Name: 937048-76-5|tert-Butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate|95%
Brand: Ambeed
SKU: A377111
Price: 49.0 USD
Availability: InStock
Rating: 96 (25 reviews)

1
[ 258515-65-0 ]
[ 937048-76-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium acetate;bis(pinacol)diborane; In 1,4-dioxane; at 100℃; for 16h;	Intermediate 27: 7-f4.4,5,5-Tetrametfayl-ri,3,21dioxaborolan-2-vIV3.4-dihvdro-lH- isoquinoline-2-carboxylic acid tert-butyl ester; A mixture of Intermediate 26 (2.6g, 8.3mmol), bis-pinacolatodiboron (2.54g, lO.Ommol), potassium acetate (1.63g, 16.6mmol) and Pd(dpff)2 (0.68g, 0.83mmol) in dioxane (30 ml) was stirred in a sealed tube at 100 0C for 16 hr. Aqueous sodium bicarbonate solution (100 ml) was added to the cooled reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated, then the residue was purified by silica gel chromatography (10% ethyl acetate in hexanes as eluant). Intermediate 27 was obtained as a slightly yellow solid (2.2 g, 74%). LCMS (Method 2) m/z 259.9 [MH+], Tr = 3.35 min.

Reference： [1]Patent: WO2008/116185,2008,A2 .Location in patent: Page/Page column 63

2
[ 258515-65-0 ]
[ 73183-34-3 ]
[ 937048-76-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 90℃;Inert atmosphere;	Intermediate 5 (945 mg, 3.03 mmol, 1.0 eq), bis(pinacolato)diboron (1.54 g, 6.06 mmol, 2.0 eq),Pd(dppf)Cl2 (222 mg, 0.303 mmol, 0.1 eq), and potassium acetate (892 mg, 9.09 mmol, 3.0 eq) werecombined in DMSO (20 mL), and the system was flushed with argon. The reaction was heated to90 C overnight. The reaction mixture was concentrated under vacuum to remove most DMSO. Theremaining mixture was diluted with water and extracted with three portions of DCM. The combinedorganic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated undervacuum. The product was purified via silica gel chromatography in ethyl acetate/hexanes to yield apale yellow oil (1.05 g, 96%). 1H-NMR (CDCl3, 500 MHz) 7.59 (d, J = 5.7 Hz, 1H), 7.14 (d, J = 5.5 Hz,1H), 4.58 (s, 2H), 3.63 (br s, 2H), 2.84 (br s, 2H), 1.48 (s, 9H), 1.34 (s, 12H).
92%	With potassium acetate; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;	To a mixture of tert-butyl 7-bromo-3 ,4-dthydroisoquinoline-2( 1 H)-carboxylate (42 g, 135 mmol) and PinB-BPin (36 g, 141 mmol) in dioxane (300 mL), KOAc (40 g, 405 mmol) was added. Then, Pd(dppf)C12.DCM (3 g, 4 mmol) was added quickly under N2 atmosphere. The mixture was stirred at 100 C for 4 h under N2 atmosphere. After cooling down, the salts were filtered out, the resulting filtrate was concentrated and purified by silica gel column (PE EA = 20: 1) to give tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dthydroisoquinoline-2(1H)-carboxylate (45 g, yield: 92%) as a white solid. ESI-MS (M+Na) :382.1. ?H NMR (400 MHz, CDC13) (5:7.59 (d, J= 7.6 Hz, 1H), 7.56 (s, 1H), 7.14 (d, J= 7.2 Hz, 1H), 4.58 (s, 2H), 3.62 (t, J = 5.2 Hz, 2H), 2.77 (t, J = 5.2 Hz, 2H), 1.48 (s, 9H), 1.34 (s, 12H).
88%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 5h;Inert atmosphere;	Into a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed <strong>[258515-65-0]tert-butyl 7-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylate</strong> (2.7 g, 8.5 mmol), dioxane (50 mL), bis(pinacolato)diboron (3.23 g, 12.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.62 g, 0.85 mmol), and potassium acetate (1.66 g, 16.9 mmol). The reaction was stirred for 5 hours at 90C. After cooling to room temperature, the resulting mixture was concentrated and purified on a silica gel column eluting with ethyl acetate/petroleum ether (1/10). Pure fractions were combined and concentrated to yield the title compound (3.0 g, 88%) as an oil.

56%	With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 3h;Inert atmosphere;	To a solution of bis(pinacolato)diboron (0.8 g, 3.15 mmol) in DMSO (1 1 mL) were added 7-bromo-2-(tert-butoxycarbonyl)-l, 2,3, 4-tetrahydroisoquino line (0.7 g, 2.25 mmol), AcOK (882 mg, 9 mmol) and Pd(PPh3)2Cl2 (158 mg, 0.23 mmol) under N2 atmosphere. The reaction was heated at 80 C for 3 h, then cooled to rt and filtered through a pad of Celite, which was washed with EtOAc (50 mL x 2). The combined filtrates were washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 30/1) to give the title compound as a white solid (0.45 g, 56%). NMR (400 MHz, CDC13) delta (ppm): 1.32 (s, 12H), 1.48 (s, 9H), 1.42 (s, 12H), 2.85 (s, 1H), 3.64 (s, 2H), 4.58 (s, 2H), 7.14-7.16 (d, J = 7.4 Hz, 1H), 7.56-7.60 (m, 2H).
56%	With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 3h;Inert atmosphere;	Under nitrogen protection,The associated acid pinacol ester (0.8g, 3.15mmol) was dissolved in dimethyl sulfoxide (11mL),To this was added 7-bromo-2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinoline (0.7 g, 2.25 mmol)Potassium acetate (882 mg, 9 mmol) andPd (PPh3) 2Cl2 (158 mg, 0.23 mmol).The reaction solution was stirred at 80 C for 3 hours,Cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate (50 mL x 2). The combined filtrates were washed with brine (50 mL), dried over anhydrous sodium sulfateFiltered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 30/1)The title compound was obtained as a white solid (0.45 g, 56%).
39%	With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium acetate; tricyclohexylphosphine; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere;	In a 250mL three-necked flask, <strong>[258515-65-0]tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate</strong> (1.1g, 3.52mmol), bis(pinacolato)diboron (1.07g, 4.21mmol), 1,4-dioxane (50mL), potassium acetate (1.03g, 10.50mmol), tricyclohexylphosphine (196mg, 0.70mmol), Pd2(dba)3?CHCl3 (181mg, 0.17mmol) were added. Reacted at 80C under nitrogen for 24 hours. The mixture was poured into water then treated with ethyl acetate (3 × 50mL). The combined organic phases were washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: 1: ethyl acetate = 15) to give the product (500mg, 39% yield).
	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃;Inert atmosphere;	Step 2: tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate To a solution of <strong>[258515-65-0]tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate</strong> (0.43 g, 1.4 mmol) and 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (0.37 g, 1.5 mmol) in 1,4-dioxane (3.9 mL) were added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (1:1) complex (0.056 g, 0.069 mmol), potassium acetate (0.40 g, 4.1 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (0.04 g, 0.07 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at 100 C. overnight. After cooled to room temperature, the mixture was filtered, washed with dichloromethane, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with 30% ethyl acetate in hexanes to afford the desired product (0.54 g, purity: 90%, yield: 98%). Analytic LCMS (M+Na)+: m/z=382.3; (M-But+H)+=304.3.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 60℃; for 3h;	A mixture of to-pinacolatodiboron (325 mg, 1.3 mmol), fer/-butyl-7-bromo- 3,4-dihydroisoquinoline-2(lH)-carboxylate (200 mg, 0.6 mmol), KOAc (189 mg, 1.9 mmol) and PdCl2(dppf) (94 mg, 0.13 mmol) in DMSO (2 mL) was stirred at 60C for 3 h. Then the reaction mixture was cooled to rt and diluted with water (30 mL). The resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2S04 and filtered. The filtrate was concentrated under reduced pressure to give the title compound. MS (ESI) m/z: 345 [M-^-butyl+MeCN+H]+.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 12h;Inert atmosphere; Sealed tube;	[0520] Procedure: A solution of <strong>[258515-65-0]tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate</strong> (1.0 g, 3.2029 mmol) in dioxane (30 mL) was added potassium acetate (0.943 g, 9.6089 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.976 g, 3.8435 mmol). The resulting mixture was purged with argon gas for 15 minutes. [1,1?-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.13 g, 0.1601 mmol) was added into reaction mixture and again purged for 5 minutes and allowed to stir in sealed tube at 80 oC for 12 h. The progress of reaction was monitored by TLC. The reaction mixture was cooled to room temperature, concentrated under reduced pressure. The crude residue was purified by combiflash using ethyl acetate in n-hexane to afford tert-butyl 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as colourless liquid (1.1 g impure). LC-MS m/z calcd for [M+H]+ 358.23, found 258.2.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 15h;Inert atmosphere;	A solution of WX128-1 (2.00 g, 6.41 mmol), bis(Pinacolato)Diboron (1.79 g, 7.05 mmol) and potassium acetate (1.89 g, 19.22 mmol) in dioxane (20.00 mL) was purged with nitrogen gas for three times, and then to the system was added Pd(dppf)Cl2 (1.41 g, 1.92 mmol). The reaction mixture was reacted at 80 C. under a nitrogen atmosphere for 15 hours. After the reaction was complete, it was concentrated under reduced pressure. The residue was dissolved in 30 mL water, and extracted with ethyl acetate (30 mL×3). The organic layers were combined, and washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to afford Compound WX128-2 (3.38 g, crude product), dark brown oil. 1H NMR (400 MHz, CDCl3) delta 7.63-7.54 (m, 2H), 7.15 (d, J=7.5 Hz, 1H), 4.59 (s, 2H), 3.65 (br s, 2H), 2.85 (br s, 2H), 1.49 (s, 9H), 1.35 (s, 12H).

Reference： [1]Molecules,2019,vol. 24
[2]Patent: WO2018/140876,2018,A1 .Location in patent: Page/Page column 45; 46
[3]Patent: WO2019/200120,2019,A1 .Location in patent: Paragraph 000570
[4]Patent: WO2014/89324,2014,A1 .Location in patent: Paragraph 0241
[5]Patent: CN104016979,2017,B .Location in patent: Paragraph 0622; 0623; 0624
[6]Patent: CN105524045,2016,A .Location in patent: Paragraph 0277; 0278; 0279
[7]Patent: US2010/240671,2010,A1 .Location in patent: Page/Page column 58
[8]Patent: WO2017/172505,2017,A1 .Location in patent: Page/Page column 53
[9]Patent: WO2019/46778,2019,A1 .Location in patent: Paragraph 0520
[10]ACS Chemical Neuroscience,2019,vol. 10,p. 3682 - 3689
[11]Patent: US2019/375744,2019,A1 .Location in patent: Paragraph 0125; 0126

3
[ 322691-38-3 ]
[ 937048-76-5 ]
[ 1246209-83-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate In 1,4-dioxane; water at 110℃;	1.3 Step 3: tert-butyl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate A mixture of 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.10 g, 0.44 mmol), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.16 g, 0.44 mmol), [1,1'-bis(diphenylphosphino)ferrocene[dichloropalladium(II) dichloromethane (1:1) complex (0.02 g, 0.02 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in 1,4-dioxane (3 mL), and water (1 mL) was heated at 110° C. overnight. After cooled to r.t., the mixture was diluted with MeOH, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluding with 10% MeOH in dichloromethane (DCM) to afford the desired product (0.14 g, yield: 75%). Analytic LCMS (M+H)+: m/z=425.4.

Reference： [1]Current Patent Assignee: INCYTE CORP - US2010/240671, 2010, A1 Location in patent: Page/Page column 59

4
[ 937048-76-5 ]
[ 1398696-76-8 ]
[ 1398695-60-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane; water / 120 °C 2: hydrogenchloride / 1,4-dioxane / 20 °C / Cooling with ice
	Multi-step reaction with 2 steps 1: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane; water / 120 °C 2: hydrogenchloride / 1,4-dioxane / 20 °C / Cooling with ice

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/123311, 2012, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/232061, 2012, A1

5
[ 937048-76-5 ]
[ 1398696-76-8 ]
[ 1398697-72-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With caesium carbonate In 1,4-dioxane; water at 120℃;	15 Intermediate 15: 1 ,1 -dimethylethyl 7-(5-fluoro-2-fr(4-methyl-2-Pyridinyl)methylloxy phenyl)-3,4-dihvdro-2(1H)-isoquinolinecarboxylateTo a degassed mixture 2-[(2-bromo-4-fluorophenyl)oxy]methyl}-4-methylpyridine (0.09g), 1 ,1-dimethylethyl 7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,4-dihydro- 2(1 H)-isoquinolinecarboxylate (0.131g) (for preparation see WO 2007/056710) and caesium carbonate (0.296g) in dioxane:water (4:1 , 5ml) was added PdCI2.dppf (0.025g). The reaction mixture was heated at 120°C overnight. The reaction mixture was added to water and extraction was carried out with ethyl acetate. The organic layer was dried over sodium sulphate and the filtrate was concentrated in vacuo. The crude product was purified through silica, eluting with 0-12% ethyl acetate in hexane. Appropriate fractions were concentrated in vacuo to yield the title compound, 0.169g, quantitative yield.LCMS (Method B): Rt = 7.95 min, [MH]+ = 449
100%	With caesium carbonate In 1,4-dioxane; water at 120℃;	15 Intermediate 15: 1,1-dimethylethyl 7-(5-fluoro-2-[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate To a degassed mixture 2-[(2-bromo-4-fluorophenyl)oxy]methyl}-4-methylpyridine (0.09 g), 1,1-dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate (0.131 g) (for preparation see WO 2007/056710) and caesium carbonate (0.296 g) in dioxane:water (4:1, 5 ml) was added PdCl2.dppf (0.025 g). The reaction mixture was heated at 120° C. overnight. The reaction mixture was added to water and extraction was carried out with ethyl acetate. The organic layer was dried over sodium sulphate and the filtrate was concentrated in vacuo. The crude product was purified through silica, eluting with 0-12% ethyl acetate in hexane. Appropriate fractions were concentrated in vacuo to yield the title compound, 0.169 g, quantitative yield. LCMS (Method B): Rt=7.95 min, [MH]+=449

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/123311, 2012, A1 Location in patent: Page/Page column 59
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/232061, 2012, A1 Location in patent: Page/Page column 32

6
[ 937048-76-5 ]
[ 1421339-96-9 ]
[ 1421340-76-2 ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: 7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester; (R)-4-((R)-1-(7-bromoquinolin-5-yloxy)ethyl)pyrrolidin-2-one With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In water; N,N-dimethyl-formamide at 90℃; for 2h; Stage #2: With trifluoroacetic acid In dichloromethane at 25℃;	4.3 Synthesis of (R)-4-((R)-1-(7-(1,2,3,4-tetrahydroisoquinolin-7-yl)quinolin-5-yloxy)ethyl)pyrrolidin-2-one (Example 101) Synthesis of (R)-4-((R)-1-(7-(1,2,3,4-tetrahydroisoquinolin-7-yl)quinolin-5-yloxy)ethyl)pyrrolidin-2-one (Example 101) 150 mg Example 27, 241 mg 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 15 mg bis(triphenylphosphine)palladium(II) chloride, 671 μL 2N aqueous sodium carbonate and 2 mL DMF were heated for 2 hours at 90° C. The mixture was partitioned between DCM and NaHCO3 (sat aq) and the organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in 10 ml 25% TFA in DCM and stirred at 25° C. overnight then concentrated in vacuo. Purification by flash chromatography using 0-25% MeOH/DCM gave 75 mg (43%) of Example 101 (R)-4-{(R)-1-[7-(1,2,3,4-Tetrahydro-isoquinolin-7-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one as yellow solid. HPLC-MS: Rt=2.28 min (method A), M+H=388.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2013/29949, 2013, A1 Location in patent: Paragraph 0359; 0360; 0361

7
[ 937048-76-5 ]
[ 1421339-96-9 ]
[ 1421341-33-4 ]

Yield	Reaction Conditions	Operation in experiment
	With bis(triphenylylphosphine)palladium(II) dichloride; sodium carbonate In N,N-dimethyl-formamide at 90℃; for 2h;	4.3 Synthesis of (R)-4-((R)-l-(7-(l,2,3,4-tetrahydroisoquinolin-7-yl)quinolin-5-yloxy)ethyl) rrolidin-2-one (Example 101) Example 27 Example 101150 mg Example 27, 241 mg 7-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,4-dihydro- lH-isoquinoline-2-carboxylic acid tert-butyl ester, 15 mg bis(triphenylphosphine)palladium(II) chloride, 671 μΐ, 2N aqueous sodium carbonate and 2 mL DMF were heated for 2 hours at 90°C. The mixture was partitioned between DCM and NaHC03 (sat aq) and the organic layer was separated, dried (Na2S04), filtered and concentrated in vacuo. The residue was dissolved in 10ml 25% TFA in DCM and stirred at 25°C overnight then concentrated in vacuo. Purification by flash chromatography using 0- 25% MeOH/DCM gave 75mg (43%) of Example 101 (R)-4- {(R)-l-[7-( 1,2,3, 4-Tetrahydro- isoquinolin-7-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one as yellow solid.HPLC-MS: Rt = 2.28 min (method A), M+H = 388.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2013/14060, 2013, A1 Location in patent: Page/Page column 99

8
[ 17680-55-6 ]
[ 937048-76-5 ]

Reference： [1]Patent: WO2014/89324,2014,A1
[2]Patent: CN105524045,2016,A
[3]Patent: CN104016979,2017,B
[4]Molecules,2019,vol. 24

9
5-bromo-3-[1 (R)-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine [ No CAS ]
[ 937048-76-5 ]
[ 1613147-76-4 ]

Yield	Reaction Conditions	Operation in experiment
77%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; water at 90℃; for 16h; Inert atmosphere;	12.3 Step 3) (R)-5-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine To a suspension of (R)-5-bromo-3-(l-(2,6-dichloro-3- fluorophenyl)ethoxy)pyridin-2-amine (475 mg, 1.26 mmol), 2-(/er/-butoxycarbonyl)-7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline (374 mg, 1.05 mmol) and Pd(PPh3)2Cl2 (75 mg, 1.11 mmol) in DME (8 mL) was added a solution of Na2C03 (374 mg, 3.36 mmol) in H20 (2 mL) under N2 atmosphere. The reaction was stirred at 90 °C for 16 h, then cooled to rt, diluted with EtOAc (250 mL) and filtered through a pad of Celite, which was washed with EtOAc (30 mL). The filtrate was washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a yellow solid (0.43 g, 77%). NMR (400 MHz, CDC13) δ (ppm): 1.50 (s, 9H), 1.85-1.87 (d, J= 6.6 Hz, 3H), 2.83 (s, 2H), 3.67 (s, 2H), 4.59 (s, 2H), 4.5 (s, 2H), 6.08-6.13 (q, J= 6.7 Hz, 1H), 6.96 (s, 1H), 7.03-7.07 (m, 2H), 7.12-7.20 (m, 2H), 7.29-7.33 (m, 1H), 7.84 (s, 1H).
77%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; water at 90℃; for 16h; Inert atmosphere;	12.3 Step 3) Preparation of (R) -5- (2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -3- (1- (2,6- Chloro-3-fluorophenyl) ethoxy) pyridin-2-amine Under nitrogen protection,(1- (2,6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine (475 mg, 1.26 mmol)2- (tert-butoxycarbonyl) -7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3,4 - tetrahydroisoquinoline (374 mg, 1.05 mmol) andPd (PPh3) 2Cl2 (75 mg, 1.11 mmol)Suspended in ethylene glycol dimethyl ether (8 mL)And thereto was added sodium carbonate (374 mg, 3.36 mmol)Of water (2 mL).The reaction solution was stirred at 90 ° C for 16 hours,Cooled to room temperature, diluted with ethyl acetate (250 mL) and filtered through celite. The filter cake was washed with ethyl acetate (30 mL)wash. The collected filtrate was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel(Petroleum ether / ethyl acetate (v / v) = 1/1) to give the title compound as a yellow solid (0.43 g, 77%).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - WO2014/89324, 2014, A1 Location in patent: Paragraph 0242
[2]Current Patent Assignee: CALITOR SCIENCES LLC; SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN104016979, 2017, B Location in patent: Paragraph 0625; 0626; 0627

10
[ 24424-99-5 ]
[ 937048-76-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium carbonate / tetrahydrofuran; water / 20 °C 2: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / dimethyl sulfoxide / 3 h / 80 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 24.17 h / 20 °C 2: potassium acetate; tris(dibenzylideneacetone)dipalladium⁽⁰⁾ chloroform complex; tricyclohexylphosphine / 1,4-dioxane / 24 h / 80 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: sodium carbonate / tetrahydrofuran; water / 20 °C 2: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / dimethyl sulfoxide / 3 h / 80 °C / Inert atmosphere

	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: potassium acetate / 1,4-dioxane / 4 h / 100 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: 0.25 h / 100 °C / Microwave irradiation; Inert atmosphere 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / dimethyl sulfoxide / 90 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: sodium carbonate / water; tetrahydrofuran / 16 h / 25 °C 2: potassium acetate; palladium bis[bis(diphenylphosphino)ferrocene] dichloride / dichloromethane; 1,2-dimethoxyethane / 25 - 90 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - WO2014/89324, 2014, A1
[2]Current Patent Assignee: BOHAI WATER INDUSTRY CO., LTD. - CN105524045, 2016, A
[3]Current Patent Assignee: CALITOR SCIENCES LLC; SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN104016979, 2017, B
[4]Current Patent Assignee: BIOGEN IDEC INC. - WO2018/140876, 2018, A1
[5]Montgomery, Deanna; Anand, Jessica P.; Baber, Mason A.; Twarozynski, Jack J.; Hartman, Joshua G.; Delong, Lennon J.; Traynor, John R.; Mosberg, Henry I. [Molecules, 2019, vol. 24, # 23]
[6]Current Patent Assignee: INNOVATION NETWORK CORPORATION OF JAPAN - WO2020/116660, 2020, A1

11
[ 937048-76-5 ]
[ 1614233-71-4 ]
[ 1614234-28-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ In 1,4-dioxane; water at 115℃; for 3h; Sealed tube; Inert atmosphere;	85.2 tert-butyl 7-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate A mixture of 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (16.7 mg, 0.0400 mmol), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (17.96 mg, 0.05000 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.0 mg, 0.0024 mmol) and potassium phosphate (25.5 mg, 0.120 mmol) in 1,4-dioxane (0.50 mL) and water (0.15 mL) in a reaction vial was sealed, and degassed and recharged with nitrogen for three times. The mixture was stirred at 115° C. for 3 h. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=524.1.

Reference： [1]Current Patent Assignee: INCYTE CORP - US2014/171405, 2014, A1 Location in patent: Paragraph 0486; 487

12
[ 937048-76-5 ]
[ 188576-49-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With dihydrogen peroxide In dichloromethane at 20℃; for 16h;	38.II Part II - Synthesis of tert-Butyl 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate Into a 100 mL round-bottom flask was placed tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboylate (3.0 g, 7.5 mmol), dichloromethane (30 mL), followed by 30% hydrogen peroxide (2.56 g, 75.2 mmol). The reaction was stirred for 16 hours at ambient temperature. The mixture was diluted with water (30 mL), extracted with ethyl acetate (3 x 20 mL) and concentrated. The residue was purified on a silica gel column eluting with ethyl acetate/petroleum ether (1/2). The collected fractions were combined and concentrated to yield the title compound (2.0 g, 96%) as a solid.
29%	With dihydrogen peroxide In tetrahydrofuran at 20℃; for 1h;	3.3 (3) Preparation of tert-butyl 7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate In a 100mL one-necked flask, tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (500mg, 1.39mmol) in tetrahydrofuran (20mL) and 30% hydrogen peroxide (10mL) were added. This was stirred at room temperature for 1h. The mixture was extracted with ethyl acetate (3 × 20mL) and extracted. The combined organic phases were washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the product (100mg, 29% yield).

Reference： [1]Current Patent Assignee: GOSSAMER BIO SERVICES; LYCERA CORPORATION - WO2019/200120, 2019, A1 Location in patent: Paragraph 000571
[2]Current Patent Assignee: BOHAI WATER INDUSTRY CO., LTD. - CN105524045, 2016, A Location in patent: Paragraph 0280; 0281; 0282

13
[ 937048-76-5 ]
N-(7'-bromo-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2,4-difluorobenzenesulfonamide [ No CAS ]
tert-butyl 7-(5’-((2,4-difluorophenyl)sulfonamido)-2’-oxospiro[cyclobutane-1,3‘-indolin]-7’-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) In 1,4-dioxane; water at 100℃; for 16h; Inert atmosphere;	XX.(i) Step-(i): tert-Butyl 7-(5’-((2,4-difluorophenyl)sulfonamido)-2’-oxospiro[cyclo butane- 1,3 ‘-indolini -7’-yl)-3 ,4-dihydroisoiuinoline-2( 1 H)-carboxylate (88.1): General procedure: The process of this step was adopted from Example-I. ‘H NMR (400 MHz, DMSO-d6): ö 10.38 (s, 1H), 10.16 (s, 1H), 7.86-7.82 (m, 1H), 7.59-7.53 (m, 1H), 7.27- 7.21 (m, 3H), 7.08-7.02 (m, 2H), 6.83 (s, 1H), 4.54 (s, 2H), 3.56 (t, J=5.4 Hz, 2H), 2.79(t, J=5.4 Hz, 2H), 2.43-2.33 (m, 2H), 2.23-2.06 (m, 4H), 1.44 (s, 9H).. To a solution of N-(7'-bromo-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2,4- difluoro benzenesulfonamide (intermediate-1) (0.15 g, 0.34 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) were added (3-hydroxyphenyl)boronic acid (0.057 g, 0.41 mmol), potassium phosphate (0.22 g, 1.02 mmol). The mixture was degassed with nitrogen purging for 20 min. Then Pd(Amphos)Cl2(0.024 g, 0.034 mmol) was added and the mixture was heated at 100°C for 16 h. The mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (100 ml), washed with water (100 mL), brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure and column purified to afford the title compound as white solid (0.07 g, 45%).1H NMR (400 MHz, DMSO-d6): δ 10.39 (s,1H), 10.04 (s, 1H), 9.51 (s, 1H), 7.88-7.82 (m, 1H), 7.58-7.53 (m, 1H), 7.27-7.19 (m, 3H), 6.82 (d, J=2.0 Hz, 1H), 6.75 (dd, J1=7.8 Hz, J2=1.5 Hz, 1H), 6.69-6.66 (m, 2H), 2.44-2.38 (m, 2H), 2.24-2.06 (m, 4H); LC-MS: m/z 457.1 (M+H)+ .

Reference： [1]Current Patent Assignee: ORION S R L - WO2016/203112, 2016, A1 Location in patent: Page/Page column 82; 83; 118

14
[ 937048-76-5 ]
methyl (Z)-3-cyclopropyl-2-methyl-3-(p-tolylsulfonyloxy)prop-2-enoate [ No CAS ]
(E)-tert-butyl 7-(1-cyclopropyl-3-methoxy-2-methyl-3-oxoprop-1-en-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In tetrahydrofuran; water at 80℃; for 1h;	2 (E)-tert-Bu y\ 7-(l-cvclopropyl-3-methoxy-2-methyl-3-oxoprop-l-en-l-yl)-3. 4- dihvdroisoquinoline-2(lH)-carboxylate A mixture of Pd(PPh3)2Cl2 (6 mg, 8.3 μιτιο), (0548) K2CO3 (23 mg, 0.17 mmol), (Z)-methyl-3-cyclopropyl-2-methyl-3-(tosyloxy)- acrylate (31 mg, 0.1 mmol) and Intermediate 1 (30.0 mg, 0.08 mmol) in THF (2.5 mL) and H20 (0.5 mL) was stirred at 80°C for lh. Then the reaction was cooled to rt and water (20 mL) was added to the reaction. The aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous MgSC>4 and filtered. (0549) The filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (Si02, PE: EtOAc=5: l, v/v) to give the title compound. l NMR (400 MHz, CDC13):5 7.01 (d, J= 7.7 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.69 (s, 1H), 4.51 (br. s., 2H), 3.63 (br. s., 2H), 3.40 (s, 3H), 2.79 (br. s., 2H), 2.13 (s, 3H), 1.89 - 1.79 (m, 1H), 1.48 (s, 9H), 0.77 - 0.69 (m, 2H), 0.38 - 0.23 (m, 2H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2017/172505, 2017, A1 Location in patent: Page/Page column 53

15
[ 937048-76-5 ]
methyl (2E)-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)prop-2-enoate [ No CAS ]
tert-butyl 7-[3-methoxy-1-(1-methylbenzotriazol-5-yl)-3-oxopropyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13.26%	With chloro(1,5-cyclooctadiene)rhodium(I) dimer; triethylamine In 1,4-dioxane; water at 95℃; for 19h;	50.2 Preparation of tert-butyl 7- [3-methoxy- 1-(1-methylbenzotriazol-5-yl)-3-oxo- propyl] -3,4-dihydro- 1H-isoquinoline-2-carboxylate Tert-butyl 7-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-3 ,4-dthydro- 1 Hisoquinoline-2-carboxylate (148.86 mg, 414.33 umol), methyl (E)-3-( 1 -methylbenzotriazol5-yl)prop-2-enoate (60.00 mg, 276.22 umol), N,N-diethylethanamine (41.93 mg, 414.33 umol, 57.43 uL) and [Rh(COD)C1j2 (6.81 mg, 13.81 umol) in dioxane (1.50 mL) and water (500.00 uL) was heated at 95 °C for overnight (19h). After filtration, purification on prep HPLC gave tert-butyl 7- [3 -methoxy- 1 -(1 -methylbenzotriazol-5-yl)-3 -oxo-propylj -3,4- dthydro-1H-isoquinoline-2-carboxylate (16.50 mg, 36.62 umol, 13.26% yield). LCMS: Rt = 1.66 mm, mlz =45 1.2.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2018/140876, 2018, A1 Location in patent: Page/Page column 90

16
[ 937048-76-5 ]
ethyl (E)-3-(6-methoxy-4-methylpyridin-3-yl)acrylate [ No CAS ]
tert-butyl 7-(3-ethoxy-1-(6-methoxy-4-methylpyridin-3-yl)-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With chloro(1,5-cyclooctadiene)rhodium(I) dimer; triethylamine In 1,4-dioxane; water at 110℃; for 18h; Inert atmosphere;	92-93.3 Preparation of tert-butyl 7-(3-ethoxy- 1 -(6-methoxy-4-methylpyridin-3-yl)-3- oxopropyl)-3 ,4-dthydroisoquinoline-2( 1 H)-carboxylate To a solution of ethyl (E)-3-(6-methoxy-4-methylpyridin-3-yl)acrylate (200 mg, 0.9 mmol, 2.0 eq.) and tert-butyl 7-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-3 ,4- dthydroisoquinoline-2(1H)-carboxylate (161 mg, 0.45 mmol, 1.0 eq.) in dioxane (3 mL) and H20 (1 mL) was added TEA (136 mg, 1.35 mmol, 3.0 eq.) and [RhC1(cod)j 2(11 mg, 0.0225 mmol, 0.05 eq.). The mixture was stirred at 110°C for 18 h under N2 atmosphere. LCMS showed the starting material was almost consumed and the desired product was observed. The mixture was diluted with H20 (5 mL) and extracted with EA (8 mL x 3). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated to give the residue, which was purified by prep-TLC (PE: EA = 8: 1) to give the compound tert-butyl 7- (3 -ethoxy- 1 -(6-methoxy-4-methylpyridin-3 -yl)-3 -oxopropyl)-3 ,4-dthydroisoquinoline-2( 1 H)carboxylate (100 mg, yield:25%) as an oil. MS: (M+H: 545.2). ‘HNMR: (400 MHz, CDC13)= 8.05 (s, 1H), 6.94 - 7.08 (m, 2H), 6.88 ( s, 1H), 6.52 (s, 1H), 4.57 (t, J = 8.3 Hz, 1H), 4.48 (s, 2H), 4.06 (m, 2H), 3.90 (s, 3H), 3.60 ( s, 2H), 3.00 (m, 2H), 2.76 ( s, 2H), 2.20 (s,3H), 1.57 (s, 1OH), 1.15 (t,J=7.OHz, 3H).

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2018/140876, 2018, A1 Location in patent: Page/Page column 155

17
[ 937048-76-5 ]
methyl (E)-3-(1-ethyl-4-methyl-1H-benzo[d] [1,2,3]triazol-5-yl)acrylate [ No CAS ]
tert-butyl 7-(1-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-methoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With chloro(1,5-cyclooctadiene)rhodium(I) dimer; triethylamine In 1,4-dioxane; water at 150℃; for 12h; Sealed tube;	1.8 Synthesis of tert-butyl 7-(1-(1-ethyl-4-methyl- 1H-benzo[d] [1,2,3]triazol-5-yl)-3- methoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A mixture of methyl (E)-3 -(1 -ethyl-4-methyl- 1 H-benzo [di [1,2,3 jtriazol-5-yl) acrylate (5 g, 20 mmol), tert-butyl 7-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-3 ,4- dthydroisoquinoline-2(1H)-carboxylate (10.7 g, 30 mmol) and TEA (6.0 g, 60 mmol) in dioxane/H20 (50 mL/10 mL) was degassed for 10 mm before [Rh(COD)C1j2 (980 mg, 2 mmol) was added, and then the mixture was degassed for another 5 mm. The mixture was stirred at 150 °C for 12 h in a sealed tube. After cooling down, the solvent was removed under reduced pressure. The residue was purified by silica gel column (PE : EA = 2 : 1) to give tert-butyl 7-( 1 -(1 -ethyl-4-methyl- 1H-benzo [di [1 ,2,3jtriazol-5-yl)-3-methoxy-3- oxopropyl)-3,4-dthydroisoquinoline-2(1H)-carboxylate (5 g, yield: 51%) as a yellow oil. ESIMS (M+H): 479.2. ‘H NMR (400 MHz, CDC13) (5: 7.32-7.3 1 (m, 2H), 7.04-7.02 (m, 2H), 6.91 (s, 1H), 4.96 (t, J = 8.0 Hz, 1H), 4.64 (q, J = 7.2 Hz, 2H), 4.48 (s, 2H), 3.63-3.54 (m, 5H), 3.17-3.01 (m, 2H), 2.85 (s, 3H), 2.76 (t, J= 4.8 Hz, 2H), 1.59 (t, J= 7.2 Hz, 3H), 1.26 (s, 9H).

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2018/140876, 2018, A1 Location in patent: Page/Page column 45; 49

18
[ 17680-55-6 ]
[ 24424-99-5 ]
[ 937048-76-5 ]

Reference： [1]Patent: WO2008/116185,2008,A2

19
[ 937048-76-5 ]
[ 13790-39-1 ]
tert-butyl 7-(6,7-dimethoxyquinazolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water at 100℃; for 12h; Inert atmosphere; Sealed tube;	32.3 Step 3: Synthesis of tert-butyl 7-(6,7-dimethoxyquinazolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [0521] Procedure: To the solution of tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.0 g, 2.7834 mmol) in dioxane (25 mL) and water (2.5 mL) was added 4-chloro-6,7-dimethoxyquinazoline (0.5 g, 2.2267 mmol) and potassium carbonate (1.15 g , 8.3502 mmol). The resulting mixture was purged by argon gas for 15 minutes. Tetrakis(triphenylphosphane)palladium(0) (0.16 g , 0.1391 mmol) was added into reaction mixture and again purged for 5 minutes and allowed to stir in sealed tube at 100 oC for 12 h. The progress of reaction was monitored by TLC. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude residue was purified by combiflash using ethyl acetate in n-hexane to afford tert-butyl 7-(6,7-dimethoxyquinazolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylateas white solid (0.89 g impure). LC-MS m/z calcd for [M+H]+ 422.20, found 422.4

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2019/46778, 2019, A1 Location in patent: Paragraph 0521

20
[ 937048-76-5 ]
4-chloro-6,7-dimethoxy-3-methylquinoline [ No CAS ]
tert-butyl 7-(6,7-dimethoxy-3-methylquinolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water at 100℃; for 15h; Inert atmosphere; Sealed tube;	60.1 Step 1: tert-butyl 7-(6,7-dimethoxy-3-methylquinolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [0593] Procedure: To a stirred solution of 4-chloro-6,7-dimethoxy-3-methylquinoline (0.19 g, 0.799 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.31 g, 0.879 mmol), K2CO3 (0.33 g, 2.397 mmol) and the reaction mixture was degassed with argon for 10 min in a sealed tube. To this reaction mixture was added Pd(PPh3)4 (0.09 mL, 0.079 mmol) and heated to 100 °C for 15 h. The progress of the reaction was monitored by TLC. Reaction mixture was cooled to room temperature, ethyl acetate (100 mL) was added. Organic layer was separated and washed with water, brine and dried over anhydrous sodium sulphate. The filtrate obtained was evaporated under reduced pressure to give the crude residue. The crude product was purified by gradient column chromatography using 1-3% methanol in DCM to afford tert-butyl 7-(6,7-dimethoxy-3-methylquinolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as colorless viscous liquid (0.145g, crude). LC-MS (ES) m/z = 435.2[M+H]+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2019/46778, 2019, A1 Location in patent: Paragraph 0593

21
[ 937048-76-5 ]
C₁₇H₁₉N [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / acetone; water 2: hydrogenchloride / 1,4-dioxane

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Griggs, Nicholas W.; Fernandez, Thomas J.; Hartman, Joshua G.; Sánchez-Santiago, Ashley A.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I. [ACS Chemical Neuroscience, 2019, vol. 10, # 8, p. 3682 - 3689]

22
[ 937048-76-5 ]
C₁₆H₁₆N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / acetone; water 2: hydrogenchloride / 1,4-dioxane

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Griggs, Nicholas W.; Fernandez, Thomas J.; Hartman, Joshua G.; Sánchez-Santiago, Ashley A.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I. [ACS Chemical Neuroscience, 2019, vol. 10, # 8, p. 3682 - 3689]

23
[ 937048-76-5 ]
C₁₇H₁₉N [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / acetone; water 2: hydrogenchloride / 1,4-dioxane

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Griggs, Nicholas W.; Fernandez, Thomas J.; Hartman, Joshua G.; Sánchez-Santiago, Ashley A.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I. [ACS Chemical Neuroscience, 2019, vol. 10, # 8, p. 3682 - 3689]

24
[ 937048-76-5 ]
C₁₆H₁₆N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / acetone; water 2: hydrogenchloride / 1,4-dioxane

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Griggs, Nicholas W.; Fernandez, Thomas J.; Hartman, Joshua G.; Sánchez-Santiago, Ashley A.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I. [ACS Chemical Neuroscience, 2019, vol. 10, # 8, p. 3682 - 3689]

25
[ 937048-76-5 ]
C₁₆H₁₆N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / acetone; water 2: hydrogenchloride / 1,4-dioxane

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Griggs, Nicholas W.; Fernandez, Thomas J.; Hartman, Joshua G.; Sánchez-Santiago, Ashley A.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I. [ACS Chemical Neuroscience, 2019, vol. 10, # 8, p. 3682 - 3689]

26
[ 937048-76-5 ]
C₃₈H₄₈N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / acetone; water 2: hydrogenchloride / 1,4-dioxane 3: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; 6-chloro-1-hydroxybenzotriazole; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Griggs, Nicholas W.; Fernandez, Thomas J.; Hartman, Joshua G.; Sánchez-Santiago, Ashley A.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I. [ACS Chemical Neuroscience, 2019, vol. 10, # 8, p. 3682 - 3689]

27
[ 937048-76-5 ]
C₃₇H₄₅N₃O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / acetone; water 2: hydrogenchloride / 1,4-dioxane 3: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; 6-chloro-1-hydroxybenzotriazole; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Griggs, Nicholas W.; Fernandez, Thomas J.; Hartman, Joshua G.; Sánchez-Santiago, Ashley A.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I. [ACS Chemical Neuroscience, 2019, vol. 10, # 8, p. 3682 - 3689]

28
[ 109-04-6 ]
[ 937048-76-5 ]
C₁₉H₂₂N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.83 g	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,4-dioxane at 25 - 100℃; for 15h; Inert atmosphere;	3.2 Step 2: Synthesis of Compound WX128-3 Under a nitrogen atmosphere, at 25° C., to a solution of WX128-2 (2.88 g, 8.02 mmol), and 2-bromopyridine (1.27 g, 8.02 mmol, 763.35 μL) in dioxane (30.00 mL) and water (7.50 mL) were added sodium carbonate (1.02 g, 9.62 mmol) and tetrakis(triphenylphosphine)palladium (185.35 mg, 160.40 μmol). The reaction mixture was reacted at 100° C. under a nitrogen atmosphere for 15 hours. After the reaction was complete, it was concentrated under reduced pressure. The residue was purified by column chromatography to afford Compound WX128-3 (1.83 g, 62.88% yield), white solid. 1H NMR (400 MHz, CDCl3) 7.63-7.54 (m, 2H), 7.15 (d, J=7.5 Hz, 1H), 4.59 (s, 2H), 3.65 (br s, 2H), 2.85 (br s, 2H), 1.49 (s, 9H), 1.35 (s, 12H). 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J=4.8 Hz, 1H), 7.84-7.68 (m, 4H), 7.27-7.21 (m, 2H), 4.68 (s, 2H), 3.69 (br s, 2H), 2.90 (br t, J=5.5 Hz, 2H), 1.51 (s, 9H).

Reference： [1]Current Patent Assignee: PHAENO THERAPEUTICS - US2019/375744, 2019, A1 Location in patent: Paragraph 0125; 0127

29
[ 937048-76-5 ]
[ 395-44-8 ]
tert-butyl 7-(2-(trifluoromethyl)benzyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetone; at 100℃; for 0.5h;Microwave irradiation; Inert atmosphere;	General procedure: The appropriate benzyl bromide (1.5-2.0 eq), intermediate 6 (1.0 eq), Pd(dppf)Cl2 (0.1 eq), andK2CO3 (3.0 eq) were combined in a microwave vessel equipped with a teflon stirbar. The system wasflushed with argon. A degassed mixture of 3:1 acetone:water (2-3 mL) was added, and the reaction washeated in a microwave to 100 C for 30 min. The product was purified via silica gel chromatography inethyl acetate/hexanes.

Reference： [1]Molecules,2019,vol. 24

30
[ 937048-76-5 ]
[ 22115-41-9 ]
tert-butyl 7-(2-cyanobenzyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; acetone at 100℃; for 0.5h; Microwave irradiation; Inert atmosphere;	4.1.3. General Procedure C for Microwave Suzuki Coupling of Boronic Ester 6 and PendantBenzyl Bromide General procedure: The appropriate benzyl bromide (1.5-2.0 eq), intermediate 6 (1.0 eq), Pd(dppf)Cl2 (0.1 eq), andK2CO3 (3.0 eq) were combined in a microwave vessel equipped with a teflon stirbar. The system wasflushed with argon. A degassed mixture of 3:1 acetone:water (2-3 mL) was added, and the reaction washeated in a microwave to 100 C for 30 min. The product was purified via silica gel chromatography inethyl acetate/hexanes.

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Baber, Mason A.; Twarozynski, Jack J.; Hartman, Joshua G.; Delong, Lennon J.; Traynor, John R.; Mosberg, Henry I. [Molecules, 2019, vol. 24, # 23]

31
[ 937048-76-5 ]
[ 874-98-6 ]
tert-butyl 7-(3-methoxybenzyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; acetone at 100℃; for 0.5h; Microwave irradiation; Inert atmosphere;	4.1.4. General Procedure D for Microwave Suzuki Coupling of Boronic Ester 6 and PendantBenzyl Bromide General procedure: The appropriate benzyl bromide (1.0 eq), intermediate 6 (1.5 eq), Pd(dppf)Cl2 (0.1 eq), and K2CO3(3.0 eq) were combined in a microwave vessel equipped with a teflon stirbar. The system was flushedwith argon. A degassed mixture of 3:1 acetone:water (2-3 mL) was added, and the reaction was heatedin a microwave to 100 C for 30 min. The product was purified via silica gel chromatography in ethylacetate/hexanes.

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Baber, Mason A.; Twarozynski, Jack J.; Hartman, Joshua G.; Delong, Lennon J.; Traynor, John R.; Mosberg, Henry I. [Molecules, 2019, vol. 24, # 23]

32
[ 937048-76-5 ]
[ 74597-04-9 ]
tert-butyl 7-(3-hydroxybenzyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; acetone at 100℃; for 0.5h; Microwave irradiation; Inert atmosphere;	4.1.3. General Procedure C for Microwave Suzuki Coupling of Boronic Ester 6 and PendantBenzyl Bromide General procedure: The appropriate benzyl bromide (1.5-2.0 eq), intermediate 6 (1.0 eq), Pd(dppf)Cl2 (0.1 eq), andK2CO3 (3.0 eq) were combined in a microwave vessel equipped with a teflon stirbar. The system wasflushed with argon. A degassed mixture of 3:1 acetone:water (2-3 mL) was added, and the reaction washeated in a microwave to 100 C for 30 min. The product was purified via silica gel chromatography inethyl acetate/hexanes.

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Baber, Mason A.; Twarozynski, Jack J.; Hartman, Joshua G.; Delong, Lennon J.; Traynor, John R.; Mosberg, Henry I. [Molecules, 2019, vol. 24, # 23]

33
[ 937048-76-5 ]
[ 402-23-3 ]
tert-butyl 7-(3-(trifluoromethyl)benzyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; acetone at 100℃; for 0.5h; Microwave irradiation; Inert atmosphere;	4.1.4. General Procedure D for Microwave Suzuki Coupling of Boronic Ester 6 and PendantBenzyl Bromide General procedure: The appropriate benzyl bromide (1.0 eq), intermediate 6 (1.5 eq), Pd(dppf)Cl2 (0.1 eq), and K2CO3(3.0 eq) were combined in a microwave vessel equipped with a teflon stirbar. The system was flushedwith argon. A degassed mixture of 3:1 acetone:water (2-3 mL) was added, and the reaction was heatedin a microwave to 100 C for 30 min. The product was purified via silica gel chromatography in ethylacetate/hexanes.

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Baber, Mason A.; Twarozynski, Jack J.; Hartman, Joshua G.; Delong, Lennon J.; Traynor, John R.; Mosberg, Henry I. [Molecules, 2019, vol. 24, # 23]

34
[ 937048-76-5 ]
[ 28188-41-2 ]
tert-butyl 7-(3-cyanobenzyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; acetone at 100℃; for 0.5h; Microwave irradiation; Inert atmosphere;	4.1.4. General Procedure D for Microwave Suzuki Coupling of Boronic Ester 6 and PendantBenzyl Bromide General procedure: The appropriate benzyl bromide (1.0 eq), intermediate 6 (1.5 eq), Pd(dppf)Cl2 (0.1 eq), and K2CO3(3.0 eq) were combined in a microwave vessel equipped with a teflon stirbar. The system was flushedwith argon. A degassed mixture of 3:1 acetone:water (2-3 mL) was added, and the reaction was heatedin a microwave to 100 C for 30 min. The product was purified via silica gel chromatography in ethylacetate/hexanes.

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Baber, Mason A.; Twarozynski, Jack J.; Hartman, Joshua G.; Delong, Lennon J.; Traynor, John R.; Mosberg, Henry I. [Molecules, 2019, vol. 24, # 23]

35
[ 937048-76-5 ]
[ 81093-21-2 ]
tert-butyl 7-(2,3-dimethylbenzyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetone; at 100℃; for 0.5h;Microwave irradiation; Inert atmosphere;	General procedure: The appropriate benzyl bromide (1.5-2.0 eq), intermediate 6 (1.0 eq), Pd(dppf)Cl2 (0.1 eq), andK2CO3 (3.0 eq) were combined in a microwave vessel equipped with a teflon stirbar. The system wasflushed with argon. A degassed mixture of 3:1 acetone:water (2-3 mL) was added, and the reaction washeated in a microwave to 100 C for 30 min. The product was purified via silica gel chromatography inethyl acetate/hexanes.

Reference： [1]Molecules,2019,vol. 24

36
[ 937048-76-5 ]
3-(bromomethyl)pyridine hydrobromide [ No CAS ]
tert-butyl 7-(pyridin-3-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; acetone at 100℃; for 0.5h; Microwave irradiation; Inert atmosphere;	4.1.3. General Procedure C for Microwave Suzuki Coupling of Boronic Ester 6 and PendantBenzyl Bromide General procedure: The appropriate benzyl bromide (1.5-2.0 eq), intermediate 6 (1.0 eq), Pd(dppf)Cl2 (0.1 eq), andK2CO3 (3.0 eq) were combined in a microwave vessel equipped with a teflon stirbar. The system wasflushed with argon. A degassed mixture of 3:1 acetone:water (2-3 mL) was added, and the reaction washeated in a microwave to 100 C for 30 min. The product was purified via silica gel chromatography inethyl acetate/hexanes.

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Baber, Mason A.; Twarozynski, Jack J.; Hartman, Joshua G.; Delong, Lennon J.; Traynor, John R.; Mosberg, Henry I. [Molecules, 2019, vol. 24, # 23]

37
[ 937048-76-5 ]
4-(bromomethyl) pyridine hydrobromide [ No CAS ]
tert-butyl 7-(pyridin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; acetone at 100℃; for 0.5h; Microwave irradiation; Inert atmosphere;	4.1.3. General Procedure C for Microwave Suzuki Coupling of Boronic Ester 6 and PendantBenzyl Bromide General procedure: The appropriate benzyl bromide (1.5-2.0 eq), intermediate 6 (1.0 eq), Pd(dppf)Cl2 (0.1 eq), andK2CO3 (3.0 eq) were combined in a microwave vessel equipped with a teflon stirbar. The system wasflushed with argon. A degassed mixture of 3:1 acetone:water (2-3 mL) was added, and the reaction washeated in a microwave to 100 C for 30 min. The product was purified via silica gel chromatography inethyl acetate/hexanes.

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Baber, Mason A.; Twarozynski, Jack J.; Hartman, Joshua G.; Delong, Lennon J.; Traynor, John R.; Mosberg, Henry I. [Molecules, 2019, vol. 24, # 23]

38
[ 937048-76-5 ]
[ 3163-27-7 ]
tert-butyl 7-(naphthalen-1-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; acetone at 100℃; for 0.5h; Microwave irradiation; Inert atmosphere;	4.1.3. General Procedure C for Microwave Suzuki Coupling of Boronic Ester 6 and PendantBenzyl Bromide General procedure: The appropriate benzyl bromide (1.5-2.0 eq), intermediate 6 (1.0 eq), Pd(dppf)Cl2 (0.1 eq), andK2CO3 (3.0 eq) were combined in a microwave vessel equipped with a teflon stirbar. The system wasflushed with argon. A degassed mixture of 3:1 acetone:water (2-3 mL) was added, and the reaction washeated in a microwave to 100 C for 30 min. The product was purified via silica gel chromatography inethyl acetate/hexanes.

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Baber, Mason A.; Twarozynski, Jack J.; Hartman, Joshua G.; Delong, Lennon J.; Traynor, John R.; Mosberg, Henry I. [Molecules, 2019, vol. 24, # 23]

39
[ 937048-76-5 ]
[ 939-26-4 ]
tert-butyl 7-(naphthalen-2-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; acetone at 100℃; for 0.5h; Microwave irradiation; Inert atmosphere;	4.1.3. General Procedure C for Microwave Suzuki Coupling of Boronic Ester 6 and PendantBenzyl Bromide General procedure: The appropriate benzyl bromide (1.5-2.0 eq), intermediate 6 (1.0 eq), Pd(dppf)Cl2 (0.1 eq), andK2CO3 (3.0 eq) were combined in a microwave vessel equipped with a teflon stirbar. The system wasflushed with argon. A degassed mixture of 3:1 acetone:water (2-3 mL) was added, and the reaction washeated in a microwave to 100 C for 30 min. The product was purified via silica gel chromatography inethyl acetate/hexanes.

Reference： [1]Montgomery, Deanna; Anand, Jessica P.; Baber, Mason A.; Twarozynski, Jack J.; Hartman, Joshua G.; Delong, Lennon J.; Traynor, John R.; Mosberg, Henry I. [Molecules, 2019, vol. 24, # 23]

40
[ 937048-76-5 ]
tert-butyl 4-[2-(2-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4-methyl-1H-benzotriazol-1-yl}ethoxy)ethyl]benzoate [ No CAS ]
tert-butyl 7-{1-[1-(2-{2-[4-(tert-butoxycarbonyl)phenyl]ethoxy}ethyl)-4-methyl-1H-benzotriazol-5-yl]-3-ethoxy-3-oxopropyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
126 mg	With triethylamine In water at 20 - 100℃;	29.H H) tert- Butyl 7- {1 -[1 -(2-{2-[4-(tert-butoxycarbonyl)phenyl]ethoxy}ethyl)-4-methyl- lH-benzotriazol-5-yl]-3-ethoxy-3-oxopropyl}-3,4-dihydroisoquinoline-2(lH)- carboxylate To a mixture of tert- butyl 4-[2-(2-{5-[(lE)-3-ethoxy-3-oxoprop-l-en-l-yl]-4- methyl-lH-benzotriazol-l-yl}ethoxy)ethyl]benzoate (163 mg), tert-butyl 7-(4, 4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,4-dihydro- 1H-isoquinoline-2-carboxylate (147 mg), sodium dodecyl sulfate (49.1 mg), triethylamine (0.14 ml), CPME (2 ml) and water (1 ml), chloro(l,5-cyclooctadiene)rhodium (I) dimer (16.8 mg) was added at room temperature. The mixture was stirred at 100°C overnight. Water was added to the mixture thus obtained, and the mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (126 mg). NMR (300 MHz, CDCb) 5 1.10 (3H, t, J = 7.1Hz), 1.46 (9H, s), 1.59 (9H, s), 2.70-2.83 (4H, m), 2.86 (3H, s), 2.98-3.19 (2H, m), 3.59 (4H, br t, J = 6.2 Hz), 3.89 (2H, br t, J = 5.0 Hz), 4.02 (2H, q, J = 7.1Hz), 4.42-4.52 (2H, m), 4.72 (2H, t, J = 5.0 Hz), 4.96 (1H, br t, J = 7.8 Hz), 6.91-6.97 (1H, m), 7.00-7.06 (2H, m), 7.11 (2H, br d, J = 8.0 Hz), 7.30-7.36 (2H, m), 7.84 (2H, d, J = 8.1Hz). MS m/z 713.4 [M+H]+.

Reference： [1]Current Patent Assignee: INNOVATION NETWORK CORPORATION OF JAPAN - WO2020/116660, 2020, A1 Location in patent: Paragraph 0162

41
[ 937048-76-5 ]
tert-butyl 4-(5-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4-methyl-1H-benzotriazol-1-yl} pentyl)benzoate [ No CAS ]
tert-butyl 7-[1-(1-{5-[4-(tert-butoxycarbonyl)phenyl]pentyl}-4-methyl-1H-benzotriazol-5-yl)-3-ethoxy-3-oxopropyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6.55 g	With chloro(1,5-cyclooctadiene)rhodium(I) dimer; sodium dodecyl-sulfate; ammonium chloride; triethylamine In water at 100℃; for 4h; Inert atmosphere;	1.I [0108] I) == tert-Butyl 7-[l-(l-{5-[4-(tert-butoxycarbonyl)phenyl]pentyl}-4-methyl-lH- benzotriazol-5-yl)-3 -ethoxy-3 -oxopropyl]-3,4-dihydroisoquinoline-2(l H)- carboxylate To a mixture of tert- butyl 4-(5-{5-[(lE)-3-ethoxy-3-oxoprop-l-en-l-yl]-4- methyl- 1 / -benzotriazol- 1 -yl} pentyl)benzoate (4.8 g), tert-butyl 7-(4,4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)-3,4-dihydro- lH-isoquinoline-2-carboxylate (10.8 g), sodium dodecyl sulfate (1.45 g), and triethylamine (4.2 ml) in CPME (100 ml) and water (50 ml), chloro(l,5-cyclooctadiene)rhodium (I) dimer (496 mg) was added. The mixture was stirred at 100°C for 4 hours under argon atmosphere. To the mixture thus obtained, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.55 g). H NMR (300 MHz, CDC13) d 1.10 (3H, t, J = 7.2 Hz), 1.32-1.43 (2H, m), 1.47 (9H, s), 1.54-1.60 (9H, m), 1.62-1.76 (2H, m), 1.93-2.03 (2H, m), 2.62 (2H, br t, J = 7.3 Hz), 2.71-2.79 (2H, m), 2.86 (3H, s), 2.95-3.22 (2H, m), 3.49-3.69 (2H, m), 4.02 (2H, q, J = 7.0 Hz), 4.45-4.51 (2H, m), 4.56 (2H, br t, J = 6.8 Hz), 4.88-5.09 (1H, m), 6.89-6.96 (1H, m), 7.03 (2H, s), 7.17 (2H, br d, J = 7.8 Hz), 7.26 (1H, s), 7.31-7.39 (1H, m), 7.88 (2H, d, J = 8.0 Hz). MS m/z 711.5 [M+H]+.

Reference： [1]Current Patent Assignee: INNOVATION NETWORK CORPORATION OF JAPAN - WO2020/116660, 2020, A1 Location in patent: Paragraph 0108

42
[ 937048-76-5 ]
tert-butyl 4-[3-(5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl)propoxy]methyl}benzoate [ No CAS ]
tert-butyl 7-[1-(3-[4-(tert-butoxycarbonyl)phenyl]methoxy}propyl)-4-methyl-1H-benzotriazol-5-yl](hydroxy)methyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
260 mg	With potassium phosphate; chloro(1,5-cyclooctadiene)rhodium(I) dimer In water at 20 - 110℃; for 1h; Inert atmosphere;	28.C; 55.H [0157] C) tert- Butyl 7-[l-(3-[4-(tert-butoxycarbonyl)phenyl]methoxy}propyl)-4-methyl- lH-benzotriazol-5-yl](hydroxy)methyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate To a mixture of tert- butyl 4-[3-(5-formyl-4-methyl-lH-benzotriazol-l- yl)propoxy]methyl} benzoate (330 mg), potassium phosphate (513 mg), tert-butyl 7- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,4-dihydro- 1H-isoquinoline-2- carboxylate (2 g), CPME (20 ml) and water (4 ml), chloro(l,5- cyclooctadiene)rhodium (I) dimer (80 mg) was added at room temperature. The mixture was stirred at 110°C for 1 hour under argon atmosphere. To the mixture thus obtained, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (260 mg). 'H NMR (300 MHz, CDC13) d 1.47 (9H, s), 1.57-1.63 (9H, m), 2.20-2.41 (2H, m), 2.60 (1H, br d, J = 2.0 Hz), 2.70-2.89 (5H, m), 3.29-3.51 (2H, m), 3.62 (2H, br t, J = 5.7 Hz), 4.40-4.57 (4H, m), 4.73 (2H, t, J = 6.6 Hz), 6.23 (1H, d, J = 3.2 Hz), 7.04- 7.18 (3H, m), 7.27-7.37 (3H, m), 7.64 (1H, d, J = 8.7 Hz), 7.89 (2H, d, J = 8.3 Hz).

Reference： [1]Current Patent Assignee: INNOVATION NETWORK CORPORATION OF JAPAN - WO2020/116660, 2020, A1 Location in patent: Paragraph 0157; 0181

43
[ 937048-76-5 ]
tert-butyl 4-[[3-[5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]-2,6-dimethylbenzoate [ No CAS ]
tert-butyl 7-[[1-[3-[[4-[[tert-butoxy]carbonyl]-3,5-dimethylphenyl] methoxy] propyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl] [hydroxy] methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
500 mg	With potassium phosphate; chloro(1,5-cyclooctadiene)rhodium(I) dimer In water at 25 - 50℃; for 2h;	58.H H) tert- butyl 7-[[l-[3-[[4-[[tert-butoxy]carbonyl]-3,5- dimethy lphenyl] methoxy] propyl] -4-methyl- 1H-1,2,3 -benzotriazol-5 - yl] [hydroxy] methyl]- 1,2,3,4-tetrahydroisoquinoline-2-carboxylate H) tert- butyl 7-[[l-[3-[[4-[[tert-butoxy]carbonyl]-3,5- dimethy lphenyl] methoxy] propyl] -4-methyl- 1H-1,2,3 -benzotriazol-5 - yl] [hydroxy] methyl]- 1,2,3,4-tetrahydroisoquinoline-2-carboxylate To a degassed solution of tert- butyl 4-[[3-[5-formyl-4-methyl-lH-l,2,3-benzotriazol- l-yl]ProPoxy]methyl]-2,6-dimethylbenzoate (700 mg) in mixture of CPME (45 ml) and water (9 ml) was added tert- butyl 7-[tetramethyl-l,3,2-dioxaborolan-2-yl]- l,2,3,4-tetrahydroisoquinoline-2-carboxylate (1.725 g), followed by K3PO4 (1.02 g) and [R Cl(COD)]2 (158 mg) at 25 °C. The reaction mixture was heated at 50°C for 2h. The reaction mixture was cooled to 25°C and quenched with sat NH4CI. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude thus obtained was purified by silica gel column chromatography (S1O2, 12g, 25% EtOAc/Hexane) to give title compound (500 mg) as light yellow sticky solid. MS m/z 671.1 [M+H] +.

Reference： [1]Current Patent Assignee: INNOVATION NETWORK CORPORATION OF JAPAN - WO2020/116660, 2020, A1 Location in patent: Paragraph 0184

44
[ 937048-76-5 ]
tert-butyl 2,6-dichloro-4-[[3-[5-formyl-4-methyl-1H-1,2,3-benzotriazol-1-yl]propoxy]methyl]benzoate [ No CAS ]
tert-butyl 7-({1-[3-({4-[(tert-butoxy)carbonyl]-3,5-dichlorophenyl}methoxy)propyl]-4-methyl-1H-1,2,3-benzotriazol-5-yl}(hydroxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
800 mg	With potassium phosphate In water at 25 - 50℃; for 2h;	60.I I) tert- butyl 7-[[l-(3-[[3,5-dichloro-4-[methoxycarbonyl] phenyl] methoxy]propyl]- 4-methyl-l H-l,2,3-benzotriazol-5-yl] [hydroxy]methyl]-l, 2,3,4- tetrahydroisoquinoline-2-carboxylate To a degassed solution of tert- butyl 2,6-dichloro-4-[[3-[5-formyl-4-methyl-lH- l,2,3-benzotriazol-l-yl]propoxy]methyl]benzoate (1.2 g) in mixture of CPME (50 ml) and water (10 ml) were added tert- butyl 7-[tetramethyl-l,3,2-dioxaborolan-2-yl]- l,2,3,4-tetrahydroisoquinoline-2-carboxylate (2.7 g) followed by K3PO4 (1.6 g) at 25°C. To this was added [RhCl(COD)]2 (627 mg) at 25°C and reaction mixture was heated at 50°C for 2h. TLC and LC/MS of reaction mixture showed formation of desired product along with un-reacted starting material. The reaction mixture was cooled to 25°C and quenched with sat. aq. NH4CI. The aqueous layer was extracted with EtOAc, combined organics were washed with water, brine, dried over anhydrous Na2SC>4, filtered and filtrate was concentrated under reduced pressure. The crude thus obtained was purified by silica gel column chromatography (S1O2, 12g, 25% EtO Ac/Hexane) to give title compound (800 mg) as yellow solid. 'H NMR (400 MHz, DMSO-de): d 1.40 (9H, s), 1.55 (9H, s), 2.18 (2H, t, J = 5.8 Hz), 2.69-2.74 (5H, m), 3.42-3.50 (4H, m), 4.36-4.42 (4H, m), 4.74 (2H, t, J = 6.1Hz), 5.86 (1H, d, J = 3.4 Hz), 6.03 (1H, d, J = 3.7 Hz), 7.04-7.13 (3H, m), 7.41 (2H, s), 7.59 (2H, s). MS m/z 711.2 [M+H] +.

Reference： [1]Current Patent Assignee: INNOVATION NETWORK CORPORATION OF JAPAN - WO2020/116660, 2020, A1 Location in patent: Paragraph 0186

45
[ 937048-76-5 ]
tert-butyl 4-[5-[5-formyl-4-methyl-1H-benzo[d][1,2,3]triazol-1-yl]pentyl]benzoate [ No CAS ]
tert-butyl 7-[[1-[5-[4-[tert-butoxycarbonyl]phenyl]pentyl]-4-methyl-1H-benzo[d] [1,2,3]triazol-5-yl] [hydroxy]methyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.25 g	With potassium phosphate; chloro(1,5-cyclooctadiene)rhodium(I) dimer In water at 20℃; for 16h; Inert atmosphere;	62.C C) tert- butyl 7-[[l-[5-[4-[r/-butoxycarbonyl]phenyl]pentyl]-4-methyl-1H- benzo [d] [1,2,3]triazol-5-yl] [hydroxyjmethyl] -3,4-dihydroisoquinoline-2(17/)- carboxylate To a solution of tert-butyl 4-[5-[5-formyl-4-methyl-1H-benzo[d][l,2,3]triazol-l- yl]pentyl]benzoate (0.50 g) and tripotassium phosphate (0.78 g) in CPME (30 mL) and water (6 ml), 7-[4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl]-3,4- dihydroisoquinoline-2(lH)-carboxylate (1.30 g) and chloro[l,5- cyclooctadiene]rhodium(I) dimer (0.21 g) were added, under argon atmosphere and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was diluted with sat. NH4CI aq. and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous Na2SC>4, filtered and solvents evaporated from the filtrate under reduced pressure. The crude obtained was purified by flash chromatography, using 12 g Redisep silica gel cartridge, on a silica gel chromatography instrument, eluted with 20-70% gradient of ethyl acetate in hexanes, to obtain title compound (0.25 g) as an off white solid. 'H NMR (400 MHz, DMSO-de) 61.04-1.13 (2H, m), 1.47 (9H, s), 1.58-1.74 (1 1H, m), 1.74-1.84 (2H, m), 2.00-2.04 (2H, m), 2.59-2.62 (2H, m), 2.80 (3H, s), 2.46-2.53 (2H, m), 2.80 (2H, brs), 3.62-3.66 (2H, m), 4.52 (1H, s), 4.59-4.61 (1H, m), 6.25 (1H, s), 7.04-7.12 (4H, m), 7.26 (1H, s), 7.65 (1H, d, J = 8.2 Hz), 7.81 (2H, d, J = 7.9 Hz). MS m/z 641.46 [M+H+].

Reference： [1]Current Patent Assignee: INNOVATION NETWORK CORPORATION OF JAPAN - WO2020/116660, 2020, A1 Location in patent: Paragraph 0188

46
[ 937048-76-5 ]
[ 1190058-21-9 ]

Yield	Reaction Conditions	Operation in experiment
760 mg	With sodium periodate; ammonium acetate In water; acetone at 25℃; for 16h;	67.C C) {2-[(tert-butoxy)carbonyl]-l,2,3,4-tetrahydroisoquinolin-7-yl}boronic acid To a stirred solution of tert- butyl 7-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4- tetrahydroisoquinoline-2-carboxylate (2.00 g) in acetone (40 mL) was added NaI04 (3.57 g) followed by ammonium acetate (1.0 M in water, 27.8 mL) at 25°C and reaction mixture was stirred at 25 °C for 16 h. After completion of reaction (as jugged by TLC), solvent was evaporated. Residue was diluted with water. The aqueous layer was extracted with EtOAc, combined organics were washed with brine; dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude thus obtained was purified by silica gel column chromatography (S1O2, 12 g, 50% EtO Ac/Hexane) to give title compound (760 mg) as white solid. H NMR (400 MHz, DMSO-d6): d 1.42 (9H, s), 2.75-2.78 (2H, m), 3.52-3.55 (2H, m), 4.48-4.54 (2H, m), 7.10-7.16 (1H, m), 7.54-7.67 (2H, m), 7.94 (2H, s).

Reference： [1]Current Patent Assignee: INNOVATION NETWORK CORPORATION OF JAPAN - WO2020/116660, 2020, A1 Location in patent: Paragraph 0193

47
[ 937048-76-5 ]
ethyl (2E)-3-[1-(but-2-en-1-yl)-4-methyl-1H-benzotriazol-5-yl]prop-2-enoate [ No CAS ]
tert-butyl 7-{l-[l-(but-2-en-1-yl)-4-methyl-1H-benzotriazol-5-yl]-3-ethoxy-3-oxopropyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4.27 g	With chloro(1,5-cyclooctadiene)rhodium(I) dimer; sodium dodecyl-sulfate; triethylamine In water at 20 - 90℃; for 4h; Inert atmosphere;	9.F F) tert-Butyl 7-{l-[l-(but-2-en-l-yl)-4-methyl-lH-benzotriazol-5-yl]-3-ethoxy-3- oxopropyl}-3,4-dihydroisoquinoline-2(lH)-carboxylate (E/Z isomer mixture) To a mixture of ethyl (2E)-3-[l-(but-2-en-l-yl)-4-methyl-lH-benzotriazol-5- yl]prop-2-enoate (E/Z isomer mixture) (3.1 g), tert-butyl 7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,4-dihydro-lH-isoquinoline-2-carboxylate (5.85 g), sodium dodecyl sulfate (1.57 g), and triethylamine (4.54 ml) in CPME (50 ml) and water (25 ml), chloro(l,5-cyclooctadiene)rhodium (I) dimer (536 mg) was added at room temperature. The mixture was stirred at 90°C for 4 hours under nitrogen atmosphere. Water was added to the mixture thus obtained, and the mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.27 g). NMK (300 MHZ, DMSO-de) d 1.01 (3H, br t, J = 7.0 Hz), 1.41 (9H, s), 1.59-1.88 (3H, m), 2.68 (2H, br t, J = 5.7 Hz), 2.77 (3H, s), 3.16 (2H, br d, J = 7.6 Hz), 3.49 (2H, br t, J = 5.4 Hz), 3.93 (2H, q, J = 7.0 Hz), 4.43 (2H, br s), 4.82 (1H, br t, J = 7.8 Hz), 5.14-5.41 (2H, m), 5.50-5.93 (2H, m), 6.96-7.24 (3H, m), 7.53 (2H, q, J = 8.5 Hz). MS m/z 519.4 [M+H]+.

Reference： [1]Current Patent Assignee: INNOVATION NETWORK CORPORATION OF JAPAN - WO2020/116660, 2020, A1 Location in patent: Paragraph 0126

48
[ 937048-76-5 ]
tert-butyl 4-[(3-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4-methyl-1H-benzotriazol-1-yl}propoxy)methyl] benzoate [ No CAS ]
tert-butyl 7-{1-[1-(3-[4-(tert-butoxycarbonyl)phenyl]methoxy}propyl)-4-methyl-1H-benzotriazol-5-yl]-3-ethoxy-3-oxopropyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10.2 g	With chloro(1,5-cyclooctadiene)rhodium(I) dimer; sodium dodecyl-sulfate; triethylamine In water at 20 - 100℃; for 3h; Inert atmosphere;	16.F [0141] F) tert- Butyl 7-{l-[l -(3-[4-(tert-butoxycarbonyl)phenyl]methoxy}propyl)-4- methyl- 1H-benzotriazol-5-yl] -3 -ethoxy-3 -oxopropyl} -3,4-dihydroisoquinoline- 2(1H)-carboxylate To a mixture of tert- butyl 4-[(3-{5-[(lE)-3-ethoxy-3-oxoprop-l-en-l-yl]-4- methyl-lH-benzotriazol-l-yl}propoxy)methyl]benzoate (6.88 g), tert-butyX 7- (4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,4-dihydro- 1H-isoquinoline-2- carboxylate (15.5 g), sodium dodecyl sulfate (2.07 g), triethylamine (6 ml), CPME (200 ml) and water (100 ml), chloro(l,5-cyclooctadiene)rhodium (I) dimer (707 mg) was added at room temperature. The mixture was stirred at 100°C for 3 hours under argon atmosphere. To the mixture thus obtained, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.2 g). NMR (300 MHz, DMSO-d6) d 1.00 (3H, t, J = 7.0 Hz), 1.40 (9H, s), 1.54 (9H, s), 2.06-2.32 (2H, m), 2.63-2.72 (2H, m), 2.77 (3H, s), 3.06-3.20 (2H, m), 3.37-3.55 (4H, m), 3.92 (2H, q, J = 7.0 Hz), 4.36-4.50 (4H, m), 4.73 (2H, br t, J = 6.3 Hz), 4.76-5.00 (1H, m), 6.99-7.20 (3H, m), 7.33 (2H, br d, J = 7.7 Hz), 7.42-7.65 (2H, m), 7.83 (2H, d, J = 7.7 Hz). MS m/z 713.4 [M+H]+.

Reference： [1]Current Patent Assignee: INNOVATION NETWORK CORPORATION OF JAPAN - WO2020/116660, 2020, A1 Location in patent: Paragraph 0141

49
[ 35654-56-9 ]
[ 937048-76-5 ]
tert-butyl 7-(6,7-dimethoxy-4-quinolyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.1 g	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium acetate In 1,4-dioxane; water at 110℃; for 12h; Inert atmosphere;	S-9.1 Step 1: Synthesis of tert-butyl 7-(6,7-dimethoxyquinazolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A mixture of 4-chloro-6,7-dimethoxyquinoline (1.1 g, 4.6 mmol), tert-butyl 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (2.0 g, 5.6 mmol), KOAc (0.91 g, 9.3 mmol), Pd(PPh3)4 (0.27 g, 0.23 mmol), dioxane (10 mL), and H2O (2 mL) was degassed and purged with N2 and then stirred at 110 °C for 12 hours under a N2 atmosphere. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mLx2). The combined extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated, and purified by silica chromatography (Petroleum ether/EtOAc, 9-100%) to provide tert-butyl 7-(6,7-dimethoxy-4-quinolyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.1 g).

Reference： [1]Current Patent Assignee: VOLASTRA THERAPEUTICS - WO2021/225969, 2021, A1 Location in patent: Paragraph 0283-0284

50
[ 937048-76-5 ]
6-bromo-N,N,5-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine [ No CAS ]
tert-butyl 7-(7-(dimethylamino)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100 mg	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium carbonate; tri tert-butylphosphoniumtetrafluoroborate In 1,2-dimethoxyethane; water at 85℃; for 12h;	S-011.1 Step 1: Synthesis of tert-butyl 7-(7-(dimethylamino)-5-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate To a degassed mixture of 6-bromo-N,N,5-trimethyl-[1,2,4]triazolo[1,5- a]pyrimidin-7-amine (500 mg, 2.0 mmol), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.8 g, 2.9 mmol), Na2CO3(620 mg, 5.9 mmol), DME (10 mL), and H2O (2.500 mL) were added Pd2(dba)3 (89 mg, 0.098 mmol) and tri-tert-butylphosphine HBF4(57 mg, 0.20 mmol) and the mixture was stirred for 12 h at 85 °C. The reaction mixture was cooled, diluted with H2O and CH2Cl2and the layers were separated. The aqueous layer was extracted with CH2Cl2. The combined extracts were concentrated and purified by flash column chromatography (0-10% MeOH in CH2Cl2) to obtain 100 mg of tert-butyl 7-(7-(dimethylamino)-5-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.
100 mg	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium carbonate; tri tert-butylphosphoniumtetrafluoroborate In 1,2-dimethoxyethane; water at 85℃; for 12h;	S-011.1 Step 1: Synthesis of tert-butyl 7-(7-(dimethylamino)-5-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate To a degassed mixture of 6-bromo-N,N,5-trimethyl-[1,2,4]triazolo[1,5- a]pyrimidin-7-amine (500 mg, 2.0 mmol), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.8 g, 2.9 mmol), Na2CO3(620 mg, 5.9 mmol), DME (10 mL), and H2O (2.500 mL) were added Pd2(dba)3 (89 mg, 0.098 mmol) and tri-tert-butylphosphine HBF4(57 mg, 0.20 mmol) and the mixture was stirred for 12 h at 85 °C. The reaction mixture was cooled, diluted with H2O and CH2Cl2and the layers were separated. The aqueous layer was extracted with CH2Cl2. The combined extracts were concentrated and purified by flash column chromatography (0-10% MeOH in CH2Cl2) to obtain 100 mg of tert-butyl 7-(7-(dimethylamino)-5-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.
100 mg	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium carbonate; tri tert-butylphosphoniumtetrafluoroborate In 1,2-dimethoxyethane; water at 85℃; for 12h;	S-011.1 Step 1: Synthesis of tert-butyl 7-(7-(dimethylamino)-5-methyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate To a degassed mixture of 6-bromo-N,N,5-trimethyl-[1,2,4]triazolo[1,5- a]pyrimidin-7-amine (500 mg, 2.0 mmol), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.8 g, 2.9 mmol), Na2CO3(620 mg, 5.9 mmol), DME (10 mL), and H2O (2.500 mL) were added Pd2(dba)3 (89 mg, 0.098 mmol) and tri-tert-butylphosphine HBF4(57 mg, 0.20 mmol) and the mixture was stirred for 12 h at 85 °C. The reaction mixture was cooled, diluted with H2O and CH2Cl2and the layers were separated. The aqueous layer was extracted with CH2Cl2. The combined extracts were concentrated and purified by flash column chromatography (0-10% MeOH in CH2Cl2) to obtain 100 mg of tert-butyl 7-(7-(dimethylamino)-5-methyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

Reference： [1]Current Patent Assignee: VOLASTRA THERAPEUTICS - WO2021/257614, 2021, A1 Location in patent: Paragraph 0258-0259
[2]Current Patent Assignee: VOLASTRA THERAPEUTICS - WO2021/257614, 2021, A1 Location in patent: Paragraph 0258-0259
[3]Current Patent Assignee: VOLASTRA THERAPEUTICS - WO2021/257614, 2021, A1 Location in patent: Paragraph 0258-0259

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	937048-76-5	MDL No. :	MFCD11044674
Formula :	C₂₀H₃₀BNO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UPDWDCOAUJYOTG-UHFFFAOYSA-N
M.W :	359.27	Pubchem ID :	53302321
Synonyms :

Num. heavy atoms :	26
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.65
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	108.1
TPSA :	48.0 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.91 cm/s

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	3.63
Log Po/w (WLOGP) :	2.75
Log Po/w (MLOGP) :	2.29
Log Po/w (SILICOS-IT) :	2.52
Consensus Log Po/w :	2.24

[ CAS No. 937048-76-5 ] {[proInfo.proName]}

Quality Control of [ 937048-76-5 ]

Related Doc. of [ 937048-76-5 ]

Product Details of [ 937048-76-5 ]

Calculated chemistry of [ 937048-76-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 937048-76-5 ]

Application In Synthesis of [ 937048-76-5 ]

[ 937048-76-5 ] Synthesis Path-Downstream 1~50

Related Functional Groups of
[ 937048-76-5 ]

Organoboron

Amides

Esters

Related Parent Nucleus of
[ 937048-76-5 ]

Tetrahydroisoquinolines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-4.26
Solubility :	0.0197 mg/ml ; 0.0000548 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.33
Solubility :	0.017 mg/ml ; 0.0000472 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.02
Solubility :	0.00346 mg/ml ; 0.00000964 mol/l
Class :	Moderately soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	3.46

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
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P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
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P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
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P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
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P307	IF exposed:
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P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
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P315	Get immediate medical advice/attention.
P320
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P321
P322
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P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 937048-76-5 ] {[proInfo.proName]}

Quality Control of [ 937048-76-5 ]

Related Doc. of [ 937048-76-5 ]

Product Details of [ 937048-76-5 ]

Calculated chemistry of [ 937048-76-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 937048-76-5 ]

Application In Synthesis of [ 937048-76-5 ]

[ 937048-76-5 ] Synthesis Path-Downstream 1~50

Related Functional Groups of [ 937048-76-5 ]

Organoboron

Amides

Esters

Related Parent Nucleus of [ 937048-76-5 ]

Tetrahydroisoquinolines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 937048-76-5 ]

Related Parent Nucleus of
[ 937048-76-5 ]