[ CAS No. 5332-26-3 ] {[proInfo.proName]}

Name: 5332-26-3|2-(Bromomethyl)isoindoline-1,3-dione|97%
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SKU: A175810
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Quality Control of [ 5332-26-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 5332-26-3 ]

CAS No. :	5332-26-3	MDL No. :	MFCD00005897
Formula :	C₉H₆BrNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UUSLLECLCKTJQF-UHFFFAOYSA-N
M.W :	240.05	Pubchem ID :	79244
Synonyms :

Calculated chemistry of [ 5332-26-3 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.11
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	54.59
TPSA :	37.38 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) :	-6.1 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.81
Log Po/w (XLOGP3) :	2.34
Log Po/w (WLOGP) :	1.25
Log Po/w (MLOGP) :	2.02
Log Po/w (SILICOS-IT) :	1.93
Consensus Log Po/w :	1.87

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.08
Solubility :	0.201 mg/ml ; 0.000835 mol/l
Class :	Soluble
Log S (Ali) :	-2.76
Solubility :	0.413 mg/ml ; 0.00172 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.33
Solubility :	0.113 mg/ml ; 0.000472 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.58

Safety of [ 5332-26-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 5332-26-3 ]

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

Upstream synthesis route of [ 5332-26-3 ]
Downstream synthetic route of [ 5332-26-3 ]

[ 5332-26-3 ] Synthesis Path-Upstream 1~13

1
[ 118-29-6 ]
[ 5332-26-3 ]

Reference： [1] Organic Syntheses, 1987, vol. 65, p. 119 - 119
[2] Tetrahedron Letters, 1992, vol. 33, # 1, p. 77 - 80
[3] Journal of the American Chemical Society, 1997, vol. 119, # 35, p. 8177 - 8190
[4] Chemische Berichte, 1908, vol. 41, p. 248
[5] Journal of the American Chemical Society, 1922, vol. 44, p. 823
[6] Journal of Organic Chemistry, 1958, vol. 23, p. 815,818
[7] Journal of Organic Chemistry, 1950, vol. 15, p. 1253
[8] Revue Roumaine de Chimie, 2010, vol. 55, # 9, p. 559 - 564

2
[ 136918-14-4 ]
[ 74-95-3 ]
[ 5332-26-3 ]

Reference： [1] PLoS ONE, 2015, vol. 10, # 3,

3
[ 550-44-7 ]
[ 5332-26-3 ]

Reference： [1] Journal of the American Chemical Society, 1987, vol. 109, # 22, p. 6758 - 6764
[2] Tetrahedron Letters, 1992, vol. 33, # 38, p. 5613 - 5616
[3] Chemische Berichte, 1898, vol. 31, p. 1229

4
[ 136918-14-4 ]
[ 5332-26-3 ]

Reference： [1] Chinese Chemical Letters, 2011, vol. 22, # 10, p. 1159 - 1162
[2] Journal of the American Chemical Society, 1922, vol. 44, p. 823
[3] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 7, p. 1678 - 1684

5
[ 85-44-9 ]
[ 5332-26-3 ]

Reference： [1] Chemische Berichte, 1898, vol. 31, p. 1229
[2] PLoS ONE, 2015, vol. 10, # 3,

6
[ 496-11-7 ]
[ 5332-26-3 ]

Reference： [1] PLoS ONE, 2015, vol. 10, # 3,

7
[ 1074-82-4 ]
[ 74-95-3 ]
[ 5332-26-3 ]

Reference： [1] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 7, p. 1678 - 1684

8
[ 4702-13-0 ]
[ 5332-26-3 ]

Reference： [1] Tetrahedron, 1987, vol. 43, # 13, p. 2977 - 2984

9
[ 550-44-7 ]
[ 7726-95-6 ]
[ 5332-26-3 ]

Reference： [1] Chemische Berichte, 1898, vol. 31, p. 1229

10
[ 7647-01-0 ]
[ 118-29-6 ]
[ 10035-10-6 ]
[ 5332-26-3 ]

Reference： [1] Chemische Berichte, 1908, vol. 41, p. 248

11
[ 5332-26-3 ]
[ 118-29-6 ]

Reference： [1] Journal of Organometallic Chemistry, 2009, vol. 694, # 21, p. 3452 - 3455
[2] Chemische Berichte, 1898, vol. 31, p. 1229

12
[ 5332-26-3 ]
[ 108-18-9 ]
[ 136918-14-4 ]
[ 118-29-6 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 93 - 96

13
[ 5332-26-3 ]
[ 7732-18-5 ]
[ 118-29-6 ]

Reference： [1] Chemische Berichte, 1898, vol. 31, p. 1229

[ 5332-26-3 ] Synthesis Path-Downstream 1~87

1
[ 550-44-7 ]
[ 5332-26-3 ]

Yield	Reaction Conditions	Operation in experiment
41%	With bromine at 130 - 140℃; for 5h;
38%	With N-Bromosuccinimide In tetrachloromethane for 4h; Heating; Irradiation;
	With bromine at 160 - 170℃;

Reference： [1]Avila, L. Z.; Loo, S. H.; Frost, J. W. [Journal of the American Chemical Society, 1987, vol. 109, # 22, p. 6758 - 6764]
[2]Easton, Christopher J.; Scharfbillig, Ilse M.; Tiekink, Edward R. T. [Tetrahedron Letters, 1992, vol. 33, # 38, p. 5613 - 5616]
[3]Sachs [Chemische Berichte, 1898, vol. 31, p. 1229]

2
[ 5332-26-3 ]
[ 122-52-1 ]
[ 1066-51-9 ]

Reference： [1]Journal of the American Chemical Society,1953,vol. 75,p. 5278

3
[ 118-29-6 ]
[ 5332-26-3 ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 15190 - 15193
[2]Organic Syntheses,1987,vol. 65,p. 119 - 119
[3]Tetrahedron Letters,1992,vol. 33,p. 77 - 80
[4]Journal of the American Chemical Society,1997,vol. 119,p. 8177 - 8190
[5]Chemische Berichte,1908,vol. 41,p. 248
[6]Journal of the American Chemical Society,1922,vol. 44,p. 823
[7]Journal of Organic Chemistry,1958,vol. 23,p. 815,818
[8]Revue Roumaine de Chimie,2010,vol. 55,p. 559 - 564

4
[ 13086-84-5 ]
[ 5332-26-3 ]
[ 139392-83-9 ]

Reference： [1]Macromolecules,2016,vol. 49,p. 3083 - 3090
[2]Tetrahedron Letters,1992,vol. 33,p. 77 - 80

5
[ 5332-26-3 ]
[ 5005-36-7 ]
[ 122376-77-6 ]

Reference： [1]Archiv der Pharmazie,1989,vol. 322,p. 165 - 171

6
[ 5332-26-3 ]
[ 7053-88-5 ]
[ 112425-53-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium fluoride In N,N-dimethyl-formamide Ambient temperature;

Reference： [1]Harris, Thomas D.; Oruganti, Subra R.; Davis, Lawrence M.; Keehn, Philip M.; Green, Bernard S. [Tetrahedron, 1987, vol. 43, # 7, p. 1519 - 1540]

7
[ 5332-26-3 ]
[ 100-49-2 ]
[ 82664-95-7 ]

Reference： [1]Chemical and pharmaceutical bulletin,1982,vol. 30,p. 1639 - 1645

8
[ 5332-26-3 ]
[ 122-52-1 ]
[ 33512-26-4 ]

Yield	Reaction Conditions	Operation in experiment
89.9%	at 85 - 100℃; for 0.5h;	N-(Bromomethyl)-phthalimide (14.4 g, 0.06 mol) and triethyl phosphite (12.0 g, 0.072 mol) were placed in a round-bottomed flask equipped with a reflux condenser and heated at 85-100 C. for 30 min. After the exothermic reaction had subsided, the flask was fitted for simple distillation and ethyl bromide was distilled from the reaction mixture with heating at 100-110 C. for 2 hours. The resulting light yellow oil solidified at room temperature. The crude product was washed with hexane and recrystallized from diethyl ether/hexane to yield white crystals. 16.0 g, 89.9%; mp 66-67 C. (lit. 67 C.); 1H NMR (CDCl3) delta 7.76 (m, 4H, C6H4), 4.19 (q, 4H, OCH2), 4.17 (d, 2H, CH2P), 1.33 (t, 6H, CH3).
	With ethyl bromide; at 20 - 120℃; for 1h;	Example 4 Diethyl phthalimidomethylphosphonate VII Triethyl phosphite (32 g, 192.59 mmol) was added to <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> III (46 g, 191.62 mmole) at room temperature and the reaction mixture was heated to 120 C. when vigorous reaction initiated by evolution of ethyl bromide gas. After 1 h at 120 C., the reaction mixture was allowed to cool down to room temperature and diluted with chloroform (250 ml). The mixture was washed with water (3100 ml), brine (3100 ml), dried over sodium sulfate and concentrated to furnish the phosphonate compound VII as a thick oil which is solidified on standing under vacuum; yield: 40 g; 70%. The crude material was carried over to the following step without further purification.
	at 120℃; for 2h;	Diethyl (aminomethyl)phosphonate was synthesized according to literature procedure (see Kalman et a. Inorg. Chem. 2007, 46, 5260) The compound was isolated as yellow liquid 64% yield (1.082g).?H NMR (300 MHz, CDC13) 4.17-4.08 (m, 4H), 3.01 (d, J 10.3 Hz, 2H), 1.85 (bs, 2H), 1.34 (t, J 7.1 Hz, 6H)

at 90℃; for 3h;

A suspension of <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> (3.6g, 15.0mmol) in triethylphosphite (3.00g, 18.0mmol) was heated to 90Cfor 3h. A distillation apparatus was then installed and volatile ethyl bromide was removed by reduced pressure distillation. The crude mixture was cooled to room temperature, and the resulting white solid was used without further purification. 1H NMR (300MHz, CDCl3) delta=1.24 (t, J=7.1Hz, 6H, 2×CH3), 4.01 (d, 2JH-P=11.4Hz, 2H, 1×CH2), 4.12 (m, 4H, 2×CH2), 7.73 (dd, J=5.5, 3.1Hz, 2H, 2×CH), 7.86 (dd, J=5.3, 3.0Hz, 2H, 2×CH) ppm. To a solution of this solid (4.5g, 15mmol) in ethanol (20mL) was added hydrazine monohydrate (1.05mL, 21.6mmol) and the resulting mixture was stirred at room temperature overnight, and then refluxed for 3h. The crude mixture was cooled down to 0C, and the white precipitate was removed by filtration and washed with ice-cold ethanol. The solution was concentrated under vacuum, and the resulting oily residue was purified by column chromatography on silica gel eluting with a gradient of Et2O/ MeOH (80:20?70:30) to afford compound 24 as a pale yellow oil (2.43g, 97%). TLC: Rf=0.30 (silica gel, Et2O/MeOH 80:20, stained with ninhydrin). 1H NMR (300MHz, CD3CN) delta=1.31 (t, J=7.1Hz, 6H, 2×CH3), 1.76 (br, 2H, NH2), 2.94 (d, 2JH-P=10.6Hz, 2H, 1×CH2), 4.08 (quintet, 3JH-H=3JH-P=7.0Hz, 2H, 1×CH2), 4.10 (quintet, 3JH-H=3JH-P=7.1Hz, 2H, 1×CH2) ppm. 31P NMR (121MHz, CDCl3) delta=27.49ppm.

Reference： [1]Chinese Chemical Letters,2011,vol. 22,p. 1159 - 1162
[2]Journal of the American Chemical Society,2018,vol. 140,p. 15190 - 15193
[3]Patent: US6746662,2004,B1 .Location in patent: Page column 7
[4]Journal of the American Chemical Society,1997,vol. 119,p. 8177 - 8190
[5]Phosphorus, Sulfur and Silicon and the Related Elements,1993,vol. 83,p. 21 - 38
[6]Chemistry - A European Journal,2008,vol. 14,p. 7250 - 7258
[7]Patent: US2011/263870,2011,A1 .Location in patent: Page/Page column 4
[8]Patent: WO2014/78957,2014,A1 .Location in patent: Page/Page column 39
[9]Organic Syntheses,1987,vol. 65,p. 119 - 119
[10]Tetrahedron,2018,vol. 74,p. 4272 - 4287

9
[ 5332-26-3 ]
[ 1066-51-9 ]

Reference： [1]Journal of the American Chemical Society,1987,vol. 109,p. 6758 - 6764

10
[ 5332-26-3 ]
[ 19677-37-3 ]
[ 199436-87-8 ]

Reference： [1]Australian Journal of Chemistry,1997,vol. 50,p. 813 - 823

11
[ 5332-26-3 ]
[ 102-16-9 ]
[ 215608-92-7 ]

Yield	Reaction Conditions	Operation in experiment
65%		To a solution of benzyl 2-phenylacetate (1 1.3 g, 50 mmol) in dry THF (100 mL) at -78 °C under nitrogen was added LiHMDS (2.5 M in THF, 40 mL, 100 mmol) dropwise over 25 min. A solution of 2-(bromomethyl)isoindoline-1,3-dione (14.4 g, 60 mmol) in THF (100 mL) was then added dropwise and the mixture was stirred at -78 °C for 2 h, then allowed to warm to r.t. and stirred overnight. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (DCM/MeOH = 100:0- 100:1) to give the desired product (12.5 g, 65percent yield) as a white solid. LCMS (ES-API): Rt 2.78 min; m/z 386.1 [M+H]+.

Reference： [1]Patent: WO2019/43139,2019,A1 .Location in patent: Page/Page column 60
[2]Tetrahedron Asymmetry,1998,vol. 9,p. 2845 - 2850

12
[ 5332-26-3 ]
sodium dibutyl phosphite [ No CAS ]
[ 1066-51-9 ]

Reference： [1]Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1947,vol. 224,p. 406,407
Annales de Chimie (Cachan, France),1949,vol. <12>4,p. 377

13
[ 5332-26-3 ]
[ 719-80-2 ]
[ 4731-71-9 ]

Yield	Reaction Conditions	Operation in experiment
76.5%	In toluene; at 20 - 90℃; for 48h;	Example 1Diphenyl(phthalimidomethyl)phosphine oxide IVToluene (25 ml) was added to a mixture of ethyl diphenylphosphinite (5 g, 21.71 mmole) and the N-(bromomethy)phthalimide III (5.21 g, 21.70 mmole) at room temperature.The reaction mixture was heated to 90° C. and maintained at this temperature for 48 h when the reaction was complete as indicated from the TLC of the reaction mixture.The reaction mixture was concentrated under reduced pressure, triturated with toluene and filtered to furnish the phosphine oxide compound IV as a solid; yield: 6 g, 76.5percent.

Reference： [1]Patent: US2011/263870,2011,A1 .Location in patent: Page/Page column 3
[2]Synlett,2001,p. 424 - 426

14
[ 5332-26-3 ]
[ 6628-68-8 ]
2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-phenethyl-malonic acid diethyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 113 - 121

15
[ 67-56-1 ]
[ 5332-26-3 ]
[ 201230-82-2 ]
[ 1954-06-9 ]
[ 23244-58-8 ]

Yield	Reaction Conditions	Operation in experiment
1: 20% 2: 65%	With 1-Methylpyrrolidine; sulfuric acid; triphenylphosphine at 120℃; for 12h;

Reference： [1]Enzmann, Armin; Eckert, Markus; Ponikwar, Walter; Polborn, Kurt; Schneiderbauer, Stefan; Beller, Matthias; Beck, Wolfgang [European Journal of Inorganic Chemistry, 2004, # 6, p. 1330 - 1340]

16
[ 5332-26-3 ]
2-(azidomethyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium azide; tetra-(n-butyl)ammonium iodide; In dichloromethane; water; for 24h;Reflux;	To a solution of <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> (2.0 g, 8.3 mmol) in CH2Cl2 (15 mL) was added sodium azide (1.62 g, 24.9 mmol), tetrabutylammonium iodide (0.10 g, 0.33 mmol) and H2O (3 mL). The reaction mixture was heated at reflux for 24 h. The mixture was cooled at room temperature, CH2Cl2 (5 mL) was added and the organic phase was washed and dried over Na2SO4, the solvent was removed in vacuo and the product was purified by crystallisation to afford a yellow solid (1.6 g, 95%); m.p. 39-40 C (lit. 37-39 C);21 FTIR (ATR, cm-1): 3474, 2962, 2872, 2129, 1776, 1712, 1610; 1H NMR (300 MHz, CDCl3) delta 7.94 (dd, J = 5.5, 3.1 Hz, 2H), 7.80 (dd, J = 5.5, 3.1 Hz, 2H), 5.08 (s, 2H); 13C NMR (75 MHz, CDCl3) delta 167.1 (2 × C), 134.6 (2 × CH), 131.7 (2 × C), 123.9 (2 × CH), 52.2 (CH2); MS [EI+] m/z (%): 202 [M]+ (5), 173 [M - HN2]+ (10), 161 [C8H5N2O2] (10), 159 [M - HN3]+ (40), 147 [C8H5NO2] (10), 133 [C8H5O2] (60), 104 [C7H4O] (100).
88%	With sodium azide; In N,N-dimethyl-formamide; at 20℃; for 12h;	General procedure: Appropriate bromide (1.5 mmol) was dissolved in 15 mL of DMF (dried) and sodium azide (1.6 mmol, 104 mg) was added. The mixture was stirred vigorously at room temperature. After 12 h the reaction was quenched by adding 15 mL of distilled water (slightly exothermic reaction). The cooled reaction mixture (room temperature) was extracted twice with 30 mL of diethyl ether and washed with water (once with 20 mL). The separated organic layer was dried over anhydrous sodium sulphate and evaporated to dryness. The product obtained as white solid was washed with 30mL of distilled water.

Reference： [1]Journal of Chemical Research,2016,vol. 40,p. 308 - 313
[2]European Journal of Medicinal Chemistry,2014,vol. 84,p. 651 - 676
[3]Synlett,2005,p. 943 - 946
[4]Chemical and Pharmaceutical Bulletin,2019,vol. 67,p. 96 - 105

17
[ 5332-26-3 ]
[ 554450-91-8 ]

Yield	Reaction Conditions	Operation in experiment
55%		(12b) To a solution of the malonate (1.0 g, 4.0 mmol) from reaction (12a) in N,N-dimethylformamide (8 mL) was added at 0° C. sodium hydride (60percent dispersion in mineral oil, 0.34 g, 2.1 eq). After 20 min, <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> (1.0 g, 1.04 eq) was added. The reaction mixture was stirred at 0° C. for 1 h before quenched with aqueous ammonium chloride, and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4), concentrated and purified by silica gel chromatography (20percent then 40percent ethyl acetate/hexane) to provide the desired alkylated product (0.9 g, 55percent).

Reference： [1]Patent: US2003/229084,2003,A1 .Location in patent: Page 35

18
[ 5332-26-3 ]
[ 927180-66-3 ]

Yield	Reaction Conditions	Operation in experiment
51%		(3a) To a THF (20 mL) solution of dimethyl methylmalonate (5.5 g, 37 mmol) at -10° C. was added NaH (60percent in mineral oil, 1.66 g, 1.1 eq). The mixture was stirred for 20 min, then N-bromomethylphthalimide (9.5 g, 1.05 eq) was added at 0° C. The mixture was allowed to slowly warm to rt, stirred for 3 h, and quenched with water. Following extraction with ethyl acetate, the combined ethyl acetate extracts were washed with 1 N HCl and brine, dried (MgSO4), filtered and concentrated. Purification by flash column chromatography (20percent ethyl acetate-hexane) yielded the phthalimide as a white crystalline solid (5.81 g, 51percent).

Reference： [1]Patent: US2003/229084,2003,A1 .Location in patent: Page/Page column 26; 32

19
[ 5332-26-3 ]
[ 3586-58-1 ]
[ 851228-78-9 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium fluoride; In DMF (N,N-dimethyl-formamide); at 80℃; for 12h;	2-Ethylacrylic acid (250 mg, 2.5 mmol) was dissolved in anhydrous dimethylformamide (8.0 mL), to the solution were added N-bromomethylphthalimide (660.0 mg, 2.8 mmol) and potassium fluoride (291.0 mg, 5.0 mmol), and the mixture was stirred for 12 hr at 80° C. under nitrogen atmosphere. The reaction mixture was concentrated in vacuo, and the obtained residue was extracted with dichloromethane after the addition of water (80 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the objective substance (463.1 mg, 72percent). 1H-NMR (CDCl3) delta: 7.94 (dd, J=5.4, 3.2 Hz, 2H), 7.79 (dd, J=2.8, 1.4 Hz, 2H), 6.16 (d, J=1.0 Hz, 1H), 5.80 (s, 2H), 5.57 (d, J=1.5 Hz, 1H), 2.35-2.25 (m, 2H), 1.06 (t, J=7.4 Hz, 3H).

Reference： [1]Patent: US2005/182032,2005,A1 .Location in patent: Page/Page column 6

20
[ 55212-79-8 ]
[ 5332-26-3 ]
methyl 3-oxo-2-(phthalimidomethyl)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With hydrogenchloride; In N-methyl-acetamide; ethanol; water;	(1) Methyl 2-(phthalimido)methyl-3-oxobutanoate Methyl 3-tetrahydropyrrolyl-2-butenoate (29.0 g, 171.3 mmol) and <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> (43 g, 179.91 mmol) were dissolved in 250 ml of dimethylformamide, and the resulting mixture was then stirred at room temperature for 16 hours under a nitrogen atmosphere. After checking completion of the reaction with TLC, 1N HCl and water were added into the reaction mixture. The produced solid was filtered under a reduced pressure while washing with hexane and then recrystallized in 100% ethanol, thereby to obtain the desired product (32.26 g, 68%). 1H NMR (CDCl3, 300 MHz) delta 7.70 (m, 2H, ph), 7.60 (m, 3H, ph), 4.04 (m, 2H, -CHC2NPht), 3.91 (dd, 1H, -CHCH2NPht, J=8.1 Hz, J'=6.6 Hz), 3.61 (s, 3H, -CO2CH3), 2.16 (s, 3H -COCH3) 13C NMR (CDCl3, 300 MHz) delta 200.8, 168.5, 168.2, 134.5, 132.1, 123.8, 57.6, 53.3, 36.3, 29.3

Reference： [1]Patent: US2003/139464,2003,A1

21
[ 5332-26-3 ]
[ 28447-26-9 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorous acid trimethyl ester; In 5,5-dimethyl-1,3-cyclohexadiene;	Step 1. Dimethyl (Phthalimidomethyl)phosphonate (ii). A mixture of N-(bromomethyl) phthalimide (i) (10.43 g, 43.46 mmol) and trimethyl phosphite (5.93 g, 47.80 mmol) was heated at reflux in xylene (20 mL) for 6 h. The reaction mixture was then cooled to room temperature and concentrated. Crystallization from CHCl3-hexane gave (ii) (7.60 g, 65percent) as a white solid: 1H NMR (300 MHz, CDCl3) deltaH 3.84 (d, JH,P=10.8 Hz, 6H), 4.12 (d, J=11.4 Hz, 2H), 7.76 (m, 2H), 7.87 (m, 2H).
	With phosphorous acid trimethyl ester;	EXAMPLE 20 Reaction of N-bromomethylphthalimide with trimethyl phosphite as described in Example 18 for N-(2-bromoethyl)phthalimide and triethyl phosphite gives dimethyl phthalimidomethylphosphonate.
	With phosphorous acid trimethyl ester; In 5,5-dimethyl-1,3-cyclohexadiene;	Step 1. Dimethyl (phthalimidomethyl)phosphonate (ii). A mixture of N-(bromomethyl) phthalimide (i) (10.43 g, 43.46 mmol) and trimethyl phosphite (5.93 g, 47.80 mmol) was heated at reflux in xylene (20 mL) for 6 h. The reaction mixture was then cooled to room temperature and concentrated. Crystallization from CHCl3-hexane gave (ii) (7.60 g, 65percent) as a white solid: 1H NMR (300 MHz, CDCl3) deltaH 3.84 (d, JH,P=10.8 Hz, 6 H), 4.12 (d, J=11.4 Hz, 2 H), 7.76 (m, 2 H), 7.87 (m, 2 H).

	With phosphorous acid trimethyl ester; In 5,5-dimethyl-1,3-cyclohexadiene;	Step 1. Dimethyl (phthalimidomethyl)phosphonate (ii). A mixture of N-(bromomethyl) phthalimide (i) (10.43 g, 43.46 mmol) and trimethyl phosphite (5.93 g, 47.80 mmol) was heated at reflux in xylene (20 mL) for 6 h. The reaction mixture was then cooled to room temperature and concentrated. Crystallization from CHCl3hexane gave (ii) (7.60 g, 65percent) as a white solid: 1H NMR (300 MHz, CDCl3) deltaH 3.84 (d, JH,P=10.8 Hz, 6 H), 4.12 (d, J=11.4 Hz, 2 H), 7.76 (m, 2 H), 7.87 (m, 2 H).
	With phosphorous acid trimethyl ester; In 5,5-dimethyl-1,3-cyclohexadiene;	Dimethyl (phthalimidomethyl)phosphonate (ii). A mixture of N-(bromomethyl) phthalimide (i) (10.43 g, 43.46 mmol) and trimethyl phosphite (5.93 g, 47.80 mmol) was heated at reflux in xylene (20 mL) for 6 h. The reaction mixture was then cooled to room temperature and concentrated. Crystallization from CHCl3-hexane gave (ii) (7.60 g, 65percent) as a white solid: 1H NMR (300 MHz, CDCl3) deltaH 3.84 (d, JH,P=10.8 Hz, 6 H), 4.12 (d, J=11.4 Hz, 2 H), 7.76 (m, 2 H), 7.87 (m, 2 H).

Reference： [1]Patent: US6472406,2002,B1
[2]Patent: US4112086,1978,A
[3]Patent: US2004/29836,2004,A1
[4]Patent: US2004/82546,2004,A1
[5]Patent: US6884791,2005,B2

22
[ 5332-26-3 ]
[ 112266-60-1 ]
[ 141494-96-4 ]

Yield	Reaction Conditions	Operation in experiment
69.4%	With triethylamine; In ethanol; chloroform;	EXAMPLE 26 Synthesis of 5-(phthalimidomethylthio)imidazo[1,2-a]pyridine (Compound 153) To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-bromomethylphthalimide (5.28 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 4.29 g of the desired product (69.4percent, pale yellow crystals). NMR (200MHz, CDCl3) delta: 5.10 (2H, s), 7.02-7.13 (2H, m), 7.61-7.84 (6H, m), 7.99 (1H, m).

Reference： [1]Patent: US5244908,1993,A

23
[ 5332-26-3 ]
[ 939036-98-3 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of (+/-)-2a,5-dihydropyrrolo[4,3,2-<^g]quinoline-2,4(lH,3//)-dione(2.00 g, 10.6 mmol, described in Intermediate 18) in degassed DMF (30 mL) at 0 0C was added sodium hydride (468 mg of a 60percent dispersion in mineral oil, 1 1.7 mmol). The mixture was stirred for 10 min, then <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> (2.55 g, 10.6 mmol) was added and stirring was continued for 2 h. An additional portion of 7V-(bromomethyl)phthalimide (500 mg) was added and stirring was continued for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted withEtOAc (3 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient ofCH2Cl2:MeOH- 100:0 to 90:10, to give the title compound. MS: mlz - 348 (M + 1).
		To a stirred solution of (+/-)-2a,5-dihydropyrrolo[4,3,2-rfe]quinolme-2,4(li?,3H)-dione (2.00 g, 10.6 mmol, described in Intermediate 17) in degassed DMF (30 mL) at 0 0C was added sodium hydride (468 mg of a 60percent dispersion in mineral oil, 11.7 mmol). The mixture was stirred for 10 min, then <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> (2.55 g, 10.6 mrnol) was added and stirring was continued for 2 h. An additional portion of <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> (500 mg) was added and stirring was continued for 1 h. The reaction mixture was quenched with saturated aqueous nuaetaCpsi3 (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH- 100:0 to 90:10, to give the title compound. MS: mlz = 348 (M + 1).

Reference： [1]Patent: WO2007/61692,2007,A2 .Location in patent: Page/Page column 124
[2]Patent: WO2007/61694,2007,A2 .Location in patent: Page/Page column 122

24
[ 5332-26-3 ]
[ 38117-54-3 ]
[ 737003-69-9 ]

Yield	Reaction Conditions	Operation in experiment
80%		In a pear-shaped flask, compound 1 (see Fig. S5b) was synthesised by reacting sodium (0.3615 g, 15.7 mmol) and mercury (2.1 mL, 13.4 mmol) under an argon atmosphere. A violent formation of the amalgam resulted and this was allowed to cool down before dry and degassed THF was added. Cyclopentadienyliron dicarbonyl dimer (1.009 g, 2.85 mmol) was added and the reaction mixture was stirred at room temperature for two hours. The yellowish brown metallate was transferred into a RBF (kept at -78 °C) by means of a canula. The reaction mixture was transferred into a flask already containing bromomethylphthalimide (0.953 g, 3.97 mmol) dissolved in approximately 15 mL of dry and degassed THF. The reaction mixture was allowed to stir at -78 °C for two hours before being allowed to stir at room temperature for a further three hours. After removal of solvent under reduced pressure the residue was chromatographed on silica using DCM as eluent. The yellow band, which eluted out second, was collected and concentrated. The final product was obtained as a yellow powder. Yield: (1.074 g, 80percent): m.p. 181 °C, 1H-NMR (400 MHz, CDCl3, ppm) deltaH = 4.05 (2H,s, Fe-CH2), 4.91 (5H, s, C5H5), 7.70 (4H, m, C6H4). 13C-NMR (100 MHz, CDCl3, ppm) deltaC =11.14 (Fe-CH2), 85.36 (Cp moiety), 122.5 (2C, Ar-CH), 132.8 (2C, Ar-C), 133.4 (2C, Ar-CH), 168.7 (NCO), 215.5 (terminal CO). IR (ATR, cm-1): 1997 (terminal CO), 1951 (terminal CO),1751, 1701. CHN analysis for C16H11FeNO4 Calculated: C; 57.01, H; 3.29, N; 4.15. Found: C;57.16, H; 3.34, N; 4.18.

Reference： [1]Journal of Organometallic Chemistry,2015,vol. 780,p. 13 - 19
[2]European Journal of Inorganic Chemistry,2004,p. 1330 - 1340

25
[ 5332-26-3 ]
[ 91292-73-8 ]
[ 108-18-9 ]
[ 362703-44-4 ]

Yield	Reaction Conditions	Operation in experiment
57%		To a solution of diisopropylamine (2.33 g, 23.0 mmol) in THF (35 mL) at -78° C. was added n-butyllithium (21.2 mmol, 13.3 mL of a 1.6 M solution). After stirring for 15 min, the imine (4.0 g, 17.7 mmol) from reaction (31a) in THF (20 mL) was added dropwise. The mixture was allowed to stir for 1 h. N-(Bromomethyl)phthalimide (5.1 g, 21.2 mmol) was dissolved in THF (20 mL) and was added dropwise to the enolate. After stirring for 1 h at -78° C., the reaction was warmed to rt overnight. The reaction was quenched with water (2 mL) and the mixture concentrated under reduced pressure. The remaining residue was treated at 0° C. with 1 M hydrochloric acid/methanol (100 mL) for 20 min followed by warming to rt for an additional 40 min. After removing the methanol in vacuo, the water layer was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried and concentrated to give the desired amine (2.6 g, 57percent). MS found: (M+H)+=263.

Reference： [1]Patent: US2004/72802,2004,A1 .Location in patent: Page/Page column 48

26
[ 5332-26-3 ]
[ 172527-71-8 ]
diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-((1,3-dioxoisoindolin-2-yl)methyl)malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: diethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.25h; Stage #2: N-(bromomethyl)phtalimide With N,N-dimethyl-formamide at 22℃; for 18h;	7 Example 7; Diethyl 2-[3-chloro-5-(trifluoromethyl)-2-pyridyl]-2-[(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]malonate (Compound 403) To a suspension of 60% sodium hydride (0.65 g) in dry dimethylformamide (20 ml) at 0°C was added a solution of diethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)malonate (5 g) in dry dimethylformamide (10 ml) and the mixture was stirred for 15 minutes. A solution of N-bromomethylphthalimide (3.55 g) in dry dimethylformamide (10 ml) was added dropwise and the mixture was warmed with stirring to 22°C over 18 hours. Glacial acetic acid (1 ml) was added and the mixture was poured into cold water (500 ml). The aqueous solution was extracted with diethyl ether (3x150 ml) and the combined extract was water washed (3x100 ml). The organic extract was dried (MgSO4) and evaporated to give a crude product. Trituration with diethyl ether/light petroleum (b.p. 40-60°C) (1:1) gave the title compound. m.p. 159-61°C.
	With sodium hydride In N,N-dimethyl-formamide at 20℃;

Reference： [1]Current Patent Assignee: BAYER AG - EP1204323, 2004, B1 Location in patent: Page 23
[2]Location in patent: scheme or table Fodor, Elena; Maftei, Catalin-Vasile; Mangalagiu, Ionel; Jones, Peter G.; Daniliuc, Constantin-Gabriel; Franz, M. Heiko; Neda, Ion [Revue Roumaine de Chimie, 2010, vol. 55, # 9, p. 559 - 564]

27
[ 5332-26-3 ]
[ 58414-52-1 ]
[ 1206786-46-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: thiophen-3-yl-acetic acid methyl ester With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: N-(bromomethyl)phtalimide In tetrahydrofuran at -78 - 0℃;	45 Preparation of methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E45) To pure methyl 2-(thiophen-3-yl)acetate (E41) in THF cooled to -78° C. was added LiHMDS, and the solution stirred at -78° C. for 30 min. Then N-(bromomethyl)phthalimide was added directly, and the solution was allowed to warm to 0° C. The mixture was poured into NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 0-40% EtOAc/Hex) gave pure methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E45).
	Stage #1: thiophen-3-yl-acetic acid methyl ester With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: N-(bromomethyl)phtalimide In tetrahydrofuran at -78 - 0℃;	429 Methyl 3-(1 ,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E429) was prepared according to the below:To pure methyl 2-(thiophen-3-yl)acetate in THF cooled to -78°C was added LiHMDS and the solution stirred at -78°C for 30 min. Then Λ/-(bromomethyl)phthalimide was added directly and the solution was allowed to warm to 00C. The mixture was poured into NaHCO3(sat) extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 0-40%EtOAc/Hex) gave pure methyl 3-(1 ,3-dioxoisoindolin-2-yl)-2-(thiophen-3- yl)propanoate (E429).
	Stage #1: thiophen-3-yl-acetic acid methyl ester With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: N-(bromomethyl)phtalimide In tetrahydrofuran at -78 - 0℃;	45 Example 45. Preparation of methyl 3-(l,3-dioxoisoindolin-2-yl)-2-(thiophen-3- yl)propanoate (E45). To pure methyl 2-(thiophen-3-yl)acetate (E41) in THF cooled to -78°C was added LiHMDS, and the solution stirred at -78°C for 30 min. Then N- (bromomethyl)phthalimide was added directly, and the solution was allowed to warm to 0°C. The mixture was poured into NaHC03(Sat), extracted with EtOAc, dried (Na2S04), filtered, and evaporated. Column chromatography (S1O2, 0-40%EtOAc/Hex) gave pure methyl 3- (l,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E45).

Reference： [1]Current Patent Assignee: AERIE PHARMACEUTICALS INC - US2010/22585, 2010, A1 Location in patent: Page/Page column 15
[2]Current Patent Assignee: AERIE PHARMACEUTICALS INC - WO2010/127329, 2010, A1 Location in patent: Page/Page column 105
[3]Current Patent Assignee: AERIE PHARMACEUTICALS INC - WO2019/178324, 2019, A1 Location in patent: Paragraph 00224

28
[ 5332-26-3 ]
[ 944407-18-5 ]
[ 1207621-36-0 ]

Yield	Reaction Conditions	Operation in experiment
28%		Example 8: 6-((R)-5-[((RS)-2-methoxy-8,9-dihydro-furo[2,3-Lambda]quinolin-9-ylmethyl)- amino] -methyl}-2-oxo-oxazolidin-3-yl)-4H-benzo [ 1 ,4] thiazin-3-one:; 8.i. rac-3-( 1 ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl)-2-(7-fluoro-2-methoxy-quinolin-8-yl)- propionic acid methyl ester:; To a solution of LiEtaMDS (IM in TEtaF, 9.6 niL) was added at -78°C a solution of (7-fluoro-2-methoxy-quinolin-8-yl)-acetic acid methyl ester (2.0 g, 8.0 mmol; prepared as in WO 2007/081597) in TEtaF (16 mL) over lO min. After stirring the resulting orange mixture for 1 h at -78°C, a solution of Lambda/-(bromomethyl)phthalimide (1.2 eq.) in TEtaF (16 mL) was added dropwise over 10 min. The mixture was stirred 1 h at -78°C and then at it overnight. The yellow solution was quenched with 17V EtaC1 (80 mL) and then extracted with DCM. The combined org layers were washed with water, dried over MgSO4, concentrated and purified by CC (Etaept/EA 1 : 1) to give 1.89 g of a yellow solid which was recrystallized from EA/MeOEta/NEta4OEta (90:10:1) to afford the title intermediate as a colourless solid (924 mg, 28percent yield). MS (ESI, m/z): 409.3 [IVB-H+].
23%		To a solution of LiHMDS (31.3 mL, \\M in THF) in THF (40 mL) was added at -78°C a solution of intermediate A.ii (6.50 g, 26 mmol) in THF (50 mL) over 10 min. After stirring for 1 h at -78°C, a solution of <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> in THF (50 mL) was added dropwise over 10 min. The mixture was stirred at -78°C for 1 h and then at rt overnight. The resulting solution was quenched with INHCl (260 mL) and extracted with DCM. The combined org. layers were washed with water, dried over MgSO4, concentrated and purified by CC (Hept/EA 1 :1). The resulting solid was triturated with EA to afford the title intermediate as a colourless solid (2.42 g, 23percent yield). MS (ESI, m/z): 409.3 [M+H+].

Reference： [1]Patent: WO2010/15985,2010,A1 .Location in patent: Page/Page column 59
[2]Patent: WO2010/41194,2010,A1 .Location in patent: Page/Page column 131

29
[ 5332-26-3 ]
[ 1207621-43-9 ]
[ 1207621-51-9 ]

Yield	Reaction Conditions	Operation in experiment
51%		Example 14: 6-((R)-5-{2-[((R5)-8-methoxy-l,2-dihydro-3-oxa-5,9-diaza- cyclopenta[fl]naphthalen-l-ylmethyl)-amino]-ethyl}-2-oxo-oxazolidin-3-yl)- 4H-benzo [ 1 ,4] thiazin-3-one:; 14.L rac-3-( 1 ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl)-2-(3-fluoro-6-methoxy- [ 1 ,5] naphthyridin-4-yl)-propionic acid ethyl ester:; A solution of (3-fluoro-6-methoxy-[l,5]naphthyridin-4-yl)-acetic acid ethyl ester (6.78 g; prepared in analogy to the corresponding methyl ester described in WO 2007/122258) in TEtaF (30 niL) was added dropwise at -78°C to a solution of LiEtaMDS (31 mL; IM in TEtaF) diluted in TEtaF (2O mL). After stirring for I h at -78°C a solution of Lambda/-(bromomethyl)phthalimide (7.40 g) in TEtaF (30 mL) was added dropwise and the mixture was stirred for an additional 1 h at -78°C and then overnight at rt. The yellow solution was quenched with \\N HCl (280 mL) and extracted with DCM. The combined org. layers were washed with H2O, dried over MgSO4, concentrated and purified by CC (Hept/EA 1 : 1), affording a light yellow foam (5.49 g; 51percent yield). MS (ESI, m/z): 424.2 [M+H+].
43%		To a solution of LiHMDS (4.54 mL, \\M in THF) in THF (11 mL) was added at -78°C a solution of intermediate E.ii (1.0 g, 3.78 mmol) in THF (3 mL) over 10 min. After stirring for 1 h at -78°C a solution of <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> (1-09 g, 1.2 eq.) in THF (4 mL) was added dropwise over 10 min. The mixture was stirred at -78°C for 1 h and then at rt overnight. The resulting solution was quenched with INHCl and extracted with DCM. The combined org. layers were washed with water, dried over MgSO4, concentrated and purified by CC (Hept/EA 1 :1) to afford the title intermediate as an off- white solid (0.361 g, 43percent yield).MS (ESI, m/z): 424.4 [M+H+].

Reference： [1]Patent: WO2010/15985,2010,A1 .Location in patent: Page/Page column 64
[2]Patent: WO2010/41194,2010,A1 .Location in patent: Page/Page column 138

30
[ 5332-26-3 ]
[ 1220978-90-4 ]
[ 1220978-91-5 ]

Yield	Reaction Conditions	Operation in experiment
66%		A solution of intermediate ACi (2.03 g) in THF (19 mL) was added dropwise at -78°C to a solution of LiHMDS (IM in THF; 10.5 mL) in THF (10 mL). The solution was further stirred at -78°C stirred for 1 h and treated dropwise with a solution of Lambda/-(bromomethyl)phthalimide (2.6 g) in THF (19 mL). The reaction mixture was further stirred at -78°C for 1 h and at rt overnight. The solution was quenched with IN HCl (30 mL) and extracted with EA. The org. layer was washed with water and brine, dried over MgSO4, concentrated under reduced pressure and purified by CC (Hept/EA 1 :1), affording, after crystallization from EA, a beige solid (2.28 g; 66percent yield). MS (ESI, m/z): 392.3 [M+H+].

Reference： [1]Patent: WO2010/41194,2010,A1 .Location in patent: Page/Page column 167-168

31
[ 5332-26-3 ]
[ 243641-04-5 ]
[ 1253954-99-2 ]

Yield	Reaction Conditions	Operation in experiment
68%		Methyl 3-(1 ,3-dioxoisoindolin-2-yl)-2-(4-(triisopropylsilyloxy)phenyl) propanoate (E3) was prepared from E2 according to the below:To a solution of LiHMDS in THF cooled to -78°C was added a cooled solution (approx - 78°C) of methyl-2-(4-(triisopropylsilyloxy) phenyl)acetate (E2) in THF via syringe. The solution was stirred at -78°C for 30 min. Bromo-methyl phthalimide was added directly to the anion, and the solution was immediately removed from the -78°C bath and placed in an ice bath and stirred for 2 h. The reaction was then poured into NH4CI(sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography 0-20percent EtOAc/Hexanes gave pure methyl 3-(1 ,3-dioxoisoindolin-2-yl)-2-(4- (triisopropylsilyloxy)phenyl)propanoate (E3).

Reference： [1]Patent: WO2010/127329,2010,A1 .Location in patent: Page/Page column 44
[2]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2475 - 2480
[3]Patent: WO2018/34702,2018,A1 .Location in patent: Paragraph 0070; 00140

32
[ 5332-26-3 ]
[ 21654-18-2 ]
[ 943321-35-5 ]

Yield	Reaction Conditions	Operation in experiment
64%		To a suspension of NaH (2.2 g, 54 mmole) in THF (200 ml_) was added diethyl 2-(phenylmethyl)butanedioate (12.5 g, 49.9 mmole). After 30 min at RT, bromomethyl phthalimide was added to the reaction mixture and the contents were stirred for 14 h at RT. The reaction was quenched with H2O (15 mL), diluted with Et2O (300 mL) and layers separated. The organic layer was concentrated under vacuum and the resulting residue recrystallized from EtOH (0°) to give the title compound (13 g, 64percent) as a white solid: LCMS (ES) m/z 410 (M+H)+.
64%		Preparation 5Preparation of 3-({r(1 ,1-dimethylethyl)oxy1carbonyl}amino)-2- (phenylmethyl)propanoic acida) diethyl 2-[(1 ,3-dioxo-1 ,3-dihydro-2/-/-isoindol-2-yl)methyl]-2- (phenylmethyl)butanedioateTo a suspension of NaH (2.2 g, 54 mmole) in THF (200 ml.) was added diethyl 2-(phenylmethyl)butanedioate (12.5 g, 49.9 mmole). After 30 min at RT, <n="45"/>bromomethyl phthalimide was added to the reaction mixture and the contents were stirred for 14 h at RT. The reaction was quenched with H2O (15 ml_), diluted with Et2O (300 ml.) and layers separated. The organic layer was concentrated under vacuum and the resulting residue recrystallized from EtOH (0°) to give the title compound (13 g, 64percent) as a white solid: LCMS (ES) m/z 410 (M+H)+.

Reference： [1]Patent: WO2007/76423,2007,A2 .Location in patent: Page/Page column 59
[2]Patent: WO2008/121786,2008,A1 .Location in patent: Page/Page column 43-44

33
[ 554450-77-0 ]
[ 5332-26-3 ]
[ 1260170-72-6 ]

Yield	Reaction Conditions	Operation in experiment
73%		3.5 g (87 mmol) of sodium hydride are added in portions to a solution of 25 g (87 mmol) of dimethyl2- (4- ert-butoxycarbonylpiperazin-l-yl) malonate in 250 ml of tetrahydrofuran cooled to 2°C. The reaction medium is stirred at ambient temperature for 30 minutes, then brought to 2°C before dropwise addition of 21 g (87 mmol) of 2- (bromomethyl) isoindole-1, 3-dione in 200 ml of tetrahydrofuran . The reaction medium is stirred at ambient temperature for 20 h, treated by addition of 500 ml of water then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum.The crude product obtained is purified by chromatography over silica gel eluted with a 70/30 heptane/ethyl acetate mixture. 27.5 g (73percent) of dimethyl 2- (4- ert-butoxycarbonylpiperazin-l-yl) -2- (1, 3-dioxo- 1, 3-dihydro-isoindol-2-ylmethyl) malonate are obtained in the form of a white solid.
73%		1-2: Dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)malonate; 3.5 g (87 mmol) of sodium hydride are added portionwise to a solution of 25 g (87 mmol) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate in 250 ml of tetrahydrofuran cooled to 2° C. The reaction medium is stirred at ambient temperature for 30 minutes and then brought back to 2° C., before adding, dropwise, 21 g (87 mmol) of 2-bromomethylisoindole-1,3-dione in 200 ml of tetrahydrofuran. The reaction medium is stirred at ambient temperature for 20 h, treated by adding 500 ml of water and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, and concentrated under vacuum.The crude product obtained is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 27.5 g (73percent) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)malonate are obtained in the form of a white solid.
73%		3.5 g (87 mmol) of sodium hydride are added portionwise to a solution of 25 g (87 mmol) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate in 250 ml of tetrahydrofuran cooled to 2° C. The reaction medium is stirred at ambient temperature for 30 minutes and then brought back to 2° C., before adding, dropwise, 21 g (87 mmol) of 2-bromomethylisoindole-1,3-dione in 200 ml of tetrahydrofuran. The reaction medium is stirred at ambient temperature for 20 h, treated by adding 500 ml of water and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, and concentrated under vacuum. [0193] The crude product obtained is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 27.5 g (73percent) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)malonate are obtained in the form of a white solid.

Reference： [1]Patent: WO2011/33009,2011,A1 .Location in patent: Page/Page column 26-27
[2]Patent: US2012/323006,2012,A1 .Location in patent: Page/Page column 11
[3]Patent: US2014/275108,2014,A1 .Location in patent: Paragraph 0192; 0193

34
[ 5332-26-3 ]
[ 172527-71-8 ]
2-(2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide / 20 °C 2: hydrogen bromide; acetic acid / 3.5 h / 110 °C

Reference： [1]Fodor, Elena; Maftei, Catalin-Vasile; Mangalagiu, Ionel; Jones, Peter G.; Daniliuc, Constantin-Gabriel; Franz, M. Heiko; Neda, Ion [Revue Roumaine de Chimie, 2010, vol. 55, # 9, p. 559 - 564]

35
[ 5332-26-3 ]
[ 1260662-63-2 ]
[ 1346427-79-9 ]

Yield	Reaction Conditions	Operation in experiment
74%		Into a solution of hexamethyldisilazane (17.5 g, 106 mmol) in THF (100 mL) was added n-butyllithium (1.58 M in hexane, 50 mL, 78.5 mmol) at -78° C. After 5 min at -78° C., the solution was allowed to warm to 0° C. for 30 min and then cooled to -78° C. again. A solution of 3-benzoyl-4-methyl-2-phenyl-1,3-oxazolidin-5-one (dried overnight in vacuo before using, 20 g, 71 mmol) in THF (250 mL) was added slowly under argon, and the dark red brown solution was stirred at this temperature for 3 h. A solution of <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> (22.2 g, 92.5 mmol) in THF (200 mL) was then added dropwise. The reaction mixture was allowed to warm to 20° C. in 4 h and stirred at this temperature overnight. The solvent was evaporated. The residue was dissolved in 10percent NH4Cl (250 mL) and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and evaporated. Recrystallization from CH2Cl2 and ether (1:4) gave white crystals of 2-((3-benzoyl-4-methyl-5-oxo-2-phenyloxazolidin-4-yl)methyl)isoindoline-1,3-dione (23 g, 74percent). LC-MS (ES, m/z): 441 [M+H]+.

Reference： [1]Patent: US2011/275636,2011,A1 .Location in patent: Page/Page column 26

36
[ 5332-26-3 ]
[ 122555-91-3 ]
C₃₅H₅₅N₅O₈*NaI [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With caesium carbonate; sodium iodide; In acetonitrile; at 80℃; for 24h;Inert atmosphere;	Bromomethylphtalimide (85 mg, 0.35 mmol), sodium iodide (53 mg, 0.56 mmol) and cesium carbonate (177 mg, 0.54 mmol) were added to a solution of DO3AtBu under argon atmosphere (172 mg, 0.33 mmol) in freshly distilled acetonitrile (5 mL). The suspension was heated to reflux for 24 h, before being filtered at room temperature. The yellow filtrate was evaporated under reduced pressure and 10 mL chloroform was added in order to precipitate residual inorganic impurities. Evaporation of the solvent and addition of 20 mL of ether led to precipitation of a yellow powder corresponding to the sodium adduct C35H55N5O8.NaI.H2O (191 mg, 67percent yield). 1H NMR (CDCl3) d: 7.82?7.71 (m, 4H), 4.66 (s, 2H), 3.27?2,34 (broad signals overlapping, 22H), 1.48?1,40 (two signals overlapping, 27H); 13C NMR (CDCl3) d: 173.91, 173.30, 169.70, 134.58, 131.69, 123.59, 83.03, 82.73, 57.62, 56.48, 55.69, 53.55, 51.77, 51.15, 48.34, 28.06, 27.88. Anal. Calcd for C35H55N5O8.NaI.H2O: C, 49.94; H, 6.83; N, 8.32. Found: C, 50.13; H, 6.67; N, 8.49.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 6115 - 6118,4

37
[ 5332-26-3 ]
[ 62451-84-7 ]
[ 1361319-26-7 ]

Yield	Reaction Conditions	Operation in experiment
22%		Example 16A Methyl 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[3-(trifluoromethyl)phenyl]propanoate Over about 5 min, a solution of n-butyllithium (1.6 M in hexane, 18.75 ml, 30 mmol) was added dropwise to a solution, pre-cooled to -20 C., of 4.91 ml (35 mmol) of diisopropylamine in 50 ml of THF. The LDA solution obtained in this manner was cooled to -78 C., and 15.1 ml of DMPU (1,3-dimethyltetrahydro-2(1H)-pyrimidinone, 125 mmol) were added. After 20 min at -78 C., a solution of 5.45 g (25 mmol) of <strong>[62451-84-7]methyl [3-(trifluoromethyl)phenyl]acetate</strong> in 35 ml of THF was slowly added dropwise. After a further 20 min at -78 C., a solution of 7.20 g (30 mmol) of N-bromomethylphthalimide in 50 ml of THF was added dropwise. Stirring of the reaction mixture was continued initially at -78 C. for 1 h, then without cooling bath at RT overnight. After addition of 100 ml of 1 N hydrochloric acid, the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was dissolved in 50 ml of DMSO and purified in several portions by preparative HPLC [Method 8]. This gave 2.20 g (22% of theory) of the title compound. LC/MS [Method 3]: Rt=1.32 min; m/z=378 (M+H)+ 1H NMR (400 MHz, DMSO-d6): delta [ppm]=3.33 (s, 3H), 4.07 (dd, 1H), 4.19 (dd, 1H), 4.33 (dd, 1H), 7.50-7.57 (m, 1H), 7.58-7.66 (m, 3H), 7.75-7.87 (m, 4H).

Reference： [1]Patent: US2013/225646,2013,A1 .Location in patent: Paragraph 0355-0358

38
[ 5332-26-3 ]
[ 16390-61-7 ]
1-methylene phtalimide-2-phenyl-1,2-carborane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		The starting carborane, 1-C6H5-1,2-C2B10H11 1.00 g (4.53 mmol) dried in vacuum, was dissolved in DME (40 ml) in Schlenk-type flask under argon, and the resulting solution was cooled down to -33° C. and BuLi (2.5 M in hexane, Aldrich, 2.0 ml, 5.0 mmol) was added under stirring from a syringe through septum. The reaction slurry was stirred for 15 min. and then left to warm up to room temperature. The reaction mixture was again cooled down and bromomethyl phtalimide 1.20 g (Aldrich, 5.0 mmol) dissolved in v 15 ml of DME was added dropwise from a syringe. The reaction mixture was stirred for 15 min. -33° C. at and then left slowly to warm up to room temperature over 4 h period. After standing overnight, the solids were filtered off under argon, and washed under argon with two portions of DME (10 ml). Diluted acetic acid (3 M, 0.5 ml) was added to the combined DME extracts and volatiles were removed under reduced pressure. A solid residue was dissolved in benzene and poured atop of a silica gel column (3*25 cm). Elution with benzene led to isolation of the starting 1-Ph-carborane (240 mg), continued elution using benzene-CH3CN (4:1, b.v.) solvent mixture afforded the methylene-phtalimide substituted intermediate carborane 0.85 g (49percent).

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 13760 - 13763
Angew. Chem.,2013,vol. 125,p. 14005 - 14008,4
[2]Patent: US2014/303390,2014,A1 .Location in patent: Paragraph 0184

39
[ 5332-26-3 ]
[ 1436855-56-9 ]
[ 1436855-87-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With tetrabutylammomium bromide; potassium hydroxide; In dichloromethane; at 20℃; for 7h;	General procedure: After the compound 1o (700 mg, 1.68 mmol) was dissolved in dichloromethane (15 mL), potassium hydroxide (278 mg, 4.22 mmol) and tetrabutylammonium bromide (60 mg) were added thereto, and iodomethyl (0.525 mL, 8.435 mmol) was slowly added thereto at room temperature. This solution was stirred for 10 hours at 25° C. Cooling water was added to the reaction material, and the result was adjusted to pH 5 to 6 using a 2N aqueous hydrochloric acid solution. After the organic layer was separated and taken, the aqueous layer was extracted once with dichloromethane, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated using silica gel column chromatography (normal-hexane/ethyl acetate=4/1) to give a pure target compound 1z (574 mg, 79percent). Step 1: Preparation of methyl 2-tert-butoxy-2-(4-(4-chlorophenyl)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (19a) A target compound 19a (780 mg, 94percent) was obtained by reacting the compound 1o (600 mg, 1.446 mmol) in the same manner as in Step 1 of Example 1, except that <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> (787 mg, 3.0 equivalents) and potassium hydroxide (400 mg, 5 equivalents) were used instead of iodomethyl and the stirring was carried out for 7 hours at 20° C. 1H-NMR (300 MHz, CDCl3) delta 0.98 (s, 9H), 1.46 (s, 3H), 2.45 (s, 3H), 2.65 (s, 3H), 3.63 (s, 3H), 5.04 (s, 1H), 6.08 (AB-q, 2H), 7.24 (m, 2H), 7.37 (m, 2H), 7.73 (m, 2H), 7.68 (m, 2H); MS (EI, m/e)=573 (M+).
94%	With tetrabutylammomium bromide; potassium hydroxide; In dichloromethane; at 20℃; for 7h;	General procedure: After the compound 1o (700 mg, 1.68 mmol) was dissolved in dichloromethane (15 mL), potassium hydroxide (278 mg, 4.22 mmol) and tetrabutylammonium bromide (60 mg) were added thereto, and iodomethyl (0.525 mL, 8.435 mmol) was slowly added thereto at room temperature. This solution was stirred for 10 hours at 25°C. Cooling water was added to the reaction material, and the result was adjusted to pH 5 to 6 using a 2N aqueous hydrochloric acid solution. After the organic layer was separated and taken, the aqueous layer was extracted once with dichloromethane, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated using silica gel column chromatography (normal-hexane/ethyl acetate=4/1) to give a pure target compound 1z (574 mg, 79percent). 1H-NMR (300 MHz, CDCl3) delta 0.97 (s, 9H), 1.49 (s, 3H), 2.28 (s, 3H), 2.71 (s, 3H), 3.65 (s, 3H), 3.75 (s, 3H), 5.07 (s, 1H), 7.24 (m, 1H), 7.43 (m, 3H); MS (EI, m/e)=428 (M+). A target compound 19a (780 mg, 94percent) was obtained by reacting the compound 1o (600 mg, 1.446 mmol) inthe same manner as in Step 1 of Example 1, except that <strong>[5332-26-3]N-(bromomethyl)phthalimide</strong> (787 mg, 3.0 equivalents) andpotassium hydroxide (400 mg, 5 equivalents) were used instead of iodomethyl and the stirring was carried out for 7hours at 20°C. 1H-NMR (300 MHz, CDCl3) delta 0.98 (s, 9H), 1.46 (s, 3H), 2.45 (s, 3H), 2.65 (s, 3H), 3.63 (s, 3H), 5.04 (s, 1H),6.08 (AB-q, 2H), 7.24 (m, 2H), 7.37 (m, 2H), 7.73 (m, 2H), 7.68 (m, 2H); MS (EI, m/e)=573 (M+).

Reference： [1]Patent: US2014/249162,2014,A1 .Location in patent: Paragraph 0118; 0119; 0120; 0208; 0209; 0210
[2]Patent: EP2781519,2014,A1 .Location in patent: Paragraph 0116; 0117; 0118;

40
[ 5332-26-3 ]
[ 16390-61-7 ]
[ 31070-99-2 ]

Yield	Reaction Conditions	Operation in experiment
53%		Dried C6H5-closo-1,2-C2B10H12 2.00 g (9.06 mmol) was dissolved in DME (40 ml) under argon, the solution was then cooled down to ?33° C. and BuLi (2.5 M in hexane, 4.0 ml, 10,0 mmol) was added dropwise from a syringe. The reaction mixture was stirred for additional 15 min., then left to warm up to room temperature and cooled down again to ?33° C., solution of bromopropyl phtalimide in DME (15 ml) was added slowly, reaction mixture was then kept at low temperature for 15 min. and then left to warm slowly under stirring to room temperature over 4 h and left to stand overnight. Solids were removed by filtration under argon and washed with DME (2×10 ml). Diluted acetic acid (3 M, 0.5 ml) was added to filtrate and the volatiles were removed in vacuum. Solids were dissolved in benzene and the injected atop of a silica gel column (25×3 cm I.D.). The unreacted starting compound (440 mg, 22percent) was eluted by benzene, whereas the propyl phtalimide intermediate was isolated by elution with benzene-CH3CN (95:5) and evaporated to dryness; yield 1.95 g (53percent).

Reference： [1]Patent: US2014/303390,2014,A1 .Location in patent: Paragraph 0191

41
[ 5332-26-3 ]
[ 65-85-0 ]
[ 21809-52-9 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	General procedure: The vacuum dried intermediate 3 (0.002 mol) was then reacted with mono- and di-substituted benzoic acids (0.003 mol) separately in presence of anhydrous potassium carbonate (0.003 mol) in DMF (10 mL). The reaction mixture was stirred at room temperature for about 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and allowed stir for 10 min. The solid obtained was filtered and washed successively with distilled water and recrystallized from ethanol to obtain4(a?n).