistry,2001,vol. 66,p. 8139 - 8144
[10]European Journal of Organic Chemistry,2016,vol. 2016,p. 4603 - 4606
[11]Angewandte Chemie - International Edition,2017,vol. 56,p. 4156 - 4159
Angew. Chem.,2017,vol. 129,p. 4220 - 4223,4
[12]Tetrahedron,2019,vol. 75,p. 3081 - 3087

3
[ 2916-76-9 ]
[ 98-95-3 ]
[ 2945-08-6 ]
[ 30095-98-8 ]

Reference： [1]Journal of Organic Chemistry,1984,vol. 49,p. 4571 - 4572
[2]Journal of Organic Chemistry,1984,vol. 49,p. 4571 - 4572
[3]Journal of the American Chemical Society,1985,vol. 107,p. 5473 - 5483

4
[ 101-41-7 ]
[ 2945-08-6 ]
[ 10268-12-9 ]
[ 30095-98-8 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1995,vol. 68,p. 1155 - 1161
[2]Journal of Organic Chemistry,1998,vol. 63,p. 952 - 958
[3]Journal of Organic Chemistry,1996,vol. 61,p. 5944 - 5947
[4]Tetrahedron Letters,2001,vol. 42,p. 1387 - 1389
[5]Journal of Organic Chemistry,2011,vol. 76,p. 8088 - 8094

5
[ 2945-08-6 ]
[ 39552-81-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; N-benzyl-N,N,N-triethylammonium chloride; iron; ammonium chloride; In water; toluene; for 12h;Reflux;	S1. Add 570g of water and 5g of ammonium chloride to a 1000mL four-necked bottle with a reflux condenser.2 g of triethylbenzylamine chloride and 82.5 g of iron powder were started to stir, 45 g of concentrated hydrochloric acid was added, and the mixture was heated to reflux for 1 h.S2. To the above mixed solution, a solution prepared by mixing 260 g of toluene with 87.5 g of methyl p-nitrophenylacetate was added dropwise.After the completion of the dropwise addition for 7 hours, the reflux reaction was continued for 5 hours. S3. The reaction solution was cooled to room temperature, suction filtered, and the filter residue was washed and filtered with 80 g of toluene.The combined mother liquor was added to a 2000 mL separatory funnel to separate the layers, the aqueous layer was removed, and the organic layer was collected.First, the toluene is distilled off under reduced pressure with water and recovered for use, and then the product is distilled off with a high vacuum pump.During the distillation, a fraction of 130-134 C / 5 mmHg is collected, which is methyl p-aminophenylacetate (62 g, purity 99.1%, yield 90%).The total yield of methyl p-aminophenylacetate was 69% based on the starting material phenylacetonitrile.

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 8092 - 8105
[2]Chemical Communications,2000,p. 401 - 402
[3]Patent: CN109096134,2018,A .Location in patent: Paragraph 0060; 0061; 0062; 0063; 0064
[4]Synthetic Communications,2010,vol. 40,p. 661 - 665
[5]Advanced Synthesis and Catalysis,2012,vol. 354,p. 1879 - 1884
[6]Journal of the Chemical Society. Perkin transactions I,1999,p. 2759 - 2770

6
[ 2945-08-6 ]
[ 69628-98-4 ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylsilane; trimethylsilyl trifluoromethanesulfonate; titanium tetrachloride In dichloromethane at 20℃; for 20h;

Reference： [1]Yato; Homma; Ishida [Tetrahedron, 2001, vol. 57, # 25, p. 5353 - 5359]

7
[ 2945-08-6 ]
[ 85259-33-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); for 15h;Reflux;	A single-neck RBFequipped with a magnetic stirrer and a reflux condenser was charged sequentiallywith <strong>[2945-08-6]methyl 2-(4-nitrophenyl)acetate</strong> (2,53.20 g, 272.58 mmol), CCl4 (600 mL), N-bromosuccinimide(NBS, 53.37 g, 299.84 mmol), and azobisisobutyronitrile (AIBN, 1.343 g, 8.18mmol). The resulting suspension was heated to reflux for 15 h. After cooling to25 C, the reaction mixture was poured into hexanes (750 mL). The resultingsuspension was filtered and the residue was rinsed with hexanes (100 mL). The combinedfiltrate was concentrated in vacuo. Theresulting oil was purified on a silica gel column (ethyl acetate: hexanes = 10:90) to afford the desired product 3as a yellow oil, which solidified into an off-white solid (60.46 g, 81%) upon standing at 25 C.
76%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane;Reflux;	Compound 4 (7.8?g, 40?mmol), N-bromosuccinimide (7.8?g, 44?mmol) and azobisisobutyronitrile (AIBN, 820?mg, 5?mmol) were mixed in tetrachloromethane (60?mL). The reaction mixture was then refluxed overnight. After the completion of the reaction, the residue was poured into deionized water (100?mL) and then extracted with CH2Cl2 (3?*?50?mL). The organic layers were combined and washed with saturated aqueous NaCl (150?mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane (1:8, v:v) as an eluent to afford 5 as a white solid. Yield: 8.3?g (76%, 30.4?mmol). 1H NMR (400?MHz, CDCl3) delta [ppm]?=?8.22 (d, 3J(H,H)?=?8.8?Hz, 2H), 7.74 (d, 3J(H,H)?=?8.8?Hz, 2H), 5.42 (s, H), 3.82 (s, 3H). 13C NMR (100?MHz, CDCl3) delta [ppm]?=?168.0, 148.2, 142.5, 129.9, 124.0, 53.8, 44.2. GC-MS (M)+ calculated for C9H8BrNO4 272.96, found 273.0.
72%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 18h;Heating / reflux;	Methyl 2-Bromo-2-(4-nitrophenyl)acetate (2); A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1 (10.6 g, 54.1 mmol), carbon tetrachloride (120 mL), N-bromosuccinimide (10.7 g, 59.9 mmol) and azobisisobutylonitrile (275 mg, 1.67 mmol), and the reaction mixture was heated at reflux for 18 h. After this time the reaction was cooled to room temperature and poured into heptane (120 mL). The resulting suspension was filtered and the filter cake washed with heptane (40 mL). The filtrate was concentrated under reduced pressure and the resulting residue was subjected to flash chromatography to afford 2 in 72% yield (10.7 g) as a clear oil: 1H NMR (500 MHz, CDCl3) delta 8.23 (d, 2H, J=9 Hz), 7.74 (d, 2H, J=9.0 Hz), 5.40 (s, 1H), 3.82 (s, 3H); MS (ESI-) m/z 272 (M-H). Reference: Tetrahedron 2002, 58, 10113.

72%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 18h;Reflux;	A l-L single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with Ig (10.6 g, 54.1 mmol), carbon tetrachloride (120 mL), iV-bromosuccinimide (10.7 g, 59.9 mmol) and azobisisobutylonitrile (275 mg, 1.67 mmol), and the reaction mixture was heated at reflux for 18 h. After this time the reaction was cooled to room temperature and poured into heptane (120 mL). The resulting suspension was filtered and the filter cake washed with heptane (40 mL). The filtrate was concentrated under reduced pressure and the resulting residue was subjected to flash chromatography to afford Ih in 72% yield (10.7 g) as a clear oil: 1U NMR (500 MHz, CDCl3) 58.23 (d, 2H, J= 9 Hz), 7.74 (d, 2H, J= 9.0 Hz), 5.40 (s, IH), 3.82 (s, 3H); MS (ESI-) m/z 272 (M-H). Reference: Tetrahedron 2002, 58, 10113.
66.47%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 100℃; for 24h;	Synthesis of compound 137.2. To a solution of compound 137.1 (3.0g, 14.35mmol, l .Oeq) in CCl4(30mL) was added NBS (3.0g, 15.9mmol, 2.5eq) and AlphaBetaNu (0.082g, 1.43mmol, 0.1 eq) Reaction was stirred at 100 C and for 24h. Reaction mixture was poured into water (300 mL) and extracted with EtOAc (100 mL x3). Organic layers were combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by column chromatography get pure compound 137.2 (2.8g, 66.47%). MS (ES): m/z 275.07 [M+H]+.
29%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 12h;Inert atmosphere; Reflux;	To a solution of compound 9-2 (20 g, 103 mmol) in carbon tetrachloride (CCl4) (200 mL) was added AIBN (0.84 g, 5.15 mmol) and NBS (20 g, 113 mmol) under nitrogen atmosphere, and then the reaction solution was heated and refluxed for 12 h, then cooled down to 20 C., filtered and concentrated. The residue was purified by column chromatography to give the title compound 9-3 (brown oil, 8 g, Yield 29%). 1H NMR (400 MHz, CDCl3): delta ppm 8.19 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.8 Hz, 2H), 5.38 (s, 1H), 3.79 (s, 3H).

Reference： [1]Tetrahedron,2002,vol. 58,p. 10113 - 10126
[2]Chemical Communications,2004,p. 1512 - 1513
[3]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 1333 - 1337
[4]Organic and Biomolecular Chemistry,2014,vol. 12,p. 5629 - 5633
[5]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3939 - 3946
[6]Patent: US2009/82330,2009,A1 .Location in patent: Page/Page column 21-23
[7]Patent: WO2009/137596,2009,A1 .Location in patent: Page/Page column 62; 66
[8]Patent: WO2015/131080,2015,A1 .Location in patent: Paragraph 00794; 00795
[9]Patent: US2017/313683,2017,A1 .Location in patent: Paragraph 0362-0363
[10]Advanced Synthesis and Catalysis,2015,vol. 357,p. 2479 - 2484

8
[ 101-41-7 ]
[ 2945-08-6 ]
[ 30095-98-8 ]

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2004,vol. 179,p. 221 - 226
[2]Tetrahedron Letters,2005,vol. 46,p. 8307 - 8310

9
[ 2945-08-6 ]
[ 74-88-4 ]
[ 59115-08-1 ]

Yield	Reaction Conditions	Operation in experiment
80%		Methyl ester 15 (1.56 g, 8 mmol) was dissolved in anhydrousDMF (20 mL). The solution was cooled to 0 C, then NaH (0.63 g,16 mmol, 60% dispersion in oil) was added slowly and cautiously.The resulting mixture was allowed to warm to r.t. and then stirredfor additional 20 min. The solution was cooled again to 0 C.Iodomethane (2 mL, 32 mmol) was added dropwise, and theresulting solution was allowed to stir at 0 C. for about 30 min. Thesolution was warmed to r.t. and stirred for additional 1 h. The solutionwas cooled to 0 C and quenched with water, maintaining0 C throughout the quenching process. The obtained mixture wasextracted with dichloromethane (CH2Cl2) (2 x 15 mL). The combinedorganic layers were washed with water (2 x 5 mL) and brine(2 x 5 mL); dried over anhydrous Na2SO4. After removing theNa2SO4 by filtration, the filtrate was concentrated under vacuum.The residue was purified by column chromatography (silica gel, 8:1petroleum ether: AcOEt) and gave the title compound as a yellowsolid material. Yield 80%. Mp. 33-35 C. lit. 45-46 C [26]. 1H NMR(DMSO-d6) delta 1.69 (s, 6H), 3.74 (s, 3H), 7.45 (d, J = 8.5 Hz, 2H), 8.13 (d,J 8.5 Hz, 2H). Anal. Calcd. for C11H13NO4 (223.22): C, 59.19; H,5.87; N, 6.27. Found: C, 59.24; H, 5.86; N, 6.30.
79%		To a solution of methyl 4-nitrophenylacetate (100 g, 512 mmol) and methyliodide (128 mL, 205 mol) in tetrahydrofuran (500 mL) and dimethylformamide (100 mL) was added drop wise a solution of potassium t-butoxide (50.0 g, 1.53 mol) in tetrahydrofuran (500 mL). The reaction temperature was maintained at 50 C. during the addition. A second portion of potassium t-butoxide (50 g) was added and the mixture was heated at 50 C. for 1 hour. The mixture was cooled to room temperature and poured into 2M hydrochloric acid (1 L) with stirring. Toluene (1 L) was added, and the organic layer was washed with water (500 mL), brine (500 mL), and dried over magnesium sulfate, filtered and concentrated to afford a red oil. Hexane (200 mL) was added and upon standing at room temperature overnight, the product crystallized and was filtered and dried to give methyl 2-methyl-2-(4-nitrophenyl)propanoate (90 g, 79%). 1H NMR (CDCl3), 400 MHz): delta ppm 8.15 (d, 2H), 7.50 (d, 2H), 3.67 (s, 3H), 1.61 (s, 6H).
	With sodium t-butanolate; In N,N-dimethyl-formamide; at 0 - 10℃; for 2.08333h;	Example 102 Preparation of methyl 2-methyl-2-(4-nitrophenyl)propanoate DMF V [0386] A solution of dimethylformamide (100 mL) at 0C was treated with sodium tert- butoxide (3.75 g, 39.0 mmol) in one portion and the suspension was stirred for 5 minutes. Methyl 2-(4-nitrophenyl)acetate (7.50 g, 38.4 mmol) was then added in one portion. This was followed by the addition of methyl iodide (8.76 g, 61.7 mmol) over 1 hour, maintaining the temperature below 10C. After the addition was complete, the mixture was stirred at 0- 5C for 15 minutes. A second addition of sodium ieri-butoxide (3.75 g, 39.0 mmol) and methyl iodide (8.76 g, 61.7 mmol) was made, as described above, and the mixture was stirred at 0-5C for a further 20 minutes. A third addition of sodium ieri-butoxide (375 mg, 3.90 mmol) and methyl iodide (880 mg, 6.17 mmol) was made, as described above, and the mixture was stirred at 0-5 C for a further 30 minutes. After this time, a mixture of water (100 mL) and acetic acid (0.83 mL) was slowly added and the resulting solution extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with 0.5 M hydrochloric acid (2 x 50 mL), then brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure to afford methyl 2-methyl-2-(4-nitrophenyl)propanoate as an off-white solid: *H NMR (300 MHz, DMSO-i: delta 8.19 (d, 2H), 7.61 (d, 2H), 3.62 (s, 3H), 1.56 (s, 6H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4457 - 4461
[2]European Journal of Medicinal Chemistry,2017,vol. 136,p. 523 - 542
[3]Patent: US2010/197591,2010,A1 .Location in patent: Page/Page column 26-27
[4]Tetrahedron Asymmetry,2003,vol. 14,p. 3503 - 3515
[5]Angewandte Chemie - International Edition,2013,vol. 52,p. 3272 - 3276
Angew. Chem.,2013,vol. 125,p. 3354 - 3358,5
[6]Patent: WO2013/188856,2013,A1 .Location in patent: Paragraph 0386

10
[ 2945-08-6 ]
[ 13305-09-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 85 percent / NBS / CCl₄ / 5 h / Irradiation 2: 73.2 percent / dimethylformamide; H₂O / 12 h / 100 °C 3: 74 percent / aq. HBF₄ / methanol / 24 h / 20 °C
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / Reflux 2: silver(II) sulfate / 1,4-dioxane; water / 3 h / Reflux
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / Reflux 2: silver sulfate / 1,4-dioxane; water / 3 h / Reflux

Reference： [1]Zhu, Qing; Girish, Aparna; Chattopadhaya, Souvik; Yao, Shao Q [Chemical Communications, 2004, # 13, p. 1512 - 1513]
[2]Chen, Bifeng; Wang, Peng; Jin, Qingqing; Tang, Xinjing [Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5629 - 5633]
[3]Guo, Xuefeng; Chen, Yiming; Seto, Christopher T. [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 3939 - 3946]

11
[ 1877-73-2 ]
[ 2945-08-6 ]

Yield	Reaction Conditions	Operation in experiment
97.9%	sulfuric acid; In methanol; dichloromethane;	EXAMPLE 5 2-(3-Amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6 mmol) in methanol (50 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 48 h. The reaction was then concentrated in vacuo. The residue was dissolved in methylene chloride (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (225 mL), water (150 mL), and a saturated aqueous sodium chloride solution (1*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-nitro-phenyl)-acetic acid methyl ester (5.27 g, 97.9%) as a pale yellow solid: mp 29-30 C.; EI-HRMS m/e calcd for C9H9NO4 (M+) 195.0531, found 195.0532.
97.9%	In methanol; dichloromethane;	EXAMPLE 109 3-Cyclopentyl-2-(3-nitrophenyl)-N-thiazol-2-yl-propionamide A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6 mmol) in methanol (50 mL) was treated with a catalytic amount of sulfuiric acid. The reaction mixture was refluxed for 48 h. The reaction was then concentrated in vacuo. The residue was dissolved in methylene chloride (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (225 mL), water (150 mL) and a saturated aqueous sodium chloride solution (1*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-nitro-phenyl)-acetic acid methyl ester (5.27 g, 97.9%) as a pale yellow solid: mp 29-30 C.; EI-HRMS mle calcd for C9H9NO4 (M+) 195.053 1, found 195.0532.
97.9%	sulfuric acid; In methanol; dichloromethane;	EXAMPLE 5 2-(3-Amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6 mmol) in methanol (50 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 48 h. The reaction was then concentrated in vacuo. The residue was dissolved in methylene chloride (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (225 mL), water (150 mL), and a saturated aqueous sodium chloride solution (1*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-nitro-phenyl)-acetic acid methyl ester (5.27 g, 97.9%) as a pale yellow solid: mp 29-30 C.; EI-HRMS m/e calcd for C9H9NO4 (M+) 195.0531, found 195.0532.

97.9%

sulfuric acid; In methanol; dichloromethane;

EXAMPLE 109 3-Cyclopentyl-2-(3-nitrophenyl)-N-thiazol-2-yl-propionamide A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6 mmol) in methanol (50 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 48 h. The reaction was then concentrated in vacuo. The residue was dissolved in methylene chloride (50 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (2*25 mL), water (1*50 mL), and a saturated aqueous sodium chloride solution (1*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-nitro-phenyl)-acetic acid methyl ester (5.27 g, 97.9%) as a pale yellow solid: mp 29-30 C.; EI-HRMS m/e calcd for C9H9NO4 (M+) 195.0531, found 195.0532.

Reference： [1]Patent: US2001/39344,2001,A1
[2]Patent: US2001/39344,2001,A1
[3]Patent: US6610846,2003,B1
[4]Patent: US6610846,2003,B1

12
[ 51-80-9 ]
[ 2945-08-6 ]
[ 28042-27-5 ]

Yield	Reaction Conditions	Operation in experiment
47%	With acetic anhydride; In dimethyl sulfoxide; at 23℃; for 2h;	Step 2: To a stirred solution of <strong>[2945-08-6]methyl 2-(4-nitrophenyl)acetate</strong> (8.0g, 40.994 mmol, 1 .0 eq) in DMSO (40 mL) was added tetramethyldiaminomethane (8.38mL, 61 .491 mmol, 1 .5 eq) followed by acetic anhydride (12.78 mL, 135.17 mmol, 3.3eq) at RT and the mixture was stirred for 2h. The reaction mixture was diluted with water (40 mL), extracted with ether (80mL x 2) and the solvent evaporated. The crude product was purified by CC using EtOAc/PE (1 :9) as eluent) to get methyl 2-(4-nitrophenyl)acrylate (4.0 g, 47%, solid; TLC system: EtOAc/PE (3:7), Rf: 0.60).
1.30 g (84%)	With acetic anhydride; In dimethyl sulfoxide;	EXAMPLE 35 2-(4-Nitro-phenyl)-acrylic acid methyl ester (compound 135) [CAS-Number: 28042-27-5] is prepared according to the following literature: Y. Todo, J. Nitta, M. Miyajima, Y. Fukuoka, Y. Yamashiro, N. Nishida, I. Saikawa, H. Narita Chem. Pharm. Bull. 1994, 42, 2063-2070. To a solution of 1.46 g (7.50 mmol) of <strong>[2945-08-6](4-nitro-phenyl)-acetic acid methyl ester</strong> (CAS-Number: 2945-08-6) in 15 ml of dimethylsulfoxide is added at room temperature 1.15 g (11.3 mmol) of N,N,N',N'-tetramethyldiaminomethane followed by 2.53 g (24.8 mmol) of acetic anhydride. The reaction mixture is stirred for 2 hours, then diluted with diethyl ether (80 ml). The organic phase is washed with 1M NaHCO3 (40 ml), brine (2*40 ml), dried over sodium sulfate and concentrated using a vacuum rotary evaporator. The solid residue is recrystallized in diethylether/hexane to give 1.30 g (84%) of compound 135, white solid, m.p. 110-111 C. (lit.: m.p. 110.5-111 C.). 1H-NMR (1H 300 MHz, CDCl3): delta=8.45-8.37 (m, 2 arom. H), 7.80-7.75 (m, 2 arom. H), 6.74 (d, J=0.6 Hz, C=CHH, 1H), 6.23 (d, J=0.6 Hz, C=CHH, 1H), 4.05 (s, OCH3, 3H).

Reference： [1]Patent: WO2013/68461,2013,A1 .Location in patent: Page/Page column 144
[2]Patent: US2008/269382,2008,A1

13
[ 2945-08-6 ]
[ 1187212-49-2 ]

Yield	Reaction Conditions	Operation in experiment
77.7%		To a stirred solution of chlorosulfonyl isocyanate (1.51 ml, 17 mmol) in DCM (50 ml ), t- Butanol (1.66 ml, 17 mmol) was added dropwise at 0 C under nitrogen atmosphere and stirred for 30 min. This solution was added dropwise maintaining 0 C to a solution of (4- nitrophenyl) acetic acid methyl ester (2.0 g, 14 mmol) and diisopropylethylamine (4.03 ml, 28 mmol) in DCM (50 ml ). After addition, reaction mixture was stirred at rt for 3 h. and quenched by addition of 0.1N HCl (50 ml). Reaction mixture was extracted with DCM (50 ml). The combined DCM layer was washed with water (40 ml), dried over Sodium sulphate. Trifluoro actic acid (35 ml ) was added to the extract containing Boc-Procteted sulfamide at 0 0 C. and the solution was stirred for 3 h. The solution was washed with saturated sodium bicarbonate solution ( 50 ml ) and water( 2x50 ml) . Solution was evaporated to dryness and to the residue hexane ( 20 ml ) was added to afford yellow color solid product (2.1 g., 77.7 % ).

Reference： [1]Patent: WO2009/109999,2009,A1 .Location in patent: Page/Page column 78-79

14
[ 96-32-2 ]
[ 100-01-6 ]
[ 2945-08-6 ]

Yield	Reaction Conditions	Operation in experiment
91.1%	With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 70 - 75℃; for 3h;	To a stirred suspension of 4-Nitroaniline (1.5 g, 10.8 mmol), Sodium Bicarbonate (2.7 g., 32.6 mmol ) in DMF (30 ml) , Methyl bromoacetate (1.99 g., 13.0 mmol) was added and reaction mixture was stirred at 70-75 C for 3 h. Reaction mixture was cooled at rt and water (200 ml) was added, product separated was filtered and washed with water (2x 50ml). The yellow solid product was dried under reduced pressure (2.1 g., 91.1 %). MS = m/z 211 [M+ 1].

Reference： [1]Patent: WO2009/109999,2009,A1 .Location in patent: Page/Page column 78

15
[ 627-31-6 ]
[ 2945-08-6 ]
methyl 1-(4-nitrophenyl)cyclobutane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%		General procedure: Compound15(2.50 g, 12.8mmol) was dissolved in anhydrous DMF (20 mL). The solution was cooled to 0 C.NaH(1.02 g, 25.6mmol, 60% dispersion in oil) was added slowly and cautiously. The resulting mixture was allowed to warm to r.t. and was stirred for additional 20 min. The solution was cooled again to 0 C, the appropriatedihaloalkane(25.6mmol) was added dropwise, and the resulting solution was allowed to stir at 0 C. for 30 min. The solution was warmed to r.t. and stirred for additional 1 h. The solution was cooled to 0 C and quenched with water, maintaining 0 C throughout the quenching process. The obtained mixture was extracted with CH2Cl2(2 x 20 mL). The combined organic layers were washed with water and brine and dried overNa2SO4. This was removed by filtration and the filtrate concentrated under vacuum to give the crude esters22-25.
41%		(b) Synthesis of 1-(4-nitro-phenyl)-cyclobutanecarboxylic acid methyl ester (4-Nitro-phenyl)-acetic acid methyl ester (15.21 g, 76.9 mmol) was dissolved in anhydrous DMF (80 mL) and allowed to stir until all solid dissolved. The solution was cooled to 0 C. with an ice bath. Sodium hydride (6.32 g, 153.8 mmol; 60% dispersion in oil) was added slowly and cautiously. The resulting mixture was allowed to warm to about 20-35 C. and was stirred for approximately 15 min. The solution was cooled again to 0 C. with an ice bath. <strong>[627-31-6]1,3-Diiodopropane</strong> (17.7 mL, 153.8 mmol) was added slowly and drop-wise, and the resulting solution was allowed to stir at 0 C. for about 30 min. The solution was warmed to about 20-35 C. and stirred at about 20-35 C. for about 1 h. The solution was cooled to 0 C. with an ice bath and quenched with H2O, maintaining 0 C. throughout the quenching process. The reaction mixture was extracted 3 times with dichloromethane. The combined organic layers were washed with water and brine; dried over sodium sulfate; filtered; and then concentrated under vacuum to give product. The material was purified by column chromatography (SiO2, 80:20 hexane: EtOAc) and gave the title compound as a yellow solid material (7.5 g, 41% yield).1H NMR (300 MHz, CDCl3, TMS) delta 1.87-2.19 (m, 2H), 2.48-2.58 (m, 2H), 2.86-2.95 (m, 2H), 3.67 (s, 3H), 7.43 to 7.48 (m, 2H), 8.17-8.21 (m, 2H).LC-MSD (ES+): (m/z) 236 [(M+H)+, 100].
		Methyl 2-(4-nitrophenyl)acetate (6.0 g, 31 mmol) was dissolved in DMF (100 mL). The solution was cooled to 0 C in an ice bath. NaH (2.50 g, 62.5 mmol, 60% in mineral oil) was added slowly and cautiously. The resulting mixture was allowed to warm to RT and stirred for 15 min. The mixture was cooled again to 0 C and 1,3-diiodopropane (6.0 mL, 52 mmol) was added dropwise. The resulting mixture was allowed to stir at 0 C for 30 min, then 0 C to 10 C for 1.5 h. The solution was cooled to 0 C and quenched with water. The reaction mixture was extracted with DCM (30 mL x3). The combined organic layers were washed with water, brine, dried over Na2SC>4, filtered and concentrated in vacuo to afford a residue. The residue was purified by column chromatography on silica gel (EtOAc in hexane, 0-20% gradient) to afford methyl l-(4-nitrophenyl)cyclobutanecarboxylate.

A solution of methyl 2-(4-nitrophenyl)acetate (6 g, 31 mmol) in DMF (100 ml) was cooled to 0 C with an ice bath. NaH (60% in oil) (2.5 g, 63 mmol) was added portion wise. The resulting mixture was allowed to warm to RT and was stirred for 15 min at RT. After 15 min the mixture was cooled again to 0 C and 1,3-diiodopropane (6 ml, 52 mmol) was added drop wise. The resulting mixture was allowed to stir at 0 C for 30 min, and from 0 C to 10 C for 1.5 h. After 1.5 h the solution was cooled to 0 C and water was added. The reaction mixture was extracted 3 times with DCM. The combined organics were concentrated under reduced pressure and the residue was purified by flash chromatography on silica (120 g flash column, 0-20% EtOAc in hexane, 10 CV) to afford methyl 1-(4-nitrophenyl)cyclobutanecarboxylate.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 523 - 542
[2]Patent: US2010/144722,2010,A1 .Location in patent: Page/Page column 18
[3]Patent: WO2019/27855,2019,A1 .Location in patent: Page/Page column 34
[4]Patent: WO2019/74747,2019,A1 .Location in patent: Page/Page column 58

16
[ 2945-08-6 ]
[ 106-93-4 ]
[ 23348-98-3 ]

Yield	Reaction Conditions	Operation in experiment
45%		General procedure: Compound15(2.50 g, 12.8mmol) was dissolved in anhydrous DMF (20 mL). The solution was cooled to 0 C.NaH(1.02 g, 25.6mmol, 60% dispersion in oil) was added slowly and cautiously. The resulting mixture was allowed to warm to r.t. and was stirred for additional 20 min. The solution was cooled again to 0 C, the appropriatedihaloalkane(25.6mmol) was added dropwise, and the resulting solution was allowed to stir at 0 C. for 30 min. The solution was warmed to r.t. and stirred for additional 1 h. The solution was cooled to 0 C and quenched with water, maintaining 0 C throughout the quenching process. The obtained mixture was extracted with CH2Cl2(2 x 20 mL). The combined organic layers were washed with water and brine and dried overNa2SO4. This was removed by filtration and the filtrate concentrated under vacuum to give the crude esters22-25.
44%		(a) Synthesis of 1-(4-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester (4-Nitro-phenyl)-acetic acid methyl ester (2.50 g, 12.8 mmol) was dissolved in anhydrous DMF (20 mL) and stirred until the entire solid dissolved. The solution was cooled to 0 C. with an ice bath. Sodium hydride (1.02 g, 25.6 mmol; 60% dispersion in oil) was added slowly and cautiously. The resulting mixture was allowed to warm to about 20-35 C. and was stirred at about 20-35 C. for approximately 20 min. The solution was cooled again to 0 C. with an ice bath. 1,2-Dibromoethane (2.2 mL, 25.6 mmol) was added drop wise, and the resulting solution was allowed to stir at 0 C. for about 30 min. The solution was warmed to about 20-35 C. and stirred at about 20-35 C. for about 1 h. The solution was cooled to 0 C. with an ice bath and quenched with H2O, maintaining 0 C. throughout the quenching process. The reaction mixture was extracted 2 times with dichloromethane. The combined organic layers were washed with water and brine; dried over sodium sulfate; filtered; and then concentrated under vacuum to give product. The material was purified by column chromatography (SiO2, 70:30 hexane: EtOAc) and gave the title compound as a white solid material (1.26 g, 44% yield).1H NMR (300 MHz, CDCl3, TMS) delta 8.15-8.19 (m, 2H), 7.54-7.49 (m, 2H), 3.64 (s, 3H), 1.79-1.68 (m, 2H), 1.26-1.22 (m, 2H).LC-MSD (ES+): (m/z) 222 [(M+H)+, 100].

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 523 - 542
[2]Patent: US2010/144722,2010,A1 .Location in patent: Page/Page column 20

17
[ 628-21-7 ]
[ 2945-08-6 ]
[ 135569-19-6 ]

Yield	Reaction Conditions	Operation in experiment
60%		General procedure: Compound15(2.50 g, 12.8mmol) was dissolved in anhydrous DMF (20 mL). The solution was cooled to 0 C.NaH(1.02 g, 25.6mmol, 60% dispersion in oil) was added slowly and cautiously. The resulting mixture was allowed to warm to r.t. and was stirred for additional 20 min. The solution was cooled again to 0 C, the appropriatedihaloalkane(25.6mmol) was added dropwise, and the resulting solution was allowed to stir at 0 C. for 30 min. The solution was warmed to r.t. and stirred for additional 1 h. The solution was cooled to 0 C and quenched with water, maintaining 0 C throughout the quenching process. The obtained mixture was extracted with CH2Cl2(2 x 20 mL). The combined organic layers were washed with water and brine and dried overNa2SO4. This was removed by filtration and the filtrate concentrated under vacuum to give the crude esters22-25.
54%		Step (a): Synthesis of 1-(4-amino-phenyl)cyclopentanecarboxylic acid methyl esterSodium hydride (2.8 g, 60% dispersion in mineral oil) was added slowly to an ice-cold solution of (4-nitro-phenyl)-acetic acid methyl ester (6.0 g, 30.7 mmol) in anhydrous DMF (30 mL) under nitrogen atmosphere. After stirring at 0 C. for 20 min, 1,4-diiodobutane (7.86 mL, 61 mmol) was added drop wise under stirring. After complete addition, the reaction mixture was warmed to about 20-35 C. and stirring continued for an additional 3 h. The reaction was stopped by adding water drop wise followed by EtOAc. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The material was purified by chromatography over silica gel to afford a pale yellow viscous liquid that solidified on standing at about 20-35 C. (4.1 g, 54% yield). The solid (3.4 g, 13.6 mmol) was dissolved in anhydrous ethanol and tin (II) chloride dihydrate (13.86 g, 61 mmol) was added slowly under nitrogen atmosphere. Thereafter, the mixture was heated at 90 C. for 3 h. After evaporation of volatiles under reduced pressure the resultant mixture was diluted with ice water, and the solution was adjusted to pH 11 by adding NaOH (aq). The mixture was extracted with EtOAc (3×50 mL) and the combined organic extracts were washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound as a granular light yellow solid (2.67 g, 88% yield).1H NMR (CDCl3, 300 MHz): delta 7.16 (dd, J=8.4, 1.8 Hz, 2H), 6.63 (dd, J=8.4, 1.8 Hz, 2H), 3.59 (s, 3H), 2.60-2.55 (m, 2H), 1.87-1.67 (m, 6H).LC-MSD (ES+): m/z [220 (M+H)+, 100].
54%		Sodium hydride (2.8 g, 60% dispersion in mineral oil) was added slowly to a solution of (4-nitro-phenyl)-acetic acid methyl ester (6.0 g, 30.7 mmol) in anhydrous DMF (30 mL) under nitrogen at a temperature in the range of 0 C. to 10 C. After stirring at a temperature in the range of 0 C. to 10 C. for 20 min, diiodobutane (7.86 mL, 61 mmol) was added drop-wise under stirring. After complete addition, the reaction mixture was warmed to a temperature in the range of 15 C. to 40 C. and stirring continued for an additional 3 hours. The reaction was quenched by adding water slowly. The mixture was extracted by ethyl acetate (3×40 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant gummy material was purified by column chromatography over silica gel to afford a pale yellow thick liquid which solidified on standing at a temperature in the range of 15 C. to 40 C. (4.1 g, 54% yield). The solid (3.4 g, 13.6 mmol) was dissolved in anhydrous EtOH and tin chloride dihydrate (13.86 g, 61 mmol) was added slowly under nitrogen. Thereafter, the mixture was heated at 90 C. for 3 hours. After evaporation of volatiles under reduced pressure, the resultant mixture was diluted with ice-water and aqueous sodium hydroxide was added to adjust pH 11. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a granular light yellow solid (2.67 g, 88% yield).1HNMR (CDCl3, 300 MHz): delta 7.16 (dd, J=8.4, 1.8 Hz, 2H), 6.63 (dd, J=8.4, 1.8 Hz, 2H), 3.59 (s, 3H), 2.60-2.55 (m, 2H), 1.87-1.67 (m, 6H).LC-MSD (ES+): (m/z) 220 [(M+H)+, 100].

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 523 - 542
[2]Patent: US2010/144722,2010,A1 .Location in patent: Page/Page column 27
[3]Patent: US2010/144731,2010,A1 .Location in patent: Page/Page column 18

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