[ CAS No. 603-62-3 ] {[proInfo.proName]}

Name: 603-62-3|3-Nitrophthalimide|98%
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2D 3D

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Quality Control of [ 603-62-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 603-62-3 ]

SDS Specification

Alternatived Products of [ 603-62-3 ]

Product Details of [ 603-62-3 ]

CAS No. :	603-62-3	MDL No. :	MFCD00041852
Formula :	C₈H₄N₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BONIIQYTWOPUQI-UHFFFAOYSA-N
M.W :	192.13	Pubchem ID :	11779
Synonyms :

Calculated chemistry of [ 603-62-3 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	50.64
TPSA :	91.99 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) :	-7.08 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.11
Log Po/w (XLOGP3) :	0.55
Log Po/w (WLOGP) :	0.1
Log Po/w (MLOGP) :	0.23
Log Po/w (SILICOS-IT) :	-0.66
Consensus Log Po/w :	0.06

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.63
Solubility :	4.52 mg/ml ; 0.0235 mol/l
Class :	Very soluble
Log S (Ali) :	-2.05
Solubility :	1.7 mg/ml ; 0.00884 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.16
Solubility :	1.32 mg/ml ; 0.00689 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.92

Safety of [ 603-62-3 ]

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

Application In Synthesis of [ 603-62-3 ]

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

Upstream synthesis route of [ 603-62-3 ]
Downstream synthetic route of [ 603-62-3 ]

[ 603-62-3 ] Synthesis Path-Upstream 1~8

1
[ 603-62-3 ]
[ 2518-24-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogen In DMF (N,N-dimethyl-formamide) at 20 - 50℃;	3-Nitrophthalimide (LOOGR) was taken into a hydrogenation vessel and dissolved using 500ML of dimethylformamide. Raney nickel catalyst (20gr, wet) was added to the solution and subjected to hydrogenation conditions initially at 20-30°C UNDER 20-40psi. After the exothermic nature of the reaction was over, hydrogen pressure was increased to 40-60psi and the temperature to 40-50°C. After the hydrogen uptake is over sample was drawn from the reaction mass and checked for the absence of 3-nitrophthalimide by TLC. The reaction mixture was filtered while hot and the catalyst removed by filtration. Solvent was removed from the filtrate under reduced pressure at 60-80°C. Water (500ML) was added to the residue and the mixture stirred for 20-30MIN. The product was isolated by filtration and dried at 60-70°C to get a yellow crystalline solid of 3-aminophthalimide (80gr, 95percent). Melting point: 262-4°C.
95%	With hydrogen In DMF (N,N-dimethyl-formamide) at 20 - 50℃;	3-NITROPHTHALIMIDE (LOOGR) was taken into a hydrogenation kettle and dissolved using 500ML of dimethylformamide. 5percent Palladium/carbon (LOGR, 50percent wet) was added to the solution and subjected to hydrogenation conditions initially at 20-30°C under 20-40psi. After the exothermic nature of the reaction was over, hydrogen pressure was increased to 40-60psi and the temperature to 40-50°C. After the hydrogen uptake was over the reaction mixture was filtered while hot and the catalyst removed by filtration. Solvent was removed from the filtrate under reduced pressure at 60-80°C. Water (500ml) was added to the residue and the mixture stirred for 30min. The product was isolated by filtration and dried at 60-70°C to get 80GR (95percent) of yellow crystalline solid of 3- aminophthalimide. Melting point: 263-4°C.
92.5%	With hydrogen In methanol; DMF (N,N-dimethyl-formamide) at 25 - 50℃;	3-Nitrophthalimide (LOOGR) was taken into a beaker and dissolved using 200ML of dimethylformamide and 300ML of methanol. The solution was transferred into a 1L hydrogenation kettle and 20gr of Raney nickel was charged into the kettle. Hydrogenation was carried out initially at 20-40psi and 25-30°C until the exothermic nature was over. Hydrogenation was further continued at 40-60psi pressure and 40-50°C. After checking the completion of reaction by TLC catalyst was removed by filtration and the solvents distilled off from the reaction mixture at 50-60°C. The residue thus obtained was suspended in water (500ML) and filtered off to get a bright yellow crystalline compound of 3-aminophthalimide (78gr, 92.5percent). Melting point: 263-4°C

Reference： [1] MedChemComm, 2016, vol. 7, # 2, p. 292 - 296
[2] Patent: WO2004/43919, 2004, A1, . Location in patent: Page 6
[3] Patent: WO2004/43919, 2004, A1, . Location in patent: Page 7
[4] Patent: WO2004/43919, 2004, A1, . Location in patent: Page 7
[5] Journal of Chemical Research, 2011, vol. 35, # 6, p. 326 - 328
[6] Chemische Berichte, 1903, vol. 36, p. 2496
[7] Journal of the American Chemical Society, 1909, vol. 31, p. 489
[8] Journal of the Chemical Society, 1937, p. 26,31
[9] Journal of the Chemical Society, 1949, p. 3304,3310
[10] Oriental Journal of Chemistry, 2011, vol. 27, # 3, p. 1261 - 1264
[11] Patent: WO2009/118596, 2009, A2, . Location in patent: Page/Page column 23-24

2
[ 603-62-3 ]
[ 2518-24-3 ]

Reference： [1] Chemical Communications, 2004, # 20, p. 2338 - 2339

3
[ 603-11-2 ]
[ 2518-24-3 ]
[ 603-62-3 ]

Reference： [1] Chemische Berichte, 1903, vol. 36, p. 2496

4
[ 603-62-3 ]
[ 521-31-3 ]

Reference： [1] Journal of Chemical Research, 2011, vol. 35, # 6, p. 326 - 328

5
[ 603-62-3 ]
[ 24666-56-6 ]
[ 19171-18-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With 1,1'-carbonyldiimidazole In acetonitrile at 80 - 82℃;	4-Nitro-lH-isoindole-l, 3(2H)-dione (117.3 g; Formula IV) followed by 1,1- carbonyldiimidazole (138.1 g) were added to a slurry of 3-aminopiperidine-2,6-dione hydrochloride (100 g, Formula III; obtained in Example 1) in acetonitrile (800 mL) to obtain a reaction mixture. The reaction mixture was heated to reflux at 80°C to 82°C and then stirred for 2 hours. 1,1-Carbonyldiimidazole (19.8 g) was further added to the reaction mixture twice over an interval of one hour. The reaction mixture was cooled to 25 °C to 30°C and then stirred for 30 minutes. The product obtained was filtered and the wet solid obtained was dried at 50°C to 55°C under reduced pressure to obtain the title compound. (0076) Yield: 162 g (88percent)

Reference： [1] Patent: WO2018/154516, 2018, A1, . Location in patent: Page/Page column 8

6
[ 603-62-3 ]
[ 38876-67-4 ]

Reference： [1] Journal of the American Chemical Society, 2015, vol. 137, # 13, p. 4445 - 4452

7
[ 603-62-3 ]
[ 135484-76-3 ]

Reference： [1] Journal of the American Chemical Society, 2015, vol. 137, # 13, p. 4445 - 4452

8
[ 603-62-3 ]
[ 1015474-32-4 ]

Reference： [1] Patent: US2012/232100, 2012, A1,
[2] Patent: WO2014/39960, 2014, A1,
[3] Patent: EP2683384, 2015, B1,
[4] Patent: WO2015/200795, 2015, A1,
[5] Patent: WO2016/60702, 2016, A1,
[6] Patent: US9365640, 2016, B2,
[7] Patent: WO2017/24019, 2017, A1,
[8] Patent: WO2017/53555, 2017, A1,
[9] Patent: WO2017/96024, 2017, A1,
[10] Patent: WO2017/117118, 2017, A1,
[11] Patent: WO2018/165142, 2018, A1,

[ 603-62-3 ] Synthesis Path-Downstream 1~88

1
[ 641-70-3 ]
[ 603-62-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With formamide; In neat (no solvent); for 0.333333h;Milling; Heating; Green chemistry;	General procedure: A mixture of anhydride (1 mmol), formamide (1.1 mmol for monoanhydrides and 2.2 mmol for dianhydrides) and 1 g clay was ground together in a mortar using pestle for the time described in Table 1. The reaction mixture was warmed. After completing the reaction (monitored by TLC, after observing no anhydride presence in the reaction mixture), the product was extracted by washing clay with chloroform (2×15 mL), the solvent was removed under vacuum to afford the relevant N-unsubstituted cyclic imide. The solid imide was washed thoroughly with water, dried, and then recrystallized from ethanol. The solid clay portion was washed with methanol and dried at 120 C under a reduced pressure to be reused in the subsequent reactions which showed the gradual decrease in the activity (Table 1). Isolated products were characterized by melting points, IR, 1H NMR spectrometric data and were compared with the literature or authentic samples.
92%	With iron(III) chloride; guanidine hydrochloride; triethylamine; at 60℃; for 0.166667h;	General procedure: A mixture of a cyclic anhydride 1 (1 mmol), guanidiniumchloride (2) (1 mmol), Et3N (2 mmol) and FeCl3 (10 mol%)in PEG-400 (0.5 mL) at 60C for aromatic derivatives andat 100C for aliphatic derivatives was stirred for an appropriatetime. The reaction progress was monitored by thinlayerchromatography. After the completion of the reaction,the reaction mixture was cooled to room temperature andthen was extracted with H2O and EtOAc. The organic layerwas dried over MgSO4 and then evaporated under reducedpressure. The residue was purified by column chromatographyon silica gel using n-hexane-EtOAc (7:3). The desired1H-isoindole-1,3(2H)-diones were obtained in 70-95%yields. Spectroscopy data for compounds 3 are in goodagreement with those previously reported.

Reference： [1]Journal of Heterocyclic Chemistry,1995,vol. 32,p. 495 - 498
[2]Journal of the Chilean Chemical Society,2017,vol. 62,p. 3501 - 3504
[3]Zeitschrift fur Naturforschung, B: Chemical Sciences,2016,vol. 71,p. 941 - 944
[4]Revue Roumaine de Chimie,2007,vol. 52,p. 883 - 886
[5]Heterocycles,2006,vol. 68,p. 1559 - 1564
[6]Monatshefte fur Chemie,1902,vol. 23,p. 418

2
[ 603-62-3 ]
furan-2,3,5(4H)-trione pyridine (1:1) [ No CAS ]
[ 50573-74-5 ]

Reference： [1]Chemische Berichte,1902,vol. 35,p. 3877,3879

3
[ 603-62-3 ]
[ 2518-24-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogen;nickel; In DMF (N,N-dimethyl-formamide); at 20 - 50℃; under 1034.32 - 3102.97 Torr;	3-Nitrophthalimide (LOOGR) was taken into a hydrogenation vessel and dissolved using 500ML of dimethylformamide. Raney nickel catalyst (20gr, wet) was added to the solution and subjected to hydrogenation conditions initially at 20-30C UNDER 20-40psi. After the exothermic nature of the reaction was over, hydrogen pressure was increased to 40-60psi and the temperature to 40-50C. After the hydrogen uptake is over sample was drawn from the reaction mass and checked for the absence of 3-nitrophthalimide by TLC. The reaction mixture was filtered while hot and the catalyst removed by filtration. Solvent was removed from the filtrate under reduced pressure at 60-80C. Water (500ML) was added to the residue and the mixture stirred for 20-30MIN. The product was isolated by filtration and dried at 60-70C to get a yellow crystalline solid of 3-aminophthalimide (80gr, 95%). Melting point: 262-4C.
95%	With hydrogen;5%-palladium/activated carbon; In DMF (N,N-dimethyl-formamide); at 20 - 50℃; under 1034.32 - 3102.97 Torr;	3-NITROPHTHALIMIDE (LOOGR) was taken into a hydrogenation kettle and dissolved using 500ML of dimethylformamide. 5% Palladium/carbon (LOGR, 50% wet) was added to the solution and subjected to hydrogenation conditions initially at 20-30C under 20-40psi. After the exothermic nature of the reaction was over, hydrogen pressure was increased to 40-60psi and the temperature to 40-50C. After the hydrogen uptake was over the reaction mixture was filtered while hot and the catalyst removed by filtration. Solvent was removed from the filtrate under reduced pressure at 60-80C. Water (500ml) was added to the residue and the mixture stirred for 30min. The product was isolated by filtration and dried at 60-70C to get 80GR (95%) of yellow crystalline solid of 3- aminophthalimide. Melting point: 263-4C.
92.5%	With hydrogen;nickel; In methanol; DMF (N,N-dimethyl-formamide); at 25 - 50℃; under 1034.32 - 3102.97 Torr;	3-Nitrophthalimide (LOOGR) was taken into a beaker and dissolved using 200ML of dimethylformamide and 300ML of methanol. The solution was transferred into a 1L hydrogenation kettle and 20gr of Raney nickel was charged into the kettle. Hydrogenation was carried out initially at 20-40psi and 25-30C until the exothermic nature was over. Hydrogenation was further continued at 40-60psi pressure and 40-50C. After checking the completion of reaction by TLC catalyst was removed by filtration and the solvents distilled off from the reaction mixture at 50-60C. The residue thus obtained was suspended in water (500ML) and filtered off to get a bright yellow crystalline compound of 3-aminophthalimide (78gr, 92.5%). Melting point: 263-4C

With hydrogen;palladium on activated charcoal; In ethyl acetate; under 1034.32 Torr; for 2h;

Intermediate 1; Preparation of (2-methyl-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl)acetic acid; <n="26"/>Step 1 : 4-Amino-l,3-isoindolinedione; A solution of 3-nitrophthalimide in ethylacetate was treated with 10% palladium on charcoal (10 wt. %) and hydrogenated at 20 psi for 2h. The catalyst was filtered through celite and the filterate was evaporated to give the crude product (97%) which was used without purification in the next step. 1H-NMR (delta ppm, DMSO-J6, 300 MHz): 10.85 (br. s, IH); 7.39 (t, J = 7.8, IH); 6.93 (d, J = 8.4, IH); 6.88 (d, J = 6.9); 6.38 (br. s, 2H).

Reference： [1]MedChemComm,2016,vol. 7,p. 292 - 296
[2]Patent: WO2004/43919,2004,A1 .Location in patent: Page 6
[3]Patent: WO2004/43919,2004,A1 .Location in patent: Page 7
[4]Patent: WO2004/43919,2004,A1 .Location in patent: Page 7
[5]Journal of Chemical Research,2011,vol. 35,p. 326 - 328
[6]Chemische Berichte,1903,vol. 36,p. 2496
[7]Journal of the American Chemical Society,1909,vol. 31,p. 489
[8]Journal of the Chemical Society,1937,p. 26,31
[9]Journal of the Chemical Society,1949,p. 3304,3310
[10]Oriental Journal of Chemistry,2011,vol. 27,p. 1261 - 1264
[11]Patent: WO2009/118596,2009,A2 .Location in patent: Page/Page column 23-24

4
[ 603-62-3 ]
[ 723332-77-2 ]
[ 3682-15-3 ]

Reference： [1]Journal of the Chemical Society,1937,p. 1841,1846

5
[ 603-62-3 ]
[ 606-18-8 ]
[ 50573-74-5 ]

Reference： [1]Chemische Berichte,1902,vol. 35,p. 472,3859

6
[ 603-62-3 ]
[ 50573-74-5 ]

Yield	Reaction Conditions	Operation in experiment
88%		Example 1 (best mode):; A solution of NaOH (2.0 mole) having a strength of 1 5% by weight was cooled to a temperature of 25C. Then 1 .0 mole of 3-nitro-phthalimide was added portionwise under stirring. While maintaining the temperature at 25-30C, 1 .2 mole solution of 12% strength sodium hypochlorite was added portionwise. During addition, the pH of the reaction mass was kept at pH 12.0 with aqueous sodium hydroxide with a concentration of of 15% by weight. After stirring for 2 hours, the reaction mass was cooled down to 5-10 C and acidified with 32% hydrochloric acid to a pH value of 1 .8. After stirring for another hour, the reaction mass was filtered with a suction filter. Then the cake was washed with cold water (8-10 C) and dried under vacuum to yield 6-nitro-anthranilic acid in an amount of 88% of theory.
	With bromine; In potassium hydroxide;	Step 1): An ice cooled solution of bromine (2.5 ml, 48.5 mmol) in 1N KOH aq.solution was added to the solution of 3-nitrophthalimide (9.66 g, 50 mmol) in 1N KOH aq.solution (150 ml) followed by 1N KOH at 0. The mixture was refluxed for 1.5 hours. After cooling, the mixture was neutralized with 2N HCl and stirred at 0 to precipitate 2-amino-6-nitrobenzoic acid, 6.23 g (68%): mp 190 C.

Reference： [1]Patent: WO2011/98386,2011,A1 .Location in patent: Page/Page column 4-5
[2]Chemistry - A European Journal,2013,vol. 19,p. 10487 - 10491
[3]Monatshefte fur Chemie,1902,vol. 23,p. 418
[4]Journal of the American Chemical Society,1977,vol. 99,p. 3734 - 3744
[5]Heterocycles,1993,vol. 35,p. 775 - 789
[6]Patent: US5872115,1999,A
[7]Patent: US2011/301178,2011,A1
[8]Patent: US2012/165330,2012,A1
[9]Patent: US2012/230983,2012,A1
[10]Patent: US2012/232100,2012,A1
[11]Patent: WO2014/39960,2014,A1
[12]Journal of the American Chemical Society,2015,vol. 137,p. 4445 - 4452
[13]Patent: WO2015/200795,2015,A1
[14]Patent: WO2016/60702,2016,A1
[15]Patent: US9365640,2016,B2
[16]Patent: WO2017/24019,2017,A1
[17]Patent: WO2017/53555,2017,A1
[18]Patent: WO2017/96024,2017,A1
[19]Patent: WO2017/117118,2017,A1
[20]Patent: WO2018/165142,2018,A1
[21]Patent: US2008/293749,2008,A1
[22]Patent: WO2007/31323,2007,A1

7
[ 603-62-3 ]
[ 65911-46-8 ]

Yield	Reaction Conditions	Operation in experiment
96%		Example 1 Preparation of 6-nitrophthalamic acid (2) Commercially available 4-nitro-isoindole-1,3-dione (1) (25 g, 0.13 mol) was stirred in water (300 mL) at 0 C. Over a few minutes, an aqueous solution of sodium hydroxide (30% w/w, 35 g, 0.26 mol) was added. The mixture was stirred for 1.5 h at 0-5 C. The cold solution was acidified with concentrated HCl (22 mL, 0.26 mol) and the product precipitated as a white solid. After allowing to stand overnight in a refrigerator, the mixture was filtered to afford the title compound (26.3 g, 96%) as a white solid: 1H NMR (300 MHz, DMSO) delta 8.2 (s, 1H), 8.15 (d, 1H), 7.93 (d, 1H), 7.88-7.65 (m, 2H); ESIMS m/z 211 ([M+H]+), m/z 209 ([M-H]-).
90%	With potassium hydroxide; at 0 - 30℃; for 6h;	To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspension was stirred at 0 C for 3 hrs, and then heated to 30 C for 3 hrs. To the solution, was added HCl (100 mL, 6N). The resulting suspension was cooled to 0 C for 1 hr. The suspension was filtered and washed with cold water (2 x 10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSO-d6) delta 7.69 (brs, 1H, NHH), 7.74 (t, J= 8 Hz, 1H, Ar), 7.92 (dd, J = 1 , 8 Hz, 1H, Ar), 8.13 (dd, J= 1 , 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); 13C NMR (DMSO-d6) delta 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31
90%	With potassium hydroxide; In water; at 0 - 30℃; for 6h;	Step 1: To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspension was stirred at 0 C for 3 hrs, and then heated to 30 C for 3 hrs. To the solution, was added HCl (100 mL, 6N). The resulting suspension was cooled to 0 C for 1 hr. The suspension was filtered and washed with cold water (2 x 10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSO-d6) delta 7.69 (brs, 1H, NHH), 7.74 (t, J = 8 Hz, 1H, Ar), 7.92 (dd, J = 1, 8 Hz, 1H, Ar), 8.13 (dd, J = 1,8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); 13C NMR (DMSO-d6) delta 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.

90%	With water; potassium hydroxide; at 0 - 30℃; for 6h;	To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspension was stirred at 0 C for 3 hrs, and then heated to 30 C for 3 hrs. To the solution, was added HC1 (100 mL, 6N). The resulting suspension was cooled to 0 C for 1 hr. The suspension was filtered and washed with cold water (2 x 10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSO-d6) delta 7.69 (brs, 1H, NHH), 7.74 (t, J = 8 Hz, 1H, Ar), 7.92 (dd, J= 1, 8 Hz, 1H, Ar), 8.13 (dd, J= 1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1Eta, OH); 13C NMR (DMSO-de)
90%	With potassium hydroxide; In water; at 0 - 30℃; for 6h;	To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspension was stirred at 0 C for 3 hrs, and then heated to 30 C for 3 hrs. To the solution, was added HCl (100 mL, 6N). The resulting suspension was cooled to 0 C for 1 hr. The suspension was filtered and washed with cold water (2 x 10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSO-d6) 7.69 (brs, 1H, NHH), 7.74 (t, J = 8 Hz, 1H, Ar), 7.92 (dd, J = 1, 8 Hz, 1H, Ar), 8.13 (dd, J = 1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); 13C NMR (DMSO- d6) 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.
90%	With water; potassium hydroxide; at 0 - 30℃; for 6h;	To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspension was stirred at 0 C for 3 hrs, and then heated to 30 C for 3 hrs. To the solution, was added HCl (100 mL, 6N). The resulting suspension was cooled to 0 C for 1 hr. The suspension was filtered and washed with cold water (2 x 10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSO-d6) S 7.69 (brs, 1H, NHH), 7.74 (t, J= 8 Hz, 1H, Ar), 7.92 (dd, J= 1, 8 Hz, 1H, Ar), 8.13 (dd, J= 1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH);13C NMR (DMSO-d6) S 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.
90%	With water; potassium hydroxide; at 0 - 30℃; for 6h;	To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspensionwas stirred at 0 C for 3 hrs, and then heated to 30 C for 3 hrs. To the solution, was addedHC1 (100 mL, 6N). The resulting suspension was cooled to 0 C for 1 hr. The suspension was filtered and washed with cold water (2 x 10 mL) to give 3-nitro-phthalamic acid as awhite solid (24.6 g, 90% yield): ?HNMR(DMSO-d6) 5 7.69 (brs, 1H, NHJ]), 7.74 (t, J 8 Hz, 1H, Ar), 7.92 (dd, J= 1, 8Hz, 1H, Ar), 8.13 (dd, J= 1, 8Hz, 1H, Ar), 8.15 (brs, 1H, NHJ]), 13.59 (s, 1H, 01]); ?3CNIVIR(DMSO-d6)5 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.
90%	With potassium hydroxide; In water; at 0 - 30℃; for 6h;	To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspension was stirred at 0 C for 3 hrs, and then heated to 30 C for 3 hrs. To the solution, was added HCl (100 mL, 6N). The resulting suspension was cooled to 0 C for 1 hr. The suspension was filtered and washed with cold water (2 x 10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H MR (DMSO-d6) delta 7.69 (brs, 1H, HH), 7.74 (t, J = 8 Hz, 1H, Ar), 7.92 (dd, J = 1, 8 Hz, 1H, Ar), 8.13 (dd, J= 1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1Eta, OH); 13C NMR (DMSO-d6) delta 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.
90%	With water; potassium hydroxide; at 0 - 30℃; for 6h;	To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspension was stirred at 0 C for 3 hrs, and then heated to 30 C for 3 hrs. To the solution, was added HC1 (100 mL, 6N). The resulting suspension was cooled to 0 C for 1 hr. The suspension was filtered and washed with cold water (2 x 10 mL) to give 3- nitro-phthalamic acid as a white solid (24.6 g, 90% yield): ?H NMR (DMSO-d6) 5 7.69 (brs, 1H, NHJ]), 7.74 (t, J= 8 Hz, 1H, Ar), 7.92 (dd, J= 1, 8 Hz, 1H, Ar), 8.13 (dd, J= 1, 8Hz, 1H, Ar), 8.15 (brs, 1H, NHJ]), 13.59 (s, 1H, 01]); ?3C NIVIR (DMSO-d6) 5125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.
77%		Step 1) Synthesis of 2-carbamoyl-6-nitrobenzoic acid This moiety was synthesized using the following protocol. To a solution of potassium hydroxide (6.44 g, 114.4 mmol) in water (200 mL), was added 3-nitrophalimide (10; 10 g, 52 mmol) in portions at 0 C. The suspension was stirred at 0 C. for 3 hours, and then heated to 30 C. for 3 hours. To the solution, was added HCl (40 mL, 6N). The resulting suspension was cooled to 0 C. for 1 hour. The suspension was filtered and washed with cooled water (2*20 mL) to give 2-carbamoyl-6-nitrobenzoic acid (11; 8.5 g, 77%) as a white solid.
73%		a) Preparation of 6-nitrophthalamic acid:; A suspension of 57.6 g of 3-nitro-phthalimide (0.3 mol) in 672 g of water is cooled to 5C. 80 g of 30% sodium hydroxide solution (0.6 mol, 2 equivalents) are added in the shortest possible time. After 2 hours at 5C, the reaction mixture is added at 5C to 65 g of 32% hydrochloric acid solution (0.57 mol, 1.9 equivalents), which is diluted beforehand with 72 ml of water. The pH value is adjusted to 2-2.5 and the crude product which crystallises out is filtered off and washed twice with water. 6-Nitrophthalamic acid is obtained in a yield of 73%.
	With potassium hydroxide; water;	The preparation of 2-amino-6-nitrobenzoic acid was carried out in accordance with the literature (R. Kahn, Chem. Ber. 1902, 35, 3857-3884; W. S. Saari, J. E. Schwering, J. Heterocycl. Chem. 1986, 23, 1253-1255) via regioselective opening of 3-nitrophthalimide with aqueous potassium hydroxide to give phthalamic acid and subsequent Hofmann degradation with sodium hypobromite to give the 2-amino-6-nitrobenzoic acid.

Reference： [1]Patent: US2011/301178,2011,A1 .Location in patent: Page/Page column 6-7
[2]Patent: WO2014/39960,2014,A1 .Location in patent: Page/Page column 58; 59
[3]Patent: EP2683384,2015,B1 .Location in patent: Paragraph 0355
[4]Patent: WO2016/60702,2016,A1 .Location in patent: Paragraph 00462
[5]Patent: WO2017/24019,2017,A1 .Location in patent: Paragraph 00341
[6]Patent: WO2017/53555,2017,A1 .Location in patent: Paragraph 00170
[7]Patent: WO2017/96024,2017,A1 .Location in patent: Paragraph 00201; 00202
[8]Patent: WO2017/117118,2017,A1 .Location in patent: Paragraph 00457
[9]Patent: WO2018/165142,2018,A1 .Location in patent: Paragraph 00426
[10]Patent: US2012/165330,2012,A1 .Location in patent: Page/Page column 25
[11]Patent: WO2007/31323,2007,A1 .Location in patent: Page/Page column 38
[12]Journal of the American Chemical Society,2015,vol. 137,p. 4445 - 4452
[13]Chemische Berichte,1902,vol. 35,p. 3877,3879
[14]Journal of the American Chemical Society,1901,vol. 23,p. 751
[15]Heterocycles,1993,vol. 35,p. 775 - 789
[16]Patent: US2008/293749,2008,A1 .Location in patent: Page/Page column 18

8
[ 603-62-3 ]
[ 5329-95-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In methanol; ethanol; at 20℃; for 3h;	In a 2500 mL round bottom flask containing 0.52 mol (100 g) of 3-nitrophthalimide, Add anhydrous ethanol 800mL, Under stirring, 385 mL of a methanolic solution of KOH at a concentration of 80 g · L -1 (1 h addition, 0.55 mol KOH) was added dropwise and stirring continued for 3 h at room temperature, filter, The resulting white solid was rinsed with absolute ethanol, drying, The quality of 119g.

Reference： [1]Journal of the American Chemical Society,1901,vol. 23,p. 751
[2]Patent: CN104447498,2017,B .Location in patent: Paragraph 0057

9
[ 603-11-2 ]
[ 2518-24-3 ]
[ 603-62-3 ]

Reference： [1]Chemische Berichte,1903,vol. 36,p. 2496

10
[ 24564-71-4 ]
[ 603-62-3 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia
	Multi-step reaction with 2 steps 1: diethyl ether; NH₃ / -10 - -5 °C / man saettigt mit Chlorwasserstoff, verduennt mit CCl₄ und dampft den Aether ab 2: Beim Erhitzen ueber die Schmelztemperatur
	Multi-step reaction with 2 steps 1: chloroform; ice water / man fuegt waessr. Ammoniak hinzu 2: Beim Erhitzen ueber die Schmelztemperatur

Reference： [1]Chambers [Journal of the American Chemical Society, 1903, vol. 25, p. 611]
[2]Chambers [Journal of the American Chemical Society, 1903, vol. 25, p. 611]
[3]Chambers [Journal of the American Chemical Society, 1903, vol. 25, p. 611]

11
[ 603-62-3 ]
[ 13441-26-4 ]
[ 142960-22-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With phenol In toluene Heating;

Reference： [1]Kumar, Devendra; Khullar, Mrignaini; Gupta, Alka D. [Phosphorus, Sulfur and Silicon and the Related Elements, 1992, vol. 68, # 1-4, p. 59 - 68]

12
[ 603-62-3 ]
2-sulfanylbenzoic acid, disodium salt [ No CAS ]
[ 92461-32-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	In N,N-dimethyl-formamide at 80℃; for 8h;

Reference： [1]Fischer, Walter [Helvetica Chimica Acta, 1991, vol. 74, # 5, p. 1119 - 1126]

13
[ 603-62-3 ]
[ 108-98-5 ]
[ 77474-64-7 ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate; In acetone; for 24h;Reflux;	General procedure: A mixture of the appropriate thiol (6 mmol), 3-nitrophthalimide(4 mmol) and K2CO3 (10 mmol) in 20 mL acetone was heated underreflux for 24 h. The reaction was cooled to room temperature anddiluted with 150 mL water. The mixture was subsequently acidifiedto pH 2 with 6 N HCl. The resulting precipitate was collectedby filtration and dried at 50 C [19].

Reference： [1]Journal of general chemistry of the USSR,1980,vol. 50,p. 1874 - 1878
Zhurnal Obshchei Khimii,1980,vol. 50,p. 2313 - 2318
[2]Bioorganic Chemistry,2015,vol. 59,p. 117 - 123

14
[ 603-62-3 ]
[ 88098-03-7 ]
[ 142960-24-5 ]

Yield	Reaction Conditions	Operation in experiment
82.5%	With phenol In toluene Heating;

Reference： [1]Kumar, Devendra; Khullar, Mrignaini; Gupta, Alka D. [Phosphorus, Sulfur and Silicon and the Related Elements, 1992, vol. 68, # 1-4, p. 59 - 68]

15
[ 50-00-0 ]
[ 603-62-3 ]
[ 101-79-1 ]
2-[4-(4-Chloro-phenoxy)-phenylamino]-methyl}-4-nitro-isoindole-1,3-dione [ No CAS ]

Reference： [1]Pharmazie,1980,vol. 35,p. 78 - 80

16
[ 603-62-3 ]
[ 3682-15-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate; In water; at 11℃; for 3h;	160 ml of 80 wt% aqueous solution of hydrazine hydrate was added to the three-necked flask, heated to reflux (110 C), refluxed for 3 hours, and the plate confirms that 3-nitrophthalimide has been consumed completely and cooled To room temperature, To obtain a mixed product B containing 3-nitrophthalhydrazide

Reference： [1]Tetrahedron Letters,1996,vol. 37,p. 3351 - 3354
[2]Patent: CN106810501,2017,A .Location in patent: Paragraph 0061

17
[ 603-62-3 ]
[ 541-41-3 ]
[ 190910-88-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 4.16667h;	Example 4; Preparation of 3-Nitro-N-ethoxycarbonyl-phthalimide According to Scheme D; Ethyl chloroformate (1.89 g, 19.7 mmol) was added dropwise over 10 minutes to a stirred solution of 3-nitrophthalimide (3.0 g, 15.6 mmol) and triethylamine (1.78 g, 17.6 mmol) in DMF (20 mL) at about 0-5 C. under nitrogen. The reaction was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was slowly added to an agitated mixture of ice and water (60 mL). The slurry was filtered and the solid was crystallized from CHCl3 (15 mL) and petroleum ether (15 mL) to yield 3.1 g (75%) of the product as an off-white solid: mp 100.0-100.5 C.; 1H NMR (CDCl3) delta 8.25(d, J=7.5 Hz, 1 H), 8.20(d, J=8.0 Hz, 1 H), 8.03(t, J=7.9 Hz, 1 H), 4.49(q, J=7.1 Hz, 2 H), 1.44(t, J=7.2 Hz, 3 H); 13C NMR (CDCl3) delta 161.45, 158.40, 147.52, 145.65, 136.60, 132.93, 129.65, 128.01, 122.54, 64.64, 13.92; HPLC, Waters Nova-Pak/C18, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4(aq), 5.17 min (98.11%); Anal. calculated for C11H8N2O6: C, 50.00; H, 3.05; N, 10.60. Found: C, 50.13; H, 2.96; N, 10.54.

Reference： [1]Patent: US6335/349,2002,B1 .Location in patent: Paragraph A
[2]Patent: US2007/4920,2007,A1 .Location in patent: Page/Page column 12
[3]Synthetic Communications,1997,vol. 27,p. 2081 - 2086
[4]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1625 - 1630

18
[ 603-62-3 ]
[ 51674-11-4 ]

Yield	Reaction Conditions	Operation in experiment
24%	With hydroxyammonium sulfate; water; potassium hydroxide; In isopropyl alcohol; at 40℃; for 0.5h;	<strong>[603-62-3]<strong>[603-62-3]3-Nitrophthalimid</strong>e</strong> (5 g) and hydroxylamine sulfate powder (11 g) were sequentially added to isopropanol (90 mL).Stir the reaction mixture.A solution of potassium hydroxide (6 g) in water (5 ml) was added in one portion.Get a red liquid.The temperature of the reaction solution was slowly raised to 40 C, the solution was stirred for 30 minutes, filtered,Recrystallization twice with water, dried at 80 to give 1.4g yellow needle crystal,After vacuum drying at 120 C, 1.12 g (24% yield) of yellow powder was obtained.

Reference： [1]Russian Chemical Bulletin,1998,vol. 47,p. 1220 - 1222
[2]Patent: CN107474007,2017,A .Location in patent: Paragraph 0051

19
[ 603-11-2 ]
ammonium carbonate [ No CAS ]
[ 603-62-3 ]

Reference： [1]Chemische Berichte,1932,vol. 65,p. 1630,1631
[2]Journal of the Chemical Society,1937,p. 26,31

Yield	Reaction Conditions	Operation in experiment
	With zinc(II) chloride at 225 - 230℃;

21
[ 603-62-3 ]
potassium hypobromite [ No CAS ]
[ 606-18-8 ]
[ 50573-74-5 ]

Reference： [1]Chemische Berichte,1902,vol. 35,p. 3866

22
[ 603-11-2 ]
[ 7664-41-7 ]
[ 603-62-3 ]

Reference： [1]Monatshefte fur Chemie,1902,vol. 23,p. 418

23
[ 603-62-3 ]
[ 100-44-7 ]
[ 92438-39-6 ]

Yield	Reaction Conditions	Operation in experiment
74%	With 18-crown-6 ether; potassium carbonate; potassium iodide In toluene for 24h; Heating;

Reference： [1]Chihab-Eddine; Daich; Jilale; Decroix [Journal of Heterocyclic Chemistry, 2000, vol. 37, # 6, p. 1543 - 1548]

24
[ 603-62-3 ]
[ 30516-87-1 ]
2-[(2R,3S,5R)-3-Azido-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-tetrahydro-furan-2-ylmethyl]-4-nitro-isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 12h;

Reference： [1]Orzeszko; Vilpo; Vilpo; Kaminska [Pharmazie, 2003, vol. 58, # 3, p. 169 - 172]

25
[ 603-62-3 ]
4-hydroxyamino-isoindole-1,3-dione [ No CAS ]

Reference： [1]Chemical Communications,2005,p. 1901 - 1903

26
[ 603-62-3 ]
4-hydroxyamino-isoindole-1,3-dione [ No CAS ]
[ 2518-24-3 ]

Reference： [1]Chemical Communications,2004,p. 2338 - 2339

27
[ 603-62-3 ]
[ 77326-45-5 ]

Yield	Reaction Conditions	Operation in experiment
90%		Step 1 : To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspension was stirred at 0 C for 3 hours, and then heated to 30 C for 3 hours. To the solution, was added HCI (100 mL, 6N). The resulting suspension was cooled to 0 C for 1 hour. The suspension was filtered and washed with cold water (2 x 10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSOd5) delta 7.69 (brs, IH, NHH), 7.74 (t, J= 8 Hz, IH, Ar), 7.92 (dd, J = 1, 8 Hz, IH, Ar), 8.13 (dd, /= 1, 8 Hz, IH, Ar), 8.15 (brs, IH, NHH), 13.59 (s, 1eta, OH); 13C NMR (DMSO-d6) delta 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.
90%	With hydrogenchloride; potassium hydroxide; In water;	Step 1: To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspension was stirred at 0 C. for 3 hrs, and then heated to 30 C. for 3 hrs. To the solution, was added HCl (100 mL, 6N). The resulting suspension was cooled to 0 C. for 1 hr. The suspension was filtered and washed with cold water (2*10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSO-d6) delta 7.69 (brs, 1H, NHH), 7.74 (t, J=8 Hz, 1H, Ar), 7.92 (dd, J=1, 8 Hz, 1H, Ar), 8.13 (dd, J=1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); 13C NMR (DMSO-d6) delta 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.
90%		Step 1: To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspension was stirred at 0 C. for 3 hrs, and then heated to 30 C. for 3 hrs. To the solution, was added HCl (100 mL, 6N). The resulting suspension was cooled to 0 C. for 1 hr. The suspension was filtered and washed with cold water (2*10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSO-d6) delta 7.69 (brs, 1H, NHH), 7.74 (t, J=8 Hz, 1H, Ar), 7.92 (dd, J=1, 8 Hz, 1H, Ar), 8.13 (dd, J=1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); 13C NMR (DMSO-d6) delta 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.

90%	With water; potassium hydroxide; at 0 - 30℃; for 6h;	To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspension was stirred at 0 C for 3 hrs, and then heated to 30 C for 3 hrs. To the solution, was added HCl (100 mL, 6N). The resulting suspension was cooled to 0 C for 1 hr. The suspension was filtered and washed with cold water (2 x 10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSO-d6) 7.69 (brs, 1H, NHH), 7.74 (t, J = 8 Hz, 1H, Ar), 7.92 (dd, J = 1, 8 Hz, 1H, Ar), 8.13 (dd, J = 1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); 13C NMR (DMSO-d6) 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.
90%	With water; potassium hydroxide; at 0 - 30℃; for 6h;	To a solution of potassium hydroxide (16.1 g, 286 mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at 0 C. The suspension was stirred at 0 C. for 3 hrs, and then heated to 30 C. for 3 hrs. To the solution, was added HCl (100 mL, 6N). The resulting suspension was cooled to 0 C. for 1 hr. The suspension was filtered and washed with cold water (2*10 mL) to give 3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSO-d6) delta 7.69 (brs, 1H, NHH), 7.74 (t, J=8 Hz, 1H, Ar), 7.92 (dd, J=1, 8 Hz, 1H, Ar), 8.13 (dd, J=1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); 13C NMR (DMSO-d6) delta 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.

Reference： [1]Patent: WO2008/39489,2008,A2 .Location in patent: Page/Page column 51
[2]Patent: US2012/230983,2012,A1
[3]Patent: US2012/232100,2012,A1 .Location in patent: Page/Page column 24
[4]Patent: WO2015/200795,2015,A1 .Location in patent: Paragraph 00374
[5]Patent: US9365640,2016,B2 .Location in patent: Page/Page column 66; 67

28
[ 603-62-3 ]
(R)-(+)-4-amino-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 2: Et₃N 3: HCl / CH₂Cl₂ 4: SOCl₂, pyridine, Et₃N 5: H₂ / 10 percent Pd/C / acetone

Reference： [1]Muller, George W.; Chen, Roger; Huang, Shaei-Yun; Corral, Laura G.; Wong, Lu Min; Patterson, Rebecca T.; Chen, Yuxi; Kaplan, Gilla; Stirling, David I. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630]

29
[ 603-62-3 ]
(S)-(-)-4-amino-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 2: Et₃N 3: HCl / CH₂Cl₂ 4: SOCl₂, pyridine, Et₃N 5: H₂ / 10 percent Pd/C / acetone

30
[ 603-62-3 ]
3-(4-methoxyphenyl)-5-aminoquinazoline-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 1.) aq. KOH, 2.) 6 N aq. HCl / 1.) RT, 4 h, 2.) 0 deg C, 90 min 2: 1.) Br₂, 1 N aq. KOH, 2.) 2 N aq. HCl / 1.) heating, 1 h, 2.) 0 deg C 3: 50 - 55 °C / 1.) 50-55 deg C, 30 min, 2.) RT, 48 h 4: 1.) acetone, RT, 3 h, 2.) DMF, reflux, 90 min 5: H₂ / 10percent Pd/C / dimethylformamide / 0.5 h / 1250.4 Torr

Reference： [1]Cheng, Chia-Chung; Liu, Den-Fu; Chou, Ting-Chao [Heterocycles, 1993, vol. 35, # 2, p. 775 - 789]

31
[ 21606-04-2 ]
[ 603-62-3 ]

Reference： [1]Chemische Berichte,1902,vol. 35,p. 3862

32
[ 603-62-3 ]
5-Fluorbenzonorbornadien [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: Br₂, aq. NaOH 2: isopentyl nitrite / CH₂Cl₂; acetone 3: Al-Hg / diethyl ether; aq. ethanol 4: (i) aq. HBF₄, aq. NaNO₂, benzene, (ii) CuO

Reference： [1]Snow,R.A. et al. [Journal of the American Chemical Society, 1977, vol. 99, p. 3734 - 3744]

33
[ 603-62-3 ]
5-Aminobenzonorbornadien [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: Br₂, aq. NaOH 2: isopentyl nitrite / CH₂Cl₂; acetone 3: Al-Hg / diethyl ether; aq. ethanol

Reference： [1]Snow,R.A. et al. [Journal of the American Chemical Society, 1977, vol. 99, p. 3734 - 3744]

34
[ 603-62-3 ]
11-Aminotetracyclo<5.4.0.0^2,4.0^3,6>undeca-1(7),8,10-trien [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: Br₂, aq. NaOH 2: isopentyl nitrite / CH₂Cl₂; acetone 3: PhCOMe / benzene / Irradiation 4: Al-Hg / diethyl ether; aq. ethanol

Reference： [1]Snow,R.A. et al. [Journal of the American Chemical Society, 1977, vol. 99, p. 3734 - 3744]

35
[ 603-62-3 ]
11-Fluortetracyclo<5,4,0,0^2,4,0^3,6>undeca-1(7),8,10-trien [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: Br₂, aq. NaOH 2: isopentyl nitrite / CH₂Cl₂; acetone 3: PhCOMe / benzene / Irradiation 4: Al-Hg / diethyl ether; aq. ethanol 5: aq. HBF₄, NaNO₂ / benzene; tetrahydrofuran

Reference： [1]Snow,R.A. et al. [Journal of the American Chemical Society, 1977, vol. 99, p. 3734 - 3744]

36
[ 603-62-3 ]
5-Nitrobenzonorbornadien [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Br₂, aq. NaOH 2: isopentyl nitrite / CH₂Cl₂; acetone

Reference： [1]Snow,R.A. et al. [Journal of the American Chemical Society, 1977, vol. 99, p. 3734 - 3744]

37
[ 603-62-3 ]
C₁₁H₉NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: Br₂, aq. NaOH 2: isopentyl nitrite / CH₂Cl₂; acetone 3: PhCOMe / benzene / Irradiation

Reference： [1]Snow,R.A. et al. [Journal of the American Chemical Society, 1977, vol. 99, p. 3734 - 3744]

38
[ 603-62-3 ]
[ 96-41-3 ]
[ 322691-68-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; diethyl ether; nitrogen; toluene	14.1 1) 2-cyclopentyl-4-nitro-1H-isoindole-1,3(2H)-dione 1 2-cyclopentyl-4-nitro-1H-isoindole-1,3(2H)-dione To a solution of 3-nitrophthalimide (3.85 g, 20.0 mmol), cyclopentanol (2.24 g, 26.0 mmol) and triphenylphosphine (6.87 g, 26.2 mmol) in tetrahydrofuran 30 ml was dropwise added 40% toluene solution (11.4 ml) of diethyl azocarboxylate under stirring in a nitrogen stream. The mixture was concentrated in vacuo, and the precipitate formed upon addition of ether was filtered off. After the filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography (hexane-ethyl acetate, 3:1) to give the title compound (3.87 g) as a colorless solid.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2003/203907, 2003, A1 Location in patent: Page/Page column 44

39
[ 603-62-3 ]
[ 2593-81-9 ]
[ 2257-85-4 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; hydrogen; acetic acid	72 4-Amino-2-methyl-1H-isoindole-1,3(2H)-dione EXAMPLE 72 4-Amino-2-methyl-1H-isoindole-1,3(2H)-dione A pressure reactor was charged with 2-methyl-4-nitro-1H-isoindole-1,3(2H)-dione (59.0 g, 0.286 mol), 1 L acetic acid, and 2 q 5% Pd/C. The reactor was pressurized to 48 psi hydrogen, and the exothermic reaction was complete in 2 hours. The catalyst was removed with hot filtration, and the filtrate combined with the contents of another reactor which contained 53.2 g of 3-nitrophthalimide under the same conditions. The acetic acid was removed at the rotovap, then the salt was cracked by adding 2 M ammonium hydroxide. The slurry was stirred 30 minutes; then filtered; washed with water, ethanol, and ether; and dried at the pump to give 91.4 g, 95% of the product.

Reference： [1]Current Patent Assignee: NEUROSEARCH A/S - US2003/114422, 2003, A1

40
[ 603-62-3 ]
[ 75-03-6 ]
[ 2778-84-9 ]

Yield	Reaction Conditions	Operation in experiment
	In 4-nitro isomer	8 EXAMPLE 8 EXAMPLE 8 3-Nitrophthalimide (30.0 g.) is ethylated with iodoethane in the same manner as the 4-nitro isomer (Example 3) to yield 35.4 g. of N-ethyl-3-nitrophthalimide melting at 102°-103° C.
	In 4-nitro isomer	5 EXAMPLE 5 EXAMPLE 5 3-Nitrophthalimide (30.0 g.) is ethylated with iodoethane in the same manner as the 4-nitro isomer (Example 3) to yield 35.4 g. of N-ethyl-3-nitrophthalimide melting at 102°-103° C.
	In 4-nitro isomer	5 EXAMPLE 5 EXAMPLE 5 3-Nitrophthalimide (30.0 g.) is ethylated with iodoethane in the same manner as the 4-nitro isomer (Example 3) to yield 35.4 g. of N-ethyl-3-nitrophthalimide melting at 102°-103°C.

In 4-nitro isomer

5 EXAMPLE 5 EXAMPLE 5 3-Nitrophthalimide (30.0 g.) is ethylated with iodoethane in the same manner as the 4-nitro isomer (Example 3) to yield 35.4 g. of N-ethyl-3-nitrophthalimide melting at 102°-103° C.

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US4324719, 1982, A
[2]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US4039522, 1977, A
[3]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US3980634, 1976, A
[4]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US4012372, 1977, A

41
[ 603-62-3 ]
[ 13182-81-5 ]
[ 29075-53-4 ]

Yield	Reaction Conditions	Operation in experiment
	In acetone	15 EXAMPLE 15 EXAMPLE 15 3-Nitrophthalimide is converted to the potassium salt by the procedure described in Example 13 and then reacted with 1-(2-chloroethyl)-2-methyl-5-nitroimidazole according to the procedure described in Example 1. The crude reaction mixture is digested with toluene and then filtered to remove some insoluble material. Evaporation of the solvent leaves a syrup which is diluted with chloroform and then filtered to remove some insoluble material. The filtrate is further diluted with toluene and again filtered to remove some precipitate. The solvent is then evaporated from the filtrate and the resulting residue is recrystallized first from ethanol and then from acetone to give N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-3-nitrophthalimide melting at about 175°-176° C.

Reference： [1]Current Patent Assignee: PFIZER INC - US3997572, 1976, A

42
[ 14690-66-5 ]
[ 603-62-3 ]
[ 57-13-6 ]
α-(OH)Mn(III)TAPc [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium sulfide; ammonium molybdate In nitrobenzene according to B.N. Acher, G.M. Fohlen, J.A. Parker, J. Keshavayya, Polyhedron 6 (1987) 1463; 3-nitrophthalimide, urea, ammonium molybdate, and MnCl3 reacted; Na2S*9H2O added; stirred (5 h, 50°C); washed with 1 M HCl and 1 M NaOH;

Reference： [1]Nombona, Nolwazi; Tau, Prudence; Sehlotho, Nthapo; Nyokong, Tebello [Electrochimica Acta, 2008, vol. 53, # 7, p. 3139 - 3148]

43
tetrabutoxytitanium [ No CAS ]
[ 603-62-3 ]
[ 57-13-6 ]
α-O=Ti(IV)TAPc [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium sulfide; ammonium molybdate In nitrobenzene according to B.N. Acher, G.M. Fohlen, J.A. Parker, J. Keshavayya, Polyhedron 6 (1987) 1463; 3-nitrophthalimide, urea, ammonium molybdate, and Ti(OC4H9)4 reacted; Na2S*9H2O added; stirred (5 h, 50°C); washed with 1 M HCl and 1 M NaOH;

Reference： [1]Nombona, Nolwazi; Tau, Prudence; Sehlotho, Nthapo; Nyokong, Tebello [Electrochimica Acta, 2008, vol. 53, # 7, p. 3139 - 3148]

44
[ 603-62-3 ]
[ 74-88-4 ]
[ 2593-81-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 25Preparation of l-[(lalpha,5alpha,6alpha)-3-(2,4-difluorophenyl)-3-azabicyclo[3.1.0]hex-6-yl]-3-(2- methyl-l,3-dioxo-2,3-dihydro-l//-isoindol-4-yl)urea:Step 1: 2-methyl-4-nitro-lH-isoindole-l,3(2H)-dione:To a stirred solution of 4-nitro-lH-isoindole-l,3(2H)-dione (0.00520 mole) in DMF (5 mL), NaH (0.000528 mole) is added at O0C and stirred the reaction mixture at RT for 30 min. To the above at 00C, methyl iodide (0.000528 mole) is added and stirred for 2 h at room temperature. On completion of reaction, the reaction mixture is quenched with water, extracted with ethyl acetate and the organic layer dried and concentrated to get the desired product. 1H NMR (DMSO- d6): delta 3.04 (s, 3H); 8.04 (t, IH, J = 9 Hz); 8.14 (d, IH, J = 9 Hz); 8.25 (d, lH, J = 6 Hz).

Reference： [1]Green Chemistry,2010,vol. 12,p. 1380 - 1382
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 6678 - 6692
[3]Patent: WO2009/90548,2009,A2 .Location in patent: Page/Page column 48

45
[ 603-62-3 ]
4-nitroisoindoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With borane-THF; In tetrahydrofuran; at 0 - 85℃; for 12h;	4-Nitroisoindoline (1): To a solution of 4-nitroisoindoline-l,3-dione (1.0 g, 5.2 mmol) in dry THF (20 mL) was added 1M borane solution in THF (21.0 mL, 20.8 mmol) at 0 C and then heated to 80-85 C for 12 h. The reaction mixture was treated with MeOH (2 mL) and 6N HC1 (5 mL) and refluxed for 1 h. The reaction mass was brought to room temperature and volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and basified with saturated NaHC03 (10 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1 (500 mg, 59%) as white solid. 1H NMR (500 MHz, DMSO-d6): delta 4.15 (s, 2H), 4.45 (s, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 7.5 Hz, 1H).

Reference： [1]Patent: WO2014/149164,2014,A1 .Location in patent: Paragraph 001151
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1218 - 1223

46
[ 556-56-9 ]
[ 603-62-3 ]
[ 92755-61-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium fluoride on basic alumina In 2-methyltetrahydrofuran for 3.5h; Inert atmosphere; Reflux; chemoselective reaction;

Reference： [1]Pace, Vittorio; Hoyos, Pilar; Fernandez, Maria; Sinisterra, Jose V.; Alcantara, Andres R. [Green Chemistry, 2010, vol. 12, # 8, p. 1380 - 1382]

47
[ 39557-31-8 ]
[ 603-62-3 ]
[ 1245937-60-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium fluoride on basic alumina In 2-methyltetrahydrofuran for 4h; Inert atmosphere; Reflux; chemoselective reaction;

Reference： [1]Pace, Vittorio; Hoyos, Pilar; Fernandez, Maria; Sinisterra, Jose V.; Alcantara, Andres R. [Green Chemistry, 2010, vol. 12, # 8, p. 1380 - 1382]

48
2-hydroxy-4-nitroisoindoline-1,3-dione [ No CAS ]
[ 603-62-3 ]

Yield	Reaction Conditions	Operation in experiment
13%	With potassium acetate; bis(pinacol)diborane In methanol at 50℃; for 5h; chemoselective reaction;

Reference： [1]Location in patent: body text Jacq, Jérôme; Berthiol, Florian; Einhorn, Cathy; Einhorn, Jacques [Synlett, 2010, # 15, p. 2263 - 2266]

49
[ 603-62-3 ]
[ 521-31-3 ]

Reference： [1]Journal of Chemical Research,2011,vol. 35,p. 326 - 328

50
[ 603-11-2 ]
[ 603-62-3 ]

Yield	Reaction Conditions	Operation in experiment
	With urea; In N,N-dimethyl-formamide; at 110℃; for 5h;	To a 5000 ml three-necked flask was added 260 g of <strong>[603-11-2]3-nitrophthalic acid</strong>, 78 g of urea and 2000 ml of dimethylformamide, Heated to reflux (110 c), Reflux for 5 hours, Point plate confirms that <strong>[603-11-2]3-nitrophthalic acid</strong> has been consumed completely, Cooled to room temperature (25 C) to give a mixed product A containing 3-nitrophthalimide.

Reference： [1]Journal of Chemical Research,2011,vol. 35,p. 326 - 328
[2]Chemistry - A European Journal,2013,vol. 19,p. 10487 - 10491
[3]Oriental Journal of Chemistry,2011,vol. 27,p. 1261 - 1264
[4]Patent: CN106810501,2017,A .Location in patent: Paragraph 0060

51
[ 603-62-3 ]
[ 78-94-4 ]
[ 325851-19-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-benzyl-trimethylammonium hydroxide; In water; ethyl acetate;Reflux;	4-Nitro-2-(3-oxobutyl)isoindoline-1,3-done (1) To a solution containing 3-nitrophthalimide (5.00 g; 26 mmol) in ethyl acetate (30 mL), methyl vinyl ketone (2.8 mL; 33 mmol; 1.25 equ.) is added dropwise. After a few minutes of stirring, 760 muL of triton B (Benzyltrimethylammonium hydroxide, 40% in water) are added. The reaction medium is refluxed for 12 hours. After cooling, the solvents are removed under reduced pressure and the solid residue is recrystallized from absolute ethanol in order to obtain the compound 1 as a yellow solid with a yield of 85%. MP: 122 C.; IR (ATR-Ge v cm-1): 1715 (C=O ketone), 1538 (C=C arom), 1373 (N=O2), 1127 (C-C); 1H NMR (CDCl3; 250 MHz) delta8.19-8.07 (m, 2H), 7.93 (dd, J=7.1 Hz, J=8.5 Hz, 1H), 3.98 (t, J=7.3 Hz, 2H), 2.91 (t, J=7.3 Hz, 2H), 2.20 (s, 3H); 13C NMR (CDCl3; 63 MHz) delta205.7 (Cq), 165.6 (Cq), 162.9 (Cq), 145.2 (Cq), 135.6 (CH), 134.2 (Cq), 128.7 (CH), 127.2 (CH), 123.9 (Cq), 41.2 (CH2), 33.8 (CH2), 30.1 (CH3). MS (IS) m/z: 263.0 [M+H]+

Reference： [1]Patent: US2012/95022,2012,A1 .Location in patent: Page/Page column 14
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 9589 - 9606

52
[ 603-62-3 ]
[ 412341-84-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium hydroxide; water / 6 h / 0 - 30 °C 1.2: 1 h / 0 °C 2.1: potassium hydroxide; bromine / water / 1.08 h / 0 - 100 °C 2.2: 1 h / 0 °C 3.1: 1 h / Reflux
	Multi-step reaction with 3 steps 1: hydrogenchloride; potassium hydroxide / water 2: hydrogenchloride; bromine; potassium hydroxide / water 3: acetic anhydride
	Multi-step reaction with 3 steps 1.1: potassium hydroxide; water / 6 h / 0 - 30 °C 1.2: 1 h / 0 °C 2.1: potassium hydroxide; bromine / water / 1.08 h / 0 °C / Heating 2.2: 1 h / 0 °C 3.1: 0.5 h / 200 °C / Microwave irradiation

	Multi-step reaction with 3 steps 1: potassium hydroxide / 6 h / 0 - 30 °C 2: potassium hydroxide; bromine / water / 1.08 h / 0 - 100 °C 3: 0.5 h / 200 °C / Microwave irradiation
	Multi-step reaction with 3 steps 1: potassium hydroxide / water / 6 h / 0 - 30 °C 2: bromine; water; potassium hydroxide / 1.08 h / 0 - 100 °C 3: 0.5 h / 200 °C / Microwave irradiation
	Multi-step reaction with 3 steps 1.1: water; potassium hydroxide / 6 h / 0 - 30 °C 2.1: bromine; potassium hydroxide / water / 1 h / 0 - 100 °C 2.2: 1 h / 0 °C 3.1: 0.5 h / 200 °C / Microwave irradiation
	Multi-step reaction with 3 steps 1.1: potassium hydroxide; water / 6 h / 0 - 30 °C 2.1: potassium hydroxide; water; bromine / 0.08 h / 0 °C 2.2: 1 h / 100 °C 3.1: 0.5 h / 200 °C / Microwave irradiation
	Multi-step reaction with 3 steps 1.1: potassium hydroxide; water / 6 h / 0 - 30 °C 2.1: potassium hydroxide; bromine / water / 1 h / 0 - 100 °C 2.2: 1 h / 0 °C 3.1: 0.5 h / 200 °C / Microwave irradiation
	Multi-step reaction with 3 steps 1: potassium hydroxide / water / 6 h / 0 - 30 °C 2: potassium hydroxide; water; bromine / 1.08 h / 0 - 100 °C 3: 0.5 h / 200 °C / Microwave irradiation
	Multi-step reaction with 3 steps 1: potassium hydroxide; water / 6 h / 0 - 30 °C 2: potassium hydroxide; bromine / water / 1.58 h / 0 - 100 °C 3: 0.5 h / 200 °C / Microwave irradiation
	Multi-step reaction with 3 steps 1: water; potassium hydroxide / 6 h / 0 - 30 °C 2: bromine; potassium hydroxide / water / 1 h / 0 - 100 °C 3: 0.5 h / 200 °C / Microwave irradiation
	Multi-step reaction with 3 steps 1: potassium hydroxide / water / 6 h / 0 - 30 °C 2: potassium hydroxide; bromine / water / 100 °C 3: 0.5 h / 200 °C / Microwave irradiation
	Multi-step reaction with 3 steps 1: potassium hydroxide; water / 6 h / 0 - 30 °C 2: potassium hydroxide; water; bromine / 1.08 h / 0 - 100 °C 3: 0.5 h / 200 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/165330, 2012, A1
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2012/230983, 2012, A1 Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2012/232100, 2012, A1
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2012/232100, 2012, A1
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2014/39960, 2014, A1
[5]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP2683384, 2015, B1
[6]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2015/200795, 2015, A1
[7]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2016/60702, 2016, A1
[8]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US9365640, 2016, B2
[9]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/24019, 2017, A1
[10]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/53555, 2017, A1
[11]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/96024, 2017, A1
[12]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/117118, 2017, A1
[13]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2018/165142, 2018, A1

53
[ 603-62-3 ]
[ 1015474-86-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium hydroxide; water / 6 h / 0 - 30 °C 1.2: 1 h / 0 °C 2.1: potassium hydroxide; bromine / water / 1.08 h / 0 °C / Heating 2.2: 1 h / 0 °C 3.1: 0.5 h / 200 °C / Microwave irradiation 4.1: pyridine / 0.17 h / 170 °C / Microwave irradiation
	Multi-step reaction with 4 steps 1: potassium hydroxide / 6 h / 0 - 30 °C 2: potassium hydroxide; bromine / water / 1.08 h / 0 - 100 °C 3: 0.5 h / 200 °C / Microwave irradiation 4: pyridine / 0.17 h / 170 °C / Microwave irradiation
	Multi-step reaction with 4 steps 1: potassium hydroxide / water / 6 h / 0 - 30 °C 2: bromine; water; potassium hydroxide / 1.08 h / 0 - 100 °C 3: 0.5 h / 200 °C / Microwave irradiation 4: pyridine / 0.17 h / 170 °C / Microwave irradiation

	Multi-step reaction with 4 steps 1.1: water; potassium hydroxide / 6 h / 0 - 30 °C 2.1: bromine; potassium hydroxide / water / 1 h / 0 - 100 °C 2.2: 1 h / 0 °C 3.1: 0.5 h / 200 °C / Microwave irradiation 4.1: pyridine / 0.17 h / 170 °C / Microwave irradiation
	Multi-step reaction with 4 steps 1.1: potassium hydroxide; water / 6 h / 0 - 30 °C 2.1: potassium hydroxide; water; bromine / 0.08 h / 0 °C 2.2: 1 h / 100 °C 3.1: 0.5 h / 200 °C / Microwave irradiation 4.1: pyridine / 0.17 h / 170 °C / Microwave irradiation
	Multi-step reaction with 4 steps 1.1: potassium hydroxide; water / 6 h / 0 - 30 °C 2.1: potassium hydroxide; bromine / water / 1 h / 0 - 100 °C 2.2: 1 h / 0 °C 3.1: 0.5 h / 200 °C / Microwave irradiation 4.1: pyridine / 0.17 h / 170 °C / Microwave irradiation
	Multi-step reaction with 4 steps 1: potassium hydroxide / water / 6 h / 0 - 30 °C 2: potassium hydroxide; water; bromine / 1.08 h / 0 - 100 °C 3: 0.5 h / 200 °C / Microwave irradiation 4: hydrogenchloride; pyridine / 0.17 h / 170 °C / Microwave irradiation
	Multi-step reaction with 4 steps 1: potassium hydroxide; water / 6 h / 0 - 30 °C 2: potassium hydroxide; bromine / water / 1.58 h / 0 - 100 °C 3: 0.5 h / 200 °C / Microwave irradiation 4: pyridine / 0.17 h / 170 °C / Microwave irradiation
	Multi-step reaction with 4 steps 1: water; potassium hydroxide / 6 h / 0 - 30 °C 2: bromine; potassium hydroxide / water / 1 h / 0 - 100 °C 3: 0.5 h / 200 °C / Microwave irradiation 4: 0.17 h / 170 °C / Microwave irradiation
	Multi-step reaction with 4 steps 1: potassium hydroxide / water / 6 h / 0 - 30 °C 2: potassium hydroxide; bromine / water / 100 °C 3: 0.5 h / 200 °C / Microwave irradiation 4: pyridine / 0.17 h / 170 °C / Microwave irradiation
	Multi-step reaction with 4 steps 1: potassium hydroxide; water / 6 h / 0 - 30 °C 2: potassium hydroxide; water; bromine / 1.08 h / 0 - 100 °C 3: 0.5 h / 200 °C / Microwave irradiation 4: hydrogenchloride; pyridine / 0.17 h / 170 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2012/232100, 2012, A1
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2014/39960, 2014, A1
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP2683384, 2015, B1
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2015/200795, 2015, A1
[5]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2016/60702, 2016, A1
[6]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US9365640, 2016, B2
[7]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/24019, 2017, A1
[8]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/53555, 2017, A1
[9]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/96024, 2017, A1
[10]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/117118, 2017, A1
[11]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2018/165142, 2018, A1

54
[ 603-62-3 ]
[ 1015474-32-4 ]

Reference： [1]Patent: US2012/232100,2012,A1
[2]Patent: WO2014/39960,2014,A1
[3]Patent: EP2683384,2015,B1
[4]Patent: WO2015/200795,2015,A1
[5]Patent: WO2016/60702,2016,A1
[6]Patent: US9365640,2016,B2
[7]Patent: WO2017/24019,2017,A1
[8]Patent: WO2017/53555,2017,A1
[9]Patent: WO2017/96024,2017,A1
[10]Patent: WO2017/117118,2017,A1
[11]Patent: WO2018/165142,2018,A1

55
[ 51762-67-5 ]
[ 603-62-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With 1,3-dimethyl-1H-imidazol-3-ium hydrogen carbonate; water In ethanol at 80℃; for 6h; Green chemistry; chemoselective reaction;

Reference： [1]Verma, Praveen Kumar; Sharma, Upendra; Bala, Manju; Kumar, Neeraj; Singh, Bikram [RSC Advances, 2013, vol. 3, # 3, p. 895 - 899]

56
[ 5292-43-3 ]
[ 603-62-3 ]
[ 1182303-06-5 ]

Yield	Reaction Conditions	Operation in experiment
90%		To a solution of 3-nitrophthalimide (1 g, 5.20 mmol) in dry DMF (35 ml), cooled in an ice bath, NaH (60% w/w dispersion in mineral oil, 0.250 g, 6.25 mmol) was added, followed after 15 minutes by t-butyl bromoacetate (0.845 ml, 5.73 mmol). After stirring for 1 hour at room temperature, the mixture was poured into water and the resulting precipitate was washed with water and with a little amount of Et2O; after drying, tert-butyl 2-(4-nitro-1,3-dioxoisoindolin-2-yl)acetate was obtained (1.44 g, 4.70 mmol, 90% yield, MS/ESI+ 328.9 [MNa]+).
90%		Example 29 (S)-3,5-Dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)- phenyl)-2-(2-(4-(methylsulfonamido)-1 ,3-dioxoisoindolin-2-yl)acetoxy)- ethyl)pyridine 1 -oxide (Compound 162) Scheme 29 Step 1 : Preparation of tert-butyl 2-(4-nitro-1 ,3-dioxoisoindolin-2- yl)acetate (157) To a solution of 3-nitrophthalimide (1 g, 5.20 mmol) in dry DMF (35 ml), cooled in an ice bath, NaH (60% w/w dispersion in mineral oil, 0.250 g, 6.25 mmol) was added, followed after 15 minutes by t-butyl bromoacetate (0.845 ml, 5.73 mmol). After stirring for 1 hour at room temperature, the mixture was poured into water and the resulting precipitate was washed with water and with a little amount of Et20; after drying, tert-butyl 2-(4-nitro-1 ,3-dioxoisoindolin-2-yl)acetate was obtained (1 .44 g, 4.70 mmol, 90% yield, MS/ESI+ 328.9 [MNa] +).

Reference： [1]Patent: US2013/102576,2013,A1 .Location in patent: Paragraph 0522
[2]Patent: WO2013/57013,2013,A2 .Location in patent: Page/Page column 135; 136

57
[ 127-19-5 ]
[ 603-62-3 ]
[ 1401870-83-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With tert.-butylhydroperoxide; potassium iodide In water at 90℃; for 12h;

Reference： [1]Lao, Zhi-Qi; Zhong, Wen-He; Lou, Qing-Hua; Li, Zhong-Jun; Meng, Xiang-Bao [Organic and Biomolecular Chemistry, 2012, vol. 10, # 39, p. 7869 - 7871]

58
[ 603-62-3 ]
[ 2153-08-4 ]
[ 1003729-23-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-benzyl-N,N,N-triethylammonium chloride; potassium iodide for 0.183333h; Milling;	Alternative Preparation of 6a-g General procedure: 4 (2.13 gms, 10mM), 5a-g (11 mM) and KI (11 mM)were ground together in a mortar with a pestle for 10-15minutes in the presence of TEBAC as a surface catalyst. Thecompletion of the reaction was checked by TLC. Then, icecoldwater (30ml) was added to the reaction mixture, thesolid that separated out was filtered, washed with water(10ml) and dried. The product was recrystallized from ethanolto obtain 6a-g.

Reference： [1]Reddy, Yervala D.; Kumar, Padam P.; Devi, Bhoomireddy R.; Dubey, Pramod K.; Kumari, Yalamanchili B. [Letters in Organic Chemistry, 2013, vol. 10, # 1, p. 70 - 76]

59
[ 50-00-0 ]
[ 603-62-3 ]
[ 53397-81-2 ]
[ 1277185-45-1 ]

Yield	Reaction Conditions	Operation in experiment
77%	In ethanol; water at 20℃;

Reference： [1]Rastogi, Nisheeth; Kant, Padam; Sethi, Rakesh; Shukla, Sarveshwar; Harrison, Darwin Anil [Indian Journal of Heterocyclic Chemistry, 2010, vol. 20, # 2, p. 149 - 152]

60
[ 50-00-0 ]
[ 603-62-3 ]
[ 6373-46-2 ]
[ 301207-22-7 ]

Yield	Reaction Conditions	Operation in experiment
67%	In ethanol; water at 20℃;

Reference： [1]Rastogi, Nisheeth; Kant, Padam; Sethi, Rakesh; Shukla, Sarveshwar; Harrison, Darwin Anil [Indian Journal of Heterocyclic Chemistry, 2010, vol. 20, # 2, p. 149 - 152]

61
[ 603-62-3 ]
[ 67-64-1 ]
4-nitro-2-(2-oxopropyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide In decane; ethyl acetate at 130℃; for 3h; Sealed tube;

Reference： [1]Lv, Yunhe; Li, Yan; Xiong, Tao; Lu, Yu; Liu, Qun; Zhang, Qian [Chemical Communications, 2014, vol. 50, # 18, p. 2367 - 2369]

62
[ 603-62-3 ]
[ 147-93-3 ]
[ 92461-32-0 ]

Yield	Reaction Conditions	Operation in experiment
95.4%		Thiosalicylic acid (15.4 g, 0.1 mol) in NaOH aqueous solution (200 mL, 1 mol/L) was warmed until the solid dissolved, and then continually warmed to remove water. Ethanol was added into the sticky mixture, and then the white precipitates were collected by filtration, washed with ethanol, and dried in vacuo to obtain sodium thiosalicylate (f). A mixture of f (18.215 g, 0.1034 mol), 3-nitrophthalimide (15.892 g, 0.0827 mol), and DMF (200 mL) was stirred at 80 C for 8 h. A HCl solution (200 mL, 2 mol/L) was added. The precipitate was filtered, washed with water, dried in vacuo, and then recrystallized from dioxane to give a yellow powder. Yield: 95.4%. 1H NMR (300 MHz, DMSO-d6): delta 7.29-7.31 (m, 2H), 7.47 (m, 2H), 7.66 (m, 2H), 7.86 (m, 1H). Anal. Calcd. for C15H9NO4S: C, 60.19; H, 3.03; N, 4.68; S, 10.71; Found: C, 59.48; H, 3.20; N, 4.54; S, 10.51.

Reference： [1]Chinese Chemical Letters,2014,vol. 25,p. 1445 - 1448

63
[ 603-62-3 ]
[ 38876-67-4 ]

Reference： [1]Journal of the American Chemical Society,2015,vol. 137,p. 4445 - 4452

64
[ 603-62-3 ]
[ 135484-76-3 ]

Reference： [1]Journal of the American Chemical Society,2015,vol. 137,p. 4445 - 4452

65
[ 603-62-3 ]
[ 100-53-8 ]
4-(benzylsulfanyl)phthalimide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium carbonate In acetone for 24h; Reflux;	2 Synthesis of the 4-sulfanylphthalimide analogues (3a-i) General procedure: A mixture of the appropriate thiol (6 mmol), 3-nitrophthalimide(4 mmol) and K2CO3 (10 mmol) in 20 mL acetone was heated underreflux for 24 h. The reaction was cooled to room temperature anddiluted with 150 mL water. The mixture was subsequently acidifiedto pH 2 with 6 N HCl. The resulting precipitate was collectedby filtration and dried at 50 C [19].

Reference： [1]Van Der Walt, Mietha M.; Terre'Blanche, Gisella; Petzer, Anél; Petzer, Jacobus P. [Bioorganic Chemistry, 2015, vol. 59, p. 117 - 123]

66
[ 4410-99-5 ]
[ 603-62-3 ]
3-[(2-phenylethyl)sulfanyl]phthalimide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With potassium carbonate In acetone for 24h; Reflux;	3 Synthesis of the 4-sulfanylphthalimide analogues (3a-i) General procedure: A mixture of the appropriate thiol (6 mmol), 3-nitrophthalimide(4 mmol) and K2CO3 (10 mmol) in 20 mL acetone was heated underreflux for 24 h. The reaction was cooled to room temperature anddiluted with 150 mL water. The mixture was subsequently acidifiedto pH 2 with 6 N HCl. The resulting precipitate was collectedby filtration and dried at 50 C [19].

Reference： [1]Van Der Walt, Mietha M.; Terre'Blanche, Gisella; Petzer, Anél; Petzer, Jacobus P. [Bioorganic Chemistry, 2015, vol. 59, p. 117 - 123]

67
[ 603-62-3 ]
[ 106-54-7 ]
3-[(4-chlorophenyl)sulfanyl]phthalimide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With potassium carbonate; In acetone; for 24h;Reflux;	General procedure: A mixture of the appropriate thiol (6 mmol), 3-nitrophthalimide(4 mmol) and K2CO3 (10 mmol) in 20 mL acetone was heated underreflux for 24 h. The reaction was cooled to room temperature anddiluted with 150 mL water. The mixture was subsequently acidifiedto pH 2 with 6 N HCl. The resulting precipitate was collectedby filtration and dried at 50 C [19].