Name: 1245816-10-7|(5-Methyl-1H-indazol-4-yl)boronic acid|97%
Brand: Ambeed
SKU: A332586
Price: 5.0 USD
Availability: InStock
Rating: 90 (28 reviews)

1
[ 1421067-10-8 ]
[ 1245816-10-7 ]
[ 1421253-66-8 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 140℃; for 1.5h;Microwave irradiation;	Example 3131-A. 6-Benzyl-4-methoxy-2-(5-methyl-lH-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidine.A mixture of 6-benzyl-2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.09 g, 3.75 mmol), (5-methyl-lH-indazol-4-yl)boronic acid (600 mg, 3.41 mmol), Pd(PPh3)4 (197 mg, 0.170 mmol), and Na2C03 (2 M, 5.97 mL, 11.9 mmol) in DME (11 mL) was heated in a microwave reactor at 140 C for 1.5 h. The reaction mixture was partitioned between EtO Ac and water. The aqueous layer was extracted with EtO Ac. The combined organics were washed with brine, dried (Na2S04), and concentrated. The residue was purified by silica gel chromatography (20-100% EtO Ac/heptane) to provide 6-benzyl-4- methoxy-2-(5-methyl-lH-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 386.2 (M+H)+.

Reference： [1]Patent: WO2013/16197,2013,A1 .Location in patent: Page/Page column 186

2
[ 1245816-10-7 ]
[ 1421253-95-3 ]
[ 1421251-36-6 ]

Yield	Reaction Conditions	Operation in experiment
2.23 g	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 130℃; for 1h;Inert atmosphere; Microwave irradiation;	41-D. 6-(5-Isopropyl-2-methylphenyl)-4-methyl-2-(5-methyl-lH-indazol-4-yl)-5,6,7,8-tetrahydro- 1,6-naphthyridine.A mixture of 2-chloro-6-(5-isopropyl-2-methylphenyl)-4-rnethyl-5,6,7,8-tetrahydro-l ,6-naphthyridine (2.50 g, 7.94 mmol), 5 -methyl- lH-indazol-4-ylboronic acid (1.817 g, 10.32 mmol), Pd(PPh3)4 (0.918 g, 0.794 mmol) and K3P04 (3.37 g, 15.88 mmol) in 1,4-dioxane (30 mL) and H20 (3 mL) was heated at 130 C for 1 h under nitrogen in a microwave reactor. The mixture was concentrated and diluted with EtOAc and brine. The products were extracted twice with EtOAc. The combined organic layer was dried over Na2S04, filtered, and concentrated. The residue was purified twice by flash column chromatography on 120 g of silica gel (with 25 g of silica gel pre-column; eluent: heptane/EtOAc = 75:25 to 30:70) to give a yellow solid. The yellow solid was suspended with 25 g of aminopropyl-modified silica gel in DCM, and the suspension was concentrated. The residue was loaded on 55 g of NH-silica gel and purified by flash column chromatography (eluent: heptane/EtOAc = 75:25 to 25:75) to give the desired product (2.50 g). The product was triturated in CH3CN/H20, collected on a funnel and dried under reduced pressure to give 6-(5-isopropyl-2-methylphenyl)-4-methyl-2-(5-methyl-lH-indazol-4-yl)-5,6,7,8-tetrahydro-l,6- naphthyridine (2.23 g) as a white solid: lU NMR (400 MHz, CDC13) delta ppm 10.03 (br s, 1 H), 7.90 (d, J = 0.67 Hz, 1 H), 7.40 (dd, J = 0.67, 8.50 Hz, 1 H), 7.32 (d, J = 8.50 Hz, 1 H), 7.19 (d, J = 7.75 Hz, 1 H), 7.16 (s, 1 H), 7.08 (d, J = 1.60 Hz, 1 H), 6.94 - 6.97 (dd, J = 1.60, 7.75 Hz, 1 H), 4.14 (s, 2 H), 3.38 (br t, J = 5.68 Hz, 2 H), 3.26 (br t, J = 5.69 Hz, 2 H), 2.87 - 2.98 (m, 1 H), 2.44 (s, 3 H), 2.37 (s, 3 H), 2.31 (s, 3 H), 1.29 (d, J = 6.82 Hz, 6 H); MS (ESI+) m/z 411.33 (M+H)+.

Reference： [1]Patent: WO2013/16197,2013,A1 .Location in patent: Page/Page column 218-219

3
[ 1245816-10-7 ]
[ 1421254-05-8 ]
[ 1421251-52-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 130℃; for 1h;Inert atmosphere; Microwave irradiation;	Example 4343-A. . 6-(5-Isopropyl-2-methylphenyl)-4-methyl-2-(5-methyl-lH-indazol-4- yl)-5,6,7,8-tetrahydro(5,5-2H2)-l,6-naphthyridine.A solution of 2-Chloro-4-methyl-5,6,7,8-tetrahydro-l,6-naphthyridine hydrochloride (3.10 g, 12.7 mmol), Boc20 (3.06 g, 14.0 mmol) and DIPEA (3.34 mL, 19.1 mmol) in DCM (30 mL) was allowed to stir at rt for 45 min. The mixture was diluted with 5% aqueous citric acid and DCM. The organic layer was separated in a separatory funnel, and concentrated. The residue was purified by flash columnchromatography on 80 g of silica gel (with 25g silica gel pre-column; eluent: heptane/EtOAc = 100:0 to 50:50) to give tert-butyl 2-chloro-4-methyl-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate. ¾ NMR (400 MHz, CDCI3) delta ppm 7.02 (s, 1 H), 4.47 (s, 2 H), 3.71 (t, J= 5.81 Hz, 2 H), 2.95 (br t, J= 5.68 Hz, 2 H), 2.23 (s, 3 H), 1.50 (s, 9 H); MS (ESI+) m/z 283.30 (M+H)+.To a suspension of ruthenium trichloride (0.141 g, 0.681 mmol) and NaI04 (8.32 g, 38.9 mmol) in H20 (30 mL) at 0 C, a solution of tert-butyl 2-chloro-4-methyl-7,8-dihydro-l,6-naphthyridine-6(5H)- carboxylate (2.75 g, 9.73 mmol) in EtOAc (30 mL) was added. After stirring for 5 min., the reaction mixture was warmed up to rt and stirred. After stirring for 21.5 h, the mixture was diluted with EtOAc and brine. The organic layer was separated, dried over Na2S04, filtered, and concentrated. The crude was purified by flash column chromatography on 80 g of silica gel (with 25g pre-column of silica gel; eluent: heptane/EtOAc = 100:0 to 70:30) to give tert-butyl 2-chloro-4-methyl-5-oxo-7,8-dihydro-l,6- naphthyridine-6(5H)-carboxylate (2.10 g) as a white solid: lU NMR (400 MHz, CDC13) delta ppm 7.15 (s, 1 H), 3.98 (t, J= 6.32 Hz, 2 H), 3.13 (t, J= 6.32 Hz, 2 H), 2.70 (s, 3 H), 1.58 (s, 9 H).A solution of tert-butyl 2-chloro-4-methyl-5-oxo-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate (2.08 g, 7.01 mmol) and borane-i 3-THF complex solution (21.0 mL, 21.0 mmol) was allowed to stir at 60 C for 17 h under nitrogen. The reaction mixture was cooled to rt, and quenched with MeOH (2 mL). The mixture was diluted with saturated aqueous NH4C1, brine and EtOAc. The products were extracted twice with EtOAc. The combined organic layer was washed with brine, dried over MgS04, filtered, and concentrated to give tert-but l 2-chloro-4-methyl-5,6,7,8-tetrahydro(5,5-2H2)-l,6-naphthyridine-6- carboxylate along with an impurity as colorless oil (94% deuterium incorporation). The obtained material was used without further purification: MS (ESI+) m/z 285.30 (M+H)+.To a solution of give tert-butyl 2-chloro-4-methyl-5,6,7,8-tetrahydro(5,5-2H2)-l,6-naphthyridine-6- carboxylate (1.59 g, 5.58 mmol) in EtOAc (8 mL), 4 M HC1 in 1,4-dioxane (6.98 mL, 27.9 mmol) was added and a white solid precipitated. After stirring for 1 h, additional 4 M HC1 in 1,4-dioxane (6.98 mL, 27.9 mmol) was added. After stirring for further 1 h, MeOH (10 mL) was added to the reaction mixture, followed by the addition of EtOAc (400 mL). The precipitated solid was collected on a funnel, washed with EtOAc (100 mL), and dried under reduced pressure to give the desired product as a hydrochloride salt (1.29 g). The solid was neutralized with 2 M Na2C03aq (10 mL) in DCM (10 mL). The mixture was allowed to stir for 1 h. The mixture was diluted with brine and DCM. The organic layer was separated and concentrated to give 2-chloro-4-methyl-5,6,7,8-tetrahydro(5,5-2H2)-l,6-naphthyridine (93%D): ¾ NMR (400 MHz, CDC13) delta ppm 6.96 (s, 1 H), 3.17 (t, J= 5.94 Hz, 2 H), 2.91 (t, J= 5.94 Hz, 2 H), 2.17 (s, 3 H).A suspension of 2-chloro-4-methyl-5,6,7,8-tetrahydro(5,5-2H2)-l,6-naphthyridine (0.92 g, 4.98 mmol), 5- isopropyl-2-methylphenyl trifluoromethanesulfonate (4.22 g, 14.95 mmol), Pd2(dba)3.CHCl3 adduct (0.206 g, 0.199 mmol), rac-BINAP (0.248 g, 0.399 mmol) and Cs2C03 (4.87 g, 14.95 mmol) in toluene (4 mL) and teri-Butanol (0.7 mL) was allowed to stir at 90 C for 17 h under nitrogen. The reaction mixture was cooled to rt and diluted with EtOAc and brine. The products were extracted three times with EtOAc. The organic layer was dried over Na2S04, and filtered. The residue was purified by flash column chromatography on 80 g of silica gel (with 15 g pre -column of silica gel; eluent: heptane/EtOAc = 100:0 to 80:20), followed by flash column chromatography on 20 g of NH-modified silica gel (with 15 g pre- column of NH-modified silica gel; eluent: heptane/EtOAc = 100:0 to 90:10) to give 2-chloro-6-(5- isopropyl-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydro(5,5-2H2)-l,6-naphthyridine (94%D) as a pale orange solid: lU NMR (400 MHz, CDC13) delta ppm 7.16 (d, J = 7.83 Hz, 1 H), 6.99 - 7.00 (m, 2 H), 6.92 - 6.95 (m, 1 H), 3.28 (t, J= 5.81 Hz, 2 H), 3.12 (t, J= 5.81 Hz, 2 H), 2.84 - 2.94 (m, 1 H), 2.29 (s, 3 H), 2.20 (s, 3 H), 1.26 (d, J= 6.82 Hz, 6 H); MS (ESI+) m/z 317.40 (M+H)+.A mixture of 2-chloro-6-(5-isopropyl-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydro(5,5-2H2)-l,6- naphthyridine (120 mg, 0.379 mmol), 5 -met...

Reference： [1]Patent: WO2013/16197,2013,A1 .Location in patent: Page/Page column 225-227

4
[ 1245816-10-7 ]
tert-butyl 4-(6-chloro-7-(5-methyl-1H-indazol-4-yl)cinnolin-4-yl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/54572,2015,A1

5
[ 1245816-10-7 ]
1-(4-(6-chloro-7-(5-methyl-1H-indazol-4-yl)cinnolin-4-yl)piperazin-1-yl)prop-2-en-1-one [ No CAS ]

Reference： [1]Patent: WO2015/54572,2015,A1

6
[ 76-09-5 ]
[ 1245816-10-7 ]
methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With magnesium sulfate; In tetrahydrofuran; at 45℃; for 3h;	Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole To a solution of <strong>[1245816-10-7]5-methyl-1H-indazol-4-yl-4-boronic acid</strong> (300 mg, 1.7 mmol) in THF (20 mL), pinacol (249 mg, 2.1 mmol) and MgSO4 (614 mg, 5.1 mmol) were added, and the resulting mixture was stirred at 45 oC for 3 h. The mixture was filtered and rinsed with brine, dried over Na2SO4 and concentrated in vacuo to afford the desired product (330 mg, 75% yield).

Reference： [1]Patent: WO2015/54572,2015,A1 .Location in patent: Page/Page column 250

7
[ 1245816-10-7 ]
1-(4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one [ No CAS ]
1-(4-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26.6%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 0.25h;Microwave irradiation;	1-(4-(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one A mixture of 1 -(4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazin- 1-yl)prop-2-en-1-one (30 mg, 0.075 mmol), <strong>[1245816-10-7](5-methyl-1H-indazol-4-yl)boronic acid</strong> (20 mg, 0.113 mmol) and Tetrakis (43 mg, 0.038 mmol) in co-solvent of 1,4-dioxane (3 mL) and 1 M Na2CO3 (0.5 mL) was heated in microwave reactor at 120 oC for 15 min. The mixture was partitioned between DCM and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified via Isolear One (MeOH/DCM = 0 - 10%) followed by prep-TLC (MeOH/DCM = 10%) to afford the desired product (9 mg, 26.6% yield). 1H NMR (500 MHz, CDCl3) delta: 8.86 (s, 1H), 9.08 (s, 1H), 7.90 (s, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 6.62 (dd, J = 10.5, 17 Hz, 1H), 6.40 (dd, J = 1.5, 17 Hz, 1H), 5.80 (dd, J = 1.5, 10.5 Hz, 1H), 3.78-4.02 (m, 8H), 2.25 (s, 3H). ESI-MS m/z: 451.1 [M+H]+.

Reference： [1]Patent: WO2015/54572,2015,A1 .Location in patent: Page/Page column 260; 261

8
[ 1086111-09-2 ]
[ 1245816-10-7 ]
4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]
tert-butyl 4-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(thiazol-5-yl)quinazolin-4-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%		tert-Butyl 4-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(thiazol-5- yl)quinazolin-4-yl)piperazine-1-carboxylate 5-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1,3-thiazole (67 mg, 1.1 eq.) and tetrakis (158 mg, 0.5 eq.) were added into tert-butyl 4-(7-bromo-2,6-dichloro- 8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (133 mg, 1.0 eq.) in dioxane (6 mL) and aqueous Na2CO3 (1 M, 3 mL) in the sealed tube. The reaction mixture was stirred at 120 oC in the Microwave Reactor for 15 min. After cooling down, into this mixture (5- methyl-1H-indazol-4-yl)boronic acid (267 mg, 5.1 eq.), tetrakis (164 mg, 0,5 eq.), 4 mL of dioxane, and 2 mL of aqueous Na2CO3 (1M) were added. The resulting mixture was stirred at 120 oC in the Microwave Reactor for 45 min. After cooling down, it was filtered and partitioned between EtOAc and water. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane / methanol = 10 : 1) to afford the desired product (88 mg, 55% yield) as a solid. ESI-MS m/z: 580 [M + H]+.

Reference： [1]Patent: WO2015/54572,2015,A1 .Location in patent: Page/Page column 296; 297

9
[ 1245816-10-7 ]
4-bromo-Ν-α-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(2H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
Ν-α-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-4-(5-methyl-1H-indazol-4 yl)-N-[4-(2H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110℃; for 1.5h;Microwave irradiation;	4-bromo-Nu-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(2H-tetrazol-5-yl)phenyl]-L-phenylalaninamide (150 mg, 0.24 mmol) and (5-methyl-1H-indazol-4-yl)boronicacid (63 mg, 0.36 mmol) was dissolved in dimethyl sulfoxide Sa (1.8 ml) at and with tetrakis (triphenylphosphine)palladium (0) ( 28 mg, 24 micromolar), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol) blend. The reaction mixture in a microwave at 110 C (Biotage Initiator) was stirred for 90 minutes, cooled, and filtered by chromatography were purified (Method 10) via HPLC. 20 mg (13% of the theoretical value) of this compound to produce the subject.

Reference： [1]Patent: TW2016/5809,2016,A .Location in patent: Page/Page column 62

10
[ 1245816-10-7 ]
3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyhyl}cyclohexyl)carbonyl]-3-(5-methyl-1H-indazol-4-yl)-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110℃; for 1.5h;Microwave irradiation;	Example 119A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyhyl}cyclohexyl)carbonyl]-3-(5-methyl-1H-indazol-4-yl)-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide (150 mg, 0.24 mmol) and <strong>[1245816-10-7](5-methyl-1H-indazol-4-yl)boronic acid</strong> (63 mg, 0.36 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 mumol), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 90 min, cooled, filtered and purified by chromatography via HPLC (Method 9). This gave 39 mg (24% of theory) of the title compound. LC-MS (Method 4): Rt=1.18 min; MS (ESIpos): m/z=678.4 [M+H]+.

Reference： [1]Patent: US2016/244437,2016,A1 .Location in patent: Paragraph 1141; 1142; 1143

11
[ 1245816-10-7 ]
3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]-L-phenylalaninamide [ No CAS ]
N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-(5-methyl-1H-indazol-4-yl)-N-[4-(5-oxo-4, 5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]-L-phenylalaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110℃; for 2.5h;Microwave irradiation;	Example 123A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-(5-methyl-1H-indazol-4-yl)-N-[4-(5-oxo-4, 5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]-L-phenylalaninamide (150 mg, 0.24 mmol) and <strong>[1245816-10-7](5-methyl-1H-indazol-4-yl)boronic acid</strong> (62 mg, 0.35 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (27 mg, 23 mumol), sodium carbonate (74 mg, 0.70 mmol) and water (0.35 ml, 19.5 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 150 min, cooled, filtered and purified by chromatography via HPLC (Method 10). This gave 47 mg (29% of theory) of the title compound. LC-MS (Method 4): Rt=1.19 min; MS (ESIpos): m/z=694.4 [M+H]+.

Reference： [1]Patent: US2016/244437,2016,A1 .Location in patent: Paragraph 1154; 1155; 1156

12
[ 1245816-10-7 ]
tert-butyl 4-(7-bromo-6-chloro-2-((1-cyclopropylpiperidin-4-yl)amino)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate [ No CAS ]
tert-butyl 4-(6-chloro-2-((1-cyclopropylpiperidin-4-yl)amino)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,3-dioxane; water; for 16h;Reflux;	tert-Butyl 4-(7-bromo-6-chloro-2-((1-cyclopropylpiperidin-4-yl)amino)- 8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (6 g, 10.28 mmol), (5-methyl-1H- indazol-4-yl)boronic acid (5.4 g, 30.83 mmol), Na2CO3 (3.3 g, 30.83 mmol), Pd(PPh3)4 (1.2 g, 1.03 mmol) were suspended in a mixture of dioxane (160 mL) and water (40 mL). The resulting mixture was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature, poured into water, and then extracted with ethyl acetate (150 mL x2). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM:MeOH = 100:1 to 20:1) to afford the desired product (3.8 g, 54% yield).

Reference： [1]Patent: WO2016/164675,2016,A1 .Location in patent: Page/Page column 235-236

13
[ 1245816-10-7 ]
tert-butyl 4-(7-bromo-6-chloroimidazo[1,2-a]pyridin-3-yl)piperazine-1-carboxylate [ No CAS ]
tert-butyl 4-(6-chloro-7-(5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22.1%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 85℃; for 15h;Inert atmosphere;	To a mixture of compound 2-2 (500.00 mg, 721.66 mumol, 1.00 eq) in dioxane (16.00 mL) and H2O (4.00 mL) was added <strong>[1245816-10-7](5-methyl-1H-indazol-4-yl)boronic acid</strong> (634.99 mg, 3.61 mmol, 5.00 eq), Pd(PPh3)4 (416.96 mg, 360.83 mumol, 0.50 eq) and Na2CO3 (382.44 mg, 3.61 mmol, 5.00 eq). The mixture was degassed and purged with N2. Then the resulting mixture was stirred at 85C for 15 hours. The reaction mixture was concentrated to remove 1,4-dioxane and water. Ethyl acetate (50 mL) was added and the organic layer was washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel prep- TLC (petroleum ether/ethyl acetate = 1:2) to afford compound 2-3 (82.00 mg, 22.1% yield) as a yellow solid. LC/MS (M+H+) m/z: calcd.467.19, found 467.1.1H NMR (400 MHz, CDCl3, delta): 8.22 (s, 1H), 7.63 (s, 1H), 7.52 - 7.46 (m, 2H), 7.40 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 5.31 (s, 1H), 3.69 (bs, 4H), 3.09 (t, J = 4.9 Hz, 4H), 2.26 (s, 3H), 1.52 (s, 9H).

Reference： [1]Patent: WO2017/58915,2017,A1 .Location in patent: Page/Page column 95

14
[ 1245816-10-7 ]
1-benzyl-7'-bromo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-2'-one [ No CAS ]
1-benzyl-7'-(5-methyl-1H-indazol-4-yl)-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-2'-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.2 g	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 80℃; for 16h;	To a stirred solution of l-benzyl-7'-bromo-l', 4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]- 2'-one pyridine (0.300 g, 0.801 mmol) and 5 -methyl- lh-indazol-4-ylboronic acid (CAS Number 1245816-10-7; 0.214 g, 1.216 mmol) in l,4-dioxane:water (4: 1, 12 ml) was added Cs2C03(0.528 g, 1.624 mmol) at rt. The reaction mixture was degassed for 15 min before addition of Pd(PPh3)4(0.046 g, 0.039 mmol) at rt. The reaction mixture was heated at 80C for 16 h. The resulting mixture was cooled to rt, diluted with water (20 ml) and extracted with EtOAc (5 x 50 ml). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (40-80 % EtOAc in n-hexane) yielding l-benzyl-7'-(5-methyl- lH-indazol-4-yl)-r,4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-2'-one (0.200 g, 0.473 mmol). LCMS: Method 1, 1.783 min, MS: ES+ 423.52.

Reference： [1]Patent: WO2017/149313,2017,A1 .Location in patent: Page/Page column 68; 69

15
[ 1245816-10-7 ]
tert-butyl 3-(6-bromo-7-fluoro-1-oxoisoindolin-2-yl)azetidine-1-carboxylate [ No CAS ]
tert-butyl 3-(7-fluoro-6-(5-methyl-1H-indazol-4-yl)-1-oxoisoindolin-2-yl)azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere;	tert-Butyl 3-(6-bromo-7-fluoro-1-oxoisoindolin-2-yl)azetidine-1- carboxylate (500 mg, 1.29 mmol), <strong>[1245816-10-7](5-methyl-1H-indazol-4-yl)boronic acid</strong> (456 mg, 2.6 mmol), sodium carbonate (410 mg, 3.87 mmol), Pd(PPh3)4 (300 mg, 0.26 mmol) were suspended in a mixture of dioxane (20 mL) and water (5 mL). The reaction was stirred at 100 C under an atmosphere of argon for 16 hours. The mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (dichloromethane / methanol = 30:1) to afford the desired product (240 mg, 19% yield). ESI-MS m/z: 437.2 [M+H]+.

Reference： [1]Patent: WO2018/68017,2018,A1 .Location in patent: Page/Page column 135; 136; 137

16
[ 1245816-10-7 ]
tert-butyl-3-(5-bromoisoindolin-2-yl)azetidine-1-carboxylate [ No CAS ]
tert-butyl 3-(5-(5-methyl-1H-indazol-4-yl)isoindolin-2-yl)azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere;	A mixture of tert-butyl-3-(5-bromoisoindolin-2-yl)azetidine-1- carboxylate (800 mg, 2.26 mmol), <strong>[1245816-10-7]5-methyl-1H-indazol-4-yl-4-boronic acid</strong> (1 g, 5.2 mmol), sodium carbonate (718 mg, 6.78 mmol), Pd(PPh3)4 (261 mg, 0.226 mmol) in water (5 mL) and dioxane (20 mL) was stirred at 90 C under an atmosphere of nitrogen for 16 hours. The mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether = 1:10 to 1:1) to afford the desired product (520 mg, 72% yield). ESI-MS m/z: 404.2 [M+H]+.

Reference： [1]Patent: WO2018/68017,2018,A1 .Location in patent: Page/Page column 139; 140

17
[ 1245816-10-7 ]
tert-butyl 3-(6-bromo-5-chloro-1-oxoisoindolin-2-yl)azetidine-1-carboxylate [ No CAS ]
tert-butyl 3-(5-chloro-6-(5-methyl-1H-indazol-4-yl)-1-oxoisoindolin-2-yl)azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.6%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃;	To a mixture of tert-butyl 3-(6-bromo-5-chloro-1-oxoisoindolin-2- yl)azetidine-1-carboxylate (130 mg, 0.32 mmol) in dioxane / water (10 mL / 3 mL), sodium carbonate (101.76 mg, 0.96 mmol), Pd(PPh3)4 (36.96 mg, 0.36 mmol) and (5- methyl-1H-indazol-4-yl)boronic acid (63.36 mg, 0.36 mmol) were added and stirred at reflux overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether = 1:1) to afford the desired product (100 mg, 85.6% yield). ESI-MS m/z: 396.9 [M+H]+.

Reference： [1]Patent: WO2018/68017,2018,A1 .Location in patent: Page/Page column 146; 148

18
[ 1245816-10-7 ]
tert-butyl 4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate [ No CAS ]
tert-butyl 4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;	Step 3: tert-butyl 4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate (115 mg, 0.205 mmol), 4-borono-5-methyl-1h-indazole (0.144 mL, 0.819 mmol, Ark Pharm Inc., Arlington Heights, Ill., USA), Sphos Pd G3 (0.016 mL, 0.020 mmol), and sodium carbonate (2 M aqueous, 0.409 mL, 0.819 mmol) were mixed in 1,2-dimethoxyethane (1 mL) under an argon atmosphere in a sealed vial. The reaction mixture was stirred at 100 C. for 24 h. The reaction mixture was cooled to rt and diluted with EtOAc (50 mL) and water (40 mL). The organic layer was separated, washed with brine (40 mL), dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 50% (3:1 EtOAc/EtOH) in heptane) gave tert-butyl 4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate. m/z (ESI) M+H: 613.2.
	With (2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1 ?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) methanesulfonate; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 24h;Inert atmosphere; Sealed tube;	tert-Butyl 4-(7-bromo-6- chloro- 1 -(2-isopropylphenyl)-2-oxo- 1 ,2-dihydroquinazolin-4-yl)piperazine- 1 -carboxylate (115 mg, 0.205 mmol), 4-borono-5-methyl-lh-indazole (0.144 mL, 0.819 mmol, Ark Pharm Inc., Arlington Heights, IL, USA), Sphos Pd G3 (0.0 16 mL, 0.020 mmol), and sodium carbonate (2 M aqueous, 0.409 mL, 0.819 mmol) were mixed in 1,2-dimethoxyethane (1 mL) under an argon atmosphere in a sealed vial. The reaction mixture was stirred at 100 C for 24h. The reaction mixture was cooled to rt and diluted with EtOAc (50 mL) and water (40 mL). The organic layer was separated, washed with brine (40 mL), dried over Mg504, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 50% (3:1 EtOAc/EtOH) in heptane) gave tert-butyl 4-(6-chloro-1-(2-isopropylphenyl)-7- (5-methyl-i H-indazol-4-yl)-2-oxo- 1 ,2-dihydroquinazolin-4-yl)piperazine- 1 -carboxylate. m/z (ESI) M+H: 613.2.
	With (2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1 ?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) methanesulfonate; sodium carbonate; In water; 1,2-dichloro-ethane; at 100℃; for 24h;Inert atmosphere; Sealed tube;	Step 3: tert-butyl 4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate tert-Butyl 4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate (115 mg, 0.205 mmol), 4-borono-5-methyl-1h-indazole (0.144 mL, 0.819 mmol, Ark Pharm Inc., Arlington Heights, Ill., USA), Sphos Pd G3 (0.016 mL, 0.020 mmol), and sodium carbonate (2 M aqueous, 0.409 mL, 0.819 mmol) were mixed in 1,2-dimethoxyethane (1 mL) under an argon atmosphere in a sealed vial. The reaction mixture was stirred at 100 C. for 24 h. The reaction mixture was cooled to rt and diluted with EtOAc (50 mL) and water (40 mL). The organic layer was separated, washed with brine (40 mL), dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 50% (3:1 EtOAc/EtOH) in heptane) gave tert-butyl 4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate. m/z (ESI) M+H: 613.2.

Reference： [1]Patent: US2018/177767,2018,A1
[2]Patent: WO2018/119183,2018,A2 .Location in patent: Paragraph 0246
[3]Patent: US2018/334454,2018,A1 .Location in patent: Paragraph 0448

19
[ 1245816-10-7 ]
(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one [ No CAS ]
6-chloro-1-(3-cyclopropyl-4-pyridinyl)-7-(5-methyl-1H-indazol-4-yl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1 ?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) methanesulfonate; potassium carbonate; In 1,4-dioxane; water; at 100℃;	General procedure: A mixture of (S)-4-(4- acryloyl-2-methylpiperazin- 1 -yl)-7-bromo-6-chloro- 1 -(2-isopropylphenyl)quinazolin-2( 1H)- one (120 mg, 0.226 mmol), 2-(2,3 -dichloro-5 -methoxyphenyl)-4,4,5 ,5-tetramethyl- 1,3,2- dioxaborolane (82 mg, 0.272 mmol), Na2CO3 (96 mg, 0.906 mmol), and Pd(PPh3)4 (26.2 mg, 0.023 mmol) in 1,4-dioxane (1.6 mL) and water (0.4 mL) was heated at 90C for 17 h. The reaction mixture was then concentrated in vacuo and chromatographically purified (silica gel, 0-100% (3:1) EtOAc-EtOH in heptane) to provide (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-chloro-7-(2,3 -dichloro-5-methoxyphenyl)- 1 -(2-isopropylphenyl)quinazolin-2( 1H)-one: m/z (ESI, +ve) 627.0 (M+H)t

Reference： [1]Patent: WO2018/119183,2018,A2 .Location in patent: Paragraph 0233; 0234

20
[ 1245816-10-7 ]
(S)-tert-butyl 10-bromo-11-chloro-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]
(13aS)-tert-butyl 11-chloro-10-(5-methyl-1H-indazol-4-yl)-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere; Microwave irradiation;	Pd(PPh3)4 (0.3 g, 0.26 mmol) was added to 2-methyl-2-propanyl (8aS)-5-bromo-6-chloro-8a,9,ll,12- tetrahydropyrazino[2',l':3,4] [l,4]oxazepino[5,6,7-c/e]quinazoline-10(8H)-carboxylate (1.18 g, 2.58 mmol) and (5-methyl-l/-/-indazol-4-yl)boronic acid (0.68 g, 3.87 mmol) in a degassed mixture of 2M Na2CC>3 (3 ml) and dioxane (12 ml). The resulting suspension was stirred at 100C for 15 hours in a microwave reactor. The mixture was diluted with DCM (150 ml), and washed with water (20 ml), then brine (20 ml). The organic phase was dried with MgS04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 2-methyl-2-propanyl (8aS)-6- chloro-5-(5-methyl-lH-indazol-4-yl)-8a,9,ll,12-tetrahydropyrazino[2',l':3,4] [l,4]oxazepino[5,6,7- de]quinazoline-10(8H)-carboxylate (1.04 g, 80%) as a white solid. 1H NM R (500 MHz, DMSO, 27C) 1.44 (9H, s), 2.13 (3H, d), 3.16 (2H, s), 3.24 (1H, td), 3.93 (1H, d), 3.99 - 4.18 (2H, m), 4.58 - 4.76 (2H, m), 4.82 (1H, d), 7.31 - 7.34 (2H, m), 7.47 (1H, dt), 7.52 (1H, d), 8.56 (1H, d), 13.10 (1H, s). m/z: ES+ [M+H]+ 507.

Reference： [1]Patent: WO2018/206539,2018,A1 .Location in patent: Page/Page column 66-67

21
[ 1245816-10-7 ]
(S)-tert-butyl 10-bromo-11-chloro-7-morpholino-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]
(13aS)-tert-butyl 11-chloro-10-(5-methyl-1H-indazol-4-yl)-7-morpholino-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium carbonate; In 1,4-dioxane; at 90 - 100℃; for 17h;	Pd-118 (20 mg, 0.03 mmol) was added to a degassed mixture of iert-butyl (S)-5-bromo-6-chloro-2- morpholino-8a,9,ll,12-tetrahydropyrazino[2',l':3,4] [l,4]oxazepino[5,6,7-c/e]quinazoline-10(8H)- carboxylate (153 mg, 0.28 mmol), (5-methyl-l/-/-indazol-4-yl)boronic acid (75 mg, 0.43 mmol) and 2N sodium carbonate (0.5 ml, 1 mmol) in 1,4-dioxane (4 ml). The reaction mixture was heated to 100C for 1 h then at 90C for 16 h then allowed to cool. The reaction mixture was diluted with ethyl acetate (50 ml) and the organic layer was washed with aqueous saturated sodium bicarbonate solution (25 ml), water (25 ml) and brine (25 ml) then dried over MgS04, filtered and concentrated. The residue was purified by flash silica chromatography, elution gradient 0 to 3% 2N methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford iert-butyl (8aS)-6-chloro-5-(5-methyl-l/-/-indazol-4-yl)- 2-morpholino-8a,9,ll,12-tetrahydropyrazino[2',l':3,4] [l,4]oxazepino[5,6,7-c/e]quinazoline-10(8H)- carboxylate (140 mg, 84%) as a pale yellow solid. 1H NM (400 MHz, DMSO) 1.46 (s, 9H), 2.15 (d, J = 1.5 Hz, 3H), 2.98 - 3.25 (m, 3H), 3.58 - 3.7 (m, 4H), 3.7 - 3.82 (m, 4H), 3.87 - 4.17 (m, 3H), 4.46 - 4.77 (m, 3H), 6.93 (s, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.43 - 7.6 (m, 2H), 13.06 (s, 1H). m/z: ES+ [M+H]+ 592 / 594.

Reference： [1]Patent: WO2018/206539,2018,A1 .Location in patent: Page/Page column 116-117

22
[ 1245816-10-7 ]
(S)-tert-butyl 10-bromo-11-chloro-7-((1-cyclopropylpiperidin-4-yl)amino)-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]
(13aS)-tert-butyl 11-chloro-7-((1-cyclopropylpiperidin-4-yl)amino)-10-(5-methyl-1H-indazol-4-yl)-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.1%	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium carbonate; In 1,4-dioxane; at 100℃; for 18h;	Pd-118 (25.6 mg, 0.04 mmol) was added to a degassed mixture of tert-butyl (5)-10-bromo-ll-chloro-7- ((l-cyclopropylpiperidin-4-yl)amino)-3,4,13,13a-tetrahydropyrazino-[2',l':3,4] [l,4]oxazepino[5,6,7- c/e]quinazoline-2(l/-/)-carboxylate (216 mg, 0.36 mmol), (5-methyl-l/-/-indazol-4-yl)boronic acid (128 mg, 0.73 mmol) and 2N sodium carbonate (1 ml, 2 mmol) in 1,4-dioxane (6 ml). The reaction mixture was heated at 100C for 18 hours then allowed to cool. The reaction mixture was diluted with ethyl acetate (50 ml) and the organic layer was washed with aqueous 2M sodium carbonate solution (2 x 25 ml), water (25 ml) and brine (25 ml) then dried over MgS04, filtered and concentrated. The residue was purified by flash silica chromatography, elution gradient 0 to 4% 2N methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford iert-butyl (8aS)-6-chloro-2-((l-cyclopropylpiperidin-4- yl)amino)-5-(5-methyl-lH-indazol-4-yl)-8a,9,ll,12-tetrahydropyrazino[2',l':3,4] [l,4]oxazepino[5,6,7- c/e]quinazoline-10(8H)-carboxylate (80 mg, 34.1 %) as a pale brown solid. 1H NMR (400 M Hz, DMSO) 0.19 - 0.38 (m, 2H), 0.41 (d, J = 4.9 Hz, 2H), 1.47 (s, 10H), 1.59 (s, 1H), 1.84 (d, J = 10.4 Hz, 2H), 2.16 (d, J = 2.8 Hz, 5H), 2.92 (d, J = 10.7 Hz, 2H), 3.14 (d, J = 31.6 Hz, 3H), 3.68 - 4.18 (m, 4H), 4.43 - 4.84 (m, 3H), 6.79 (d, J = 53.4 Hz, 2H), 7.32 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 2H), 13.06 (s, 1H). m/z: ES+ [M+H]+ 645 / 646.

Reference： [1]Patent: WO2018/206539,2018,A1 .Location in patent: Page/Page column 121-122

23
[ 1245816-10-7 ]
(S)-tert-butyl 10-bromo-11-chloro-7-(3-(dimethylamino)azetidin-1-yl)-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]
(13aS)-tert-butyl 11-chloro-7-(3-(dimethylamino)azetidin-1-yl)-10-(5-methyl-1H-indazol-4-yl)-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium carbonate; In 1,4-dioxane; at 100℃; for 17h;	Pd-118 (30 mg, 0.05 mmol) was added to a degassed mixture of iert-butyl (5)-10-bromo-ll-chloro-7- (3-(dimethylamino)azetidin-l-yl)-3,4,13,13a-tetrahydropyrazino[2',l':3,4]-[l,4]oxazepino [5,6,7- c/e]quinazoline-2(l/-/)-carboxylate (230 mg, 0.42 mmol), (5-methyl-l/-/-indazol-4-yl)boronic acid (150 mg, 0.85 mmol) and 2N sodium carbonate (1.14 ml, 2.28 mmol) in 1,4-dioxane (8 ml). The reaction mixture was heated at 100C for 17 hours then allowed to cool. The reaction mixture was diluted with ethyl acetate (100 ml) and the organic layer was washed with aqueous 2M sodium carbonate solution (2 x 50 ml) and brine (50 ml) then dried over MgS04, filtered and concentrated. The residue was purified by flash silica chromatography, elution gradient 0 to 5% 2N methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford te/t-butyl (8aS)-6-chloro-2-(3-(dimethylamino)azetidin-l-yl)-5-(5- methyl-lH-indazol-4-yl)-8a,9,ll,12-tetrahydropyrazino[2',l':3,4] [l,4]oxazepino [5,6,7-c/e]quinazoline- 10(8H)-carboxylate (208 mg, 83%) as a pale brown solid. 1H NM (400 M Hz, DMSO) 1.45 (s, 9H), 2.1 - 2.17 (m, 9H), 3.04 - 3.2 (m, 4H), 3.8 - 3.89 (m, 2H), 3.93 (d, J = 11.2 Hz, 2H), 3.99 - 4.14 (m, 3H), 4.52 - 4.64 (m, 2H), 4.71 (d, J = 11.8 Hz, 1H), 6.91 (s, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.44 - 7.53 (m, 2H), 13.05 (s, 1H). m/z: ES+ [M+H]+ 605 / 607.

Reference： [1]Patent: WO2018/206539,2018,A1 .Location in patent: Page/Page column 125-126

24
[ 1245816-10-7 ]
(S)-tert-butyl 10-bromo-11-chloro-7-((2-(dimethylamino)ethyl)amino)-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]
(13aS)-tert-butyl 11-chloro-7-((2-(dimethylamino)ethyl)amino)-10-(5-methyl-1H-indazol-4-yl)-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium carbonate; In 1,4-dioxane; at 100℃; for 25.4h;	Pd-118 (45.5 mg, 0.07 mmol) was added to a degassed mixture of te/t-butyl (S)-5-bromo-6-chloro-2- ((2-(dimethylamino)ethyl)amino)-8a,9,ll,12-tetrahydropyrazino[2',l':3,4]-[l,4]oxazepino[5,6,7- c/e]quinazoline-10(8H)-carboxylate (350 mg, 0.65 mmol), (5-methyl-l/-/-indazol-4-yl)boronic acid (227 mg, 1.29 mmol) and 2N sodium carbonate (1.78 ml, 3.55 mmol) in 1,4-dioxane (11 ml). The reaction mixture was heated at 100C for 18 hours then further added Pd-118 (20 mg) and boronic acid (80 mg) were added and stirred at 100C for a further 7.5 hours, then allowed to cool. The reaction mixture was diluted with ethyl acetate (100 ml) and the organic layer was washed with aqueous 2M sodium carbonate solution (2 x 50 ml), water (50 ml) and brine (50 ml) then dried over MgS04, filtered and concentrated. The residue was purified by flash silica chromatography, elution gradient 0 to 10% 2N methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford te/t-butyl (8aS)-6- chloro-2-((2-(dimethylamino)ethyl)am (1076) tetrahydropyrazino [2',l':3,4] [l,4]oxazepino[5,6,7-c/e]quinazoline-10(8/-/)-carboxylate (209 mg, 55%) as a pale brown solid. 1H NM (400 MHz, DMSO) 1.46 (s, 9H), 2.15 (d, J = 3.0 Hz, 3H), 2.19 (s, 6H), 2.44 (t, J = 6.8 Hz, 2H), 3.11 (s, 3H), 3.40 (q, J = 6.3 Hz, 2H), 3.93 (d, J = 11.5 Hz, 2H), 4.04 (d, J = 12.2 Hz, 1H), 4.46 - 4.63 (m, 2H), 4.66 (s, 1H), 6.61 (s, 1H), 6.86 (s, 1H), 7.31 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 7.8 Hz, 2H), 13.06 (s, 1H). m/z: ES+ [M+H]+ 593 / 595.

Reference： [1]Patent: WO2018/206539,2018,A1 .Location in patent: Page/Page column 130-131

25
[ 1245816-10-7 ]
(R)-tert-butyl 10-bromo-11-chloro-3,4,14,14a-tetrahydro-1H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazoline-2(13H)-carboxylate [ No CAS ]
(14aR)-11-chloro-10-(5-methyl-1H-indazol-4-yl)-2,3,4,13,14,14a-hexahydro-1H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		Pd-118 (30 mg, 0.05 mmol) was added to a degassed mixture of te/t-butyl (6a ?)-2-bromo-3-chloro- 5,6,6a,7,9,10-hexahydro-8/-/-pyrazino[l',2':5,6] [l,5]oxazocino[4,3,2-c/e]quinazoline-8-carboxylate (225 mg, 0.48 mmol), (5-methyl-l/-/-indazol-4-yl)boronic acid (136 mg, 0.77 mmol), acetonitrile (4 ml) and 2M aq. K2CO3. The reaction mixture was heated at 100C for 1 hour in a microwave reactor and cooled to room temperature. The mixture was extracted with EtOAc and the organic phase was concentrated in vacuo. The residue was re-dissolved in MeOH (2 ml) and methanesulfonic acid (0.1 ml, 1.54 mmol) was added. The mixture was stirred at reflux for 60 min. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1M NHs/MeOH and pure fractions were evaporated to dryness to afford the crude amine as a mixture of 2 diasteroisomers. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 column, 30 x 100 mm id, 5 micron particle size), using decreasingly polar mixtures of water (containing 0.3% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (6a ?)-3-chloro-2-(5-methyl-lH-indazol-4-yl)-6,6a,7,8,9,10-hexahydro-5H- pyrazino[l',2':5,6] [l,5]oxazocino-[4,3,2-de]quinazoline (80 mg, 40%). m/z: ES+ [M+H]+ 421.

Reference： [1]Patent: WO2018/206539,2018,A1 .Location in patent: Page/Page column 134-135

26
[ 1245816-10-7 ]
(S)-tert-butyl 10-bromo-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]
(S)-tert-butyl 10-(5-methyl-1H-indazol-4-yl)-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere; Microwave irradiation;	Pd(PPh3)4 (102 mg, 0.09 mmol) was added to iert-butyl (8aS)-5-bromo-8a,9,ll,12- tetrahydropyrazino[2',l':3,4] [l,4]oxazepino[5,6,7-c/e]quinazoline-10(8/-/)-carboxylate (373 mg, 0.89 mmol), (5-methyl-l/-/-indazol-4-yl)boronic acid (203 mg, 1.15 mmol) in a degassed mixture of 2M Na2CC>3 (3 ml) and dioxane (12 ml). The resulting suspension was stirred at 100C for 16 hours in microwave. The mixture was diluted with DCM (150 ml), and washed with water (20 ml), then brine (20 ml). The organic phases was dried with MgS04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford iert-butyl (8aS)-5-(5-methyl-l/-/-indazol-4- yl)-8a,9,ll,12-tetrahydropyrazino[2',l':3,4] [l,4]oxazepino[5,6,7-c/e]quinazoline-10(8H)-carboxylate (395 mg, 94%) as a yellow foam. IH NMR (500 M Hz, CDCI3, 27C) 1.52 (9H, s), 2.37 (3H, s), 2.98 - 3.29 (3H, m), 3.82 - 3.98 (IH, m), 4 - 4.31 (2H, m), 4.41 (IH, dd), 4.51 (IH, dd), 4.95 - 5.15 (IH, m), 7.11 (IH, d), 7.3 - 7.35 (IH, m), 7.43 (IH, dd), 7.60 (IH, d), 7.80 (IH, d), 8.65 (IH, s), 10.44 (IH, s). m/z: ES+ [M+H]+ 473

Reference： [1]Patent: WO2018/206539,2018,A1 .Location in patent: Page/Page column 71

27
[ 1245816-10-7 ]
(R)-tert-butyl 10-bromo-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]
(R)-tert-butyl 10-(5-methyl-1H-indazol-4-yl)-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere; Microwave irradiation;	Pd(PPh3)4 (70.2 mg, 0.06 mmol) was added to te/t-butyl (8a ?)-5-bromo-8a,9, ll,12- tetrahydropyrazino [2',l':3,4] [l,4]oxazepino[5,6,7-c/e]quinazoline-10(8/-/)-carboxylate (256 mg, 0.61 mmol) and (5-methyl-l/-/-indazol-4-yl)boronic acid (160 mg, 0.91 mmol) in a degassed mixture of 2M Na2CC>3 (3 ml) and dioxane (12 ml). The resulting suspension was stirred at 100C for 16 hours in a microwave. The reaction mixture was diluted with DCM (150 ml), and washed with water (20 ml), then brine (20 ml). The organic phase was dried with MgS04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM . Pure fractions were evaporated to dryness to afford te/t-butyl (8a ?)-5-(5-methyl-l/-/- indazol-4-yl)-8a,9, ll, 12-tetrahydropyrazino[2',l':3,4] [l,4]oxazepino[5,6,7-c/e]quinazoline-10(8H)- carboxylate (307 mg, >100%) as a yellow foam. IH NM R (500 M Hz, CDCI3, 27C) 1.52 (9H, s), 2.37 (3H, s), 2.99 - 3.31 (3H, m), 3.81 - 3.95 (IH, m), 4.12 (2H, bs), 4.41 (IH, dd), 4.51 (IH, dd), 5.09 (IH, bd), 7.11 (IH, d), 7.31 - 7.35 (IH, m), 7.43 (IH, dd), 7.61 (IH, d), 7.80 (IH, d), 8.65 (IH, s), 10.50 (IH, s). m/z: ES+ [M+H]+ 473

Reference： [1]Patent: WO2018/206539,2018,A1 .Location in patent: Page/Page column 74-75

28
[ 1245816-10-7 ]
(R)-tert-butyl 10-bromo-11-chloro-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]
(13aR)-tert-butyl 11-chloro-10-(5-methyl-1H-indazol-4-yl)-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 100℃; for 18h;Microwave irradiation; Inert atmosphere;	Pd(PPh3)4 (66 mg, 0.06 mmol) was added to te/t-butyl (8a ?)-5-bromo-6-chloro-8a,9,ll,12- tetrahydropyrazino[2',l':3,4] [l,4]oxazepino[5,6,7-c/e]quinazoline-10(8/-/)-carboxylate (260 mg, 0.57 mmol) and (5-methyl-l/-/-indazol-4-yl)boronic acid (151 mg, 0.86 mmol) in a degassed mixture of 2M Na2CC>3 (3 ml) and dioxane (12 ml). The resulting suspension was stirred at 100C for 16 hours in a microwave. The mixture was diluted with DCM (150 ml), and washed with water (20 ml), then brine (20 ml). The organic phase was dried with MgS04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford te/t-butyl (8a ?)-6-chloro-5-(5-methyl-l/-/-indazol- 4-yl)-8a,9,ll,12-tetrahydropyrazino[2',l':3,4] [l,4]oxazepino[5,6,7-c/e]quinazoline-10(8H)-carboxylate (186 mg, 64%) as a yellow foam, m/z: ES+ [M+H]+ 507.

Reference： [1]Patent: WO2018/206539,2018,A1 .Location in patent: Page/Page column 78

29
[ 1245816-10-7 ]
(S)-tert-butyl 10-bromo-9-chloro-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]
(13aS)-tert-butyl 9-chloro-10-(5-methyl-1H-indazol-4-yl)-3,4,13,13a-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 100℃; for 18h;Microwave irradiation; Inert atmosphere;	Pd(PPh3)4 (167 mg, 0.14 mmol) was added to te/t-butyl (8aS)-5-bromo-4-chloro-8a,9,ll,12- tetrahydropyrazino[2',l':3,4] [l,4]oxazepino[5,6,7-c/e]quinazoline-10(8/-/)-carboxylate (659 mg, 1.45 mmol) and (5-methyl-l/-/-indazol-4-yl)boronic acid (382 mg, 2.17 mmol) in a degassed mixture of 2M Na2CC>3 (3 ml) and dioxane (12 ml). The resulting suspension was stirred at 100C for 18 hours in a microwave. The mixture was diluted with DCM (150 ml), and washed with water (20 ml), then brine (20 ml). The organic phase was dried with MgS04, filtered and evaporated to afford crude product which was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions were evaporated to dryness to afford crude product. This crude product was purified by flash silica chromatography, elution gradient 0 to 5% 2N NHs/MeOH in DCM. Pure fractions were evaporated to dryness to afford te/t-butyl (8aS)-4-chloro-5-(5-methyl-lH-indazol-4-yl)-8a,9,ll,12- tetrahydropyrazino[2',l':3,4] [l,4]oxazepino[5,6,7-c/e]quinazoline-10(8H)-carboxylate (540 mg, 74%) as film. 1H NMR (500 MHz, DMSO, 27C) 1.39 - 1.45 (9H, m), 2.13 (3H, d), 3.22 - 3.3 (1H, m), 3.31 (2H, s), 3.93 (1H, d), 3.97 - 4.13 (2H, m), 4.43 - 4.64 (2H, m), 4.86 (1H, d), 6.97 (1H, s), 7.31 (1H, d), 7.47 (1H, d), 7.51 (1H, d), 8.65 (1H, s), 13.10 (1H, s). m/z: ES+ [M+H]+ 507.

Reference： [1]Patent: WO2018/206539,2018,A1 .Location in patent: Page/Page column 82

30
[ 1245816-10-7 ]
(2R,5S)-tert-butyl 4-(2-(1-cyclopropylpiperidin-4-ylamino)-7-bromo-6-chloro-8-fluoroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate [ No CAS ]
(2R,5S)-tert-butyl 4-(2-(1-cyclopropylpiperidin-4-ylamino)-6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water;Reflux;	To a solution of (2R,5S)-tert-butyl 4-(2-(l-cyclopropylpiperidin-4-ylamino)-7-bromo-6-chloro-8-fluoroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (3.7 g, 6.06 mmol), 5-methyl-1H-indazol-4-yl-4-boronicacid (5.33 g, 30.28 mmol) in dioxane/water (80 mL/20 mL), Pd(PPh3)4 (0.7 g, 0.61 mmol) and Na2C03 (1.93 g, 18.18 mmol) were added. The mixture was stirred at reflux overnight. The mixture was extracted with EA, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desire product (3.4 g, 84%). ESI-MS m/z: 662.39 [M+H]+.

Reference： [1]Patent: WO2018/218070,2018,A2 .Location in patent: Page/Page column 185; 186

31
[ 1245816-10-7 ]
tert-butyl (2R,5S)-4-(7-bromo-6-chloro-8-fluoro-2-(((R)-4-methylmorpholin-2-yl)methoxy)quinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate [ No CAS ]
tert-butyl (2R,5S)-4-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(((R)-4-methylmorpholin-2-yl)methoxy)quinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.7%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	To a solution of 11C (1.22 g, 2.02 mmol) in 1,4-dioxane/H20 (20 mL / 5mL) at RT, 5- methyl-1H-indazol-4-ylboronic acid (1.78 g, 10.12 mmol), Tetrakis(triphenylphosphine)palladium (233.3 mg, 0.20 mmol) and Na2C03 (1.07 g, 10.12 mmol) were added and the resulting mixture was at 100 C under argon overnight. The mixture was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product 11D (1.0 g, 75.7% yield). ESI-MS m/z: 654 [M+H]+.

Reference： [1]Patent: WO2018/218070,2018,A2 .Location in patent: Page/Page column 196-197; 198

32
[ 1245816-10-7 ]
(2R,5S)-tert-butyl 4-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate [ No CAS ]
tert-butyl (2R,5S)-4-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With dichloro[1,1?-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P?]palladium; sodium carbonate; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	The mixture of compound 2F (500 mg, 0.87 mmol), (5-methyl-lH-indazol-4-yl)boronic acid (184 mg, 1.04 mmol) and PdCl2(dtBPf) (60 mg, 0.09 mmol) in 5 mL of 1,4- dioxane and 3 mL of 1 M Na2C03 was stirred at 120 C in microwave reactor for 2 hours. The mixture was partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via Isolera One (10% methanol and 0.035% ammonia in dichloromethane) to afford the desired product 3A (487 mg, 90%). ESI-MS m/z: 623.3 [M+H]+. tert-Butyl (2R,5S)-4-(6-chloro-2-(3-(dimethylamino)azetidin-l-yl)-8-fluoro-7-(3- iodo-5-methyl-lH-indazol-4-yl)quinazolin-4-yl)-2,5-dimethylpiperazine-l- carboxylate (3B)

Reference： [1]Patent: WO2018/218070,2018,A2 .Location in patent: Page/Page column 176

33
[ 1245816-10-7 ]
tert-butyl (2R,5S)-4-(7-bromo-6-chloro-8-fluoro-2-(methylsulfonamido)quinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate [ No CAS ]
tert-butyl (2R,5S)-4-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(methylsulfonamido)quinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	To a stirred solution of tert-butyl compound 5-2 (410 mg, 0.72 mmol) and (5-methyl- 1H-indazol-4-yl)boronic acid (636 mg, 3.62 mmol) in 1,4-dioxane (16 mL) and H20 (4mL) under argon, were added Tetrakis(triphenylphosphine) palladium (83 mg, 0.072mmol) and Na2CO3 (384 mg,3.62 mmol) and the resulting mixture was stirred at 100 C overnight. The mixture was partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography to afford the product 5-3 (440 mg, 98%yield). ESI-MS m/z: 618.20 [M+H].

Reference： [1]Patent: WO2018/218069,2018,A1 .Location in patent: Page/Page column 91; 92

34
[ 1245816-10-7 ]
tert-butyl 4-(7-bromo-6-chloro-3-cyano-8-fluoroquinolin-4-yl)piperazine-1-carboxylate [ No CAS ]
tert-butyl 4-(6-chloro-3-cyano-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinolin-4-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	To a stirred solution of tert-butyl 4-(7-bromo-6-chloro-3-cyano-8-fluoroquinolin-4-yl) piperazine -1-carboxylate (1g, 2.12 mmol ) and <strong>[1245816-10-7](5-methyl-1H-indazol-4-yl)boronic acid</strong> (1.87 g, 10.6 mmol) in 1,4-dioxane (30 mL) and H2O (7 mL) were added Tetrakis(triphenylphosphine)palladium (245 mg, 0.212 mmol) and Na2CO3 (674 mg, 6.36 mmol). The mixture was degassed and backfilled with argon several cycles and then stirred at 100 oC overnight. H2O (30 mL) was added and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography to afford the product (930 mg, 84% yield). ESI-MS m/z: 520.98 [M+H]+.

Reference： [1]Patent: WO2018/218071,2018,A1 .Location in patent: Page/Page column 99; 101

35
[ 1245816-10-7 ]
tert-butyl (4aS)-10-bromo-11-chloro-6-(2-(dimethylamino)ethyl)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c]quinoline-3-carboxylate [ No CAS ]
tert-butyl (4aS)-11-chloro-6-[2-(dimethylamino)ethyl]-10-(5-methyl-1H-indazol-4-yl)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c]quinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 20 - 100℃; for 1h;Inert atmosphere;	Tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.06 mmol) was added to 212 tert-butyl (4aS)-10-bromo-11-chloro-6-(2-(dimethylamino)ethyl)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1?,2?:4,5]pyrazino[2,3-c]quinoline-3-carboxylate (300 mg, 0.57 mmol), 82 <strong>[1245816-10-7](5-methyl-1H-indazol-4-yl)boronic acid</strong> (101 mg, 0.57 mmol) and 67 K2CO3 (158 mg, 1.14 mmol) in 68 1,4-dioxane/135 H2O (15 mL, 4:1 ratio) at rt. The resulting suspension was stirred at 100 C. for 1 h. The solvent was removed in vacuo. The residue obtained was purified by C18-flash chromatography (0 to 100%, 142 MeCN in 42 water (0.1% HCOOH)) to afford crude product as an orange solid. This was purified by preparative chiral-HPLC (Column: Chiralpak ID-2, 2*25 cm, 5 m; Mobile Phase A: MTBE (0.1% DEA)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 17 mL/min; Gradient: 20 B to 20 B in 13 min; 220/254 nm) to afford atropisomer 823 1 of tert-butyl (4aS)-11-chloro-6-[2-(dimethylamino)ethyl]-10-(5-methyl-1H-indazol-4-yl)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1?,2?:4,5]pyrazino[2,3-c]quinoline-3-carboxylate (113 mg, 34%) as a yellow solid; 1H NMR (300 MHz, DMSO, 30 C.) 1.46 (9H, s), 2.18 (3H, s), 2.21 (6H, s), 2.39-2.50 (1H, m), 2.52-2.60 (1H, m), 2.69-2.93 (3H, m), 3.06-3.37 (2H, m), 3.38-3.56 (2H, m), 3.66 (1H, t), 3.75-4.09 (3H, m), 7.34 (1H, d), 7.46 (1H, s), 7.51 (1H, dd), 7.71 (1H, s), 8.04 (1H, s), 8.73 (1H, s), 13.11 (1H, s); m/z: ES+ [M+H]+=576. This was followed by atropisomer 2 of tert-butyl (4aS)-11-chloro-6-[2-(dimethylamino)ethyl]-10-(5-methyl-1H-indazol-4-yl)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1?,2?:4,5]pyrazino[2,3-c]quinoline-3-carboxylate (117 mg, 36%) as a yellow solid; 1H NMR (300 MHz, DMSO, 30 C.) 1.46 (9H, s), 2.16 (3H, s), 2.21 (6H, s), 2.37-2.50 (1H, m), 2.52-2.58 (1H, m), 2.71-2.89 (3H, m), 3.07-3.39 (2H, m), 3.39-3.56 (2H, m), 3.66 (1H, t), 3.77-3.89 (1H, m), 3.90-4.08 (2H, m), 7.34 (1H, d), 7.51 (2H, d), 7.71 (1H, s), 8.04 (1H, s), 8.72 (1H, s), 13.10 (1H, s); m/z: ES+ [M+H]+=576.

Reference： [1]Patent: US2019/177338,2019,A1 .Location in patent: Paragraph 0348; 0922-0923

36
[ 1245816-10-7 ]
tert-butyl (R)-10-bromo-11-chloro-1,2,4a,5-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c]quinoline-3(4H)-carboxylate [ No CAS ]
tert-butyl (4aR)-11-chloro-10-(5-methyl-1H-indazol-4-yl)-1,2,4a,5-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c]quinoline-3(4H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With trans-bis(triphenylphosphine)palladium dichloride; potassium carbonate; In 1,4-dioxane; water; at 105℃; for 8h;Inert atmosphere; Microwave irradiation;	Pd-100 (30.1 mg, 0.04 mmol) was added to a degassed mixture of 64 tert-butyl (R)-10-bromo-11-chloro-1,2,4a,5-tetrahydropyrazino[1?,2?:4,5][1,4]oxazino[2,3-c]quinoline-3(4H)-carboxylate (195 mg, 0.43 mmol), 82 <strong>[1245816-10-7](5-methyl-1H-indazol-4-yl)boronic acid</strong> (189 mg, 1.07 mmol) and 67 potassium carbonate (178 mg, 1.29 mmol) in 68 1,4-dioxane (4 ml) and 42 water (1.5 ml). The mixture was sealed in a microwave tube and heated at 105 C. for 8 hours then allowed to cool to room temperature. The reaction mixture was diluted with water (60 ml) and extracted with DCM (3×60 ml). The combined organic layers were washed with brine, dried and evaporated to give a crude residue. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% 57 EtOAc in 58 heptane. Pure fractions were evaporated to dryness to afford 83 tert-butyl (4aR)-11-chloro-10-(5-methyl-1H-indazol-4-yl)-1,2,4a,5-tetrahydropyrazino[1?,2?:4,5][1,4]oxazino[2,3-c]quinoline-3(4H)-carboxylate (213 mg, 98%) as a white solid. 1H NMR (500 MHz, DMSO, 27 C.) 1.44 (9H, s), 2.15 (3H, d), 3.27 (1H, s), 3.35 (1H, d), 3.52 (2H, d), 3.64 (1H, d), 3.80 (2H, d), 4.24 (1H, t), 4.38 (1H, dt), 7.35 (1H, dd), 7.42-7.55 (2H, m), 7.83 (1H, d), 8.14 (1H, s), 8.55 (1H, d), 13.09 (1H, s). m/z: ES+ [M+H]+ 506.

Reference： [1]Patent: US2019/177338,2019,A1 .Location in patent: Paragraph 0348; 0383-0384
[2]Journal of Medicinal Chemistry,2020,vol. 63,p. 4468 - 4483

37
[ 1245816-10-7 ]
tert-butyl (4aR)-10-chloro-11-[(trimethylsilyl)ethynyl]-1,2,4a,5-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c]quinoline-3(4H)-carboxylate [ No CAS ]
tert-butyl (4aR)-11-ethynyl-10-(5-methyl-1H-indazol-4-yl)-1,2,4a,5-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c]quinoline-3(4H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; In 1,4-dioxane; water; at 20 - 140℃; for 1h;Microwave irradiation; Inert atmosphere;	XPhos-Pd-G2 (41.7 mg, 0.05 mmol) was added to tert-butyl (4aR)-10-chloro-11-[(trimethylsilyl)ethynyl]-1,2,4a,5-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c]quinoline-3(4H)-carboxylate (250 mg, 0.53 mmol), <strong>[1245816-10-7](5-methyl-1H-indazol-4-yl)boronic acid</strong> (140 mg, 0.79 mmol) and K2CO3 (146 mg, 1.06 mmol) in 1,4-dioxane/water (15 mL, 4:1 ratio) at 20 C. and sealed into a microwave tube. The reaction was heated to 140 C. for 1 h in the microwave reactor and cooled to rt. The solvent was removed in vacuo to afford crude product. This was purified by flash silica chromatography (0 to 100% EtOAc in petroleum ether) to afford tert-butyl (4aR)-11-ethynyl-10-(5-methyl-1H-indazol-4-yl)-1,2,4a,5-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c]quinoline-3(4H)-carboxylate (130 mg, 50%) as a yellow solid; m/z: ES+ [M+H]+=496.

Reference： [1]Patent: US2019/177338,2019,A1 .Location in patent: Paragraph 0348; 0948-0949

38
[ 1245816-10-7 ]
tert-butyl (S)-10-bromo-11-chloro-1,2,4a,5-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c]quinoline-3(4H)-carboxylate [ No CAS ]
tert-butyl (4aS)-11-chloro-10-(5-methyl-1H-indazol-4-yl)-1,2,4a,5-tetrahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c]quinoline-3(4H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With trans-bis(triphenylphosphine)palladium dichloride; potassium carbonate; In 1,4-dioxane; water; at 105℃; for 8h;Microwave irradiation; Inert atmosphere;	Pd-100 (40 mg, 0.06 mmol) and Pd-118 (38 mg, 0.06 mmol) were added to a mixture of 94 tert-butyl (S)-10-bromo-11-chloro-1,2,4a,5-tetrahydropyrazino[1?,2?:4,5][1,4]oxazino[2,3-c]quinoline-3(4H)-carboxylate (130 mg, 0.29 mmol), 82 <strong>[1245816-10-7](5-methyl-1H-indazol-4-yl)boronic acid</strong> (276 mg, 1.55 mmol) and 67 potassium carbonate (240 mg, 1.72 mmol) in 68 1,4-dioxane (3 ml) and 42 water (1 ml). The mixture was sealed in a microwave tube and heated at 105 C. for a total of 8 hours then allowed to cool to room temperature. The reaction mixture was diluted with water (60 ml) and extracted with DCM (3×60 ml). The combined organic layers were washed with brine, dried and evaporated to give a crude residue. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% 57 EtOAc in 58 heptane. Pure fractions were evaporated to dryness to afford 96 tert-butyl (4aS)-11-chloro-10-(5-methyl-1H-indazol-4-yl)-1,2,4a,5-tetrahydropyrazino[1?,2?:4,5][1,4]oxazino[2,3-c]quinoline-3(4H)-carboxylate as a mixture of atropisomers (102 mg, 71%) as a white solid. 1H NMR (500 MHz, DMSO, 27 C.) 1.44 (9H, s), 2.15 (3H, d), 3.28 (1H, d), 3.37 (1H, s), 3.52 (2H, d), 3.64 (1H, d), 3.78 (2H, s), 4.24 (1H, t), 4.38 (1H, dt), 7.33-7.38 (1H, m), 7.43-7.48 (1H, m), 7.51 (1H, t), 7.83 (1H, d), 8.14 (1H, s), 8.55 (1H, d), 13.06 (1H, d). m/z: ES+ [M+H]+ 506

Reference： [1]Patent: US2019/177338,2019,A1 .Location in patent: Paragraph 0348; 0393-0394
[2]Journal of Medicinal Chemistry,2020,vol. 63,p. 4468 - 4483

39
[ 1245816-10-7 ]
tert-butyl (4aR)-10-bromo-11-chloro-9-fluoro-6-methyl-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c]quinoline-3-carboxylate [ No CAS ]
tert-butyl (4aR)-11-chloro-9-fluoro-6-methyl-10-(5-methyl-1H-indazol-4-yl)-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c]quinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With methanesulfonato(2-dicyclohexylphosphino-2?,6?-di-i-propoxy-1,1?-biphenyl)(2?-methylamino-1,1?-biphenyl-2-yl)palladium(II); potassium carbonate; ruphos; In 1,4-dioxane; water; at 20 - 100℃; for 1h;Inert atmosphere;	tert-Butyl (4aR)-11-chloro-9-fluoro-6-methyl-10-(5-methyl-1H-indazol-4-yl)-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c]quinoline-3-carboxylate RuPhos-Pd-G3 (134 mg, 0.16 mmol) was added to a mixture of tert-butyl (4aR)-10-bromo-11-chloro-9-fluoro-6-methyl-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c]quinoline-3-carboxylate (800 mg, 1.60 mmol), <strong>[1245816-10-7](5-methyl-1H-indazol-4-yl)boronic acid</strong> (338 mg, 1.92 mmol), K2CO3 (442 mg, 3.20 mmol) and RuPhos (74.7 mg, 0.16 mmol) in 1,4-dioxane/H2O (20 mL, 4:1 ratio) at rt. The resulting suspension was stirred at 100 C. for 1 h. The solvent was removed in vacuo and the residue purified by flash C18-flash chromatography (0 to 100%, MeCN in water (0.1% formic acid)) to give crude product as a pale yellow solid. This was purified by preparative chiral-H PLC (Column: CHIRALPAK IC, 2*25 cm, 5m; Mobile Phase A: Hex:DCM=3:1 (10 mM NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 16 mL/min; Gradient: 50 B to 50 B in 23 min; 220/254 nm) to give atropisomer 1 of tert-butyl (4aR)-11-chloro-9-fluoro-6-methyl-10-(5-methyl-1H-indazol-4-yl)-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c]quinoline-3-carboxylate (339 mg, 43%); m/z: ES+ [M+H]+=551.

Reference： [1]Patent: US2019/177338,2019,A1 .Location in patent: Paragraph 0348; 0751-0752

40
[ 1245816-10-7 ]
(M,S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one [ No CAS ]
6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18.5%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; dichloromethane; at 90℃;Sealed tube;	[0308] Step 2: (M)-6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(4-methyl-2-(2-propanyl)- 3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin- 2(1H)-one . To a pressure vial was added (M,S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6,7- dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (Intermediate 73D; 0.20 g, 0.40 mmol), <strong>[1245816-10-7]5-methyl-1H-indazol-4-boronic acid</strong> (0.105 g, 0.598 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with DCM (0.016 g, 0.02 mmol), potassium acetate (0.196 g, 1.99 mmol) and 1,4-dioxane (10 mL). The vial was purged with N2 for 3 min, sealed and then heated at 90C for 1 h. The reaction mixture was partitioned between EtOAc and water and the organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified twice by silica gel chromatography (eluent: 0-60% (EtOAc:EtOH (3:1)/heptane) to provide (M)-4-((S)-4- acryloyl-2-methylpiperazin-1-yl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl- 1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.044 g, 0.074 mmol, 18.5 % yield) as a light brown solid.1H NMR (DMSO-d6) d: 12.95-13.29 (m, 1H), 8.48 (br d, J=6.0 Hz, 1H), 8.30 (dd, J=11.2, 5.0 Hz, 1H), 7.40-7.52 (m, 2H), 7.23 (dd, J=8.6, 2.2 Hz, 1H), 7.08-7.18 (m, 1H), 6.81-6.95 (m, 1H), 6.22 (br d, J=16.0 Hz, 1H), 5.74-5.81 (m, 1H), 4.88-5.03 (m, 1H), 4.05-4.47 (m, 3H), 3.50-3.86 (m, 2H), 3.10-3.24 (m, 1H), 2.71-2.86 (m, 1H), 1.86-2.09 (m, 6H), 1.38 (dd, J=6.6, 2.1Hz, 3H), 1.06 (dd, J=6.6, 3.5 Hz, 3H), 0.76-0.94 (m, 3H). m/z (ESI, +ve ion): 597.2 (M+H)+.

Reference： [1]Patent: WO2019/213516,2019,A1 .Location in patent: Paragraph 0308

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[ 1245816-10-7 ]
tert-butyl 4-[7-bromo-6-chloro-2-[(3-ethoxy-3-oxo-propyl)amino]-8-fluoroquinazolin-4-yl]piperazine-1-carboxylate [ No CAS ]
C₃₀H₃₅ClFN₇O₄ [ No CAS ]