Name: 127168-84-7|5-Bromoisoindoline|97%
Brand: Ambeed
SKU: A853263
Rating: 94 (28 reviews)

1
[ 215790-29-7 ]
[ 127168-84-7 ]
[ 437651-72-4 ]

Yield	Reaction Conditions	Operation in experiment
	With NaBH(OAc)2 In 1,2-dichloro-ethane at 20℃; for 16h;

Reference： [1]Austin, Nigel E; Avenell, Kim Y; Boyfield, Izzy; Branch, Clive L; Hadley, Michael S; Jeffrey, Phillip; Johnson, Christopher N; Macdonald, Gregor J; Nash, David J; Riley, Graham J; Smith, Alexander B; Stemp, Geoffrey; Thewlis, Kevin M; Vong, Antonio K.K; Wood, Martyn D [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 5, p. 685 - 688]

2
[ 127168-85-8 ]
[ 127168-84-7 ]

Yield	Reaction Conditions	Operation in experiment
65%	With hydrogen bromide; propionic acid; phenol at 150℃; for 6h;
	With hydrogen bromide; propionic acid; phenol In water for 10h; Reflux;	36.3 Step 3. Synthesis of 5-bromoisoindoline Step 3. Synthesis of 5-bromoisoindoline To a solution of aqueous hydrobromic acid (16 mL, 48% solution in water), propionic acid (2.8 mL) and phenol (2 g) was added 5-bromo-2-(p-tolylsulfonyl)isoindoline (2.4 g, 6.8 mmol). The resulting mixture was heated to reflux and stirred at this temperature for 10 hr then cooled to room temperature. This mixture was diluted with water (20 mL) and extracted with ether (250 mL). The aqueous extract was brought to pH 14 with 5M sodium hydroxide solution. This solution was extracted with ether (3). The ether extract is washed with brine, dried over magnesium sulfate, and concentrated to give the title compound as an oil.

Reference： [1]Austin, Nigel E; Avenell, Kim Y; Boyfield, Izzy; Branch, Clive L; Hadley, Michael S; Jeffrey, Phillip; Johnson, Christopher N; Macdonald, Gregor J; Nash, David J; Riley, Graham J; Smith, Alexander B; Stemp, Geoffrey; Thewlis, Kevin M; Vong, Antonio K.K; Wood, Martyn D [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 5, p. 685 - 688]
[2]Current Patent Assignee: VENATORX PHARMACEUTICALS INC - US2014/194386, 2014, A1 Location in patent: Paragraph 0462

3
[ 6941-75-9 ]
[ 127168-84-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium tetrahydridoborate; boron trifluoride diethyl ether complex In tetrahydrofuran at 80℃;	4 Synthesis of 4b To a solution of 4a (10 g, 44.4 mmol) in TRF (200 mE) was added NaI3R4 (17.6 g, 464.8 mmol), followed by 13F3.Et20 (170 ml, 519.2 mmol) drop- wise at room temperature. The mixture was then heated at 80° C. overnight, cooled to 0° C. and adjusted to pH 13 with aqueous NaOH solution. The mixture was extracted with ethyl acetate (100 mEx3). The combined organic phase was washed with water, brine and dried over anhydrous Na2504. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (DCM:MeOR=10:1, v: v) to provide 4b (7.3 g, 83% yield). EC-MS: 198 [M+1].
76%	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With sodium tetrahydridoborate In tetrahydrofuran Stage #2: With boron trifluoride diethyl ether complex at -10 - 70℃;
68%	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With boron trifluoride diethyl ether complex In tetrahydrofuran at 20℃; for 0.5h; Stage #2: With borane-THF In tetrahydrofuran at 40℃; for 36h; Stage #3: With hydrogenchloride; methanol; sodium hydroxide more than 3 stages;	5; 21 As an example of a synthesis method of core Formula VIi-VIj, 4-bromophthalimide(25) can be treated with a reducing agent (e.g., BF OEt followed by BH THF) in an appropriate solvent (e.g., tetrahydrofuran, THF) for the appropriate length of time at the appropriate temperature, to yield 4-bromoisoindoline, 26. The appropriate temperature and appropriate length of time are determined by referenece to Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21.; 5-bromoisoindoline-l,3-dione (5 g, 22.1 mmol) is dissolved in anhydrous THF (30 ml), treated with BF3 OEt2 (6.667 ml, 132.7 mmol) is added and the reaction was stirred at ambient temperature for 30 minutes. To the reaction mixture 1.0M BH3 THF complex (176.94 ml, 525.3 mmol ) is added and the reaction is heated to 4O0C for 36 h. The progress of the reaction is followed by LC/MS. After completion, the reaction mixture is cooled to ambient temperature and quenched with MeOH (6 ml, drop wise) until the bubbling ceases. Then 2N HCl in water (-40 ml, 80 mmol) are added and the mixture is refluxed for 3 h. The reaction is then cooled to ambient temperature and is washed with diethyl ether (2 x 40 ml). The water layer is brought to pH 14 with 6N NaOH (aq) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts are dried over anhydrous Na2Sθ4 and solvent is removed under reduced pressure to yield 5-bromoisoindoline (68%), (m/z 413[MH+]).

64.1%	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole In tetrahydrofuran at 80℃; for 24h; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water monomer for 4h; Reflux; Cooling with ice;	I.1.1.5 Preparation of the intermediate 7 5-bromoisoindole-1,3-dione (10 g, 44.2 mmol) was added to THF (50 mL). The temperature was raised to 80 ° C, stirred for 24 h, ice water bath, methanol (30 mL) was added dropwise, 3N hydrochloric acid (30 mL), refluxed for 4 h, concentrated, diluted with water (100 mL), then washed with diethyl ether (50 mL × 2), water phase The mixture was adjusted to pH = 10 with saturated aqueous sodium carbonate, and extracted with EA (50mL×2), dried and concentrated to give 5.7 g (64.1%) of yellow oil.
52%	With dimethylsulfide borane complex In tetrahydrofuran at 20℃; Reflux;	1 Step 1: 5-bromoisoindoline To a solution of 4-bromophthalimide (22.6 g, 100 mmol) in dried tetrahydrofuran (250 mL) was added dropwise borane-dimethyl sulfide complex (51 mL, 500 mmol), stirred at room temperature for 2 hours, and then refluxed overnight. After cooling, methanol was carefully added dropwise to quench the excess borane. The resulting mixture was evaporated and concentrated, and then the residue was purified by silica gel column chromatography to give 5-bromoisoindoline (10.36 g). Yield: 52%. MS m/z[ESI]: 198.0[M+1].
41.3%	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran at -5 - 80℃; for 19h; Stage #2: With hydrogenchloride In methanol; water monomer at 0 - 80℃; for 3h;	Preparation of 5-bromo-2,3-dihydro-1H-isoindole (13); 564.2 ml of a 1M borane/THF solution are added dropwise to 42.5 g (188 mmol) of 5-bromoisoindole-1,3-dione in 300 ml of THF (dry) at -5° C. over a period of 60 min. The mixture is subsequently stirred for 2 h at 22° C. and then for 16 h at 80° C. The mixture is then cooled to 0° C., before 200 ml of methanol (exothermic.) and 200 ml of 2M hydrochloric acid are slowly added. The resultant mixture is stirred for 3 h at 80° C., cooled to 22° C., and 100 ml of water are added. The aqueous solution is extracted three times with 150 ml of dichloromethane each time, dried over sodium sulfate, filtered and evaporated to dryness: 5-bromo-2,3-dihydro-1H-isoindole; yield 15.4 g of “13” (41.3%); MW 198.06; Rt 1.099 min (“polar” method).
41%	With borane-THF Reflux;
22.16%	With dimethylsulfide borane complex In tetrahydrofuran at 0 - 70℃; for 16h; Inert atmosphere;	1.1 Step 1: Synthesis of Compound WX042-2 Under a nitrogen atmosphere, at 0° C., to a solution of WX042-1 (5.00 g, 22.12 mmol) in tetrahydrofuran (50.00 mL) was added borane dimethyl sulfide (10 M, 11.06 mL) dropwise, and the system was stirred at 70° C. for 16 hours. After the reaction was complete, at 0° C. to the system was added 100 mL methanol to quench the reaction system. After concentration under reduced pressure, the residue was purified by column chromatography (dichloromethane:methanol=20:1) to afford Compound WX042-2 (1.00 g, 22.16% yield, 97.1% purity), white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.43 (s, 1H), 7.40-7.34 (m, 2H), 7.11 (d, J=8.5 Hz, 1H), 4.48 (d, J=16.6 Hz, 4H).
18.2%	With dimethylsulfide borane complex In tetrahydrofuran at 80℃; for 17h;	26 5-Bromoisoindo line To a solution of 5-bromoisoindoline-1,3-dione (25.0 g, 0.11 mmol) in THF(1000 mL) were added BH3Me2S (100 mL). The resulting mixture was heated at 80 °C for 17h. After LCMS showed the reaction was completed, the reaction mixture was quenched withMeOH and concentrated. The residue was purified by column chromatograph on silica gel(eluted with PE: EA=20:1) to give the title compound (3.98 g, 18.2%). ‘HNMR(400MHz, MeOD) 5 7.62 (1 H, s) 7.55 (1 H, d, J=8.0 Hz) 7.35 (1 H, d, J=8.0 Hz) 4.62 (2 H, s)4.58 (2 H, s).
	With sodium tetrahydridoborate; boron trifluoride diethyl ether complex for 3h; Heating;
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With boron trifluoride diethyl ether complex In tetrahydrofuran at 25℃; for 0.5h; Stage #2: With borane-THF In tetrahydrofuran at 40℃; for 24h; Stage #3: With hydrogenchloride; methanol more than 3 stages;	To a solution of 5-bromophthalimide (44.2 mmol; 1.0 equiv) in THF (221 mL) under N2 atmosphere is added BF3-OEt2 (265.5 mmol; 6.0 equiv) and the reaction is stirred for 30 minutes at 25 C. BH3-THF (353.6 mmol; 8.0 equiv) is added to the reaction mixture which is then heated to 40 C for 24 h. The reaction is cooled to room temperature and quenched with 60 mL MeOH until gas evolution ceases; 400 mL HCl is added and the reaction is refluxed for 3 h. The reaction is then cooled to room temperature and the water layer is washed with ethyl acetate. The water layer is then brought to pH 14 with 6 N NaOH and extracted with ethyl acetate. The combined organic extracts are dried (MgSO4), filtered, and concentrated to crude product 5-bromo-2,3-dihydro-lH-isoindole, which is carried onto the next step without further manipulation.
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With dimethylsulfide borane complex In tetrahydrofuran at 0℃; Heating / reflux; Stage #2: With hydrogenchloride; water monomer In tetrahydrofuran; methanol for 3h; Heating / reflux; Stage #3: With sodium hydroxide In water monomer	1.1 Step 1: tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate To a solution of 5-bromo-1H-isoindole-1,3(2H)-dione (4 mmol) in THF (10 mL) was added borane-dimethyl sulfide complex (2M in THF, 14 mL) at 0° C. The reaction mixture was allowed to stir at reflux overnight and was then cooled to 0° C. The reaction mixture was quenched by the slow addition of MeOH (10 mL) and then 2N HCl (10 mL). The reaction mixture was allowed to stir at reflux for 3 hr and then concentrated. Water (10 mL) was added to the residue. Remaining starting material was removed by extraction with DCM. To the aqueous solution was added 4N NaOH until pH>9. The solution was extracted with DCM. The organic solutions from this basic extraction were combined, dried over Na2SO4, filtered and concentrated to give 5-bromoisoindoline, which was dissolved in THF (20 mL). To this solution was added potassium carbonate (8 mmol) in water (1 mL), and BOC2O. The reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate (2.5 mmol, 60%).
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran at 0℃; Heating / reflux; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water monomer at 0℃; for 3h; Heating / reflux;	C.C20 A mixture of 4-bromophthalic anhydride (25 g) in formamide (75 ml) was heated at 2000C for 16 hours then allowed to cool to room temperature. The reaction mixture was diluted with water (200 ml), filtered, the filter cake was washed with water then diethyl ether and sucked dry to give 20.85 g of light mustard solid.280 ml of 1 M Borane-THF complex was added dropwise to a stirred solution of 4-bromophthalimide (20.85 g; 92.2 mmol) in anhydrous THF (200 ml) at O0C then heated at reflux overnight. The reaction was cooled to 00C then treated cautiously with methanol (100 ml) followed by 2M HCI (100 ml) then heated at reflux for 3 hours. The reaction mixture was cooled and the organics evaporated. The aqueous was diluted with water (100 ml) the extracted with DCM (x3). The aqueous was basified with 2M NaOH then extracted with DCM (x3). The combined DCM extracts were dried (MgSO4), filtered and evaporated to give 6.99 g of 5-bromo-2,3-dihydro-1 H-isoindole as a dark brown gummy solid. 1H NMR (DMSO-d6) 7.45 (1H, s), 7.36 (1 H, d), 7.20 (1H, d), 4.05 (4H, s).
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran at 0℃; Heating / reflux; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water monomer at 0℃; for 3h; Heating / reflux;	C20 280 ml of 1M Borane-THF complex was added dropwise to a stirred solution of 4-bromophthalimide (20.85 g; 92.2 mmol) in anhydrous THF (200 ml) at O0C then heated at reflux overnight. The reaction was cooled to 00C then treated cautiously with methanol (100 ml) followed by 2M HCI (100 ml) then heated at reflux for 3 hours. The reaction mixture was cooled and the organics evaporated. The aqueous was diluted with water (100 ml) the extracted with DCM (x3). The aqueous was basified with 2M NaOH then extracted with DCM (x3). The combined DCM extracts were dried (MgSO4), filtered and evaporated to give 6.99 g of 5-bromo-2,3-dihydro-1 H-isoindole as a dark brown gummy solid. 1H NMR (DMSO-d6) 7.45 (1 H, s), 7.36 (1H, d), 7.20 (1H, d), 4.05 (4H, s).
	With borane-THF In tetrahydrofuran at 0℃; Heating / reflux;	C.20 280 ml of 1 M Borane-THF complex was added dropwise to a stirred solution of 4-bromophthalimide (20.85 g; 92.2 mmol) in anhydrous THF (200 ml) at O0C then heated at reflux overnight. The reaction was cooled to 00C then treated cautiously with methanol (100 ml) followed by 2M HCI (100 ml) then heated at reflux for 3 hours. The reaction mixture was cooled and the organics evaporated. The aqueous was diluted with water (100 ml) the extracted with DCM (x3). The aqueous was basified with 2M NaOH then extracted with DCM (x3). The combined DCM extracts were dried (MgSO4), filtered and evaporated to give 6.99 g of 5-bromo-2,3-dihydro-1 H-isoindole as a dark brown gummy solid. 1H NMR (DMSO-d6) 7.45 (1 H, s), 7.36 (1H, d), 7.20 (1 H, d), 4.05 (4H, s).
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran at 0℃; Heating / reflux; Stage #2: With methanol In tetrahydrofuran	C20 A mixture of 4-bromophthalic anhydride (25 g) in formamide (75 ml) was heated at 2000C for 16 hours then allowed to cool to room temperature. The reaction mixture was diluted with water (200 ml), filtered, the filter cake was washed with water then diethyl ether and sucked dry to give 20.85 g of light mustard solid.280 ml of 1 M Borane-THF complex was added dropwise to a stirred solution of 4-bromophthalimide (20.85 g; 92.2 mmol) in anhydrous THF (200 ml) at O0C then heated at reflux overnight. The reaction was cooled to O0C then treated cautiously with methanol (100 ml) followed by 2M HCI (100 ml) then heated at reflux for 3 hours. The reaction mixture was cooled and the organics evaporated. The aqueous was diluted with water (100 ml) the extracted with DCM (x3). The aqueous was basified with 2M NaOH then extracted with DCM (x3). The combined DCM extracts were dried (MgSO4), filtered and evaporated to give 6.99 g of 5-bromo-2,3-dihydro-1H-isoindole as a dark brown gummy solid. 1H NMR (DMSO-d6) 7.45 (1H, s), 7.36 (1 H1 d), 7.20 (1H, d), 4.05 (4H, s).
	With borane In tetrahydrofuran
	With borane-THF In tetrahydrofuran at 0℃; Reflux;	C.20 280 ml of 1M Borane-THF complex was added dropwise to a stirred solution of 4-bromophthalimide (20.85 g; 92.2 mmol) in anhydrous THF (200 ml) at 0° C. then heated at reflux overnight. The reaction was cooled to 0° C. then treated cautiously with methanol (100 ml) followed by 2M HCl (100 ml) then heated at reflux for 3 hours. The reaction mixture was cooled and the organics evaporated. The aqueous was diluted with water (100 ml) the extracted with DCM (×3). The aqueous was basified with 2M NaOH then extracted with DCM (×3). The combined DCM extracts were dried (MgSO4), filtered and evaporated to give 6.99 g of 5-bromo-2,3-dihydro-1H-isoindole as a dark brown gummy solid. 1H NMR (DMSO-d6) 7.45 (1H, s), 7.36 (1H, d), 7.20 (1H, d), 4.05 (4H, s).
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With boron trifluoride diethyl ether complex Stage #2: With borane-THF at 40℃;
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran Reflux; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water monomer for 2h; Reflux;	11.2 Step 2) 5-bromoisoindoline To a suspension of 5-bromoisoindoline-l,3-dione (2.73 g, 12.1 mmol) in THF (20 mL) was added Borane-THF complex (1 M, 48 mL). The reaction was heated at reflux overnight, then cooled to 0 °C, and treated with MeOH (30 mL), followed by 2 M HCI (30 mL). The mixture was heated at reflux for 2 h, then cooled to rt and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and H20 (50 mL). The separated aqueous phase was washed with DCM (50 mL x 2), then adjusted to pH 11 with 1 M NaOH (6 mL), and extracted with DCM (80 mL x 4). The combined organic phases were dried over anhydrous a2S04, filtered and concentrated in vacuo to give the crude product as dark brown oil (1.3 g, 54%), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 198.0 [M + H]+.
22 g	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With boron trifluoride In tetrahydrofuran at 0℃; for 1.5h; Inert atmosphere; Stage #2: With BH₃ In tetrahydrofuran at 0 - 80℃; for 20h; Inert atmosphere;
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran Reflux; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water monomer at 0℃; for 2h; Reflux;	11.2 Step 2) Preparation of 5-bromoisoindoline 5-bromoisoindoline-1,3-dione (2.73 g, 12.1 mmol)Was suspended in tetrahydrofuran (20 mL)To this was added borane-tetrahydrofuran (1 M, 48 mL).The reaction was refluxed overnight and cooled to 0 ° C,Followed by methanol (30 mL),2M hydrochloric acid (30 mL).The mixture was refluxed for 2 hours,Cooled to room temperature and concentrated under reduced pressure.The residue was partitioned between dichloromethane(50 mL) and water (50 mL). The separated aqueous phase was washed with dichloromethane (50 mL x 2) and adjusted to pH with 1 M sodium hydroxide solutionTo 11 and extraction with dichloromethane (80 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure,The crude product was obtained as a dark brown oil (1.3 g, 54%),The product was purified and used directly in the next step.
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With boron trifluoride In tetrahydrofuran at 0℃; for 1.5h; Inert atmosphere; Stage #2: With BH₃ In tetrahydrofuran at 0 - 80℃; for 20h; Inert atmosphere;	5-Bromoisoindoline (4). To a solution of 5-bromoisoindoline- 1, 3-dione (3) (25 g, 110.6 mmol, 1.0 equiv) in THF (60 mL) was added BF3 (30 g, 442.4 mmol, 4.0 equiv) dropwise at 0 °C. The mixture was stirred at 0 °C for 1.5 h and BH3 (650 ml, 1.0 M, 6.0 equiv) was added dropwise at 0 °C. Then the mixture was heated to 80°C for 20 h and quenched by addition of methanol (100 mL) dropwise for 1 h at 0°C. The mixture was concentrated to give a crude product of 5-bromoisoindoline (4) (22 g), which was used for next step directly.
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With boron trifluoride In tetrahydrofuran Reflux; Stage #2: With borane-THF In tetrahydrofuran for 16h; Reflux; Stage #3: With hydrogenchloride; water monomer In tetrahydrofuran at 0 - 20℃;	1.30.A Step A: Preparation of 5-BromoisoindoIine.To a solution of 5-bromoisoindoline-l,3-dione (8.117 g, 35.9 mmol) in THF (10 mL) was added boron trifluoride (8.40 mL, 108 mmol) dropwise. The reaction mixture was heated to reflux. After refluxing temperature was reached, borane tetrahydrofuran complex (144 mL, 144 mmol) was added dropwise and the reaction was stirred at reflux for 16 h. The mixture was cooled to 0 0C, cautiously treated with 3 N HCl (10 mL), and stirred at room temperature for 1 h. The aqueous mixture was washed with EtOAc, and the organic phase was discarded. The aqueous layer was basifed (pH 9-10) and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (4.02 g). LCMS m/z = 198.0 [M+H]+.
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran for 24h; Inert atmosphere; Reflux; Stage #2: With hydrogenchloride In methanol; water monomer at 0℃; for 1.66667h; Inert atmosphere; Reflux;
	With BH₃ In tetrahydrofuran for 24h; Reflux;
	With sodium tetrahydridoborate; borane-THF In tetrahydrofuran at -10℃; for 24h; Reflux;	4.1.35. 5-Bromo-isoindoline (47) Sodium borohydride (3.48 g, 92.0 mmol) was added to the solutionof 5-bromopthalamide (2.0 g, 8.8 mmol) in THF, and theresultant suspensionwas cooled to 10 C. Then, BF3.Et2O (12.7 mL,102.6 mmol) was added slowly and the reaction mixture wasrefluxed. After 24 h, the reaction mixture was allowed to cool to0 C and cold H2O (18 mL) was added. EtOAc (100 ml) was addedand the reaction mixture was made alkaline using 6.0 M aqueousNaOH. The organic layer was separated and concentrated using arotary evaporator. The residue was diluted with Et2O (50 mL) andacidified to pH 2. The aqueous layerwas separated, made alkaline topH 10 using 6.0 M aqueous NaOH and extracted with EtOAc(70 mL). The organic layer was separated, washed with brine(3 70 mL), dried (Na2SO4) and concentrated using rotary evaporatorto yied the 5-bromo-isoindoline (47). The residue was used infurther reactions without purification.
	With dimethylsulfide borane complex In tetrahydrofuran at 80℃; for 12h;	13.1 Step 1: BH3•SMe2 (10 M, 38.49 mL, 3 eq) was added to a solution of compound 13_1 (29 g, 128.30 mmol, 1 eq) in THF (300 mL). The mixture was reacted at 80 °C for 12 hours, then cooled to 0°C and quenched by adding methanol (100 mL). Then, dilute hydrochloric acid (90 mL, 1 M) was added to the mixture, and the mixture was stirred at 80 °C for 1 hour, concentrated under reduced pressure to remove the solvent. The residue was diluted with water (100 mL), extracted with ethyl acetate (150 mL 2). The pH value of the aqueous phase was adjusted to 10-11 by sodium hydroxide aqueous solution (1 M), the obtained aqueous phase was then extracted with ethyl acetate (150 mL 2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 13_2.
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With dimethylsulfide borane complex In tetrahydrofuran at 80℃; for 12h; Stage #2: With hydrogenchloride In methanol; water monomer at 80℃; for 1h;	1.1 Step 1: to a solution of compound 1_1 (29 g, 128.30 mmol, 1 eq) in THF (300 mL) was added BH3•SMe2 (10 M, 38.49 mL, 3 eq). The mixture was reacted at 80°C for 12 h, then cooled to 0°C, and quenched with methanol (100 mL); diluted hydrochloric acid (90 mL, 1 M) was then added by stirring at 80°C for 1 h, and the mixture was concentrated under reduced pressure to remove the solvent; the residue was diluted with water (100 mL) and extracted with ethyl acetate (150 mL 2); the aqueous layer was then adjusted to pH = 10-11 with aqueous sodium hydroxide (1 M) and the resulting aqueous phase was extracted with ethyl acetate (150 mL 2); the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain Compound 1_2.
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF at 70℃; Stage #2: With hydrogenchloride In water monomer at 70℃; for 4h;	8.1.2 8.1.2 Synthesis of 5-bromoisoindoline (40b) 5-bromoisoindole-1,3-dione (4 g, 17.7 mmol) was added to 120 ml of BH3/THF, overnight at 70°C, and the reaction was stopped by adding 10 ml of MeOH dropwise. The mixed solution was concentrated under vacuum, and the blend was added. 40 ml of hydrochloride was added, and the mixture was stirred at 70°C for 4 hours. Then 1M NaOH aq was added to adjust the pH to 14. After static separation of layers, the aqueous layer was extracted with DCM 100 ml×3. Then the organic layer was mixed and washed with brine 50ml×2, water 50ml, and the organic solvent was concentrated under vacuum to obtain 2.0 g of crude product. LC-MS: RT = 0.95 min; ESI m/z [M+H]+=198 FA mobile system.
	Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF at 70℃; Stage #2: With hydrogenchloride In water monomer at 70℃; for 4h;	8.1.2 8.1.2 Synthesis of 5-bromoisoindoline (40b) 5-bromoisoindole-1,3-dione (4 g, 17.7 mmol) was added to 120 ml of BH3/THF, overnight at 70°C, and the reaction was stopped by adding 10 ml of MeOH dropwise. The mixed solution was concentrated under vacuum, and the blend was added. 40 ml of hydrochloride was added, and the mixture was stirred at 70°C for 4 hours. Then 1M NaOH aq was added to adjust the pH to 14. After static separation of layers, the aqueous layer was extracted with DCM 100 ml×3. Then the organic layer was mixed and washed with brine 50ml×2, water 50ml, and the organic solvent was concentrated under vacuum to obtain 2.0 g of crude product. LC-MS: RT = 0.95 min; ESI m/z [M+H]+=198 FA mobile system.

Reference： [1]Current Patent Assignee: HELSINN HEALTCARE S.A. - US2017/275301, 2017, A1 Location in patent: Paragraph 0226; 0227
[2]Patel, Bhavesh H.; Barrett, Anthony G. M. [Journal of Organic Chemistry, 2012, vol. 77, # 24, p. 11296 - 11301]
[3]Current Patent Assignee: PATNAIK (inventors); ZHU; NOVARTIS AG; DOBLE R; GROB JONATHON E, MASSACHUSETTS; Novartis (w/o Sandoz); RADETICH; SCHULTZ (inventors) - WO2007/38459, 2007, A2 Location in patent: Page/Page column 65; 76
[4]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN110294744, 2019, A Location in patent: Paragraph 0163-0165; 0186-0188
[5]Current Patent Assignee: SHOUYAO HOLDINGS BEIJING CO LTD; SINO BIOPHARMACEUTICAL LIMITED - EP3257857, 2017, A1 Location in patent: Paragraph 0102; 0103
[6]Current Patent Assignee: MERCK KGAA - US2010/311745, 2010, A1 Location in patent: Page/Page column 19
[7]Zhu, Dongsheng; Huang, Huocong; Pinkas, Daniel M.; Luo, Jinfeng; Ganguly, Debolina; Fox, Alice E.; Arner, Emily; Xiang, Qiuping; Tu, Zheng-Chao; Bullock, Alex N.; Brekken, Rolf A.; Ding, Ke; Lu, Xiaoyun [Journal of Medicinal Chemistry, 2019, vol. 62, # 16, p. 7431 - 7444]
[8]Current Patent Assignee: PHAENO THERAPEUTICS - US2019/375744, 2019, A1 Location in patent: Paragraph 0107; 0108
[9]Current Patent Assignee: SANOFI - WO2015/54317, 2015, A1 Location in patent: Paragraph 0270; 0271
[10]Wang, Qiuping; Lucien, Edlaine; Hashimoto, Akihiro; Pais, Godwin C. G.; Nelson, David M.; Song, Yongsheng; Thanassi, Jane A.; Marlor, Christopher W.; Thoma, Christy L.; Cheng, Jijun; Podos, Steven D.; Ou, Yangsi; Deshpande, Milind; Pucci, Michael J.; Buechter, Douglas D.; Bradbury, Barton J.; Wiles, Jason A. [Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210]
[11]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2008/76954, 2008, A2 Location in patent: Page/Page column 48-49
[12]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2008/171754, 2008, A1 Location in patent: Page/Page column 103
[13]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44029, 2008, A1 Location in patent: Page/Page column 214
[14]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44041, 2008, A1 Location in patent: Page/Page column 236
[15]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44045, 2008, A1 Location in patent: Page/Page column 288-289
[16]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44054, 2008, A2 Location in patent: Page/Page column 132-133
[17]Location in patent: scheme or table Van Goethem, Sebastiaan; Van der Veken, Pieter; Dubois, Veronique; Soroka, Anna; Lambeir, Anne-Marie; Chen, Xin; Haemers, Achiel; Scharpe, Simon; De Meester, Ingrid; Augustyns, Koen [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 14, p. 4159 - 4162]
[18]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - US2010/152184, 2010, A1 Location in patent: Page/Page column 80
[19]Location in patent: scheme or table Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]
[20]Current Patent Assignee: CALITOR SCIENCES LLC; SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2014/89324, 2014, A1 Location in patent: Paragraph 0235
[21]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[22]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - CN104016979, 2017, B Location in patent: Paragraph 0599; 0600; 0601
[23]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1 Location in patent: Paragraph 058; 062; 0116
[24]Current Patent Assignee: PFIZER INC - WO2009/105206, 2009, A1 Location in patent: Page/Page column 75
[25]Lu, Cong; Su, Zhishan; Jing, Dong; Jin, Songyang; Xie, Lijuan; Li, Liangrui; Zheng, Ke [Organic Letters, 2019, vol. 21, # 5, p. 1438 - 1443]
[26]Xie, Lijuan; Lu, Cong; Jing, Dong; Ou, Xinrui; Zheng, Ke [European Journal of Organic Chemistry, 2019, vol. 2019, # 22, p. 3649 - 3653]
[27]Ojha, Ritu; Nepali, Kunal; Chen, Chun-Han; Chuang, Kuo-Hsiang; Wu, Tung-Yun; Lin, Tony Eight; Hsu, Kai-Cheng; Chao, Min-Wu; Lai, Mei-Jung; Lin, Mei-Hsiang; Huang, Han-Li; Chang, Chao-Di; Pan, Shiow-Lin; Chen, Mei-Chuan; Liou, Jing-Ping [European Journal of Medicinal Chemistry, 2020, vol. 190]
[28]Current Patent Assignee: WUXI APPTEC CO., LTD. - EP3747883, 2020, A1 Location in patent: Paragraph 0095
[29]Current Patent Assignee: WUXI APPTEC CO., LTD. - EP3901150, 2021, A1 Location in patent: Paragraph 0057
[30]Current Patent Assignee: EPITAS BIOSCIENCES SHANGHAI; SHANGHAI EPITAS BIOTECHNOLOGY - EP3971180, 2022, A1 Location in patent: Paragraph 0148; 0150
[31]Current Patent Assignee: EPITAS BIOSCIENCES SHANGHAI; SHANGHAI EPITAS BIOTECHNOLOGY - EP3971180, 2022, A1 Location in patent: Paragraph 0148; 0150

4
[ 24424-99-5 ]
[ 127168-84-7 ]
[ 201940-08-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium carbonate; In tetrahydrofuran; at 20℃; for 2h;	To a solution of 4b (6 g, 30 mmol) in THF (100 mE) was added saturated Na2CO3 solution (25 mE), followed by 13oc20 (33 g, 151 mmol). The mixture was stirred at room temperature for 2 hours and evaporated under reduced pressure. The residue was extracted with ethyl acetate (50 mEx3). The combined organic phase was washed with brine, dried over anhydrous Na2504 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA1O:1, v: v) to provide 4c (9 g, ca. 100% yield). EC-MS: 298 [M+1].
85%	With sodium carbonate; In dichloromethane; water; for 4h;Cooling with ice;	5-Bromoisoindoline (10.36 g, 52.3 mmol) was dissolved in 80 mL dichloromethane, and cooled in an ice bath. Boc anhydride (22.8 g, 104.6 mmol) was added dropwise followed by the addition of sodium carbonate (16.6 g, 156.9 mmol) and water (150 mL), and stirred in an ice bath for 4 hours. The organic phase was separated, washed with brine, and concentrated, and then the residue was purified by silica gel column chromatography to give the product 5-bromo-2-tert-butoxycarbonylisoindoline (13.3 g). Yield: 85 %. MS m/z [ESI]: 298.0[M+1]. 1H-NMR (400 MHz, CDCl3): delta= 7.37 (2H, m) , 7.11 (1H, m), 4.62 (4H, m), 1.51 (9H, s).
83.4%	With dmap; In N,N-dimethyl-formamide; at 25℃; for 10h;	To a solution of 5-bromoisoindoline (3.98 g, 20.2 mmol) in DMF (20 ml) was added DMAP (40.0 mg) and BOC2O (8.81 g, 40.4 mmol). The mixture was stirred at 25C for 10 h. After LC-MS showed the reaction was completed. The reaction mixture was concentrated to give the crude product, which was washed with pe to give the title compound(5.00 g, 83.4%). ?HNMR(400 MHz, CDC13) oe7.39-7.43 (2H,m) 7.09-7.18(1 H, m) 4.61- 4.68(4 H, m) 1.53(9 H, s).

82.1%	With dmap; In tetrahydrofuran; at 20℃; for 4h;	Intermediate 7 (5.0 g, 25.4 mmol) was dissolved in tetrahydrofuran (100 mL).Add DMAP (0.5 g, 4.0 mmol) in turn,Boc anhydride (10.0 g, 44.2 mmol), stirred at room temperature for 4 h, concentrated and then purified.6.2 g (82.1%) of an oil was obtained.
64%		Example 7 [1-(pyridin-4-yl)piperidin-4-yl]methyl 2-[amino(imino)methyl]isoindoline-5-carboxylate ditrifluoroacetate; step 1 Synthesis of tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate; To a solution (45 mL) of 5-bromoisoindoline (1.78 g, 9.00 mmol) in dichloromethane were added triethylamine (1.25 mL, 9.00 mmol) and di-tert-butyl dicarbonate (1.96 g, 9.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hr. N,N-Dimethylethylamine (0.988 mL, 9.00 mmol) was added under ice-cooling, the mixture was stirred at room temperature for 1 hr, and 1 N hydrochloric acid was added to the reaction mixture. The mixture was extracted with dichloromethane, and the extract was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate 100:0 - 92:8) to give the title compound. yield (1.72 g, 5.76 mmol, 64%) MS (ESI, m/z) 284 [(M-Me)+H]+ 1H-NMR (CDCl3)delta1.51 (s, 9H), 4.59-4.67 (m, 4H), 7.08-7.15 (m, 1H), 7.36-7.42 (m, 2H).
61%	With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃;	To a solution of 5-bromoisoindoline (1.3 g, 6.6 mmol) in THF (30 mL) were added NaHCC (1.66 g, 19.8 mmol) and (Boc)20 (4.3 g, 19.8 mmol). The reaction was stirred at rt overnight, then concentrated in vacuo. The residue was partitioned between H20 (40 mL) and DCM (40 mL), and the aqueous phase was extracted with DCM (60 mL x 2). The combined organic phases were dried over anhydrous a2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a pale yellow solid (1.2 g, 61%). MS (ESI, pos. ion) m/z: 244.0 [M-56+l]+; NMR (400 MHz, CDC13) delta (ppm): 7.35-7.41 (m, 2H), 7.07-7.14 (m, 1H), 4.58-4.66 (m, 4H), 1.51 (s, 9H).
61%	With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃;	5-bromoisoindoline (1.3 g, 6.6 mmol)Was dissolved in tetrahydrofuran (30 mL)To this was added sodium bicarbonate (1.66 g, 19.8 mmol) andBoc anhydride (4.3 g, 19.8 mmol).The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure.The residue was partitioned between dichloromethane (40 mL) and water (40 mL) and the separated aqueous phase was extracted with dichloromethane (60 mL x 2).There are mergersThe organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5/1) to give the title compound as a pale yellow solid (1.2 g, 61%).
59.8%	With dmap; In N,N-dimethyl-formamide; at 20℃; for 12h;	At 20 C., to a system of WX042-2 (5.00 g, 22.12 mmol) and Boc2O (1.21 g, 5.56 mmol) in N, N-dimethylformamide (10.00 mL) was added DMAP (61.70 mg, 505.00 mumol), and the system was stirred at 20 C. for 12 hours. After the reaction was complete, the system was extracted with ethyl acetate (15 mL×3). The organic layer was washed separately with water (10 mL×3) and brine (10 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to afford Compound WX042-3 (900.00 mg, 59.80% yield), white solid. 1H NMR (400 MHz, CDCl3) delta 7.42-7.36 (m, 2H), 7.17-7.08 (m, 1H), 4.67-4.59 (m, 4H), 1.51 (s, 9H).
53%	With dmap; In tetrahydrofuran; at 20℃; for 3h;	To a solution of 5-bromo-2,3-dihydro-lH-isoindole (8.75 g; 1.0 equiv) in THF (126 mL) are added di-fert-butyldicarbonate (10.8 g; 1.12 equiv) and 4-dimethylaminopyridine (5.4 g; 1.0 equiv) and the reaction is stirred at room temperature for 3 h. The reaction is quenched with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic extracts are dried (MgSO4), filtered, and concentrated to afford crude product, which is purified by silica gel chromatography to yield 7.0 g 5-bromo-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester (23.49 mmol; 53% yield over two steps). 1H NMR (400 MHz, CD3OD): delta 7.39 (dd, J= 4.0, 16.0 Hz, 1 H), 7.26 (s, 1 H), 7.12 (dd, J = 20.0, 4.0 Hz), 4.67 (s, 1 H), 4.62 (s, 2 H), 4.59 (s, 1 H), 1.51 (s, 9 H).
	With potassium carbonate; In tetrahydrofuran; water; at 20℃;	Step 1: tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate To a solution of 5-bromo-1H-isoindole-1,3(2H)-dione (4 mmol) in THF (10 mL) was added borane-dimethyl sulfide complex (2M in THF, 14 mL) at 0 C. The reaction mixture was allowed to stir at reflux overnight and was then cooled to 0 C. The reaction mixture was quenched by the slow addition of MeOH (10 mL) and then 2N HCl (10 mL). The reaction mixture was allowed to stir at reflux for 3 hr and then concentrated. Water (10 mL) was added to the residue. Remaining starting material was removed by extraction with DCM. To the aqueous solution was added 4N NaOH until pH>9. The solution was extracted with DCM. The organic solutions from this basic extraction were combined, dried over Na2SO4, filtered and concentrated to give 5-bromoisoindoline, which was dissolved in THF (20 mL). To this solution was added potassium carbonate (8 mmol) in water (1 mL), and BOC2O. The reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate (2.5 mmol, 60%).
	dmap; In N,N-dimethyl-formamide; at 20℃;	A mixture of 5-bromo-2,3-dihydro-1H-isoindole (1.26 g; 6.4 mmol), di-tert-butyl dicarbonate (1.53 g; 1.1 equiv.) and 4-dimethylaminopyridine (catalytic amount) in DMF (20 ml) was stirred at room temperature overnight then evaporated. The residue was partitioned between EtOAc and brine, the EtOAc layer was separated, dried (MgSO4) and evaporated. Purification by flash column chromatography using a Biotage SP4 (4OS, 40 ml/min) eluting with 0% to 5% MeOH / DCM gave 695 mg of 5-bromo-1 ,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester as a brown gum. 1HNMR (DMSO-d6) 7.55 (1H, d), 7.48 (1H1 d), 7.30 (1H, dd), 4.63-4.51 (4H, m), 1.46 (9H, s).
	dmap; In N,N-dimethyl-formamide; at 20℃;	A mixture of 5-bromo-2,3-dihydro-1 H-isoindole (1.26 g; 6.4 mmol), di-tert-butyl dicarbonate (1.53 g; 1.1 equiv.) and 4-dimethylaminopyridine (catalytic amount) in DMF (20 ml) was stirred at room temperature overnight then evaporated. The residue was partitioned between EtOAc and brine, the EtOAc layer was separated, dried (MgSO4) and evaporated. Purification by flash column chromatography using a Biotage SP4 (4OS, 40 ml/min) eluting with 0% to 5% MeOH / DCM gave 695 mg of 5-bromo-1 ,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester as a brown gum. 1HNMR (DMSO-d6) 7.55 (1H, d), 7.48 (1 H, d), 7.30 (1 H, dd). 4.63-4.51 (4H, m), 1.46 (9H, s).
	dmap; In N,N-dimethyl-formamide; at 20℃;	A mixture of 5-bromo-2,3-dihydro-1H-isoindole (1.26 g; 6.4 mmol), di-tert-butyl dicarbonate (1.53 g; 1.1 equiv.) and 4-dimethylaminopyridine (catalytic amount) in DMF (20 ml) was stirred at room temperature overnight then evaporated. The residue was partitioned between EtOAc and brine, the EtOAc layer was separated, dried (MgSO4) and evaporated. Purification by flash column chromatography using a Biotage SP4 (4OS, 40 ml/min) eluting with 0% to 5% MeOH / DCM gave 695 mg of 5-bromo-1 ,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester as a brown gum. 1HNMR (DMSO-d6) 7.55 (1H, d), 7.48 (1H, d), 7.30 (1 H, dd), 4.63-4.51 (4H1 m), 1.46 (9H, s).
	dmap; In N,N-dimethyl-formamide; at 20℃;	A mixture of 5-bromo-2,3-dihydro-1 H-isoindole (1.26 g; 6.4 mmol), di-tert-butyl dicarbonate (1.53 g; 1.1 equiv.) and 4-dimethylaminopyridine (catalytic amount) in DMF (20 ml) was stirred at room temperature overnight then evaporated. The residue was partitioned between EtOAc and brine, the EtOAc layer was separated, dried (MgSO4) and evaporated. Purification by flash column chromatography using a Biotage SP4 (4OS, 40 ml/min) eluting with 0% to 5% MeOH / DCM gave 695 mg of 5-bromo-1 ,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester as a brown gum. 1HNMR (DMSO-d6) 7.55 (1 H, d), 7.48 (1 H, d), 7.30 (1 H, dd), 4.63-4.51 (4H, m), 1.46 (9H, s).
	With dmap; In N,N-dimethyl-formamide; at 20℃;	A mixture of 5-bromo-2,3-dihydro-1H-isoindole (1.26 g; 6.4 mmol), di-tert-butyl dicarbonate (1.53 g; 1.1 equiv.) and 4-dimethylaminopyridine (catalytic amount) in DMF (20 ml) was stirred at room temperature overnight then evaporated. The residue was partitioned between EtOAc and brine, the EtOAc layer was separated, dried (MgSO4) and evaporated. Purification by flash column chromatography using a Biotage SP4 (40S, 40 ml/min) eluting with 0% to 5% MeOH/DCM gave 695 mg of 5-bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester as a brown gum. 1HNMR (DMSO-d6) 7.55 (1H, d), 7.48 (1H, d), 7.30 (1H, dd), 4.63-4.51 (4H, m), 1.46 (9H, s).

Reference： [1]Patent: US2017/275301,2017,A1 .Location in patent: Paragraph 0226; 0228
[2]Patent: EP3257857,2017,A1 .Location in patent: Paragraph 0102; 0104
[3]Journal of Organic Chemistry,2012,vol. 77,p. 11296 - 11301
[4]Patent: WO2015/54317,2015,A1 .Location in patent: Paragraph 0272; 0273
[5]Patent: CN110294744,2019,A .Location in patent: Paragraph 0163-0165; 0189-0191
[6]Patent: EP2311810,2011,A1 .Location in patent: Page/Page column 24
[7]Patent: WO2014/89324,2014,A1 .Location in patent: Paragraph 0236
[8]Patent: CN104016979,2017,B .Location in patent: Paragraph 0602; 0603; 0604; 0605
[9]Patent: US2019/375744,2019,A1 .Location in patent: Paragraph 0107; 0109
[10]Journal of Medicinal Chemistry,2019,vol. 62,p. 7431 - 7444
[11]Patent: WO2008/76954,2008,A2 .Location in patent: Page/Page column 54
[12]Journal of Medicinal Chemistry,2007,vol. 50,p. 199 - 210
[13]Patent: US2008/171754,2008,A1 .Location in patent: Page/Page column 103
[14]Patent: WO2008/44029,2008,A1 .Location in patent: Page/Page column 235
[15]Patent: WO2008/44041,2008,A1 .Location in patent: Page/Page column 257
[16]Patent: WO2008/44045,2008,A1 .Location in patent: Page/Page column 310
[17]Patent: WO2008/44054,2008,A2 .Location in patent: Page/Page column 154
[18]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4159 - 4162
[19]Patent: US2010/152184,2010,A1 .Location in patent: Page/Page column 97
[20]Journal of Medicinal Chemistry,2010,vol. 53,p. 5956 - 5969
[21]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4909 - 4912

5
[ 127168-84-7 ]
[ 905273-91-8 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 199 - 210
[2]Patent: WO2014/89324,2014,A1
[3]Patent: CN104016979,2017,B

6
[ 127168-84-7 ]
9-cyclopropyl-7-(2,3-dihydro-1H-isoindol-5-yl)-8-methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 600 mg / DMAP / dimethylformamide / 15 h / 20 °C 2: 80 percent / Pd(PPh₃)4; KOAc / dimethylsulfoxide / 80 °C 3: NaHCO₃ / Pd(PPh₃)4 / dimethylformamide; H₂O / 130 °C / microwave irradiation 4: CF₃CO₂H

Reference： [1]Wang, Qiuping; Lucien, Edlaine; Hashimoto, Akihiro; Pais, Godwin C. G.; Nelson, David M.; Song, Yongsheng; Thanassi, Jane A.; Marlor, Christopher W.; Thoma, Christy L.; Cheng, Jijun; Podos, Steven D.; Ou, Yangsi; Deshpande, Milind; Pucci, Michael J.; Buechter, Douglas D.; Bradbury, Barton J.; Wiles, Jason A. [Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210]

7
[ 127168-84-7 ]
9-cyclopropyl-7-(2,3-dihydro-1H-isoindol-5-yl)-6-fiuoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 600 mg / DMAP / dimethylformamide / 15 h / 20 °C 2: 80 percent / Pd(PPh₃)4; KOAc / dimethylsulfoxide / 80 °C 3: NaHCO₃ / Pd(PPh₃)4 / dimethylformamide; H₂O / 130 °C / microwave irradiation 4: CF₃CO₂H

Reference： [1]Wang, Qiuping; Lucien, Edlaine; Hashimoto, Akihiro; Pais, Godwin C. G.; Nelson, David M.; Song, Yongsheng; Thanassi, Jane A.; Marlor, Christopher W.; Thoma, Christy L.; Cheng, Jijun; Podos, Steven D.; Ou, Yangsi; Deshpande, Milind; Pucci, Michael J.; Buechter, Douglas D.; Bradbury, Barton J.; Wiles, Jason A. [Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210]

8
[ 127168-84-7 ]
9-cyclopropyl-6-fluoro-7-(isoindol-5-yl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 600 mg / DMAP / dimethylformamide / 15 h / 20 °C 2: 80 percent / Pd(PPh₃)4; KOAc / dimethylsulfoxide / 80 °C 3: NaHCO₃ / Pd(PPh₃)4 / dimethylformamide; H₂O / 130 °C / microwave irradiation 4: CF₃CO₂H

Reference： [1]Wang, Qiuping; Lucien, Edlaine; Hashimoto, Akihiro; Pais, Godwin C. G.; Nelson, David M.; Song, Yongsheng; Thanassi, Jane A.; Marlor, Christopher W.; Thoma, Christy L.; Cheng, Jijun; Podos, Steven D.; Ou, Yangsi; Deshpande, Milind; Pucci, Michael J.; Buechter, Douglas D.; Bradbury, Barton J.; Wiles, Jason A. [Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210]

9
[ 127168-84-7 ]
5-(9-cyclopropyl-8-methoxy-3,4-dioxo-2,3,4,9-tetrahydro-isothiazolo[5,4-b]quinolin-7-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 600 mg / DMAP / dimethylformamide / 15 h / 20 °C 2: 80 percent / Pd(PPh₃)4; KOAc / dimethylsulfoxide / 80 °C 3: NaHCO₃ / Pd(PPh₃)4 / dimethylformamide; H₂O / 130 °C / microwave irradiation

Reference： [1]Wang, Qiuping; Lucien, Edlaine; Hashimoto, Akihiro; Pais, Godwin C. G.; Nelson, David M.; Song, Yongsheng; Thanassi, Jane A.; Marlor, Christopher W.; Thoma, Christy L.; Cheng, Jijun; Podos, Steven D.; Ou, Yangsi; Deshpande, Milind; Pucci, Michael J.; Buechter, Douglas D.; Bradbury, Barton J.; Wiles, Jason A. [Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210]

10
[ 127168-84-7 ]
[ 846566-17-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 600 mg / DMAP / dimethylformamide / 15 h / 20 °C 2: 80 percent / Pd(PPh₃)4; KOAc / dimethylsulfoxide / 80 °C 3: NaHCO₃ / Pd(PPh₃)4 / dimethylformamide; H₂O / 130 °C / microwave irradiation

Reference： [1]Wang, Qiuping; Lucien, Edlaine; Hashimoto, Akihiro; Pais, Godwin C. G.; Nelson, David M.; Song, Yongsheng; Thanassi, Jane A.; Marlor, Christopher W.; Thoma, Christy L.; Cheng, Jijun; Podos, Steven D.; Ou, Yangsi; Deshpande, Milind; Pucci, Michael J.; Buechter, Douglas D.; Bradbury, Barton J.; Wiles, Jason A. [Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210]

11
[ 127168-84-7 ]
5-(9-cyclopropyl-6-fluoro-8-methoxy-3,4-dioxo-2,3,4,9-tetrahydro-isothiazolo[5,4-b]quinolin-7-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 600 mg / DMAP / dimethylformamide / 15 h / 20 °C 2: 80 percent / Pd(PPh₃)4; KOAc / dimethylsulfoxide / 80 °C 3: NaHCO₃ / Pd(PPh₃)4 / dimethylformamide; H₂O / 130 °C / microwave irradiation

Reference： [1]Wang, Qiuping; Lucien, Edlaine; Hashimoto, Akihiro; Pais, Godwin C. G.; Nelson, David M.; Song, Yongsheng; Thanassi, Jane A.; Marlor, Christopher W.; Thoma, Christy L.; Cheng, Jijun; Podos, Steven D.; Ou, Yangsi; Deshpande, Milind; Pucci, Michael J.; Buechter, Douglas D.; Bradbury, Barton J.; Wiles, Jason A. [Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210]

12
[ 127168-84-7 ]
[ 437652-06-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NaBH(OAc)2 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 90 percent / TFA / CH₂Cl₂ / 0.5 h / 40 °C

Reference： [1]Austin, Nigel E; Avenell, Kim Y; Boyfield, Izzy; Branch, Clive L; Hadley, Michael S; Jeffrey, Phillip; Johnson, Christopher N; Macdonald, Gregor J; Nash, David J; Riley, Graham J; Smith, Alexander B; Stemp, Geoffrey; Thewlis, Kevin M; Vong, Antonio K.K; Wood, Martyn D [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 5, p. 685 - 688]

13
[ 127168-84-7 ]
N-{4-[2-(5-bromo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclohexyl}-3-(4-fluoro-phenyl)-acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: NaBH(OAc)2 / 1,2-dichloro-ethane / 16 h / 20 °C 2: 90 percent / TFA / CH₂Cl₂ / 0.5 h / 40 °C 3: EDC; HOBt / CH₂Cl₂ / 16 h / 20 °C

Reference： [1]Austin, Nigel E; Avenell, Kim Y; Boyfield, Izzy; Branch, Clive L; Hadley, Michael S; Jeffrey, Phillip; Johnson, Christopher N; Macdonald, Gregor J; Nash, David J; Riley, Graham J; Smith, Alexander B; Stemp, Geoffrey; Thewlis, Kevin M; Vong, Antonio K.K; Wood, Martyn D [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 5, p. 685 - 688]

14
[ 6941-75-9 ]
[ 1423-27-4 ]
[ 127168-84-7 ]

Yield	Reaction Conditions	Operation in experiment
36%	With lithium aluminium tetrahydride; sulfuric acid In tetrahydrofuran; diethyl ether at 20℃; for 2.75h;	10 Compound 10a: 5-bromo-2,3-dihydro-1H-isoindole A solution of LIALH4 (8.8 mL of 1 M solution in Et20, 8.8 mmol) in dry THF (13 mL) was cooled to 0 °C. Concentrated H2S04 (0.42 g, 4.3 mmol) was added dropwise, and the resulting mixture was stirred at 0 °C for 30 min. 5-Bromo-lH-isoindole-1, 3 (2H)- dione (0.409 g, 1. 81 mmol) was added in portions over 15 minutes, and the reaction was allowed to warm to room temperature when the addition was complete. The reaction was stirred at room temperature for 2. 5H, and then cooled back to 0 °C and quenched by the addition OF MEOH (2 mL). Et2O was added (50 mL), followed by NA2S04-10H20. The mixture was stirred vigorously until the organic layer was clear. The mixture was then filtered and concentrated in VACUO. Purification by column chromatography (4: 1 CH2CL2; MeOH + 0. 1% conc. NH3) provided the title compound (0.128 g, 36%). 1H-NMR (CDCl3): No. 7.38 (s 1H), 7.33 (D,@ J=7. 6 Hz, 1H), 7.12 (d, J=8. 0 Hz, 1H), 4.21 (s, 2H), 4.17 (s, 2H), 2.09 (s, 1H). MS (ESI) (M+H) +=198/200.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2004/60882, 2004, A1 Location in patent: Page 41

15
[ 94695-52-0 ]
[ 127168-84-7 ]
7(5-bromo-2-isoindolinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide	32 7(5-bromo-2-isoindolinyl)-1-cyclopropyl-6,8-difluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid STR180 Example 32 7(5-bromo-2-isoindolinyl)-1-cyclopropyl-6,8-difluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid STR180 142 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 150 mg of 5-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 82 mg of the target compound. Melting Point: 243°-251° C. (decomposed) 1 H-NMR (DMSO-d6) δ:8.63 1H, s, C2 --H), 7.78 (1H, d, J=14HZ, C5 --H), 7.32-7.70 (3H, m, ARM-H), 5.00-5.20 (4H, m, 2 x --CH2 N--), 4.00-4.16 (1H, m, STR181 1.20 (4H, brs, STR182

Reference： [1]Current Patent Assignee: WAKUNAGA PHARMACEUTICAL CO., LTD. - US5026856, 1991, A

16
[ 82419-35-0 ]
[ 127168-84-7 ]
[ 127167-96-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;	Example 33 10-(5-bromo-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid STR183 142 mg of <strong>[82419-35-0]9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid</strong>, 150 mg of 5-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 63 mg of the target compound. Melting Point: 290-294 C. (decomposed) 1 H-NMR (DMSO-d6) delta:8.95 (1H, s, C5 --H), 7.30-7.70 (4H, 1 H-NMR (DMSO-d6) delta:8.95 (1H, s, C5 --H), 7.30-7.70 (4H, m, C8 --H, ARM-H), 4.96-5.23 (4H, m, 2 x --CH2 N--), 4.30-4.96 (3H, m, C2 --H, C3 --H), 1.48 (3H, d, J=7HZ)

Reference： [1]Patent: US5026856,1991,A

17
[ 103772-14-1 ]
[ 127168-84-7 ]
7-(5-bromo-2-isoindolinyl)-1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide	47 7-(5-bromo-2-isoindolinyl)-1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid STR215 Example 47 7-(5-bromo-2-isoindolinyl)-1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid STR215 290 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 200 mg of 5-bromoisoindoline, 290 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 220 mg of the target compound. Melting Point: 266°-267° C. (decomposed) 1 H-NMR (CDCl3 --CF3 COOD, 10:1) δ:8.90 (1H, s, C2 --H), 7.19-7.50 (3H, m, ARM-H), 5.20-5.40 (4H, m, 2 x --CH2 N--), 4.19 (1H, m, STR216 1.20-1.40 (4H, m, STR217

Reference： [1]Current Patent Assignee: WAKUNAGA PHARMACEUTICAL CO., LTD. - US5026856, 1991, A

18
[ 103994-87-2 ]
[ 127168-84-7 ]
7-(5-bromo-2-isoindolinyl)-1-(4-fluorophenyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide	70 7-(5-bromo-2-isoindolinyl)-1-(4-fluorophenyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid STR262 Example 70 7-(5-bromo-2-isoindolinyl)-1-(4-fluorophenyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid STR262 170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 300 mg of 5- bromoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 144 mg of the target compound. Melting Point: above 300° C.

Reference： [1]Current Patent Assignee: WAKUNAGA PHARMACEUTICAL CO., LTD. - US5026856, 1991, A

19
[ 105859-15-2 ]
[ 127168-84-7 ]
7-(5-bromo-2-isoindolinyl)-1-(2,4-difluorophenyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide	71 7-(5-bromo-2-isoindolinyl)-1-(2,4-difluorophenyl)-6,8- difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid STR263 Example 71 7-(5-bromo-2-isoindolinyl)-1-(2,4-difluorophenyl)-6,8- difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid STR263 178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 119 mg of 5-bromoisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 44 mg of the target compound. Melting Point: 251°-257° C. 1 H-NMR (CDCl3) δ:8.48 (1H, s, C2 --H), 7.98 (1H, d, J=13HZ, C5 --H), 7.05-7.60 (6H, m, ARM-H), 4.95-5.10 (4H, m, 2 x --CH2 N--)

Reference： [1]Current Patent Assignee: WAKUNAGA PHARMACEUTICAL CO., LTD. - US5026856, 1991, A

20
[ 76-83-5 ]
[ 127168-84-7 ]
[ 405150-03-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In dichloromethane for 18h;	78.78A Trityl chloride (2.30 g, 8.23 mmol) was added to a solution of 5-bromo-2,3-dihydro-1 H-isoindole (1.64 g, 8.23 mmol) and triethylamine (1.4 mL, 9.9 mmol) in dichloromethane (20 mL). After 18 hours the solvent was removed in vacuo, the residue taken up in ethyl acetate and washed with water (*2) and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography on silica eluting with 1 % triethylamine/10% ethyl acetate/petrol to give 5-bromo-2- trityl-2,3-dihydro-1 H-isoindole as a reddish-brown solid (3.10 g, 85%). 1H NMR (CDCI3) 7.91-7.84 (1H, m), 7.57 (6H, d), 7.45-7.41 (1H, m), 7.33-7.14 (9H, m), 6.95 (1H, d), 3.90 (2H, s), 3.86 (2H, s). MS: Ph3C+ 243.
85%	With triethylamine In dichloromethane for 18h;	78.A Trityl chloride (2.30 g, 8.23 mmol) was added to a solution of 5-bromo-2,3-dihydro-1 H-isoindole (1.64 g, 8.23 mmol) and triethylamine (1.4 mL, 9.9 mmol) in dichloromethane (20 mL). After 18 hours the solvent was removed in vacuo, the residue taken up in ethyl acetate and washed with water (*2) and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography on silica eluting with 1 % triethylamine/10% ethyl acetate/petrol to give 5-bromo-2- trityl-2,3-dihydro-1 H-isoindole as a reddish-brown solid (3.10 g, 85%). 1H NMR (CDCI3) 7.91-7.84 (1 H, m), 7.57 (6H, d), 7.45-7.41 (1 H, m), 7.33-7.14 (9H, m), 6.95 (1 H, d), 3.90 (2H, s), 3.86 (2H, s). MS: Ph3C+ 243.
85%	With triethylamine In dichloromethane for 18h;	78.A Trityl chloride (2.30 g, 8.23 mmol) was added to a solution of 5-bromo-2,3-dihydro-1 H-isoindole (1.64 g, 8.23 mmol) and triethylamine (1.4 mL, 9.9 mmol) in dichloromethane (20 mL). After 18 hours the solvent was removed in vacuo, the residue taken up in ethyl acetate and washed with water (*2) and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography on silica eluting with 1% triethylamine/10% ethyl acetate/petrol to give 5-bromo-2- trityl-2,3-dihydro-1 H-isoindole as a reddish-brown solid (3.10 g, 85%). 1H NMR (CDCI3) 7.91-7.84 (1H, m), 7.57 (6H, d), 7.45-7.41 (1 H, m), 7.33-7.14 (9H, m), 6.95 (1H, d), 3.90 (2H, s), 3.86 (2H, s). MS: Ph3C+ 243.

85%	With triethylamine In dichloromethane for 18h;	78.78A Trityl chloride (2.30 g, 8.23 mmol) was added to a solution of 5-bromo-2,3-dihydro-1 H-isoindole (1.64 g, 8.23 mmol) and triethylamine (1.4 mL, 9.9 mmol) in dichloromethane (20 mL). After 18 hours the solvent was removed in vacuo, the residue taken up in ethyl acetate and washed with water (χ2) and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography on silica eluting with 1% triethylamine/10% ethyl acetate/petrol to give 5-bromo-2- trityl-2,3-dihydro-1 H-isoindole as a reddish-brown solid (3.10 g, 85%). 1H NMR (CDCI3) 7.91-7.84 (1 H, m), 7.57 (6H, d), 7.45-7.41 (1 H, m), 7.33-7.14 (9H, m), 6.95 (1 H, d), 3.90 (2H, s), 3.86 (2H, s). MS: Ph3C+ 243
85%	With triethylamine In dichloromethane for 18h;	78.A 78A. Trityl chloride (2.30 g, 8.23 mmol) was added to a solution of 5-bromo-2,3-dihydro-1H-isoindole (1.64 g, 8.23 mmol) and triethylamine (1.4 mL, 9.9 mmol) in dichloromethane (20 mL). After 18 hours the solvent was removed in vacuo, the residue taken up in ethyl acetate and washed with water (×2) and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography on silica eluting with 1% triethylamine/10% ethyl acetate/petrol to give 5-bromo-2-trityl-2,3-dihydro-1H-isoindole as a reddish-brown solid (3.10 g, 85%). 1H NMR (CDCl3) 7.91-7.84 (1H, m), 7.57 (6H, d), 7.45-7.41 (1H, m), 7.33-7.14 (9H, m), 6.95 (1H, d), 3.90 (2H, s), 3.86 (2H, s). MS: Ph3C+ 243.

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44029, 2008, A1 Location in patent: Page/Page column 257-258
[2]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44041, 2008, A1 Location in patent: Page/Page column 279
[3]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44045, 2008, A1 Location in patent: Page/Page column 332
[4]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44054, 2008, A2 Location in patent: Page/Page column 175
[5]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - US2010/152184, 2010, A1 Location in patent: Page/Page column 113

21
[ 888216-48-6 ]
[ 127168-84-7 ]
[ 913000-29-0 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide at 20℃;	53.53E To a mixture of 5-isopropyl-2,4-dimethoxybenzoic acid (2.45 g, 10.9 mmol), HOBt (1.61 g, 11.9 mmol) and EDC (1.85 g, 11.9 mmol) in anhydrous DMF (33 ml) under N2 was added 5-bromo-2,3- dihydro-1 H-isoindole (1.97 g, 9.95 mmol) and stirred at room temperature overnight. The reaction was quenched by diluting with NaOH (1M1 aq.) and extracting the product with EtOAc (x2). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to leave a brown oil. The product was purified by flash column chromatography using gradient elution (ether/petrol) to yield (5-bromo-1 ,3-dihydro-isoindol-2-yl)-(5- isopropyl-2,4-dimethoxyphenyl)-methanone as a beige solid (3 g). 1H NMR (Me-Cf3-OD) 7.60-7.13 (3H, m), 7.14 (1 H, s), 6.71 (1 H, s), 4.89 (2H, d), 4.64 (2H, d), 3.93 (3H, s), 3.90 (3H, s), 3.27 (1H, sept), 1.20 (6H, d). MS: [M+H]+ 404/406.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	53.E To a mixture of 5-isopropyl-2,4-dimethoxybenzoic acid (2.45 g, 10.9 mmol), HOBt (1.61 g, 11.9 mmol) and EDC (1.85 g, 11.9 mmol) in anhydrous DMF (33 ml) under N2 was added 5-bromo-2,3- dihydro-1 H-isoindole (1.97 g, 9.95 mmol) and stirred at room temperature overnight. The reaction was quenched by diluting with NaOH (1M1 aq.) and extracting the product with EtOAc (x2). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to leave a brown oil. The product was purified by flash column chromatography using gradient elution (ether/petrol) to yield (5-bromo-1 ,3-dihydro-isoindol-2-yl)-(5- isopropyl-2,4-dimethoxyphenyl)-methanone as a beige solid (3 g). 1H NMR (Me-Cf3-OD) 7.60-7.13 (3H, m), 7.14 (1 H, s), 6.71 (1 H1 s), 4.89 (2H, d), 4.64 (2H, d), 3.93 (3H1 s), 3.90 (3H, s), 3.27 (1 H, sept), 1.20 (6H, d). MS: [M+H]+ 404/406.
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide at 20℃;	53.E To a mixture of 5-isopropyl-2,4-dimethoxybenzoic acid (2.45 g, 10.9 mmol), HOBt (1.61 g, 11.9 mmol) and EDC (1.85 g, 11.9 mmol) in anhydrous DMF (33 ml) under N2 was added 5-bromo-2,3- dihydro-1 H-isoindole (1.97 g, 9.95 mmol) and stirred at room temperature overnight. The reaction was quenched by diluting with NaOH (1M, aq.) and extracting the product with EtOAc (x2). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to leave a brown oil. The product was purified by flash column chromatography using gradient elution (ether/petrol) to yield (5-bromo-1 ,3-dihydro-isoindol-2-yl)-(5- isopropyl-2,4-dimethoxyphenyl)-methanone as a beige solid (3 g). 1H NMR (Me-cfe-OD) 7.60-7.13 (3H1 m), 7.14 (1H1 s), 6.71 (1H, s), 4.89 (2H1 d), 4.64 (2H, d), 3.93 (3H, s), 3.90 (3H, s), 3.27 (1 H, sept), 1.20 (6H, d). MS: [M+H]+ 404/406.

	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	53.53E To a mixture of 5-isopropyl-2,4-dimethoxybenzoic acid (2.45 g, 10.9 mmol), HOBt (1.61 g, 11.9 mmol) and EDC (1.85 g, 11.9 mmol) in anhydrous DMF (33 ml) under N2 was added 5-bromo-2,3- dihydro-1 H-isoindole (1.97 g, 9.95 mmol) and stirred at room temperature overnight. The reaction was quenched by diluting with NaOH (1M, aq.) and extracting the product with EtOAc (x2). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to leave a brown oil. The product was purified by flash column chromatography using gradient elution (ether/petrol) to yield (5-bromo-1 ,3-dihydro-isoindol-2-yl)-(5- isopropyl-2,4-dimethoxyphenyl)-methanone as a beige solid (3 g). 1H NMR (Me-Cf3-OD) 7.60-7.13 (3H, m), 7.14 (1 H, s), 6.71 (1 H, s), 4.89 (2H, d), 4.64 (2H, d), 3.93 (3H, s), 3.90 (3H, s), 3.27 (1H, sept), 1.20 (6H, d). MS: [M+H]+ 404/406.
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	53.E 53E. To a mixture of 5-isopropyl-2,4-dimethoxybenzoic acid (2.45 g, 10.9 mmol), HOBt (1.61 g, 11.9 mmol) and EDC (1.85 g, 11.9 mmol) in anhydrous DMF (33 ml) under N2 was added 5-bromo-2,3-dihydro-1H-isoindole (1.97 g, 9.95 mmol) and stirred at room temperature overnight. The reaction was quenched by diluting with NaOH (1M, aq.) and extracting the product with EtOAc (×2). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to leave a brown oil. The product was purified by flash column chromatography using gradient elution (ether/petrol) to yield (5-bromo-1,3-dihydro-isoindol-2-yl)-(5-isopropyl-2,4-dimethoxyphenyl)-methanone as a beige solid (3 g). 1H NMR (Me-d3-OD) 7.60-7.13 (3H, m), 7.14 (1H, s), 6.71 (1H, s), 4.89 (2H, d), 4.64 (2H, d), 3.93 (3H, s), 3.90 (3H, s), 3.27 (1H, sept), 1.20 (6H, d). MS: [M+H]+ 404/406.

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44029, 2008, A1 Location in patent: Page/Page column 240
[2]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44041, 2008, A1 Location in patent: Page/Page column 262
[3]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44045, 2008, A1 Location in patent: Page/Page column 315
[4]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44054, 2008, A2 Location in patent: Page/Page column 159
[5]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - US2010/152184, 2010, A1 Location in patent: Page/Page column 101

22
[ 912545-09-6 ]
[ 127168-84-7 ]
[ 913000-21-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 25℃; for 13h;	(2,4-bis(benzyloxy)-5-(prop-1-en-2-yl)phenyl)(5-bromoisoindolin-2-yl)methanone (36)^[33] N,N-diisopropylethylamine (2.3 mL, 13.35 mmol, 2.0 eq.) was added to a stirred solution of 2,4-Bis(benzyloxy)-5-(prop-1-en-2-yl)benzoic acid (2.5 g, 6.67 mmol, 1.0 eq.), 5-bromoisoindoline (1.98 g, 10 mmol, 1.5 eq.), hydroxybenzotriazole (1.22 g, 8.0 mmol, 1.2 eq.) and ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (3.8 g, 20.0 mmol, 3 eq.) in anhydrous dichloromethane (60 mL) at 0°C. The resulting mixture was stirred at room temperature for 13 hours, before it was diluted with water and extracted with DCM. The organic layer was separated and washed with 2N HCl solution, followed by washing with brine and was dried over anhydrous MgSO4. The crude product obtained upon the removal of solvent under reduced pressure was purified by normal-phase chromatography (0-10% MeOH:DCM) to afford (2,4-bis(benzyloxy)-5-(prop-1-en-2-yl)phenyl)(5-bromoisoindolin-2-yl)methanone (3.5 g 95%) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 7.46 - 7.33 (m, 7H), 7.27-7.18 (m, 7H), 6.56 (s, 1H), 5.11 (s, 2H), 5.06 (br s, 4H), 4.92 (d, J = 16.0 Hz, 2H), 4.60 (d, J = 12.0 Hz, 2H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.20 (+168.17, rotamer), 157.55 (+157.73), 154.70, 142.65, 139.08, 138.83, 136.56 (+136.51), 135.79, 135.56, 130.73 (+130.57), 128.79 (+128.76), 128.63 (+128.60), 128.01, 127.15, 126.96, 126.54 (+126.26), 125.72, 124.58, 124.03, 121.37 (+121.11), 119.47 (+119.40), 115.53, 99.54 (+99.50), 71.11, 70.57, 53.04 (+53.00), 51.70 (+51.67), 23.30; ESI-MS: 556.05 [M(79Br)+H]+, 558.13 [M(81Br)+H]+
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide at 20℃;	51.51A A solution of benzyloxy-5-isopropenyl-benzoic acid (2.85 g; 7.6 mmol), 5-bromo-2,3-dihydro-1 H- isoindole (1.5 g; 1 equiv.) , EDC (1.75g; 1.2 equiv.) and HOBt (1.25 g; 1.2 equiv.) in DMF (25 ml) was stirred at room temperature overnight then evaporated. The residue was dissolved in EtOAc, washed with 2M HCI then saturated NaHCO3, dried (MgSO4) and evaporated. Purification using a Biotage SP4 (40S1 40 ml/min) eluting with 1:4-1 :3-1 :2 EtOAc / P.E. gave 2.45 g of (2,4-bis- benzyloxy-5-isopropenyl-phenyl)-(5-bromo-1 ,3-dihydro-isoindol-2-yl)-methanone as a light brown solid.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	51.A A solution of benzyloxy-5-isopropenyl-benzoic acid (2.85 g; 7.6 mmol), 5-bromo-2,3-dihydro-1H- isoindole (1.5 g; 1 equiv.) , EDC (1.75g; 1.2 equiv.) and HOBt (1.25 g; 1.2 equiv.) in DMF (25 ml) was stirred at room temperature overnight then evaporated. The residue was dissolved in EtOAc, washed with 2M HCI then saturated NaHCO3, dried (MgSO4) and evaporated. Purification using a Biotage SP4 (4OS, 40 ml/min) eluting with 1:4-1 :3-1:2 EtOAc / P.E. gave 2.45 g of (2,4-bis- benzyloxy-5-isopropenyl-phenyl)-(5-bromo-1,3-dihydro-isoindol-2-yl)-methanone as a light brown solid.

	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide at 20℃;	51.A A solution of benzyloxy-5-isopropenyl-benzoic acid (2.85 g; 7.6 mmol), 5-bromo-2,3-dihydro-1H- isoindole (1.5 g; 1 equiv.) , EDC (1.75g; 1.2 equiv.) and HOBt (1.25 g; 1.2 equiv.) in DMF (25 ml) was stirred at room temperature overnight then evaporated. The residue was dissolved in EtOAc, washed with 2M HCI then saturated NaHCO3, dried (MgSO4) and evaporated. Purification using a Biotage SP4 (4OS, 40 ml/min) eluting with 1 :4-1 :3-1 :2 EtOAc / P.E. gave 2.45 g of (2,4-bis- benzyloxy-5-isopropenyl-phenyl)-(5-bromo-1 ,3-dihydro-isoindol-2-yl)-methanone as a light brown solid.
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	76.A Coupling of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid (5.0 g, 13.4 mmol) (Preparation B9) and 5-bromo-2,3-dihydro-1 H-isoindole (Preparation C20) was completed according to method A4, using CH2CI2 as the reaction solvent to give the title compound (8.34 g) as a beige solid.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	51.51A A solution of benzyloxy-5-isopropenyl-benzoic acid (2.85 g; 7.6 mmol), 5-bromo-2,3-dihydro-1 H- isoindole (1.5 g; 1 equiv.) , EDC (1.75g; 1.2 equiv.) and HOBt (1.25 g; 1.2 equiv.) in DMF (25 ml) was stirred at room temperature overnight then evaporated. The residue was dissolved in EtOAc, washed with 2M HCI then saturated NaHCO3, dried (MgSO4) and evaporated. Purification using a Biotage SP4 (4OS, 40 ml/min) eluting with 1 :4-1 :3-1 :2 EtOAc / P.E. gave 2.45 g of (2,4-bis- benzyloxy-5-isopropenyl-phenyl)-(5-bromo-1 ,3-dihydro-isoindol-2-yl)-methanone as a light brown solid.
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide at 20℃;	51.A 51A. A solution of benzyloxy-5-isopropenyl-benzoic acid (2.85 g; 7.6 mmol), 5-bromo-2,3-dihydro-1H-isoindole (1.5 g; 1 equiv.), EDC (1.75 g; 1.2 equiv.) and HOBt (1.25 g; 1.2 equiv.) in DMF (25 ml) was stirred at room temperature overnight then evaporated. The residue was dissolved in EtOAc, washed with 2M HCl then saturated NaHCO3, dried (MgSO4) and evaporated. Purification using a Biotage SP4 (40S, 40 ml/min) eluting with 1:4-1:3-1:2 EtOAc/P.E. gave 2.45 g of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(5-bromo-1,3-dihydro-isoindol-2-yl)-methanone as a light brown solid.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;

Reference： [1]Kaur, Jatinder; Bhardwaj, Atul; Melancon, Bruce J.; Blagg, Brian S. J. [Synthetic Communications, 2019, vol. 49, # 11, p. 1436 - 1443]
[2]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44029, 2008, A1 Location in patent: Page/Page column 236
[3]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44041, 2008, A1 Location in patent: Page/Page column 258-259
[4]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44045, 2008, A1 Location in patent: Page/Page column 311-312
[5]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44045, 2008, A1 Location in patent: Page/Page column 330
[6]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44054, 2008, A2 Location in patent: Page/Page column 155-156
[7]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - US2010/152184, 2010, A1 Location in patent: Page/Page column 98
[8]Woodhead, Andrew J.; Angove, Hayley; Carr, Maria G.; Chessari, Gianni; Congreve, Miles; Coyle, Joseph E.; Cosme, Jose; Graham, Brent; Day, Philip J.; Downham, Robert; Fazal, Lynsey; Feltell, Ruth; Figueroa, Eva; Frederickson, Martyn; Lewis, Jonathan; McMenamin, Rachel; Murray, Christopher W.; O'Brien, M. Alistair; Parra, Lina; Patel, Sahil; Phillips, Theresa; Rees, David C.; Rich, Sharna; Smith, Donna-Michelle; Trewartha, Gary; Vinkovic, Mladen; Williams, Brian; Woolford, Alison J.-A. [Journal of Medicinal Chemistry, 2010, vol. 53, # 16, p. 5956 - 5969]

23
[ 6941-75-9 ]
[ 24424-99-5 ]
[ 64990-51-8 ]
[ 919346-89-7 ]
[ 127168-84-7 ]

Yield	Reaction Conditions	Operation in experiment
3.0 g (42.8%)	With triethylamine In tetrahydrofuran; methanol; BH₃-THF; ethyl acetate	Intermediate 20: 5-Bromoisoindoline In a dried 500 mL three necked round bottom flask equipped with a reflux condenser and addition funnel was taken BH3-THF (160 mL) solution with dry THF (50 mL). The mixture was cooled to 0° C. To this cold solution 5-bromo-1H-isoindole-1,3(2H)-dione (8.0 g, 35.4 mmol) in dry THF (100 mL) was added gradually and allowed to warm to room temperature. After 10 min at room temperature the mixture was refluxed for 16 h. The reaction mixture was then cooled to 0° C. and quenched with methanol. (Caution: vigorous foaming will occur). 20-30 mL of 2N HCL was added and refluxed the mixture for 1 h. Cooled the mixture and basified with NaOH solution and extracted with ethyl acetate. Combined organic extracts were washed with water, saturated NaCl solution, dried over Na2SO4 and concentrated under vacuo. To the crude product in MeOH (150 mL), Et3N (12 mL) and di-tert-butyl dicarbonate (13.8 g, 63.23 mmol) were added and stirred at room temperature for 16 h. The reaction mixture was then concentrated under vacuo. The crude product was diluted with CH2Cl2 (200 mL), washed with water, saturated NaCl solution, and dried over Na2SO4. Crude product was purified by column chromatography using 20% ethyl acetate in hexanes as eluant to afford a colourless solid. To this dioxane-HCl was added at room temperature and stirred for 10 min, the solid obtained was then filtered and dried to give 3.0 g (42.8%) of 5-bromoisoindoline hydrochloride salt as an ash colour solid.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2009/143372, 2009, A1

24
[ 1147391-39-6 ]
[ 127168-84-7 ]
[ 1181690-78-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In water; benzene at 100℃; for 2h; Microwave irradiation;	1.30.B Step B: Preparation of (λ)-5-(4-(2-(2-Methylpyrrolidin-l- yl)ethyl)phenyl)isoindoline.To a Smith Microwave Synthesizer vial was added 5-bromoisoindoline (4.02 g 20.3 mmol), (λ)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid hydrochloride (5.47 g, 20.3 mmol), aqueous Na2CO3 (2 M solution, 25.4 mL, 50.7 mmol), and Pd(PPh3)4 (0.704 g, 0.609 mmol) in a mixture of EtOH (10 mL) and benzene (30 mL). The resulting reaction mixture was heated at 100 0C under microwave irradiation for 120 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a brown solid (1.27 g). LCMS m/z = 307.4 [M+H]+.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2009/105206, 2009, A1 Location in patent: Page/Page column 75-76

25
[ 1034266-31-3 ]
[ 127168-84-7 ]
[ 1208147-37-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-cyanomethyl-1H-pyrazole-3-carboxylic acid With benzotriazol-1-ol In dichloromethane Stage #2: 5-bromoisoindoline In dichloromethane

Reference： [1]Location in patent: body text Cooper, Martin; Receveur, Jean-Marie; Bjurling, Emelie; Norregaard, Pia K.; Nielsen, Peter Aadal; Skoeld, Niklas; Hoegberg, Thomas [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 1, p. 26 - 30]

26
[ 1240040-80-5 ]
[ 127168-84-7 ]
[ 1240040-82-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-(4-chlorophenyl)-3-(4-[(3-ethoxy-3-oxopropyl)amino]carbonyl}phenyl)hexanoic acid With N-ethyl-N,N-diisopropylamine; HATU In 1-methyl-pyrrolidin-2-one at 20℃; for 1h; Stage #2: 5-bromoisoindoline In 1-methyl-pyrrolidin-2-one at 20℃;	4.A Step A. Ethyl iV-f4-{ 1 -r2-(5-ljromo-L3-dihvdro-2i/-isoindol-2-ylVl-(4-chlorophenvl)-2- oxoethyllbutyi)benzoyl)-β-alaninateTo a solution of a single stereoisomer (of the four possible) of 2-(4- chloropheiyl)-3-(4-{ [(3-ethoxy-3-oxopropyl)amino]carbonyl}phenyl)hexanoic acid (EXAMPLE 1, Step C, 142 mg, 0.318 mmol) in NMP (3 mL) at room temperature was added HATU (133 mg, 0.350 mmol) and DIPEA (222 μl, 1.27 mmol). After one hour, 5-bromoisoindoline (94 mg, 0.48 mmol) was added, then the mixture was stirred at rt until the reaction was complete by LC- MS analysis. The mixture was then diluted with EtOAc then washed with water then saturated NaCl (aq). The organic layer was then dried over Na2SO4, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to provide the title compound as a white solid. LC2 1.53 min. (M+H)+ 627.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2010/93535, 2010, A1 Location in patent: Page/Page column 41-42

27
[ 1126832-32-3 ]
[ 127168-84-7 ]
[ 1126832-42-5 ]

Yield	Reaction Conditions	Operation in experiment
42%	Stage #1: 5-[(N-methyl-N-butylamino)carbonyl]-2,4-bisbenzyloxybenzoic acid With thionyl chloride In tetrahydrofuran; toluene at 22 - 40℃; Stage #2: 5-bromoisoindoline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; dichloromethane at 22℃; for 2h;	9 Example 9; Preparation of 2,4-bisbenzyloxy-N-butyl-2,4-dihydroxy-5-(5-bromo-1,3-dihydroisoindole-2-carbonyl)-N-methylbenzamide (“A16a”); 652.9 μl (9 mmol) of thionyl chloride are added to a suspension of 2.06 g (4.6 mmol) of 2,4-bisbenzyloxy-5-[(N-methyl-N-butylamino)carbonyl]benzoic acid (5) in 20 ml of THF (dry), and the mixture is stirred for 15 min at 22° C. 10 ml of toluene are subsequently added, and the mixture is evaporated to dryness in vacuo at 40° C. The residue is dissolved in 20 ml of THF and added to a suspension of 923 mg (4.661 mmol) of 5-bromo-2,3-dihydro-1H-isoindole (13) in 30 ml of dichloromethane, 5 ml of THF and 1.7 ml (10 mmol) of N-ethyldiisopropylamine. After 2 h at 22° C., the mixture is evaporated and chromatographed over an RP18 column. Evaporation to dryness in vacuo gives 1.2 g (42%) of 2,4-bisbenzyloxy-N-butyl-5-(5-bromo-1,3-dihydroisoindole-2-carbonyl)-N-methylbenzamide (“A16a”), MW 627.6; Rt 2.478 min.

Reference： [1]Current Patent Assignee: MERCK KGAA - US2010/311745, 2010, A1 Location in patent: Page/Page column 26-27

28
[ 127168-84-7 ]
[ 253801-14-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium carbonate / tetrahydrofuran / 2 h / 20 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine / N,N-dimethyl-formamide / 80 °C 3: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: HELSINN HEALTCARE S.A. - US2017/275301, 2017, A1

29
[ 127168-84-7 ]
C₁₂H₁₄N₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: triethylamine / dichloromethane 5: hydroxylamine; sodium methylate / methanol

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

30
[ 127168-84-7 ]
C₁₅H₂₀N₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: triethylamine / dichloromethane 5: hydroxylamine; sodium methylate / methanol

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

31
[ 127168-84-7 ]
C₁₄H₁₆N₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: triethylamine / dichloromethane 5: hydroxylamine; sodium methylate / methanol

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

32
[ 127168-84-7 ]
C₁₈H₁₈N₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: triethylamine / dichloromethane 5: hydroxylamine; sodium methylate / methanol

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

33
[ 127168-84-7 ]
C₁₇H₁₆N₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: triethylamine / dichloromethane 5: hydroxylamine; sodium methylate / methanol

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

34
[ 127168-84-7 ]
C₁₅H₁₄N₂O₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: triethylamine / dichloromethane 5: hydroxylamine; sodium methylate / methanol

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

35
[ 127168-84-7 ]
C₁₆H₁₅N₃O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: triethylamine / dichloromethane 5: hydroxylamine; sodium methylate / methanol

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

36
[ 127168-84-7 ]
C₁₆H₁₅N₃O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: triethylamine / dichloromethane 5: hydroxylamine; sodium methylate / methanol

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

37
[ 127168-84-7 ]
C₁₅H₁₆N₄O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: triethylamine / dichloromethane 5: hydroxylamine; sodium methylate / methanol

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

38
[ 127168-84-7 ]
C₁₈H₁₈N₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: triethylamine / dichloromethane 5: hydroxylamine; sodium methylate / methanol

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

39
[ 127168-84-7 ]
C₁₆H₂₀N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: 4-methyl-morpholine / dichloromethane 5: hydroxylamine; sodium methylate / methanol

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

40
[ 127168-84-7 ]
[ 1034573-47-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

41
[ 127168-84-7 ]
C₁₂H₁₃NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

42
[ 127168-84-7 ]
C₁₇H₂₁NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: 4-methyl-morpholine / dichloromethane

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

43
[ 127168-84-7 ]
C₁₆H₁₇NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: dmap / tetrahydrofuran 2: palladium diacetate; triethylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane 4: 4-methyl-morpholine / dichloromethane

Reference： [1]Shultz, Michael; Fan, Jianmei; Chen, Christine; Cho, Young Shin; Davis, Nicole; Bickford, Sheri; Buteau, Kristen; Cao, Xueying; Holmqvist, Mats; Hsu, Meier; Jiang, Lei; Liu, Gang; Lu, Qiang; Patel, Chetan; Suresh, Joghee Raju; Selvaraj, Mannangatti; Urban, Laszlo; Wang, Ping; Yan, Yan-Neale; Whitehead, Lewis; Zhang, Haiyan; Zhou, Liping; Atadja, Peter [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912]

44
[ 127168-84-7 ]
[ 912999-49-6 ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 11296 - 11301

45
[ 86-90-8 ]
[ 127168-84-7 ]

Reference： [1]Patent: WO2014/89324,2014,A1
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 1142 - 1150
[3]Patent: CN104016979,2017,B
[4]Patent: WO2018/95260,2018,A1
[5]Organic Letters,2019,vol. 21,p. 1438 - 1443
[6]European Journal of Organic Chemistry,2019,vol. 2019,p. 3649 - 3653
[7]Journal of Medicinal Chemistry,2019,vol. 62,p. 7431 - 7444

46
[ 69189-19-1 ]
[ 127168-84-7 ]

Reference： [1]Patent: US2014/194386,2014,A1

47
[ 501-53-1 ]
[ 127168-84-7 ]
[ 178445-27-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In hexane; dichloromethane for 2h;	36.4 Step 4. Synthesis of benzyl 5-bromoisoindoline-2-carboxylate Step 4. Synthesis of benzyl 5-bromoisoindoline-2-carboxylate To a cooled solution of 5-bromoisoindoline (1.1 g, 5.5 mmol) in dichloromethane (15 mL) was added N,N-diisopropylethylamine (1.16 mL, 6.6 mmol) followed by benzyl chloroformate (942 μL, 6.6 mmol). The cold bath was removed and stirring continued for 2 hr. The reaction mixture was then diluted with dichloromethane, washed with water, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (25 g silica eluted with 0-50% ethyl acetate in hexane) to give the title compound as a white solid.

Reference： [1]Current Patent Assignee: VENATORX PHARMACEUTICALS INC - US2014/194386, 2014, A1 Location in patent: Paragraph 0463

48
[ 127168-84-7 ]
[ 590-17-0 ]
[ 1428738-31-1 ]

Yield	Reaction Conditions	Operation in experiment
73.6%	With triethylamine In dichloromethane at 20℃; for 4h;	1.1 (1) Preparation of 5-bromoisoindolin-2-carbonitrile (1) Preparation of 5-bromoisoindolin-2-carbonitrile 5-Bromoisoindoline (20 g, 85.28 mmol) and triethylamine (21.6 mL, 154.97 mmol) were dissolved in 250 mL dichloromethane, and bromoacetonitrile (9.03 g, 85.3 mmol) was added slowly. The mixture was stirred at room temperature and reacted for 4 h. Water was added. After being extracted with ethyl acetate, dried, and concentrated, 5-bromo isoindolin-2-carbonitrile (14 g) was obtained at a yield of 73.6 %. The solid was used directly for the next step of reaction without purification.

Reference： [1]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - EP2762480, 2014, A1 Location in patent: Paragraph 0084; 0085

49
[ 50-00-0 ]
[ 127168-84-7 ]
[ 107834-37-7 ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: paraformaldehyd; 5-bromo-2,3-dihydro-1H-isoindole With methanol In water monomer for 0.25h; Stage #2: With sodium cyanotrihydridoborate In water monomer for 12h;	Synthesis of 5-bromo-2-methylisoindoline (R4) The pH of a mixture of R26 (1.85 g, 7.9 mmol) in methanol (100 mL) and water (10 mL) is adjusted to 5 with acetic acid. Then a 37% formalin solution (1.28 mL, 15.8 mmol) is added and the mixture is stirred for 15 min. Sodium cyanoborohydride (0.74 g, 11.8 mmol) is added and the reaction mixture is stirred for additional 12 h. The mixture is concentrated and ethyl acetate and aq. 1M NaOH solution are added to the residue. The organic layer is washed with NaCl solution, dried over MgSO4 and concentrated. The residue is dissolved in diethyl ether and ethereal HCl is added dropwise. The resulting precipitate is filtered off. Yield 62% m/z 212/214 [M+H]+, rt 0.65 min, LC-MS Method V012_S01.
49.5%	In formic acid at 150℃; for 0.25h; Microwave irradiation;	172 5-Bromo-2-methylisoindoline 5-Bromo-2-methylisoindolineTo a solution of 5-bromoisoindoline (1.5 g, 7.57 mmol) in formic acid (12 mL) was added formaldehyde (3 mL, 109 mmol) and the reaction mixture was heated to 150 °C in microwave vial for 15 min. The reaction mixture was concentrated under reduced pressure. The residue was neutralised with sat. bicarbonate solution up to pH 7 and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine and the organic layer was dried over anhydrous Na2S04and concentrated to afford crude residue. The crude residue was purified usung using 3% MeOH in DCM as eluent to afford 5-bromo-2-methylisoindoline (900 mg, 3.75 mmol, 49.5 % yield). LC-MS m/z 211.8 (M+H)+, 1.15 min (ret. time).
	With sodium tetrahydridoborate In methanol; water monomer at 15℃; for 1h; Inert atmosphere;	57 Intermediate 57 Into an 100-mL round-bottom flask was placed 5-bromo-2,3-dihydro-lH- isoindole (l .OOg, 5.05 mmol), formaldehyde(0.23 g, 40% in water, 7.60 mmol), sodium borohydride (0.29g, 7.60 mmol) and methanol (50 mL). The resulting solution was stirred for 1 h at 15°C, then extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to afford a residue that was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 : 1) to afford the title compound. LRMS (ESI) calc'd for: C9Hi0BrN [M+H]+: 212, 214 (1 : 1), found 212, 214 (1 : 1).

	With sodium tetrahydridoborate In methanol at 15℃; for 1h; Inert atmosphere;	5-bromo-2-methylisoindoline Into an 100-mi. round-bottom flask was placed 5-bromo-2,3-dihydro-1H-isoindole (1.005.05 mmol), formaldehyde (0.23 g, 40% in water, 7.60 mmol), sodium borohydride (0.29 g,7.60 mmol) and methanol (50 mL). The resulting solution was stirred for 1 h at 15 °C, then extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and was concentrated in vacuo to afford a residue that was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) to affordcompound 1-48. MS (ESI) calc’d for: C9H,0BrN [M + H]: 212, found 212.
	Stage #1: paraformaldehyd; 5-bromo-2,3-dihydro-1H-isoindole In methanol; water monomer for 0.25h; Stage #2: With sodium cyanotrihydridoborate In methanol; water monomer at 20℃; for 16h; Inert atmosphere;	Intermediate A10: 5-bromo-2-methvlisoindoline To a solution of 5-bromoisoindoline [127168-84-7] (0.50 g, 2.52 mmol) in MeOH (31.9 mL) / H2O (3.19 mL) at RT was added CH3COOH to reach pH 5. To the reaction mixture was added formaldehyde (37% in water, 0.376 ml, 5.05 mmol) followed after 15 min by NaCNBH3 (0.24 g, 3.79 mmol). The reaction mixture was stirred at RT for 16 h under a nitrogen atmosphere. The RM was concentrated, diluted with EtOAc and washed with NaOH (1 N) and brine. The organic layer was dried (Na2S04), filtered and evaporated to give the title compound which was used without purification in the next step. UPLC-MS-1 : Rt = 0.39 min; MS m/z [M+H]+: 212 / 214.
	Stage #1: paraformaldehyd; 5-bromo-2,3-dihydro-1H-isoindole In methanol; water monomer for 0.25h; Stage #2: With sodium cyanotrihydridoborate In methanol; water monomer at 20℃; for 16h; Inert atmosphere;	Intermediate A10: 5-bromo-2-methvlisoindoline To a solution of 5-bromoisoindoline [127168-84-7] (0.50 g, 2.52 mmol) in MeOH (31.9 mL) / H2O (3.19 mL) at RT was added CH3COOH to reach pH 5. To the reaction mixture was added formaldehyde (37% in water, 0.376 ml, 5.05 mmol) followed after 15 min by NaCNBH3 (0.24 g, 3.79 mmol). The reaction mixture was stirred at RT for 16 h under a nitrogen atmosphere. The RM was concentrated, diluted with EtOAc and washed with NaOH (1 N) and brine. The organic layer was dried (Na2S04), filtered and evaporated to give the title compound which was used without purification in the next step. UPLC-MS-1 : Rt = 0.39 min; MS m/z [M+H]+: 212 / 214.
	Stage #1: paraformaldehyd; 5-bromo-2,3-dihydro-1H-isoindole In methanol; water monomer for 0.25h; Stage #2: With sodium cyanotrihydridoborate In methanol; water monomer at 20℃; for 16h; Inert atmosphere;	Intermediate A10: 5-bromo-2-methvlisoindoline To a solution of 5-bromoisoindoline [127168-84-7] (0.50 g, 2.52 mmol) in MeOH (31.9 mL) / H2O (3.19 mL) at RT was added CH3COOH to reach pH 5. To the reaction mixture was added formaldehyde (37% in water, 0.376 ml, 5.05 mmol) followed after 15 min by NaCNBH3 (0.24 g, 3.79 mmol). The reaction mixture was stirred at RT for 16 h under a nitrogen atmosphere. The RM was concentrated, diluted with EtOAc and washed with NaOH (1 N) and brine. The organic layer was dried (Na2S04), filtered and evaporated to give the title compound which was used without purification in the next step. UPLC-MS-1 : Rt = 0.39 min; MS m/z [M+H]+: 212 / 214.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2014/275025, 2014, A1 Location in patent: Paragraph 0521; 0522
[2]Current Patent Assignee: OTSUKA HOLDINGS CO LTD; GLAXOSMITHKLINE PLC - WO2015/92713, 2015, A1 Location in patent: Page/Page column 428
[3]Current Patent Assignee: PHARMARON INC - WO2014/146490, 2014, A1 Location in patent: Page/Page column 85
[4]Current Patent Assignee: PHARMARON INC - WO2014/146246, 2014, A1 Location in patent: Page/Page column 72
[5]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2021/124222, 2021, A1 Location in patent: Page/Page column 183
[6]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2021/124222, 2021, A1 Location in patent: Page/Page column 183
[7]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2021/124222, 2021, A1 Location in patent: Page/Page column 183

50
4-((aR)-6-aminospiro[3.3]heptan-2-yl)phthalazin-1-(2H)-one trifluoroacetate [ No CAS ]
[ 7693-46-1 ]
[ 127168-84-7 ]
5-bromo-N-((aR)-6-(4-oxo-3,4-dihydrophthalazin-1-yl)spiro[3.3]heptan-2-yl)isoindoline-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 4-((aR)-6-aminospiro[3.3]heptan-2-yl)phthalazin-1-(2H)-one trifluoroacetate; 4-Nitrophenyl chloroformate With hydrogenchloride; N-ethyl-N,N-diisopropylamine In water at 0℃; for 0.5h; Stage #2: 5-bromoisoindoline With N-ethyl-N,N-diisopropylamine In water at 50℃; for 16h;	Intermediate 74: 5 -bromo-N-((aR)-6-(4-oxo-3 ,4-dihydrophthalazin- 1- yl)spiro [3.3 ]heptan-2-yl)isoindoline-2-carboxamide Intermediate 2, HC1 (300 mg, 1.028 mmol) was suspended in THF (15 mL), and DIEA (0.449 mL, 2.57 mmol) was added. The reaction mixture was cooled to 0 °C, and 4- nitrophenyl carbonochloridate (249 mg, 1.23 mmol) was added. The reaction mixture wasstirred at 0 °C for 30 mm, then 5-bromoisoindoline (407 mg, 2.06 mmol) and DIEA (0.449 mL, 2.57 mmol) were added. The cooling bath was removed, and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to rt, quenched with MeOH (3 mL) and concentrated. The residue was purified by flash chromatography (30-100% EtOAc/DCM gradient) to afford Intermediate 74 (400 mg, 81% yield) as a lightyellow solid. MS(ESI) m/z: 481.2 (M+H) ‘HNMR: (500 MHz, DMSO-d6) ö ppm 12.45(s, 1H), 8.25 (dd, J=7.8, 1.0 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.88 - 7.85 (m, 1H), 7.85 - 7.80(m, 1H), 7.54 (s, 1H), 7.46 (dd, J=8.1, 1.8 Hz, 1H), 7.28 (d, J8.0 Hz, 1H), 6.47 (d, J7.7Hz, 1H), 4.55 (br d, J=20.9 Hz, 4H), 4.15 - 4.05 (m, 1H), 3.88 (quin, J8.5 Hz, 1H), 2.58- 2.53 (m, 2H), 2.40 - 2.28 (m, 3H), 2.19 - 2.12 (m, 2H), 1.98 - 1.93 (m, 1H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2016/10950, 2016, A1 Location in patent: Page/Page column 214; 215

51
[ 98-09-9 ]
[ 127168-84-7 ]
C₁₄H₁₂BrNO₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃; for 24h;

Reference： [1]Éliás, Olivér; Kovács, Zoltán; Wágner, Gábor; Némethy, Zsolt; Tarcsay, Ákos; Greiner, István [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 17, p. 4211 - 4215]

52
[ 75-36-5 ]
[ 127168-84-7 ]
1-(5-bromo-1,3-dihydroisoindol-2-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
850 mg	With triethylamine In dichloromethane for 1h;	Intermediate B2: Synthesis of l-(5-bromo-l,3-dihydro-isoindol-2-yl)-ethanone Intermediate B2: Synthesis of l-(5-bromo-l,3-dihydro-isoindol-2-yl)-ethanone 5-Bromo-2,3-dihydro-lH-isoindole (1.0 g, 5.0 mmol) is dissolved in DCM (50 mL) and acetyl chloride (7.6 mL, 7.6 mmol) and triethyl amine (1.4 mL, 10 mmol) are added. The mixture is stirred for 1 hr before saturated NaHC03 aqueous solution (30 mL) and water (30 mL) are added. The mixture is stirred for 10 min and the organic layer is separated. The aqueous layer is extracted with DCM (2x 35 mL) and all the organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 850 mg of the title product.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2016/89800, 2016, A1 Location in patent: Page/Page column 55-56

53
isocyanate [ No CAS ]
[ 127168-84-7 ]
C₅₅H₆₅BrN₆O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 25℃;

Reference： [1]Carney, Daniel W.; Lukesh, John C.; Brody, Daniel M.; Brütsch, Manuela M.; Boger, Dale L. [Proceedings of the National Academy of Sciences of the United States of America, 2016, vol. 113, # 35, p. 9691 - 9698]

54
[ 63624-28-2 ]
[ 127168-84-7 ]
5-bromo-2-((2, 4-dimethoxyphenyl)sulfonyl)isoindoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27 g	With triethylamine; In acetonitrile; at 25℃; for 48h;Inert atmosphere;	To a mixture of 5- bromoisoindoline (4) (22 g crude material, 111.6 mmol, 1.0 equiv) and triethylamine (50 mL) in acetonitrile (500 mL) was added <strong>[63624-28-2]2, 4-dimethoxybenzenesulfonyl chloride</strong> (7) (27.6 g, 117.1 mmol, 1.05 equiv) in portions. The mixture was stirred at 25C for 48 h. Then the reaction mixture was concentrated to give a residue, to which ethyl acetate (1000 mL) was added and the mixture was washed with iN HC1 (100 mL x 2). The organic layer was concentrated to give a residue, to which EtOAc (50 mL) was added and the mixture was stirred for 1 h. The mixture was filtered to give a white solid ,which was dried in vacuo to give 5-bromo-1-(2,4- dimethoxybenzenesulfonyl) isoindoline (8) (27 g, 60% yield).1H-NMR (400 MHz, CDC13) 7.92 (d, J= 8.80 Hz, 1H), 7.33-7.38 (m, 2H), 7.06 (d, J= 8.80 Hz, 1H) , 6.40-6.44 (m, 2H), 4.73 (s, 2H), 4.66 (s, 2H), 3.90 (s, 3H), 3.73 (s, 3H).

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1142 - 1150
[2]Patent: WO2018/95260,2018,A1 .Location in patent: Paragraph 058; 065; 0116

55
[ 85-44-9 ]
[ 127168-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: bromine; sodium hydroxide / water / 12 h / 90 °C / Inert atmosphere 1.2: 5 h / Reflux; Inert atmosphere 2.1: formamide / 2 h / 200 °C / Inert atmosphere 3.1: boron trifluoride / tetrahydrofuran / 1.5 h / 0 °C / Inert atmosphere 3.2: 20 h / 0 - 80 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: sodium hydroxide; bromine / water / 12 h / 90 °C / Inert atmosphere 1.2: 5 h / Reflux; Inert atmosphere 2.1: formamide / 2 h / 200 °C / Inert atmosphere 2.2: 1.5 h / 20 °C / Inert atmosphere 3.1: boron trifluoride / tetrahydrofuran / 1.5 h / 0 °C / Inert atmosphere 3.2: 20 h / 0 - 80 °C / Inert atmosphere

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

56
[ 127168-84-7 ]
4-((5-bromoisoindolin-2-yl)sulfonyl)benzene-1,3-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

57
[ 127168-84-7 ]
2-((2,4-bis(benzyloxy)phenyl)sulfonyl)-5-bromoisoindoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

58
[ 127168-84-7 ]
tert-butyl 4-((2-((2,4-bis(benzyloxy)phenyl)sulfonyl)isoindolin-5-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate / toluene / 18 h / 110 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 18 h / 110 °C / Inert atmosphere

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

59
[ 127168-84-7 ]
tert-butyl 4-(benzyl(2-((2,4-bis(benzyloxy)phenyl)sulfonyl)isoindoline-5-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate / toluene / 18 h / 110 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 18 h / 110 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

60
[ 127168-84-7 ]
N-benzyl-2-((2,4-bis(benzyloxy)phenyl)sulfonyl)-N-(piperidin-4-yl)isoindolin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate / toluene / 18 h / 110 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 6: hydrogenchloride / water; methanol / 24 h / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 18 h / 110 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 6: hydrogenchloride / methanol; water / 24 h / 20 °C / Inert atmosphere

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

61
[ 127168-84-7 ]
2-((2,4-bis(benzyloxy)phenyl)sulfonyl)-5-(piperazin-1-yl)isoindoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate / toluene / 18 h / 110 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 18 h / 110 °C / Inert atmosphere

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

62
[ 127168-84-7 ]
(4-((2-((2,4-dihydroxyphenyl)sulfonyl)isoindolin-5-yl)amino)piperidin-1-yl)((3R,5R)-3,4,5-trihydroxycyclohexyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate / toluene / 18 h / 110 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 6: hydrogenchloride / water; methanol / 24 h / 20 °C / Inert atmosphere 7: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 8: palladium on activated charcoal; hydrogen / methanol / 12 h / 20 °C / Inert atmosphere
	Multi-step reaction with 8 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 18 h / 110 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 6: hydrogenchloride / methanol; water / 24 h / 20 °C / Inert atmosphere 7: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 8: palladium on activated charcoal; hydrogen / methanol / 12 h / 20 °C

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

63
[ 127168-84-7 ]
(4-(benzyl(2-((2,4-bis(benzyloxy)phenyl)sulfonyl)isoindolin-5-yl)amino)piperidin-1-yl)((3R,5R)-3,4,5-trihydroxycyclohexyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate / toluene / 18 h / 110 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 6: hydrogenchloride / water; methanol / 24 h / 20 °C / Inert atmosphere 7: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere
	Multi-step reaction with 7 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 18 h / 110 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 6: hydrogenchloride / methanol; water / 24 h / 20 °C / Inert atmosphere 7: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

64
[ 127168-84-7 ]
3-(4-(benzyl(2-((2,4-bis(benzyloxy)phenyl)sulfonyl)isoindolin-5-yl)amino)piperidin-1-yl)propane-1,2-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate / toluene / 18 h / 110 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 6: hydrogenchloride / water; methanol / 24 h / 20 °C / Inert atmosphere 7: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere
	Multi-step reaction with 7 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 18 h / 110 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 6: hydrogenchloride / methanol; water / 24 h / 20 °C / Inert atmosphere 7: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

65
[ 127168-84-7 ]
4-((5-((1-(2,3-dihydroxypropyl)piperidin-4-yl)amino)isoindolin-2-yl)sulfonyl)benzene-1,3-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate / toluene / 18 h / 110 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 6: hydrogenchloride / water; methanol / 24 h / 20 °C / Inert atmosphere 7: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 8: palladium on activated charcoal; hydrogen / methanol / 12 h / 20 °C / Inert atmosphere
	Multi-step reaction with 8 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 18 h / 110 °C / Inert atmosphere 5: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 6: hydrogenchloride / methanol; water / 24 h / 20 °C / Inert atmosphere 7: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C / Inert atmosphere 8: palladium on activated charcoal; hydrogen / methanol / 12 h / 20 °C

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

66
[ 127168-84-7 ]
(S)-3-amino-4-(4-(2-((2,4-dihydroxyphenyl)sulfonyl)isoindolin-5-yl)piperazin-1-yl)-4-oxobutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate / toluene / 18 h / 110 °C / Inert atmosphere 5: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 6: palladium on activated charcoal; hydrogen / methanol / 12 h / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 18 h / 110 °C / Inert atmosphere 5: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 6: palladium on activated charcoal; hydrogen / methanol / 12 h / 20 °C

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

67
[ 127168-84-7 ]
(S)-3-amino-4-(4-(2-((2,4-bis(benzyloxy)phenyl)sulfonyl)isoindolin-5-yl)piperazin-1-yl)-4-oxobutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate / toluene / 18 h / 110 °C / Inert atmosphere 5: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: triethylamine / acetonitrile / 48 h / 25 °C / Inert atmosphere 2: boron tribromide / dichloromethane; cyclohexene / 12 h / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 48 h / 20 °C / Inert atmosphere 4: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 18 h / 110 °C / Inert atmosphere 5: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere

Reference： [1]Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang; Gui, Wen-Jun; Chuang, Jacinta L.; Morlock, Lorraine K.; Williams, Noelle S.; Wynn, R. Max; Qi, Xiangbing; Chuang, David T. [Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1142 - 1150]
[2]Current Patent Assignee: NAT INSTITUTE OF BIOLOGICAL SCIENCES BEIJING - WO2018/95260, 2018, A1

68
(2S,4R)-1-(2-(3-acetyl-1H-indazol-1-yl)acetyl)-4-fluoro-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-carboxamide [ No CAS ]
[ 127168-84-7 ]
(2S,4R)-1-(2-(3-acetyl-1H-indazol-1-yl)acetyl)-4-fluoro-N-(2-fluoro-3-(isoindolin-5-yl)phenyl)pyrrolidine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 100℃; for 0.75h; Inert atmosphere; Microwave irradiation;	6 (2S,4R)-1-(2-(3-Acetyl-1H-indazol-1-yl)acetyl)-4-fluoro-N-(2-fluoro-3-(isoindolin-5- yl)phenyl)pyrrolidine-2-carboxamide (439) [0672] (2S,4R)- 1 -(2-(3 -Acetyl- 1H-indazol- 1 -yl)acetyl)-4-fluoro-N-(2-fluoro-3 -(4,4,5,5- tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-carboxamide (0.167 g), 5- bromoisoindoline (0.050 g), Pd(dppf)Cl2 (41 mg) and potassium carbonate (0.174 g) were mixed in a pressure tube under argon. To this mixture, 4 mL of dioxane and 1 mL of water were added. The mixture were bubbled with argon for 5 mm and the vial stoppered and subjected to microwave irradiation at 100 °C for 45 mm. The volatiles were removed under reduced pressure and the residue was purified by ISCO (0-23 % MeOH in CH2C12) to afford the desired product.[0673] ‘H NIVIR (400 MHz, DMSO) (major rotamer) 2.05 - 2.20 (m, 1H), 2.54-2.63 (m,1H), 2.61 (s, 3H), 3.92- 4.07 (m, 1H), 4.20 (s, 4H), 4.20-4.31 (m, 1H), 4.76 (t, J 8.4 Hz, 1H),5.56 (d, J = 52.4 Hz, 1H), 5.58 (d, J = 17.4 Hz, 1H), 5.79 (d, J= 17.4 Hz, 1H), 7.19 (d, J = 6 Hz,2H), 7.29-7.52 (m, 6H), 7.68 (d, J= 8.4 Hz, 1H), 7.79-7.83 (m, 1H), 8.18 (d, J 8.1 Hz, 1H), 9.92(s, 1H). ‘9F-NIVIR (DMSO-d6) (major rotamer): -130.4, -175.9.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35360, 2017, A1 Location in patent: Paragraph 0672; 0673

69
[ 105-36-2 ]
[ 127168-84-7 ]
ethyl 2-(5-bromo-2,3-dihydro-1H-isoindol-2-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3h;	7.a (a) ethyl 2-(5-bromo-2,3-dihydro-1 H-isoindol-2-yl)acetate 5-Bromoisoindoline (1 g, 5.05 mmol) was dissolved in DCM (12 mL) followed by addition of N,N-diisopropylethylamine (1.06 mL, 6.06 mmol). Ethyl bromoacetate (0.61 mL, 5.55 mmol) was then added and the mixture stirred at room temperature for 3 h. The reaction mixture was diluted with DCM and washed with saturated aq. NaHCC>3 solution. The organic was dried over MgSCU, filtered and evaporated under reduced pressure to a dark liquid. The resulting crude product was purified by column chromatography, eluting with a gradient of 0- 40% EtOAc in petroleum ether (40-60) to give ethyl 2-(5-bromo-2,3-dihydro-1 H-isoindol-2-yl)acetate (760 mg, 53 %). LC-MS (Method D) 284.4/286.3 [M+H]+; RT 1.15 min

Reference： [1]Current Patent Assignee: REDX PHARMA PLC - WO2017/46605, 2017, A1 Location in patent: Page/Page column 77

70
[ 127168-84-7 ]
[ 368441-44-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium carbonate / tetrahydrofuran / 2 h / 20 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine / N,N-dimethyl-formamide / 80 °C
	Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / tetrahydrofuran / 20 °C 2: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / N,N-dimethyl-formamide / 100 °C

Reference： [1]Current Patent Assignee: HELSINN HEALTCARE S.A. - US2017/275301, 2017, A1
[2]Zhu, Dongsheng; Huang, Huocong; Pinkas, Daniel M.; Luo, Jinfeng; Ganguly, Debolina; Fox, Alice E.; Arner, Emily; Xiang, Qiuping; Tu, Zheng-Chao; Bullock, Alex N.; Brekken, Rolf A.; Ding, Ke; Lu, Xiaoyun [Journal of Medicinal Chemistry, 2019, vol. 62, # 16, p. 7431 - 7444]

71
[ 39982-01-9 ]
[ 127168-84-7 ]
[ 201940-08-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium carbonate;	Step 2: 5-bromo-2-tert-butoxycarbonylisoindoline (5) The compound represented by Formula 4 (10.36 g, 52.3 mmol) was dissolved in 80 mL dichloromethane, and cooled in an ice bath. Boc anhydride (22.8 g, 104.6 mmol) was added dropwise followed by the addition of sodium carbonate (16.6 g, 156.9 mmol) and water (150 mL), and stirred for 4 hours in an ice bath. The organic phase was separated, washed with brine, and concentrated, and then the residue was purified by silica gel column chromatography to afford the product 5-bromo-2-tert-butoxycarbonylisoindoline (13.3 g). Yield: 85%. MS m/z [ESI]: 298.0[M+1]. 1H-NMR (400 MHz, CDCl3): delta=7.37 (2H, m), 7.11 (1H, m), 4.62 (4H, m), 1.51 (9H, s).

Reference： [1]Patent: US2019/284153,2019,A1

72
[ 127168-84-7 ]
5-methylsulfonylisoindoline hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium carbonate / dichloromethane; water / 4 h / Cooling with ice 2: copper(l) iodide; <i>L</i>-proline / dimethyl sulfoxide / 48 h / 120 °C / Inert atmosphere 3: hydrogenchloride / dichloromethane; methanol / 1 h / 20 °C
	Multi-step reaction with 3 steps 1: sodium carbonate

Reference： [1]Current Patent Assignee: SHOUYAO HOLDINGS BEIJING CO LTD; SINO BIOPHARMACEUTICAL LIMITED - EP3257857, 2017, A1
[2]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED; SHOUYAO HOLDINGS BEIJING CO LTD - US2019/284153, 2019, A1

73
[ 7559-81-1 ]
[ 127168-84-7 ]
2-((5-bromoisoindolin-2-yl)methyl)-5-hydroxy-4H-pyran-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.22 g	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 50℃; for 2.5h;	Intermediate 137: 2-((5 -Bromoisoindolin-2-yl)methyl)-5 -hydroxy-4H-pyran-4-one To a solution of 5-bromoisoindoline (1.21g, 6.11 mmol) and 2-(chloromethyl)-5- hydroxy-4H-pyran-4-one (0.98 1 g, 6.11 mmol) in DMF (10 ml) at 0°C was added DIPEA (2.66 ml, 15.27 mmol) dropwise. The reaction mixture was stirred at 50 °C for 2.5 h and poured on ice. The aqueous layer was extracted with EtOAc. The organiclayers were combined, washed with water and brine, dried with Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography to afford the title compound (0.22 g). LC-MS: m/z 322.2 (M+H).

Reference： [1]Current Patent Assignee: ORION CORP; ORION OYJ; ORION S R L - WO2018/115591, 2018, A1 Location in patent: Page/Page column 106; 107

74
(5-(4-cyanobenzyloxy)-4-oxo-4H-pyran-2-yl)methyl methanesulfonate [ No CAS ]
[ 127168-84-7 ]
4-((6-((5-bromoisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3-yloxy)methyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9 mg	With potassium carbonate In dimethyl sulfoxide at 60℃; for 0.5h;	17.c Compound 278c: 4-((6-((5 -Bromoisoindolin-2-yl)methyl)-4-oxo-4H-pyran-3 -yloxy)methyl)benzonitrile A solution of 5-bromoisoindoline (0.07 g, 0.353 mmol) and (5-(4-cyano-benzyloxy)-4-oxo-4H-pyran-2-yl)methyl methanesulfonate (0.119 g, 0.353 mmol) andpotassium carbonate (0.098 g, 0.707 mmol) in DMSO (2 ml) was stirred at 60 °C for 30 mm. Water was added, and the aqueous layer was extracted with DCM. The organic layers were combined, washed with water and brine, dried with Na2SO4, filtered, evaporated, and purified with semipreparative HPLC to afford the title compound (9mg). 1H NMR (400 MHz, Chloroform-d) ö ppm 7.66 - 7.70 (m, 1 H), 7.63 (s, 1 H),7.52 - 7.56 (m, 2 H), 7.33 - 7.37 (m, 2 H), 7.05 - 7.17 (m, 1 H), 6.50 (s, 1 H), 5.13 -5.16 (m, 1 H), 3.95 -4.04 (m, 4 H), 3.74 - 3.76 (m, 2 H), 1.54 - 1.83 (m, 2 H); LC-MS:m1z437.3(M+H)+.

Reference： [1]Current Patent Assignee: ORION CORP; ORION OYJ; ORION S R L - WO2018/115591, 2018, A1 Location in patent: Page/Page column 207

75
[ 38870-89-2 ]
[ 127168-84-7 ]
1-(5-bromoisoindolin-2-yl)-2-methoxyethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With triethylamine In dichloromethane at 20℃; for 1h;	1a.1 Step 1 to a solution of 5-bromoisoindoline (300 mg, 1.51 mmol) and Et3N (633 pL, 4.54 mmol) in CH2CI2 (2 mL) was added dropwise 2-methoxyacetyl chloride (208 pL, 2.27 mmol). The reaction mixture was stirred at rt for lh. The solution was poured onto a mixture of cold water and CH2CI2. The phases were separated and the aqueous layer was extracted twice with CH2CI2. Thecombined organic layers were dried over Mg504, filtered and the solution was concentrated to dryness. The residue was triturated in Et20 and filtered-off. Thefiltrate was concentrated under reduced pressure and triturated with a mixture of Et20 (3 mL) and petroleum ether (3 mL). The solid formed was collected by filtration to afford 1 -(5-bromoisoindolin-2-yl)-2-methoxyethanone Ex.67a (205 mg, 50%) as pale brown solid. 1H NMR (300 MHz, DMSO-d6, d in ppm): 3.33 (s, 3H), 4.12 (s, 2H), 4.63 (d, 2H, J13.4Hz), 4.75 (d, 2H, J12.8Hz), 7.32 (t, 1H, J8.lHz), 7.48 (dd, 1H, J=8.lHz, J=1.9Hz), 7.58 (d, 1H, J=8.3Hz).

Reference： [1]Current Patent Assignee: SA GENFIT - WO2018/138362, 2018, A1 Location in patent: Page/Page column 68; 107

76
[ 127168-84-7 ]
[ 1181690-76-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; benzene / 2 h / 100 °C / Microwave irradiation 2: triethylamine / dichloromethane / 2 h / 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2009/105206, 2009, A1

77
[ 127168-84-7 ]
(R)-(5-(4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenyl)isoindolin-2-yl)(pyrimidin-5-yl)methanone trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; benzene / 2 h / 100 °C / Microwave irradiation 2: PS-carbodiimide; triethylamine / dichloromethane / 1 h / 120 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: PFIZER INC - WO2009/105206, 2009, A1

78
N-(tert-butyl)-5-isobutyl-3-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiophene-2-sulfonamide [ No CAS ]
[ 127168-84-7 ]
C₂₀H₂₈N₂O₂S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,2-dimethoxyethane; water Sealed tube; Heating;

Reference： [1]Isaksson, Rebecka; Lindman, Jens; Wannberg, Johan; Sallander, Jessica; Backlund, Maria; Baraldi, Dhaniel; Widdop, Robert; Hallberg, Mathias; Åqvist, Johan; Gutierrez de Teran, Hugo; Gising, Johan; Larhed, Mats [ChemistryOpen, 2019, vol. 8, # 1, p. 114 - 125]

79
[ 127168-84-7 ]
C₂₃H₃₀N₂O₅S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / water; 1,2-dimethoxyethane / Sealed tube; Heating 3: trifluoroacetic acid

Reference： [1]Isaksson, Rebecka; Lindman, Jens; Wannberg, Johan; Sallander, Jessica; Backlund, Maria; Baraldi, Dhaniel; Widdop, Robert; Hallberg, Mathias; Åqvist, Johan; Gutierrez de Teran, Hugo; Gising, Johan; Larhed, Mats [ChemistryOpen, 2019, vol. 8, # 1, p. 114 - 125]

80
[ 127168-84-7 ]
C₂₁H₂₆N₂O₅S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / water; 1,2-dimethoxyethane / Sealed tube; Heating 3: trifluoroacetic acid

Reference： [1]Isaksson, Rebecka; Lindman, Jens; Wannberg, Johan; Sallander, Jessica; Backlund, Maria; Baraldi, Dhaniel; Widdop, Robert; Hallberg, Mathias; Åqvist, Johan; Gutierrez de Teran, Hugo; Gising, Johan; Larhed, Mats [ChemistryOpen, 2019, vol. 8, # 1, p. 114 - 125]

81
[ 127168-84-7 ]
C₂₂H₃₀N₂O₃S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / water; 1,2-dimethoxyethane / Sealed tube; Heating

Reference： [1]Isaksson, Rebecka; Lindman, Jens; Wannberg, Johan; Sallander, Jessica; Backlund, Maria; Baraldi, Dhaniel; Widdop, Robert; Hallberg, Mathias; Åqvist, Johan; Gutierrez de Teran, Hugo; Gising, Johan; Larhed, Mats [ChemistryOpen, 2019, vol. 8, # 1, p. 114 - 125]

82
[ 108-24-7 ]
[ 127168-84-7 ]
1-(5-bromo-1,3-dihydroisoindol-2-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine In tetrahydrofuran at 20℃; for 2h;	59.1 Step 1 : Preparation of l-(5-bromoisoindolin-2-yl)ethan-l-one To a round-bottom flask was added 5-bromo-2,3-dihydro-li7-isoindole (2 g, 10 mmol), THF (20 mL), AC2O (2.06 g, 20.1 mmol) and Et3N (2.04 g, 20.1 mmol). The mixture was stirred for 2 h at room temperature and then quenched with H2O. The aqueous layer was extracted with EtOAc and the combined organic extracts were concentrated under vacuum. The residue was purified by silica gel column chromatography (eluent: 1% EtOAc in PE) to afford the title compound (2.1 g, 86% yield) as a yellow oil.
	With potassium carbonate In acetonitrile

Reference： [1]Current Patent Assignee: IDEAYA BIOSCIENCES INC. - WO2020/160134, 2020, A1 Location in patent: Paragraph 0301
[2]Isaksson, Rebecka; Lindman, Jens; Wannberg, Johan; Sallander, Jessica; Backlund, Maria; Baraldi, Dhaniel; Widdop, Robert; Hallberg, Mathias; Åqvist, Johan; Gutierrez de Teran, Hugo; Gising, Johan; Larhed, Mats [ChemistryOpen, 2019, vol. 8, # 1, p. 114 - 125]

83
C₂₀H₁₆FN₄O₄^(1-)*Li⁽¹⁺⁾ [ No CAS ]
[ 127168-84-7 ]
(5-bromoisoindolin-2-yl)(5-((2,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,2-c]quinazolin-2-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide at 20℃;	23 Example 23, General Procedure for preparing amide analogs General procedure: Additional amide analogs were prepared by adding 1.5 equivalents of an amine which will provide the desired substituents into a 1 dram vial (1.5 eq.) along with lithium 5-amino-7- methoxyimidazo[1,2-c]quinazoline-2-carboxylate (30 mg, 0.114 mmol) and a DMF solution (1.0 ml) solution of DIPEA (0.079 ml, 0.454 mmol), shaking the vial for 5 minutes in a Bohdan Miniblock Shaker and then adding 1-propanephosphonic acid cyclic anhydride (50% w/w in EtOAc, 64.7 µl, 0.109 mmol), and continuing to shake the vial at RT overnight. The completed reaction was quenched with 1.0 ml water and the organic layer separated by filtering through a Varian 2 ml Reservior Frit and a Whatman 0.45µm syringe filter to remove emulsion, followed by solvent removal using a Genevac. The crude residue was dissolved in 1.0 ml DMSO and purified by LC/MS.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2019/118313, 2019, A1 Location in patent: Page/Page column 00140-00141

84
[ 398489-26-4 ]
[ 127168-84-7 ]
tert-butyl-3-(5-bromoisoindolin-2-yl)azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.9%	With sodium tris(acetoxy)borohydride; acetic acid In tetrahydrofuran for 5h;

Reference： [1]Malamas, Michael S.; Farah, Shrouq I.; Lamani, Manjunath; Pelekoudas, Dimitrios N.; Perry, Nicholas Thomas; Rajarshi, Girija; Miyabe, Christina Yume; Chandrashekhar, Honrao; West, Jay; Pavlopoulos, Spiro; Makriyannis, Alexandros [Bioorganic and Medicinal Chemistry, 2020, vol. 28, # 1]

85
[ 127168-84-7 ]
[ 1939-99-7 ]
C₁₅H₁₄BrNO₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃; for 12h; Inert atmosphere;	Step 3 General procedure: To the solution of amine (2a-10a) (1mmol) in DCM (5mL), triethylamine (2mmol) was added followed by benzylsulfonyl chloride, 2-Phenylethanesulfonyl chloride, benzene sulfonyl chloride, benzoyl chloride or phenylacetyl chloride (1.5mmol), and the mixture was stirred overnight at room temperature. The reaction was filtered, concentrated and solved by EA (20mL), then washed with ethyl acetate (3×15mL). The organic was combined and was dried over Na2SO4. After filtration, the filtrate was removed in vacuo. The residue was purified by silica gel column chromatography to give 2b-12b, 16b-17b.

Reference： [1]Sun, Nannan; Ma, Xiaojun; Zhou, Kaifeng; Zhu, Chen; Cao, Zhonglian; Wang, Yonghui; Xu, Jun; Fu, Wei [European Journal of Medicinal Chemistry, 2020, vol. 187]

86
2-(3-cyano-1H-1,2,4-triazol-1-yl)acetic acid [ No CAS ]
[ 127168-84-7 ]
1-(2-(5-bromoisoindolin-2-yl)-2-oxoethyl)-1H-1,2,4-triazole-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h;	Intermediate I-5: Synthesis of 1 -(2-(5-bromoisoindolin-2-yl)-2-oxoethyl)-1 /-/-1 ,2,4-triazole- 3-carbonitrile To a solution of amine (2.46 g, 12.4 mmol) in DMF (25 ml.) was added acid I- 3 (1 .89 g, 12.4 mmol, 1 .0 equiv), T3P (9.61 ml_, 50% solution in DMF, 1 .3 equiv.) and Et3N (3.46 ml_, 24.8 mmol, 2.0 equiv.). The resultant mixture was stirred at RT for 16 hours before 10% LiCI solution was added. The mixture was extracted with EtOAc (5 x 100 ml.) and the combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under vacuo. The crude material was purified by silica gel chromatography (20%MeOFi/CFi2Cl2) to afford I-5 (2.37 g, 55% yield) as a grey solid. 1 FI NMR (400 MHz, DMSO-d6) d 8.87 (d, J = 1 .6 Hz, 1 H), 7.64 (d, J = 5.8 Hz, 1 H), 7.52 (d, J = 8.1 Hz, 1 H), 7.37 (dd, J = 8.2, 4.2 Hz, 1 H), 5.49 (s, 2H), 4.94 (d, J = 15.9 Hz, 2H), 4.68 (d, J = 17.9 Hz, 2H); LC-MS m/z 332, 334 [M+H]+, retention time = 0.90 min (Method A).

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2019/244049, 2019, A1 Location in patent: Paragraph 00181

87
[ 1184181-48-3 ]
[ 127168-84-7 ]
(2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-bromo-1,3-dihydro-isoindol-2-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		General procedure: A mixture of 3,5-bis(benzyloxy)-2-isopropylbenzoic acid(2.29 g, 6.09 mmol), EDC.HCl (1.88g, 12.18 mmol), HOBt (1.39 g,9.13 mmol) and DIPEA (1.96 g, 15.22 mmol) in DCM (10 mL) wasstirred at rt for 30 min before adding 5-nitroisoindoline (20) (1 g,6.09 mmol). After being stirred for a further 5 h, the reactionmixture was quenched with H2O and extracted with EtOAc (50 mLx 3). The combined organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The residuewas purifiedby silica gel chromatography (EtOAc:n-hexane 1:4) to give 21 in70% yield.

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 190

88
((2R,6R)-4-(8-cyanoquinolin-5-yl)-6-methylmorpholin-2-yl)methyl trifluoromethanesulfonate [ No CAS ]
[ 127168-84-7 ]
5-[(2S,6R)-2-[(5-bromoisoindolin-2-yl)methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
500 mg	Stage #1: 5-bromoisoindoline With potassium carbonate In dichloromethane; acetonitrile at 20℃; for 48h; Stage #2: ((2R,6R)-4-(8-cyanoquinolin-5-yl)-6-methylmorpholin-2-yl)methyl trifluoromethanesulfonate With potassium carbonate In acetonitrile for 2h; Reflux;	46.1 Step 1: To a solution of 5-bromoisoindoline hydrochloride (352 mg, 1.50 mmol) in ACN/ DCM (50 mL, v/v = 3/2) was added K2CO3 (300 mg, 2.17 mmol). The suspension was stirred at rt for 48 hrs, then filtered through celite. The filtrate was concentrated to give 5-bromoisoindoline (90 mg) which was dissolved in ACN (5 mL). To the solution was added ((2R,6R)-4-(8-cyanoquinolin-5-yl)-6-methylmorpholin-2-yl)methyl trifluoromethanesulfonate (Intermediate D, 519 mg, 1.25 mmol) and K2CO3 (518 mg, 3.75 mmol). The suspension was heated under reflux for 2 hrs, then diluted with ACN (10 mL), and filtered through celite. The filtrate was concentrated to give a crude product which was purified by column chromatography to give compound 46a (500 mg) as a brown foamy solid. MS: calc'd 463 and 465 (MH+), measured 463 and 465 (MH+).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - EP3623369, 2020, A1 Location in patent: Paragraph 0155; 0156

89
[ 166538-98-3 ]
[ 127168-84-7 ]
2-(5-bromoisoindoline-2-carbonyl)-8-chlorochromen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11.1%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 18h; Inert atmosphere;	4 2-(5-bromoisoindolme-2-carbonyl)-8-chloro-chromen-4-one To a solution of 8-chloro-4-oxo-chromene-2-carboxylic acid (Int-1, 150 mg, 668 m mol) in DCM (20 mL) was added 5-bromoisoindoline (198 mg, 1 mmol), DIPEA (138 mg, 1.07 mmol) and HATU (381 mg, 1 mmol) at room temperature and the resulting mixture was then stirred at room temperature for 18 hours. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by preparative HPLC to give 2-(5-bromoisoindoline-2-carbonyl)-8-chloro-chromen-4- one (30 mg, 11.1 %) as a white foam. XH NMR (400 MHz, DMSO-^) d 8.01-8.12 (m, 2H), 7.61- 7.69 (m, 1H), 7.49-7.60 (m, 2H), 7.30-7.43 (m, 1H), 6.90-6.93 (m, 1H), 5.23-5.36 (m, 2H), 4.83- 4.96 (m, 2H). MS obsd. (ESE) [(M+H)+]: 404.1 & 406.1.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/79106, 2020, A1 Location in patent: Page/Page column 42; 43

90
methyl 2,4-bis(benzyloxy)-6-((1-(2-ethoxy-2-oxoethyl)-3-phenyl-1H-pyrazol-5-yl)amino)benzoate [ No CAS ]
[ 127168-84-7 ]
ethyl 2-(5-((3,5-bis(benzyloxy)-2-(5-bromoisoindoline-2-carbonyl)phenyl)amino)-3-phenyl-1H-pyrazol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methyl 2,4-bis(benzyloxy)-6-((1-(2-ethoxy-2-oxoethyl)-3-phenyl-1H-pyrazol-5-yl)amino)benzoate With water; potassium hydroxide In methanol at 95℃; for 1h; Stage #2: 5-bromoisoindoline With benzotriazol-1-ol; trimethylamine In tetrahydrofuran; dichloromethane at 20℃;	[00599] To a solution of ester (1 equiv) in EtOH/water (1 : 1 ratio, 0.06 M) was added potassium hydroxide (9.2 equiv), and then the mixture was heated to 95 °C for 1 h. After cooling to room temperature, volatile materials were condensed in vacuo. The residue was suspended in saturated NEECl (aq) and CH2CI2. The layers were separated, and the aqueous layer was extracted three times with CH2CI2. The combined organic layers were washed twice with water, brine and then dried with anhydrous Na2SC>4. The salts were removed via gravity filtration, and volatile materials were condensed in vacuo. [00600] The crude acid and (1 equiv) and 5-bromoisoindoline (1.5 equiv) in THF/CH2C2 (1 : 1 ratio, 77 mM) was added trimethylamine (4 equiv) followed by HOBt hydrate (1.2 equiv) and PS-carbodiimide (1.18 mmol/g loading, 1.2 equiv). The suspension was stirred overnight at room temperature. The resin was removed via filtration materials were condensed in vacuo. The resulting residue was purified by silica flash chromatography. [00601] ethyl 2-(5-((3,5-bis(benzyloxy)-2-(5-bromoisoindoline-2-carbonyl)phenyl)amino)-3-phenyl-1H-pyrazol-1-yl)acetate is prepared from methyl 2,4-bis(benzyloxy)-6-((1-(2-ethoxy-2-oxoethyl)-3-phenyl-1H-pyrazol-5-yl)amino)benzoate according to General procedure O.

Reference： [1]Current Patent Assignee: BOSTON UNIVERSITY - WO2020/227368, 2020, A1 Location in patent: Paragraph 00598-00600; 00601

91
[ 127168-84-7 ]
[ 226070-47-9 ]