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[ CAS No. 16281-97-3 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}

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3d Animation Molecule Structure of 16281-97-3

Chemical Structure| 16281-97-3

Chemical Structure| 16281-97-3

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Quality Control of [ 16281-97-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 16281-97-3 ]

CAS No. :	16281-97-3	MDL No. :	MFCD18452043
Formula :	C₁₀H₁₁BrO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IXZOUWPYWNKWCX-UHFFFAOYSA-N
M.W :	243.10	Pubchem ID :	12342351
Synonyms :

Calculated chemistry of [ 16281-97-3 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.3
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	55.36
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.44 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.64
Log Po/w (XLOGP3) :	3.3
Log Po/w (WLOGP) :	2.6
Log Po/w (MLOGP) :	2.99
Log Po/w (SILICOS-IT) :	2.89
Consensus Log Po/w :	2.88

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.57
Solubility :	0.0655 mg/ml ; 0.000269 mol/l
Class :	Soluble
Log S (Ali) :	-3.53
Solubility :	0.0721 mg/ml ; 0.000297 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.77
Solubility :	0.0415 mg/ml ; 0.000171 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.11

Safety of [ 16281-97-3 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501	UN#:	3261
Hazard Statements:	H302-H314	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 16281-97-3 ]

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

Downstream synthetic route of [ 16281-97-3 ]

[ 16281-97-3 ] Synthesis Path-Downstream 1~50

1
[ 7364-20-7 ]
[ 133446-40-9 ]

Yield	Reaction Conditions	Operation in experiment
	With Bromotrichloromethane; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; In dichloromethane; at 20℃;Schlenk technique; Inert atmosphere; Irradiation;	General procedure: To a 25 mL Schlenk tube was charged with ethylbenzene (0.5 mmol), tetrabromomethane (0.75 mmol), Ir(dtb-bpy)(ppy)2PF6 (4.6mg, 0.005 mmol, 1 mol %), and CH2Cl2 (2 mL). After being degassed by standardfrozen-thaw procedure, the reaction mixture were placed at a distance of 5 cm from a14 W compact fluorescent lamp and stirred at room temperature. After reaction completed, morpholine (20.0 equiv.) was added to the reaction mixture and stirredovernight. The reaction was quenched by water (5 mL), and extracted by ethyl acetate(3× 20mL). The combined organic layers were washed with brine and dried overanhydrous MgSO4. The mixture was filtered and the filtrate was concentrated underreduced pressure. The crude materials were purified by silica gel flashchromatography (PE/EtOAc) to give the desired products.

Reference： [1]Organic Letters,2009,vol. 11,p. 5514 - 5517
[2]Organic Letters,2012,vol. 14,p. 2414 - 2417
[3]Journal of Organic Chemistry,1959,vol. 24,p. 549
[4]Journal of Medicinal Chemistry,1991,vol. 34,p. 2209 - 2218
[5]Organic and Biomolecular Chemistry,2016,vol. 14,p. 3574 - 3583
[6]Tetrahedron Letters,2016,vol. 57,p. 2273 - 2276

2
[ 17329-24-7 ]
[ 16281-97-3 ]
[ 133446-83-0 ]

Yield	Reaction Conditions	Operation in experiment
	With calcium carbonate In N,N-dimethyl-formamide at 95℃; for 1h;

Reference： [1]Marsham, Peter R.; Jackman, Ann L.; Hayter, Anthony J.; Daw, Melanie R.; Snowden, Jayne L.; et al. [Journal of Medicinal Chemistry, 1991, vol. 34, # 7, p. 2209 - 2218]

3
[ CAS Unavailable ]
[ 16281-97-3 ]
[ 212132-39-3 ]

Yield	Reaction Conditions	Operation in experiment
25%	With 4,4-di-tert-butyl-2,2-bipyridine; copper(II) bis(trifluoromethanesulfonate); copper In benzene at 65 - 70℃; for 14h;

Reference： [1]Marque; Fischer; Baier; Studer [Journal of Organic Chemistry, 2001, vol. 66, # 4, p. 1146 - 1156]

4
[ 16281-97-3 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-Methoxybenzyl (3-bromophenyl)acetate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.166667h; Stage #2: methyl R,S-4-(1-bromoethyl)-benzoate In tetrahydrofuran at -78 - 20℃; for 1.5h;	3.B Methyl 4-{2-(3-bromophenyl)-3-[(4-methoxybenzyl)oxy]-1-methyl-3-oxopropyl}benzoate LHMDS (1.0M THF, 2.6 mL) was added dropwise to a -78° C. THF (4 mL) solution containing the intermediate from Step A (0.827 g, 2.47 mmol). After stirring 10 minutes a THF (4 mL) solution containing methyl 4-(1-bromoethyl)benzoate (0.6 g, 2.47 mmol) was added dropwise. The solution was allowed to warm to room temperature. After 1.5 hours the solution was partitioned between ethyl acetate and aqueous 1N HCl. The organic phase was washed with water, brine and dried over magnesium sulfate. The solution was filtered and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compounds as a 1.67/1 mixture of diastereomers. 1H NMR (400 MHz, CDCl3): selected data δ 5.16 (d, J=12.0 Hz); 5.01 (d, J=12.0 Hz); 4.82 (d, J=12.0 Hz); 4.64 (d, J=11.9 Hz); 1.34 (d, J=6.8 Hz); 1.02 (d, J=7.0 Hz). Minor diastereomer: LCMS1 4.08 min (M+Na)=519. Major diastereomer: LC1 4.19 min (M+Na)=519.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2008/85926, 2008, A1 Location in patent: Page/Page column 27

5
[ 16281-97-3 ]
[ 133446-84-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: CaCO₃ / dimethylformamide / 1 h / 95 °C 2: 3.83 g / 1 N aq. NaOH / ethanol / 0.5 h / 52 °C

Reference： [1]Marsham, Peter R.; Jackman, Ann L.; Hayter, Anthony J.; Daw, Melanie R.; Snowden, Jayne L.; et al. [Journal of Medicinal Chemistry, 1991, vol. 34, # 7, p. 2209 - 2218]

6
[ 16281-97-3 ]
[ 133446-86-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: CaCO₃ / dimethylformamide / 1 h / 95 °C 2: 550 mg / NaCNBH₃, glacial acetic acid / acetonitrile; dimethylformamide; H₂O / 56 h / Ambient temperature 3: 70 percent / 1 N aq. NaOH / ethanol / 0.5 h / 52 °C

Reference： [1]Marsham, Peter R.; Jackman, Ann L.; Hayter, Anthony J.; Daw, Melanie R.; Snowden, Jayne L.; et al. [Journal of Medicinal Chemistry, 1991, vol. 34, # 7, p. 2209 - 2218]

7
[ 16281-97-3 ]
[ 133446-85-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: CaCO₃ / dimethylformamide / 1 h / 95 °C 2: 550 mg / NaCNBH₃, glacial acetic acid / acetonitrile; dimethylformamide; H₂O / 56 h / Ambient temperature

Reference： [1]Marsham, Peter R.; Jackman, Ann L.; Hayter, Anthony J.; Daw, Melanie R.; Snowden, Jayne L.; et al. [Journal of Medicinal Chemistry, 1991, vol. 34, # 7, p. 2209 - 2218]

8
[ 16281-97-3 ]
[ 133446-55-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: CaCO₃ / dimethylformamide / 1 h / 95 °C 2: 3.83 g / 1 N aq. NaOH / ethanol / 0.5 h / 52 °C 3: 48 percent / diphenyl phosphorazidate (DPPA), Et₃N / dimethylformamide / 16 h / Ambient temperature 4: 82 percent / aq. NaOH / ethanol / 2 h

Reference： [1]Marsham, Peter R.; Jackman, Ann L.; Hayter, Anthony J.; Daw, Melanie R.; Snowden, Jayne L.; et al. [Journal of Medicinal Chemistry, 1991, vol. 34, # 7, p. 2209 - 2218]

9
[ 16281-97-3 ]
[ 133446-56-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: CaCO₃ / dimethylformamide / 1 h / 95 °C 2: 550 mg / NaCNBH₃, glacial acetic acid / acetonitrile; dimethylformamide; H₂O / 56 h / Ambient temperature 3: 70 percent / 1 N aq. NaOH / ethanol / 0.5 h / 52 °C 4: 72 percent / diphenyl phosphorazidate (DPPA), Et₃N / dimethylformamide / 16 h / Ambient temperature 5: 59 percent / aq. NaOH / ethanol / 2 h

Reference： [1]Marsham, Peter R.; Jackman, Ann L.; Hayter, Anthony J.; Daw, Melanie R.; Snowden, Jayne L.; et al. [Journal of Medicinal Chemistry, 1991, vol. 34, # 7, p. 2209 - 2218]

10
[ 16281-97-3 ]
[ 133447-13-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: CaCO₃ / dimethylformamide / 1 h / 95 °C 2: 3.83 g / 1 N aq. NaOH / ethanol / 0.5 h / 52 °C 3: 48 percent / diphenyl phosphorazidate (DPPA), Et₃N / dimethylformamide / 16 h / Ambient temperature

Reference： [1]Marsham, Peter R.; Jackman, Ann L.; Hayter, Anthony J.; Daw, Melanie R.; Snowden, Jayne L.; et al. [Journal of Medicinal Chemistry, 1991, vol. 34, # 7, p. 2209 - 2218]

11
[ 16281-97-3 ]
[ 133447-14-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: CaCO₃ / dimethylformamide / 1 h / 95 °C 2: 550 mg / NaCNBH₃, glacial acetic acid / acetonitrile; dimethylformamide; H₂O / 56 h / Ambient temperature 3: 70 percent / 1 N aq. NaOH / ethanol / 0.5 h / 52 °C 4: 72 percent / diphenyl phosphorazidate (DPPA), Et₃N / dimethylformamide / 16 h / Ambient temperature

Reference： [1]Marsham, Peter R.; Jackman, Ann L.; Hayter, Anthony J.; Daw, Melanie R.; Snowden, Jayne L.; et al. [Journal of Medicinal Chemistry, 1991, vol. 34, # 7, p. 2209 - 2218]

12
[ CAS Unavailable ]
[ 16281-97-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: methanol. H₂SO₄; 1,2-dichloro-ethane 2: dibenzoyl peroxide; CCl₄; <i>N</i>-bromo-succinimide
	Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide; dmap / dichloromethane; methanol 2: N-Bromosuccinimide / dichloromethane / Irradiation
	Multi-step reaction with 2 steps 1: thionyl chloride / 12 h / 70 °C 2: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / toluene / 12 h / 120 °C

Reference： [1]Bergmann; Blum [Journal of Organic Chemistry, 1959, vol. 24, p. 549]
[2]Audran, Gérard; Brémond, Paul; Joly, Jean-Patrick; Marque, Sylvain R. A.; Yamasaki, Toshihide [Organic and Biomolecular Chemistry, 2016, vol. 14, # 14, p. 3574 - 3583]
[3]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2020/251971, 2020, A1

13
[ 16281-97-3 ]
[ 17882-18-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: NaOEt 2: aq. NaOH 3: methanol; diethyl ether

Reference： [1]Efimova,O.V. et al. [Journal of general chemistry of the USSR, 1970, vol. 40, p. 2497 - 2499][Zhurnal Obshchei Khimii, 1970, vol. 40, p. 2511 - 2514]

14
[ 271576-76-2 ]
[ 16281-97-3 ]
[ 635725-06-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In DMF (N,N-dimethyl-formamide) at 50℃; for 16h;	18.A 4- [3- (4-CHLOROPHENYL)-5-PIPERIDIN-4-YL-LH-PYRAZOL-4-] yl] pyrimidine (3 g, 8.8 mmol, Compound A) was added to methyl [4- (1-] bromoethyl) benzoate (2.1 g, 8.7 mmol, Compound B), 20 ml [OF DIMETHYLFORMAMIDE] (DMF), and 5.7 g [CS2CO3] (17.6 mmol). The mixture was heated to [50°C] and stirred for 16 hr. The mixture was then cooled to room temperature and quenched it with 200 ml of water. The resulting suspension was extracted ethyl acetate (2 x 250 ml). The combined organic layers were washed with brine (1 x 300 ml), dried over [MGS04,] and evaporated to dryness. The resulting residue was crystallized from MeOH/ethyl acetate and hexane to afford 3.1 g of white [SOLID. 1H] NMR (400 MHz, [CDC13)] : 9.17 (d, J [= 1.] 34 Hz, 1H), 8.47 (d, J = 5.24 Hz, 1H), 7.98 (d, J = 8.32 Hz, 2H), 7.38 (d, J = 8.32 Hz, 2H), 7.31 (s, 4H), 6.93 (dd, J = 5.26, 1.4 Hz, 1H), 3.9 (s, 3H), 3.51 (m, 1H), 3.21 (m, 1H), 3.13 (d, J [= 10.] 7 Hz, 1H), 2.86 (d, J [= 11.] 1 Hz, 1H), 1.92 (m, 6H), 1.38 (d, J = 6.7 Hz, 3H); [LC/MS,] tr = 2.36 min (5 to 95% AcCN/water over 6 min at 1 [ML/MIN,] at 254 nm, at 50 C), (M+H), Calculated = 502, Found = 502.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2003/104223, 2003, A1 Location in patent: Page 169-170

15
[ 7364-20-7 ]
benzoic peroxyanhydride [ No CAS ]
[ 133446-40-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; In tetrachloromethane;	(2) Preparation of methyl 4-(alpha-bromoethyl)benzoate To a solution of methyl 4-ethylbenzoate (5.12 g) in carbon tetrachloride (50 ml) were added perbenzoic anhydride (0.20 g) and N-bromosuccinimide (6.07 g) in turn, and the mixture was heated and refluxed. After 30 minutes, the mixture was allowed to cool, and the precipitate was separated by filtration, and washed with carbon tetrachloride. The filtrate and the washings were combined, and concentrated under reduced pressure to give the title compound (8.28 g) NMR (CDCl3) delta: 8.02 (d, J=8.35Hz, 2H), 7.49 (d, J=8.35Hz, 2H), 5.19 (q, J=7.03Hz, 1H), 3.91 (s, 3H), 2.04 (d, J=7.03Hz, 3H)

Reference： [1]Patent: US5409928,1995,A

16
[ 16281-97-3 ]
[ 160505-15-7 ]

Yield	Reaction Conditions	Operation in experiment
	In benzene	R.26.3 (3) (3) Preparation of methyl 4-(α-methylbenzyl)benzoate In the same manner as in Reference Example 25, by using methyl 4-(α-bromoethyl)benzoate and benzene, there was prepared the title compound. NMR (CDCl3) δ: 7.94 (d, J=8.35Hz, 2H), 7.1-7.4 (m, 7H), 4.19 (q, J=7.95Hz, 1H), 3.88 (s, 3H), 1.65 (d, J=7.25Hz, 3H)

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - US5409928, 1995, A

17
methanolic hydrochloric acid [ No CAS ]
[ 3609-53-8 ]
[ 84851-56-9 ]
[ 133446-40-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride; In methanol; chloroform; water;	(a) Methyl 4-(1-bromoethyl)benzoate was obtained as follows: 2 M Methanolic hydrochloric acid was added in portions to a stirred suspension of 3.6 g. of methyl 4-acetylbenzoate (obtained as a solid, m.p. 90-92 C., by conventional esterification of the corresponding acid) and 1.4 g. of sodium cyanoborohydride in methanol containing a single crystal of the indicator methyl orange, so that a red colour persisted. After 4 hours a further 173 mg. of sodium cyanoborohydride was added and the red colour again maintained by addition of 2 M methanolic hydrochloric acid. One hour after the final addition of reagents the solvents were evaporated and the residue was dissolved in water. The solution obtained was extracted with ether. The extracts were then dried (Na2 SO4) and evaporated. The residue was purified by chromatography on silica using 3:97 v/v ether and chloroform as eluant to give 2.9 g. (80%) methyl 4-(1-hydroxyethyl)benzoate as a yellow oil; partial NMR: 1.50 (d,3H,CH3), 3.91 (s,3H, OCH3), 4.94 (q, 1H,CH.OH).

Reference： [1]Patent: US4997844,1991,A

18
[ 113023-73-7 ]
[ 133446-40-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid In methanol; ethyl acetate	64.A Step A. Step A. Preparation of methyl R,S-4-(1-bromoethyl)-benzoate 2.5 g (10 mmol) of 4-(1-bromoethyl)-benzoic acid was dissolved in 100 ml of methanol and treated with 1 ml of concentrated sulfuric acid. The solution was stirred for 18 hours, concentrated in vacuo and the residue was dissolved in 100 ml of EtOAc. The solution was washed with saturated sodium bicarbonate solution (3*25 ml) and was dried over MgSO4, filtered and was concentrated in vacuo to give 1.5 g of an oil. 300 MHz 1H NMR (CDCl3): 2.05 (d, 3H); 3.91 (s, 3H); 5.20 (q, 1H); 7.50 (d, 2H); 8.00 (d, 2H).
	With sodium hydroxide; benzotriazol-1-ol In methanol; chloroform	9.1 Example 9-1 Example 9-1 Synthesis of methyl 4-bromoethylbenzoate (Compound IV-2) Commercially available 4-bromoethylbenzoic acid (997.9 mg) was dissolved in methanol (30 ml). After the addition of WSCI hydrochloride (1.2527 g) and HOBt (598.5 mg), the solution was stirred for 24 hours at 60°C. After the reaction, the solvent was removed by distillation. The residue was dissolved in chloroform, washed with 1 mol/l hydrochloric acid, 1 mol/l aqueous solution of sodium hydroxide, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was purified by silica gel column chromatography to obtain the title compound (829.5 mg) as a colorless solid. MS(FAB,Pos.):m/z=243,245[M+1]+ 1H-NMR(60MHz,CDCl3):δ=3.0-3.5(2H,m),3.5-3.9(2H,m),3.91(3H, s),7.1-7.4(2H,m),7.8-8.1(2H,m).

Reference： [1]Current Patent Assignee: MERCK & CO INC - US6191171, 2001, B1
[2]Current Patent Assignee: KUREHA CORP. - EP1273571, 2003, A1

19
[ 16281-97-3 ]
[ CAS Unavailable ]
[ 1076-96-6 ]
[ 499220-11-0 ]

Yield	Reaction Conditions	Operation in experiment
1: 61% 2: 43%	With dichloro bis(acetonitrile) palladium(II); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran; acetonitrile at 20℃; for 14h; Inert atmosphere;

Reference： [1]Lopez-Perez, Ana; Adrio, Javier; Carretero, Juan C. [Organic Letters, 2009, vol. 11, # 23, p. 5514 - 5517]

20
[ 16281-97-3 ]
[ 5713-61-1 ]
[ 1192278-65-1 ]
[ 1076-96-6 ]

Yield	Reaction Conditions	Operation in experiment
1: 72% 2: 17%	With dichloro bis(acetonitrile) palladium(II); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran; acetonitrile at 20℃; for 14h; Inert atmosphere;

Reference： [1]Lopez-Perez, Ana; Adrio, Javier; Carretero, Juan C. [Organic Letters, 2009, vol. 11, # 23, p. 5514 - 5517]

21
[ 16281-97-3 ]
[ 352-13-6 ]
[ 1192278-64-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	With dichloro bis(acetonitrile) palladium(II); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran; acetonitrile at 20℃; for 14h; Inert atmosphere;

Reference： [1]Lopez-Perez, Ana; Adrio, Javier; Carretero, Juan C. [Organic Letters, 2009, vol. 11, # 23, p. 5514 - 5517]

22
[ 910819-64-6 ]
[ 16281-97-3 ]
[ CAS Unavailable ]
[ 910819-65-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-Methoxybenzyl (3-bromophenyl)acetate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.166667h; Stage #2: methyl R,S-4-(1-bromoethyl)-benzoate In tetrahydrofuran at -78 - 20℃; for 1.5h;	207A.B; 207B.B; 207C.B Step B. Methyl 4-(2-(3-bromophenyl)-3-[(4-methoxybenzyl)oxyl-l-methyl-3-oxopropyl}benzoate LHMDS (1.0M THF, 2.6mL) was added dropwise to a -780C THF (4mL) solution containing the intermediate from Step A (0.827g, 2.47mmol). After stirring 10 minutes a THF (4mL) solution containing methyl 4-(l-bromoethyl)benzoate (0.6g, 2.47mmol) was added dropwise. The EPO solution was allowed to warm to room temperature. After 1.5 hours the solution was partitioned between ethyl acetate and aqueous IN HCl. The organic phase was washed with water, brine and dried over magnesium sulfate. The solution was filtered and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compounds as a 1.67/1 mixture of diastereomers. 1H NMR (400 MHz, CDCl3): selected data δ 5.16 (d, J = 12.0 Hz); 5.01 (d, J = 12.0 Hz); 4.82 (d, J = 12.0 Hz); 4.64 (d, J = 11.9 Hz); 1.34 (d, J = 6.8 Hz); 1.02 (d, J = 7.0 Hz). Minor diastereomer: LCMSl 4.08 min (M+Na) = 519. Major diastereomer: LCMSl 4.19 min (M+Na) = 519.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2006/102067, 2006, A1 Location in patent: Page/Page column 77-78

23
[ 67-56-1 ]
[ 113023-73-7 ]
[ 133446-40-9 ]

Yield	Reaction Conditions	Operation in experiment
62%	With thionyl chloride at 0 - 70℃; for 2h; Inert atmosphere;
	With sulfuric acid at 20℃;	10 Intermediate 10: Methyl 4-(1-bromoethyl)benzoateDissolve 4-(1-bromoethyl)benzoic acid (2.18×10-3 mol) in methanol (12 ml). Place the mixture under stirring and then slowly add sulphuric acid (0.5 ml). After stirring for one night at ambient temperature, the reaction mixture is poured into water (50 ml). Extract with dichloromethane (3×30 ml). The organic phase is washed with brine, dried over magnesium sulphate, filtered and then evaporated to dryness under reduced pressure.The title product is obtained in the form of a colourless oil which is used without subsequent purification.

Reference： [1]Schmidt, Jurema; Rotter, Marco; Weiser, Tim; Wittmann, Sandra; Weizel, Lilia; Kaiser, Astrid; Heering, Jan; Goebel, Tamara; Angioni, Carlo; Wurglics, Mario; Paulke, Alexander; Geisslinger, Gerd; Kahnt, Astrid; Steinhilber, Dieter; Proschak, Ewgenij; Merk, Daniel [Journal of Medicinal Chemistry, 2017, vol. 60, # 18, p. 7703 - 7724]
[2]Current Patent Assignee: SERVIER MONDE - US2010/286225, 2010, A1 Location in patent: Page/Page column 5

24
[ 1160295-56-6 ]
[ 16281-97-3 ]
[ 1184924-55-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 72h;	15.A EXAMPLE 15([(1Z)-2,2-Diethyl-1-oxidohydrazono]amino}oxy)methyl 4-{1-[({2-chloro-5-[(2-methyl-2,3-dihydro-1H-indol-1yl)carbamoyl]phenyl}-sulphonyl)amino]ethyl}benzoateStep A: Methyl 4-{1-[(tert-butoxycarbonyl)({2-chloro-5-[(2-methyl-2,3-dihydro-1H-indol-1-yl)carbamoyl]phenyl}sulphonyl)amino]ethyl}-benzoateDissolve the compound obtained in Step A of Example 1 (2.42×10-3 mol) in acetonitrile (8 ml) and place the solution under stirring. Add diisopropylethylamine (2.90×10-3 mol) and then, after stirring for 10 minutes, intermediate 10 (3.38∴10-3 mol) dissolved in acetonitrile (2 ml). Heat the mixture at 60° C. After 3 days, the reaction mixture is evaporated to dryness under reduced pressure. The oily yellow residue obtained is chromatographed on a silica column using as eluant a 75/25 n-heptane/ethyl acetate mixture.The title product is obtained in the form of a pale yellow meringue.

Reference： [1]Current Patent Assignee: SERVIER MONDE - US2010/286225, 2010, A1 Location in patent: Page/Page column 12

25
[ CAS Unavailable ]
[ 16281-97-3 ]
[ 1322084-83-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 20 - 50℃; for 18h;	14.4.2 Intermediate 14.4.2 4-[1 -(3,4-Dichloro-phenoxy)-ethyl]-benzoic acid methyl esterA mixture of 4-(1 -bromo-ethyl)-benzoic acid methyl ester (intermediate 14.4.1 , 0.5 g, 2.05 mmol), 3,4-dichlorophenol (0.34 g, 2.1 mmol) and Cs2C03 (0.34 g, 1.0 mmol) indimethylformamide (5 mL) was stirred at room temperature for 12 h and at 50°C for additional 6 h. The reaction mixture was poured into water and extracted twice with diethyl ether. The organic layer was separated, dried over MgS04 and evaporated under reduced pressure.Yield: 480 mgESI mass spectrum: [M+H]+ = 325/327/329 (Cl2) Retention time HPLC: 3.04 min (method G)
	With caesium carbonate In N,N-dimethyl-formamide at 20 - 50℃; for 18h;	14.4.14.4.2 Intermediate 14.4.24-[1-(3,4-Dichloro-phenoxy)-ethyl]-benzoic acid methyl esterA mixture of 4-(1-bromo-ethyl)-benzoic acid methyl ester (intermediate 14.4.1, 0.5 g, 2.05 mmol), 3,4-dichlorophenol (0.34 g, 2.1 mmol) and Cs2CO3 (0.34 g, 1.0 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 12 h and at 50° C. for additional 6 h. The reaction mixture was poured into water and extracted twice with diethyl ether. The organic layer was separated, dried over MgSO4 and evaporated under reduced pressure.Yield: 480 mgESI mass spectrum: [M+H]+=325/327/329 (Cl2)Retention time HPLC: 3.04 min (method G)

Reference： [1]Current Patent Assignee: GOSSAMER BIO INC - WO2011/92140, 2011, A1 Location in patent: Page/Page column 110-111
[2]Current Patent Assignee: GOSSAMER BIO INC - US2012/28938, 2012, A1 Location in patent: Page/Page column 66

26
[ 113023-73-7 ]
[ 18107-18-1 ]
[ 133446-40-9 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol In diethyl ether at 0℃; for 1h;	14.4.1 Intermediate 14.4.1 4-(1 -Bromo-ethyl)-benzoic acid methyl esterA solution of 4-(1 -bromo-ethyl)-benzoic acid (2.70 g, 1 1 .8 mmol) in diethyl ether (20 mL) and methanol (5 mL) was cooled to 0°C and treated with trimethylsilyldiazomethane (2 M in diethylether, 1 1 .8 mL). After 1 h at 0° C the solvents were removed under reduced pressure, the residue was re-dissolved in ethyl acetate (20 mL) and washed with aqueous NaHC03 solution. The organic layer was collected, dried over MgS04 and evaporated under reduced pressure.Yield: 3.0 gESI mass spectrum: [M+H]+ = 243/245 (Br)Retention time HPLC: 2.80 min (method F)
	With methanol In diethyl ether at 0℃; for 1h;	14.4.14.4.1 Example 14.4(1-{4-[1-(3,4-Dichloro-phenoxy)-ethyl]-benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acidIntermediate 14.4.14-(1-Bromo-ethyl)-benzoic acid methyl esterA solution of 4-(1-bromo-ethyl)-benzoic acid (2.70 g, 11.8 mmol) in diethyl ether (20 mL) and methanol (5 mL) was cooled to 0° C. and treated with trimethylsilyldiazomethane (2 M in diethylether, 11.8 mL). After 1 h at 0° C. the solvents were removed under reduced pressure, the residue was re-dissolved in ethyl acetate (20 mL) and washed with aqueous NaHCO3 solution. The organic layer was collected, dried over MgSO4 and evaporated under reduced pressure.Yield: 3.0 gESI mass spectrum: [M+H]+=243/245 (Br)Retention time HPLC: 2.80 min (method F)
	In tetrahydrofuran; methanol at 0 - 23℃; for 3h;	6.A Step A. Methyl 4-(l-bromoethyl benzoate INTERMEDIATES 6A & 6B Intermediate 6A Intermediate 6B (IR.2S and IS, 2R)-l-Methyl-2'-oxo-l . l'.2'.3-tetrahvdrospirorindene-2.3'-pyrrolor2.3- blpyridinel-5-carboxylic acid (Intermediate 6 A) and (1R.2R and IS, 2S)- 1 -methyl-2'-oxo- U',2',3-tetrahvdrospirorindene-2,3'-pyrrolor2,3-b1pyridine1-5-carboxylic acid (Intermediate 6B) Step A. Methyl 4-(l-bromoethyl benzoate A solution of trimethylsillyldiazomethane in THF (2M, 49.1 mL, 98.3 mmol) was added dropwise to a solution of 4-(l-bromoethyl)benzoic acid (15 g, 66 mmol) in methanol (75 mL) and THF (75 mL) at 0 °C. The resulting mixture was stirred at 23 °C for 3 h, then concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution (2x). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound. XH NMR (400 MHz, CDC13): δ 8.02 (d, 2H, J= 8.5 Hz), 7.51 (d, 2H, J= 8.2 Hz), 5.21 (q, 1H, J= 6.7 Hz), 3.92 (s, 3H), 2.06 (d, 3H, J= 7.0 Hz).

Reference： [1]Current Patent Assignee: GOSSAMER BIO INC - WO2011/92140, 2011, A1 Location in patent: Page/Page column 110
[2]Current Patent Assignee: GOSSAMER BIO INC - US2012/28938, 2012, A1 Location in patent: Page/Page column 66
[3]Current Patent Assignee: MERCK & CO INC - WO2013/169567, 2013, A1 Location in patent: Page/Page column 70

27
[ 16281-97-3 ]
[ 1488337-93-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 23 °C 1.2: 5.25 h / 0 - 20 °C 2.1: potassium carbonate / tetrahydrofuran / 20 h / Reflux 3.1: trifluoroacetic acid / dichloromethane / 5 h / 23 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2013/169567, 2013, A1

28
[ 16281-97-3 ]
[ 1488337-99-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 23 °C 1.2: 5.25 h / 0 - 20 °C 2.1: potassium carbonate / tetrahydrofuran / 20 h / Reflux 3.1: trifluoroacetic acid / dichloromethane / 5 h / 23 °C 4.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 23 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2013/169567, 2013, A1

29
[ 27784-76-5 ]
[ 16281-97-3 ]
[ 1488337-87-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl diethylphosphonoacetate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 23℃; for 0.333333h; Stage #2: methyl R,S-4-(1-bromoethyl)-benzoate In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 5.25h;	6.B Step B. Methyl 4-(4-(ter?-butoxy)-3-(diethoxyphosphoryl)-4-oxobutan-2-yl)benzoate Step B. Methyl 4-(4-(ter?-butoxy)-3-(diethoxyphosphoryl)-4-oxobutan-2-yl)benzoate Sodium hydride (60% dispersion in mineral oil, 2.98 g, 74.7 mmol) was added portionwise to a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (12.6 g, 49.8 mmol) in anhydrous DMF (150 mL) at 23 °C over 20 min. The reaction mixture was cooled to 0 °C, and then a solution of methyl 4-(l-bromoethyl)benzoate (12. lg, 49.8 mmol) in anhydrous DMF (100 mL) was added dropwise over 15 min. The resulting mixture was stirred at room temperature for 5 h, then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water (2*). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 25% ethyl acetate in petrolum ethers to give the title compound. MS: m/z = 829.4 (2M + 1).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2013/169567, 2013, A1 Location in patent: Page/Page column 70

30
[ 16281-97-3 ]
[ 1582754-31-1 ]
[ 1582754-29-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methyl R,S-4-(1-bromoethyl)-benzoate With sodium azide In water; <i>tert</i>-butyl alcohol at 65℃; Inert atmosphere; Stage #2: 6-ethynyl-4-methylpyridin-2-amine With copper(ll) sulfate pentahydrate; sodium L-ascorbate In water; <i>tert</i>-butyl alcohol at 65℃; for 4h;	18.3 Step 3: Sodium azide (295 mg, 4.54 mmol) was added to a solution of methyl 4-(l- bromoethyl)benzoate (809 mg, 3.33 mmol) in i-butanol (3.0 mL) and water (3.0 mL) under argon, and the resulting mixture was stirred at 65 °C overnight. 6-ethynyl-4-methylpyridin-2-amine (400 mg, 3.03 mmol), copper(II) sulfate pentahydrate (76 mg, 0.303 mmol), and sodium ascorbate (240 mg, 1.21 1 mmol) were added and the mixture was stirred at 65 °C for 4 hours. The reaction mixture was quenched with water and product was extracted with EtOAc (3X). The combined organic fractions were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0 to 15% methanol/dichloromethane) to afford methyl 4-{ l-[4-(6-amino-4-methylpyridin- 2-yl)-lH-l ,2,3-triazol-l-yl]ethyl}benzoate (racemic) as a brown oil. MS ESI calcd. for Ci8H2oN502 [M + H]+ 338, found 338. 1H NMR (500 MHz, DMSO-d6) δ 7.94 (d, / = 8.3, 2H), 7.47 (d, / = 8.3, 2H), 7.03 (s, 1H), 6.23 (s, 1H), 6.09 (q, / = 6.9, 1H), 5.88 - 5.77 (m, 2H), 5.74 (s, 1H), 3.82 (s, 3H), 2.18 (s, 3H), 2.01 - 1.86 (m, 3H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/48065, 2014, A1 Location in patent: Page/Page column 87

31
[ 16281-97-3 ]
[ 59794-53-5 ]
[ 1809265-29-9 ]

Yield	Reaction Conditions	Operation in experiment
55.2%	With caesium carbonate In N,N-dimethyl-formamide at 50℃; for 17h;	75.2 Step 2: Synthesis of methyl4-( 1 -((3R.55’)-4-benzyl-3 .5-dimethylpiperazin- 1 -yflethyl)benzoate [9001 Step 2: Synthesis of methyl4-( 1 -((3R.55’)-4-benzyl-3 .5-dimethylpiperazin- 1 -yflethyl)benzoate [9011 (3R,55)-1-benzyl-3,5-dimethylpiperazine (formula 8-3, 0.200 g, 0.83 1 mmol),methyl 4-(1-bromoethyl)benzoate (formula 8-4, 0.222 g, 0.9 14 mmol) and Cs2CO3 (0.8 12 g, 2.492 mmol) were dissolved in N,N-dimethylformamide (4 mL) at room temperature, and the reaction solution was stirred at 50 °C for 17 hours. The reaction mixture was filtered through a glass filter to remove solids, and water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silicon dioxide; ethyl acetate/hexane = 25 %) and concentrated to afford the desired compound (0.168 g, 55.2 %) as a pale yellow oil.

Reference： [1]Current Patent Assignee: CHONG KUN DANG PHARMACEUTICAL CORP. - WO2015/137750, 2015, A1 Location in patent: Paragraph 900; 901

32
[ 84851-56-9 ]
[ 133446-40-9 ]

Yield	Reaction Conditions	Operation in experiment
68%	With dibromotriphenylphosphorane; In dichloromethane; at 20℃; for 3h;	Into a 250-mL round-bottom flask, was placed a solution of methyl 4-(1-hydroxyethyl)benzoate (2.5 g, 13.87 mmol, 1 equiv), triphenylphosphine dibromide (5.9 g, 13.87 mmol, 1 equiv) in DCM (100 mL). The resulting mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (v:v=1:12). This resulted in 2.3 g (68%) of methyl 4-(1-bromoethyl)benzoate as a colorless oil.
60.8%	With phosphorus tribromide; In toluene; at 0℃; for 1.33333h;	[8981 Step 1: Synthesis of methyl 4-(1-bromoethyflbenzoate[8991 Methyl 4-(1-hydroxyethyl)benzoate (0.500 g, 2.775 mmol) was dissolved in toluene (10 mL), and PBr3 (0.079 mL, 0.832 mmol) was added thereto at 0 C. The mixture was stirred at the same temperature for 1 hour and 20 minutes, and the reaction mixture was concentrated under reduced pressure to yield the desired compound (0.4 10 g, 60.8 %) as a purple oil.
260 mg	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 12h;	To a stirred solution of compound 4- 1 (310 mg, 1.72 mmol) in DCM (20 mL) were added CBr4 (855 mg, 2.52 mmol) and PPI13 (660 mg, 2.52 mmol) at 0 C. Then the resulting mixture was stirred at room temperature overnight. The reaction was quenched with water (10 mL), extracted with DCM (3 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0 - 20% EtOAc/hexanes), and the desired compound was obtained as colorless oil (260 mg, 62%). 1H NMR (400 MHz, CDCI3) delta 8.01 (d, = 8.4 Hz, 2H), 7.50 (d, = 8.2 Hz, 2H), 5.20 (q, = 6.9 Hz, 1H), 3.92 (s, 3H), 2.05 (d, = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCI3) delta 166.5, 148.0, 130.0 (2C), 126.9 (2C), 52.2, 48.0, 26.6.

Reference： [1]Patent: US2019/300521,2019,A1 .Location in patent: Paragraph 1189-1191
[2]Patent: WO2015/137750,2015,A1 .Location in patent: Paragraph 898; 899
[3]Patent: WO2017/142883,2017,A1 .Location in patent: Paragraph 0179; 0181

33
[ CAS Unavailable ]
[ 16281-97-3 ]
[ 1821249-34-6 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: NH-pyrazole With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Stage #2: methyl R,S-4-(1-bromoethyl)-benzoate In N,N-dimethyl-formamide at 20℃; for 2h;	591 4-(1-(1H-pyrazol-1-yl)ethyl)benzoate 4-(1-(1H-pyrazol-1-yl)ethyl)benzoateTo a solution of 1H-pyrazole (0.44 g; 6.52 mmol; 1.10 eq.) in DMF (6 mL) was added Sodium hydride (0.25 g; 6.22 mmol; 1.05 eq.) at 0° C. and the mixture was warmed to room temperature. After stirred for 30 min, it was added methyl 4-(1-bromoethyl)benzoate (1.44 g; 5.92 mmol; 1.00 eq.) in DMF (2 mL) and the mixture was further stirred for 2 hr at room temperature, the solution was then quenched with water, the aqueous layer was extracted with EtOAc, organic layers were combined, washed with brine, dried and concentrated to give crude product, which was purified by column chromatography to give methyl 4-(1-(1H-pyrazol-1-yl)ethyl)benzoate (1.06 g, 78%).

Reference： [1]Current Patent Assignee: PFIZER INC - US2015/315198, 2015, A1 Location in patent: Paragraph 1436; 1437

34
[ 16281-97-3 ]
[ 1899859-88-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: copper(I) bromide; N,N,N',N'',N'''-pentamethyldiethylenetriamine; copper / benzene / 3 h / 20 °C / Inert atmosphere 2: lithium hydroxide monohydrate / tetrahydrofuran; water / 5 h / 20 °C

Reference： [1]Audran, Gérard; Brémond, Paul; Joly, Jean-Patrick; Marque, Sylvain R. A.; Yamasaki, Toshihide [Organic and Biomolecular Chemistry, 2016, vol. 14, # 14, p. 3574 - 3583]

35
[ 110-91-8 ]
[ 16281-97-3 ]
[ 1917329-64-6 ]

Yield	Reaction Conditions	Operation in experiment
71.4 mg	In dichloromethane at 20℃; Schlenk technique; Inert atmosphere;	General experimental procedure: General procedure: To a 25 mL Schlenk tube was charged with ethylbenzene (0.5 mmol), tetrabromomethane (0.75 mmol), Ir(dtb-bpy)(ppy)2PF6 (4.6mg, 0.005 mmol, 1 mol %), and CH2Cl2 (2 mL). After being degassed by standardfrozen-thaw procedure, the reaction mixture were placed at a distance of 5 cm from a14 W compact fluorescent lamp and stirred at room temperature. After reaction completed, morpholine (20.0 equiv.) was added to the reaction mixture and stirred overnight. The reaction was quenched by water (5 mL), and extracted by ethyl acetate(3× 20mL). The combined organic layers were washed with brine and dried overanhydrous MgSO4. The mixture was filtered and the filtrate was concentrated underreduced pressure. The crude materials were purified by silica gel flashchromatography (PE/EtOAc) to give the desired products.
	With potassium carbonate In acetonitrile at 20℃; for 18h;	1.4 Methyl 4-(1-morpholinoethyl)benzoate (1f) Methyl 4-(1-bromoethyl)benzoate 1e (242 mg, 1 mmol), morpholine (87 mg, 1 mmol), potassium carbonate (151.8 mg, 1.1 mmol) and acetonitrile (1 mL) were mixed at room temperature and stirred for 18 hour, then water (3 mL) was added and extracted with ethyl acetate (3 x 3 mL). The combined organic phases were washed with water (3 x 2 mL), then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain the target product 1f (280 mg, crude). This product was used directly in the next reaction without further purification.

Reference： [1]Hou, Tianyuan; Lu, Ping; Li, Pixu [Tetrahedron Letters, 2016, vol. 57, # 21, p. 2273 - 2276]
[2]Current Patent Assignee: BEIJING NUOCHENG JIANHUA MEDICINE TECH; BEIJING INNOCARE PHARMA TECH - CN113896711, 2022, A Location in patent: Paragraph 0098-0100; 0113-0116

36
[ 16281-97-3 ]
[ 2055097-55-5 ]

Yield	Reaction Conditions	Operation in experiment
	With tetraethylammonium (F<SUP>18</SUP>)-flouride In acetonitrile at 130℃; for 0.166667h;

Reference： [1]Yuan, Gengyang; Wang, Feng; Stephenson, Nickeisha A.; Wang, Lu; Rotstein, Benjamin H.; Vasdev, Neil; Tang, Pingping; Liang, Steven H. [Chemical Communications, 2017, vol. 53, # 1, p. 126 - 129]

37
[ 16281-97-3 ]
[ 1801602-63-0 ]

Yield	Reaction Conditions	Operation in experiment
27%	With benzophenone; disodium phosphate heptahydrate; 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)-2-trisilanol; N-fluorobis(benzenesulfon)imide In water; acetonitrile at 20℃; for 4h; Irradiation; Inert atmosphere;
	With tetrabutyl ammonium fluoride In tetrahydrofuran Inert atmosphere; Reflux;

Reference： [1]Lovett, Gabrielle H.; Chen, Shuming; Xue, Xiao-Song; Houk; MacMillan, David W. C. [Journal of the American Chemical Society, 2019, vol. 141, # 51, p. 20031 - 20036]
[2]Yuan, Gengyang; Wang, Feng; Stephenson, Nickeisha A.; Wang, Lu; Rotstein, Benjamin H.; Vasdev, Neil; Tang, Pingping; Liang, Steven H. [Chemical Communications, 2017, vol. 53, # 1, p. 126 - 129]

38
[ 49716-18-9 ]
[ 133446-40-9 ]
methyl 4-(1-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)ethyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;	To a round bottom flask charged with compound 4-3 (260 mg, 1.07 mmol) and 6- chloro- l,2,3,4-tetrahydroquinoline (121 mg, 0.71 mmol) in DMF (3 mL) was added K2C03 (196 mg, 1.42 mmol). The resulting mixture was allowed to stir overnight at 80 C. The mixture was cooled to room temperature and after addition of water (15 mL) extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0 - 80% EtOAc/hexanes) to afford as colorless oil (60 mg, 17%).1H NMR (400 MHz, CDC13) delta 7.99 (d, = 8.4 Hz, 2H), 7.37 (d, = 8.2 Hz, 2H), 6.96 - 6.88 (m, 2H), 6.51 (d, 7 = 8.5 Hz, 1H), 5.11 - 5.00 (m, 1H), 3.90 (s, 3H), 3.20 - 3.10 (m, 1H), 3.06 - 2.96 (m, 1H), 2.74 (dd, J = 9.3, 4.8 Hz, 2H), 1.92 - 1.78 (m, 2H), 1.59 (d, = 7.0 Hz, 3H). 13C NMR (100 MHz, CDC13) delta 166.9, 148.0, 143.9, 129.9 (2C), 128.9 (2C), 126.8 (2C), 126.7, 124.7, 120.4, 111.9, 55.3, 52.1, 42.9, 28.3, 22.0, 16.2.

Reference： [1]Patent: WO2017/142883,2017,A1 .Location in patent: Paragraph 0179; 0182

39
[ 16281-97-3 ]
[ 1648577-59-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With Caswell No_. 744A In dimethyl sulfoxide at 20℃;	40.A Step A A solution of methyl 4-(1 -bromoethyl)benzoate (2 g, 8.22 mmol, 1 equiv.) in DMSO (10 mL) was added to a solution of sodium azide (1.4 equiv.) in DMSO. The reaction mixture was vigorously stirred at r.t. overnight. The reaction was quenched with water (200 mL) and the product extracted with EtOAc (3 times). The organic layers were collected together, washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford the product as a colorless oil which was used in the next step without any further purification (1 .69 g, 8.22 mmol, 100% yield).
100%	With Caswell No_. 744A In dimethyl sulfoxide at 20℃;	40.A Step A A solution of methyl 4-(1 -bromoethyl)benzoate (2 g, 8.22 mmol, 1 equiv.) in DMSO (10 mL) was added to a solution of sodium azide (1.4 equiv.) in DMSO. The reaction mixture was vigorously stirred at r.t. overnight. The reaction was quenched with water (200 mL) and the product extracted with EtOAc (3 times). The organic layers were collected together, washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford the product as a colorless oil which was used in the next step without any further purification (1 .69 g, 8.22 mmol, 100% yield).
99%	With Caswell No_. 744A In N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere;

Reference： [1]Current Patent Assignee: ITALFARMACO SPA - WO2022/29041, 2022, A1 Location in patent: Page/Page column 146
[2]Current Patent Assignee: ITALFARMACO SPA - WO2022/29041, 2022, A1 Location in patent: Page/Page column 146
[3]Schmidt, Jurema; Rotter, Marco; Weiser, Tim; Wittmann, Sandra; Weizel, Lilia; Kaiser, Astrid; Heering, Jan; Goebel, Tamara; Angioni, Carlo; Wurglics, Mario; Paulke, Alexander; Geisslinger, Gerd; Kahnt, Astrid; Steinhilber, Dieter; Proschak, Ewgenij; Merk, Daniel [Journal of Medicinal Chemistry, 2017, vol. 60, # 18, p. 7703 - 7724]

40
[ 7364-20-7 ]
(2,2’-bipyridine)Zn(CF₃)₂ [ No CAS ]
[ 1147531-35-8 ]
[ 133446-40-9 ]

Yield	Reaction Conditions	Operation in experiment
28%; 20%	With Bromotrichloromethane; zinc diacetate; copper(l) cyanide; zinc trifluoromethanesulfonate; N-fluorobis(benzenesulfon)imide; at 20℃; for 24h;Sealed tube; Glovebox; Inert atmosphere;	To a dried sealed tube (10 mL) equipped with a Teflon septum and a magneticstirring bar in a glove box were added successively CuCN (1.8 mg, 0.02 mmol), NFSI(189 mg, 0.60 mmol), (bpy)Zn(CF3)2 (144 mg, 0.40 mmol), Zn(OTf)2 (36 mg, 0.1 mmol)and Zn(OAc)2 (18 mg, 0.1 mmol)). The mixture of methyl 4-ethylbenzoate (3u, 33 mg,0.20 mmol) and BrCCl3 (119 mg, 0.60 mmol) in PhCF3 (4.0 mL) was then added intothe tube under nitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 24 h. The resulting mixture was filtered through celite, and the filtratewas concentrated under reduced pressure. The residue was then purified by columnchromatography on silica gel with a gradient eluent of petroleum ether and ethyl acetateto give 4u (13.0 mg, 28%) and 4u-Br (9.7 mg, 20%).

Reference： [1]Chem,2019,vol. 5,p. 940 - 949

41
[ 16281-97-3 ]
[ 2378049-55-7 ]
[ 2378052-76-5 ]

Yield	Reaction Conditions	Operation in experiment
26%	With potassium carbonate; sodium iodide at 60℃; for 3h;	2 Step 2 Into a 30-mL vial, was placed methyl 4-(1-bromoethyl)benzoate (1.2 g, 4.94 mmol, 1 equiv), 6-[2-(methoxymethoxy)phenyl]-4-(1H-pyrazol-4-yl)pyridazin-3-amine (1.2 g, 3.95 mmol, 0.80 equiv), K2CO3 (2.0 g, 14.81 mmol, 3.00 equiv), NaI (739.9 mg, 4.94 mmol, 1.00 equiv) in DMF (15 mL). The resulting mixture was stirred for 3 hours at 60° C. in an oil bath. The reaction mixture was then diluted by water (50 mL) and extracted with dichloromethane (50 mL3). The combined organic layer was washed with water (50 mL2) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (v:v=10:1). This resulted in 600 mg (26%) of methyl 4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]benzoate as a yellow oil.

Reference： [1]Current Patent Assignee: ARVINAS; ROCHE HOLDING AG - US2019/300521, 2019, A1 Location in patent: Paragraph 1192-1193

42
[ 944937-53-5 ]
[ 133446-40-9 ]
[ 35634-10-7 ]
C₂₂H₂₁BrN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With tris[2-phenylpyridinato-C₂,N]iridium(III); copper acetylacetonate; N,N,N′,N′-tetramethyl-N″-tert-butylguanidine In 1,4-dioxane Irradiation;

Reference： [1]Carruthers, Nicholas I.; Le, Chip; MacMillan, David W. C.; McCarver, Stefan J.; Shireman, Brock T.; Smith, Russell T.; Zhang, Xiaheng [Nature, 2020, vol. 580, # 7802, p. 220 - 226]

43
[ CAS Unavailable ]
[ 16281-97-3 ]
[ 2114711-88-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃; Inert atmosphere;

Reference： [1]Gaisina, Irina N.; Peet, Norton P.; Wong, Letitia; Schafer, Adam M.; Cheng, Han; Anantpadma, Manu; Davey, Robert A.; Thatcher, Gregory R. J.; Rong, Lijun [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7211 - 7225]

44
[ 269410-08-4 ]
[ 16281-97-3 ]
[ 1522240-93-2 ]

Yield	Reaction Conditions	Operation in experiment
10 g	With caesium carbonate In N,N-dimethyl-formamide at 25℃; for 12h;	24.3 Step 3: methyl 4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1- yl)ethyl)benzoate To a solution of methyl 4-(1-bromoethyl)benzoate (13 g, 53.5 mmol) and 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole (15.6 g, 80.2 mmol) in DMF (130 mL) was added Cs2CO3 (52.3 g, 160 mmol), then the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O 100 mL and extracted with ethyl acetate 200 mL (2 * 100 mL). The combined organic layers were washed with brine 400 mL (2 * 200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1 to 5/1) to give the title compound (10 g, 52% yield) as a yellow oil. LC-MS (ESI+) m/z 357.1 (M+H)+.

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2020/251971, 2020, A1 Location in patent: Paragraph 00895; 00896

45
[ 16281-97-3 ]
[ CAS Unavailable ]
[ 2567646-95-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With Tetrakis(dimethylamino)ethylen In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; Irradiation;
52%	With N,N,N',N'-tetramethyl-7,8-dihydro-6H-dipyrido[1,2-a;2',1'-c][1,4]diazepine-2,12-diamine In N,N-dimethyl-formamide at 20℃; for 16h; Glovebox; Inert atmosphere; Schlenk technique;

Reference： [1]Bertrand, Morgane; Remusat, Vincent; Spitz, Cédric; Terme, Thierry; Vanelle, Patrice [Journal of Organic Chemistry, 2022, vol. 87, # 6, p. 4483 - 4488]
[2]Spitz, Cédric; Matteudi, Mélanie; Tintori, Guillaume; Broggi, Julie; Terme, Thierry; Vanelle, Patrice [Journal of Organic Chemistry, 2020, vol. 85, # 23, p. 15736 - 15742]

46
[ 3609-53-8 ]
[ 16281-97-3 ]

Yield	Reaction Conditions	Operation in experiment
49%	Stage #1: methyl 4-acetylbenzoate With sodium tetrahydroborate In ethanol at 0℃; for 1h; Stage #2: With carbon tetrabromide; triphenylphosphine at 0 - 20℃;

Reference： [1]Shen, Sida; Picci, Cristina; Ustinova, Kseniya; Benoy, Veronick; Kutil, Zsófia; Zhang, Guiping; Tavares, Maurício T.; Pavlíček, Jiří; Zimprich, Chad A.; Robers, Matthew B.; Van Den Bosch, Ludo; Bařinka, Cyril; Langley, Brett; Kozikowski, Alan P. [Journal of Medicinal Chemistry, 2021, vol. 64, # 8, p. 4810 - 4840]

47
[ 16281-97-3 ]
[ 171364-81-1 ]
[ 2642182-95-2 ]

Yield	Reaction Conditions	Operation in experiment
60%	With copper(l) iodide; water; C₂₄H₂₅N₂OP; lithium tert-butoxide In dimethyl sulfoxide at 20℃; for 3h; Inert atmosphere;	General procedures B for cross-coupling of racemic alkylbromides with organoboronate esters General procedure: To a flame-dried Schlenk tube equipped with a magnetic stir barwere added CuI (3.8 mg, 0.020 mmol, 10 mol%), L7 (9.4 mg,0.024 mmol,12 mol%), LiOtBu (32 mg, 0.40 mmol, 2.0 equiv), and anappropriate organoboronate esters (0.20 mmol, 1.0 equiv). The tubewas evacuated and backfilled with argon for three times, and then,an appropriate alkyl bromide (0.30 mmol, 1.5 equiv), and anhydrousDMSO (2.4 mL) were sequentially added. The reactionmixture was stirred at room temperature for 3 h. The resultingreaction mixture was diluted with 10 mL ethyl acetate and washedwith brine (10mL 3). The organic layer was dried over anhydrousNa2SO4 and filtered through a pad of celite. The organic solvent wasremoved under vacuum and the residue was purified by columnchromatography on silica gel to afford the desired product

Reference： [1]Su, Xiao-Long; Jiang, Sheng-Peng; Ye, Liu; Xu, Guo-Xing; Chen, Ji-Jun; Gu, Qiang-Shuai; Li, Zhong-Liang; Liu, Xin-Yuan [Tetrahedron, 2021, vol. 89]

48
[ 16281-97-3 ]
[ 150884-50-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
61%	With Tetrakis(dimethylamino)ethylen In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; Irradiation;

Reference： [1]Bertrand, Morgane; Remusat, Vincent; Spitz, Cédric; Terme, Thierry; Vanelle, Patrice [Journal of Organic Chemistry, 2022, vol. 87, # 6, p. 4483 - 4488]

49
[ 909186-56-7 ]
[ 16281-97-3 ]
[ 2757469-67-1 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 19h;	18.1; 19.1 Methyl 4-(1-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)benzoate (18a) Methyl 4-(1-bromoethyl)benzoate 1e (243 mg, 1 mmol) and 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (136 mg, 1 mmol) were dissolved in DMF ( 4 mL), then potassium carbonate (553 mg, 4 mmol) was added. After stirring at room temperature for 19 hours, it was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with water (3 x 30 mL), then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100/0 to 4/1) to obtain the target product 18a (212 mg, 81%).

Reference： [1]Current Patent Assignee: BEIJING NUOCHENG JIANHUA MEDICINE TECH; BEIJING INNOCARE PHARMA TECH - CN113896711, 2022, A Location in patent: Paragraph 0434-0440

50
[ 16281-97-3 ]
[ CAS Unavailable ]
[ 2851117-74-1 ]
[ 2851117-75-2 ]

Yield	Reaction Conditions	Operation in experiment
1: 14 % 2: 15 %	Stage #1: methyl 4-(1-bromoethyl)benzoate; methyl 4-((2R,3S,4S,5S)-4-(aminomethyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-5-neopentylpyrrolidine-2-carboxamide)-3-methoxybenzoate With potassium carbonate; potassium iodide In N,N-dimethyl-formamide; acetonitrile at 60 - 110℃; Stage #2: With lithium hydroxide monohydrate; water In tetrahydrofuran; methanol at 20℃;	37 Final product 37: 4-((2'S,3S,4'S,5'R)-1-((R)-1-(4-carboxyphenyl)ethyl)-6-chloro-4'-(3-chloro -2-fluorophenyl)-2'-neopentylspiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid (YI094-2) YI045 (30mg, 0.047mmol) was weighed in a dry 50mL round bottom flask,Acetonitrile was dissolved, and methyl 4-(1-bromoethyl)benzoate (17mg, 0.071mmol) was added,Potassium carbonate (13mg, 0.094mmol) and potassium iodide (8mg, 0.047mmol),React overnight at 60°C, spin dry, add water, extract with dichloromethane,The organic phase was spin-dried, and after vacuum drying, potassium carbonate (13mg, 0.094mmol) and potassium iodide (8mg, 0.047mmol) were added, dissolved in DMF,React overnight at 110°C, add water, extract with ethyl acetate,After the organic phase was spin-dried, it was dissolved in a mixed solvent of 10 mL of water/tetrahydrofuran/MeOH (V/V/V=1/1/1), and lithium hydroxide monohydrate (10 mg, 0.24 mmol) was added, and left overnight at room temperature.The reaction solution was spin-dried, and purified by reverse-phase HPLC to obtain the target product YI094-1: 4.9 mg,Yield 14%; YI094-2: 5.2 mg,Yield 15%. YI094-1:

Reference： [1]Current Patent Assignee: Shanghai Institute of Materia Medica (in: CAS); CHINESE ACADEMY OF SCIENCES - WO2022/218379, 2022, A1 Location in patent: Page/Page column 30-31

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