[ CAS No. 5454-83-1 ] {[proInfo.proName]}

Name: 5454-83-1|Methyl 5-Bromovalerate|97%
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Quality Control of [ 5454-83-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 5454-83-1 ]

Product Details of [ 5454-83-1 ]

CAS No. :	5454-83-1	MDL No. :	MFCD00000265
Formula :	C₆H₁₁BrO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RAVVJKCSZXAIQP-UHFFFAOYSA-N
M.W :	195.05	Pubchem ID :	79557
Synonyms :

Calculated chemistry of [ 5454-83-1 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.83
Num. rotatable bonds :	5
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	40.11
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.16 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.0
Log Po/w (XLOGP3) :	1.87
Log Po/w (WLOGP) :	1.72
Log Po/w (MLOGP) :	1.79
Log Po/w (SILICOS-IT) :	1.73
Consensus Log Po/w :	1.83

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.9
Solubility :	2.47 mg/ml ; 0.0127 mol/l
Class :	Very soluble
Log S (Ali) :	-2.04
Solubility :	1.76 mg/ml ; 0.00904 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.43
Solubility :	0.723 mg/ml ; 0.00371 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.12

Safety of [ 5454-83-1 ]

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 [ 5454-83-1 ]

* 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 [ 5454-83-1 ]
Downstream synthetic route of [ 5454-83-1 ]

[ 5454-83-1 ] Synthesis Path-Upstream 1~13

1
[ 5454-83-1 ]
[ 34626-51-2 ]

Reference： [1] Synthetic Communications, 1996, vol. 26, # 6, p. 1143 - 1147
[2] Synthesis, 1991, # 8, p. 641 - 643

2
[ 67-56-1 ]
[ 2067-33-6 ]
[ 5454-83-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 110℃; Flow reactor	General procedure: Lauric acid (1a) (2.01 g, 10.0 mmol) was dissolved in methanol (10 mL) and then placed in a syringe, which wasthen attached to a syringe pump. The methanol solution was fedinto a stainless steel column (inner volume: 0.53 mL, 4.0 mm i.d. © 50 mm) filled in HO-SAS (334 mg) with a flow rate of0.177 mL.min^-¹. The column was immersed into an oil bath(110°C). A back-pressure regulator (75 psi) was connected.The reaction mixture was collected from the outlet. The reaction mixture eluted during the first 10 min was discarded. Thereaction mixture was collected during 3 min and added n-decane as an internal standard for GC analysis. The followingportion was collected for a 30 min period in a glass flask, andsolvent was evaporated. The crude mixture was purified byflash column chromatography on SiO2 (hexane/ethyl acetate =5/1) to give 3a (1.13 g, 99percent).

Reference： [1] Journal of Materials Chemistry B, 2013, vol. 1, # 34, p. 4225 - 4230
[2] Bulletin of the Chemical Society of Japan, 2017, vol. 90, # 5, p. 607 - 612
[3] Organic Letters, 2015, vol. 17, # 1, p. 138 - 141
[4] Synlett, 2004, # 10, p. 1735 - 1738
[5] New Journal of Chemistry, 2001, vol. 25, # 9, p. 1182 - 1184
[6] Heterocycles, 2017, vol. 94, # 8, p. 1518 - 1541
[7] Journal of the American Chemical Society, 1938, vol. 60, p. 1375
[8] Collection of Czechoslovak Chemical Communications, 1967, vol. 32, # 3, p. 1035 - 1044
[9] Tetrahedron Letters, 1999, vol. 40, # 17, p. 3471 - 3474
[10] Journal of the American Chemical Society, 1999, vol. 121, # 49, p. 11425 - 11431
[11] Organic and Biomolecular Chemistry, 2009, vol. 7, # 9, p. 1821 - 1828
[12] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 22, p. 6981 - 6995
[13] Angewandte Chemie - International Edition, 2014, vol. 53, # 13, p. 3400 - 3404[14] Angew. Chem., 2014, vol. 126, # 13, p. 3468 - 3472,5
[15] Supramolecular Chemistry, 2014, vol. 26, # 1, p. 25 - 31

3
[ 542-28-9 ]
[ 67-56-1 ]
[ 5454-83-1 ]

Reference： [1] Canadian Journal of Chemistry, 2003, vol. 81, # 8, p. 937 - 960

4
[ 67-56-1 ]
[ 14660-52-7 ]
[ 5454-83-1 ]

Reference： [1] Synlett, 2007, # 3, p. 491 - 493

5
[ 186581-53-3 ]
[ 2067-33-6 ]
[ 5454-83-1 ]

Reference： [1] Molecules, 2006, vol. 11, # 6, p. 435 - 443
[2] Journal of Organometallic Chemistry, 1983, vol. 253, # 1, p. 31 - 38

6
[ 67-56-1 ]
[ 5414-21-1 ]
[ 5454-83-1 ]

Reference： [1] Journal of the American Chemical Society, 1959, vol. 81, p. 3356

7
[ 591235-26-6 ]
[ 5454-83-1 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1966, vol. 34, p. 262 - 271

8
[ 142685-59-4 ]
[ 5454-83-1 ]

Reference： [1] Gazzetta Chimica Italiana, 1960, vol. 90, p. 1299 - 1306

9
[ 67-56-1 ]
[ 120-92-3 ]
[ 5454-83-1 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1981, p. 336 - 343

10
[ 67-56-1 ]
[ 18622-31-6 ]
[ 5454-83-1 ]

Reference： [1] Journal of Organic Chemistry, 1962, vol. 27, p. 2064 - 2067

11
[ 50995-48-7 ]
[ 624-24-8 ]
[ 5454-83-1 ]
[ 765-85-5 ]

Reference： [1] Journal of Chemical Research, Miniprint, 1983, # 11, p. 2401 - 2416
[2] Journal of Chemical Research, Miniprint, 1983, # 11, p. 2401 - 2416

12
[ 624-24-8 ]
[ 5454-83-1 ]
[ 19129-92-1 ]
[ 75411-76-6 ]
[ 77085-21-3 ]

Reference： [1] Chemical Communications (London), 1967, p. 903 - 904

13
[ 56-23-5 ]
[ 627-91-8 ]
[ 7726-95-6 ]
[ 5454-83-1 ]

Reference： [1] DRP/DRBP Org.Chem.,
[2] Chemische Berichte, 1942, vol. 75, p. 294

[ 5454-83-1 ] Synthesis Path-Downstream 1~88

1
[ 67-56-1 ]
[ 2067-33-6 ]
[ 5454-83-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With acetyl chloride for 5h; Reflux;
99%	With hydroxy-substituted sulfonic acid-functionalized silica (HO-SAS) at 110℃; Flow reactor;	Typical Procedure for Flow Esterification (Table1,Entry 6) General procedure: Lauric acid (1a) (2.01 g, 10.0 mmol) was dissolved in methanol (10 mL) and then placed in a syringe, which wasthen attached to a syringe pump. The methanol solution was fedinto a stainless steel column (inner volume: 0.53 mL, 4.0 mm i.d. 50 mm) filled in HO-SAS (334 mg) with a flow rate of0.177 mL.min-1. The column was immersed into an oil bath(110°C). A back-pressure regulator (75 psi) was connected.The reaction mixture was collected from the outlet. The reaction mixture eluted during the first 10 min was discarded. Thereaction mixture was collected during 3 min and added n-decane as an internal standard for GC analysis. The followingportion was collected for a 30 min period in a glass flask, andsolvent was evaporated. The crude mixture was purified byflash column chromatography on SiO2 (hexane/ethyl acetate =5/1) to give 3a (1.13 g, 99%).
99%	With acetyl chloride for 5h; Reflux;

90%	With p-toluenesulfonic acid monohydrate In methanol for 0.75h; Reflux;
87%	With chloro-trimethyl-silane
82%	With sulfuric acid Heating;
82%	With acetyl chloride at 70℃; for 24h;
72%	With toluene-4-sulfonic acid for 1h; Reflux;	S2.4.1 Methyl 5-bromovalerate (25) A solution of 5-bromovaleric acid (24; 10 mmol) and p-toluenesulfonic acid (6 mmol) in MeOH was refluxed for 1 h. The solvent was then removed under reduced pressure, and the residue was dissolved in EtOAc and washed with saturated aqueous solutions of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give methyl 5-bromovalerate (25). MS m/z: 195.10, 197.10 [M+H] + Yield: 72% 1H NMR (400 MHz, DMSO) δ 3.57 (s, 3H, -OCH3), 3.51 (t, J = 6.6 Hz, 2H, -CH2Br), 2.33 (t, J = 7.4 Hz, 2H, -CH2CO-), 1.85-1.75 (m, 2H, -CH2-CH2-CH2-), 1.68 - 1.57 (m, 2H, -CH2-CH2-CH2-).
	With sulfuric acid
	With sulfuric acid
	for 16h; Ambient temperature;
	With sulfuric acid Heating;
	With SOCl₂ or oxalyl chloride at 20℃;
	With thionyl chloride at 20℃; for 2h;	Representative procedure for 10a-e General procedure: SOCl2 (15.0 mmol) was added dropwise into a solution of bromo carboxylic acid (10.0 mmol) in methanol (30 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated to give the crude product, which was used directly for the next step.
	With thionyl chloride at 20℃; for 3h;
	With sulfuric acid
	With toluene-4-sulfonic acid

Reference： [1]Voliani, Valerio; Signore, Giovanni; Vittorio, Orazio; Faraci, Paolo; Luin, Stefano; Perez-Prieto, Julia; Beltram, Fabio [Journal of Materials Chemistry B, 2013, vol. 1, # 34, p. 4225 - 4230]
[2]Furuta, Akihiro; Fukuyama, Takahide; Ryu, Ilhyong [Bulletin of the Chemical Society of Japan, 2017, vol. 90, # 5, p. 607 - 612]
[3]Gu, Lingyue; Renault, Kévin; Romieu, Anthony; Richard, Jean-Alexandre; Srinivasan, Rajavel [New Journal of Chemistry, 2020, vol. 44, # 28, p. 12208 - 12215]
[4]Nishiyama, Junya; Makita, Yoshimasa; Kihara, Nobuhiro [Organic Letters, 2015, vol. 17, # 1, p. 138 - 141]
[5]Doussineau, Tristan; Durand, Jean-Olivier; Granier, Michel; Smaïhi, Monique; Valtchev, Valentin [Synlett, 2004, # 10, p. 1735 - 1738]
[6]Lion; Da Conceicao; Delmas; Magnaud [New Journal of Chemistry, 2001, vol. 25, # 9, p. 1182 - 1184]
[7]Meindl, Alina; Ryan, Aoife A.; Flanagan, Keith J.; Senge, Mathias O. [Heterocycles, 2017, vol. 94, # 8, p. 1518 - 1541]
[8]Erdmann, Frank; Günther, Stefan; Ghazy, Ehab; Hügle, Martin; Herp, Daniel; Jung, Manfred; Morales, Elizabeth R.; Robaa, Dina; Romier, Christophe; Schmidt, Matthias; Schmidtkunz, Karin; Sippl, Wolfgang; Zeyen, Patrik [European Journal of Medicinal Chemistry, 2020, vol. 200]
[9]Campbell; Campbell [Journal of the American Chemical Society, 1938, vol. 60, p. 1375]
[10]Cerny,A. et al. [Collection of Czechoslovak Chemical Communications, 1967, vol. 32, # 3, p. 1035 - 1044]
[11]Bui, Chinh T.; Bray, Andrew M.; Ercole, Francesca; Pham, Yen; Rasoul, Firas A.; Maeji, N. Joe [Tetrahedron Letters, 1999, vol. 40, # 17, p. 3471 - 3474]
[12]Mizutani, Tadashi; Wada, Kenji; Kitagawa, Susumu [Journal of the American Chemical Society, 1999, vol. 121, # 49, p. 11425 - 11431]
[13]Srinivasan, Rajavel; Tan, Lay Pheng; Wu, Hao; Yang, Peng-Yu; Kalesh, Karunakaran A.; Yao, Shao Q. [Organic and Biomolecular Chemistry, 2009, vol. 7, # 9, p. 1821 - 1828]
[14]Zhang, Xuan; Bao, Bin; Yu, Xiuhua; Tong, Linjiang; Luo, Yu; Huang, Qingqing; Su, Mingbo; Sheng, Li; Li, Jia; Zhu, Hong; Yang, Bo; Zhang, Xiongwen; Chen, Yi; Lu, Wei [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 22, p. 6981 - 6995]
[15]Stoffelen, Carmen; Voskuhl, Jens; Jonkheijm, Pascal; Huskens, Jurriaan [Angewandte Chemie - International Edition, 2014, vol. 53, # 13, p. 3400 - 3404][Angew. Chem., 2014, vol. 126, # 13, p. 3468 - 3472,5]
[16]Oezkan, Seyda Cigdem; Yilmaz, Aydan; Oezmen, Ismail [Supramolecular Chemistry, 2014, vol. 26, # 1, p. 25 - 31]
[17]Aparicio, Fátima; Casado, Santiago; Chamorro, Paula B.; Chamorro, Raquel; González-Rodríguez, David [Angewandte Chemie - International Edition, 2020, vol. 59, # 39, p. 17091 - 17096][Angew. Chem., 2020, vol. 132, # 39, p. 17239 - 17244,6]

2
[ 40786-69-4 ]
[ 5454-83-1 ]
[ 106627-38-7 ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate In N,N-dimethyl-formamide	7 Preparation of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid methyl ester EXAMPLE 7 Preparation of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid methyl ester A mixture of 2.92 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.91 g of methyl 5-bromopentanoate and 3.1 g of anhydrous potassium carbonate in 35 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 16 hours. The usual workup followed by chromatography on 350 g of silica gel and elution with 5% ethyl acetate-toluene gave 3.07 g (66% yield) of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid methyl ester, the titled compound, as an oil. Analysis Calculated for C17 H24 O5: C, 66.21; H, 7.85. Found: C, 66.39; H, 7.80.
66%	With potassium carbonate In N,N-dimethyl-formamide	19 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid methyl ester EXAMPLE 19 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid methyl ester A mixture of 2.92 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.91 g of methyl 5-bromopentanoate and 3.1 g of anhydrous potassium carbonate in 35 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 16 hours. The usual workup followed by chromatography on 350 g of silica gel and elution with 5% ethyl acetate-toluene gave 3.07 g (66% yield) of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy) pentanoic acid methyl ester, the titled compound, as an oil. Analysis Calculated for C17 H24 O5: C, 66.21; H, 7.85. Found: C, 66.39; H, 7.80.
66%	With potassium carbonate In N,N-dimethyl-formamide	52 Preparation of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy) pentanoic acid methyl ester EXAMPLE 52 Preparation of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy) pentanoic acid methyl ester A mixture of 2.92 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 2.91 g of methyl 5-bromopentanoate and 3.1 g of anhydrous potassium carbonate in 35 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 16 hours. The usual workup followed by chromatography on 350 g of silica gel and elution with 5% ethyl acetate-toluene gave 3.07 g (66% yield) of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy) pentanoic acid methyl ester, the titled compound, as an oil. Analysis Calculated for C17 H24 O5: C, 66.21; H, 7.85. Found: C, 66.39; H, 7.80.

32%

With potassium carbonate; potassium iodide In acetone for 18h; Heating;

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US4628115, 1986, A
[2]Current Patent Assignee: ROCHE HOLDING AG - US4663332, 1987, A
[3]Current Patent Assignee: ROCHE HOLDING AG - US4672066, 1987, A
[4]Marshall; Goodson; Cullinan; Swanson-Bean; Haisch; Rinkema; Fleisch [Journal of Medicinal Chemistry, 1987, vol. 30, # 4, p. 682 - 689]

3
[ 5454-83-1 ]
[ 127811-93-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium azide In water; dimethyl sulfoxide at 20℃; for 0.5h;	22 Add sodium azide (12.5 g, 193 mmol) to a rapidly stirred solution of methyl 5- bromovalerate (25.08 g, 129 mmol) in DMSO (200 mL, anhydrous). Stir at room temperature overnight under N2. Add water (400 mL) and stir for 30 minutes. Extract with ET2O (X3) and wash combined ET20 layers with brine (x3). Dry organic layer over MGS04 and concentrate to give the title compound (20.3 g, 100%).
100%	With sodium azide In N,N-dimethyl-formamide at 80℃;
99.7%	With sodium azide In methanol; water	165 2-(4-Asidobutyl)-3-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-5-carboxamido-6-ethyl-1,4-dihydro-4-(4-nitrophenyl)pyridine (165) EXAMPLE 165 2-(4-Asidobutyl)-3-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-5-carboxamido-6-ethyl-1,4-dihydro-4-(4-nitrophenyl)pyridine (165) A solution of methyl 5-bromovalerate (5.00 g, 25.6 mmol), NaN3 (3.33 g, 51.2 mmol) and 15 ml of water in 40 ml of MeOH was refluxed for 3.5 hrs. The MeOH was removed in vacuo and residue was partitioned between CHCl3 (200 ml) and water (50 ml). The organic layer was separated and washed with water. After drying and removal of solvent, methyl 5-azidovalerate (4.01 g, 99.7%) was obtained as a colorless oil.

95%	With sodium azide In N,N-dimethyl-formamide
95%	With sodium azide In N,N-dimethyl-formamide at 80℃;
91%	With sodium azide; potassium iodide In dimethyl sulfoxide at 90℃; for 48h; Inert atmosphere;	12 12. Synthesis of Methyl-5-azido valerate Methyl-5-bromovalerate (2.18 ml, 15.38 mmol) andSodium azide (10 g, 10 eq) were dissolved in 20 ml DMSO ina round bottom flask and a pinch of KI was added. The mixture was stirred at 90° C. under N2 atmosphere for 48 h. The reaction was cooled, diluted with water and extractedwith hexanes. Organic layers were combined and dried overanhydrous Na2504. Solvent was evaporated to yield oily liquid. Yield: 2.2 g (91%); ‘H NMR (600 MHz, CDC13, 25°C.): ö=1 .56-1.59 (m, 2H; CH2), 1.65-1.67 (m, 2H; CH2), 2.30 (t, J=12 Hz, 2H; CH2), 3.24 (t, J=12 Hz, 211; CH2), 3.62 (s,3H; CH3); ‘3C NMR (150 MHz, CDC13, 25° C.): ö=18.0,24.2, 29.3, 47.0, 47.5, 169.5.
85%	With sodium azide In N,N-dimethyl-formamide for 18h;
	With Merrifield resin supported tetra-alkyl ammonium azide In dimethyl amine at 25℃; for 72h;
	With sodium azide In N,N-dimethyl-formamide at 80℃; for 0.333333h; Microwave irradiation;
	With sodium azide In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
	With sodium azide In N,N-dimethyl-formamide at 60℃;
	With sodium azide In water; acetone Reflux;
	With sodium azide In dimethyl sulfoxide at 60℃; for 24h;
	With sodium azide In dimethyl sulfoxide at 25℃;
	With sodium azide In N,N-dimethyl-formamide at 60℃; for 6h;
	With sodium azide In N,N-dimethyl-formamide at 80℃; for 8h;

Reference： [1]Current Patent Assignee: NOVO NORDISK A/S - WO2005/19184, 2005, A1 Location in patent: Page/Page column 61
[2]Tona, Veronica; De La Torre, Aurélien; Padmanaban, Mohan; Ruider, Stefan; González, Leticia; Maulide, Nuno [Journal of the American Chemical Society, 2016, vol. 138, # 27, p. 8348 - 8351]
[3]Current Patent Assignee: H. LUNDBECK A/S - US5767131, 1998, A
[4]McGeary, Ross P. [Tetrahedron Letters, 1998, vol. 39, # 20, p. 3319 - 3322]
[5]Gu, Lingyue; Renault, Kévin; Romieu, Anthony; Richard, Jean-Alexandre; Srinivasan, Rajavel [New Journal of Chemistry, 2020, vol. 44, # 28, p. 12208 - 12215]
[6]Current Patent Assignee: CITY UNIVERSITY OF NEW YORK - US9242010, 2016, B2 Location in patent: Page/Page column 52
[7]Moss, William O.; Wakefield, Emma; Mahon, Mary F.; Molloy, Kieran C.; Bradbury, Robert H.; et al. [Tetrahedron, 1992, vol. 48, # 36, p. 7551 - 7564]
[8]Blass, Benjamin E.; Coburn, Keith R.; Faulkner, Amy L.; Seibel, William L.; Srivastava, Anil [Tetrahedron Letters, 2003, vol. 44, # 10, p. 2153 - 2155]
[9]Srinivasan, Rajavel; Tan, Lay Pheng; Wu, Hao; Yang, Peng-Yu; Kalesh, Karunakaran A.; Yao, Shao Q. [Organic and Biomolecular Chemistry, 2009, vol. 7, # 9, p. 1821 - 1828]
[10]Brown, Sarah D.; Graham, Duncan [Tetrahedron Letters, 2010, vol. 51, # 38, p. 5032 - 5034]
[11]Location in patent: experimental part Vang, Torkel; Xie, Yuli; Liu, Wallace H.; Vidović, Dušica; Liu, Yidong; Wu, Shuangding; Smith, Deborah H.; Rinderspacher, Alison; Chung, Caty; Gong, Gangli; Mustelin, Tomas; Landry, Donald W.; Rickert, Robert C.; Schürer, Stephan C.; Deng, Shi-Xian; Tautz, Lutz [Journal of Medicinal Chemistry, 2011, vol. 54, # 2, p. 562 - 571]
[12]Su, Bo; Chen, Fazhong; Wang, Qingmin [Journal of Organic Chemistry, 2013, vol. 78, # 6, p. 2775 - 2779]
[13]Voliani, Valerio; Signore, Giovanni; Vittorio, Orazio; Faraci, Paolo; Luin, Stefano; Perez-Prieto, Julia; Beltram, Fabio [Journal of Materials Chemistry B, 2013, vol. 1, # 34, p. 4225 - 4230]
[14]Zhang, Tao; Hu, Xuejiao; Wang, Zhen; Yang, Tiantian; Sun, Hao; Li, Guigen; Lu, Hongjian [Chemistry - A European Journal, 2016, vol. 22, # 9, p. 2920 - 2924]
[15]Xu, Xiaoying; Zhang, Kaifan; Li, Panpan; Yao, Hequan; Lin, Aijun [Organic Letters, 2018, vol. 20, # 7, p. 1781 - 1784]
[16]Fang, Kun; Dong, Guoqiang; Li, Yu; He, Shipeng; Wu, Ying; Wu, Shanchao; Wang, Wei; Sheng, Chunquan [ACS Medicinal Chemistry Letters, 2018, vol. 9, # 4, p. 312 - 317]

4
[ 50995-48-7 ]
[ 624-24-8 ]
[ 5454-83-1 ]
[ 765-85-5 ]

Reference： [1]Journal of Chemical Research, Miniprint,1983,p. 2401 - 2416
[2]Journal of Chemical Research, Miniprint,1983,p. 2401 - 2416

5
[ 5454-83-1 ]
[ 19812-93-2 ]
[ 144529-80-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 72h;	5-(4’-Cyano-biphenyl-4-yloxy)-pentanoic acid methyl ester [14] To a suspension in dry DMF (10 mL) of 4’-hydroxy-4-biphenylcarbonitrile (0.976 g, 5.0 mmol) and Cs2CO3 (1.95 g, 6.0 mmol) was added methyl 5-bromovalerate (1.17 g, 6.0 mmol), and the reaction mixture was stirred for 72 h at ambient temperature. The reaction mixture was diluted with Et2O (50 mL) and extracted with pH 7 buffer (50 mL). The organic layer was washed with brine (2 × 50 mL), dried over Na2SO4, filtered and then concentrated in vacuo to afford 14 as white solid (1.6 g, >95%). 1HNMR (300 MHz, CDCl3) δ 7.71-7.62 (c, 4H), 7.53 (d, J= 8.8 Hz, 2H), 6.98 (d, J= 9.1 Hz, 2H), 4.03 (t, J= 5.8 Hz, 2H), 3.68 (s, 3H), 2.42 (t, J= 7.1 Hz, 2H), 1.89-1.80 (m, 4H) ppm
1.49 g	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 72h;

Reference： [1]Wilfong, Erin M.; Du, Yu; Toone, Eric J. [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 20, p. 6521 - 6524]
[2]Hajduk; Sheppard; Nettesheim; Olejniczak; Shuker; Meadows; Steinman; Carrera Jr.; Marcotte; Severin; Walter; Smith; Gubbins; Simmer; Holzman; Morgan; Davidsen; Summers; Fesik [Journal of the American Chemical Society, 1997, vol. 119, # 25, p. 5818 - 5827]

6
[ 5454-83-1 ]
[ 123-08-0 ]
methyl 5-(4-formylphenoxy)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate In acetone for 16h; Heating;
84%	With potassium carbonate In acetone for 16h; Reflux;	S2.4.2. Methyl 5-(4-formylphenoxy)pentanoate (27) To a mixture of 4-hydroxybenzaldehyde (26; 10 mmol) and potassium carbonate (20 mmol) in acetone was added methyl 5-bromovalerate (25; 12.5 mmol) and the reaction mixture was refluxed for 16 h. The insoluble material was filtered and washed with acetone, then the acetone was removed in vacuo. The residue was dissolved in EtOAc and washed with saturated aqueous solutions of sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The product was pure enough for the next step. MS m/z: 237.20 [M+H] + Yield: 84% 1H NMR (400 MHz, DMSO) δ 9.85 (s, 1H, -CHO), 7.88 - 7.80 (m, 2H, Ar-H), 7.13 - 7.06 (m, 2H, Ar-H), 4.08 (t, J = 6.2 Hz, 2H, -CH2-O-), 3.57 (s, 3H, -OCH3), 2.37 (t, J = 7.2 Hz, 2H, -CH2CO-), 1.79 - 1.62 (m, 4H, -CH2-C2H4-CH2-).
78%	Stage #1: 4-hydroxy-benzaldehyde With sodium hydride In N,N-dimethyl-formamide Stage #2: 5-bromovaleric acid methyl ester In N,N-dimethyl-formamide at 20℃;

	With potassium carbonate In acetone for 16h; Reflux;	10 Example 10 Synthesis of 5-(4-formylphenoxy)pentanoic acid Methyl 5-bromovelerate (13.4 g, 68.6 mmol) and anhydrous potassium carbonate (18.93 g, 137 mmol) was added to a solution of 4-hydroxybenzaldehyde (8.38 g, 68.6 mmol) in anhydrous acetone (140 ml). The mixture was heated at reflux for 16 hours with vigorous stirring. After the mixture was cooled to room temperature and filtered, the solvent was removed under vacuum. The residue was dissolved in dichloromethane (200 mL) and washed sequentially with aqueous sodium hydroxide (1 N, 200 ml), water (200 ml) and brine (200 ml). The solvent was evaporated under vacuum to give a yellowish crystal. The crystal was dissolved in a mixture of THF (200 ml) and hydrochloric acid (6 N, 30 ml). The mixture was then heated to reflux for 3 hours, after which the THF was removed under vacuum. The oil was then extracted with chloroform (450 ml). The combined chloroform layer was washed with water (2150 ml) and brine (200 ml), and then dried with anhydrous sodium sulfate. After the solvent was removed, the acid was obtained as a yellow liquid. The structure of 5-(4-formylphenoxy)pentanoic acid is:
	With potassium carbonate In ethanol at 85℃; for 5h;	Methyl 4-(4-formylphenoxy)butanoate (3a) General procedure: To a stirred solution of 4-hydroxybenzaldehyde (1, 1.00 g, 8.19 mmoL, 1.0 equiv) and methyl 4-bromobutyrate (2a, 2.52 g, 13.9 mmoL, 1.7 equiv) in 35 mL ethanol, then K2CO3 (2.26 g, 16.4 mmoL, 2.0 equiv) was added. The mixture was stirred at 85 for 5 h. Then the mixture was cooled to room temperature, filtered and concentrated under the reduced pressure to remove solvent. The residue was diluted with water and extracted with EtOAc (30 mL × 3). The combined organic layers were dried with Na2SO4, filtered, and concentrated under the reduced pressure. The residue was purified via silica gel column chromatography (n-hexane/EtOAc, 15/1, v/v) to afford intermediate 3a (1.45 g, 80% yield) as a white oil.

Reference： [1]Bourne, Gregory T.; Meutermans, Wim D.F.; Smythe, Mark L. [Tetrahedron Letters, 1999, vol. 40, # 40, p. 7271 - 7274]
[2]Erdmann, Frank; Günther, Stefan; Ghazy, Ehab; Hügle, Martin; Herp, Daniel; Jung, Manfred; Morales, Elizabeth R.; Robaa, Dina; Romier, Christophe; Schmidt, Matthias; Schmidtkunz, Karin; Sippl, Wolfgang; Zeyen, Patrik [European Journal of Medicinal Chemistry, 2020, vol. 200]
[3]Folkes, Adrian; Roe, Michael B.; Sohal, Sukhjit; Golec, Julian; Faint, Richard; Brooks, Teresa; Charlton, Peter [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 19, p. 2589 - 2592]
[4]Current Patent Assignee: ENZO BIOCHEM INC; ENZO LIFE SCIENCES INC - US2013/89853, 2013, A1 Location in patent: Paragraph 0096
[5]Zhu, Tianbao; Chen, Xi; Li, Chenglan; Tu, Jie; Liu, Na; Xu, Defeng; Sheng, Chunquan [European Journal of Medicinal Chemistry, 2021, vol. 221]

7
[ 847978-36-3 ]
[ 5454-83-1 ]
[ 936030-69-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	With caesium carbonate In N,N-dimethyl-formamide at 25℃;
61.9%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	9 To a well-dried vessel were added anhydrous dimethylformamide (1 ml), Compound 14 (63.8 mg, 0.20 mmol), methyl 5-bromovalerate (21 μl, 0.18 mmol), and cesium carbonate (400 mg, 1.2 mmol). The atmosphere in the vessel was substituted with argon, and the reaction was allowed to continue overnight at room temperature. The precipitates were removed with a Kiriyama funnel, and the solvent was evaporated with a vacuum pump. The resulting residue was dissolved in purified water, and extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and dichloromethane was evaporated. The residue was purified with a silica gel column (eluent: dichloromethane/methanol (100:5)) to obtain Compound 17 (53.7 mg, yield: 61.9%, red powder).1H NMR (300 MHz/CDCl3) δ 7.10 (d, J=9.2 Hz, 2H), 7.07 (d, J=8.3 Hz, 1H), 6.91-6.84 (m, 4H), 6.81 (dd, J=9.2 Hz, 2.0 Hz, 2 H), 4.06 (m, 2H), 3.70 (s, 3H), 2.45 (m, 2H), 2.02 (s, 3H), 1.88 (m, 4H)HR-MS (ESI-MS): [M+Na]+ calcd for 455.14706, found 455.14692.Φf1 (100 mM sodium phosphate buffer, pH 9.0)=0.82

Reference： [1]Kamiya, Mako; Kobayashi, Hisataka; Hama, Yukihiro; Koyama, Yoshinori; Bernardo, Marcelino; Nagano, Tetsuo; Choyke, Peter L.; Urano, Yasuteru [Journal of the American Chemical Society, 2007, vol. 129, # 13, p. 3918 - 3929]
[2]Current Patent Assignee: SEKISUI CHEMICAL CO., LTD. - US7868147, 2011, B2 Location in patent: Page/Page column 18; 20; 21

8
[ 5454-83-1 ]
[ 23956-12-9 ]
1-(4-methylcarboxybutyl)-5-(2-hydroxyethyl)uracil [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With chloro-trimethyl-silane; In 1,1,1,3,3,3-hexamethyl-disilazane; toluene; acetonitrile;	Preparation of 1-(4-methylcarboxybutyl)-<strong>[23956-12-9]5-(2-hydroxyethyl)uracil</strong>(13.2) 5-(2-Hydroxyethyl)uracil (13.1) (5.38 g, 19.9 mmol) was suspended in 1,1,1,3,3,3-hexamethyldisilazane (27 ml) and chlorotrimethylsilane (4 ml) under a nitrogen atmosphere. The mixture was refluxed for 2 hours. The reaction mixture was cooled to ambient temperature and then reduced to a yellow oil by rotary evaporation. The oil was redissolved in anhydrous toluene (5 ml) and again reduced to an oil. The oil was dissolved in anhydrous acetonitrile (20 ml) and methyl-5-bromovalerate (13 ml, 91 mmol) was added. This reaction was heated at reflux under an atmosphere of argon for 18 hours. The mixture was then cooled and reduced to an oil by rotary evaporation. The product was purified by liquid chromatography on silica gel eluding with a stepped gradient of chloroform and methanol. The product was isolated and recrystallized from petroleum ether to yield 1-(4-methylcarboxybutyl)-<strong>[23956-12-9]5-(2-hydroxyethyl)uracil</strong> (13.2) (6.63 g, 71.2%), MP 105 C. The structure was confirmed by mass spectroscopy and proton NMR.

Reference： [1]Patent: US6313286,2001,B1

9
[ 5454-83-1 ]
[ 130200-58-7 ]
[ 220297-15-4 ]

Yield	Reaction Conditions	Operation in experiment
94%		EXAMPLE 129A The resulting product from Example 119A (250 mg, 1.477 mmol) was treated with methyl 5-bromovalerate in an analogous manner as described in Example 1 19B to yield the desired compound (394 mg, 94%). MS (DCI (NH3)) m/z 301 (M+NH4)+.
94%		EXAMPLE 129A The resulting product from Example 119A (250 mg, 1.477 mmol) was treated with methyl 5-bromovalerate in an analogous manner as described in Example 119B to yield the desired compound (394 mg, 94%). MS (DCI (NH3)) m/z 301 (M+NH4)+.

Reference： [1]Patent: US6258822,2001,B1
[2]Patent: US6284796,2001,B1

10
[ 215606-58-9 ]
[ 5454-83-1 ]
[ 215606-74-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 3-(4-Hydroxybenzyl)-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene With sodium hydride; potassium iodide In DMF (N,N-dimethyl-formamide) at 20℃; for 0.166667 - 0.25h; Stage #2: 5-bromovaleric acid methyl ester for 2h;	33.A A. 3-[4-(S-Methoxy-5-oxopentyloxy)benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene To a stirred solution of 3-(4-hydroxybenzyl)-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (1.5 g, 3.5 mmole) and KI (0.87 g, 5.2 mmol) in anhydrous DMF(50 mL) was added NaH (0.28 g, 7.0 mmol) under nitrogen at room temperature. The reaction mixture was stirred for 10-15 min before methyl 5-bromovalerate (0.75 mL, 5.25 mmol)was added, and it was stirred for an additional 2 hours and then diluted with ethyl acetate and NH4Cl solution. The organic layer was washed with brine, dried with Na2SO4 and concentrated in vacuo. The residue was subjected to a SiO2 column, eluted with 5% methanol in CH2Cl2, to give the ester product as a yellow oil (1.42 g, 75%). FDMS m/e 543.19 (M+)

Reference： [1]Current Patent Assignee: ELI LILLY & CO - US6350774, 2002, B1 Location in patent: Page column 66

11
[ 5454-83-1 ]
[ 610-78-6 ]
[ 1093798-97-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In N,N-dimethyl acetamide; at 60℃; for 16h;	Reaction under N2 atmosphere. A mixture of <strong>[610-78-6]4-chloro-3-nitrophenol</strong> (0.055 mol), 5- bromopentanoic acid, methyl ester (0.055 mol) and K2CO3 (0.055 mol) in DMA (50 ml) was stirred for 16 hours at 60 C. The reaction mixture was cooled. H2O was added. This mixture was extracted with EtOAc (3x). The separated organic layer was washed with H2O (2x), dried, filtered and the solvent evaporated. Yield: 16.5 g of intermediate 73 (100 %).

Reference： [1]Patent: WO2008/155421,2008,A2 .Location in patent: Page/Page column 74-75

12
[ 5454-83-1 ]
[ 1093798-82-3 ]
[ 1093798-83-4 ]

Yield	Reaction Conditions	Operation in experiment
79%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 60℃;	A20.d A mixture of intermediate 58 (0.00815 mol), 5-bromo-pentanoic acid, methyl ester (0.00815 mol) and DIPEA (1.58 g) in DMA (25 ml) was stirred for 5 days at 60 0C. More 5-bromo-pentanoic acid, methyl ester (0.5 g) was added and the reaction mixture was stirred over the weekend at 60 0C. The mixture was poured out into H2O. This mixture was extracted with EtOAc (3x), washed with H2O (2x), dried, filtered and the solvent evaporated. The residue was purified by high-performance liquid chromatography (HPLC). The product fractions were collected and worked-up. Yield: 2.55 g of intermediate 59 (79 %).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2008/155421, 2008, A2 Location in patent: Page/Page column 70

13
[ 5454-83-1 ]
[ 177429-27-5 ]
Ethyl 4-(benzyloxy)-3-(5-methoxy-5-oxopentyloxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		Step 10a: Ethyl 4-(benzyloxy)-3-(5-methoxy-5-oxopentyloxy)benzoate (Compound 503-18) The title compound 503-18 (1.5 g, 100%) was prepared as a yellow oil from compound 502 (1.0 g, 3.7 mmol), methyl 5-bromopentanoate (1.0 g, 4.4 mmol) using a procedure similar to that described for compound 307-9 (Example 3): LCMS: 437 [M+23]+; 1H NMR (DMSO-d6): delta 7.54 (d, J=8.7 Hz, 1H), 7.44-7.33 (m, 6H), 7.14 (d, J=8.4 Hz, 1H), 5.18 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 4.01 (t, J=6.0 Hz, 2H), 3.56 (s, 3H), 2.33 (m, 2H), 1.80-1.61 (m, 4H), 1.28 (t, J=7.2 Hz, 3H).

Reference： [1]Patent: US2009/76044,2009,A1 .Location in patent: Page/Page column 31

14
[ 5454-83-1 ]
[ 574745-76-9 ]
[ 1133461-51-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h;	3.f Step 3f: Step 3f: Methyl 5-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolin-7-yloxy)pentanoate (Compound 307-9) A mixture of compound 306 (300 mg, 0.88 mmol), K2CO3 (365 mg, 2.64 mmol) and DMF (10 mL) was stirred for 10 min followed by addition of methyl 5-bromopentanoate (202 mg, 1.06 mmol). The resulting mixture was stirred at 80° C. for 3 h. The mixture was filtered and the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4, and concentrated to give the title compound 307-9 as a brown solid (280 mg, 70%): LCMS: 454 [M+1]+.

Reference： [1]Current Patent Assignee: CURIS INC - US2009/76044, 2009, A1 Location in patent: Page/Page column 28

15
[ 5454-83-1 ]
[ 13395-85-2 ]
[ 1135825-33-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; N,N-dimethyl-formamide;	Example 1 Synthesis of 5-(2-tert-Butyl-4-chlorophenoxy)pentanoic Acid Methyl 5-bromovalerate (1.52 mL, 2.09 g, 10.7 mmol), 2-tert-butyl-4-chloro-phenol (2.4 g, 13 mmol) and potassium carbonate (1.4 g, 10.1 mmol) were suspended in dry DMF (10 mL) and stirred for 2 h at 120 C. To the resulting mixture water was added (80 mL) and extracted with ethyl acetate (320 mL). The organic layers were washed two times with 10% sodium hydroxide (220 mL), water (1*20 mL), dried over sodium sulfate and evaporated in vacuo. To afford 3.46 g (quant) crude la that was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) delta ppm 7.21 (d, J=2.6 Hz, 1H), 7.10 (dd, J=8.6, 2.6 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 3.97 (t, J=5.8 Hz, 2H), 2.46 (t, J=6.9 Hz, 2H), 1.84-1.94 (m, 4H), 1.36 (s, 9H).

Reference： [1]Patent: US2009/88435,2009,A1

16
[ 5454-83-1 ]
[ 207115-22-8 ]
[ 1236230-68-4 ]

Reference： [1]Organic Letters,2010,vol. 12,p. 3414 - 3417

17
[ 5454-83-1 ]
[ 153707-56-3 ]
[ 1239587-43-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate In acetonitrile at 86℃; for 6h;	6 Compound 22:[224] To a solution of triol 21 (827 mg, 5.37 mmol) and methyl 5 -bromo valerate (998 mg, 5.12 mmol) in acetonitrile (40 mL) was added potassium carbonate (3.71 g, 26.9 mmol). The mixture was put in a 86 0C oil bath and refluxed for 6 hours. The reaction mixture was removed from the oil bath, cooled to room temperature and the solvents were evaporated under reduced pressure (temperature 0C). The residue was diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was stripped under reduced pressure and the residue was purified through silica gel chromatography (Hexanes/Ethyl acetate, 1 :2, 1 :3) to give compound 22 (1.15 g, y = 84%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 6.89 (s, IH), 6.80 (s, 2H), 4.62 (s, 4H), 3.98-3.95 (m, 2H), 3.67 (s, 3H), 2.41-2.37 (m, 2H), 2.23 (bs, -OHx2), 1.84-1.78 (m, 4H); MS (m/z): found 291.1 (M + Na)+.

Reference： [1]Current Patent Assignee: IMMUNOGEN INC - WO2010/91150, 2010, A1 Location in patent: Page/Page column 117-118

18
[ 494799-18-7 ]
[ 5454-83-1 ]
[ 877279-12-4 ]

Yield	Reaction Conditions	Operation in experiment
57%	Stage #1: methyl 3-cyclohexyl-1H-indole-6-carboxylate With sodium hydride In DMF (N,N-dimethyl-formamide) at 20℃; for 0.25h; Stage #2: 5-bromovaleric acid methyl ester In DMF (N,N-dimethyl-formamide) at 20℃;	Methyl 3-cyclohexyl-1-(5-methoxy-5-oxopentyl)-1H-indole-6-carboxylate Methyl 3-cyclohexyl-1-(5-methoxy-5-oxopentyl)-1H-indole-6-carboxylate Methyl 3-cyclohexyl-1H-indole-6-carboxylate (500 mg, 1.94 mmol) was added to a suspension of NaH (85.5 mg of 60% dispersion in mineral oil, 2.14 mmol) in DMF (5 mL), and the reaction mixture stirred at RT for 15 min. Methyl 5-bromovalerate (0.305 mL, 2.14 mmol) was then added and the reaction mixture stirred at RT overnight, after which the reaction was quenched with ice and extracted with ethyl acetate (2*50 mL). The extracts were then combined, washed with 1N HCl solution, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography using hexanes to 25% ethyl acetate in hexanes as eluant to give the title compound as a colorless thick oil (0.41 g, 57% yield). MS m/z 372(MH+). 1H NMR (300 MHz, CDCl3) ppm 1.23 (m, 1 H) 1.35-1.48 (m, 5 H) 1.62 (m, 2 H) 1.69-1.89 (m, 6 H) 2.03 (m, 2 H) 2.29 (t, J=7.32 Hz, 2 H) 2.78 (m, 1 H) 3.62 (s, 3 H) 3.90 (s, 3 H) 4.11 (t, J=6.95 Hz, 2 H) 6.97 (s, 1 H) 7.60 (d, J=8.42 Hz, 1 H) 7.72 (d, J=9.51 Hz, 1 H) 8.00 (s, 1 H).
57%	Stage #1: methyl 3-cyclohexyl-1H-indole-6-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.25h; Stage #2: 5-bromovaleric acid methyl ester In N,N-dimethyl-formamide; mineral oil at 20℃;

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2006/46983, 2006, A1 Location in patent: Page/Page column 176-177
[2]Location in patent: experimental part Ding, Min; He, Feng; Poss, Michael A.; Rigat, Karen L.; Wang, Ying-Kai; Roberts, Susan B.; Qiu, Dike; Fridell, Robert A.; Gao, Min; Gentles, Robert G. [Organic and Biomolecular Chemistry, 2011, vol. 9, # 19, p. 6654 - 6662]

19
[ 5454-83-1 ]
[ 4877-80-9 ]
[ 1325232-68-5 ]

Yield	Reaction Conditions	Operation in experiment
60%		<strong>[4877-80-9]2,3,6,7,10,11-hexahydroxytriphenylene</strong> 1 (HHTP) was prepared according to the reported procedure [34]. To give compounds 2, 3 and 4, th e mixture of HHTP (1 mmol) and K2CO3 (8 mmol) in 50.0 mL of dry acetone was refluxed for 1 h. Then, ethyl bromoacetate, methyl 5-bromovalerate or methyl (4-bromomethyl)benzoate (8 mmol) upon this solution were added and refluxed for 24 h. The reactionwas monitored by TLC. The resulting solutionwas allowed to warm up to room temperature. At the end of the reaction, the reaction mixture was filtered and the organic layer was removed under reduced pressure. The observed solid product was dissolved in CHCl3 and washed twice with 0.2 N HCl and water. The combined organic phase was dried over Na2SO4 filtered, andconcentrated under reduced pressure to afford the desired pure product (2, 3 and 4).

Reference： [1]Journal of Organometallic Chemistry,2011,vol. 696,p. 3106 - 3112

20
[ 5454-83-1 ]
[ 4877-80-9 ]
[ 1325232-70-9 ]

Reference： [1]Journal of Organometallic Chemistry,2011,vol. 696,p. 3106 - 3112

21
[ 865236-21-1 ]
[ 5454-83-1 ]
[ 1332725-00-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate In N,N-dimethyl-formamide at 70℃;	5.1.1. (4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenoxy)-acetic acid ethyl ester (8a) General procedure: To a solution of 7 (32.3 mg, 0.084 mmol) in DMF (1.0 mL) were added K2CO3 (23 mg, 0.169 mmol) and ethyl bromoacetate (28 mg, 0.169 mmol). The mixture was stirred at 70 °C overnight. Then the mixture was diluted with AcOEt, washed with water and brine, dried over anhydrous MgSO4, and concentrated. The obtained residue was purified by silicagel chromatography (n-hexane/AcOEt = 100:0 to 20:80) to give 8a (20.6 mg, 52%) as a colorless oil.

Reference： [1]Location in patent: experimental part Kashiwagi, Hirotaka; Ono, Yoshiyuki; Shimizu, Kazuki; Haneishi, Tsuyoshi; Ito, Susumu; Iijima, Shigeyuki; Kobayashi, Takamitsu; Ichikawa, Fumihiko; Harada, Suguru; Sato, Hideki; Sekiguchi, Nobuo; Ishigai, Masaki; Takahashi, Tadakatsu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 16, p. 4721 - 4729]

22
[ 5454-83-1 ]
[ 1182669-71-1 ]
[ 1428858-58-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	With nickel(II) triflate; triphenylphosphine; sodium iodide In toluene at 140℃; for 24h; Glovebox;
76%	With nickel(II) triflate; sodium carbonate; triphenylphosphine; sodium iodide In toluene at 140℃; for 24h; Glovebox; regioselective reaction;	IV. General Procedure for Direct Alkylation: Ni-Catalyzed Alkylation of Amides 1a with BuBr General procedure: To an oven-dried 5 mL screw-capped vial, in a glove box 2-methyl-N-(8-quinolinyl)benzamide (79 mg, 0.3 mmol), 1-bromobutane (82 mg, 0.6 mmol), Ni(OTf)2 (10.6 mg, 0.03 mmol), PPh3 (15.6 mg, 0.06 mmol), Na2CO3 (64 mg, 0.6 mmol) and toluene (1 mL) were added. The mixture was stirred for 24 h at 140 °C followed by cooling. The resulting mixture was filtered through a celite pad and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc= 20/1) to afford the desired alkylated product (84 mg, 88%) as a colorless oil.

Reference： [1]Aihara, Yoshinori; Chatani, Naoto [Journal of the American Chemical Society, 2013, vol. 135, # 14, p. 5308 - 5311]
[2]Aihara, Yoshinori; Wuelbern, Jendrik; Chatani, Naoto [Bulletin of the Chemical Society of Japan, 2015, vol. 88, # 3, p. 438 - 446]

23
[ 5454-83-1 ]
[ 68011-66-5 ]
[ 1335422-95-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate In acetonitrile at 20℃;	1 6. Synthesis of Compound 7 To a solution of compound 6 (1.0 g, 4.0 mmol) in 30 mL of ACN K2CO3 (1.38 g, 10.0 mmol) and compound A (1.16 g, 6.0 mmol) were added, and the solution was then stirred at room temperature overnight. The solution was filtered, concentrated under reduced pressure, and partitioned between water and EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent: EA/PE=1/3) to give 1.1 g of compound 7 as white solid (Yield: 76%).

Reference： [1]Current Patent Assignee: HANGZHOU KINGMED DIAGNOSTICS INSTITUTE - US8563713, 2013, B2 Location in patent: Page/Page column 6; 9; 10

24
[ 5454-83-1 ]
[ 1448177-14-7 ]
[ 1448177-15-8 ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium methylate In methanol at 20℃; Inert atmosphere;	Methyl 5-[3-(R,S)-3-(methoxycarbonylamino)-3-(dimethoxyphosphoryl)propyl]sulfanyl} pentanoate (26) Phosphonate 25 (1.36 g; 4.5 mmol) and sodium methanolate (0.24 g; 4.5 mmol) were dissolved in 20 mL of anhydrous methanol under a nitrogen atmosphere.One portion of methyl 5-bromovalerate (0.88 g; 4.5mmol)was added after 10 min of stirring, and the reaction mixture was left at rt overnight. The solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel using a linear gradient of the S H3mixture in ethyl acetate Yield: 1.3 g (77%). Viscous colorless oil, Rf = 0.67 (S1). 1H NMR (600 MHz, CDCl3): δ = 5.34 (bd, J = 10.3 Hz, 1H, NH), 4.26 (dm, J(H,P) = 16.6 Hz, 1H), 3.79 (d, J(P,H) = 10.6 Hz, 3H, PeOMe), 3.78 (d, J(P,H) = 10.6Hz, 3H, PeOMe), 3.71 (s,3H,OMe), 3.67 (s, 3H,OMe), 2.67 (m,1H), 2.55 (m,1H), 2.52(m, 2H), 2.33 (t, J=7.4Hz,2H), 2.09(m,1H), 1.87 (m, 1H), 1.72 (m, 2H), 1.61 (m, 2H). 13C NMR (150.9 MHz, CDCl3): δ = 173.73 (-CO-O), 156.61 (d, J(C,P) = 5.5 Hz, N-CO-O), 53.26 (d, J(C,P) = 7.1 Hz), 53.05 (d, J(C,P) = 6.6 Hz), 52.54, 51.45, 46.33 (d, J(C,P) = 156.7 Hz), 33.44, 31.46, 30.04 (d, J(C,P) = 4.0 Hz), 28.77, 28.10 (d, J(C,P) = 14.4Hz), 23.94. IR (CCl4) nmax (cm-1): 3247m(NH);1726vs (C=O carbamate); 1538 s, 1508 s (amide II); 1736 vs (C=O ester); 1062 vs,1049 vs,1035 vs, 834 s (P-O-C); 1235 s (P=O); 1215 s,1195 s (C-O); 2954 s, 1447 s (CH3). HRMS (ESI) calc for C13H26O7NNaPS [M + Na]+ 394.10598, found: 394.10593

Reference： [1]Pićha, Jan; Vaňek, Václav; Budě̌́sińsky, Miloš; Mlad́ková, Jana; Garrow, Timothy A.; Jiŕ̌acek, Jiř́i [European Journal of Medicinal Chemistry, 2013, vol. 65, p. 256 - 275]

25
[ 5454-83-1 ]
2-(5-hydroxypentyl)-6-(piperazin-1-yl)-1H-benzo[de]isoquinoline-1,3-(2H)-dione [ No CAS ]
methyl 5-(4-(2-(5-hydroxypentyl)-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl)piperazin-1-yl)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate In acetone for 3h; Reflux;	Methyl 5-(4-(2-(5-Hydroxypentyl)-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl)piperazin-1-yl)pentanoate(4) A mixture of compound 3 (800 mg, 2.16 mmol), 5-bromopentanoate (465 mg, 2.38 mmol) and K2CO3 (299 mg,2.16 mmol) in acetone (15 mL) was refluxed for 3 h. After concentrating the mixture under reduced pressure, the resultingresidue was dissolved in CHCl3 and washed with water.The organic layer was dried (MgSO4) and concentrated togive a crude product, which was purified by columnchromatography (SiO2) eluting with a mixture of CHCl3/MeOH (5:1) to afford the ester 4 (797 mg, 76%) as a yellow solid.
76%	With potassium carbonate; potassium iodide In acetone at 60℃; for 3h;	1 preparaion of methyl 5-(4-(2-(5-hydroxypentyl)-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl)piperazin-1-yl)pentanoate 2-(5-hydroxypentyl)-6-(piperazin-1-yl)-1H-benzo[de]isoquinoline-1,3-(2H)-dione (800mg, 2.16mmol) prepared in Preparation Example 2 in acetone (12ml) and methyl 5-bromopentanoate (465mg, 2.38mmol) were added, and potassium carbonate (299mg, 2.16mmol) and potassium iodide (360mg, 2.16mmol) were added at 60°C. The mixture was stirred at reflux for 3 hours. The result of the reaction was confirmed by TLC (MeOH:CHCl3=1:5, Rf=0.7), and after completion of the reaction, the solvent was removed by distillation under reduced pressure, distilled water was added to remove the salt, and the organic layer was extracted with chloroform and moistened with anhydrous MgSO4. After removal, distillation was carried out under reduced pressure. The obtained residue was separated and purified by column chromatography (MeOH:CHCl3=1:5) to obtain a yellow solid (797 mg, yield 76%).

Reference： [1]Kim, Kang-Hyeon; Lee, Wan-Jin; Kim, Jae Nyoung; Kim, Hyung Jin [Bulletin of the Korean Chemical Society, 2013, vol. 34, # 8, p. 2261 - 2266]
[2]Current Patent Assignee: CHONNAM NATIONAL UNIVERSITY - KR101482641, 2015, B1 Location in patent: Paragraph 0059-0064

26
[ 5454-83-1 ]
[ 23288-92-8 ]
methyl 5-((5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl)thio)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate In acetone at 25℃; for 6h; Inert atmosphere;	4 methyl 5-((5-(2,4-dichlorophenyl)- 1 ,3,4-oxadiazol-2-yl)thio)pentanoate To a solution of 5-(2,4-dichlorophenyl)-1,3,4-oxadiazole-2-thiol (275 mg, 1.11mmol) in acetone (10 mL), was added potassium carbonate (230 mg, 1.67 mmol) followed methyl 5-bromopentanoate (330 mg, 1.67 mmol). The reaction was stirred under nitrogen at25 °C for 6 h. The crude mixture was poured into water and extracted with dichloromethane.The organic layer was washed with brine, dried over magnesium sulfate, filtered andconcentrated. The crude residue was purified by column chromatography eluting with 10- 30% ethyl acetate in hexanes to give the title compound as an oil which solidified uponstanding (330 mg, 82%). ‘H NMR (400 MHz, DMSO-d6) ppm 7.97, 7.90, 7.64, 3.55, 3.30, 2.35, 1.77, 1.65.
82%	With potassium carbonate In acetone at 25℃; Inert atmosphere;

Reference： [1]Current Patent Assignee: UNIVERSITY OF MICHIGAN - WO2015/138326, 2015, A1 Location in patent: Page/Page column 62
[2]Kahl, Dylan J.; Hutchings, Kim M.; Lisabeth, Erika Mathes; Haak, Andrew J.; Leipprandt, Jeffrey R.; Dexheimer, Thomas; Khanna, Dinesh; Tsou, Pei-Suen; Campbell, Phillip L.; Fox, David A.; Wen, Bo; Sun, Duxin; Bailie, Marc; Neubig, Richard R.; Larsen, Scott D. [Journal of Medicinal Chemistry, 2019, vol. 62, # 9, p. 4350 - 4369]

27
[ 5454-83-1 ]
tert-butyl ((1S)-1-(4-((2-((cyclopropylmethyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazol-5-yl)ethyl)carbamate [ No CAS ]
methyl 5-(5-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-4-((2-((cyclopropylmethyl)amino)-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 5h; Sealed tube;	124.5 Step 5: Methyl 5- (5- (5- ( (S) -1- ( (tert-butoxycarbonyl) amino) ethyl) -4- ( (2- ( (cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate Step 5: Methyl 5- (5- (5- ( (S) -1- ( (tert-butoxycarbonyl) amino) ethyl) -4- ( (2- ( (cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate[1916]To 15 mL of N, N-dimethylformamide were added tert-butyl ( (1S) -1- (4- ( (2- ( (cyclopropylmethyl) amino) -1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (4- (difluoromethoxy) -3-hydroxyphenyl) oxazol-5-yl) ethyl) carbamate (246 mg, 0.386 mmol) , methyl 5-bromovalerate (113 mg, 0.58 mmol) and potassium carbonate (107 mg, 0.773 mmol) . The mixture was stirred at 60 in a sealed tube for 5 hours. The mixture was filtered to remove potassium carbonate. The filtrate was concentrated and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) 1/1) to give a white solid (232 mg, 80) .[1917]1H NMR (400 MHz, CDCl3) : δ ppm 7.63 -7.65 (m, 2H) , 7.48 -7.55 (m, 1H) , 7.26 (d, J 8.8 Hz, 1H) , 6.84 -6.95 (m, 2H) , 6.65 (t, JF-H 74.8 Hz, 1H) , 5.86 -5.89 (m, 1H) , 5.28 -5.36 (m, 1H) , 4.18 -4.21 (m, 2H) , 3.70 (s, 3H) , 3.13 -3.23 (m, 2H) , 2.45 -2.49 (m, 2H) , 1.89 -1.97 (m, 4H) , 1.47 -1.48 (m, 3H) , 1.40 -1.44 (m, 9H) , 1.30 -1.31 (m, 1H) , 0.51 -0.53 (m, 2H) , 0.18 -0.22 (m, 2H) and MS-ESI: m/z 751.20 [M+H]+.

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2015/161830, 2015, A1 Location in patent: Paragraph 00682

28
[ 5454-83-1 ]
tert-butyl ((1S)-1-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazol-5-yl)ethyl)carbamate [ No CAS ]
methyl 5-(5-(4-((2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)carbamoyl)-5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.8%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4h; Sealed tube;	128.3 Step 3: Methyl 5- (5- (4- ( (2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -5- ( (S) -1- ( (tert-butoxycarbonyl) amino) ethyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate Step 3: Methyl 5- (5- (4- ( (2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -5- ( (S) -1- ( (tert-butoxycarbonyl) amino) ethyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate[1960]To 15 mL of N, N-dimethylformamide were dissolved tert-butyl ( (1S) -1- (4- ( (2-amino-1- (2, 4-difluorophenyl) -2-oxoethyl) carbamoyl) -2- (4- (difluoromethoxy) -3-hydroxyphenyl) oxazol-5-yl) ethyl) carbamate (442 mg, 0.818 mmol) , methyl 5-bromovalerate (239 mg, 1.23 mmol) and potassium carbonate (226 mg, 1.64 mmol) . The whole mixture was stirred at 60 for 4 hours in a sealed tube. The reaction mixture was filtered to remove potassium carbonate and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) 1/1) to give colourless oil (454 mg, 84.8) .[1961]1H NMR (400 MHz, CDCl3) : δ ppm 7.63 -7.65 (m, 2H) , 7.50 -7.56 (m, 1H) , 7.26 (d, J 8.4 Hz, 1H) , 6.90 -6.96 (m, 2H) , 6.65 (t, JF-H 74.4 Hz, 1H) , 5.94 (d, J 6.8 Hz, 1H) , 5.29 -5.37 (m, 1H) , 4.17 -4.20 (m, 2H) , 3.71 (s, 3H) , 2.45 -2.49 (m, 2H) , 1.89 -1.97 (m, 4H) , 1.48 -1.53 (m, 3H) , 1.40 -1.45 (m, 9H) and MS-ESI: m/z 697.25 [M+H]+.

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2015/161830, 2015, A1 Location in patent: Paragraph 00694

29
[ 5454-83-1 ]
[ 50-33-9 ]
C₂₅H₃₀N₂O₄ [ No CAS ]

Reference： [1]Chemical Biology and Drug Design,2016,vol. 87,p. 936 - 945

30
[ 5454-83-1 ]
(S)-tert-butyl (1-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)-1,3-oxazol-5-yl)ethyl)carbamate [ No CAS ]
(S)-methyl 5-(5-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)-1,3-oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 5h; Inert atmosphere; Sealed tube;	150.10 Step 10) : (S) -methyl 5- (5- (5- (1- ( (tert-butoxycarbonyl) amino) ethyl) -4- (4- (cyclopropanecarbonyl) piperazine-1-carbonyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate A mixture of (S) -tert-butyl (1- (4- (4- (cyclopropanecarbonyl) piperazine-1-carbonyl) -2- (4- (difluoromethoxy) -3-hydroxyphenyl) oxazol-5-yl) ethyl) carbamate (200 mg, 0.36 mmol) , methyl 5-bromopentanoate (106 mg, 0.55 mmol) and potassium carbonate (100 mg, 0.73 mmol) in DMF (10 mL) was stirred in a sealing tube at 60 for 5 h. The reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 1/1 to give the title compound as a white solid (200 mg, 83)1H NMR (600 MHz, CDCl3) : δ ppm 7.60 (d, J 8.4 Hz, 1H) , 7.57 (d, J 1.8 Hz, 1H) , 7.26 (d, J 8.4 Hz, 1H) , 6.64 (t, JF-H 74.4 Hz, 1H) , 5.24-5.27 (m, 1H) , 4.15 (t, J 6.0 Hz, 2H) , 3.76-3.83 (m, 8H) , 3.71 (s, 3H) , 2.46 (t, J 7.1 Hz, 2H) , 1.88-1.95 (m, 5H) , 1.57 (d, J 7.2 Hz, 3H) , 1.44 (s, 9H) , 1.33-1.35 (m, 1H) , 1.04-1.06 (m, 2H) , 0.84-0.91 (m, 2H) and MS-ESI: m/z 665.30 [M+H] +.

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2016/34134, 2016, A1 Location in patent: Paragraph 00753

31
[ 5454-83-1 ]
(S)-methyl 4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)-1,3-oxazole-4-carbonyl)piperazine-1-carboxylate [ No CAS ]
(S)-methyl 4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-methoxy-5-oxopentyl)oxy)phenyl)-1,3-oxazole-4-carbonyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4h; Inert atmosphere; Sealed tube;	151.3 Step 3) : (S) -methyl 4- (5- (1- ( (tert-butoxycarbonyl) amino) ethyl) -2- (4- (difluoromethoxy) -3-( (5-methoxy-5-oxopentyl) oxy) phenyl) oxazole-4-carbonyl) piperazine-1-carboxylate A mixture of (S) -methyl 4- (5- (1- ( (tert-butoxycarbonyl) amino) ethyl) -2- (4-(difluoromethoxy) -3-hydroxyphenyl) oxazole-4-carbonyl) piperazine-1-carboxylate (442 mg, 0.82 mmol) , methyl 5-bromopentanoate (239 mg, 1.23 mmol) and potassium carbonate (226 mg, 1.64 mmol) in DMF (15 mL) was stirred in a sealing tube at 60 for 4 h. The reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 2/1 to give the title compound as colorless oil (454 mg, 85)1H NMR (600 MHz, CDCl3) : δ ppm 7.60 (dd, J1 8.4 Hz, J2 1.8 Hz, 1H) , 7.56 (d, J 1.8 Hz, 1H) , 7.26 (d, J 8.4 Hz, 1H) , 6.64 (t, JF-H 75.0 Hz, 1H) , 5.23-5.27 (m, 1H) , 4.14-4.15 (m, 2H) , 3.94-3.99 (m, 2H) , 3.76 (s, 3H) , 3.71 (s, 3H) , 3.60 (br. s, 4H) , 2.45-2.47 (m, 2H) , 1.86-1.95 (m, 4H) , 1.56 (d, J 7.2 Hz, 3H) , 1.43 (s, 9H) and MS-ESI: m/z 655.25 [M+H] +.

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2016/34134, 2016, A1 Location in patent: Paragraph 00757

32
[ 5454-83-1 ]
(S)-tert-butyl (1-(4-(4 (1-naphthoyl)piperazine-1-carbonyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)-1,3-oxazol-5-yl)ethyl)carbamate [ No CAS ]
(S)-methyl 5-(5-(4-(4-(1-naphthoyl)piperazine-1-carbonyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-1,3-oxazol-2-yl)-2-(difluoromethoxy)phenoxy)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4h; Inert atmosphere; Sealed tube;	154.3 Step 3) : (S) -methyl 5- (5- (4- (4- (1-naphthoyl) piperazine-1-carbonyl) -5- (1- ( (tert-butoxy carbonyl) amino) ethyl) oxazol-2-yl) -2- (difluoromethoxy) phenoxy) pentanoate A mixture of (S) -tert-butyl (1- (4- (4- (1-naphthoyl) piperazine-1-carbonyl) -2- (4-(difluoromethoxy) -3-hydroxyphenyl) oxazol-5-yl) ethyl) carbamate (209 mg, 0.329 mmol) , methyl 5-bromopentanoate (80 mg, 0.395 mmol) and potassium carbonate (90 mg, 0.658 mmol) in DMF (10 mL) was stirred in a sealing tube at 60 for 4 h. The reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 1/2 to give the title compound as a white solid (224 mg, 91) .MS-ESI: m/z 751.35 [M+H] +.

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2016/34134, 2016, A1 Location in patent: Paragraph 00773

33
[ 5454-83-1 ]
tert-butyl 4-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)-1,3-oxazole-4-carbonyl)-3-carbamoylpiperazine-1-carboxylate [ No CAS ]
tert-butyl 4-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-methoxy-5-oxopentyl)oxy)phenyl)-1,3-oxazole-4-carbonyl)-3-carbamoylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4h; Inert atmosphere; Sealed tube;	155.3 Step 3) : tert-butyl 4- (5- ( (S) -1- ( (tert-butoxycarbonyl) amino) ethyl) -2- (4- (difluoromethoxy) -3- ( (5-methoxy-5-oxopentyl) oxy) phenyl) oxazole-4-carbonyl) -3-carbamoylpiperazine-1-carb oxylate A mixture of tert-butyl 4- (5- ( (S) -1- ( (tert-butoxycarbonyl) amino) ethyl) -2- (4-(difluoromethoxy) -3-hydroxyphenyl) oxazole-4-carbonyl) -3-carbamoylpiperazine-1-carboxylate (241 mg, 0.385 mmol) , methyl 5-bromopentanoate (90 mg, 0.087 mmol) and potassium carbonate (106 mg, 0.14 mmol) in DMF (10 mL) was stirred in a sealing tube at 60 for 4 h. The reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 1/1 to give the title compound as a white solid (229 mg, 80)MS-ESI: m/z 740.20 [M+H] +.

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2016/34134, 2016, A1 Location in patent: Paragraph 00779

34
[ 5454-83-1 ]
methyl 4-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-hydroxyphenyl)-1,3-oxazole-4-carbonyl)-2-methylpiperazine-1-carboxylate [ No CAS ]
methyl 4-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(4-(difluoromethoxy)-3-((5-methoxy-5-oxopentyl)oxy)phenyl)-1,3-oxazole-4-carbonyl)-2-methylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4h; Inert atmosphere; Sealed tube;	158.3 Step 3) : methyl 4- (5- ( (S) -1- ( (tert-butoxycarbonyl) amino) ethyl) -2- (4- (difluoromethoxy) -3-( (5-methoxy-5-oxopentyl) oxy) phenyl) oxazole-4-carbonyl) -2-methylpiperazine-1-carboxylate A mixture of methyl 4- (5- ( (S) -1- ( (tert-butoxycarbonyl) amino) ethyl) -2- (4-(difluoromethoxy) -3-hydroxyphenyl) oxazole-4-carbonyl) -2-methylpiperazine-1-carboxylate (308 mg, 0.555 mmol) , methyl 5-bromopentanoate (130 mg, 0.667 mmol) and potassium carbonate (154 mg, 1.11 mmol) in DMF (10 mL) was stirred in a sealing tube at 60 for 4 h. The reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 1/1 to give the title compound as a white solid (326 mg, 88)MS-ESI: m/z 669.30 [M+H] +.

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2016/34134, 2016, A1 Location in patent: Paragraph 00797

35
[ 5454-83-1 ]
[ 151266-23-8 ]
methyl 5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 4℃; for 0.5h; Stage #2: 5-bromovaleric acid methyl ester In N,N-dimethyl-formamide; mineral oil at 4 - 20℃; for 108h;	5 Preparation of 5-(4-amino-3-iodo-lH-pyrazolo[3,4-<]pyrimidin-l-yl)pentanoic acid 8c Preparation of 5-(4-amino-3-iodo-lH-pyrazolo[3,4-4. The insoluble was filtered off and the filtrate was evaporated in vacuo. The obtained material was triturated with 20% EtOAc in hexanes (100 mL) for 15 min. The resulting precipitate was collected by filtration. Drying the solid gave the titled compound (1.94 g, 64%) as a pale beige powder. [0347] lH NMR (400 MHz, DMSO-i) δ 8.20 (1H, s), 4.27 (2H, t, J= 6.8 Hz), 3.56 (3H, s), 2.32 (2H, t, J= 7.6 Hz), 1.74-1.84 (2H, m), 1.40-1.50 (2H, m), 2H protons were not identified. [0348] LC-MS (ESI) m/z = 376.14 (M+H)+.
54%	With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 1h; Microwave irradiation;	4.2.1 General procedure for the synthesis of compounds A01-A09 General procedure: Dry DMF (10mL) was added to a mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1 equiv.), CsCO3 (2 equiv.) and ethyl bromoacetate (1.2 equiv.) in a microwave tube (30mL). The mixture was heated in a microwave at 120°C for 1h. Subsequently, the reaction mixture was transferred into a 100mL flask and the solvent removed in vacuo at 60°C. The crude product was redissolved in water/ethyl acetate and the mixture was extracted with ethyl acetate (3×50mL). The combined organic layers were collected and then washed with water (50mL) and brine (50mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was then purified by flash chromatography eluting with PE/EA (0%-66% EA). The EA used for the elution contained 1% triethylamine.

Reference： [1]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2016/40806, 2016, A1 Location in patent: Paragraph 0346-0348
[2]Zhai, Shiyang; Zhang, Huimin; Chen, Rui; Wu, Jiangxia; Ai, Daiqiao; Tao, Shunming; Cai, Yike; Zhang, Ji-Quan; Wang, Ling [European Journal of Medicinal Chemistry, 2021, vol. 225]

36
[ 5454-83-1 ]
(S)-3-(tert-butoxymethyl)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one [ No CAS ]
methyl (S)-5-(3-(tert-butoxymethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: (S)-3-(tert-butoxymethyl)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one With sodium hydride In N,N-dimethyl-formamide Inert atmosphere; Stage #2: 5-bromovaleric acid methyl ester In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	4.2.4. General procedure (B) for the synthesis of N-alkylated BZDs (3a-3s) General procedure: Cyclized BZD (2a-2s) (1.27 mmol) with NaH (2.54 mmol) were stirred in DMF (10 mL) for 1-1.5h under nitrogen. Methyl-5-bromovalerate (1.9 mmol) was added to the reaction mixture, which was stirred for overnight at rt. The DMF was removed in vacuo and the reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 30-50% EtOAc in hexane (Supplementary material S2).

Reference： [1]Reddy, D. Rajasekhar; Ballante, Flavio; Zhou, Nancy J.; Marshall, Garland R. [European Journal of Medicinal Chemistry, 2017, vol. 127, p. 531 - 553]

37
[ 5454-83-1 ]
(S)-3-(4-(tert-butoxy)benzyl)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one [ No CAS ]
methyl (S)-5-(3-(4-(tert-butoxy)benzyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: (S)-3-(4-(tert-butoxy)benzyl)-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one With sodium hydride In N,N-dimethyl-formamide Inert atmosphere; Stage #2: 5-bromovaleric acid methyl ester In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	4.2.4. General procedure (B) for the synthesis of N-alkylated BZDs (3a-3s) General procedure: Cyclized BZD (2a-2s) (1.27 mmol) with NaH (2.54 mmol) were stirred in DMF (10 mL) for 1-1.5h under nitrogen. Methyl-5-bromovalerate (1.9 mmol) was added to the reaction mixture, which was stirred for overnight at rt. The DMF was removed in vacuo and the reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 30-50% EtOAc in hexane (Supplementary material S2).

Reference： [1]Reddy, D. Rajasekhar; Ballante, Flavio; Zhou, Nancy J.; Marshall, Garland R. [European Journal of Medicinal Chemistry, 2017, vol. 127, p. 531 - 553]

38
[ 939784-02-8 ]
[ 5454-83-1 ]
methyl (S)-5-(3-(4-((tert-butoxycarbonyl)amino)butyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: tert-butyl (S)-(4-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)butyl)carbamate With sodium hydride In N,N-dimethyl-formamide Inert atmosphere; Stage #2: 5-bromovaleric acid methyl ester In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	4.2.4. General procedure (B) for the synthesis of N-alkylated BZDs (3a-3s) General procedure: Cyclized BZD (2a-2s) (1.27 mmol) with NaH (2.54 mmol) were stirred in DMF (10 mL) for 1-1.5h under nitrogen. Methyl-5-bromovalerate (1.9 mmol) was added to the reaction mixture, which was stirred for overnight at rt. The DMF was removed in vacuo and the reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 30-50% EtOAc in hexane (Supplementary material S2).

Reference： [1]Reddy, D. Rajasekhar; Ballante, Flavio; Zhou, Nancy J.; Marshall, Garland R. [European Journal of Medicinal Chemistry, 2017, vol. 127, p. 531 - 553]

39
[ 52602-39-8 ]
[ 5454-83-1 ]
methyl 5-((9H-carbazol-4-yl)oxy)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.5%	With potassium carbonate In N,N-dimethyl-formamide at 50 - 60℃; for 4h;	Synthesis of methyl 5-((9H-carbazol-4-yl)oxy)pentanoate (2) Methyl 5-bromo velarate (12.8 g, 66 mmol) was added to a mixture of 4-hydroxycarbazole 1 (10 g, 55 mmol), dimethylformamide (50 mL) and potassium carbonate (11.4 g, 82.5 mmol) at 25 °C. Then, it was heated to 50-60 °C and maintained for 4 h. Progress of the reaction was monitored by TLC (30% ethylacetate in n-hexane), after disappearance of the starting material the mass was cooled to 25°C and it was slowly poured into ice-water. The obtained solid was stirred well, filtered, washed with hexane and dried under vacuum.Yield 15 g, (92.5%); brown solid; melting range 111-114 °C; IR (KBr, cm-1):3440(N-H), 3079 (C-H, aromatic), 2988 (C-H, aliphatic), 1720 (C=O, ester), 1622(C=C, alkene);1H NMR (400 MHz, DMSO-d 6 ): d 1.83-1.94 (m, 4H), 2.45-2.49 (t,J = 8 Hz, 2H), 3.61 (s, 3H), 4.16-4.22 (m, 4H), 6.67-6.69 (d, J = 8 Hz, 1H),7.06-7.08 (d, J = 8 Hz, 2H), 7.13-7.17 (t, J = 8 Hz, 1H), 7.27-7.36 (m, 2H),7.45-7.47 (d, J = 8 Hz, 1H), 8.15-8.17 (d, J = 8 Hz, 1H), 11.26 (s, 1H);13C NMR(100 MHz, DMSO-d 6 ): d 21.39, 28.26, 32.91, 51.20, 66.90, 100.32, 103.72, 110.36,111.36, 118.57, 121.69, 122.09, 124.47, 126.47, 138.86, 141.04, 154.88, 173.29;purity 97.7% by HPLC; EI-MS: m/z 298.1 (M ? 1, 100%). Anal. Calcd forC 18 H 19 NO 3 : C, 72.71; H, 6.44; N, 4.71. Found C, 72.89; H, 6.49; N, 4.69.

Reference： [1]Muniyappan, Govindhan; Kathvarayan, Subramanian; Kella, Chennakesava Rao; Kalliyappan, Easwaramoorthi; Ponnusamy, Senthilkumar; Thirumalai, Perumal P. [Research on Chemical Intermediates, 2017, vol. 43, # 5, p. 3377 - 3393]

40
[ 5454-83-1 ]
[ 22112-79-4 ]
C₆₈H₇₀N₄O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		5,10,15,20-Tetrakis(3’-hydroxy)phenylporphyrin 14 (400 mg, 0.59 mmol) was dissolved in anhydrous DMF (12 mL) underargon. K2CO3 (976 mg, 7.07 mmol) was added and the solution was stirred at rt for 0.5 h. Methyl5-bromovalerate (1.01 mL, 7.072 mmol) was added and the reaction was stirred for 24 h at roomtemperature. The solvents were removed in vacuo, the residue dissolved in CH2Cl2, washed withsaturated aqueous NaHCO3 (4×100 mL), brine (2×100 mL) and water (2×100 mL), dried over Na2SO4,and filtered. The solvents were removed in vacuo and the residue purified via columnchromatography on silica gel (CH2Cl2). The solvents were removed to yield an oil-like, purpleproduct. Yield: 512 mg (0.45 mmol, 77%)

Reference： [1]Heterocycles,2017,vol. 94,p. 1518 - 1541

41
[ 5454-83-1 ]
[ 22112-79-4 ]
C₆₈H₆₈N₄O₁₂Zn [ No CAS ]

Reference： [1]Heterocycles,2017,vol. 94,p. 1518 - 1541

42
[10,20-is(3,5-di-tert-butyl)phenyl-5-(3’-hydroxy)phenyl]porphyrin [ No CAS ]
[ 5454-83-1 ]
C₆₀H₆₈N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: [10,20-is(3,5-di-tert-butyl)phenyl-5-(3’-hydroxy)phenyl]porphyrin With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 5-bromovaleric acid methyl ester In N,N-dimethyl-formamide at 20℃; for 24h;	[10,20-Bis(3,5-di-tert-butyl)phenyl-5-{methyl-5’-(m-phenoxy)pentanoate}]porphyrin (27) [10,20-Bis(3,5-di-tert-butyl)phenyl-5-(3’-hydroxy)phenyl]porphyrin 26 (240 mg, 0.31 mmol) was reactedwith K2CO3 (213 mg, 1.54 mmol) in anhydrous DMF (10 mL) for 0.5 h, followed by the addition ofmethyl 5-bromovalerate (0.22 mL, 1.54 mmol) and subsequent stirring for 18 h. The crude productwas purified via column chromatography on silica gel (CH2Cl2/n-hexane, 1:1, v/v) followed by recrystallization from CH2Cl2/n-hexane. Yield: 211 mg (0.24 mmol, 77%) of purple crystals

Reference： [1]Meindl, Alina; Ryan, Aoife A.; Flanagan, Keith J.; Senge, Mathias O. [Heterocycles, 2017, vol. 94, # 8, p. 1518 - 1541]

43
[ 5454-83-1 ]
[ 22990-19-8 ]
methyl 5-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)pentanoate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 824 - 829

44
[ 5454-83-1 ]
[ 941685-27-4 ]
methyl 5-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)pentanoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 8336 - 8357

45
[ 5454-83-1 ]
C₁₈H₇Cl₄NO₃ [ No CAS ]
C₂₃H₁₅Cl₄NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: C₁₈H₇Cl₄NO₃ With 1,8-diazabicyclo[5.4.0]undec-7-ene In 1-methyl-pyrrolidin-2-one at 120℃; Stage #2: 5-bromovaleric acid methyl ester In 1-methyl-pyrrolidin-2-one for 4h; Heating; Stage #3: With water; sodium hydroxide at 20℃; for 1h; Heating;	31 10 parts of Intermediate 17, 1000 parts of N-methylpyrrolidone, 4.3 parts of 1,8-diazabicyclo [5,4,0] -7-undecene, and the mixture was heated and stirred at 120 ° C.6.9 parts of methyl 5-bromovalerate was added thereto, and the mixture was heated and stirred for 4 hours.Then, 50 parts of 25% sodium hydroxide aqueous solution was added, and the mixture was heated and stirred.After cooling to room temperature for 1 hour,The reaction mixture was poured into 100 parts of a 35% hydrochloric acid aqueous solution and 4,000 parts of methanol, and the mixture was stirred at room temperature for 1 hour.The precipitated crystals were separated by filtration, further washed with methanol, and dried under reduced pressure to obtain 10.9 parts (yield 88%) of Intermediate 38.

Reference： [1]Current Patent Assignee: TOYO INK SC HOLDINGS COMPANY, LIMITED - JP2017/197640, 2017, A Location in patent: Paragraph 0186

46
[ 5454-83-1 ]
[ 16834-13-2 ]
1-(5-methoxy-5-oxopentyl)-4-(10,15,20-tri(pyridin-4-yl)porphyrin-5-yl)pyridin-1-ium bromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	In ethanol; chloroform; for 144h;Reflux;	STEP 1: Synthesis of 1-(5-methoxy-5-oxopentyl)-4-(10,15,20-tri(pyridin-4- yl)porphyrin-5-yl)pyridin-1-ium bromide (3). A mixture of meso-tetrakis(4-pyridyl)porphyrin (1) (420 mg, 0.67 mmol) and methyl 5-bromopentanoate 2 (1.58 g, 8.08 mmol) in 33 mL EtOH and 100 mL chloroform was stirred at reflux for 6 days. The reaction mixture was purified by two successive column chromatography over silica gel using EtOH/Chloroform (3/7) as eluent to give 3 as a purple solid (186 mg, 30%).1H-NMR (300 MHz, DMSO-d6): ^ 11.95 (s, 2H), 9.52- 9.55 (d, 2H), 8.94-9.10 (m, 16H), 8.29-8.31(t, 6H), 4.94 (t, 2H), 3.68 (s, 3H), 2.51-2.58 (m, 2H), 2.66 (m, 2H), 1.84 (m, 2H). MS m/z = 733 [M]+. Purity by HPLC: >95%, tR = 3.48.

Reference： [1]Patent: WO2017/218959,2017,A1 .Location in patent: Page/Page column 00109

47
[ 5454-83-1 ]
[ 16834-13-2 ]
1-(4-carboxybutyl)-4-(10,15,20-tri(pyridin-4-yl)porphyrin-5-yl)pyridin-1-ium chloride [ No CAS ]

Reference： [1]Patent: WO2017/218959,2017,A1

48
[ 5454-83-1 ]
3-(4-methoxybenzoyl)-1-[(oxan-4-yl)methyl]-1H-indol-7-ol [ No CAS ]
methyl 5-[3-(4-methoxybenzoyl)-1-[(oxan-4-yl)methyl]-1Hindol-7-yl]oxy}pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 20h;	3-(4-Methoxybenzoyl)-1-[(oxan-4-yl)methyl]-5-propoxy-1H-indole (16a) General procedure: To a solution of 9e (50mg, 0.14mmol) in anhydrous DMF (3mL) was added NaH (60% by mass dispersion in mineral oil) (20mg, 0.50mmol), followed by dropwise addition of 1-bromopropane (18.6μL, 0.21mmol) in anhydrous DMF (2mL). After stirring for 20h, the reaction was quenched with sat. aq. NH4Cl (2mL) and H2O (3mL) and extracted with EA (4×5mL). The combined organics were washed with H2O (4×20mL), dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (99:1 DCM:MeOH) to yield the desired 16a (46mg, 0.11mmol, 83%), as a white-opaque solid (Rf 0.57, 99:1 DCM:MeOH).

Reference： [1]Cooper, Anna G.; MacDonald, Christa; Glass, Michelle; Hook, Sarah; Tyndall, Joel D.A.; Vernall, Andrea J. [European Journal of Medicinal Chemistry, 2018, vol. 145, p. 770 - 789]

49
[ 5454-83-1 ]
[ 1267610-26-3 ]
C₂₁H₂₉N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10.3 g	With triethylamine; In N,N-dimethyl-formamide; at 80 - 90℃;	a: Compound 1 (10.0 g), methyl 5-bromovalerate (8.5 g), triethylamine (2.7 g) were added to DMF (20 mL),Keep warm at 80-90C until the reaction of compound 1 is complete. After cooling down to 20-30C,The reaction solution was slowly poured into 200 mL of water and the precipitated white solid was collected by suction filtration under reduced pressure.After drying, 10.3 g of compound 3 was obtained.

Reference： [1]Patent: CN107722007,2018,A .Location in patent: Paragraph 0027; 0028

50
[ 5454-83-1 ]
[ 76115-06-5 ]
C₃₂H₃₀O₃ [ No CAS ]

Reference： [1]Chemistry - An Asian Journal,2019,vol. 14,p. 781 - 788

51
[ 5454-83-1 ]
[ 106-48-9 ]
methyl 5-(4-chlorophenoxy)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 30h;	I Synthesis of methyl 5- (4-chlorophenoxy) -2-hydroxypentanoate (I-4-3) Potassium carbonate (3.3 mmol, 0.46 g)4-chlorophenol (3.0 mmol, 0.39 g) andMethyl 5-bromopentanoate(3.0 mmol, 0.43 mL) in DMF (15 mL) was added at room temperature. The mixture was stirred for 30 hours.Saturated aqueous ammonium chloride solution was added to the mixture to stop the reaction, and the mixture was extracted with diethyl ether.The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.After filtering the organic phase, the filtrate was concentrated under reduced pressure.Silica gel column chromatography of the obtained residue(Hexane / ethyl acetate)Methyl 5- (4-chlorophenoxy) pentanoate (0.61 g)Was obtained as a colorless liquid in a yield of 84%.

Reference： [1]Current Patent Assignee: KANAGAWA UNIVERSITY; YOKOHAMA CITY UNIVERSITY - JP2019/131540, 2019, A Location in patent: Paragraph 0117; 0195

52
[ 5454-83-1 ]
[ 1570-64-5 ]
methyl 5-(4-chloro-2-methylphenoxy)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 30h;	Potassium carbonate (8.25 mmol, 1.14 g)4-chloro-2-methylphenol (7.5 mmol, 1.07 g) andMethyl 5-bromopentanoate (5.0 mmol, 0.72 mL) was added to a DMF (37.5 mL) solution at room temperature. The mixtureStir for 30 hours. Saturated aqueous ammonium chloride solution was added to the mixture to stop the reaction, and the mixture was extracted with diethyl ether.The organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate.After filtering the organic phase, the filtrate was concentrated under reduced pressure.The obtained residue was subjected to silica gel column chromatography.(Hexane / ethyl acetate)Methyl 5- (4-chloro-2-methylphenoxy) pentanoate(0.99 g) was obtained as a colorless liquid in a yield of 52%.

Reference： [1]Patent: JP2019/131540,2019,A .Location in patent: Paragraph 0117; 0201

53
[ 5454-83-1 ]
[ 16766-30-6 ]
methyl 5-(4-chloro-2-methoxyphenoxy)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 30h;	I Synthesis of methyl 5- (4-chloro-2-methoxyphenoxy) -2-hydroxypentanoate (I-4-9) Potassium carbonate (7.7 mmol, 1.07 g), 4-chloro-2-methoxyphenol (5.7 mmol, 0.7 mL) and methyl 5-bromopentanoate(5.7 mmol, 0.81 mL) was added to a DMF (29 mL) solution at room temperature.The mixture was stirred for 30 hours.Saturated aqueous ammonium chloride solution was added to the mixture to stop the reaction, and the mixture was extracted with diethyl ether.The organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate.After filtering the organic phase, the filtrate was concentrated under reduced pressure.The obtained residue was subjected to silica gel column chromatography.(Hexane / ethyl acetate)Methyl 5- (4-chloro-2-methoxyphenoxy) pentanoate(1.5 g) was obtained as a yellow solid in 99% yield.

Reference： [1]Current Patent Assignee: KANAGAWA UNIVERSITY; YOKOHAMA CITY UNIVERSITY - JP2019/131540, 2019, A Location in patent: Paragraph 0117; 0217

54
[ 5454-83-1 ]
[ 95-95-4 ]
methyl 5-(2,4,5-trichlorophenoxy)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 140h;	I Synthesis of methyl 5- (2,4,5-trichlorophenoxy) -2-hydroxypentanoate (I-4-11) Potassium carbonate (5.8 mmol, 0.80 g) with 2,4,5-trichlorophenol(5.0 mmol, 0.99 g) and methyl 5-bromopentanoate(5.0 mmol, 0.71 mL) in DMF (15 mL) was added at room temperature.The mixture was stirred for 140 hours.Saturated aqueous ammonium chloride solution was added to the mixture to stop the reaction, and the mixture was extracted with diethyl ether.The organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate.After filtering the organic phase, the filtrate was concentrated under reduced pressure.The resulting residue was subjected to silica gel column chromatography.(Hexane / ethyl acetate)Methyl 5- (2,4,5-trichlorophenoxy) pentanoate (1.3 g) was obtained as a yellow solid in a yield of 85%.

Reference： [1]Current Patent Assignee: KANAGAWA UNIVERSITY; YOKOHAMA CITY UNIVERSITY - JP2019/131540, 2019, A Location in patent: Paragraph 0117; 0224

55
[ 5454-83-1 ]
[ 4720-29-0 ]
methyl 5-(benzyl(3-hydroxypropyl)amino)pentanoate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 13942 - 13947
Angew. Chem.,2019,vol. 131,p. 14080 - 14085,6

56
[ 5454-83-1 ]
[ 100-46-9 ]
[ 4783-65-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With iron(III) chloride; In neat (no solvent); at 80℃; for 1.5h;Sealed tube;	General procedure: An oven-dried pressuretube equipped with a magnetic stirrer was evacuated with nitrogen. To this was added of ester 1a(492 uL, 5.04 mmol), followed by amine 2a (0.5 mL, 4.58 mmol), and finally FeCl3 (111 mg, 0.684 mmol).The mixture was then sealed and stirred at 80 C (0.5 mL of CH3CN was added if the reaction mixturesolidified). The reaction was monitored by TLC until completion upon which it was diluted withEtOAc and washed once with saturated NaHCO3 and once with distilled H2O. The combined aqueouslayers were extracted once with ethyl acetate. The combined organic layers were then dried overMgSO4, filtered and solvents removed under reduced pressure. The crude product was purified bysilica gel flash column chromatography using a combination of hexane and ethyl acetate (3:2).

Reference： [1]Molecules,2020,vol. 25

57
[ 5454-83-1 ]
2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole [ No CAS ]
methyl 5-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate In acetone at 80℃; for 72h; Sealed tube;	Methyl 5-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)pentanoate (8a) DMAT[74] (0.5 mmol, 238 mg), K2CO3(3.5 mmol, 0.48 g), methyl 5-bromopentanoate (2 mmol, 0.39 g) and acetone (10 mL) were placed in a sealed tube and the mixture was heated at 80 °C for 72 h. After removing the solvent under reduced pressure, the crude was purified by column chromatography on silica gel (hexane/EtOAc 8:2) affording compound8a(183 mg, 62%) as a colorless oil.1H- NMR (400 MHz, CDCl3): δ 4.27 (t,J= 7.2 Hz, 2H), 3.64 (s, 3H), 3.06 (s, 6H), 2.28 (t,J= 7.3 Hz, 2H), 1.63-1.60 (m, 2H), 1.42-1.49 (m, 2H).13C-NMR (100 MHz, CDCl3): δ 173.4, 162.9, 143.5, 132.7, 121.2, 120.5, 114.1, 105.9, 51.6, 46.1, 42.4, 33.3, 29.7, 21.4.

Reference： [1]Coderch, Claire; Geronimo, Bruno Di; Martínez, Regina; Maslyk, Maciej; Panchuk, Rostyslav; Pastor, Miryam; Ramos, Ana; Skorokhyd, Nadia; Zapico, José María; de Pascual-Teresa, Beatriz [Molecules, 2020, vol. 25, # 7]

58
[ 487-03-6 ]
[ 5454-83-1 ]
5-(7-oxy-1-methyl-9-H-b-carbolin)pentanoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: harmol With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 1h; Stage #2: 5-bromovaleric acid methyl ester In N,N-dimethyl-formamide at 50℃; for 12h;	General procedure for the synthesis of (1-2) General procedure: A solution of harmalol1-1(2.02 mmol) and cesium carbonate (1.5 eq.) in DMF (7 mL) was stirred at 60 °C for 1 h. To this solution was added alkyl bromide (1.5 eq.) and stirred at 50 °C for 12 h. After completion of the reaction confirmed by TLC, the reaction mixture was diluted with water, transferred to separatory funnel and extracted with ethyl acetate (50 mL × 2). The organic layer was washed with water, dried over magnesium sulfate, filtered, evaporated and purified by flash column chromatography to yield the desired product1-2as white solid.

Reference： [1]Kumar, Kunal; Wang, Peng; Swartz, Ethan A.; Khamrui, Susmita; Secor, Cody; Lazarus, Michael B.; Sanchez, Roberto; Stewart, Andrew F.; DeVita, Robert J. [Molecules, 2020, vol. 25, # 8]

59
[ 5454-83-1 ]
[ 14176-52-4 ]
methyl 5-((2-oxo-1-(thiophen-2-yl)cyclohexyl)amino)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate; potassium iodide In acetonitrile at 112℃; for 20h; Sealed tube;	Methyl 5-((1-(4-chlorophenyl)-2-oxocyclohexyl)amino)pentanoate (15b). General procedure: A solution of 22 (0.9 g,4.03 mmol), methyl 5-bromovalerate (1.02 g, 5.2 mmol), KI (0.23 g, 1.4 mmol), K2CO3 (1.67 g, 12.0 mmol)in MeCN (20 mL) was heated to a 112 C in sealed tube for 20 h. The reaction mixture was cooledto room temperature, filtered and the solvent evaporated. The residue was purified by columnchromatography on silica gel eluting with EtOAc/hexanes (30-60%) to obtain 15b (1 g, 74%) as paleyellow oil. This was dissolved in Et2O (10 mL) and cooled to 0 C, HCl in Et2O (2M, 4.45 mmol) wereadded dropwise. The solvent was evaporated under reduced pressure, the residue was taken up inEtOAc (5 mL) and sonicated at room temperature for 2 min. The white precipitate was diluted withEtOAc (5 mL), filtered washed with EtOAc and dried under vacuum to give 15b as the solid HClsalt.