[ CAS No. 19171-19-8 ] {[proInfo.proName]}

Name: 19171-19-8|4-Amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione|98%
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Quality Control of [ 19171-19-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 19171-19-8 ]

SDS Specification

Alternatived Products of [ 19171-19-8 ]

Product Details of [ 19171-19-8 ]

CAS No. :	19171-19-8	MDL No. :	MFCD12756407
Formula :	C₁₃H₁₁N₃O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UVSMNLNDYGZFPF-UHFFFAOYSA-N
M.W :	273.24	Pubchem ID :	134780
Synonyms :	CC-4047;3-amino Thalidomide;Pomalidomide. Brand name: Pomalyst.	Chemical Name :	4-Amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Calculated chemistry of [ 19171-19-8 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.23
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	75.36
TPSA :	109.57 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.82 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.93
Log Po/w (XLOGP3) :	0.2
Log Po/w (WLOGP) :	-1.08
Log Po/w (MLOGP) :	0.74
Log Po/w (SILICOS-IT) :	0.3
Consensus Log Po/w :	0.22

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.82
Solubility :	4.17 mg/ml ; 0.0153 mol/l
Class :	Very soluble
Log S (Ali) :	-2.06
Solubility :	2.38 mg/ml ; 0.00872 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.69
Solubility :	0.558 mg/ml ; 0.00204 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.36

Safety of [ 19171-19-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P501-P202-P201-P280-P308+P313-P405	UN#:	N/A
Hazard Statements:	H361	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 19171-19-8 ]

* 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 [ 19171-19-8 ]
Downstream synthetic route of [ 19171-19-8 ]

[ 19171-19-8 ] Synthesis Path-Upstream 1~17

1
[ 19171-18-7 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
93.3%	With palladium 10% on activated carbon; hydrogen In water; N,N-dimethyl-formamide at 35℃; for 3 h;	To the reaction flask was added 33-nitro-N-(2,6-dioxo-3-piperidinyl)phthalimide (II) (100.0g, 0.33mol), 10percent palladium on carbon 12.0g, DMF 1000ml, 70ml water, vacuum, hydrogen gas was introduced (replacement three times), the reaction normal pressure at 35 °C for 3h, TLC monitored the reaction was completed, the palladium carbon was filtered off, the DMF solution was slowly added to 5-fold amount of water, stirring about 30min, then the solid was filtered, the filter cake was washed with an appropriate amount of water (2L * 3 times, 30min/time), the filter cake was washed with 200ml of ethanol, and the solid was transferred to a one-neck 3L flask was charged with 2L of ethyl acetate at 73 °C stirred 0.5h, filtered hot and the solid was dried at 45 °C to constant weight to give a yellow solid powder 84.1g, a yield of 93.3percent. percent HPLC purity 99.9,
91%	With palladium on activated charcoal; hydrogen In 1-methyl-pyrrolidin-2-one at 45℃;	(1) 100g 3-nitro-N-(2,6-dioxo-3-piperidinyl)phthalimide, 10g of the palladium-carbon and 1000 ml N-methylpyrrolidone were added into a 2000 ml hydrogenation reactor. Vacuum. After nitrogen replacement 3 times, place hydrogen gas, regulating the reactor pressure to 0.3 MPa, control temperature at 45 °C. After the reaction is complete, filtering, the filtrate by adding 30g charcoal, heating up to 70 °C, stirring 3 hours, filtered; (2) to the step (1) and the finally obtained by adding sodium carbonate aqueous solution in the filtrate (2g sodium carbonate dissolved in 10 ml purified water to prepare water), stirring at room temperature for 0.5 hours, then slowly dropping 2000 ml purified water, lowering the temperature to 10 °C crystallization, filtered, the filter cake is added to 500 ml of purified water, stirring at room temperature for 0.5 hours, filtered, washed with water purification cake, solid 60 °C obtained by vacuum drying the yellow powdery solid 82g, yield 91percent. HPLC detection the purity is 99.88percent.
80%	With palladium 10% on activated carbon; hydrogen In N,N-dimethyl acetamide at 30℃; for 7 h;	Add 5 g of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline and 0.4 g of 10percent palladium carbon to 50 mL of N,N - in dimethylacetamide,The hydrogenation reaction is then carried out at 0.45 MPa at 30 ° C.Lasted 7 hours,Filter to remove the catalyst,The filtrate was concentrated under vacuum.The concentrate was beaten with water overnight.Obtained 3.6 g of a yellow solid.That is, the target compound.Yield 80percent,The purity measured by HPLC was 99.4percent.

79.5%	With palladium 10% on activated carbon; hydrogen In 1,4-dioxane at 60 - 65℃; for 6 h;	In a mixer equipped with a mechanical stirrer, A thermometer and a ventilator was charged with 31.7 g (wet product 48.2 g, 0.105 mol, 1.0 eq) 3-nitro-N-(2,6-dioxo-3-piperidinyl) phthalimide,1.6 g of 10percent palladium on carbon and 395 mL of solvent 1,4-dioxane,Stirring to form a suspension of hydrogen gas bubbling, bubbling speed 1 times / second, the temperature of the reaction solution to 60 ~ 65 ° C, continue stirring for 6 hours, HPLC control: to be raw materials and intermediate content <0.5percent The filtrate was concentrated under reduced pressure and 158 mL of ethyl acetate was added to the residue. The mixture was stirred for 2 hours and then filtered. The cake was transferred to another 500 mL reaction flask and 158 mL of N , N-dimethylformamide, heating to 55 ~ 60 ° C stirring, 55 ~ 60 ° C drop 316 mL of purified water, heating to 70 ~ 75 ° C for 2 hours, cooling to a temperature of 30 ~ 35 ° C, filter, wet goods to vacuum drying oven 50 ~ 55 ° C drying, 3-amino-N - (2,6-dioxo-3-piperidyl) phthalimide 22.7 G, pale yellow powdery solid, yield 79.5percent, m.p. 315.0~318.0 ° C (DSC). The purity of the product was 99.73percent by HPLC, with a single impurity <0.10percent, of which 13percent UV retention time = 11.5 min.), And using 0.1percent (v (v / v)) as the mobile phase, / Ν) phosphoric acid aqueous solution and acetonitrile as a mobile phase at a flow rate of 1.0 ml / min.
77.7%	With hydrogen In 1,4-dioxane; water at 20 - 25℃; for 60 h;	A round bottomed flask was charged with 1,4-dioxane (600 ml) and 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (10 g). The mixture was stirred at 25° C. to 30° C. for 15 minutes, the temperature was raised up to 80° C. and the reaction mass stirred to obtain a clear solution. To the clear solution activated charcoal (5 g) was added at 80° C., the mixture stirred and the solution cooled to 25° C. to 30° C. The reaction mass was further stirred for 20 minutes at this temperature and filtered. To the obtained solution 1,4-dioxane (300 ml), water (180 ml) and Raney nickel (0.5 g) were added. The reaction mixture was stirred at 20° C. to 25° C. under 70 psi hydrogen pressure for 12 hrs. Raney nickel (0.5 g) was added to the reaction mixture at 20° C. to 25° C. and the reaction continued at the same temperature and pressure for 12 hrs. Another portion of Raney nickel (0.5 g) was added to the reaction mixture and the reaction continued at the same temperature and pressure for 12 hr. Another portion of Raney nickel (0.5 g) was added to the mixture and the reaction continued at the same temperature and pressure for 12 hr. Another portion of Raney nickel (0.5 g) was added to the reaction mixture and the reaction continued at the same temperature and pressure for 12 hr. The reaction mixture was then filtered through a celite bed and the solvent was distilled off from the reaction mixture under vacuum at 50° C. to obtain a solid. To the solid obtained 1,4-dioxane (50 ml) and ethyl acetate (5 ml) were added and the mixture was heated to 80° C. with stirring for 1 hr. The reaction mass was filtered at 80° C. and the obtained cake washed with 1,4-dioxane (10 ml) at 80° C. To the wet cake ethyl acetate (100 ml) was added and the mixture was refluxed with stirring for 1 hr. Then the reaction mass was cooled to 25° C. to 30° C., the solid filtered, washed with ethyl acetate (20 ml) and dried under vacuum to get 4-amino-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (7 g). Yield: 77.7percent Purity: 99percent.
46%	With triethylsilane; potassium fluoride; palladium diacetate In tetrahydrofuran; water at 20℃; for 1 h;	A solution of 2-(2,6-dioxopiperidin-3 -yl)-4-nitroisoindoline- 1,3 -dione (173 mg, 0.854 mmol), Pd(OAc)2 (12.8 mg, 0.0854 mmol, 10 molpercent) and potassium fluoride (66 mg, 1.71 mmol, 2 equiv) in THF:water (8:1) (5.7 mL, 0.1 M) was stirred at room temperature. Triethylsilane (3651iL, 3.41 mmol, 4 equiv) was added slowly, and the resulting black solution was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of celite, which was washed excessively with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (CH2C12:MeOH (7:1)) to afford the titlecompound as a yellow powder (72 mg, 46percent). 1H NMR (500 IVIHz, DMSO-d6) 11.08 (s, 1H),7.47 (dd, J 8.5, 7.0 Hz, 1H), 7.06 — 6.95 (m, 1H), 6.59 —6.44 (m, 1H), 5.04 (dd, J= 12.7, 5.4Hz, 1H), 2.93 — 2.82 (m, 1H), 2.64 — 2.45 (m, 2H), 2.05 — 1.98 (m, 1H); MS (ESI) calcd forC13H11N304 [M+H] 274.08, found 274.23.
46%	With triethylsilane; potassium fluoride; palladium diacetate In tetrahydrofuran; water at 20℃; for 1 h;	A solution of 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (173 mg, 0.854 mmol), Pd(OAc)2 (12.8 mg, 0.0854 mmol, 10 molpercent) and potassium fluoride (66 mg, 1.71 mmol, 2 equiv) in THF:water (8:1) (5.7 mL, 0.1 M) was stirred at room temperature. Triethylsilane (365 μL, 3.41 mmol, 4 equiv) was added slowly, and the resulting black solution was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of celite, which was washed excessively with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (CH2Cl2:MeOH (7:1)) to afford the title compound as a yellow powder (72 mg, 46percent). ¹H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.47 (dd, J = 8.5, 7.0 Hz, 1H), 7.06- 6.95 (m, 1H), 6.59- 6.44 (m, 1H), 5.04 (dd, J = 12.7, 5.4 Hz, 1H), 2.93- 2.82 (m, 1H), 2.64- 2.45 (m, 2H), 2.05- 1.98 (m, 1H); MS (ESI) calcd for C13H11N3O4 [M+H]⁺ 274.08, found 274.23.
44.4%	With iron; ammonium chloride In ethanol; water at 20℃;	9 (410.0 mg, 1.4 mmol), NH4Cl(360.0 mg, 7.0 mmol) and iron powders (380.0 mg, 7.0 mmol) weremixed in a EtOH/H2O (v:v=7:3) solution (40 mL). The resultingmixture was kept stirring at room temperature overnight. Then saturatedNaHCO3 solution was added to the reaction mixture which wasthen extracted with ethyl acetate. The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure togive compound 10 as a yellow powder (Yield: 163.0 mg, 44.4percent). ESIMS:calcd m/z=273.07, found [M+H]+=274.07, [M+Na]+=296.05 and [2 M+Na]+=569.12 . 1H NMR (ppm,400 MHz, DMSO‑d6): δ 11.11 (s, 1H), δ 7.47 (q, J=6.0 Hz, 1H), δ 7.01(q, J=6.0 Hz, 2H), δ 6.54 (s, 2H), δ 5.05 (q, J=10.0 Hz, 1H), δ 2.89(m, 1H), δ 2.57 (m, 2H), δ 2.02 (m, 1H). 13C NMR (ppm, 100 MHz,DMSO‑d6): δ 173.32, 170.63, 169.04, 167.85, 147.19, 135.94, 132.47,122.18, 111.46, 108.97, 48.95, 31.46, 22.62
136 g	With palladium 10% on activated carbon; hydrogen In N,N-dimethyl-formamide at 20℃; for 3 h;	Dimethylformamide (1500 ml) was added to 3-(4-nitro-l-oxoisoindolin-2- yl)piperidine-2,6-dione (150 gm) and then stirred for 30 minutes at room temperature to obtain a clear solution. To the solution was added 10percent palladium carbon and then applied 4 Kg of hydrogen pressure at room temperature. The reaction mass was stirred for 3 hours at room temperature and temperature of the reaction mass was raised to 60 to 65°C. The reaction mass was filtered through hi-flow bed and then concentrated to obtain a residual solid. To the residual solid was added ethyl acetate (600 ml) and then heated to reflux. The reaction mass was maintained for 30 minutes at reflux and then cooled to room temperature. The contents were stirred for 1 hour at room temperature and filtered. The solid obtained was then dried to obtain 136 gm of pomalidomide. Chromatographic purity: 97.5percent.
8.2 g	With palladium 10% on activated carbon; hydrogen In N,N-dimethyl-formamideInert atmosphere	Example 3: Synthesis of 4-amino-2-(2,6-dioxopiperidin-3-yl)-isoindoIine-l,3-(lione (Pomalidomide) Catalyst palladium (10percent) on carbon (0.5 g. or 5percent w/w of substrate ) was added to a stirred solution of 3-nitrophthalidomide (10 g or 0.033 mole) (Example 1 ) in N,N- dimethyl formamide (100 ml) maintained under nitrogen. Hydrogen gas was bubbled through the reaction mixture at atmospheric pressure. After completion of hydrogenation reaction, as monitored by TLC, hydrogen bubbling was stopped and the catalyst was separated by filtration of the reaction mixture on celite bed. The filtrate was distilled at 60 to 65 °C under reduced pressure until half of the solvent was removed. The solution was then cooled at ambient temperature and methanol (50 ml) was added while stirring. The solid obtained was filtered, washed with methanol (50 ml), and suck dried to obtain pomalidomide 8.2 g (90percent molar yield) having HPLC purity > 99.0percent.
216.7 g	at 105℃; for 5 h;	Add 240g iron powder in batches,Control reaction temperature does not exceed 105 stirring reaction 5 hours,Cool to room temperature.filter,Filter cake washed with water,And then washed with sodium bicarbonate solution,After filtration, the crude product.The crude product was dissolved in 2400 ml of dimethylsulfoxide,filter.Add water to the filtrate,The precipitated solid was collected by filtration,Dry at 60 for 4 h.216.7 g of a yellow solid, yield: 79.3percent, purity: 99.93percent.
3.7 g	With palladium 10% on activated carbon; hydrogen In N,N-dimethyl acetamide at 30℃; for 6 h;	5 g of 1,3-dioxo-2- (2,6-dioxopiperidin-3-yl) -5-nitroisoindoline 10percent palladium carbon 0.4g mixed into 70 mL of N, N-dimethylacetamide, The hydrogenation reaction was then carried out at 0.4 MPa, The reaction temperature was 30 ° C, Lasted 6 hours, Filter out the catalyst, The filtrate was concentrated in vacuo, The residue was beaten overnight at 40 ° C with 40 mL of water, Get 3.7g Yellow-green solid of thalidomide crude. HPLC with a purity of 99.0percent.
85 g	With palladium 10% on activated carbon; hydrogen In N,N-dimethyl-formamide at 15 - 20℃;	In to a well cleaned and oven dried 3 .OL 4neck RB flask, to a mechanical stirrer and equipped with thermometer socket, condenser (fitted with gas outlet dipped in to the water), gas-inlet(connected with single trap filled with dimethylfonnamide up to bubbling nossile), 100.Og of 2-(2, 6-dioxo-3 -piperidyl)-4-nitro-isoindoline- 1, 3 -dione, 1 550.Oml of dimethylformamide were charged. Reaction mass was stirred for 10-15mm at 25-35°C, clear solution was observed. 13.0g of 10percent Pd/c was charged in to the reaction mass, in presence of N2 gas atmosphere, washing was given with 50.0 ml of dimethylfonnamide. H2 gas was bubbled in to the reaction mass, for 6.5-7.0 hours, at 15-20°C. After completion of reaction, eaction mass is filtered under vacuum, through hyflow, in presence of N2 gas atmosphere, washing is given with 300.Oml of dimethylfonnamide. Filtrate is transferred in to a 5.OL 4 neck RB flask. Slowly added DM Water (1900.0m1) to the reaction mass over a period of 45-60mm at 15-20°C, Stirred the reaction mass at 15-20°C for 60-90mm. Solid reaction mass was filtered under vacuum, washing was given with 200.Oml DM Water, suck dried for 45-60mm. wet compound is dried in a vacuum oven at 60-650C, under vacuum (600-65OmmJHg) for 2-3hours and characterized as form A of pomalidomide.Yield: 85.0 g

Reference： [1] Patent: CN105348257, 2016, A, . Location in patent: Paragraph 0051; 0052; 0053
[2] Patent: CN106565668, 2017, A, . Location in patent: Paragraph 0053; 0054; 0055; 0056-0061
[3] Patent: CN104557858, 2018, B, . Location in patent: Paragraph 0032; 0033; 0036; 0038; 0040; 0042; 0044; 0046
[4] Patent: CN103804350, 2016, B, . Location in patent: Paragraph 0029; 0031
[5] Patent: US2017/260157, 2017, A1, . Location in patent: Paragraph 0057; 0058; 0059; 0060; 0061; 0062; 0063
[6] Synthetic Communications, 2016, vol. 46, # 16, p. 1343 - 1348
[7] Patent: WO2018/148440, 2018, A1, . Location in patent: Page/Page column 297; 300; 301
[8] Patent: WO2018/148443, 2018, A1, . Location in patent: Page/Page column 281-282
[9] Bioorganic Chemistry, 2018, vol. 81, p. 536 - 544
[10] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630
[11] Chemical and Pharmaceutical Bulletin, 2006, vol. 54, # 6, p. 855 - 860
[12] Patent: US6335/349, 2002, B1, . Location in patent: Example 1
[13] Patent: US6335349, 2002, B1, . Location in patent: Example 1
[14] Patent: US2013/143922, 2013, A1, . Location in patent: Paragraph 0091
[15] Patent: WO2014/170909, 2014, A2, . Location in patent: Page/Page column 5
[16] Patent: WO2015/75694, 2015, A1, . Location in patent: Page/Page column 2; 4; 9
[17] Patent: CN104402863, 2016, B, . Location in patent: Paragraph 0035
[18] Patent: CN107188884, 2017, A, . Location in patent: Paragraph 0019; 0033; 0034; 0036
[19] Patent: CN107365295, 2017, A, . Location in patent: Paragraph 0014; 0015
[20] Patent: WO2017/221261, 2017, A1, . Location in patent: Page/Page column 5; 6
[21] Patent: WO2018/154516, 2018, A1, . Location in patent: Page/Page column 8
[22] ACS Chemical Biology, 2018, vol. 13, # 9, p. 2771 - 2782

2
[ 24666-56-6 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium acetate; acetic acid In acetonitrile at 80 - 85℃; for 8 h;	Acetonitrile (100 mL),Acetic acid (25.41 mL, 444.2 mmol),Anhydrous sodium acetate (18.22 g, 222.1 mmol),Disodium 3-aminophthalate (10 g, 44.4 mmol),Aminopiperidine-2,6-dione hydrochloride (7.68 g, 46.6 mmol)Added to the reaction flask, heated to 80 ~ 85 ° C reflux,The reaction was complete after 8h, the reaction was cooled to 20 ~ 25 ° C, purified water was slowly added, stirred crystallization 2h, filtered, the filter cake was dried under reduced pressure 8 ± 5 ° C for 8h to give 10.2g of a yellow solid, yield 84.0percent Purity 99.4percent.

Reference： [1] Patent: CN107325075, 2017, A, . Location in patent: Paragraph 0019; 0020; 0021; 0022; 0023; 0024-0028

3
[ 24666-56-6 ]
[ 6946-22-1 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: for 0.25 h; Stage #2: With triethylamine In water; acetonitrile at 15 - 87℃; for 49.0833 - 50.8333 h;	Example 14; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; Example 14 was prepared similarly according to the procedure for Example 13 except that there was no acetic acid; the amount of triethylamine was reduced from 4.6 mol to 3.2 mol; and the refluxing time was increased from about 5 to 7 hours to about 47 hours. The amount of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reaction mixture was found to be 94percent.
92%	Stage #1: for 0.25 h; Stage #2: With 1H-imidazole In water; acetonitrile at 15 - 87℃; for 7.08333 - 10.8333 h;	Example 15; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; Example 15 was prepared similarly according to the procedure for Example 13 except that there was no acetic acid and the 4.6 mol of triethylamine was replaced with 9.2 mole of imidazole. The amount of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reaction mixture was found to be 92percent
85%	Stage #1: With acetic acid In acetonitrile for 0.25 h; Stage #2: With 1H-imidazole In water; acetonitrile at 15 - 87℃; for 7.08333 - 10.8333 h;	Example 16; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; Example 16 was prepared similarly according to the procedure for Example 13 except that the 4.6 mol of triethylamine was replaced with 9.2 mole of imidazole. The amount of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reaction mixture was found to be 85percent.

84%	Stage #1: With acetic acid In acetonitrile for 0.25 h; Stage #2: With triethylamine In water; acetonitrile at 15 - 87℃; for 7.08333 - 10.8333 h;	Example 13; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; According to Scheme E A mixture of 3-aminophthalic acid hydrochloride (200 g, 0.92 mol, from Prosynth Ltd., Suffolk, UK), 3-aminoglutarimide hydrochloride (159 g, 0.96 mol, from Evotec OAI, Hamburg, Germany), acetonitrile (2.0 L), and acetic acid (577 g, 9.6 mol, from Fisher Scientifc) was charged into a reaction vessel. After the mixture was stirred for 15 minutes, triethylamine (465.0 g, 4.6 mol, from Aldrich, Milwaukee, Wis.) was added dropwise over 30-35 minutes while the reaction temperature was maintained at 20-25° C. Next, the reaction mixture was stirred further for 10-15 minutes and then refluxed at about 85 to 87° C. for about 5 to 7 hours or until the in-process control, i.e., HPLC AP at 240 nm, indicates that <2percent of the 3-aminophthalic acid remained in the reaction mixture. After the reaction mixture was cooled to about 20 to 25° C. over 1-2 hours, 1.0 L of water was charged over 15-30 minutes at about 20 to 25° C. The resulting mixture was stirred at about 15 to 20° C. for about 20 to 30 minutes to provide a yellow solid precipitate, which was filtered, washed with DI water (3.x.1.0 L) and acetonitrile (2.x.500 mL), and then dried at about 35 to 40° C in vacuo to a constant weight at 210.0 g (84 percent).
68.5%	With acetic acid; triethylamine In acetone at 80 - 85℃; for 6 h;	Acetonitrile (100 mL), acetic acid (26.28 mL, 459.5 mmol),Triethylamine (31.85 mL, 229.8 mmol), 3-aminophthalic acid hydrochloride (10 g, 46.0 mmol),Aminopiperidine-2,6-dione hydrochloride (7.68 g, 46.6 mmol)Added to the reaction flask, heated to 80 ~ 85 ° C reflux, the reaction was complete after 6h,The reaction solution was cooled to 20 ~ 25 ° C, purified water was slowly added, the crystallization was stirred for 2h, filtered, the filter cake was dried under reduced pressure at 60 ± 5 ° C for 8h to obtain 8.6g black solid, yield 68.5percent

Reference： [1] Patent: US2007/4920, 2007, A1, . Location in patent: Page/Page column 13
[2] Patent: US2007/4920, 2007, A1, . Location in patent: Page/Page column 13-14
[3] Patent: US2007/4920, 2007, A1, . Location in patent: Page/Page column 14
[4] Patent: US2007/4920, 2007, A1, . Location in patent: Page/Page column 13
[5] Patent: CN107325075, 2017, A, . Location in patent: Paragraph 0029; 0030; 0031

4
[ 530-62-1 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: at 40 - 45℃; Stage #2: for 4.5 h; Heating / reflux	To a round bottom flask equipped with a mechanical stirrer, a condenser, a nitrogen inlet and a heating mantel was charged with a mixture of acetonitrile (42 L) and N-(3-aminophthaloyl)-glutamine (2120 g, 7.28 moles). After the mixture was stirred and heated to 40-45° C., 1,1'-carbonyldiimidazole (1290 g, 7.95 moles) was added. The reaction mixture was stirred and refluxed for 4.5 hours. The progress of the reaction was monitored by HPLC using a Waters Nova-Pak C18 column (3.9.x.150 mm, particle size=4 micron, UV wavelength=240 nm, retention time=3.64 minutes) and a 20/80 mixture of acetonitrile and 0.1percent aqueous H₃PO₄by volume as an eluent at a flow rate of 1 mL/min. After cooled to room temperature, the reaction mixture was filtered to yield a yellow solid which was subsequently washed with acetonitrile (6.5 L). The yellow solid was air dried and then dried in a vacuum oven at 60° C. and a pressure <1 mm to yield 1760 g (88percent) of the product. The product purity was found to be 99.57percent by HPLC using a Waters Nova-Pak C18 column (3.9.x.150 mm, particle size=4 micron, UV wavelength=240 nm, retention time=3.64 minutes) and a 20/80 mixture of acetonitrile and 0.1percent aqueous H₃PO₄by volume as an eluent at a flow rate of 1 mL/min. The product in DMSO-d₆was characterized by a ¹H NMR spectrum showing the following chemical shifts (δ in ppm): 11.10 (s, 1H), 7.47(t, J=7.9 Hz, 1H), 7.03-6.99 (dd, J=4.8 and 8.4 Hz, 2H), 6.52 (s, 2H), 5.09-5.02 (dd, J=5.3 and 12.4 Hz, 1H), 2.96-2.82 (m, 1H), 2.62-2.46 (m, 2H), 2.07-2.00 (m, 1H); and by a ¹³C NMR spectrum showing the following chemical shifts (δ in ppm): 172.82, 170.11, 168.57, 167-37, 146.71, 135.46, 131.99, 121.70, 110.97, 108.52, 48.47, 30.97, 22.14. The melting point of the product was found to be 315.5-317.5° C. An elemental analysis yielded the following results in weight percent: C, 56.98; H, 3.86; N, 15.35, which compared with calculated values for C₁₃H₁₁N₃O₄, in weight percent: 57.14; H, 4.06; N, 15.38.

Reference： [1] Patent: US2007/155791, 2007, A1, . Location in patent: Page/Page column 14-15

5
[ 340020-02-2 ]
[ 2353-44-8 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
96.6%	With sodium acetate In acetonitrile for 4 h; Reflux	40.0 g (170.8 mmol) of ethyl 4-amino-1,3-dioxo-1,3-dihydro-2H-isomdole-2-carboxylate, 800 cm³ of acetonitrile, 28.4 g (342.0 mmol) of anhydrous sodium acetate, 28.1 g (170.7 mmol) of 3-aminopiperidine-2,6-dione are measured into a 1000 cm³ round-bottomed flask, then the suspension obtained in this way is heated to reflux temperature. The stirring is continued at unchanged temperature for 4 hours. The reaction mixture is concentrated to about 40 cm³ at 40 °C with the help of a vacuum. 800 cm³ of distilled water is added to the concentrated residue, which is then stirred at room temperature for 30 minutes. (The water may also be added at an earlier stage.) Following this the crystalline product is filtered, washed with 2x400 cm³ of distilled water, then dried at 50 °C in a vacuum until constant weight is achieved. In this way 45.10 g (96.6percent) of the product according to the title is obtained. Mp. : 314-315 °C (decomposes) IR (KBr): 3481 , 3378, 3248, 1752, 1703, 1635, 1362, 1197 cm ¹. 1H NMR (DMSO-d6, 400 MHz): δ = 11.10 (b, 1H), 7.47 (m, 1H), 7.02 (m, 1H), 7.00 (m, 1H), 5.06 (m, 1H), 2.89 (m, 1H), 2.58 (m, 1H), 2.56 (m, 1H), 2.03 (m, 1H) ppm. HPLC: Waters Acquity UPLC BEH C18; 2.1 x50 mm; 1.7 μm; 0.5 mL/min; 225 nm; 10/90 CH₃CN/0.1 percent HClO₄ (aq); 1.38 min (99.90percent).

Reference： [1] Patent: WO2017/134476, 2017, A1, . Location in patent: Page/Page column 16

6
[ 24666-56-6 ]
[ 19171-19-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630
[2] Patent: CN103724323, 2016, B,
[3] Patent: CN103724323, 2016, B,
[4] Patent: CN103724323, 2016, B,
[5] Patent: CN103724323, 2016, B,

7
[ 641-70-3 ]
[ 19171-19-8 ]

Reference： [1] Patent: US2013/143922, 2013, A1,
[2] Synthetic Communications, 2016, vol. 46, # 16, p. 1343 - 1348
[3] Synthetic Communications, 2016, vol. 46, # 16, p. 1343 - 1348
[4] Patent: CN103724323, 2016, B,
[5] Patent: CN103724323, 2016, B,
[6] Patent: CN103724323, 2016, B,
[7] Patent: CN103724323, 2016, B,
[8] Patent: CN107365295, 2017, A,
[9] ACS Chemical Biology, 2018, vol. 13, # 9, p. 2771 - 2782
[10] Bioorganic Chemistry, 2018, vol. 81, p. 536 - 544

8
[ 17395-99-2 ]
[ 31140-42-8 ]
[ 19171-19-8 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 15, p. 1508 - 1512

9
[ 2650-64-8 ]
[ 19171-19-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630

10
[ 24666-55-5 ]
[ 19171-19-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630

11
[ 603-11-2 ]
[ 19171-19-8 ]

Reference： [1] Synthetic Communications, 2016, vol. 46, # 16, p. 1343 - 1348
[2] Synthetic Communications, 2016, vol. 46, # 16, p. 1343 - 1348
[3] Patent: CN104402863, 2016, B,
[4] Patent: WO2017/221261, 2017, A1,

12
[ 19171-18-7 ]
[ 67-64-1 ]
[ 19171-19-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 3, p. 878 - 881

13
[ 617-65-2 ]
[ 19171-19-8 ]

Reference： [1] Patent: CN107365295, 2017, A,

14
[ 18636-08-3 ]
[ 19171-19-8 ]

Reference： [1] Patent: CN107365295, 2017, A,

15
[ 85535-45-1 ]
[ 19171-19-8 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 15, p. 1508 - 1512

16
[ 116-69-8 ]
[ 19171-19-8 ]

Reference： [1] Patent: CN108276380, 2018, A,

17
[ 31140-42-8 ]
[ 19171-19-8 ]

Reference： [1] ACS Chemical Biology, 2018, vol. 13, # 9, p. 2771 - 2782

[ 19171-19-8 ] Synthesis Path-Downstream 1~88

1
[ 19171-18-7 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With 5%-palladium/activated carbon; hydrogen; In N,N-dimethyl-formamide; for 24h;	To 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (2.7g, 8.91 mmol) was added dry DMF (50 mL) followed by addition of 5% Pd/C (300 mg). The reaction mixture was stirred under hydrogen atmosphere for 24h. Reaction was filtered through celite and concentrate to yield as a green solid. The crude was dissolved in ethyl acetate and refluxed for 30 minutes, cooled and filtered to yield 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2.3 g, 94% ).1H NMR (500 MHz, DMSO-d6) delta 11.08 (s, 1H), 7.47 (t, 2H, 8.0 Hz), 6.52 (br, 1H), 5.04 (dd, 1H, 5, 40 Hz), 2.91 - 2.84 (m, H), 2.60 - 2.50 (m, 2H), 2.03 - 2.00 (m, 1H). 13C NMR (125 MHz, DMSO-d6) delta 172.36, 169.64, 168.10, 166.91, 146.24, 135.01, 131.51, 121.24, 110.54, 108.06, 48.01, 30.49, 21.67.
94%	With palladium 10% on activated carbon; hydrogen; acetic acid; In N,N-dimethyl-formamide; at 30 - 40℃; under 18751.9 - 26252.6 Torr;Large scale;	Compound 4 (3.03 g, 10.0 mmol) was dissolved in 120 mLIn N,N-dimethylformamide,Add 4 mL of acetic acid and 0.14 g of 10% Pd/C and transfer to a hydrogenation vessel.Keep the temperature of the reaction solution at 30-40 C, hydrogen pressure 2.5-3.5 MPa,The reaction was carried out for 10-12 h, and the reaction end point was determined by HPLC. At the end of the reaction, diatomaceous earth is filtered to remove palladium carbon.1.2g of activated carbon was added to the filtrate, stirred for 0.5 h, and suction filtered.46mL of pure water was added to the filtrate.Stir for 1-2 h, suction filtration, and filter cake washed twice with water.Drying at 50-60 C for 10-12 h, giving 2.59 g of crude pomrabiamine.Yield: 95%.Pomhexamine recrystallization refining method:The crude pomamide (2.73 g, 10 mmol) was dissolved in 45 mL of dimethyl sulfoxide.The mixture was dissolved by stirring at 20-25 C, and the insoluble matter was filtered off, and 165 mL of methanol was added dropwise to the filtrate.Stir the crystal for 3-4 h. Filtering, filter cake washed with 70-80 C pure water 2-3 times,Drain and dry the solid at 50-60 C for 10-12 h to give a pale yellow solid(Compound 1)2.56g,The yield is 94%.HPLC: purity was 99.55%.
93.3%	With palladium 10% on activated carbon; hydrogen; In water; N,N-dimethyl-formamide; at 35℃; under 760.051 Torr; for 3h;	To the reaction flask was added 33-nitro-N-(2,6-dioxo-3-piperidinyl)phthalimide (II) (100.0g, 0.33mol), 10% palladium on carbon 12.0g, DMF 1000ml, 70ml water, vacuum, hydrogen gas was introduced (replacement three times), the reaction normal pressure at 35 C for 3h, TLC monitored the reaction was completed, the palladium carbon was filtered off, the DMF solution was slowly added to 5-fold amount of water, stirring about 30min, then the solid was filtered, the filter cake was washed with an appropriate amount of water (2L * 3 times, 30min/time), the filter cake was washed with 200ml of ethanol, and the solid was transferred to a one-neck 3L flask was charged with 2L of ethyl acetate at 73 C stirred 0.5h, filtered hot and the solid was dried at 45 C to constant weight to give a yellow solid powder 84.1g, a yield of 93.3%. % HPLC purity 99.9,

91%	With palladium on activated charcoal; hydrogen; In 1-methyl-pyrrolidin-2-one; at 45℃; under 2250.23 Torr;	(1) 100g 3-nitro-N-(2,6-dioxo-3-piperidinyl)phthalimide, 10g of the palladium-carbon and 1000 ml N-methylpyrrolidone were added into a 2000 ml hydrogenation reactor. Vacuum. After nitrogen replacement 3 times, place hydrogen gas, regulating the reactor pressure to 0.3 MPa, control temperature at 45 C. After the reaction is complete, filtering, the filtrate by adding 30g charcoal, heating up to 70 C, stirring 3 hours, filtered;(2) to the step (1) and the finally obtained by adding sodium carbonate aqueous solution in the filtrate (2g sodium carbonate dissolved in 10 ml purified water to prepare water), stirring at room temperature for 0.5 hours, then slowly dropping 2000 ml purified water, lowering the temperature to 10 C crystallization, filtered, the filter cake is added to 500 ml of purified water, stirring at room temperature for 0.5 hours, filtered, washed with water purification cake, solid 60 C obtained by vacuum drying the yellow powdery solid 82g, yield 91%. HPLC detection the purity is 99.88%.
80%	With palladium 10% on activated carbon; hydrogen; In N,N-dimethyl acetamide; at 30℃; for 7h;	Add 5 g of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline and 0.4 g of 10% palladium carbon to 50 mL of N,N - in dimethylacetamide,The hydrogenation reaction is then carried out at 0.45 MPa at 30 C.Lasted 7 hours,Filter to remove the catalyst,The filtrate was concentrated under vacuum.The concentrate was beaten with water overnight.Obtained 3.6 g of a yellow solid.That is, the target compound.Yield 80%,The purity measured by HPLC was 99.4%.
79.5%	With palladium 10% on activated carbon; hydrogen; In 1,4-dioxane; at 60 - 65℃; for 6h;	In a mixer equipped with a mechanical stirrer, A thermometer and a ventilator was charged with 31.7 g (wet product 48.2 g, 0.105 mol, 1.0 eq) 3-nitro-N-(2,6-dioxo-3-piperidinyl) phthalimide,1.6 g of 10% palladium on carbon and 395 mL of solvent 1,4-dioxane,Stirring to form a suspension of hydrogen gas bubbling, bubbling speed 1 times / second, the temperature of the reaction solution to 60 ~ 65 C, continue stirring for 6 hours, HPLC control: to be raw materials and intermediate content <0.5% The filtrate was concentrated under reduced pressure and 158 mL of ethyl acetate was added to the residue. The mixture was stirred for 2 hours and then filtered. The cake was transferred to another 500 mL reaction flask and 158 mL of N , N-dimethylformamide, heating to 55 ~ 60 C stirring, 55 ~ 60 C drop 316 mL of purified water, heating to 70 ~ 75 C for 2 hours, cooling to a temperature of 30 ~ 35 C, filter, wet goods to vacuum drying oven 50 ~ 55 C drying, 3-amino-N - (2,6-dioxo-3-piperidyl) phthalimide 22.7 G, pale yellow powdery solid, yield 79.5%, m.p. 315.0~318.0 C (DSC). The purity of the product was 99.73% by HPLC, with a single impurity <0.10%, of which 13% UV retention time = 11.5 min.), And using 0.1% (v (v / v)) as the mobile phase, / Nu) phosphoric acid aqueous solution and acetonitrile as a mobile phase at a flow rate of 1.0 ml / min.
77.7%	With hydrogen; In 1,4-dioxane; water; at 20 - 25℃; under 3620.13 Torr; for 60h;	A round bottomed flask was charged with 1,4-dioxane (600 ml) and 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (10 g). The mixture was stirred at 25 C. to 30 C. for 15 minutes, the temperature was raised up to 80 C. and the reaction mass stirred to obtain a clear solution. To the clear solution activated charcoal (5 g) was added at 80 C., the mixture stirred and the solution cooled to 25 C. to 30 C. The reaction mass was further stirred for 20 minutes at this temperature and filtered. To the obtained solution 1,4-dioxane (300 ml), water (180 ml) and Raney nickel (0.5 g) were added. The reaction mixture was stirred at 20 C. to 25 C. under 70 psi hydrogen pressure for 12 hrs. Raney nickel (0.5 g) was added to the reaction mixture at 20 C. to 25 C. and the reaction continued at the same temperature and pressure for 12 hrs. Another portion of Raney nickel (0.5 g) was added to the reaction mixture and the reaction continued at the same temperature and pressure for 12 hr. Another portion of Raney nickel (0.5 g) was added to the mixture and the reaction continued at the same temperature and pressure for 12 hr. Another portion of Raney nickel (0.5 g) was added to the reaction mixture and the reaction continued at the same temperature and pressure for 12 hr. The reaction mixture was then filtered through a celite bed and the solvent was distilled off from the reaction mixture under vacuum at 50 C. to obtain a solid. To the solid obtained 1,4-dioxane (50 ml) and ethyl acetate (5 ml) were added and the mixture was heated to 80 C. with stirring for 1 hr. The reaction mass was filtered at 80 C. and the obtained cake washed with 1,4-dioxane (10 ml) at 80 C. To the wet cake ethyl acetate (100 ml) was added and the mixture was refluxed with stirring for 1 hr. Then the reaction mass was cooled to 25 C. to 30 C., the solid filtered, washed with ethyl acetate (20 ml) and dried under vacuum to get 4-amino-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (7 g). Yield: 77.7% Purity: 99%.
64.5%	With palladium 10% on activated carbon; hydrogen; In N,N-dimethyl acetamide; at 40℃; for 16h;	To a solution of 2-(2,6-dioxo-3-piperidyl)-4-nitro-isoindoline-1,3-dione (43.0 g, 142 mmol) in DMA (1.5 L) was added Pd/C (15.0 g, 14.1 mmol, 10% Pd) under a blanket of N2. The mixture was degassed under vacuum and purged with H2 (3*). The purged mixture was stirred at 40 C. under an atmosphere of H2 (40 psi) for 16 hours. The reaction mixture was purged with N2, filtered and the filtrate was concentrated under vacuum. The residual solid was washed with ethyl acetate (200 mL) and dried under vacuum to give 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione as a yellow solid (75 g, 64.5% yield). 1H NMR (400 MHz DMSO-d6) delta ppm 11.07 (s, 1H), 7.46 (d, J=6.4 Hz, 1H), 7.00 (t, J=7.0 Hz, 2H), 6.51 (br s, 2H), 5.06-5.01 (m, 1H), 2.93-2.89 (m, 1H), 2.60-2.49 (m, 2H), 2.03-2.00 (m, 1H).
46%	With triethylsilane; potassium fluoride; palladium diacetate; In tetrahydrofuran; water; at 20℃; for 1h;	A solution of 2-(2,6-dioxopiperidin-3 -yl)-4-nitroisoindoline- 1,3 -dione (173 mg, 0.854 mmol), Pd(OAc)2 (12.8 mg, 0.0854 mmol, 10 mol%) and potassium fluoride (66 mg, 1.71 mmol, 2 equiv) in THF:water (8:1) (5.7 mL, 0.1 M) was stirred at room temperature. Triethylsilane (3651iL, 3.41 mmol, 4 equiv) was added slowly, and the resulting black solution was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of celite, which was washed excessively with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (CH2C12:MeOH (7:1)) to afford the titlecompound as a yellow powder (72 mg, 46%). 1H NMR (500 IVIHz, DMSO-d6) 11.08 (s, 1H),7.47 (dd, J 8.5, 7.0 Hz, 1H), 7.06 - 6.95 (m, 1H), 6.59 -6.44 (m, 1H), 5.04 (dd, J= 12.7, 5.4Hz, 1H), 2.93 - 2.82 (m, 1H), 2.64 - 2.45 (m, 2H), 2.05 - 1.98 (m, 1H); MS (ESI) calcd forC13H11N304 [M+H] 274.08, found 274.23.
46%	With triethylsilane; potassium fluoride; palladium diacetate; In tetrahydrofuran; water; at 20℃; for 1h;	A solution of 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (173 mg, 0.854 mmol), Pd(OAc)2 (12.8 mg, 0.0854 mmol, 10 mol%) and potassium fluoride (66 mg, 1.71 mmol, 2 equiv) in THF:water (8:1) (5.7 mL, 0.1 M) was stirred at room temperature. Triethylsilane (365 muL, 3.41 mmol, 4 equiv) was added slowly, and the resulting black solution was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of celite, which was washed excessively with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (CH2Cl2:MeOH (7:1)) to afford the title compound as a yellow powder (72 mg, 46%). 1H NMR (500 MHz, DMSO-d6) delta 11.08 (s, 1H), 7.47 (dd, J = 8.5, 7.0 Hz, 1H), 7.06- 6.95 (m, 1H), 6.59- 6.44 (m, 1H), 5.04 (dd, J = 12.7, 5.4 Hz, 1H), 2.93- 2.82 (m, 1H), 2.64- 2.45 (m, 2H), 2.05- 1.98 (m, 1H); MS (ESI) calcd for C13H11N3O4 [M+H]+ 274.08, found 274.23.
44.4%	With iron; ammonium chloride; In ethanol; water; at 20℃;	9 (410.0 mg, 1.4 mmol), NH4Cl(360.0 mg, 7.0 mmol) and iron powders (380.0 mg, 7.0 mmol) weremixed in a EtOH/H2O (v:v=7:3) solution (40 mL). The resultingmixture was kept stirring at room temperature overnight. Then saturatedNaHCO3 solution was added to the reaction mixture which wasthen extracted with ethyl acetate. The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure togive compound 10 as a yellow powder (Yield: 163.0 mg, 44.4%). ESIMS:calcd m/z=273.07, found [M+H]+=274.07, [M+Na]+=296.05 and [2 M+Na]+=569.12 . 1H NMR (ppm,400 MHz, DMSO-d6): delta 11.11 (s, 1H), delta 7.47 (q, J=6.0 Hz, 1H), delta 7.01(q, J=6.0 Hz, 2H), delta 6.54 (s, 2H), delta 5.05 (q, J=10.0 Hz, 1H), delta 2.89(m, 1H), delta 2.57 (m, 2H), delta 2.02 (m, 1H). 13C NMR (ppm, 100 MHz,DMSO-d6): delta 173.32, 170.63, 169.04, 167.85, 147.19, 135.94, 132.47,122.18, 111.46, 108.97, 48.95, 31.46, 22.62
	With palladium 10% on activated carbon; hydrogen; In methanol; dichloromethane; at 20℃; for 7h;	3. Pomalidomide (9) A mixture of 2-(2,6-dioxopiperidine-3-yl)-4-nitrophthalimide (7) (66.0 mg, 0.2 mmol) and palladium on activated carbon (10 wt. %, 45.0 mg) in methanol (80.0 mL) was shaken under an atmosphere of hydrogen (44 lbs) at room temperature for 7.0 h. Thereafter, the catalyst was filtered through Celite and the filtrate was concentrated by rotary evaporator. The residue was purified by chromatography using CH2Cl2:methanol as the eluent to afford compound (9).
136 g	With palladium 10% on activated carbon; hydrogen; In N,N-dimethyl-formamide; at 20℃; for 3h;	Dimethylformamide (1500 ml) was added to 3-(4-nitro-l-oxoisoindolin-2- yl)piperidine-2,6-dione (150 gm) and then stirred for 30 minutes at room temperature to obtain a clear solution. To the solution was added 10% palladium carbon and then applied 4 Kg of hydrogen pressure at room temperature. The reaction mass was stirred for 3 hours at room temperature and temperature of the reaction mass was raised to 60 to 65C. The reaction mass was filtered through hi-flow bed and then concentrated to obtain a residual solid. To the residual solid was added ethyl acetate (600 ml) and then heated to reflux. The reaction mass was maintained for 30 minutes at reflux and then cooled to room temperature. The contents were stirred for 1 hour at room temperature and filtered. The solid obtained was then dried to obtain 136 gm of pomalidomide. Chromatographic purity: 97.5%.
8.2 g	With palladium 10% on activated carbon; hydrogen; In N,N-dimethyl-formamide; under 760.051 Torr;Inert atmosphere;	Example 3: Synthesis of 4-amino-2-(2,6-dioxopiperidin-3-yl)-isoindoIine-l,3-(lione (Pomalidomide) Catalyst palladium (10%) on carbon (0.5 g. or 5% w/w of substrate ) was added to a stirred solution of 3-nitrophthalidomide (10 g or 0.033 mole) (Example 1 ) in N,N- dimethyl formamide (100 ml) maintained under nitrogen. Hydrogen gas was bubbled through the reaction mixture at atmospheric pressure. After completion of hydrogenation reaction, as monitored by TLC, hydrogen bubbling was stopped and the catalyst was separated by filtration of the reaction mixture on celite bed. The filtrate was distilled at 60 to 65 C under reduced pressure until half of the solvent was removed. The solution was then cooled at ambient temperature and methanol (50 ml) was added while stirring. The solid obtained was filtered, washed with methanol (50 ml), and suck dried to obtain pomalidomide 8.2 g (90% molar yield) having HPLC purity > 99.0%.
216.7 g	With iron; at 105℃; for 5h;	Add 240g iron powder in batches,Control reaction temperature does not exceed 105 stirring reaction 5 hours,Cool to room temperature.filter,Filter cake washed with water,And then washed with sodium bicarbonate solution,After filtration, the crude product.The crude product was dissolved in 2400 ml of dimethylsulfoxide,filter.Add water to the filtrate,The precipitated solid was collected by filtration,Dry at 60 for 4 h.216.7 g of a yellow solid, yield: 79.3%, purity: 99.93%.
3.7 g	With palladium 10% on activated carbon; hydrogen; In N,N-dimethyl acetamide; at 30℃; under 3000.3 Torr; for 6h;	5 g of 1,3-dioxo-2- (2,6-dioxopiperidin-3-yl) -5-nitroisoindoline 10% palladium carbon 0.4g mixed into 70 mL of N, N-dimethylacetamide, The hydrogenation reaction was then carried out at 0.4 MPa, The reaction temperature was 30 C, Lasted 6 hours, Filter out the catalyst, The filtrate was concentrated in vacuo, The residue was beaten overnight at 40 C with 40 mL of water, Get 3.7g Yellow-green solid of thalidomide crude. HPLC with a purity of 99.0%.
	With palladium 10% on activated carbon; hydrogen; In 1,4-dioxane; methanol; at 35℃;Industrial scale;	N,N-Dimethylformamide (50kg) was drawn into the reactor.Glutamic acid (32 kg), 3-nitrophthalic anhydride (40 kg) was added under stirring, followed by heating and reaction at 95-100C for 3 hours.Then, N,N-dimethylformamide was evaporated under reduced pressure, acetic anhydride (50 kg) was added with cooling, and the mixture was heated to 100-110 C. for 1 hour. The excess anhydride was distilled off under reduced pressure. DMSO (400 L) was added and the reaction was heated to 200C,Ammonia was slowly introduced under stirring. After the reaction was complete, methanol (800 L) was added to cool to room temperature, the crystals were centrifuged, and dried to obtain 3-nitrophoramide (62.76 kg) in a yield of 71%. Purity 99.99%.3-nitrophoramide (30kg) was dissolved in 1,4-dioxanemethanol=300L300L, 10% palladium on carbon, 35C, 0.4M,Hydrogenation to the completion of the reaction, pressure filter, concentrated under reduced pressure, add DMF (300L) dissolved, isopropyl ether (600L) crystallization, centrifugedThe yellow product was recrystallized from ethanol to obtain high-purity pomametide. HPLC: 99.84%.
85 g	With palladium 10% on activated carbon; hydrogen; In N,N-dimethyl-formamide; at 15 - 20℃;	In to a well cleaned and oven dried 3 .OL 4neck RB flask, to a mechanical stirrer and equipped with thermometer socket, condenser (fitted with gas outlet dipped in to the water), gas-inlet(connected with single trap filled with dimethylfonnamide up to bubbling nossile), 100.Og of 2-(2, 6-dioxo-3 -piperidyl)-4-nitro-isoindoline- 1, 3 -dione, 1 550.Oml of dimethylformamide were charged. Reaction mass was stirred for 10-15mm at 25-35C, clear solution was observed. 13.0g of 10% Pd/c was charged in to the reaction mass, in presence of N2 gas atmosphere, washing was given with 50.0 ml of dimethylfonnamide. H2 gas was bubbled in to the reaction mass, for 6.5-7.0 hours, at 15-20C. After completion of reaction, eaction mass is filtered under vacuum, through hyflow, in presence of N2 gas atmosphere, washing is given with 300.Oml of dimethylfonnamide. Filtrate is transferred in to a 5.OL 4 neck RB flask. Slowly added DM Water (1900.0m1) to the reaction mass over a period of 45-60mm at 15-20C, Stirred the reaction mass at 15-20C for 60-90mm. Solid reaction mass was filtered under vacuum, washing was given with 200.Oml DM Water, suck dried for 45-60mm. wet compound is dried in a vacuum oven at 60-650C, under vacuum (600-65OmmJHg) for 2-3hours and characterized as form A of pomalidomide.Yield: 85.0 g
	With palladium 10% on activated carbon; hydrogen; In N,N-dimethyl-formamide; at 25 - 30℃; under 2250.23 - 2625.26 Torr;	10% Palladium on carbon (50% wet; 5 g) was added to a solution of 2-(2,6- dioxopiperidin-3-yl)-4-nitro-lH-isoindole-l,3(2H)-dione (100 g; Formula II; obtained in Example 2) in N, N-dimethylformamide (1000 mL). The solution was hydrogenated with 3.0 kg/cm2 to 3.5 kg/cm2 hydrogen pressure for 2 hours to 3 hours at 25C to 30C. The catalyst was removed by filtration and the filtrate was treated with activated carbon. The filtrate was heated to 50C to 55C and then water was added slowly at 50C to 55C to obtain a slurry. The slurry was slowly cooled to 25 C to 30C and then stirred for 30 minutes at 25C to 30C. The slurry was filtered to obtain a wet solid. The wet solid was dried at 50C to 55C under reduced pressure to obtain the title compound. (0079) Yield: 85 g (94%)
	With palladium 10% on activated carbon; hydrogen; In water; N,N-dimethyl-formamide; at 20℃; under 3102.97 Torr; for 18h;	To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (29a, 10.0 g, 33.00 mmol) in DMF:H20 (9: 1, 75 mL) was added 10 % Pd/C (2.0 g). The reaction was performed in par shaker at 60 psi under hydrogen atmosphere at RT for 18 h. After completion of the reaction (monitored by TLC) the reaction mixture was filtered though celite. Then cold water was added to the filtrate to get the solid which was filtered off and dried under vacuum to afford the title compound (5.50 g, 61.1 %) which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) d 11.07 (bs, 1H), 7.46 (t, / = 6.8 Hz, 1H), 7.00 (t, / = 8.0 Hz, 2H), 6.51 (bs, 2H), 5.06-5.01 (m, 1H), 2.89-2.84 (m, 1H), 2,60-2.54 (m, 2H), 2.03-2.0 (m, 1H); LC-MS: m/z 274.1 (M+l)+.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 1375 - 1379
[2]Patent: CN109553603,2019,A .Location in patent: Paragraph 0017; 0019; 0020; 0021; 0023-0025; 0027; 0028
[3]Patent: CN105348257,2016,A .Location in patent: Paragraph 0051; 0052; 0053
[4]Patent: CN106565668,2017,A .Location in patent: Paragraph 0053; 0054; 0055; 0056-0061
[5]Patent: CN104557858,2018,B .Location in patent: Paragraph 0032; 0033; 0036; 0038; 0040; 0042; 0044; 0046
[6]Patent: CN103804350,2016,B .Location in patent: Paragraph 0029; 0031
[7]Patent: US2017/260157,2017,A1 .Location in patent: Paragraph 0057; 0058; 0059; 0060; 0061; 0062; 0063
[8]Synthetic Communications,2016,vol. 46,p. 1343 - 1348
[9]Patent: US2019/322647,2019,A1 .Location in patent: Paragraph 0188; 0190
[10]Patent: WO2018/148440,2018,A1 .Location in patent: Page/Page column 297; 300; 301
[11]Patent: WO2018/148443,2018,A1 .Location in patent: Page/Page column 281-282
[12]Bioorganic Chemistry,2018,vol. 81,p. 536 - 544
[13]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630
[14]Chemical and Pharmaceutical Bulletin,2006,vol. 54,p. 855 - 860
[15]Patent: US6335/349,2002,B1 .Location in patent: Example 1
[16]Patent: US2013/143922,2013,A1 .Location in patent: Paragraph 0091
[17]Patent: WO2014/170909,2014,A2 .Location in patent: Page/Page column 5
[18]Patent: WO2015/75694,2015,A1 .Location in patent: Page/Page column 2; 4; 9
[19]Patent: CN104402863,2016,B .Location in patent: Paragraph 0035
[20]Patent: CN107188884,2017,A .Location in patent: Paragraph 0019; 0033; 0034; 0036
[21]Patent: CN107365295,2017,A .Location in patent: Paragraph 0014; 0015
[22]Patent: WO2017/221261,2017,A1 .Location in patent: Page/Page column 5; 6
[23]Patent: WO2018/154516,2018,A1 .Location in patent: Page/Page column 8
[24]ACS Chemical Biology,2018,vol. 13,p. 2771 - 2782
[25]Patent: WO2019/207538,2019,A1 .Location in patent: Page/Page column 111

2
[ 641-70-3 ]
(+-)-2-methyl-pentanol-⁽¹⁾ [ No CAS ]
[ 19171-19-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630

3
[ 2650-64-8 ]
[ 19171-19-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630

4
[ 24666-56-6 ]
[ 19171-19-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630
[2]Patent: CN103724323,2016,B
[3]Patent: CN103724323,2016,B
[4]Patent: CN103724323,2016,B
[5]Patent: CN103724323,2016,B
[6]Patent: WO2019/191112,2019,A1

5
[ 24666-55-5 ]
[ 19171-19-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630

6
[ 98-01-1 ]
[ 19171-19-8 ]
[ 444287-71-2 ]

Yield	Reaction Conditions	Operation in experiment
0.25 g (35%)	With sodium borohydrid; In acetic acid; ethyl acetate;	2-(2,6-Dioxo(3-piperidyl))-4-[(2-furylmethyl)amino]isoindoline-1,3-dione I-28 To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in acetic acid (20 ml) was added furan-2-carbaldehyde (0.20 g, 2.05 mmol). The mixture was heated to reflux for 5 hours and allowed to cool at room temperature. Sodium borohydride (80 mg, 2 mmol) was added to the reaction mixture. The reaction mixture was stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml), washed with H2O (3100 ml), saturated aqueous NaHCO3 (2100 ml), brine (1*100 ml), and dried. The solvent was evaporated and the residue was purified by chromatography (ethyl acetate/hexane, 1:1) to give 0.25 g (35%) of product as a yellow solid: mp 171-173 C.; 1H NMR (DMSO-d6) delta11.10 (s, 1H), 7.58 (t, J=7.1 Hz, 2H), 7.18 (d, J=8.6 Hz, 1H), 7.08-6.97 (m, 2H), 6.39-6.36 (m, 2H), 5.06 (dd, J=5.2 and 12.4 Hz, 1H), 4.57 (d, J=6.0 Hz, 2H), 2.96-2.82 (m, 1H), 2.63-2.46 (m, 2H), 2.06-2.02 (m, 1H; 13C NMR (DMSO-d6) delta172.76, 170.01, 168.75, 167.21, 151.97, 145.81, 142.42, 136.05, 132.09, 117.60, 111.04, 110.42, 109.73, 107.38, 48.57,30.95,22.10; Anal. Calcd. For C18H15N3O5: C, 61.19; H, 4.28; N, 11.89. Found: C, 61.02; H, 4.24; N, 11.81.

Reference： [1]Patent: US2003/96841,2003,A1

7
[ 5271-67-0 ]
[ 19171-19-8 ]
N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-2-thienylcarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.50 g (65%)	In tetrahydrofuran; diethyl ether;	N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-2-thienylcarboxamide I-33 To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55g, 2.0 mmol) in THF (30 ml) was added thiophene-2-carbonyl chloride (0.59 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. To the reaction mixture was added additional thiophene-2-carbonyl chloride (0.30 g, 2 mmol). The mixture was heated to reflux for an additional 8 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give an of off-white solid which was recrystallized from acetic acid to give 0.50 g (65%) of product: mp 284-286 C.; 1H NMR (DMSO-d6) delta11.19 (s, 1H), 10.34 (s, 1H), 8.47(d, J=8.3 Hz, 1H), 7.98-7.86 (m, 3H), 7.68 (d, J=7.3 Hz, 1H), 7.29 (dd, J=4.0 and 4.8 Hz, 1H), 5.19 (dd, J=5.4 and 12.6 Hz, 1H), 2.99-2.85 (m, 1H), 2.67-2.49(m, 2H), 2.12-2.08 (m, 1H); 13C NMR (DMSO-d6) delta172.72, 169.69, 167.96, 166.60, 159.67, 138.02, 136.26, 136.19, 133.26, 131.42, 129.91, 128.58, 126.42, 118.82, 117.94, 49.00, 30.93, 22.00; Anal. Calcd. For C18H13N3O5S: C, 55.77; H, 3.54; N, 10.60. Found: C, 55.67; H, 3.36; N, 10.42+0.2 AcOH+0.05 H2O.

Reference： [1]Patent: US2003/96841,2003,A1

8
[ 122-04-3 ]
[ 19171-19-8 ]
[ 444288-17-9 ]

Yield	Reaction Conditions	Operation in experiment
73%	In tetrahydrofuran; methanol;	N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-nitro-benzamide I-68 A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (2.2 g, 8.0 mmol) and 4-nitrobenzoyl chloride (3.0 g, 16.0 mmol) in THF (80 mL) was heated to reflux for 15 h. To the mixture was added methanol (20 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-nitro-benzamide as a white solid (2.5 g, 73% yield): mp, 298-300 C.; 1H NMR (DMSO-d6) delta2.06-2.10 (m, 1H, CHH), 2.49-2.65 (m, 2H, CH2), 2.83-2.98 (m, 1H, CHH), 5.18 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.73 (d, J=7.2 Hz, 1H, Ar), 7.93 (t, J=8.0 Hz, 1H, Ar), 8.19-8.22 (m, 2H, Ar), 8.42-8.47 (m, 3H, Ar), 10.65 (s, 1H, NH), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) delta21.99,30.92, 48.99, 119.30, 119.56, 124.06, 127.49, 129.01, 131.58, 135.77, 136.23, 138.96, 149.69, 163.65, 166.57, 167.48, 169.68, 172.72; Anal Calcd for C20H14N4O7: C, 56.88; H, 3.34; N, 13.27. Found: C, 57.15; H, 3.02; N, 13.22.

Reference： [1]Patent: US2003/96841,2003,A1

9
[ 122-01-0 ]
[ 19171-19-8 ]
[ 444288-12-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	In tetrahydrofuran; methanol;	A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.2 g, 4.5 mmol) and 4-chlorobenzoyl chloride (1.1 mL, 8.8 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with ether (2*10 nmL) then methanol (5 mL) to give 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-benzamide as a white solid (1.5 g, 81% yield): mp, 261-263 C.; 1H NMR (DMSO-d6) delta 2.05-2.09 (m, 1H, CHH), 2.49-2.65 (m, 2H, CH2), 2.83-2.98 (m, 1H, CHH), 5.18 (dd, J=5.5, 12.8 Hz, 1H, NCH), 7.68-7.72 (m, 3H, Ar), 7.89-8.01 (m, 3H, Ar), 8.52 (d, J=8.2, Hz, 1H, Ar), 10.47 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) delta 21.99, 30.92, 48.98, 118.48, 119.06, 126.76, 129.10, 129.29, 131.46, 132.13, 136.28, 137.47, 164.08, 166.60, 167.86, 169.67, 172.72; Anal Calcd for C20H14N3O5Cl+0.2 H2O: C, 57.83; H, 3.49; N, 10.12; Cl, 8.53; H2O, 0.87. Found: C, 57.88; H, 3.33; N, 9.93; Cl, 8.53; H2O, 0.73.
81%	In tetrahydrofuran; methanol;	4-Chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-benzamide I-63 A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.2 g, 4.5 mmol) and 4-chlorobenzoyl chloride (1.1 mL, 8.8 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with ether (2*10 mL) then methanol (5 mL) to give 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-benzamide as a white solid (1.5 g, 81% yield): mp, 261-263 C.; 1H NMR (DMSO-d6) delta2.05-2.09 (m, 1H, CHH), 2.49-2.65 (m, 2H, CH2), 2.83-2.98 (m, 1H, CHH), 5.18 (dd, J=5.5, 12.8 Hz, 1H, NCH), 7.68-7.72 (m, 3H, Ar), 7.89-8.01 (m, 3H, Ar), 8.52 (d, J=8.2, Hz, 1H, Ar), 10.47 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) delta21.99, 30.92, 48.98, 118.48, 119.06, 126.76, 129.10, 129.29, 131.46, 132.13, 136.28, 137.47, 164.08, 166.60, 167.86, 169.67, 172.72; Anal Calcd for C20H14N3O5Cl+0.2 H2O: C, 57.83; H, 3.49; N, 10.12; Cl, 8.53; H2O, 0.87. Found: C, 57.88; H, 3.33; N, 9.93; Cl, 8.53; H2O, 0.73.

Reference： [1]Patent: US2003/45552,2003,A1
[2]Patent: US2003/96841,2003,A1

10
[ 111-71-7 ]
[ 19171-19-8 ]
[ 444288-11-3 ]

Yield	Reaction Conditions	Operation in experiment
41%	With sodium borohydrid; acetic acid; In ethyl acetate; N,N-dimethyl-formamide;	A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and heptanal (3.4 mL, 24 mmol) and acetic acid (2 mL) in DMF (20 mL) was heated until all solid was dissolved. To the mixture was added sodium borohydride (605 mg, 16 mmol) and kept at room temperature for 18h. To the mixture was added sodium borohydride (150 mg, 3.9 mmol) and kept at room temperature for 1 d. The mixture was extracted with ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with water (100 mL). The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (Silca Gel, 33% EtOAc:CH2Cl2) to give 2-(2,6-Dioxo-piperidin-3-yl)-4-heptylamino-isoindole-1,3-dione as a yellow solid (610 mg, 41% yield): mp, 107-109 C.; 1H NMR (DMSO-d6) delta 0.82-0.87 (m, 3H, CH3), 1.24-1.29 (m, 8H, 4 CH2), 2.00-2.04 (m, 1H, CHH), 2.43-2.62 (m, 2H, CH2), 2.82-2.96 (m, 1H, CHH), 3.23-3.31 (m, 2H, CH2), 5.06 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.51 (t, J=5.9 Hz, 1H, NH), 7.01 (d, J=7.0 Hz, 1H, Ar), 7.07 (d, J=8.6 Hz, 1H, Ar), 7.57 (dd, J=7.4, 8.4 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) delta 13.91,22.03,22.17, 26.28,28.42,28.69, 30.98, 31.22,34.84,48.55, 109.03, 110.36, 117.13, 132.18, 136.24, 146.43, 167.29, 168.96, 170.05, 172.77; Anal Calcd for C20H25N3O4: C, 64.67; H, 6.78; N, 11.31. Found: C, 64.62; H, 6.76; N, 11.13.
41%	With sodium borohydrid; acetic acid; In ethyl acetate; N,N-dimethyl-formamide;	2-(2,6-Dioxo-piperidin-3-yl)-4-heptylamino-isoindole-1,3-dione I-62 A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and heptanal (3.4 mL, 24 mmol) and acetic acid (2 mL) in DMF (20 mL) was heated until all solid was dissolved. To the mixture was added sodium borohydride (605 mg, 16 mmol) and kept at room temperature for 18h. To the mixture was added sodium borohydride (150 mg, 3.9 mmol) and kept at room temperature for 1 d. The mixture was extracted with ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with water (100 mL), The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (Silca Gel, 33% EtOAc:CH2Cl2) to give 2-(2,6-Dioxo-piperidin-3-yl)-4-heptylamino-isoindole-1,3-dione as a yellow solid (610 mg, 41% yield): mp, 107-109 C.; 1H NMR (DMSO-d6) delta0.82-0.87 (m, 3H, CH3), 1.24-1.29 (m, 8H, 4 CH2), 2.00-2.04 (m, 1H, CHH), 2.43-2.62 (m, 2H, CH2), 2.82-2.96 (m, 1H, CHH), 3.23-3.31 (m, 2H, CH2), 5.06 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.51 (t, J=5.9 Hz, 1H, NH), 7.01 (d, J=7.0 Hz, 1H, Ar), 7.07 (d, J=8.6 Hz, 1H, Ar), 7.57 (dd, J=7.4, 8.4 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) delta13.91, 22.03, 22.17, 26.28, 28.42, 28.69, 30.98, 31.22, 34.84, 48.55, 109.03, 110.36, 117.13, 132.18, 136.24, 146.43, 167.29, 168.96, 170.05, 172.77; Anal Calcd for C20H25N3O4: C, 64.67; H, 6.78; N, 11.31. Found: C, 64.62; H, 6.76; N, 11.13.

Reference： [1]Patent: US2003/45552,2003,A1
[2]Patent: US2003/96841,2003,A1

11
[ 4023-34-1 ]
[ 19171-19-8 ]
[ 444288-13-5 ]

Yield	Reaction Conditions	Operation in experiment
84%	In tetrahydrofuran; methanol;	Cyclopropanecarboxylic acid [2-(2,6-dioxo-piperidin-3-1)-1yl)-3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-amide I-64 A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.60 g, 2.2 mmol) and cyclopropanecarbonyl chloride (0.4 mL, 4.4 mmol) in THF (20 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL). The solvent was removed in vacuo to give a solid. The solid was slurried in ether (30 mL0 for 1 h. The suspension was filtered and washed with ether (30 mL) to give cyclopropanecarboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-amide as a solid (630 mg, 84% yield): mp, 237-239 C.; 1H NMR (DMSO-d6) delta0.87-0.90 (m, 4H, 2CH2), 1.93-2.09 (m, 2H, CH, CHH), 2.49-2.65 (m, 2H, CH2), 2.64-2.96 (m, 1H, CHH), 5.15 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.61 (d, J=7.2 Hz, 1H, Ar), 7.82 (t, J=7.7 Hz, 1H, Ar), 8.41 (d, J=8.3 Hz, 1H, Ar), 9.99 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) delta8.10, 14.93, 22.00, 30.93, 48.92, 117.07, 118.30, 126.69, 131.49, 135.97, 136.43, 166.67, 167.57, 169.77, 172.55, 172.74; Anal Calcd for C17H15N3O5: C, 59.82; H, 4.43; N, 12.31. Found: C, 59.50; H, 4.39; N, 12.04.

Reference： [1]Patent: US2003/96841,2003,A1

12
[ 403-43-0 ]
[ 19171-19-8 ]
[ 444288-14-6 ]

Yield	Reaction Conditions	Operation in experiment
77%	In tetrahydrofuran; methanol;	A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 4-fluorobenzoyl chloride (0.95 mL, 8.0 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with ether (2*10 mL) then methanol (5 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-fluoro-benzamide as a yellow solid (1.2 g, 77% yield): mp, 283-285 C.; 1H NMR (DMSO-d6) delta 2.06-2.10 (m, 1 H, CIIH), 2.48-2.65 (mn, 2H, CH2), 2.83-2.97 (mn, 1H, CHH), 5.18 (dd, J=5.4, 12.6 Hz, 1H, NCH), 7.42-7.49 (mn, 2H, Ar), 7.69 (d, J=7.2, Hz, 1H, Ar), 7.91 (t, J=8.2 Hz, 1H, Ar), 8.03-8.08 (m, 2H, Ar), 8.54 (d, J=8.3 Hz, 1H, Ar), 10.41 (s, 1H, NH), 11.15 (s, 1H, NH); 13C NMR(DMSO-d6) delta 22.10, 30.98, 49.29, 115.96 (d, JC-F=22 Hz); 118.03, 118.67, 128.09 (d, JC-F=235 Hz), 130.12, 131.49, 136.18, 136.75, 162.70, 164.08, 166.56, 168.22, 169.29, 172.27; Anal Calcd for C20H14N3O5F+0.2 H2O: C, 60.21; H, 3.64; N, 10.53; F, 4.76; H2O, 0.90. Found: C, 60.17; H, 3.55; N, 10.47; F, 4.90; H2O, 0.95.
77%	In tetrahydrofuran; methanol;	N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-fluoro-benzamide I-65 A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 4-fluorobenzoyl chloride (0.95 mL, 8.0 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with ether (2*10 mL) then methanol (5 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-fluoro-benzamide as a yellow solid (1.2 g, 77% yield): mp, 283-285 C.; 1H NMR (DMSO-d6) delta2.06-2.10 (m, 1H, CHH), 2.48-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.18 (dd, J=5.4, 12.6 Hz, 1H, NCH), 7.42-7.49 (m, 2H, Ar), 7.69 (d, J=7.2, Hz, 1H, Ar), 7.91 (t, J=8.2 Hz, 1H, Ar), 8.03-8.08 (m, 2H, Ar), 8.54 (d, J=8.3 Hz, 1H, Ar), 10.41 (s, 1H, NH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) delta22.10, 30.98, 49.29, 115.96 (d, JC-F=22 Hz); 118.03, 118.67, 128.09 (d, JC-F=235 Hz), 130.12, 131.49, 136.18, 136.75, 162.70, 164.08, 166.56, 168.22, 169.29, 172.27; Anal Calcd for C20H14N3O5F+0.2 H2O: C, 60.21; H, 3.64; N, 10.53; F, 4.76; H2O, 0.90. Found: C, 60.17; H, 3.55; N, 10.47; F, 4.90; H2O, 0.95.

Reference： [1]Patent: US2003/45552,2003,A1
[2]Patent: US2003/96841,2003,A1

13
[ 79-37-8 ]
[ 2444-37-3 ]
[ 19171-19-8 ]
[ 444288-19-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	In tetrahydrofuran; methanol; N,N-dimethyl-formamide;	To a solution of (methylthio)acetic acid (0.77 mL, 8.9 mmol) and oxalyl chloride (0.7 mL, 8.0 mmol) in ether (5 mL) was added DMF (0.02 mL) at room temperature. After 3h, 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and THF (40 mL) was added to the mixture. Then the mixture was heated to reflux for 15 h. To the mixture was added methanol (10 mL) to give a suspension. The suspension was filtered and washed with methanol (10 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methylsulfanyl-acetamide as a white solid (1.0 g, 69% yield): mp, 228-230 C.; 1H NMR (DMSO-d6) delta 2.05-2.10 (m, 1H, CHH), 2.18 (s, 3H, CH3), 2.46-2.65 (m, 2H, CH2), 2.82-2.95 (m, 1H, CHH), 3.53 (s, 2H, CH2), 5.17 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.63 (d, J=7.2 Hz, 1H, Ar), 7.86 (t, J=7.5 Hz, 1H, Ar), 8.61 (d, J=8.4 Hz, 1H, Ar), 10.39(s, 1H,NH), 11.16 (s, 1H,NH); 13C-NMR(DMSO-d6) delta 15.62,21.96, 30.93, 37.99, 48.94, 116.69, 118.46, 125.28, 131.44, 136.31, 166.67, 167.88, 168.63, 169.78, 172.75; Anal Calcd for C16H15N3O5S: C, 53.18; H, 4.18; N, 11.63. Found: C, 53.26; H, 4.17; N, 11.52.

Reference： [1]Patent: US2003/45552,2003,A1

14
[ 79-37-8 ]
[ 2444-37-3 ]
[ 19171-19-8 ]
[ 444288-19-1 ]
[ 444288-20-4 ]

Yield	Reaction Conditions	Operation in experiment
69%	In tetrahydrofuran; methanol; N,N-dimethyl-formamide;	N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methoxy-benzamide I-70 To a solution of (methylthio)acetic acid (0.77 mL, 8.9 mmol) and oxalyl chloride (0.7 mL, 8.0 mmol) in ether (5 mL) was added DMF (0.02 mL) at room temperature. After 3 h, 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and THF (40 mL) was added to the mixture. Then the mixture was heated to reflux for 15 h. To the mixture was added methanol (10 mL) to give a suspension. The suspension was filtered and washed with methanol (10 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methylsulfanyl-acetamide as a white solid (1.0 g, 69% yield): mp, 228-230 C.; 1H NMR (DMSO-d6) delta2.05-2.10 (m, 1H, CHH), 2.18 (s, 3H, CH3), 2,46-2.65 (m, 2H, CH2), 2.82-2.95 (m, 1H, CHH), 3.53 (s, 2H, CH2), 5.17 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.63 (d, J=7.2 Hz, 1H, Ar), 7.86 (t, J=7.5 Hz, 1H, Ar), 8.61 (d, J=8.4 Hz, 1H, Ar), 10.39 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) delta15.62,21.96, 30.93, 37.99, 48.94, 116.69, 118.46, 125.28, 131.44, 136.31, 166.67, 167.88, 168.63, 169.78, 172.75; Anal Calcd for C16H15N3O5S: C, 53.18; H, 4.18; N, 11.63. Found: C, 53.26; H, 4.17; N, 11.52.

Reference： [1]Patent: US2003/96841,2003,A1

15
[ 79-37-8 ]
[ 627-03-2 ]
[ 19171-19-8 ]
[ 444288-18-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	In tetrahydrofuran; methanol; N,N-dimethyl-formamide;	To a solution of ethoxyacetic acid (0.8 mL, 8.5 mmol) and oxalyl chloride (0.7 mL, 8.0 mmol) in ether (5 mL) was added DMF (0.03 mL) at room temperature. After 3h, 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and THF (40 mL) was added to the mixture. Then the mixture was heated to reflux for 15 h. To the mixture was added methanol (10 mL) to give a suspension. The suspension was filtered and washed with methanol (10 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-ethoxy-acetamide as a white solid (1.3 g, 87% yield): mp, 253-255 C.; 1H NMR (DMSO-d6) delta 1.27 (t, J=7.0 Hz, 3H, CH3), 2.06-2.10 (m, 1H, CHH), 2.46-2.64 (m, 2H, CH2), 2.84-2.98 (m, 1H, CHH), 3.66 (q, J=7.0 Hz, 2H, CH2), 4.14 (s, 2H, CH2), 5.17 (dd, J=5.2, 12.7 Hz, 1H, NCH), 7.62 (d, J=7.2 Hz, 1H, Ar), 7.87 (t, J=8.2 Hz, 1H, Ar), 8.75 (d, J=8.4 Hz, 1H, Ar), 10.39 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) delta 14.88, 21.93, 30.92, 48.98, 66.89, 69.49, 116.00, 118.28, 124.25, 131.31, 135.99, 136.53, 166.69, 168.31, 169.49, 169.73, 174.71; Anal Calcd for C17H17N3O6: C, 56.82; H, 4.77; N, 11.69. Found: C, 56.82; H, 4.71; N, 11.60.
87%	In tetrahydrofuran; methanol; N,N-dimethyl-formamide;	N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-ethoxy-acetamide I-69 To a solution of ethoxyacetic acid (0.8 mL, 8.5 mmol) and oxalyl chloride (0.7 mL, 8.0 mmol) in ether (5 mL) was added DMF (0.03 mL) at room temperature. After 3 h, 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and THF (40 mL) was added to the mixture. Then the mixture was heated to reflux for 15 h. To the mixture was added methanol (10 mL) to give a suspension. The suspension was filtered and washed with methanol (10 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-ethoxy-acetamide as a white solid (1.3 g, 87% yield): mp, 253-255 C.; 1H NMR (DMSO-d6) delta1.27 (t, J=7.0 Hz, 3H, CH3), 2.06-2.10 (m, 1H, CHH), 2.46-2.64 (m, 2H, CH2), 2.84-2.98 (m, 1H, CHH), 3.66 (q, J=7.0 Hz, 2H, CH2), 4.14 (s, 2H, CH2), 5.17 (dd, J=5.2, 12.7 Hz, 1H, NCH), 7.62 (d, J=7.2 Hz, 1H, Ar), 7.87 (t, J=8.2 Hz, 1H, Ar), 8.75 (d, J=8.4 Hz, 1H, Ar), 10.39 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) delta14.88, 21.93, 30.92, 48.98, 66.89, 69.49, 116.00, 118.28, 124.25, 131.31, 135.99, 136.53, 166.69, 168.31, 169.49, 169.73, 174.71; Anal Calcd for C17H17N3O6: C, 56.82; H, 4.77; N, 11.69. Found: C, 56.82; H, 4.71; N, 11.60.

Reference： [1]Patent: US2003/45552,2003,A1
[2]Patent: US2003/96841,2003,A1

16
[ 19171-19-8 ]
[ 13831-31-7 ]
[ 444287-74-5 ]

Yield	Reaction Conditions	Operation in experiment
0.56 g (75%)	In tetrahydrofuran; diethyl ether;	{N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]carbamoyl}methyl acetate I-31 To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added (chlorocarbonyl)methyl acetate (0.55 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.56 g (75%) of product as an off-white solid: mp 234-236 C.; 1H NMR (DMSO-d6) delta11.15 (s, 1H), 10.06 (s, 1H), 8.55 (d, J=8.3 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 5.17 (dd, J=5.0 and 12.4 Hz, 1H), 4.78 (s, 2H), 2.99-2.85 (m, 1H), 2.65-2.52 (m, 2H), 2.22 (s, 2H), 2.11-2.07 (m, 1H); 13C NMR (DMSO-d6) delta172.70, 169.69, 169.50, 167.99, 166.57, 136.40, 135.59, 131.35, 125.34, 118.72, 116.96, 62.60, 48.98, 30.90, 21.91, 20.41; Anal. Calcd. For C17H15N3O7: C, 54.69; H, 4.05; N, 11.26. Found: C, 54.43; H, 4.05; N, 10.97.

Reference： [1]Patent: US2003/96841,2003,A1

17
[ 1711-05-3 ]
[ 19171-19-8 ]
[ 444288-06-6 ]

Yield	Reaction Conditions	Operation in experiment
0.51 g (63%)	In tetrahydrofuran; methanol; diethyl ether; ethyl acetate;	N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-3-methoxy-benzamide I-57 To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added m-anisoyl chloride (0.56 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid that was slurried in diethyl ether (20 ml), filtered, reslurried in ethyl acetate (20 ml), filtered, and recrystallized from minimal acetic acid to give 0.51 g (63%) of product as an off-white solid: mp 240-242 C.; 1H NMR (DMSO-d6) d 11.15 (s, 1H), 10.38 (s, 1H), 8.60 (d, J=8.3 Hz, 1H), 7.91 (t, J=7.5 Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.55-7.50 (m, 3H), 7.29-7.22 (m, 1H), 5.19 (dd, J=5.3 and 12.5 Hz, 1H), 3.86 (s, 3H), 2.99-2.84 (m, 1H), 2.66-2.50 (m, 2H), 2.12-2.07 (m, 1H); 13C NMR (DMSO-d6) d 172.02, 169.71, 168.12, 166.64, 164.70, 159.56, 136.52, 136.31, 134.73, 131.36, 130.26, 126.18, 119.19, 118.78, 118.26, 117.92, 112.74, 55.41, 48.97, 30.93, 21.99; Anal. Calcd. For C21H17N3O6: C, 59.73; H, 4.46; N, 9.29. Found: C, 59.37; H, 4.34; N, 9.10+0.75 AcOH.

Reference： [1]Patent: US2003/96841,2003,A1

18
[ 38870-89-2 ]
[ 19171-19-8 ]
[ 444287-72-3 ]

Yield	Reaction Conditions	Operation in experiment
0.69 g (100%)	In tetrahydrofuran; diethyl ether;	N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-2-methoxyacetamide I-29 To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added 2-methoxyacetyl chloride (0.43 g, 4.0 mmol). The stirred mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.69 g (100%) of product as an off-white solid: mp 246-248 C.; 1H NMR (DMSO-d6) delta11.15 (s, 1H), 10.30 (s, 1H), 8.70 (d, J=8.4 Hz, 1H), 7.86 (t, J=7.8 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H), 5.17 (dd, J=5.2 and 12.7 Hz, 1H), 4.11 (s, 2H), 3.49 (s, 3H), 2.98-2.84 (m, 1H), 2.66-2.47 (m, 2H), 2.12-2.07 (m, 1H); 13C NMR (DMSO-d6) delta172.67, 169.66, 169.02, 168.25, 166.61, 136.48, 135.91, 131.24, 124.35, 118.31, 116.04, 71.40, 59.10, 48.96, 30.91, 21.94; Anal. Calcd. For C16H15N3O6: C, 55.65; H, 4.38; N, 12.17. Found: C, 55.58; H, 4.40; N, 12.08.

Reference： [1]Patent: US2003/96841,2003,A1

19
[ 98-88-4 ]
[ 19171-19-8 ]
[ 444287-79-0 ]

Yield	Reaction Conditions	Operation in experiment
0.49 g (65%)	In tetrahydrofuran; diethyl ether;	N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]benzamide I-36 To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added benzoyl chloride (0.56 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. To the reaction mixture was added additional benzoyl chloride (0.28 g, 2.0 mmol). The mixture was heated at reflux for an additional 8 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give an of off-white solid which was recrystallized from acetic acid to give 0.49 g (65%) of product: mp 268-270 C.; 1H NMR (DMSO-d6) delta11.18 (s, 1H), 10.43 (s, 1H), 8.64-8.59 (m, 1H), 8.00-7.89 (m, 3H), 7.72-7.60 (m, 4H), 5.19 (dd, J=5.2 and 12.5 Hz, 1H), 2.98-2.84 (m, 1H), 2.66-2.50(m, 2H), 2.12-2.07 (m, 1H) (DMSO-d6) delta172.62, 169.59, 168.16, 166.64, 164.91, 136.50, 136.36, 133.23, 132.67, 131.36, 129.06, 127.24, 126.00, 118.74, 117.74, 48.98, 30.89, 21.98; Anal. Calcd. For C20H15N3O5: C, 63.02; H, 4.08; N, 10.90. Found: C, 63.05; H, 4.06; N, 10.69+0.11 AcOH+0.08 H2O.

Reference： [1]Patent: US2003/96841,2003,A1

20
[ 618-46-2 ]
[ 19171-19-8 ]
[ 444287-99-4 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; methanol; diethyl ether;	3-Chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-benzamide I-52 To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added 3-chlorobenzoyl chloride (0.51 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid which was slurried in diethyl ether (20 ml) and filtered to give 0.82 (100%) of product as an off-white solid: mp 257-259 C.; 1H NMR (DMSO-d6) d 11.06 s, 1H), 10.43 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 7.99-7.88 (m, 3H), 7.75-7.61 (m, 3H), 5.17 dd, J=5.5 and 12.7 Hz, 1H), 2.99-2.84 (m, 1H), 2.67-2.49 (m, 2H), 2.12-2.07 (m, 1H); 13C NMR (DMSO-d6) d 172.36, 169.78, 169.36, 167.59, 166.39, 163.57, 135.99, 135.31, 133.59, 132.11, 131.33, 130.73, 127.07, 126.76, 125.78, 118.93, 118.55, 48.91, 30.77, 21.85; Anal. Calcd. For C20H14CIN3O5: C, 58.33; H, 3.43; N, 10.20. Found: C, 58.38; H, 3.23; N, 9.95.

Reference： [1]Patent: US2003/96841,2003,A1

21
[ 20260-53-1 ]
[ 19171-19-8 ]
N-(2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl)-3-pyridylcarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	N-[2-(2,6-Dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-3-pyridylcarboxamide I-11 A stirred mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.09 g, 4.0 mmol) and nicotinoyl chloride hydrochloride (1.42 g, 8.0 mmol) in tetrahydrofuran (60 ml) was heated to reflux for 22 h. The suspension was filtered and washed with tetrahydrofuran (20 ml) and ether (10 ml) to yield a white solid.

Reference： [1]Patent: US2003/96841,2003,A1

22
[ 701-99-5 ]
[ 19171-19-8 ]
[ 444288-00-0 ]

Yield	Reaction Conditions	Operation in experiment
0.76 g (93%)	In tetrahydrofuran; methanol; diethyl ether;	N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-phenoxy-acetamide I-53 To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added phenoxyacetyl chloride (0.55 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid which was slurried in diethyl ether (20 ml) and filtered to give 0.76 g (93%) of product as an off-white solid: mp 236-238 C.; 1H NMR (DMSO-d6) d 11.19 (s, 1H), 10.53 (s, 1H), 8.73 (d, J=8.4 Hz, 1H), 7.88 (t, J=7.6 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.38 (t, J=7.6 Hz, 2H) 7.14-7.01 (m, 3H), 5.21 (dd, J=5.3 and 12.6 Hz, 1H), 4.81 (s, 2H), 3.00-2.86 (m, 1H), 2.67-2.51 (m, 2H), 2.13-2.09 (m, 1H); 13C NMR (DMSO-d6) d 172.77, 169.77, 168.37, 167.59, 166.67, 156.85, 136.58, 135.84, 131.28, 129.74, 124.45, 121.91, 118.50, 116.28, 114.86, 67.03, 49.02, 30.96, 21.93; Anal. Calcd. For C21, H17N3O6: C, 61.92; H, 4.21; N, 10.31. Found: C, 61.87; H, 4.27; N, 10.25.

Reference： [1]Patent: US2003/96841,2003,A1

23
[ 21615-34-9 ]
[ 19171-19-8 ]
[ 444288-20-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	In tetrahydrofuran; methanol;	N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methoxy-benzamide I-71 A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (660 mg, 2.4 mmol) and 2-methoxybenzoyl chloride (0.7 mL, 4.7 mmol) in THF (20 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methoxy-benzamide as a white solid (760 mg, 78% yield): mp, 286-287 C.; 1H NMR (DMSO-d6) (at 340K) delta2.09-2.14 (m, 1H, CHH), 2.55-2.66 (m, 2H, CH2), 2.85-2.98 (m, 1H, CHH), 4.14 (s, 3H, OCH3),5.19 (dd, J=5.5, 12.9 Hz, 1H, NCH), 7.17 (t, J=7.2 Hz, 1H, Ar), 7.30 (d, J=8.3 Hz, 1H, Ar), 7.61-7.68 (m, 2H, Ar), 7.89 (t, J=7.7 Hz, 1H, Ar), 8.12 (dd, J=1.8, 7.9 Hz, 1H Ar), 9.03 (d, J=8.5 Hz, 1H, Ar), 11.17 (s, 1H, NH), 11.64 (s, 1H, NH); 13C NMR (DMSO-d6) (at 340K) delta22.09, 31.02, 49.29, 56.19, 112.65, 116.31, 117.93, 120.66, 121.14, 125.52, 131.59, 131.75, 134.34, 136.22, 137.00, 157.64, 163.82, 166.69, 168.15, 169.43, 172.32; Anal Calcd for C21H17N3O6: C, 61.92; H, 4.21; N, 10.31. Found: C, 62.05; H, 4.10; N, 10.38.

Reference： [1]Patent: US2003/96841,2003,A1

24
[ 19171-19-8 ]
[ 444288-15-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	In tetrahydrofuran; methanol;	A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.6 g, 2.2 mmol) and 4-(trifluoromethyi)benzoyi chloride (1 g, 4.8 mmol) in THF (20 mL) was heated to reflux for 15 h. The solvent was removed in vacuo to give a solid. The solid was slurried in methanol (20 mL) for 2h. The suspension was filtered and washed with ether (15 mL) then methanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3 -dihydro-1H-isoindol-4-yl]-4-trifluoromethyl-benzamide as a white solid (750 mg, 77% yield): mp, 213-215 C.; 1H NMR (DMSO-d6) delta 2.05-2.10 (m, 1H, CHH), 2.49-2.65 (m, 2H, CH2), 2.83-2.98 (m, 1 H, CHH), 5.18 (dd, J=5.2, 12.5 Hz, 1H, NCH), 7.72 (d, J=7.2 Hz, 1H, Ar), 7.90-8.02 (m, 3H, Ar), 8.16-8.19 (m, 2H, Ar), 8.49 (d, J=8.4 Hz, 1H, Ar), 10.58 (s, 1H, NH), 11.17 (s, 1H, NH); 13C NMR (DMSO-d6) delta 21.99, 30.92, 48.99, 118.88, 119.36, 119.32,123.76 (q, JC-F=271 Hz); 125.99 (q, JC-F=3.6 Hz), 127.10 128.37, 131.54, 132.16 (q, JC-F=32 Hz), 136.00, 136.26, 13721, 164.05, 166.59, 167.65, 169.68, 172.73; Anal Calcd for C21H14N3O5F3: C, 56.64; H, 3.17; N, 9.44; F, 12.80. Found: C, 56.25; H, 3.05; N, 9.32; F, 12.69.

Reference： [1]Patent: US2003/45552,2003,A1

25
[ 393-52-2 ]
[ 19171-19-8 ]
[ 444288-21-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	In tetrahydrofuran; methanol;	A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 2-fluorobenzoyl chloride (1.0 mL, 8.4 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (10 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-fluoro-benzamide as a white solid (1.5 g, 93% yield): mp, 300-302 C.; 1H NMR (DMSO-d6) delta 2.05-2.12 (m, 1H, CHH), 2.45-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.18 (dd, J=5.5, 12.9 Hz, 1H, NCH), 7.40-7.49 (m, 2H, Ar), 7.67-7.76 (m, 2H, Ar), 7.88-7.98 (m, 1H, Ar), 8.01-8.05 (m, 1H, Ar), 8.76 (d, J=8.4 Hz, 1H Ar), 10.56 (d, JN-F=10 Hz, 1H, NH), 11.17 (s, 1H, NH); 13C NMR (DMSO-d6) delta 21.96, 30.92, 48.97, 116.48, 116.97 (d, JC-F=14 Hz), 118.82, 120.87 (d, JC-F=12 Hz), 125.32 (d, JC-F=1.5 Hz), 125.74, 131.32, 131.39, 134.88 (d, JC-F=9 Hz), 136.22, 136.48, 159.75 (d, JC-F=252 Hz), 161.76 (d, JC-F=7 Hz), 166.58, 168.04, 169.70, 172.71; Anal Calcd for C20H14N3O5F: C, 60.76; H, 3.57; N, 10.63; F, 4.81. Found: C, 60.70; H, 3.64; N, 10.64; F, 4.91.
93%	In tetrahydrofuran; methanol;	N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-fluoro-benzamide I-72 A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 2-fluorobenzoyl chloride (1.0 mL, 8.4 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (10 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-fluoro-benzamide as a white solid (1.5 g, 93% yield): mp, 300-302 C.; 1H NMR (DMSO-d6) delta2.05-2.12 (mn, 1H, CHH), 2.45-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.18 (dd, J=5.5, 12.9 Hz, 1H, NCH), 7.40-7.49 (m, 2H, Ar), 7.67-7.76 (m, 2H, Ar), 7.88-7.98 (mn, 1H, Ar), 8.01-8.05 (m, 1H, Ar), 8.76 (d, J=8.4 Hz, 1H Ar), 10.56 (d, JN-F=10 Hz, 1H, NH), 11.17 (s, 1H, NH); 13C NMR (DMSO-d6) delta21.96, 30.92, 48.97, 116.48, 116.97 (d, JC-F=14 Hz), 118.82, 120.87 (d, JC-F=12 Hz), 125.32 (d,JC-F=1.5 Hz), 125.74, 131.32, 131.39, 134.88 (d,JC-F=9 Hz), 136.22, 136.48, 159.75 (d, JC-F=252 Hz), 161.76 (d, JC-F=7 Hz), 166.58, 168.04, 169.70, 172.71; Anal Calcd for C20H14N3O5F: C, 60.76; H, 3.57; N, 10.63; F, 4.81. Found: C, 60.70; H, 3.64; N, 10.64; F, 4.91.

Reference： [1]Patent: US2003/45552,2003,A1
[2]Patent: US2003/96841,2003,A1

26
[ 2251-65-2 ]
[ 19171-19-8 ]
[ 444288-07-7 ]

Yield	Reaction Conditions	Operation in experiment
0.41 g (46%)	In tetrahydrofuran; methanol; diethyl ether;	N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-3-trifluoromethyl-benzamide I-58 To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added 3-trifluoromethylbenzoyl chloride (0.60 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid that was slurried in diethyl ether (20 ml) and filtered to give 0.41 g (46%) of product as an off-white solid: mp 257-259 C.; 1H NMR (DMSO-d6) d 10.86 (s, 1H), 10.45 (s, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.24-8.25 (m, 2H), 8.02-7.82 (m, 3H), 7.69 (d, J=7.3 Hz, 1H), 5.14 (dd, J=5.7 and 12.8 Hz, 1H), 2.95-2.82 (m, 1H), 2.67-2.48 (m, 2H), 2.14-2.07 (m, 1H); 13C NMR (DMSO-d6) d 171.75,168.80, 167.31, 166.06, 163.43, 135.80, 135.60, 134.28, 131.16, 130.71, 129.75, 128.35, 128.29, 126.63, 123.59, 123.52, 118.65, 118.55, 48.84, 30.51, 21.62; Anal. Calcd. For C21H14F3N3O5: C, 56.64; H, 3.17; N, 9.44. Found: C, 56.48; H, 3.15; N, 9.41.

Reference： [1]Patent: US2003/96841,2003,A1

27
[ 121-90-4 ]
[ 19171-19-8 ]
[ 444288-08-8 ]

Yield	Reaction Conditions	Operation in experiment
1.60 g (95%)	In tetrahydrofuran; methanol; diethyl ether;	N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-3-nitro-benzamide I-59 To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.10 g, 4 mmol) in THF (30 ml) was added 3-nitrobenzoyl chloride (1.48 g, 8 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid that was slurried in diethyl ether (30 ml) and filtered to give 1.60 g (95%) of product as an off-white solid: mp 245-247 C.; 1H NMR (DMSO-d6) d 10.85 (s, 1H), 10.53 (s, 1H), 8.76 (s, 1H), 8.50-8.37 (m, 3H), 7.95-7.87 (m, 2H), 7.70 (d, J=7.4 Hz, 5.14 (dd, J=5.7 and 12.7 Hz, 1H), 3.02-2.83 (m, 1H), 2.67-2.47 (m, 2H), 2.15-2.07 (m, 1H); 13C NMR (DMSO-d6) d 171.73, 168.79, 167.19, 166.04, 162.85, 147.84, 135.60, 134.79, 132.92, 131.21, 130.19, 126.87, 126.20, 121.69, 118.83, 48.86, 30.51, 21.63; Anal. Calcd. For C20H14N4O7: C, 56.88; H, 3.34; N, 13.27. Found: C, 56.87; H, 3.33; N, 13.05.

Reference： [1]Patent: US2003/96841,2003,A1

28
[ 103-80-0 ]
[ 19171-19-8 ]
[ 444287-82-5 ]

Yield	Reaction Conditions	Operation in experiment
0.72 g (92%)	In tetrahydrofuran; diethyl ether;	N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-2-phenylacetamide I-39 To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added 2-phenylacetyl chloride (0.62 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.72 g (92%) of product as an off-white solid: mp 217-218C.; 1H NMR (DMSO-d6) delta11.15 (s, 1H), 9.79 (s, 1H), 8.49 (d, J=8.4 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.60 (t, J=7.3 Hz, 1H), 7.41-7.27 (m, 5H), 5.13 (dd, J=5.1 and 12.7 Hz, 1H), 3.85 (s, 2H), 2.98-2.83 (m, 1H), 2.64-2.44(m, 2H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) delta172.71, 170.07, 169.74, 167.60, 166.61, 136.38, 136.10, 134.70, 131.41, 129.41, 128.58, 126.97, 125.96, 118.39, 116.90, 48.89, 43.47, 30.90, 21.91; Anal. Calcd. For C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.23; H, 4.34; N, 10.53.

Reference： [1]Patent: US2003/96841,2003,A1

29
[ 79-03-8 ]
[ 19171-19-8 ]
[ 444287-80-3 ]

Yield	Reaction Conditions	Operation in experiment
0.58 g (88%)	In tetrahydrofuran; diethyl ether;	N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]propanamide I-37 To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added propanoyl chloride (0.37 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.58 g (88%) of product as an off-white solid: mp 221-223 C.; 1H NMR (DMSO-d6) delta11.15 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 5.16 (dd, J=5.2 and 12.6 Hz, 1H), 2.99-2.85 (m, 1H), 2.66-2.45 (m, 4H), 2.11-2.07(m, 1H), 1.14 (t, J=7.5 Hz, 3H); 13C NMR (DMSO-d6) delta172.69, 172.65, 169.71, 167.79, 166.62, 136.65, 136.09, 131.35, 125.93, 118.12, 116.66, 48.91, 30.91, 29.73, 21.97, 9.13; Anal. Calcd. For C16H15N3O5: C, 58.36; H, 4.59; N, 12.76. Found: C, 58.01; H, 4.45; N, 12.61.

Reference： [1]Patent: US2003/96841,2003,A1

30
[ 141-75-3 ]
[ 19171-19-8 ]
[ 444288-09-9 ]

Yield	Reaction Conditions	Operation in experiment
0.55 g (80%)	In tetrahydrofuran; methanol; diethyl ether;	N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-butyramide I-60 To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added butanoyl chloride (0.42 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid that was slurried in diethyl ether (20 ml) and filtered to give 0.55 g (80%) of product as an off-white solid: mp 171-173 C.; 1H NMR (DMSO-d6) d 11.14 (s, 1H), 9.68 (s, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 5.15 (dd, J=5.2 and 12.6 Hz, 1H), 2.96-2.84 (m, 1H), 2.65-2.42 (m, 4H), 2.11-2.06 (m, 1H), 1.73-1.58 (m, 2H), 0.95 (t, J=7.4 Hz, 3H); 13C NMR (DMSO-d6) d 172.70, 171.84, 169.72, 167.70,166.63,136.54, 136.07,131.41,126.17, 118.23, 116.89,48.90,30.91,21.96, 18.25, 13.46; Anal. Calcd. For C17H17N3O5: C, 59.47; H, 4.99; N, 12.24. Found: C, 59.45; H, 4.82; N, 12.15.

Reference： [1]Patent: US2003/96841,2003,A1

31
[ 638-29-9 ]
[ 19171-19-8 ]
N-(2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl)pentanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.61 g (85%)	In tetrahydrofuran; diethyl ether;	N-[2-(2,6-dioxo(3-piperidyl))-1 3-dioxoisoindolin-4-yl]pentanamide I-32 To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added pentanoyl chloride (0.48 g, 4.0 mmol). The stirred mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.61 g (85%) of product as an off-white solid: mp 178-179 C.; 1H NMR (DMSO-d6) delta11.17 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.5 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 5.18 (dd, J=5.0 and 12.4 Hz, 1H), 2.99-2.89 (m, 1H), 2.68-2.45 (m, 4H), 2.13-2.09 (m, 1H), 1.69-1.57 (m, 2H), 1.44-1.30 (m, 2H), 0.92 (t, J=7.2 Hz, 3H); 13C NMR (DMSO-d6) 172.72, 171.99, 169.73, 167.83, 166.64, 136.64, 136.07, 131.36, 125.96, 118.15, 116.68, 48.97, 36.32, 30.97, 26.88, 22.03, 21.70, 13.64; Anal. Calcd. For C19H19N3O5: C, 60.50; H, 5.36; N, 11.76. Found: C, 60.10; H, 5.37; N, 11.58.

Reference： [1]Patent: US2003/96841,2003,A1

32
[ 2528-61-2 ]
[ 19171-19-8 ]
[ 444287-73-4 ]

Yield	Reaction Conditions	Operation in experiment
0.61 g (79%)	In tetrahydrofuran; diethyl ether;	N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]heptanamide I-30 To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added heptanoyl chloride (0.59 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.61 g (79%) of product as an off-white solid: mp 200-202 C.; 1H NMR (DMSO-d6) delta11.16 (s, 1H), 9.65 (s, 1H), 8.48 (d, J=8.3 Hz, 1H), 7.81 (t, J=7.7 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 5.15 (dd, J=4.8 and 12.2 Hz, 1H), 2.97-2.87 (m, 1H), 2.65-2.43 (m, 4H), 2.10-2.06 (m, 1H), 1.61-1.58 (m, 2H), 1.28 (bs, 6H), 0.85 (bs, 3H); 13C NMR (DMSO-d6) delta172.67, 171.96, 169.69, 167.78, 166.61, 136.62, 136.04, 131.36, 125.97, 118.13, 116.67, 48.93, 36.56, 30.95, 28.16, 24.69, 21.94, 13.84; Anal. Calcd. For C20H23N3O5: C, 62.3 3; H, 6.02; N, 10.90. Found: C, 62.14; H, 6.05; N, 10.72.

Reference： [1]Patent: US2003/96841,2003,A1

33
[ 19810-31-2 ]
[ 19171-19-8 ]
[ 444287-95-0 ]

Yield	Reaction Conditions	Operation in experiment
1.35 g (80%)	In tetrahydrofuran; methanol; diethyl ether; ethyl acetate;	2-Benzyloxy-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-acetamide I-50 To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.10 g, 4 mmol) in THF (30 ml) was added benzyloxyacetyl chloride (1.26 ml, 8 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo and the residue was slurried in diethyl ether (30 ml), filtered, recrystallized from a minimal amount of acetic acid, slurried in ethyl acetate (15 ml), and filtered to give 1.35 g (80%) of product: mp 204-206 C.; 1H NMR (DMSO-d6) d 11.20 (s, 1H), 10.40 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.86 (t, J=7.9 Hz, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.50-7.28 (m, 5H), 5.17 (dd, J=5.0 and 12.5 Hz, 1H), 4.72 (s, 2H), 4.21 (s, 2H), 2.99-2.85 (m, 1H), 2.67-2.51 (m, 2H), 2.12-2.08 (m, 1H); 13C NMR (DMSO-d6) d 172.78, 169.78, 169.01, 168.27, 166.67, 137.04, 136.52, 135.93, 131.29, 128.36, 127.82, 124.40, 118.38, 116.08, 72.78, 69.23, 48.97, 30.92, 21.98; Anal. Calcd. For C22H19N3O6: C, 62.70; H, 4.54; N, 9.97. Found: C, 62.77; H, 4.54; N, 9.82.

Reference： [1]Patent: US2003/96841,2003,A1

34
[ 874-60-2 ]
[ 19171-19-8 ]
[ 444288-16-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	In tetrahydrofuran; methanol;	A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 4-methylbenzoyl chloride (1.1 g, 8.0 mmol) in THF (40 mL) was heated to reflux for 36 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with methanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-methyl-benzamide as a yellow solid (1.3 g, 83% yield): mp, 322-324 C.; 1H NMR (DMSO-d6) delta 2.06-2.10 (m, 1H, CHH), 2.41 (s, 3H, CH3), 2.50-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.19 (dd, J=5.3, 12.6 Hz, 1H, NCH), 7.42 (d, J=8.1 Hz, 2H, Ar), 7.67 (d, J=7.2 Hz, 1H, Ar), 7.86-7.93 (m, 3H, Ar), 8.62 (d, J=8.4 Hz, 1H, Ar), 10.37 (s, 1H, NH), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) delta 21.07,21.99,30.93,48.99, 117.57, 118.58,125.94,127.28, 129.58, 130.44, 131.33, 136.34, 136.77, 142.96, 164.80, 166.65, 168.29, 169.69, 172.72; Anal Calcd for C2,H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.65; H, 4.17; N, 10.70.
83%	In tetrahydrofuran; methanol;	N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-methyl-benzamide I-67 A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 4-methylbenzoyl chloride (1.1 g, 8.0 mmol) in THF (40 mL) was heated to reflux for 36 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with methanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-methyl-benzamide as a yellow solid (1.3 g, 83% yield): mp, 322-324 C.; 1H NMR (DMSO-d6) delta2.06-2.10 (m, 1H, CHH), 2.41 (s, 3H, CH3), 2.50-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.19 (dd, J=5.3, 12.6 Hz, 1H, NCH), 7.42 (d, J=8.1 Hz, 2H, Ar), 7.67 (d, J=7.2 Hz, 1H, Ar), 7.86-7.93 (m, 3H, Ar), 8.62 (d, J=8.4 Hz, 1H, Ar), 10.37 (s, 1H, NH), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) delta21.07, 21.99, 30.93, 48.99, 117.57, 118.58 125.94, 127.28, 129.58, 130.44, 131.33, 136.34, 136.77, 142.96, 164.80, 166.65, 168.29, 169.69, 172.72; Anal Calcd for C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.65; H, 4.17; N, 10.70.

Reference： [1]Patent: US2003/45552,2003,A1
[2]Patent: US2003/96841,2003,A1

35
[ 39901-94-5 ]
[ 19171-19-8 ]
[ 444287-83-6 ]

Yield	Reaction Conditions	Operation in experiment
0.30 g (40%)	With ammonium hydroxide; In tetrahydrofuran; methanol; diethyl ether;	N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-2-pyridylcarboxamide I-40 To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added pyridine-2-carbonyl chloride hydrochloride (0.71 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in a biphasic mixture of diethyl ether (20 ml)/20 % NH4OH (20 ml) and filtered to give an off-white solid. The solid was re-slurried in methanol (20 ml) and filtered to give 0.30 g (40%) of product: mp 336-338 C.; 1H NMR (DMSO-d6) delta11.83 (s, 1H), 11.20 (s, 1H), 8.92 (d, J=8.4 Hz, 1H), 8.81 (d, J=3.6 Hz, 1H), 8.22 (d, J=7.7 Hz, 1H), 8.15 (t, J=7.4 Hz, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.77-7.72 (m, 1H), 7.65 (d, J=7.2 Hz, 1H), 5.22 (dd, J=5.2 and 12.5 Hz, 1H), 3.00-2.86 (m, 1H), 2.69-2.52 (m, 2H), 2.15-2.11 (m, 1H); 13C NMR (DMSO-d6) delta172.67, 169.67, 168.20, 166.61, 162.69, 148.83, 148.19, 138.45, 136.50, 136.16, 131.39, 127.72, 124.23, 122.46, 118.29, 116.32, 48.96, 30.91, 21.98; Anal. Calcd. For C19H14N4O5: C, 60.32; H, 3.73; N, 14.81. Found: C, 60.05; H, 3.57; N, 14.45.

Reference： [1]Patent: US2003/96841,2003,A1

36
[ 79-04-9 ]
[ 19171-19-8 ]
[ 444287-84-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	In tetrahydrofuran; for 1h;Reflux;	To a solution of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (500 mg, 1.83 mmol) in THF (30 mL) was added 2-chloroacetyl chloride (413 mg, 3.66 mmol), and the mixture heated to reflux for 1 h. The solvent was evaporated in vacuo and the resulting solid slurried in diethyl ether (20 mL) and filtered to give 2-chloro-77-(2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)acetamide (XS01-115) (620 mg, 97%) as a white solid. HPLC 97.7% (/ = 9.90 min, CH3OH in 0.1% TFA water 5%~95% in 20 min); NMR (500 MHz, DMSO-ifc) d 11.15 (s, 1H), 10.31 (s, 1H), 8.55 (dd, J = 8.4, 0.7 Hz, 1H), 7.89 (dd, J = 8.5, 7.3 Hz, 1H), 7.69 (dd, J = 7.4, 0.7 Hz, 1H), 5.17 (dd, 7 = 12.9, 5.4 Hz, 1H), 4.54 (s, 2H), 2.90 (m, 1H), 2.68-2.59 (m, 1H), 2.59-2.52 (m, 1H), 2.08 (m, 1H); HPLC-MS (ESI+) m/z 350.1 (M+H)+. (See US2003/96841.)
90.3%	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere; Cooling with ice;	Dissolve 2.73 g (10 mmol) of <strong>[19171-19-8]pomalidomide</strong> in 45 ml of DMF, add 3.03 g (30 mmol) of triethylamine, and protect with nitrogen, add 3.38 g (30 mmol) of chloroacetyl chloride (dissolved in 15 ml of DMF) dropwise in an ice bath, and dropwise add After completion, stir in an ice bath for 1 h, warm to room temperature, and continue stirring for 1 h. TLC monitors the progress of the reaction. After the reaction, the reaction solution was slowly added to 150 ml of water to precipitate a tan solid, which was filtered, and the filter cake was the crude product of compound Ia. The crude product was slurried with 10 ml of methanol to obtain 3.15 g of off-white solid compound Ia with a yield of 90.3%.
88.4%	In tetrahydrofuran; at 60℃; for 2h;	<strong>[19171-19-8]pomalidomide</strong> (0.1 mg, 0.37 mmol) was dissolved in 10 mL of THF. 3-Chloropropionyl chloride (0.046 mg, 0.4 mmol) was added at room temperature, and the mixture was heated at 60 C for 2 h. TLC detects the remaining EA material. After cooling to room temperature, concentrate under reduced pressure. The white crystals were crystallized from diethyl ether, filtered, and dried to give a white solid.

87.2%	In tetrahydrofuran;Reflux;	Chloroacetyl chloride (450 muL) wasadded to a suspension solution of 10 (500.0 mg, 1.83 mmol) in THF,then the mixture was kept stirring under reflux overnight. The mixture was concentrated under reduced pressure, and solids began to depositafter adding diethyl ether. The solid was filtered out and washed withdiethyl ether to give compound 11 as a white solid (Yield: 558.0 mg,87.2%). ESI-MS: calcd m/z=349.05, found [M+H]+=350.05 and[M+Na]+=372.03. 1H NMR (ppm, 400 MHz, DMSO-d6): delta 11.19 (s,1H), delta 10.32 (s, 1H), delta 8.54 (d, J=4.0 Hz, 1H), delta 7.89 (t, J=8.0 Hz,1H), delta 7.69 (d, J=4.0 Hz, 1H), delta 5.18 (q, J=8.0 Hz, 1H), delta 4.55 (s,2H), delta 2.89 (m, 1H), delta 2.57 (m, 2H), delta 2.02 (m, 1H).
70%	In tetrahydrofuran; for 5h;Reflux;	Weigh <strong>[19171-19-8]pomalidomide</strong> (546mg, 2mmol), dissolve in 100mL THF, add chloroacetyl chloride (452mg, 4mmol), reflux for 5h,The reaction was monitored by TLC. First, it was concentrated under reduced pressure to remove THF, dissolved in 200 mL of EA, and then backwashed three times with water. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography using PE / EA as a mobile phase. A white solid was obtained with a yield of about 70%.
65%	In tetrahydrofuran;Reflux;	A solution of <strong>[19171-19-8]pomalidomide</strong> (90 mg, 0.33mmol) and 2-chloroacetyl chloride (0.026 mL, 0.33 mmol) in THF (2 ml) was heated at reflux overnight. After being cooled to RT, the reaction mixture was concentrated, and the resulting residue was washed with ethyl acetate to yield the intermediate 21 (75 mg, 65%) as yellowsolid. To a stirring solution of intermediate 13 (36 mg, 0.082 mmol) in DMSO (lmL) were added DIEA (0.043 mL, 0.24 mmol) and palbociclib (39 mg, 0.087 mmol). The mixture was heated at 80C. After the starting materials were consumed, the reaction was concentratedunder reduced pressure. The resulting residue was purified by prep-HPLC to yield the title compound (36 mg, 54%) as yellow solid. ?H NMR (600 MI-Tz, CDC13) oe 11.19 (s, 1H), 8.89 (d, J= 8.5 Hz, 1H), 8.81 (s, 1H), 8.20 (d, J= 9.1 Hz, 1H), 8.14 (d, J 2.8 Hz, 1H), 7.71 (t, J 4.2 Hz, 1H), 7.55 (d, J= 7.3 Hz, 1H), 7.38 (dd, J= 9.1, 2.9 Hz, 1H), 5.87 (p, J 9.0 Hz, 1H), 4.94(dd, J= 12.7, 5.3 Hz, 1H), 3.39 (br, 4H), 3.34 (AB, Jab = 17.4 Hz, 1H), 3.27 (AB, Jab = 17.4 Hz, 1H), 2.92 - 2.73 (m, 8H), 2.54 (s, 3H), 2.40 - 2.29 (m, 4H), 2.14 - 2.09 (m, 1H), 2.08 -2.00 (m, 2H), 1.90 - 1.81 (m, 2H), 1.70 - 1.59 (m, 2H). HRMS (ESI-TOF) m/z: [M+Hj calculated for C39H41N1007, 761.3154; found: 761.3157.
1.67 g (96%/0)	In tetrahydrofuran; diethyl ether;	N-[2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl]-2-chloroacetamide I-41 To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.37 g, 5.00 mmol) in THF (30 ml) was added chloroacetyl chloride (0.62 g, 5.5 mmol). The mixture was heated to reflux for 30 minutes. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 1.67 g (96%/0) of product as an off-white solid: 1H NMR (DMSO-d6) delta11.18 (s, 1H), 10.31 (s, 1H), 8.54 (d, J=8.4 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.68 (d, J=7.3 Hz, 1H), 5.17(dd, J=5.2 and 12.7 Hz, 1H), 4.54 (s, 2H), 2.90-2.85 (m, 1H), 2.65-2.51 (m, 2H), 2.10-2.06(m, 1H).

Reference： [1]Patent: WO2020/14489,2020,A2 .Location in patent: Page/Page column 175
[2]Patent: CN110713480,2020,A .Location in patent: Paragraph 0070-0072
[3]Patent: CN109928956,2019,A .Location in patent: Paragraph 0112; 0113-0115
[4]Bioorganic Chemistry,2018,vol. 81,p. 536 - 544
[5]Patent: CN110684015,2020,A .Location in patent: Paragraph 0043; 0206-0211
[6]Patent: WO2018/106870,2018,A1 .Location in patent: Page/Page column 85; 125; 126
[7]Patent: US2003/96841,2003,A1

37
KP-C₁₈-HS [ No CAS ]
[ 19171-19-8 ]
4-(benzylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	With CF3COOH; sodium borohydrid; benzaldehyde; In water; acetic acid; ethyl acetate; acetonitrile;	A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.0 g, 3.7 mmol) and benzaldehyde (0.4 ml, 3.9 mmol) in acetic acid (20 ml) was stirred at room temperature for 17h, then was heated to reflux for 3h. The mixture was cooled to room temperature. To the stirred mixture was added sodium borohydride (140 mg, 3.7 mmol) and kept at room temperature for 18h. The mixture was then heated to reflux for 2h. To the mixture was added additional benzaldehyde (0.4 ml, 3.9 mmol) during reflux. After 30 min of reflux the reaction was allowed to cool to room temperature. To the mixture was added sodium borohydride (180 mg, 4.8 mmol) and the mixture stirred at room temperature for 3 days. The solvent was removed in vacuo to yield an oil. The oil was diluted with ethyl acetate (90 ml) and aqueous sodium hydrogen carbonate (sat, 100 ml). The organic layer was separated and was washed with aqueous sodium hydrogen carbonate (sat, 2*100 ml), brine (100 ml) and dried over MgSO4. The solvent was removed in vacuo to give a solid. The solid was purified by column chromatography (Silca Gel, 50% EtOAc:CH2Cl2) to give a yellow solid. The solid was further purified by column chromatography (KP-C18-HS, 35:65 CH3CN:0.1% CF3COOH in water) to give 2-(2,6-dioxo(3-piperidyl))-4-[benzylamino]isoindoline-1,3-dione as a yellow solid (210 mg, 16% yield): mp, 209-211 C.; 1H NMR (DMSO-d6) delta 2.02-2.08 (m, 1H, CHH), 2.46-2.63 (m, 2H, CH2), 2.82-2.97 (m, 1IH, CHH), 4.56 (d, J=6.2 Hz, 2H, CH2), 5.07 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.96 (d, J=8.6 Hz, 1H, Ar), 7.02 (d, J=7.0 Hz, 1H, Ar), 7.19-7.40 (m, 6H, Ar, NH), 7.51 (dd, J=7.5, 8.4 Hz, 1H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) delta 22.15, 30.99, 45.44, 48.59, 109.58, 110.74, 117.63, 126.95, 126.99, 128.53, 132.21, 136.09, 138.95, 146.09, 167.27, 168.78, 170.07, 172.79; Anal Calcd for C20H17N3O4: C, 66.11; H, 4.72; N, 11.56. Found: C, 65.96; H, 4.60; N, 11.49.
16%	With CF3COOH; sodium borohydrid; benzaldehyde; In water; acetic acid; ethyl acetate; acetonitrile;	2-(2,6-Dioxo(3-piperidyl))-4-[benzylamino]isoindoline-1,3-dione-I-13 A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.0 g, 3.7 mmol) and benzaldehyde (0.4 ml, 3.9 mmol) in acetic acid (20 ml) was stirred at room temperature for 17 h, then was heated to reflux for 3 h. The mixture was cooled to room temperature. To the stirred mixture was added sodium borohydride (140 mg, 3.7 mmol) and kept at room temperature for 18 h. The mixture was then heated to reflux for 2 h. To the mixture was added additional benzaldehyde (0.4 ml, 3.9 mmol) during reflux. After 30 min of reflux the reaction was allowed to cool to room temperature. To the mixture was added sodium borohydride (180 mg, 4.8 mmol) and the mixture stirred at room temperature for 3 days. The solvent was removed in vacuo to yield an oil. The oil was diluted with ethyl acetate (90 ml) and aqueous sodium hydrogen carbonate (sat, 100 ml). The organic layer was separated and was washed with aqueous sodium hydrogen carbonate (sat, 2*100 ml), brine (100 ml) and dried over MgSO4. The solvent was removed in vacuo to give a solid. The solid was purified by column chromatography (Silca Gel, 50% EtOAc:CH2Cl2) to give a yellow solid. The solid was further purified by column chromatography (KP-C18-HS, 35:65 CH3CN:0.1% CF3COOH in water) to give 2-(2,6-dioxo(3-piperidyl))-4-[benzylamino]isoindoline-1,3-dione as a yellow solid (210 mg, 16% yield): mp, 209-211 C.; 1H NMR (DMSO-d6) delta2.02-2.08 (m, 1H, CHH), 2.46-2.63 (m, 2H, CH2), 2.82-2.97 (m, 1H, CHH), 4.56 (d, J=6.2 Hz, 2H, CH2), 5.07 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.96 (d, J=8.6 Hz, 1H, Ar), 7.02 (d, J=7.0 Hz, 1H, Ar), 7.19-7.40 (m, 6H, Ar, NH), 7.51 (dd, J=7.5, 8.4 Hz, 1H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) delta22.15, 30.99, 45.44, 48.59, 109.58, 110.74, 117.63, 126.95, 126.99, 132.21, 136.09, 138.95, 146.09, 167.27, 168.78, 170.07, 172.79; Anal Calcd for C20H17N3O4: C, 66.11; H, 4.72; N, 11.56. Found: C, 65.96; H, 4.60; N, 11.49.

Reference： [1]Patent: US2003/45552,2003,A1
[2]Patent: US2003/96841,2003,A1

38
[ 5781-53-3 ]
[ 19171-19-8 ]
[ 444287-77-8 ]

Yield	Reaction Conditions	Operation in experiment
0.55 g (76%)	In tetrahydrofuran; diethyl ether;	Methyl {N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]carbamoyl}formate I-34 To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55g, 2.0 mmol) in THF (30 ml) was added methyl (chlorocarbonyl)formate (0.49 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.55 g (76%) of product as an off-white solid: mp 247-249 C.; 1H NMR (DMSO-d6) delta11.17 (s, 1H), 10.81 (s, 1H), 8.59 (d, J=8.3 Hz, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.70 (d, J=7.3 Hz, 1H), 5.19 (dd, J=5.0 and 12.5 Hz, 1H), 3.91 (s, 3H), 2.98-2.85 (m, 1H), 2.68-2.50 (m, 2H), 2.14-2.09 (m, 1H); 13C NMR (DMSO-d6) delta172.70, 169.63, 168.03, 166.45, 159.81, 154.57, 136.65, 134.93, 131.36, 124.67, 119.34, 117.17, 53.80, 49.06, 30.92, 21.94; Anal. Calcd. For C18H13N3O7: C, 53.49; H, 3.65; N, 11.70. Found: C, 53.53; H, 3.66; N, 11.52.

Reference： [1]Patent: US2003/96841,2003,A1

39
[ 527-69-5 ]
[ 19171-19-8 ]
[ 444287-78-9 ]

Yield	Reaction Conditions	Operation in experiment
0.65 g (88%)	In tetrahydrofuran; diethyl ether;	N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-2-furylcarboxamide I-35 To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added furan-2-carbonyl chloride (0.52 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. To the reaction mixture was added additional furan-2-carbonyl chloride (0.26 g, 2 mmol). The mixture was heated to reflux for an additional 8 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.65 g (88%) of product as an off-white solid: mp 299-301 C.; 1H NMR (DMSO-d6) delta11.19 (s, 1H), 10.37 (s, 1H), 8.68 (dd, J=1.4 and 8.4 Hz, 1H), 8.06 (s, 1H), 7.90 (t, J=8.1 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.39 (d, J=3.5 Hz, 1H), 6.79 (dd, J=1.5 and 3.2 Hz, 1H), 5.19 (dd, J=5.1 and 12.5 Hz, 1H), 2.98-2.84 (m, 1H), 2.67-2.49(m, 2H), 2.13-2.08 (m, 1H); 13C NMR (DMSO-d6) delta172.66, 169.62, 168.44 166.59, 155.71, 146.80, 146.34, 136.55, 136.23, 136.12, 131.30, 124.86, 118.54, 116.64, 113.06, 48.98, 30.90, 22.01; Anal. Calcd. For C18H13N3O6: C, 58.86; H. 3.57; N8 11.44 Found: C, 58.69; H, 3.54; N, 11.41.

Reference： [1]Patent: US2003/96841,2003,A1

40
[ 24666-56-6 ]
[ 6946-22-1 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
94%		Example 14; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; Example 14 was prepared similarly according to the procedure for Example 13 except that there was no acetic acid; the amount of triethylamine was reduced from 4.6 mol to 3.2 mol; and the refluxing time was increased from about 5 to 7 hours to about 47 hours. The amount of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reaction mixture was found to be 94percent.
92%		Example 15; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; Example 15 was prepared similarly according to the procedure for Example 13 except that there was no acetic acid and the 4.6 mol of triethylamine was replaced with 9.2 mole of imidazole. The amount of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reaction mixture was found to be 92percent
85%		Example 16; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; Example 16 was prepared similarly according to the procedure for Example 13 except that the 4.6 mol of triethylamine was replaced with 9.2 mole of imidazole. The amount of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione in the reaction mixture was found to be 85percent.

84%		Example 13; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; According to Scheme E A mixture of 3-aminophthalic acid hydrochloride (200 g, 0.92 mol, from Prosynth Ltd., Suffolk, UK), 3-aminoglutarimide hydrochloride (159 g, 0.96 mol, from Evotec OAI, Hamburg, Germany), acetonitrile (2.0 L), and acetic acid (577 g, 9.6 mol, from Fisher Scientifc) was charged into a reaction vessel. After the mixture was stirred for 15 minutes, triethylamine (465.0 g, 4.6 mol, from Aldrich, Milwaukee, Wis.) was added dropwise over 30-35 minutes while the reaction temperature was maintained at 20-25° C. Next, the reaction mixture was stirred further for 10-15 minutes and then refluxed at about 85 to 87° C. for about 5 to 7 hours or until the in-process control, i.e., HPLC AP at 240 nm, indicates that <2percent of the 3-aminophthalic acid remained in the reaction mixture. After the reaction mixture was cooled to about 20 to 25° C. over 1-2 hours, 1.0 L of water was charged over 15-30 minutes at about 20 to 25° C. The resulting mixture was stirred at about 15 to 20° C. for about 20 to 30 minutes to provide a yellow solid precipitate, which was filtered, washed with DI water (3.x.1.0 L) and acetonitrile (2.x.500 mL), and then dried at about 35 to 40° C in vacuo to a constant weight at 210.0 g (84 percent).
68.5%	With acetic acid; triethylamine; In acetone; at 80 - 85℃; for 6h;	Acetonitrile (100 mL), acetic acid (26.28 mL, 459.5 mmol),Triethylamine (31.85 mL, 229.8 mmol), 3-aminophthalic acid hydrochloride (10 g, 46.0 mmol),Aminopiperidine-2,6-dione hydrochloride (7.68 g, 46.6 mmol)Added to the reaction flask, heated to 80 ~ 85 ° C reflux, the reaction was complete after 6h,The reaction solution was cooled to 20 ~ 25 ° C, purified water was slowly added, the crystallization was stirred for 2h, filtered, the filter cake was dried under reduced pressure at 60 ± 5 ° C for 8h to obtain 8.6g black solid, yield 68.5percent

Reference： [1]Patent: US2007/4920,2007,A1 .Location in patent: Page/Page column 13
[2]Patent: US2007/4920,2007,A1 .Location in patent: Page/Page column 13-14
[3]Patent: US2007/4920,2007,A1 .Location in patent: Page/Page column 14
[4]Patent: US2007/4920,2007,A1 .Location in patent: Page/Page column 13
[5]Patent: CN107325075,2017,A .Location in patent: Paragraph 0029; 0030; 0031

41
2-(4-amino-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid [ No CAS ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With 1,1'-carbonyldiimidazole; In acetonitrile; at 40 - 45℃; for 4.5h;Heating / reflux;Product distribution / selectivity;	Example 3; Preparation of 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; According to Scheme A A mixture of acetonitrile (42 L) and Example 2 (2120 g, 7.28 moles) was added to a round bottom flask equipped with a mechanical stirrer, a condenser, a nitrogen inlet and a heating mantel to form a solution. When the solution was stirred and heated to about 40 to 45 C., 1,1'-carbonyldiimidazole (1290 g, 7.95 moles) was added. The reaction mixture was stirred and refluxed for 4.5 hours. The progress of the reaction was monitored by HPLC using a Waters Nova-Pak C18 column (3.9×150 mm, particle size=4 micron, UV wavelength=240 nm, retention time=3.64 minutes) and an eluent mixture of acetonitrile and 0.1% aqueous H3PO4 in a ratio of 20:80 by volume at a flow rate of 1 mL/min. After cooled to room temperature, the reaction mixture was filtered to yield a yellow solid which was subsequently washed with acetonitrile (6.5 L). The yellow solid was air dried and then dried in a vacuum oven at 60 C. and <1 mm pressure to yield 1760 g (88%) of the product. The product purity was found to be 99.57% by HPLC using a Waters Nova-Pak C18 column (3.9×150 mm, particle size=4 micron, UV wavelength=240 nm, retention time=3.64 minutes) and an eluent mixture of acetonitrile and 0.1% aqueous H3PO4 in a ratio of 20:80 by volume as at a flow rate of 1 mL/min. The product in DMSO-d6 was characterized by a 1H NMR spectrum showing the following chemical shifts (delta, ppm): 11.10 (s, 1 H), 7.47 (t, J=7.9 Hz, 1 H), 7.03-6.99 (dd, J=4.8 and 8.4 Hz, 2 H), 6.52 (s, 2 H), 5.09-5.02 (dd, J=5.3 and 12.4 Hz, 1 H), 2.96-2.82 (m, 1 H), 2.62-2.46 (m, 2 H), 2.07-2.00 (m, 1 H); and by a 13C NMR spectrum showing the following chemical shifts (delta, ppm): 172.82, 170.11, 168.57, 167-37, 146.71, 135.46, 131.99, 121.70, 110.97, 108.52, 48.47, 30.97, 22.14. The melting point of the product was found to be 315.5-317.5 C. An elemental analysis yielded the following results in weight percent: C, 56.98; H, 3.86; N, 15.35, which compared with calculated values for C13H11N3O4, in weight percent: 57.14; H, 4.06; N, 15.38.

Reference： [1]Patent: US2007/4920,2007,A1 .Location in patent: Page/Page column 11-12

Yield	Reaction Conditions	Operation in experiment
80%	In 2,2,2-trifluoroethanol; at 150℃; for 2h;Microwave irradiation;	General procedure: A suspension of tert-butyl N-(2,6-dioxo-3-piperidyl)carbamate (1 eq.) and the corresponding anhydride (1 eq.) in Trifluoroethanol was heated for 2 h at 150 C under microwave conditions. After cooling to r.t. the reaction mixture was cooled to -20 C for 4 h. If the desired product did not precipitate after cooling to -20 C, ethyl acetate (3 drops) was added and the mixture kept at -20 C for additional 4 h. The precipitated product was filtered off, washed with ethyl acetate (3 x 2 ml) and dried to constant weight; 2-(2,6-dioxopiperidin-3-yl)hexahydro-1H-isoindole-1,3(2H)-dione, 1; Compound 1 was prepared according to GP1 using 400 mg of tert-butyl N-(2,6-dioxo-3- piperidyl)carbamate to yield 399 mg (86%) of 2-(2,6-dioxopiperidin-3-yl)hexahydro-1H- isoindole-1,3(2H)-dione.1H NMR (500 MHz, DMSO-d6) delta 11.00 (s, 1H), 4.88 (dd, J = 12.8, 5.5 Hz, 1H), 3.05-2.93 (m, 2H), 2.81 (ddd, J = 17.1, 14.0, 5.5 Hz, 1H), 2.52 (ddd, J = 17.0, 4.4, 2.5 Hz, 1H), 2.40 (qd, J = 13.1, 4.4 Hz, 1H), 1.86 (dtd, J = 13.1, 5.4, 2.4 Hz, 1H), 1.78- 1.57 (m, 4H), 1.47-1.19 (m, 4H).13C NMR (126 MHz, DMSO-d6) delta 179.30, 179.21, 173.14, 169.85, 49.22, 31.17, 23.58, 23.39, 21.58, 21.53, 21.48. HRMS: calc. [M-H]- for C13H16N2O4 = 263.1110; found = 263.1165 [M-H]- .
		Specific immunomodulatory compounds include, but are not limited to: ... 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.
		Specific immunomodulatory compounds include, but are not limited to: 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.

		Particularly preferred compounds include: 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline 1,3dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline 1,3dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline
		Specific immunomodulatory compounds include, but are not limited to: 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.
		Specific immunomodulatory compounds include, but are not limited to: 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline; oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.

43
[ 19171-18-7 ]
[ 67-64-1 ]
(±)-2-(2,6-dioxopiperidin-3-yl)-4-(isopropylamino)isoindoline-1,3-dione [ No CAS ]
[ 19171-19-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 878 - 881

44
N-(3-aminophthaloyl)-glutamine [ No CAS ]
[ 530-62-1 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
88%		To a round bottom flask equipped with a mechanical stirrer, a condenser, a nitrogen inlet and a heating mantel was charged with a mixture of acetonitrile (42 L) and N-(3-aminophthaloyl)-glutamine (2120 g, 7.28 moles). After the mixture was stirred and heated to 40-45 C., 1,1'-carbonyldiimidazole (1290 g, 7.95 moles) was added. The reaction mixture was stirred and refluxed for 4.5 hours. The progress of the reaction was monitored by HPLC using a Waters Nova-Pak C18 column (3.9×150 mm, particle size=4 micron, UV wavelength=240 nm, retention time=3.64 minutes) and a 20/80 mixture of acetonitrile and 0.1% aqueous H3PO4 by volume as an eluent at a flow rate of 1 mL/min. After cooled to room temperature, the reaction mixture was filtered to yield a yellow solid which was subsequently washed with acetonitrile (6.5 L). The yellow solid was air dried and then dried in a vacuum oven at 60 C. and a pressure <1 mm to yield 1760 g (88%) of the product. The product purity was found to be 99.57% by HPLC using a Waters Nova-Pak C18 column (3.9×150 mm, particle size=4 micron, UV wavelength=240 nm, retention time=3.64 minutes) and a 20/80 mixture of acetonitrile and 0.1% aqueous H3PO4 by volume as an eluent at a flow rate of 1 mL/min. The product in DMSO-d6 was characterized by a 1H NMR spectrum showing the following chemical shifts (delta in ppm): 11.10 (s, 1H), 7.47(t, J=7.9 Hz, 1H), 7.03-6.99 (dd, J=4.8 and 8.4 Hz, 2H), 6.52 (s, 2H), 5.09-5.02 (dd, J=5.3 and 12.4 Hz, 1H), 2.96-2.82 (m, 1H), 2.62-2.46 (m, 2H), 2.07-2.00 (m, 1H); and by a 13C NMR spectrum showing the following chemical shifts (delta in ppm): 172.82, 170.11, 168.57, 167-37, 146.71, 135.46, 131.99, 121.70, 110.97, 108.52, 48.47, 30.97, 22.14. The melting point of the product was found to be 315.5-317.5 C. An elemental analysis yielded the following results in weight percent: C, 56.98; H, 3.86; N, 15.35, which compared with calculated values for C13H11N3O4, in weight percent: 57.14; H, 4.06; N, 15.38.

Reference： [1]Patent: US2007/155791,2007,A1 .Location in patent: Page/Page column 14-15

45
(RS)-2,6-dioxopiperidin-3-yl-ammonium trifluoroacetate [ No CAS ]
[ 19171-19-8 ]

Reference： [1]Patent: US2013/143922,2013,A1
[2]Bioorganic Chemistry,2018,vol. 81,p. 536 - 544

46
[ 641-70-3 ]
[ 19171-19-8 ]

Reference： [1]Patent: US2013/143922,2013,A1
[2]Synthetic Communications,2016,vol. 46,p. 1343 - 1348
[3]Synthetic Communications,2016,vol. 46,p. 1343 - 1348
[4]Patent: CN103724323,2016,B
[5]Patent: CN103724323,2016,B
[6]Patent: CN103724323,2016,B
[7]Patent: CN103724323,2016,B
[8]Patent: CN107365295,2017,A
[9]ACS Chemical Biology,2018,vol. 13,p. 2771 - 2782
[10]Bioorganic Chemistry,2018,vol. 81,p. 536 - 544
[11]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 1375 - 1379
[12]Patent: WO2019/207538,2019,A1
[13]Patent: US2019/322647,2019,A1

47
[ 7693-46-1 ]
[ 19171-19-8 ]
4-nitrophenyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	In tetrahydrofuran; at 75℃; for 0.5h;Inert atmosphere;	Pomolidamide 58 (218 mgs, 0.8 mmoles) and 4-nitrophenyl chloroformate (242 mgs, 1.2 mmoles) were combined in anhydrous tetrahydrofuran (20 mis). The reaction was placed under nitrogen atmosphere and heated at 75 C for 30 mins. The tetrahydrofuran was evaporated in vacuo and the resulting yellow solid was suspended in ethyl acetate. This was filtered to yield 4-nitrophenyl (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)carbamate (224 mgs, 64%). [001828] 1H NMR (400 MHz, DMSO-J6) delta 11.15 (s, 1H), 9.77 (s, 1H), 9.66 (s, 1H), 9.06 (s, 1H), 8.84 (t, 7 = 5.7 Hz, 1H), 8.43 (d, 7 = 8.5 Hz, 1H), 7.78 (dd, 7 = 8.5, 7.3 Hz, 1H), 7.50 (d, 7 = 7.2 Hz, 1H), 7.29 - 7.16 (m, 4H), 6.73 (s, 1H), 6.44 (s, 1H), 5.14 (dd, 7 = 12.8, 5.4 Hz, 1H), 3.48 (dd, 7 = 10.0, 5.2 Hz, 6H), 3.29 - 3.14 (m, 2H), 3.02 - 2.83 (m, 2H), 2.65 - 2.52 (m, 2H), 2.42 (t, 7= 5.0 Hz, 4H), 2.09 - 2.01 (m, 1H), 1.07 (t, 7= 7.2 Hz, 3H), 0.91 (d, 7 = 6.8 Hz, 6H). ESMS calculated for C40H41N7O9: 763.3; found: 764.7(M+H+).
55%	In tetrahydrofuran;Reflux;	A solution of <strong>[19171-19-8]pomalidomide</strong> (278 mg, 1 mmol), 4-nitrophenyl carbonochloridate (307 mg, 1.52 mmol) in THF (5 ml) was heated at reflux overnight. After being cooled to RT, the reaction mixture was concentrated. The resultingresidue was washed with ethyl acetate, dried over NaSO4, and concentrated to yield the intermediate 13 (240 mg, 55%) as yellow solid. To a stirring solution of intermediate 13 (19 mg, 0.043 mmol) in DMF (1 mL) were added DIEA (0.014 mL, 0.1 mmol) and palbociclib (18 mg, 0.041 mmol). The mixture was stirred at RT overnight, before being concentrated. The resulting residue was purified by prep-HPLC to yield the title compound (14 mg, 46%) asyellow solid. ?H NMR (600 MHz, CD3OD) 39.07 (s, 1H), 8.56 (d, J= 8.5 Hz, 1H), 8.10 (dd,J 9.6, 2.6 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.64 (d, J= 8.8 Hz, 1H), 7.51 (d, J= 7.3 Hz, 1H),5.97 (p, J 8.9 Hz, 1H), 5.07 (dd, J 12.5, 5.5 Hz, 1H), 3.86 - 3.79 (m, 4H), 3.45 - 3.40 (m,4H), 2.89-2.72 (m, 3H), 2.54 (s, 3H), 2.44 (s, 3H), 2.33 -2.27 (m, 2H), 2.22-2.15 (m, 1H),2.11 -2.06 (m, 2H), 1.96- 1.86 (m, 2H), 1.73 - 1.59 (m, 2H). HRMS (ESI-TOF) m/z: [M+Hjcalculated for C38H39N1007, 747.2998; found: 747.2970.
180 mg	In tetrahydrofuran; for 4h;Reflux;	To a solution of compound 27 (200 mg, 0.70 mmol) in dry THF (20 ml) was added 4- nitrophenyl carbonochloridate (233 mg, 1.10 mmol). The mixture was stirred at reflux for 4 hours. The mixture was concentrated to 5 mL, and filtered to give compound 28 as a solid (180 mg).

In tetrahydrofuran; for 4h;

The 4-nitrophenylchloroformate (2, 230 mg, 1.14 mmol) was added to a stirring suspension of <strong>[19171-19-8]pomalidomide</strong> (1, 208 mg, 0.76 mmol) in dry THF (30 mL) at ambient temperature. After the resulting mixture was heated at 70C (oil bath) for 4 h. After cool down to ambient temperature, volatiles were removed under the reduced pressure to give yellowish solid, which was washed with DCM to give product 3 in xx mg (xx %). The corresponding product was used without further purification.

Reference： [1]Patent: WO2015/38649,2015,A1 .Location in patent: Paragraph 001827; 001828
[2]Patent: WO2018/106870,2018,A1 .Location in patent: Page/Page column 85; 116
[3]Patent: WO2016/65139,2016,A1 .Location in patent: Page/Page column 53
[4]Patent: WO2019/241766,2019,A1 .Location in patent: Paragraph 0041; 0444-0045

48
[ 139053-41-1 ]
[ 19171-19-8 ]
C₅₆H₈₄O₄₉*C₁₃H₁₁N₃O₄ [ No CAS ]
C₅₆H₈₄O₄₉*C₁₃H₁₁N₃O₄ [ No CAS ]

Reference： [1]Chirality,2016,vol. 28,p. 199 - 203

49
α-cyclodextrin sulfate sodium salt [ No CAS ]
[ 19171-19-8 ]
C₃₆H₅₄O₄₈S₆^(6-)*6Na⁽¹⁺⁾*C₁₃H₁₁N₃O₄ [ No CAS ]
C₃₆H₅₄O₄₈S₆^(6-)*6Na⁽¹⁺⁾*C₁₃H₁₁N₃O₄ [ No CAS ]

Reference： [1]Chirality,2016,vol. 28,p. 199 - 203

50
β-cyclodextrin sulfate sodium salt [ No CAS ]
[ 19171-19-8 ]
C₄₂H₆₃O₅₆S₇^(7-)*7Na⁽¹⁺⁾*C₁₃H₁₁N₃O₄ [ No CAS ]
C₄₂H₆₃O₅₆S₇^(7-)*7Na⁽¹⁺⁾*C₁₃H₁₁N₃O₄ [ No CAS ]

Reference： [1]Chirality,2016,vol. 28,p. 199 - 203

51
γ-cyclodextrin sulfate sodium salt [ No CAS ]
[ 19171-19-8 ]
C₄₈H₇₂O₆₄S₈^(8-)*8Na⁽¹⁺⁾*C₁₃H₁₁N₃O₄ [ No CAS ]
C₄₈H₇₂O₆₄S₈^(8-)*8Na⁽¹⁺⁾*C₁₃H₁₁N₃O₄ [ No CAS ]

Reference： [1]Chirality,2016,vol. 28,p. 199 - 203

52
sulfobutylether-α-cyclodextrin sodium salt [ No CAS ]
[ 19171-19-8 ]
C₆₀H₁₀₂O₄₈S₆^(6-)*6Na⁽¹⁺⁾*C₁₃H₁₁N₃O₄ [ No CAS ]
C₆₀H₁₀₂O₄₈S₆^(6-)*6Na⁽¹⁺⁾*C₁₃H₁₁N₃O₄ [ No CAS ]

Reference： [1]Chirality,2016,vol. 28,p. 199 - 203

53
6-O-(sulfobutyl)-β-cyclodextrin sodium salt [ No CAS ]
[ 19171-19-8 ]
C₇₀H₁₁₉O₅₆S₇^(7-)*7Na⁽¹⁺⁾*C₁₃H₁₁N₃O₄ [ No CAS ]
C₇₀H₁₁₉O₅₆S₇^(7-)*7Na⁽¹⁺⁾*C₁₃H₁₁N₃O₄ [ No CAS ]

Reference： [1]Chirality,2016,vol. 28,p. 199 - 203

54
sulfobutylether-γ-cyclodextrin sodium salt [ No CAS ]
[ 19171-19-8 ]
C₈₀H₁₃₆O₆₄S₈^(8-)*8Na⁽¹⁺⁾*C₁₃H₁₁N₃O₄ [ No CAS ]
C₈₀H₁₃₆O₆₄S₈^(8-)*8Na⁽¹⁺⁾*C₁₃H₁₁N₃O₄ [ No CAS ]

Reference： [1]Chirality,2016,vol. 28,p. 199 - 203

55
C₁₅H₂₈Cl₂O₄ [ No CAS ]
[ 19171-19-8 ]
6-(2-(2-(((6-chlorohexyl)oxy)ethoxy))ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2016,vol. 55,p. 807 - 810
Angew. Chem.,2016,vol. 128,p. 818 - 821,4

56
[ 19171-19-8 ]
N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-6-(2-(2-((6-iodohexyl)oxy)ethoxy)ethoxy)hexanamide [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2016,vol. 55,p. 807 - 810
Angew. Chem.,2016,vol. 128,p. 818 - 821,4
[2]Patent: WO2017/79267,2017,A1

57
[ 19171-19-8 ]
N-(2-chloro-6-methylphenyl)-2-((6-(4-(6-(2-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-6-oxohexyl)oxy)ethoxy)ethoxy)hexyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2016,vol. 55,p. 807 - 810
Angew. Chem.,2016,vol. 128,p. 818 - 821,4
[2]Patent: WO2017/79267,2017,A1

58
[ 19171-19-8 ]
C₂₉H₃₀N₄O₉ [ No CAS ]

Reference： [1]Patent: WO2016/65139,2016,A1

59
[ 19171-19-8 ]
C₂₅H₂₂N₄O₉ [ No CAS ]

Reference： [1]Patent: WO2016/65139,2016,A1

60
[ 19171-19-8 ]
C₂₁H₁₈N₄O₆S₂ [ No CAS ]

Reference： [1]Patent: WO2016/65139,2016,A1

61
[ 19171-19-8 ]
C₃₂H₃₆N₄O₉S₂ [ No CAS ]

Reference： [1]Patent: WO2016/65139,2016,A1

62
[ 19171-19-8 ]
C₂₈H₂₈N₄O₉S₂ [ No CAS ]

Reference： [1]Patent: WO2016/65139,2016,A1

63
[ 19171-19-8 ]
C₃₂H₃₆N₄O₉S₂ [ No CAS ]

Reference： [1]Patent: WO2016/65139,2016,A1

64
[ 19171-19-8 ]
C₂₈H₂₈N₄O₉S₂ [ No CAS ]

Reference： [1]Patent: WO2016/65139,2016,A1

65
[ 603-11-2 ]
[ 19171-19-8 ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1343 - 1348
[2]Synthetic Communications,2016,vol. 46,p. 1343 - 1348
[3]Patent: CN104402863,2016,B
[4]Patent: WO2017/221261,2017,A1

66
3-amino-2-((2,6-dioxopiperidin-3-yl)carbamoyl)benzoic acid [ No CAS ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	In toluene; at 100℃; for 3h;	Compound IV-1 (1.0g, 3.44mmol), dissolved in 15mL toluene at 100 C, reacted for 3.0 hours. After completion of the reaction, the reaction was stopped and the temperature was reduced to 5 C. The system had a yellow solid precipitated, filtered, ethanol washed cake (10 mL × 3) and vacuum dried to give pomalidomide 0.84 g, 89%.
71.43%	In methanol; for 2h;Reflux; Green chemistry;	The above solution of intermediate 12 in methanol was heated to reflux for 2 hours. On cooling, the precipitate was collected to deliver desired product (1) as ayellow solid (9.11 g, 71.43%), 99.56% (HPLC).

Reference： [1]Patent: CN103724323,2016,B .Location in patent: Paragraph 0079-0081
[2]Synthetic Communications,2016,vol. 46,p. 1343 - 1348

67
[ 10027-07-3 ]
[ 19171-19-8 ]
8-((2(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-8-oxooctanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	In tetrahydrofuran; at 80℃; for 1h;Sealed tube; Inert atmosphere;	8-((2(2,6-dioxopiperidin3yI)-1 ,3dioxoisoindo1in-4-yI)amino)-8-oxooctanoic acid (16). To aflame dried vial with a stir bar 25 ing of pomalidornide was added. The vial Was capped and purged with argon and 1.5 ml. of dry IHF was added. While stirring al 25C 82 iLof Suberoyl chloride was added dropwise. The reaction was heated to 80C for 1 hour after which the reaction was cooled to room temperature. Water was added and the reaction was allowed to stir for 15 minutes. The mixture was then extracted ith EtOAc three times, The pooled organic layer was dried with MgSO4, filtered, and evaporated under reduced pressure. The material was purified by column chromatography (eluent: DCM to 5% MeOH/DCM.Product containing fractions were, pooled, and reduced in vacuo to give 10.7 rng (27%) of 16. MS (ES+) m/z 430.8 (M + H

Reference： [1]Patent: WO2017/40982,2017,A1 .Location in patent: Paragraph 0453; 0486; 0487

68
C₁₅H₁₇N₃O₅ [ No CAS ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	In ethanol; at 75℃; for 2.7h;	Compound IV-3 (1.0 g, 3.13 mmol) was dissolved in 65 mL of ethanol at 75 C for 2.7 hours,After the reaction is completed, stop heating, naturally down to 30 , the system has a yellow solid precipitation, filtration,Acetonitrile washed cake (10 mL x 3) and vacuum dried to give pomalidomide 0.88g, 94%.

Reference： [1]Patent: CN103724323,2016,B .Location in patent: Paragraph 0097-0099

69
C₁₆H₁₉N₃O₅ [ No CAS ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	In isopropyl alcohol; at 82℃; for 2.7h;	Compound IV-4 (1.0 g, 3.19 mmol) was dissolved in 40 mL of isopropanol at 82 C,Reaction for 2.7 hours, the reaction is completed, stop heating, naturally dropped to 30 , the system has a yellow solid precipitation,The filter cake (10 mL x 3) was filtered and dried in vacuo to give 0.82 g of pomalidomide, 87%.

Reference： [1]Patent: CN103724323,2016,B .Location in patent: Paragraph 0100-0102

70
2-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-nitrobenzoic acid [ No CAS ]
[ 19171-19-8 ]

Reference： [1]Patent: CN103724323,2016,B
[2]Patent: CN103724323,2016,B
[3]Patent: CN103724323,2016,B
[4]Patent: CN103724323,2016,B

71
C₁₄H₁₃N₃O₇ [ No CAS ]
[ 19171-19-8 ]

Reference： [1]Patent: CN103724323,2016,B

72
C₁₅H₁₅N₃O₇ [ No CAS ]
[ 19171-19-8 ]

Reference： [1]Patent: CN103724323,2016,B

73
C₁₄H₁₅N₃O₅ [ No CAS ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
96%	In acetonitrile; at 80℃; for 2.5h;	Compound IV-2 (1.0 g, 3.28 mmol) was dissolved in 50 mL of acetonitrile at 80 C,Reaction for 2.5 hours, after the completion of the reaction, stop heating, naturally dropped to 25 , the system has a yellow solid precipitation,Filtered, tetrahydrofuran washed cake (10 mL x 3) and vacuum dried to give pomalidomide 0.90 g, 96%.

Reference： [1]Patent: CN103724323,2016,B .Location in patent: Paragraph 0091-0093

74
6-[2-[2-(6-chlorohexoxy)ethoxy]ethoxy]hexanoyl chloride [ No CAS ]
[ 19171-19-8 ]
6-(2-(2-(((6-chlorohexyl)oxy)ethoxy))ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.8%	In tetrahydrofuran; for 4h;Reflux;	(6-[2-[2-(6-chiorohexoxy)ethoxyiethoxy]hexanoyi chloride (110 mg. 0.31 rnmol) was dissolved in IHF (2 ml), To this solution was added 4-arnino-2-(2,6-dioxo-3- piperidvi)isoindoline-l,3-dione (84.12 mg. 0.31 rnmoi). 113e resulting suspension was heated to reflux for 4 hours. The solvent was evaporated in vacuo and the resulting solid was purified by flash chromatography (50/50 to 0/100 hexane/ethyl acetate) to give a lightyellow solid 157 mg (85.8%) of the desired product. 1H NMR (500 MHz, Chioroform-d) oe9.41 (s, IH), 8.82 (d, J = 7.8 Hz, 1H), 8.45 (s, 1H), 7.70 (t, J = 7.8 Hz. 1H), 7.54 (d, J = 7.8Hz, 1H, 4.96 (dd, J 12.0 Hz, J 6.5 Hz, 1Ff), 3.66-3.61 (in, 4Ff), 3.60-3.57 (m, 4H), 3.52(t, J 6.3 Hz, 2H), 3.50-3.43 (m, 4H), 2.91 (d, J == 13.6 Hz. 1H), 2.85-2.72 (m, 2H), 2.46 (t, J= 7.3 Hz, 2H), 2.21-2.12 (rn, 1H), 1.80-i .73 (in. 4H), 1.67-1.55 (in, 4H), 1.50-1.34 (in, 6H).13CNMR(151 MFIz, Chioroform-d) oe 172.2, 170.9, 169.1. 167.9. 166.7, 137.8, 136.4. 131.1,125.2, 118.4, 115.2, 71.2, 71.0, 70.6, 70.0, 49.2, 45.0, 37.9. 32.5, 31.4, 29.4, 29.3, 26.7, 25.7,25.4, 25.0, 22.6. MS (ESI); rnIz: [M+Hj caicd for C29H41C1N305: 594.2, found 594.1.

Reference： [1]Patent: WO2017/79267,2017,A1 .Location in patent: Page/Page column 91; 92

75
[ 340020-02-2 ]
[ 2353-44-8 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
96.6%	With sodium acetate; In acetonitrile; for 4h;Reflux;	40.0 g (170.8 mmol) of ethyl 4-amino-1,3-dioxo-1,3-dihydro-2H-isomdole-2-carboxylate, 800 cm3 of acetonitrile, 28.4 g (342.0 mmol) of anhydrous sodium acetate, 28.1 g (170.7 mmol) of 3-aminopiperidine-2,6-dione are measured into a 1000 cm3 round-bottomed flask, then the suspension obtained in this way is heated to reflux temperature. The stirring is continued at unchanged temperature for 4 hours. The reaction mixture is concentrated to about 40 cm3 at 40 C with the help of a vacuum. 800 cm3 of distilled water is added to the concentrated residue, which is then stirred at room temperature for 30 minutes. (The water may also be added at an earlier stage.) Following this the crystalline product is filtered, washed with 2x400 cm3 of distilled water, then dried at 50 C in a vacuum until constant weight is achieved. In this way 45.10 g (96.6%) of the product according to the title is obtained. Mp. : 314-315 C (decomposes) IR (KBr): 3481 , 3378, 3248, 1752, 1703, 1635, 1362, 1197 cm 1. 1H NMR (DMSO-d6, 400 MHz): delta = 11.10 (b, 1H), 7.47 (m, 1H), 7.02 (m, 1H), 7.00 (m, 1H), 5.06 (m, 1H), 2.89 (m, 1H), 2.58 (m, 1H), 2.56 (m, 1H), 2.03 (m, 1H) ppm. HPLC: Waters Acquity UPLC BEH C18; 2.1 x50 mm; 1.7 mum; 0.5 mL/min; 225 nm; 10/90 CH3CN/0.1 % HClO4 (aq); 1.38 min (99.90%).

Reference： [1]Patent: WO2017/134476,2017,A1 .Location in patent: Page/Page column 16

76
[ 490-79-9 ]
[ 19171-19-8 ]
(R,S)-4-amino-2-(2,6-dioxo-3-piperidinyl)isoindol-1,3-dione gentisicate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	In acetonitrile; at 20℃;	Preparation of the co-crystal <strong>[19171-19-8]Pomalidomide</strong>: Gentisic acid 1 : 1 Form 1 by suspension in acetonitrile <strong>[19171-19-8]Pomalidomide</strong> (Form 0, example 1 , 150 mg, 0.55 mmol) and Gentisic acid (169 mg, 1.1 mmol, 2 eq.) were introduced into a test tube equipped with magnetic stirring. Acetonitrile was added (1 ml, 6.7 vol.), the resulting mixture was seeded with Form 1 and stirred at room temperature overnight. The solid was filtered with a sintered glass filter (No. 3) and washed with ACN (2x2 vol, 2x0.3 ml). After vacuum drying at room temperature, 232 mg were obtained of pure Form 1 co-crystal <strong>[19171-19-8]Pomalidomide</strong>: Gentisic acid as a white solid (yield 99%). (0297) Characterization of Form 1 of the co-crystal <strong>[19171-19-8]Pomalidomide</strong>: Gentisic acid (1 : 1 ) (0298) The Form 1 co-crystal <strong>[19171-19-8]Pomalidomide</strong>: Ac Gentisic prepared in Example 7, was characterized by 1H- NMR, XRPD, DSC and TGA. (0299) 1H-NMR (DMSO-d6) (0300) The 1H-NMR spectrum of the sample of Form 1 (Figure 3) resulted the exact superposition of the spectra of <strong>[19171-19-8]Pomalidomide</strong> Form 0 and Gentisic acid. Neither degradation nor signal shifts were observed. The ratio between the signals confirmed the 1 :1 ratio of the components in the co-crystal deduced from the wet milling experiments. Acetonitrile was not present. (0301) XRPD (0302) The XRPD analysis of the co-crystal Form 1 was performed (Figure 8). In the following table 8, the peaks with relative intensity higher than or equal to 1 % have been reported: (0303) Table 8 (0304) 21.5 4.1 77 (0305) 21.9 4.1 14 (0306) 22.6 3.9 11 (0307) 23.1 3.8 10 (0308) 23.9 3.7 10 (0309) 24.4 3.6 6 (0310) 25.2 3.5 50 (0311) 25.3 3.5 64 (0312) 26.0 3.4 81 (0313) 26.4 3.4 26 (0314) 26.8 3.3 24 (0315) 27.4 3.2 18 (0316) 28.0 3.2 6 (0317) 28.6 3.1 48 (0318) 29.5 3.0 6 (0319) 30.2 3.0 6 (0320) 30.8 2.9 5 (0321) 31.5 2.8 6 (0322) 31.7 2.8 6 (0323) 32.2 2.8 6 (0324) 32.6 2.7 13 (0325) 32.9 2.7 14 (0326) 33.8 2.7 6 (0327) 33.7 2.7 8 (0328) 34.8 2.6 1 (0329) 35.7 2.5 1 (0330) 36.4 2.5 3 (0331) 37.2 2.4 1 (0332) 38.3 2.3 4 (0333) 38.9 2.3 7 (0334) 39.5 2.3 2 (0335) DSC (0336) The co-crystal Form 1 is characterized by an endothermic peak starting at 226C (melting enthalpy - 271.93 J/g) and peak at about 232C, corresponding to the melting and degradation of the Form 1 , measured by DSC analysis (10C / min) (Figure 5). (0337) TGA The thermogravimetric analysis of the co-crystal Form 1 showed only a negligible weight loss before the melting point (Figure 6). Therefore, the co-crystal Form 1 does not appear to be a hydrate. The thermal event after the melting point would correspond to decomposition.

Reference： [1]Patent: WO2017/121530,2017,A1 .Location in patent: Page/Page column 26-27

77
(R,S)-4-amino-2-(2,6-dioxo-3-piperidinyl)isoindol-1,3-dione gentisicate [ No CAS ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 24℃;	The effect of various solvents (ethyl acetate, methyl isobutyl ketone, ethanol, isopropanol and acetone) has been studied on the purity of Pomalidomide by suspension and stirring of the co-crystal Form 1. (0417) Co-Crystal Form 1 , prepared in ACN at 50C (example 10d *see Table 11), was suspended in 10 volumes of solvent and the resulting mixture stirred at room temperature for one night. The solid was filtered, washed with the same solvent (2 x 2 volumes) and dried under vacuum at room temperature. The chemical purity of Pomalidomide has been checked after 3.5 hours and after a night (see the following Table 14). A sample of each product was analyzed by HPLC in duplicate. In all solvents, after 3.5 hours, the co-crystal has been shown to be dissociated (as confirmed by XRPD). (0418) Table 14 (0419) Operating AG Imp. 1 PMD Imp. 2 Imp. 3 (0420) Ex. (0421) Conditions area % area % area % area % area % (0422) 24.0 0.07 75.2 0.10 0.50 (0423) 10d - (0.09) (98.9) (0.13) (0.66) (0424) 10d (Form 1) (0425) 11a 0.10 0.10 98.9 0.28 0.61 (0426) EtOAc, 3.5h (0427) 10d (Form 1) (0428) 11 b 0.23 0.09 98.8 0.20 0.62 (0429) EtOAc, night (0430) 10d (Form 1) (0431) 11c 0.11 0.10 98.9 0.22 0.62 (0432) MIBK, 3.5h (0433) 10d (Form 1) (0434) 11d 0.98 0.09 98.0 0.24 0.62 (0435) MIBK, night 10d (Form 1) (0436) 11e 0.25 0.10 98.8 0.23 0.61 (0437) EtOH, 3.5h (0438) 10d (Form 1) (0439) 11f 0.53 0.10 97.4 0.24 0.62 (0440) EtOH, night (0441) 10d (Form 1) (0442) n g 0.31 0.10 98.8 0.20 0.62 (0443) IPA, 3.5h (0444) 10d (Form 1) (0445) 11 h 0.11 0.10 99.0 0.19 0.57 (0446) IPA, night (0447) 10d (Form 1) (0448) 11 i 0.25 0.10 98.8 0.22 0.58 (0449) Acetone, 3.5h (0450) 10d (Form 1) (0451) 111 0.39 0.10 98.6 0.20 0.63 (0452) Acetone, night (0453) As it can be seen from the data shown in Table 14, the tested solvents (EtOAc, MIBK, EtOH, IPA and acetone) have not led to a significant decrease of the impurities after 3.5 h, not even after one night. These data further confirm that the purification of Pomalidomide is attributable to the formation and crystallization of the co-crystal Form 1 and not to the effect of the solvent itself in simple conditions of slurrying.

Reference： [1]Patent: WO2017/121530,2017,A1 .Location in patent: Page/Page column 35-36

78
2-azidoethoxyacetyl chloride [ No CAS ]
[ 19171-19-8 ]
2-(2-azidoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.13%	In 1-methyl-pyrrolidin-2-one; at 20℃; for 4h;	willPomodamine(0.26 g, 0.95 mmol) was dissolved in 3 mL of N-methylpyrrolidone and 1 e (0.32 g,1.9 mmol). After 4 hours at room temperature, 20 mL of water was added, precipitated as a solid, filtered and dried to give the crude product which was purified by silica gel column chromatography Purification by chromatography using dichloromethane / methanol (V / V = 150 / 1-100 / 1) gave a yellow solid, 0.21 g in yield55.13%
	In 1-methyl-pyrrolidin-2-one; at 20℃; for 3h;	General procedure: Lenalidomide (0.73 mmol) and 43a-d (1.46 mmol) were dissolvedin NMP (3 mL) and stirred at room temperature for 3 h. Then the reactionmixture was diluted with water (15 mL) and extracted with ethylacetate (15 mL). The organic layer was washed twice with saturatedbrine and dried over anhydrous sodium sulfate. After concentration, thecrude residue was purified by flash column chromatography (dichloromethane/methanol = 30:1) to give 44a-d. Intermediates 44e-hwere obtained by the same procedure starting from <strong>[19171-19-8]pomalidomide</strong> and43a-d.

Reference： [1]Patent: CN107056772,2017,A .Location in patent: Paragraph 0087; 0088; 0089
[2]Bioorganic and Medicinal Chemistry,2020,vol. 28

79
3-aminophthalic acid disodium salt [ No CAS ]
[ 24666-56-6 ]
[ 19171-19-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium acetate; acetic acid; In acetonitrile; at 80 - 85℃; for 8h;	Acetonitrile (100 mL),Acetic acid (25.41 mL, 444.2 mmol),Anhydrous sodium acetate (18.22 g, 222.1 mmol),Disodium 3-aminophthalate (10 g, 44.4 mmol),Aminopiperidine-2,6-dione hydrochloride (7.68 g, 46.6 mmol)Added to the reaction flask, heated to 80 ~ 85 C reflux,The reaction was complete after 8h, the reaction was cooled to 20 ~ 25 C, purified water was slowly added, stirred crystallization 2h, filtered, the filter cake was dried under reduced pressure 8 ± 5 C for 8h to give 10.2g of a yellow solid, yield 84.0% Purity 99.4%.

Reference： [1]Patent: CN107325075,2017,A .Location in patent: Paragraph 0019; 0020; 0021; 0022; 0023; 0024-0028

80
[ 19171-19-8 ]
[ 74-88-4 ]
4-amino-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%		To a solution of NaOtBu (0.074 g, 0.769 mmol) in DMSO (0.8 mL) was added a solution of <strong>[19171-19-8]pomalidomide</strong> (0.100 g, 0.366 mmol) in DMSO (0.5 mL plus 0.5 mL rinse) dropwise. The reaction was stirred for 10 min at room temperature followed by the addition of methyl iodide (0.025 mL, 0.403 mmol). After 18 h, glacial acetic acid (0.1 mL) was added to the reaction volatiles were removed in vacuo, and the crude dark-brown residue was purified by preparative reverse phase HPLC to afford 29 (0.02 g, 19%) as light yellow powder. 1H NMR (400 MHz, DMSO) delta 7.46 (dd, J = 8.4, 7.0 Hz, 1H), 7.00 (dd, J = 7.6, 5.6 Hz, 2H), 6.53 (br s, 2H), 5.11 (dd, J = 13.2, 5.7 Hz, 1H), 2.97 - 2.83 (m, 1H), 2.76 (s, 1H), 2.57 - 2.51 (m, 1H), 2.06 - 1.91 (m, 1H). MS (ESI) m/z calcd for C14H14N3O4 [M+H]+ 288.3, found: 288.5.

Reference： [1]Patent: EP2582836,2018,B1 .Location in patent: Paragraph 0191; 0197; 0198

81
[ 617-65-2 ]
[ 19171-19-8 ]

Reference： [1]Patent: CN107365295,2017,A

82
[ 18636-08-3 ]
[ 19171-19-8 ]

Reference： [1]Patent: CN107365295,2017,A

83
[ 22809-37-6 ]
[ 19171-19-8 ]
6-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	In tetrahydrofuran; for 12h;Inert atmosphere; Reflux;	Thionyl chloride (40 mL, 0.55 mol) and DMF (2.01 g, 27.40 mmol) were added to a stirred solution of 6-bromohexanoic acid (12.80 g, 65.90 mmol) in THF (300 mL).The resulting reaction mixture was stirred at 70C for 2 h. The progress of the reaction was monitored by TLC (30% EtOAc in -hexane) to ensure completion of the reaction. The solvent was evaporated under reduced pressure. A solution of 4-amino-2-(2,6-dioxopiperidin-3- yl)isoindoline-l,3-dione (15.0 g, 54.90 mmol) in THF (300 mL) was added to the reaction mixture. The reaction mixture was stirred at reflux for 12 h. The progress of the reaction was monitored by TLC (5% MeOH in DCM) to ensure completion of the reaction. The solvent was distilled out under reduced pressure. Water (700 mL) was added to the residue and the product was extracted with EtOAc (2 chi 750 mL). The combined EtOAc extracts were washed with brine (750 mL), dried over Na2S04, and concentrated under reduced pressure to afford 6-bromo-N-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hexanamide (17.80 g, 72.0%) as an off-white solid. NMR (300 MHz, DMSO-d6):511.15(s, 1H), 9.71 (s, 1H), 8.47 (d, 1H), 7.83 (d, 1H), 7.62 (d, 1H), 5.15 (m, 1H), 3.58 (m, 2H), 2.90 (m, 2H), 2.60 (m, 2H), 2.47 (d, 2H), 2.07 (m, 1H), 1.84 (m, 2H), 1.66 (m, 2H), 1.47 (m, 2H) ppm. MS (ESI): Calculated for Ci9H2oBrN305, 449.06, found, 449.80 (M-H)".
63%	In tetrahydrofuran; for 4h;Reflux;	General procedure: To a solution of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1, 1 mmol) in dry THF (4 mL) was added into 4-bromobutanoyl chloride (3 mmol). The reaction was heated toreflux for 4 h. The reaction mixture was concentrated and the residuewas extracted with DCM. The organic layer was washed withsaturated NaHCO3 and dried with anhydrous MgSO4. The residuewas purified by chromatography (DCM/MeOH, 50:1) to give thelight yellow solid 2a (0.24 g, 58% yield).
	In tetrahydrofuran; for 4h;Reflux;	<strong>[19171-19-8]pomalidomide</strong> (200 mg, 0.73 mmol) was dissolved in 15 mL of tetrahydrofuran. 6-bromohexanoyl chloride (187 mg, 0.88 mmol) was injected at room temperature. After the completion of the injection, the reaction was heated to reflux for 4 h. Concentrated under reduced pressure, the solid was washed with diethyl ether, filtered, and washed with diethyl ether. A white solid 276 mg was obtained in a crude yield of 83.9%. White solid.

Reference： [1]Patent: WO2018/200981,2018,A1 .Location in patent: Paragraph 0209; 0256
[2]European Journal of Medicinal Chemistry,2018,vol. 151,p. 237 - 247
[3]Chemical Communications,2019,vol. 55,p. 2704 - 2707
[4]Patent: CN109928956,2019,A .Location in patent: Paragraph 0112; 0125-0127

84
[ 19171-19-8 ]
4-(4-((4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 151,p. 237 - 247

85
[ 19171-19-8 ]
6-azido-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 151,p. 237 - 247
[2]Chemical Communications,2019,vol. 55,p. 2704 - 2707

86
[ 19171-19-8 ]
6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-6-oxohexan-1-aminium chloride [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 151,p. 237 - 247

87
[ 19171-19-8 ]
1-(6-(4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-6-oxohexyl)-N₄-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-4-oxobutyl)succinamide [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 151,p. 237 - 247

88
[ 19171-19-8 ]
6-(4-(4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazole-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-4-oxobutanamido)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 151,p. 237 - 247

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P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 19171-19-8 ] {[proInfo.proName]}

Quality Control of [ 19171-19-8 ]

Related Doc. of [ 19171-19-8 ]

Product Details of [ 19171-19-8 ]

Calculated chemistry of [ 19171-19-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 19171-19-8 ]

Application In Synthesis of [ 19171-19-8 ]

[ 19171-19-8 ] Synthesis Path-Upstream 1~17

[ 19171-19-8 ] Synthesis Path-Downstream 1~88

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry