[ CAS No. 388116-27-6 ] {[proInfo.proName]}

Name: 388116-27-6|4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole|97%
Brand: Ambeed
SKU: A194704
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2D 3D

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Quality Control of [ 388116-27-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 388116-27-6 ]

SDS Specification

Alternatived Products of [ 388116-27-6 ]

Product Details of [ 388116-27-6 ]

CAS No. :	388116-27-6	MDL No. :	MFCD08689896
Formula :	C₁₄H₁₈BNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QDCIXBBEUHMLDN-UHFFFAOYSA-N
M.W :	243.11	Pubchem ID :	11322471
Synonyms :

Calculated chemistry of [ 388116-27-6 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.43
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	74.77
TPSA :	34.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.62 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	3.04
Log Po/w (WLOGP) :	2.47
Log Po/w (MLOGP) :	1.49
Log Po/w (SILICOS-IT) :	2.42
Consensus Log Po/w :	1.88

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.57
Solubility :	0.066 mg/ml ; 0.000271 mol/l
Class :	Soluble
Log S (Ali) :	-3.43
Solubility :	0.0914 mg/ml ; 0.000376 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.89
Solubility :	0.00314 mg/ml ; 0.0000129 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.88

Safety of [ 388116-27-6 ]

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

Application In Synthesis of [ 388116-27-6 ]

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

Upstream synthesis route of [ 388116-27-6 ]
Downstream synthetic route of [ 388116-27-6 ]

[ 388116-27-6 ] Synthesis Path-Upstream 1~7

1
[ 52488-36-5 ]
[ 73183-34-3 ]
[ 388116-27-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium acetate In dimethyl sulfoxide at 90℃; for 4 h;	(a) 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole. A 50 mL flask was charged with 4-bromoindole (1.00 g, 5.10 mmol), bis(pinacolato)diboron (1.68 g, 6.63 mmol), KOAc (1.44 g, 15.3 mmol) and PdCl₂(dppf) CH₂Cl₂complex (206 mg, 0.26 mmol) under argon. Dry DMSO (16 mL) was added and the mixture was heated at 90° C. for 4 h. The reaction mixture was cooled, filtered over silica gel and the filter cake was washed with TBME (2.x.50 mL). The filtrate was washed with brine (3.x.50 mL), dried (Na₂SO₄) and concentrated. The residue was purified by flash chromatography (AcOEt/heptane 1:4) to give 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole as an off-white solid (1.24 g, quant.).
100%	With potassium acetate In dimethyl sulfoxide at 90℃; for 4 h;	A 50 mL flask was charged with 4-bromoindole (1.00 g, 5.10 mmol), <n="83"/>bis(pinacolato)diboron (1.68 g, 6.63 mmol), KOAc (1.44 g, 15.3 mmol) and PdCl₂(dρρf) CH₂Cl₂ complex (206 mg, 0.26 mmol) under argon. Dry DMSO (16 mL) was added and the mixture was heated 'at 9O⁰C for 4 h. The reaction mixture was cooled, filtered over silica gel and the filter cake was washed with TBME (2x50 mL). The filtrate was washed with brine (3x50 mL), dried (Na₂SO₄) and concentrated. The residue was purified by flash chromatography (AcOEt/heptane 1:4) to give 4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-lH-indoIe as an off-white solid (1.24 g, quant.).[0262] (b) 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2~yl)-l- triisopropylsilanyl-lH-indole. To a stirred mixture of sodium hydride (60percent disp. in oil, 365 mg, 9.1 mmol, 1.06 eq.) in THF (7 mL) at ca. 0°C was added a THF (8 mL) solution of 4-(4,4,5,5~Tetrametfiyl-[l,3,2]dioxaborolan-2-yl)- lH-indole (2.1 g, 8.64 mmol, 1 eq., -75percent purity) dropwise under N₂. The mixture was stirred at 0°-5°C for 30 min., whereupon triisopropylsilyl chloride (2.03 mL, 9.5 mmol, 1.1 eq.) was added dropwise. The reaction mixture was stirred under N₂ returning to ambient overnight. The reaction was quenched with the addition of water and the organics were extracted into EtOAc. The organic phase was washed with H₂O, brine, dried over MgSO₄, filtered and concentrated to an oil, which was chromatographed (2percent EtOAc/hexanes) yielding 1.59 g of 4-(4₅4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-l- triisopropylsilanyl-lH-indole, as a white solid.
72%	With potassium acetate In 1,4-dioxane at 100℃; for 18 h; Inert atmosphere	Scheme 16: S nthesis of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole [74]73 74 Compound [73] (lg, 2.68 5.1 mmol) was dissolved in l,4dioxane (30 ml) in a clean oven- dried two necked RB flask (250 ml) and degassed with nitrogen. To this clear solution, bis(pinnacaloto)-diboron (1.64 g, 6.12 mmol) was added, followed by potassium acetate (1.5 g, 15.3 mol) and [1 , l '-bis (diphenylphosphino)ferrocene]palladium(II)chloride with dichloromethane (0.43 g, 0 .51 mmol). The reaction mixture was stirred under a nitrogen atmosphere and heated at 100 °C for 18 h. The reaction was monitored by TLC . The reaction mixture was filtered through celite, washed well with ethyl acetate, the filtrate was then extracted with ethyl acetate (2 x 30 ml). The organic extracts were combined, washed with brine and dried over Na₂S0₄. The organic layer was then evaporated to give [74] as a crude black oil (1.2 g) which was washed with ether to yield [74] (0.9 g, 72percent) as a brown solid .ESIMS: 244 (M⁺ +1)

72%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 100℃; for 18 h; Inert atmosphere	Scheme 11 : Synthesis of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole [74] 73 74 Compound [73] ( 1 g, 2.68 5. 1 mmol) was dissolved in 1 ,4-dioxane (30 ml) in a clean oven- dried two necked RB flask (250 ml) and degassed with nitrogen. To this clear solution, bis(pinnacaloto)-diboron ( 1.64 g, 6. 12 mmol) Was added, followed by potassium acetate ( 1.5 g, 1 5.3 mol) and [ 1 , I '-bis (diphenylphosphi no)ferrocene]palladium(II)chloride (0.43 g, 0 .5 1 mmol) with dichloromethane. The reaction mixture was stirred under a nitrogen reaction mixture was filtered through celite and washed well with ethyl acetate. The filtrate was then extracted with ethyl acetate (2 x 30 ml). The organic extracts were combined, washed with brine and dried over Na₂SC>4. The organic layer was then evaporated to give [74] as a crude black oil ( 1.2 g) which was washed with ether to yield [74] (0.9 g, 72percent) as a brown solid. ES1MS: 244 (JVT + 1 )
60%	With potassium acetate In dimethyl sulfoxide at 80℃; for 22 h; Inert atmosphere	Step 1 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 4-Bromo-1H-indole 6a (29.4 g, 150 mmol) was dissolved in 600 ml of dimethyl sulfoxide under stirring, and added successively with bis(pinacolato)diboron (41.9 g, 165 mmol), potassium acetate (44.1 g, 450 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (3.6 g, 4.8 mmol) under an argon atmosphere. Upon completion of the addition, the reaction mixture was stirred at 80° C. in an oil bath for 22 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with water (2 L) and extracted with ethyl acetate (2 L3). The combined organic extracts were washed with saturated brine (2 L5), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized to obtain 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 6b (20 g, yield 60percent) as a white solid. MS m/z (ESI): 243.9 [M+1]
60%	With potassium acetate In dimethyl sulfoxide at 80℃; for 22 h; Inert atmosphere	4-Bromo-1H-indole 6a (29.4 g, 150 mmol) was dissolved in 600 ml of dimethyl sulfoxide under stirring, and added successively with bis(pinacolato)diboron (41.9 g, 165 mmol), potassium acetate (44.1 g, 450 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (3.6 g, 4.8 mmol) under an argon atmosphere. Upon completion of the addition, the reaction mixture was stirred at 80°C in an oil bath for 22 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with water (2 L) and extracted with ethyl acetate (2 L.x.3). The combined organic extracts were washed with saturated brine (2 L.x.5), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized to obtain 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 6b (20 g, yield 60percent) as a white solid. MS m/z (ESI): 243.9[M+1]
60%	With potassium acetate In water; dimethyl sulfoxide at 80℃; for 22 h; Inert atmosphere	4-Bromo-1H-indole 3a (29.4 g, 150 mmol) was dissolved in 600 mL of dimethyl sulfoxide under stirring under an argon atmosphere, and bis(pinacolato)diboron (41.9 g, 165 mmol), potassium acetate (44.1 g, 450 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (3.6 g, 4.8 mmol) were then added to the solution. Upon completion of the addition, the reaction mixture was stirred at 80°C in an oil bath for 22 hours. The reaction was completed until TLC showed the disappearance of starting materials, and 2 L of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (2 L3). The combined organic extracts were washed with saturated brine (2 L5), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized to give the title compound 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 3b (20 g, yield 60percent) as a white solid. MS m/z (ESI): 243.9[M+1]
60%	With potassium acetate In dimethyl sulfoxide at 80℃; for 22 h; Inert atmosphere	Step 1 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 4-Bromo-1H-indole 3a (29.4 g, 150 mmol) was dissolved in 600 mL of dimethyl sulfoxide under stirring under an argon atmosphere, and bis(pinacolato)diboron (41.9 g, 165 mmol), potassium acetate (44.1 g, 450 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (3.6 g, 4.8 mmol) were then added to the solution. Upon completion of the addition, the reaction mixture was stirred at 80° C. in an oil bath for 22 hours. The reaction was completed until TLC showed the disappearance of starting materials, and 2 L of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (2 L3). The combined organic extracts were washed with saturated brine (2 L 5), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized to give the title compound 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 3b (20 g, yield 60percent) as a white solid. MS m/z (ESI): 243.9[M+1]
38%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 40 - 80℃; for 96 h; Inert atmosphere	4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (62a) (0306) 4-Bromoindole (1.00 g, 5.10 mmol, 1.0 equiv), bis(pinacolato)diboron (1.42 g, 5.61 mmol, 1.1 equiv), potassium acetate (1.50 g, 15.3 mmol, 3.0 equiv) and Pd(dppf)Cl₂(112 mg, 0.153 mmol, 0.03 equiv) were dissolved under Argon atmosphere in 15 ml DMSO and the mixture was stirred at 80° C. for 24 h and afterwards at 40° C. for 72 h. Water was added and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to dryness. The raw product was purified by flash chromatography and by preparative HPLC (water with 0.1percent formic acid/acetonitrile with 0.1percent formic acid); yield: 38percent (470 mg). ¹H NMR (500 MHz, acetone-d⁶): δ 10.21 (br. s, 1H), 7.55-7.49 (m, 2H), 7.34 (dt, J=3.0, 1.3 Hz, 1H), 7.10 (dd, J=8.0, 7.1 Hz, 1H), 6.93-6.91 (m, 1H), 1.37 (s, 12H).
3.65 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In toluene for 16 h; Reflux	the obtained 38-6-a (3.92 g, 20 mmol), Bis(pinacolato)diboron (6.22 g, 24 mmol), 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.49 g, 0.6 mmol), potassium acetate (5.90 g, 60 mmol) and 79 ml of toluene were reacted under reflux for 16 hours.After cooling, 26 ml of water was added and stirred for 30 minutes, the organic phase was separated, filtered through a short bed of celite, soon afterwards the organic solvent was evaporated off, and the obtained crude product was recrystallized from heptane / toluene; Under argon atmosphere, the obtained solid 38-6-b (3.65g, 15mmol), 38-6-c (4.45g, 14.3mmol), Tetrakis(triphenylphosphine)palladium (0·35 g, 0.3 mmol), toluene (43 ml), aqueous sodium carbonate (2M, 21 ml) was added to the flask and refluxed for 8 hours.After cooling to room temperature, it was extracted with toluene, and the organic phase was washed with brine, and then dried, and then purified by column chromatography to obtain bromide 38-6-d; Tri-tert-butylphosphine (4.4 mL of a 1.0 M solution in toluene, 1.48 g, 0.05 mmol), palladium acetate (0.4 g, 1.83 mmol) and sodium tert-butoxide (52.7 g, 549 mmol) were added to a solution of 38-6-d (22.04 g, 73.42 mmol) and bromobenzene (11.53 g, 73.42 mmol) in degassed toluene (500 mL) and the mixture was Heat under reflux for 2 hours. This reaction mixture was cooled to room temperature, diluted with toluene and filterated through celite. This filtrate was diluted with water and extracted with toluene, and the organic phases were combined and evaporated in vacuo. This residue was filtered through silica gel (heptane / dichloromethane) and crystallised from isopropyl alcohol to give compound 38-6-e;the obtained 38-6-a (3.92 g, 20 mmol), Bis(pinacolato)diboron (6.22 g, 24 mmol), 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.49 g, 0.6 mmol), potassium acetate (5.90 g, 60 mmol) and 79 ml of toluene were reacted under reflux for 16 hours.After cooling, 26 ml of water was added and stirred for 30 minutes, the organic phase was separated, filtered through a short bed of celite, soon afterwards the organic solvent was evaporated off, and the obtained crude product was recrystallized from heptane / toluene to obtain compound 38-6.

Reference： [1] Patent: US2008/280891, 2008, A1, . Location in patent: Page/Page column 30
[2] Patent: WO2008/8059, 2008, A1, . Location in patent: Page/Page column 81-82
[3] Organic Letters, 2012, vol. 14, # 2, p. 600 - 603
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 12, p. 2496 - 2500
[5] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8267 - 8276
[6] Synlett, 2003, # 8, p. 1204 - 1206
[7] Patent: WO2012/101654, 2012, A2, . Location in patent: Page/Page column 58-59
[8] Patent: WO2014/16849, 2014, A2, . Location in patent: Page/Page column 114; 115
[9] Organic Process Research and Development, 2018, vol. 22, # 3, p. 368 - 376
[10] Patent: US2010/75952, 2010, A1, . Location in patent: Page/Page column 47
[11] Patent: EP2157093, 2010, A1, . Location in patent: Page/Page column 38-39
[12] Patent: EP2179998, 2010, A1, . Location in patent: Page/Page column 14; 15
[13] Patent: US2010/160317, 2010, A1, . Location in patent: Page/Page column 14
[14] Patent: US2016/318895, 2016, A1, . Location in patent: Paragraph 0306
[15] Patent: US2006/270686, 2006, A1, . Location in patent: Page/Page column 30-31
[16] Patent: WO2012/55846, 2012, A1, . Location in patent: Page/Page column 56-57
[17] Patent: US2013/203772, 2013, A1, . Location in patent: Paragraph 0327; 0328
[18] Patent: CN108530336, 2018, A, . Location in patent: Paragraph 0101; 0103; 0106; 0107

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[ 25235-85-2 ]
[ 73183-34-3 ]
[ 388116-27-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine; triphenylphosphine In methanol at 20 - 50℃; Inert atmosphere	Under a nitrogen atmosphere, a reaction vessel of 20 ml in volume was charged with bis(pinacolate)diboron (0.50 g (2.0 mmol)), degassed methanol (7.2 g) and diisopropylethylamine (0.51 g (4.0 mmol)) and stirred at room temperature. The reaction vessel was charged with bis(l,5-cyclooctadiene)nickel (15 mg (0.05 mmol)), triphenylphosphine (28 mg (0.11 mmol)), and 4-chloroindole (0.20 g (1.32 mmol)) and stirred at 30⁰C for 21 hours, and thereafter stirred at 50⁰C for 3 hours. The reaction solution was analyzed by gas chromatography. As a result, 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)indole was contained in an amount of 0.26 g (1.05 mmol, yield:80percent).
80%	With N-ethyl-N,N-diisopropylamine; triphenylphosphine In methanol at 20 - 50℃; for 24 h; Inert atmosphere	Under a nitrogen atmosphere, a reaction vessel of 20 ml in volume was charged with bis(pinacolate)diboron (0.50 g (2.0 mmol)), degassed methanol (7.2 g) and diisopropylethylamine (0.51 g (4.0 mmol)) and stirred at room temperature. The reaction vessel was charged with bis(1,5-cyclooctadiene)nickel (15 mg (0.05 mmol)), triphenylphosphine (28 mg (0.11 mmol)), and 4-chloroindole (0.20 g (1.32 mmol)) and stirred at 30° C. for 21 hours, and thereafter stirred at 50° C. for 3 hours. The reaction solution was analyzed by gas chromatography. As a result, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole was contained in an amount of 0.26 g (1.05 mmol, yield: 80percent).

Reference： [1] Patent: WO2010/110782, 2010, A1, . Location in patent: Page/Page column 47
[2] Patent: US2012/123122, 2012, A1, . Location in patent: Page/Page column 13-14
[3] Tetrahedron, 2001, vol. 57, # 49, p. 9813 - 9816

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[ 73183-34-3 ]
[ 120-72-9 ]
[ 388116-27-6 ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium acetate In dichloromethane; dimethyl sulfoxide at 80℃; for 22 h;	To a mixture OF 4-BROMOINDOLE (9. 80G, 50 MMOL), pinacle diborate (13. 97G, 55 MMOL), and KOAc (14. 72G, 150 MMOL) in DMSO (200 mL) was added palladium catalyst PdCl2(dppf) CH2Cl2 (1.22g, 1. 5 MMOL). The system was degassed, and then charged with nitrogen for three times. The mixture was stirred at 80 C oil bath under nitrogen for 22 hours. TLC showed the complete disappearance of the starting material 4-bromoindole. The mixture was cooled to room temperature, and then poured to water (1 L). The product was extracted with ethyl acetate for three times. The combined extracts were washed by brine for five times to remove DMSO solvent, and then dried over NA2SO4. During the washing step, the catalyst may precipitate out, which was removed by filtration. The ethyl acetate solution was filtered and condensed. The residue was purified on a silica gel column eluting with EtOAc-hexane (9 : 1). The first fraction provided the side product indole (1. 25G, 21percent yield), Rf 0. 55 (EtOAc-Hexane 5 : 1). The second fraction provided 4- (4, 4, 5, 5-TETRAMETHYL- [1, 3, 2] DIOXABOROLAN-2-YL)-1H- indole as a white solid (8. 01g, 66percent), RF 0. 46 (EtOAc-Hexane 5 : 1). H NMR (300 MHz, DMSO-D6) : 11. 03 (bs, 1H, N-H)), 7. 49 (d, J 7. 7 Hz, 1H, H-5), 7. 38 (dd, J 0. 9 Hz, J 7. 0 Hz, 1H, H-7), 7. 38 (t, J 2. 6Hz, 1H, H-2), 7. 06 (dd, J 7. 7 Hz, J 7. 0 Hz, 1H, H-6), 6. 73 (bd, J 2. 2 Hz, 1H, H-3), 1. 32 (s, 12H, 4CH3) ; MS (m/e) : 244 (M+H) +.

Reference： [1] Patent: WO2004/76412, 2004, A2, . Location in patent: Page 96

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[ 73183-34-3 ]
[ 388116-27-6 ]

Yield	Reaction Conditions	Operation in experiment
39%	With potassium acetate In dimethyl sulfoxide at 90℃;	A tube was charged with trifluoro-methanesulfonic acid 2-cyano-1H-indol-4-yl ester (0.136 g, 0.469 mmol), 0.150 g (0.61 mmol) bis(pinacolato)diboron, 0.138 g (1.41 mmol) potassium acetate, Pd(dppf)Cl₂.CH₂Cl₂complex (0.039 g, 0.047 mmol) and 3 mL anhydrous DMSO. The tube was flushed with nitrogen and sealed, and the reaction mixture was heated at 90° C. overnight. The reaction mixture was cooled, filtered through silica gel and the filter cake was washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography to give 0.049 g (39percent yield) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole. This material was protected with triisopropylsilyl chloride to give 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-indole using conditions similar to those described in Example 21.

Reference： [1] Patent: US2006/270686, 2006, A1, . Location in patent: Page/Page column 49-50

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[ 120-72-9 ]
[ 52488-36-5 ]
[ 388116-27-6 ]

Reference： [1] Patent: US2003/69297, 2003, A1,

6
[ 52488-36-5 ]
[ 73183-34-3 ]
[ 388116-26-5 ]
[ 388116-27-6 ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium acetate In dimethyl sulfoxide	4-Pyridin-4-yl-1,3-dihydroindol-2-one Palladium catalyst PdCl₂(dppf).CH₂Cl₂ (1.22 g, 1.5 mmol) was added to a mixture of 4-bromoindole (9.80 g, 50 mmol), bis(pinacolato)diboron (13.97 g, 55 mmol), and potassium acetate (14.72 g, 150 mmol) in DMSO (200 mL). The system was degassed, and then purged three times with nitrogen. The mixture was stirred at 80° C. in an oil bath under nitrogen for 22 hours. It was then cooled to room temperature and poured into water (1 L). The aqueous mixture was extracted with three portions of ethyl acetate. The combined extracts were washed five times with brine to remove DMSO and then dried over anhydrous Na₂SO₄. The residue was purified on a silica gel column, eluding with EtOAc-hexane (9:1), to give 8.01 g (66percent) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole. ¹H NMR (300 MHz, DMSO-d₆): δ 11.03 (br s, 1H, NH)), 7.49 (d, J=7.7 Hz, 1H), 7.38 (dd, J=0.9 and 7.0 Hz, 1H), 7.38 (t, J=2.6 Hz, 1H), 7.06 (dd, J=7.7 and 7.0 Hz, 1H), 6.73 (br d, J=2.2 Hz, 1H), 1.32 (s, 12H, 4CH₃). MS m/e 244 [M⁺+1].

Reference： [1] Patent: US2002/187978, 2002, A1,

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[ 388116-27-6 ]

Reference： [1] Heterocycles, 2010, vol. 80, # 2, p. 1267 - 1274
[2] Patent: US2015/318483, 2015, A1,

[ 388116-27-6 ] Synthesis Path-Downstream 1~57

1
[ 25235-85-2 ]
[ 73183-34-3 ]
[ 388116-27-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine; triphenylphosphine;bis(1,5-cyclooctadiene)nickel (0); In methanol; at 20 - 50℃;Inert atmosphere;	Under a nitrogen atmosphere, a reaction vessel of 20 ml in volume was charged with bis(pinacolate)diboron (0.50 g (2.0 mmol)), degassed methanol (7.2 g) and diisopropylethylamine (0.51 g (4.0 mmol)) and stirred at room temperature. The reaction vessel was charged with bis(l,5-cyclooctadiene)nickel (15 mg (0.05 mmol)), triphenylphosphine (28 mg (0.11 mmol)), and 4-chloroindole (0.20 g (1.32 mmol)) and stirred at 300C for 21 hours, and thereafter stirred at 500C for 3 hours. The reaction solution was analyzed by gas chromatography. As a result, 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)indole was contained in an amount of 0.26 g (1.05 mmol, yield:80%).
80%	With N-ethyl-N,N-diisopropylamine; triphenylphosphine;(1,5-cyclooctadiene)(cyclopentadienyl)nickel; In methanol; at 20 - 50℃; for 24h;Inert atmosphere;	Under a nitrogen atmosphere, a reaction vessel of 20 ml in volume was charged with bis(pinacolate)diboron (0.50 g (2.0 mmol)), degassed methanol (7.2 g) and diisopropylethylamine (0.51 g (4.0 mmol)) and stirred at room temperature. The reaction vessel was charged with bis(1,5-cyclooctadiene)nickel (15 mg (0.05 mmol)), triphenylphosphine (28 mg (0.11 mmol)), and 4-chloroindole (0.20 g (1.32 mmol)) and stirred at 30 C. for 21 hours, and thereafter stirred at 50 C. for 3 hours. The reaction solution was analyzed by gas chromatography. As a result, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole was contained in an amount of 0.26 g (1.05 mmol, yield: 80%).

Reference： [1]Patent: WO2010/110782,2010,A1 .Location in patent: Page/Page column 47
[2]Patent: US2012/123122,2012,A1 .Location in patent: Page/Page column 13-14
[3]Tetrahedron,2001,vol. 57,p. 9813 - 9816

2
[ 52488-36-5 ]
[ 73183-34-3 ]
[ 388116-27-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 90℃; for 4h;	(a) 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole. A 50 mL flask was charged with 4-bromoindole (1.00 g, 5.10 mmol), bis(pinacolato)diboron (1.68 g, 6.63 mmol), KOAc (1.44 g, 15.3 mmol) and PdCl2(dppf) CH2Cl2 complex (206 mg, 0.26 mmol) under argon. Dry DMSO (16 mL) was added and the mixture was heated at 90 C. for 4 h. The reaction mixture was cooled, filtered over silica gel and the filter cake was washed with TBME (2×50 mL). The filtrate was washed with brine (3×50 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (AcOEt/heptane 1:4) to give 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole as an off-white solid (1.24 g, quant.).
100%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 90℃; for 4h;	A 50 mL flask was charged with 4-bromoindole (1.00 g, 5.10 mmol), <n="83"/>bis(pinacolato)diboron (1.68 g, 6.63 mmol), KOAc (1.44 g, 15.3 mmol) and PdCl2(drhorhof) CH2Cl2 complex (206 mg, 0.26 mmol) under argon. Dry DMSO (16 mL) was added and the mixture was heated 'at 9O0C for 4 h. The reaction mixture was cooled, filtered over silica gel and the filter cake was washed with TBME (2x50 mL). The filtrate was washed with brine (3x50 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (AcOEt/heptane 1:4) to give 4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-lH-indoIe as an off-white solid (1.24 g, quant.).[0262] (b) 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2~yl)-l- triisopropylsilanyl-lH-indole. To a stirred mixture of sodium hydride (60% disp. in oil, 365 mg, 9.1 mmol, 1.06 eq.) in THF (7 mL) at ca. 0C was added a THF (8 mL) solution of 4-(4,4,5,5~Tetrametfiyl-[l,3,2]dioxaborolan-2-yl)- lH-indole (2.1 g, 8.64 mmol, 1 eq., -75% purity) dropwise under N2. The mixture was stirred at 0-5C for 30 min., whereupon triisopropylsilyl chloride (2.03 mL, 9.5 mmol, 1.1 eq.) was added dropwise. The reaction mixture was stirred under N2 returning to ambient overnight. The reaction was quenched with the addition of water and the organics were extracted into EtOAc. The organic phase was washed with H2O, brine, dried over MgSO4, filtered and concentrated to an oil, which was chromatographed (2% EtOAc/hexanes) yielding 1.59 g of 4-(454,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-l- triisopropylsilanyl-lH-indole, as a white solid.
84%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 130℃; for 12h;Inert atmosphere;	Under a nitrogen stream 4-bromo-1H-indole (100.0 g, 510.1 mmol), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (142.5 g, 561.1 mmol) Pd (dppf) Cl 2 (44.7 g, 51.0 mmol), KOAc (144.1 g, 1.52 mol) And 2500 ml of 1,4-dioxane were mixed and stirred at 130 C for 12 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, the water was removed with MgSO 4 and purified by column chromatography (Hexane: EA = 8: 1 (v / v)) to obtain 4- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) -1H-indole (104.2 g, yield 84%).

72%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;	Scheme 16: S nthesis of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole [74]73 74 Compound [73] (lg, 2.68 5.1 mmol) was dissolved in l,4dioxane (30 ml) in a clean oven- dried two necked RB flask (250 ml) and degassed with nitrogen. To this clear solution, bis(pinnacaloto)-diboron (1.64 g, 6.12 mmol) was added, followed by potassium acetate (1.5 g, 15.3 mol) and [1 , l '-bis (diphenylphosphino)ferrocene]palladium(II)chloride with dichloromethane (0.43 g, 0 .51 mmol). The reaction mixture was stirred under a nitrogen atmosphere and heated at 100 C for 18 h. The reaction was monitored by TLC . The reaction mixture was filtered through celite, washed well with ethyl acetate, the filtrate was then extracted with ethyl acetate (2 x 30 ml). The organic extracts were combined, washed with brine and dried over Na2S04. The organic layer was then evaporated to give [74] as a crude black oil (1.2 g) which was washed with ether to yield [74] (0.9 g, 72%) as a brown solid .ESIMS: 244 (M+ +1)
72%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;	Scheme 11 : Synthesis of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole [74] 73 74 Compound [73] ( 1 g, 2.68 5. 1 mmol) was dissolved in 1 ,4-dioxane (30 ml) in a clean oven- dried two necked RB flask (250 ml) and degassed with nitrogen. To this clear solution, bis(pinnacaloto)-diboron ( 1.64 g, 6. 12 mmol) Was added, followed by potassium acetate ( 1.5 g, 1 5.3 mol) and [ 1 , I '-bis (diphenylphosphi no)ferrocene]palladium(II)chloride (0.43 g, 0 .5 1 mmol) with dichloromethane. The reaction mixture was stirred under a nitrogen reaction mixture was filtered through celite and washed well with ethyl acetate. The filtrate was then extracted with ethyl acetate (2 x 30 ml). The organic extracts were combined, washed with brine and dried over Na2SC>4. The organic layer was then evaporated to give [74] as a crude black oil ( 1.2 g) which was washed with ether to yield [74] (0.9 g, 72%) as a brown solid. ES1MS: 244 (JVT + 1 )
60%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 22h;Inert atmosphere;	Step 1 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 4-Bromo-1H-indole 6a (29.4 g, 150 mmol) was dissolved in 600 ml of dimethyl sulfoxide under stirring, and added successively with bis(pinacolato)diboron (41.9 g, 165 mmol), potassium acetate (44.1 g, 450 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (3.6 g, 4.8 mmol) under an argon atmosphere. Upon completion of the addition, the reaction mixture was stirred at 80 C. in an oil bath for 22 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with water (2 L) and extracted with ethyl acetate (2 L3). The combined organic extracts were washed with saturated brine (2 L5), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized to obtain 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 6b (20 g, yield 60%) as a white solid. MS m/z (ESI): 243.9 [M+1]
60%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 22h;Inert atmosphere;	4-Bromo-1H-indole 6a (29.4 g, 150 mmol) was dissolved in 600 ml of dimethyl sulfoxide under stirring, and added successively with bis(pinacolato)diboron (41.9 g, 165 mmol), potassium acetate (44.1 g, 450 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (3.6 g, 4.8 mmol) under an argon atmosphere. Upon completion of the addition, the reaction mixture was stirred at 80C in an oil bath for 22 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with water (2 L) and extracted with ethyl acetate (2 L×3). The combined organic extracts were washed with saturated brine (2 L×5), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized to obtain 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 6b (20 g, yield 60%) as a white solid. MS m/z (ESI): 243.9[M+1]
60%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; dimethyl sulfoxide; at 80℃; for 22h;Inert atmosphere;	4-Bromo-1H-indole 3a (29.4 g, 150 mmol) was dissolved in 600 mL of dimethyl sulfoxide under stirring under an argon atmosphere, and bis(pinacolato)diboron (41.9 g, 165 mmol), potassium acetate (44.1 g, 450 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (3.6 g, 4.8 mmol) were then added to the solution. Upon completion of the addition, the reaction mixture was stirred at 80C in an oil bath for 22 hours. The reaction was completed until TLC showed the disappearance of starting materials, and 2 L of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (2 L3). The combined organic extracts were washed with saturated brine (2 L5), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized to give the title compound 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 3b (20 g, yield 60%) as a white solid. MS m/z (ESI): 243.9[M+1]
60%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 22h;Inert atmosphere;	Step 1 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 4-Bromo-1H-indole 3a (29.4 g, 150 mmol) was dissolved in 600 mL of dimethyl sulfoxide under stirring under an argon atmosphere, and bis(pinacolato)diboron (41.9 g, 165 mmol), potassium acetate (44.1 g, 450 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (3.6 g, 4.8 mmol) were then added to the solution. Upon completion of the addition, the reaction mixture was stirred at 80 C. in an oil bath for 22 hours. The reaction was completed until TLC showed the disappearance of starting materials, and 2 L of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (2 L3). The combined organic extracts were washed with saturated brine (2 L 5), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized to give the title compound 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 3b (20 g, yield 60%) as a white solid. MS m/z (ESI): 243.9[M+1]
38%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 40 - 80℃; for 96h;Inert atmosphere;	4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (62a) (0306) 4-Bromoindole (1.00 g, 5.10 mmol, 1.0 equiv), bis(pinacolato)diboron (1.42 g, 5.61 mmol, 1.1 equiv), potassium acetate (1.50 g, 15.3 mmol, 3.0 equiv) and Pd(dppf)Cl2 (112 mg, 0.153 mmol, 0.03 equiv) were dissolved under Argon atmosphere in 15 ml DMSO and the mixture was stirred at 80 C. for 24 h and afterwards at 40 C. for 72 h. Water was added and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to dryness. The raw product was purified by flash chromatography and by preparative HPLC (water with 0.1% formic acid/acetonitrile with 0.1% formic acid); yield: 38% (470 mg). 1H NMR (500 MHz, acetone-d6): delta 10.21 (br. s, 1H), 7.55-7.49 (m, 2H), 7.34 (dt, J=3.0, 1.3 Hz, 1H), 7.10 (dd, J=8.0, 7.1 Hz, 1H), 6.93-6.91 (m, 1H), 1.37 (s, 12H).
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 90℃; for 4h;	A 50 mL flask was charged with 4-bromoindole (1.00 g, 5.10 mmol), bis(pinacolato)diboron (1.68 g, 6.63 mmol), KOAc (1.44 g, 15.3 mmol) and PdCl2(dppf) CH2Cl2 complex (206 mg, 0.26 mmol) under argon. Dry DMSO (16 mL) was added and the mixture was heated at 90 C. for 4 h. The reaction mixture was cooled, filtered over silica gel and the filter cake was washed with TBME (2×50 mL). The filtrate was washed with brine (3×50 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (AcOEt/heptane 1:4) to give 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole as an off-white solid (1.24 g, quant.).
	With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In toluene; at 95 - 100℃; for 3h;Inert atmosphere;	Intermediate 94-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indoleAll weights, volumes and equivalents are relative to 4-bromoindole.Bis(pinacolato)diboron (1 .555 wt, 1.20 eq, 31.1 g), potassium acetate (1.00 wt, 2.0 eq, 20.0 g) and 4-bromoindole (1.00 wt, 0.64 vols, 1.00 eq, 20.0 g), are charged sequentially under N2 to a clean, dry vessel containing toluene (5 vols, 100 ml) and washed in with toluene (2 vols, 40 ml). The mixture is degassed by vacuum/N2 purge x3 and heated to 100 C. In a separate clean, dry vessel, trisbenzylideneacetonedipalladium (0.0234 wt, 0.005 eq, 0.467 g) and tricyclohexylphosphine (0.0286 wt, 0.02 eq, 0.572 g) are combined under N2 and toluene (1 vol, 20 ml) is added. The mixture is degassed by vacuum/N2 purge x3 and stirred for 30 mins. The catalyst solution is added to the reaction vessel and the mixture heated at 95-100 C for at least 3 hrs, until all the 4-bromoindole is consumed as indicated by HPLC analysis. The mixture is cooled to 60 C and filtered to remove inorganics. The cake is washed with toluene (2 x 2 vols, 2 x 40 ml). The dark solution is then distilled down to 4 vols (80 ml) under vacuum (50-60 C, 100 mbar) and aged at 60 C for 1 hr. The resultant slurry is cooled to 20 C over 2 hrs and heptane (12 vols, 240 ml) added over 1 hr. The mixture is aged for at least 1 hr and filtered. The cake is washed with toluene:heptane (1 :4, 2 vols, 40 ml) followed by heptane (2 vols, 40 ml) and dried in vacuo at 50-60 C to constant probe temperature to afford 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-indole as a beige solid.Recrystallisation - All weights, volumes and equivalents are relative to 4-(4, 4,5,5- tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1 H-indole. Isopropanol (6 vols, 4.72 wts, 54.3 Kg) is charged to a clean vessel followed by 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- indole (1 wt, 1 1.5 Kg) and the mixture stirred and heated to reflux (82 C) for 40 mins. The batch is cooled to 70 + 3 C and water (6 vols, 6 wts, 69 Kg) is added via peristaltic pump water over 1 hour maintaining temperature at 70 + 3 C. The contents are aged at 70 + 3 C for 60 mins and cooled to 20 C over 2 hours. The slurry is aged at 20 C for at least 6 hrs and filtered. The cake is washed with 1 :1 IPA:water (2 vols, 23 L) and 1 :3 IPA:water (2 vols, 23 L) and dried in vacuo at 60 C to constant temperature to afford 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole as a white solid.
	With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; tricyclohexylphosphine; In toluene; at 95 - 100℃; for 3h;Inert atmosphere;	Bis(pinacolato)diboron (1.555 wt, 1.20 eq, 31.1 g), potassium acetate (1.00 wt, 2.0 eq, 20.0 g) and 4-bromoindole (1.00 wt, 0.64 vols, 1.00 eq, 20.0 g), are charged sequentially under N2 to a clean, dry vessel containing toluene (5 vols, 100 ml) and washed in with toluene (2 vols, 40 ml). The mixture is degassed by vacuum/N2 purge ×3 and heated to 100 C. In a separate clean, dry vessel, trisbenzylideneacetonedipalladium (0.0234 wt, 0.005 eq, 0.467 g) and tricyclohexylphosphine (0.0286 wt, 0.02 eq, 0.572 g) are combined under N2 and toluene (1 vol, 20 ml) is added. The mixture is degassed by vacuum/N2 purge ×3 and stirred for 30 mins. The catalyst solution is added to the reaction vessel and the mixture heated at 95-100 C. for at least 3 hrs, until all the 4-bromoindole is consumed as indicated by HPLC analysis. The mixture is cooled to 60 C. and filtered to remove inorganics. The cake is washed with toluene (2×2 vols, 2×40 ml). The dark solution is then distilled down to 4 vols (80 ml) under vacuum (50-60 C., 100 mbar) and aged at 60 C. for 1 hr. The resultant slurry is cooled to 20 C. over 2 hrs and heptane (12 vols, 240 ml) added over 1 hr. The mixture is aged for at least 1 hr and filtered. The cake is washed with toluene:heptane (1:4, 2 vols, 40 ml) followed by heptane (2 vols, 40 ml) and dried in vacuo at 50-60 C. to constant probe temperature to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole as a beige solid.Recrystallisation-All weights, volumes and equivalents are relative to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole. Isopropanol (6 vols, 4.72 wts, 54.3 Kg) is charged to a clean vessel followed by 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1 wt, 11.5 Kg) and the mixture stirred and heated to reflux (82 C.) for 40 mins. The batch is cooled to 70±3 C. and water (6 vols, 6 wts, 69 Kg) is added via peristaltic pump water over 1 hour maintaining temperature at 70±3 C. The contents are aged at 70±3 C. for 60 mins and cooled to 20 C. over 2 hours. The slurry is aged at 20 C. for at least 6 hrs and filtered. The cake is washed with 1:1 IPA:water (2 vols, 23 L) and 1:3 IPA:water (2 vols, 23 L) and dried in vacuo at 60 C. to constant temperature to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole as a white solid.
3.65 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In toluene; for 16h;Reflux;	the obtained 38-6-a (3.92 g, 20 mmol), Bis(pinacolato)diboron (6.22 g, 24 mmol), 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.49 g, 0.6 mmol), potassium acetate (5.90 g, 60 mmol) and 79 ml of toluene were reacted under reflux for 16 hours.After cooling, 26 ml of water was added and stirred for 30 minutes, the organic phase was separated, filtered through a short bed of celite, soon afterwards the organic solvent was evaporated off, and the obtained crude product was recrystallized from heptane / toluene; Under argon atmosphere, the obtained solid 38-6-b (3.65g, 15mmol), 38-6-c (4.45g, 14.3mmol), Tetrakis(triphenylphosphine)palladium (0·35 g, 0.3 mmol), toluene (43 ml), aqueous sodium carbonate (2M, 21 ml) was added to the flask and refluxed for 8 hours.After cooling to room temperature, it was extracted with toluene, and the organic phase was washed with brine, and then dried, and then purified by column chromatography to obtain bromide 38-6-d; Tri-tert-butylphosphine (4.4 mL of a 1.0 M solution in toluene, 1.48 g, 0.05 mmol), palladium acetate (0.4 g, 1.83 mmol) and sodium tert-butoxide (52.7 g, 549 mmol) were added to a solution of 38-6-d (22.04 g, 73.42 mmol) and bromobenzene (11.53 g, 73.42 mmol) in degassed toluene (500 mL) and the mixture was Heat under reflux for 2 hours. This reaction mixture was cooled to room temperature, diluted with toluene and filterated through celite. This filtrate was diluted with water and extracted with toluene, and the organic phases were combined and evaporated in vacuo. This residue was filtered through silica gel (heptane / dichloromethane) and crystallised from isopropyl alcohol to give compound 38-6-e;the obtained 38-6-a (3.92 g, 20 mmol), Bis(pinacolato)diboron (6.22 g, 24 mmol), 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.49 g, 0.6 mmol), potassium acetate (5.90 g, 60 mmol) and 79 ml of toluene were reacted under reflux for 16 hours.After cooling, 26 ml of water was added and stirred for 30 minutes, the organic phase was separated, filtered through a short bed of celite, soon afterwards the organic solvent was evaporated off, and the obtained crude product was recrystallized from heptane / toluene to obtain compound 38-6.

Reference： [1]Patent: US2008/280891,2008,A1 .Location in patent: Page/Page column 30
[2]Patent: WO2008/8059,2008,A1 .Location in patent: Page/Page column 81-82
[3]Organic Letters,2012,vol. 14,p. 600 - 603
[4]Organic Letters,2019,vol. 21,p. 8158 - 8163
[5]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 2496 - 2500
[6]Patent: KR2019/71245,2019,A .Location in patent: Paragraph 0157-0162
[7]Journal of the American Chemical Society,2017,vol. 139,p. 8267 - 8276
[8]Synlett,2003,p. 1204 - 1206
[9]Patent: WO2012/101654,2012,A2 .Location in patent: Page/Page column 58-59
[10]Patent: WO2014/16849,2014,A2 .Location in patent: Page/Page column 114; 115
[11]Organic Process Research and Development,2018,vol. 22,p. 368 - 376
[12]Patent: US2010/75952,2010,A1 .Location in patent: Page/Page column 47
[13]Patent: EP2157093,2010,A1 .Location in patent: Page/Page column 38-39
[14]Patent: EP2179998,2010,A1 .Location in patent: Page/Page column 14; 15
[15]Patent: US2010/160317,2010,A1 .Location in patent: Page/Page column 14
[16]Patent: US2016/318895,2016,A1 .Location in patent: Paragraph 0306
[17]Journal of Medicinal Chemistry,2018,vol. 61,p. 10724 - 10738
[18]Patent: US2006/270686,2006,A1 .Location in patent: Page/Page column 30-31
[19]Patent: WO2012/55846,2012,A1 .Location in patent: Page/Page column 56-57
[20]Patent: US2013/203772,2013,A1 .Location in patent: Paragraph 0327; 0328
[21]Patent: CN108530336,2018,A .Location in patent: Paragraph 0101; 0103; 0106; 0107

3
[ 1073-06-9 ]
[ 388116-27-6 ]
[ 442562-62-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium hydroxide;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 70℃; for 15h;	To a mixture of 4-(<strong>[388116-27-6]4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole</strong>, (2.43 g, 10 mmol), and 3-bromofluorobenzene (1.09 mL, 10 mmol) in tetrahydrofuran (34 mL)) was added tetrakis(triphenylphosphine)palladium(0) (347 mg, 0.3 mmol) and a freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degassing procedure was repeated three times. The mixture was stirred under nitrogen at 70 C. in an oil bath for 15 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from the water layer. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column eluting with hexanes:ethyl acetate 9:1 to give 1.88 g (88% yield) of 4-(3-fluoro-phenyl)-1H-indole as a colorless syrup. 1H-NMR (400 MHz, DMSO-d6) delta11.30 (br s, 1H), 7.52 (m, 2H), 7.45 (m, 3H), 7.20 (m, 2H), 7.12 (m, 1H), 6.55 (m, 1H). MS (m/z) 212 [M++1].
1.88 g (88%)	With nitrogen;Pd(PPh3)4; palladium; In tetrahydrofuran; water;	Example A-3 4-(3-Fluoro-phenyl)-1H-indole To a mixture of <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole</strong> (3, 2.43 g, 10 mmol), and 3-bromofluorobenzene (1.09 mL, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70 C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluding with hexanes-EtOAc (9:1) to provide 1.88 g (88%) of the product 4-(3-fluoro-phenyl)-1H-indole as a colorless syrup. 1H-NMR (400 MHz, DMSO-d6) delta 11.30 (br s, 1H, NH), 7.52 (m, 2H, aromatic), 7.45 (m, 3H, aromatic), 7.20 (m, 2H, aromatic), 7.12 (m, 1H, aromatic), 6.55 (m, 1H, aromatic). MS m/z 212 [M++1].

Reference： [1]Patent: US2004/186160,2004,A1 .Location in patent: Page/Page column 23
[2]Patent: US2003/69297,2003,A1

4
[ 663191-76-2 ]
[ 388116-27-6 ]
[ 855291-44-0 ]

Yield	Reaction Conditions	Operation in experiment
20%	With sodium carbonate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride;tris-(dibenzylideneacetone)dipalladium(0); In water; toluene; at 110℃;	Example 8A 4-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indole Under N2, the mixture of Example 7A (168 mg, 0.7 mmol), <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole</strong> (ref. WO02055517, 170 mg, 0.7 mmol), Pd2(dba)3 (Aldrich, 19 mg, 0.02 mmol), 1,3-bis(2,6-iso-propylphenyl)imidazolium chloride (Strem Chemicals, 26 mg, 0.06 mmol) and aqueous Na2CO3 (2 M, 1 mL) in toluene (10 mL) was stirred at 110 C. overnight, After the reaction was complete, it was cooled down to room temperature and diluted with EtOAc (30 mL). The mixture was then washed with brine (2*5 mL) and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.10) as solid (45 mg, yield, 20%). 1H NMR (300 MHz, CD3OD) delta 1.51-1.65 (m, 1H), 1.70-1.93 (m, 2H), 2.01-2.16 (m, 1H), 2.31-2.39 (m, 1H), 2.78-3.09 (m, 5H), 3.45-3.56 (m, 1H), 5.30-5.38 (m, 1H), 6.78 (dd, J=3.4, 1.0 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.30 (d, J=9.5 Hz, 1H), 7.36 (d, J=3.1 Hz, 1H), 7.40 (dd, J=7.5, 1.0 Hz, 1H), 7.52 (dt, J=8.1, 1.0 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H) ppm. MS (DCl/NH3): m/z 321 (M+H)+.
20%	With sodium carbonate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride;tris-(dibenzylideneacetone)dipalladium(0); In water; toluene; at 110℃;	Under N2, the mixture of Example 7A (168 mg, 0.7 mmol), <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole</strong> (ref. WO02055517, 170 mg, 0.7 mmol), Pd2(dba)3 (Aldrich, 19 mg, 0.02 mmol), 1,3-bis(2,6-iso-propylphenyl)imidazolium chloride (Strem Chemicals, 26 mg, 0.06 mmol) and aqueous Na2CO3 (2 M, 1 mL) in toluene (10 mL) was stirred at 110 C. overnight, After the reaction was complete, it was cooled down to room temperature and diluted with EtOAc (30 mL). The mixture was then washed with brine (2×5 mL) and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.10) as solid (45 mg, yield, 20%). 1H NMR (300 MHz, CD3OD) delta 1.51-1.65 (m, 1H), 1.70-1.93 (m, 2H), 2.01-2.16 (m, 1H), 2.31-2.39 (m, 1H), 2.78-3.09 (m, 5H), 3.45-3.56 (m, 1H), 5.30-5.38 (m, 1H), 6.78 (dd, J=3.4, 1.0 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.30 (d, J=9.5 Hz, 1H), 7.36 (d, J=3.1 Hz, 1H), 7.40 (dd, J=7.5, 1.0 Hz, 1H), 7.52 (dt, J=8.1, 1.0 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H) ppm. MS (DCl/NH3): m/z 321 (M+H)+.
20%	With sodium carbonate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride;tris-(dibenzylideneacetone)dipalladium(0); In water; toluene; at 110℃;	Under N2, the mixture of Example 7A (168 mg, 0.7 mmol), 4-(4 ,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-indole (ref. WO02055517, 170 mg, 0.7 mmol), Pd2(dba)3 (Aldrich, 19 mg, 0.02 mmol), 1 ,3-bis(2,6-iso- EPO <DP n="59"/>propylphenyl)imidazolium chloride (Strem Chemicals, 26 mg, 0.06 mmol) and aqueous Na2CO3 (2 M, 1 ml_) in toluene (10 mL) was stirred at 1 10 0C overnight, After the reaction was complete, it was cooled down to room temperature and diluted with EtOAc (30 mL). The mixture was then washed with brine (2 x 5 mL) and the title compound was purified by chromatography (SiO2, CH2CI2 : MeOH : NH3 H2O,90:10:1 , Rf. 0.10) as solid (45 mg, yield, 20%). 1H NMR (300 MHz, CD3OD) delta 1.51- 1.65 (m, 1 H), 1.70-1 .93 (m, 2H), 2.01-2.16 (m, 1 H), 2.31-2.39 (m, 1 H), 2.78-3.09 (m, 5H), 3.45-3.56 (m, 1 H), 5.30-5.38 (m, 1 H), 6.78 (dd, J=3.4, 1 .0 Hz, 1 H), 7.25 (t, J=7.8 Hz, 1 H), 7.30 (d, J=9.5 Hz, 1 H), 7.36 (d, J=3.1 Hz, 1 H), 7.40 (dd, J=7.5, 1.0 Hz, 1 H), 7.52 (dt, J= 8.1 , 1.0 Hz, 1 H), 8.07 (d, J=9.2 Hz, 1 H) ppm. MS (DCI/NH3): m/z 321 (M+H)+.

Reference： [1]Patent: US2005/137184,2005,A1 .Location in patent: Page/Page column 22
[2]Patent: US2005/137204,2005,A1 .Location in patent: Page/Page column 25
[3]Patent: WO2006/65233,2006,A1 .Location in patent: Page/Page column 57-58

5
[ 52488-36-5 ]
[ 73183-34-3 ]
[ 120-72-9 ]
[ 388116-27-6 ]

Yield	Reaction Conditions	Operation in experiment
21%; 66%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dichloromethane; dimethyl sulfoxide; at 80℃; for 22h;	To a mixture OF 4-BROMOINDOLE (9. 80G, 50 MMOL), pinacle diborate (13. 97G, 55 MMOL), and KOAc (14. 72G, 150 MMOL) in DMSO (200 mL) was added palladium catalyst PdCl2(dppf) CH2Cl2 (1.22g, 1. 5 MMOL). The system was degassed, and then charged with nitrogen for three times. The mixture was stirred at 80 C oil bath under nitrogen for 22 hours. TLC showed the complete disappearance of the starting material 4-bromoindole. The mixture was cooled to room temperature, and then poured to water (1 L). The product was extracted with ethyl acetate for three times. The combined extracts were washed by brine for five times to remove DMSO solvent, and then dried over NA2SO4. During the washing step, the catalyst may precipitate out, which was removed by filtration. The ethyl acetate solution was filtered and condensed. The residue was purified on a silica gel column eluting with EtOAc-hexane (9 : 1). The first fraction provided the side product indole (1. 25G, 21% yield), Rf 0. 55 (EtOAc-Hexane 5 : 1). The second fraction provided 4- (4, 4, 5, 5-TETRAMETHYL- [1, 3, 2] DIOXABOROLAN-2-YL)-1H- indole as a white solid (8. 01g, 66%), RF 0. 46 (EtOAc-Hexane 5 : 1). H NMR (300 MHz, DMSO-D6) : 11. 03 (bs, 1H, N-H)), 7. 49 (d, J 7. 7 Hz, 1H, H-5), 7. 38 (dd, J 0. 9 Hz, J 7. 0 Hz, 1H, H-7), 7. 38 (t, J 2. 6Hz, 1H, H-2), 7. 06 (dd, J 7. 7 Hz, J 7. 0 Hz, 1H, H-6), 6. 73 (bd, J 2. 2 Hz, 1H, H-3), 1. 32 (s, 12H, 4CH3) ; MS (m/e) : 244 (M+H) +.

Reference： [1]Patent: WO2004/76412,2004,A2 .Location in patent: Page 96

6
[ 108-86-1 ]
[ 388116-27-6 ]
[ 35577-92-5 ]

Yield	Reaction Conditions	Operation in experiment
1.38 g (78%)	With nitrogen In tetrahydrofuran; water	A.1 4-Phenyl-1H-indole Example A-1 4-Phenyl-1H-indole To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (pinacole 4-indoleboronate (2 g, 8.2 mnmol) and 3-bromobenzene (0.87 mL, 8.3 mmol) in THF (28 mL) were added Palladium catalyst Pd(PPh3)4 (284 mg, 0.25 mmol) and the freshly prepared sodium hydroxide solution (984 mg in 9 mL of water). The system was degassed and then charged with nitrogen for three times. The mixture was stirred under nitrogen at 70 C. oil bath for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluding with hexanes: EtOAc 9:1 to give 1.38 g (78%) of 4-phenyl-1H-indole as a colorless liquid. 1H NMR (360 MHz, DMSO-d6) δ 11.26 (br s, 1H, NH), 7.66 (d, J=7.9 Hz, 2H), 7.50 (t, J=7.5 Hz, 2H), 7.35-7.43 (m, 3H), 7.18 (t, J=7.5 Hz, 1H), 7.08 (d, J=7.1 Hz, 1H),6.41 (brs, 1H). MS m/z 194 [M++1].

Reference： [1]Current Patent Assignee: PFIZER INC - US2003/69297, 2003, A1

7
[ 64248-56-2 ]
[ 388116-27-6 ]
[ 442562-79-0 ]

Yield	Reaction Conditions	Operation in experiment
9.77 g (91%)	With nitrogen;Pd(PPh3)4; palladium; In 1,2-dimethoxyethane; water; ethyl acetate;	Example A-22 4-(2,6-Difluoro-phenyl)-1H-indole To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (11.34 g, 46.6 mmol), and <strong>[64248-56-2]1-bromo-2,6-difluorobenzene</strong> (9 g, 46.6 mmol) in 1,2-dimethoxyethane (204 mL) were added Palladium catalyst Pd(PPh3)4 (1.62 g, 1.4 mmol) and the freshly prepared sodium carbonate solution (15.19 g in 66 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 110 C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 9.77 g (91%) of 4-(2,6-difluoro-phenyl)-1H-indole.

Reference： [1]Patent: US2003/69297,2003,A1

8
[ 38573-88-5 ]
[ 388116-27-6 ]
[ 442562-83-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydroxide;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 70℃;Inert atmosphere;	Step 2 4-(2,3-Difluoro-phenyl)-1H-indole 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 6b (1.22 g, 5 mmol) was dissolved in 20 ml of tetrahydrofuran under stirring, and added with <strong>[38573-88-5]1-bromo-2,3-difluoro-benzene</strong> (0.97 g, 5 mmol), tetrakis (triphenylphosphine)palladium (0.17 g, 0.15 mmol) and sodium hydroxide solution (7 ml, 2 mol/L) under an argon atmosphere. Upon completion of the addition, the reaction system was stirred at 75° C. in an oil bath overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature and extracted with ethyl acetate (20 ml*3). The combined organic extracts were washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4-(2,3-difluoro-phenyl)-1H-indole 6c (800 mg, yield 70percent) as a white solid. MS m/z (ESI): 228.4 [M-1]
70%	With sodium hydroxide;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 75℃;Inert atmosphere;	4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 6b (1.22 g, 5 mmol) was dissolved in 20 ml of tetrahydrofuran under stirring, and added with <strong>[38573-88-5]1-bromo-2,3-difluoro-benzene</strong> (0.97 g, 5 mmol), tetrakis (triphenylphosphine)palladium (0.17 g, 0.15 mmol) and sodium hydroxide solution (7 ml, 2 mol/L) under an argon atmosphere. Upon completion of the addition, the reaction system was stirred at 75°C in an oil bath overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature and extracted with ethyl acetate (20 ml.x.3). The combined organic extracts were washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4-(2,3-difluoro-phenyl)-1H-indole 6c (800 mg, yield 70percent) as a white solid. MS m/z (ESI): 228.4[M-1]
70%	With sodium hydroxide;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 75℃;Inert atmosphere;	4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 3b (1.22 g, 5 mmol) was dissolved in 20 mL of tetrahydrofuran under stirring under an argon atmosphere, and <strong>[38573-88-5]1-bromo-2,3-difluoro-benzene</strong> (0.97 g, 5 mmol), tetrakis (triphenylphosphine) palladium (0.17 g, 0.15 mmol) and 7 mL of sodium hydroxide solution (2M) were then added to the solution. Upon completion of the addition, the reaction system was stirred at 75°C in an oil bath overnight. The reaction was completed until TLC showed the disappearance of starting materials. The reaction mixture was naturally cooled down to room temperature and extracted with ethyl acetate (20 mL*3). The combined organic extracts were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography to give the title compound 4-(2,3-difluoro-phenyl)-1H-indole 3c (800 mg, yield 70percent) as a white solid. MS m/z (ESI): 228.4[M-1]

70%	With sodium hydroxide;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 75℃;Inert atmosphere;	Step 2 4-(2,3-difluoro-phenyl)-1H-indole 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 3b (1.22 g, 5 mmol) was dissolved in 20 mL of tetrahydrofuran under stirring under an argon atmosphere, and <strong>[38573-88-5]1-bromo-2,3-difluoro-benzene</strong> (0.97 g, 5 mmol), tetrakis (triphenylphosphine) palladium (0.17 g, 0.15 mmol) and 7 mL of sodium hydroxide solution (2M) were then added to the solution. Upon completion of the addition, the reaction system was stirred at 75° C. in an oil bath overnight. The reaction was completed until TLC showed the disappearance of starting materials. The reaction mixture was naturally cooled down to room temperature and extracted with ethyl acetate (20 mL*3). The combined organic extracts were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography to give the title compound 4-(2,3-difluoro-phenyl)-1H-indole 3c (800 mg, yield 70percent) as a white solid. MS m/z (ESI): 228.4[M-1]
2.92 g (82%)	With nitrogen;Pd(PPh3)4; palladium; In tetrahydrofuran; water; ethyl acetate;	Example A-26 4-(2,3-Difluoro-phenyl)-1H-indole To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3.78 g, 15.5 mmol), and <strong>[38573-88-5]1-<strong>[38573-88-5]bromo-2,3-difluorobenzene</strong></strong> (3 g, 15.5 mmol) in THF (55 mL) were added Palladium catalyst Pd(PPh3)4 (0.54 g, 0.47 mmol) and the freshly prepared sodium hydroxide solution (1.865 g, 47 mmol in 22 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 2.92 g (82percent) of 4-(2,3-difluoro-phenyl)-1H-indole.

Reference： [1]Patent: US2010/75952,2010,A1 .Location in patent: Page/Page column 47
[2]Patent: EP2157093,2010,A1 .Location in patent: Page/Page column 39
[3]Patent: EP2179998,2010,A1 .Location in patent: Page/Page column 14; 15
[4]Patent: US2010/160317,2010,A1 .Location in patent: Page/Page column 14
[5]Patent: US2003/69297,2003,A1

9
[ 915412-89-4 ]
[ 73183-34-3 ]
[ 388116-27-6 ]

Yield	Reaction Conditions	Operation in experiment
39%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 90℃;	A tube was charged with trifluoro-methanesulfonic acid 2-cyano-1H-indol-4-yl ester (0.136 g, 0.469 mmol), 0.150 g (0.61 mmol) bis(pinacolato)diboron, 0.138 g (1.41 mmol) potassium acetate, Pd(dppf)Cl2.CH2Cl2 complex (0.039 g, 0.047 mmol) and 3 mL anhydrous DMSO. The tube was flushed with nitrogen and sealed, and the reaction mixture was heated at 90 C. overnight. The reaction mixture was cooled, filtered through silica gel and the filter cake was washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography to give 0.049 g (39% yield) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole. This material was protected with triisopropylsilyl chloride to give 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-indole using conditions similar to those described in Example 21.

Reference： [1]Patent: US2006/270686,2006,A1 .Location in patent: Page/Page column 49-50

10
[ 1072084-76-4 ]
[ 388116-27-6 ]
[ 1072270-24-6 ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 125℃; for 0.833333h;	A stirred mixture of 4-(6-chloro-2-methanesulfonyl-pyrimidin-4-yl)-morpholine (1.04 g; 3.74 mmol), indole-4-boronic acid (0.71 g; 4.41 mmol), Pd2dba3 (34 mg; 0.037 mmol), PCy3 (25 mg; 0.089 mmol), K3PO4 (5 mL of a 1.27M aqeuous solution; 6.4 mmol) and dioxane (10 mL) was heated at 125C in a microwave for 50 min. The organic layer was separated and the aqueous extracted with a further portion of dioxane (30 ml). The combined organic layers were filtered through a pad of silica (EtOAc as eluent), the solvent was evaporated and the residue triturated with MeOH to afford the title compound as an off-white solid (0.83 g; 62 %). deltaH (400 MHz, CDCl3) 3.41 (s, 3H), 3.82-3.85 (m, 8H), 7.08-7.10 (m, 2H), 7.32, (t, J = 8.0, IH), 7.37 (t, J = 2.8, IH), 7.57 (d, J = 8.0), 7.65 (d, J = 7.6, IH), 8.43 (br s, IH). [M+H]+ 359.

Reference： [1]Patent: WO2008/125833,2008,A1 .Location in patent: Page/Page column 30; 59

11
[ 1072269-67-0 ]
[ 388116-27-6 ]
[ 1072269-71-6 ]

Yield	Reaction Conditions	Operation in experiment
31%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 125℃; for 0.166667 - 0.5h;Microwave irradiation;	Method B.; A mixture of 2-chloro-pyrimidine (1 eq.), Cs2CO3 (1.5 eq.), indole boronate ester (1.2 eq.) and tetrakis(triphenylphosphine)palladium (0.05 eq.) in dioxane/water (3: 1) was heated at 1250C, for 10 - 30 min in a microwave reactor (Smith synthetiser). The resulting mixture was diluted with water then extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated then purified by either preparative HPLC or column <n="37"/>chromatography to give the desired product.; Reference Example 25: {2- [4-(l/Mndol-4-yl)-6-morpholin-4-vI-pyrimidin-2-vIl - ethyl} -carbamic acid fert-butyl ester; Prepared using method B. The title compound was obtained as a pale yellow oil(35 mg, 31 %). [M + H]+ 424.6

Reference： [1]Patent: WO2008/125833,2008,A1 .Location in patent: Page/Page column 28; 35-36; 47

12
[ 1072269-69-2 ]
[ 388116-27-6 ]
[ 1072268-16-6 ]

Yield	Reaction Conditions	Operation in experiment
43%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 125℃; for 0.166667 - 0.5h;Microwave irradiation;	Method C.; A mixture of 2-chloro-pyrimidine (1 eq.), Cs2CO3 (1.5 eq.), indole boronate ester (1.2 eq.) and tetrakis(triphenylphosphine)palladium (0.05 eq.) in dioxane/water (3:1) was heated at 125C, for 10 - 30 min in a microwave reactor (Smith synthetiser). The resulting mixture was loaded onto Isolute SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.; Example 6: 4- [6-Morpholin-4-yI-2-(p yridin-3-yImethoxymethyl)-pyrimidin-4-yll - IH- indole; Prepared using Method C of Reference Example 2. The title compound was obtained0 as a white solid (54 mg, 43 %). [M + H]+ 402.1 1H NMR (400 MHz, CHCl3-d): delta 3.68-3.76 (m, 4 H), 3.77-3.85 (m, 4 H), 4.75 (s, 2 H), 4.81 <n="66"/>(s, 2 H), 6.89 (s, 1 H), 7.03 (m, 1 H), 7.22-7.31 (m, 3 H), 7.46 (d, J = 8.5 Hz, 1 H), 7.57 (dd, J = 7.5, 1 Hz, 1 H), 7.82 (m, 1 H), 8.47 (bs, 1 H), 8.53 (dd, J = 5, 1.5 Hz, 1 H) and 8.67 (d, , J = 1.5 Hz, 1 H).

Reference： [1]Patent: WO2008/125833,2008,A1 .Location in patent: Page/Page column 36; 64-65

13
[ 1093075-13-8 ]
[ 388116-27-6 ]
[ 1093075-37-6 ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 140℃; for 0.166667 - 0.5h;Microwave irradiation;	A mixture of the appropriate 5-chloro-thiazolopyrimidine (1 eq.), Na2CO3 (1.5 eq.), the appropriate indole boronate ester (1.2 eq.) and tetrakis(triphenylphosphine)palladium (0.1 eq.) in acetonitrile/water (2:1) was heated at 140 C, for 10 - 30 min in a microwave reactor. The resulting mixture was diluted with water then extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo then purified by either preparative HPLC or column chromatography to give the desired product.Alternatively, the reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.

Reference： [1]Patent: WO2008/152390,2008,A1 .Location in patent: Page/Page column 43; 75; 76-77

14
[ 1093075-16-1 ]
[ 388116-27-6 ]
[ 1093075-42-3 ]

Yield	Reaction Conditions	Operation in experiment
52%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 140℃; for 0.166667 - 0.5h;Microwave irradiation;	A mixture of the appropriate 5-chloro-thiazolopyrimidine (1 eq.), Cs2CO3 (1.5 eq.), the appropriate indole boronate ester (1.2 eq.) and tetrakis(triphenylphosphine)palladium (0.05 eq.) in acetonitrile/water (3:1) was heated at 140 C, for 10 - 30 min in a microwave reactor. The resulting mixture was diluted with water then extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo then purified by either preparative HPLC or column chromatography to give the desired product. Alternatively, the reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed <n="44"/>with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.

Reference： [1]Patent: WO2008/152390,2008,A1 .Location in patent: Page/Page column 42-43; 78

15
[ 885518-50-3 ]
[ 388116-27-6 ]
[ 1198409-41-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 115℃; for 18h;	6-Bromo-1 /-/-indazol-4-amine (10 g) (available from Sinova Inc.) and 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-indole (16.05 g) (available from Frontier Scientific, Europe Ltd) were dissolved in 1 ,4-dioxane (60 ml) and water (60 ml). 2 M sodium carbonate (70.7 ml) and Pd(dppf)CI2-DCM adduct (1 .93 g) were added and the mixture was heated at 1 15 C for 18 h. The reaction mixture was diluted with DCM (200 ml) and the organic and aq layers were separated using a hydrophobic frit. The aq layer was extracted with further quantities of DCM (2 x 200 ml), using a hydrophobic frit to separate the layers. The organic layers were combined and silica (80 g) was added. The solvent was removed in vacuo to give a crude material that was purified by chromatography on silica gel (750 g cartridge, Flashmaster II) eluting with 0 - 100 % ethyl acetate in cyclohexane over 60 min. The oil was dried in vacuo on a drying rack overnight. The yellow foam was dissolved in DCM (3 x 400 ml), removing the solvent in vacuo after each dissolution, ethyl acetate (50 ml) was then added and the solvent was removed in vacuo. The solid obtained was dried in a vacuum oven to afford the title compound (12.8 g) as a yellow foam.LCMS (Method A); Rt = 2.71 min, MH+ = 249.
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 115℃; for 18h;	6-Bromo-1 /-/-indazol-4-amine (10 g) (available from Sinova Inc.) and 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-indole (16.05 g) (available from Frontier Scientific, Europe Ltd) were dissolved in 1 ,4-dioxane (60 ml) and water (60 ml). 2 M sodium carbonate (70.7 ml) and Pd(dppf)CI2-DCM adduct (1 .93 g) were added and the mixture was heated at 1 15 C for 18 h. The reaction mixture was diluted with DCM (200 ml) and the organic and aq layers were separated using a hydrophobic frit. The aq layer was extracted with further quantities of DCM (2 x 200 ml), using a hydrophobic frit to separate the layers. The organic layers were combined and silica (80 g) was added. The solvent was removed in vacuo to give a crude material that was purified by chromatography on silica gel (750 g cartridge, Flashmaster II) eluting with 0 - 100 % ethyl acetate in cyclohexane over 60 min. The oil was dried in vacuo overnight. The yellow foam was dissolved in DCM (3 x 400 ml), removing the solvent in vacuo after each dissolution, ethyl acetate (50 ml) was then added and the solvent was removed in vacuo. The solid obtained was dried in a vacuum oven to afford the title compound (12.8 g) as a yellow foam.LC/MS (method A); Rt = 2.71 min, MH+ = 249.
12.8 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 115℃; for 18h;	6-(1H-Indol-4-yl)-1H-indazol-4-amine 6-Bromo-1H-indazol-4-amine (10 g) (available from Sinova Inc.) and <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (16.05 g) (available from Frontier Scientific, Europe Ltd) were dissolved in 1,4-dioxane (60 ml) and water (60 ml). 2 M sodium carbonate (70.7 ml) and Pd(dppf)Cl2-DCM adduct (1.93 g) were added and the mixture was heated at 115 C. for 18 h. The reaction mixture was diluted with DCM (200 ml) and the organic and aq layers were separated using a hydrophobic frit. The aq layer was extracted with further quantities of DCM (2200 ml), using a hydrophobic frit to separate the layers. The organic layers were combined and silica (80 g) was added. The solvent was removed in vacuo to give a crude material that was purified by chromatography on silica gel (750 g cartridge, Flashmaster II) eluting with 0-100% ethyl acetate in cyclohexane over 60 min. The oil was dried in vacuo on a drying rack overnight. The yellow foam was dissolved in DCM (3400 ml), removing the solvent in vacuo after each dissolution. ethyl acetate (50 ml) was then added and the solvent was removed in vacuo. The solid obtained was dried in a vacuum oven to afford the title compound (12.8 g) as a yellow foam. ECMS (Method B); R=2.71 mi MH=249.

	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 115℃; for 18h;	6-Bromo-1 H-indazol-4-amine (available from Sinova, 10.Og, 47.2mmol) and 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole (available from Frontier Scientific, Europe Ltd, 16.05g, 66.0mmol) were dissolved in 1 ,4-dioxane (60ml) and water (60ml). Sodium carbonate solution (2M, 70.7ml) and Pd(dppf)CI2-DCM adduct (1.926g, 2.36mmol) were added and the mixture was heated at 1 15 0C for 18 hr. The reaction mixture was diluted with dichloromethane (200ml) and the organic and aqueous layers were separated by hydrophobic frit. The aqueous layer was extracted with further quantities of dichloromethane (2 x 200ml), using a hydrophobic frit to separate the layers. The organic layers were combined and silica (8Og) was added. The solvent was removed in vacuo to give a crude material which was purified by chromatography on silica gel (750 g cartridge, Flashmaster II) eluting with 0-100% ethyl acetate in cyclohexane over 60 minutes. The oil was dried in vacuo on a drying rack overnight. The yellow foam was dissolved in dichloromethane (3 x 400ml), removing the solvent in vacuo after each dissolution, ethyl acetate (50ml) was then added and the solvent was removed in vacuo. The solid obtained was dried in a vacuum oven to give the title compound (12.8 g) as a yellow foam. LCMS (Method A) R1 = 2.71 mins, MH+ = 249
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 115℃; for 18h;	Intermediate 336-(1 H-lndol-4-yl)-1 H-indazol-4-amine 6-Bromo-1 H-indazol-4-amine (1 Og) (available from Sinova Inc.) and 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole (16.05g) (available from Frontier Scientific, Europe Ltd) were dissolved in 1 ,4-dioxane (60ml) and water (60ml). 2M sodium carbonate (70.7ml) and Pd(dppf)CI2-DCM adduct (1.93g) were added and the mixture was heated at 1 15C for 18h. The reaction mixture was diluted with DCM (200ml) and the organic and aqueous layers were separated using a hydrophobic frit. The aqueous layer was extracted with further quantities of DCM (2x200ml), using a hydrophobic frit to separate the layers. The organic layers were combined and silica (8Og) was added. The solvent was removed in vacuo to give a crude material that was purified by chromatography on silica gel (750 g cartridge, Flashmaster II) eluting with 0-100% ethyl acetate in cyclohexane over 60min. The oil was dried in vacuo on a drying rack overnight. The yellow foam was dissolved in DCM (3x400ml), removing the solvent in vacuo after each dissolution, ethyl acetate (50ml) was then added and the solvent was removed in vacuo. The solid obtained was dried in a vacuum oven to afford the title compound (12.8g) as a yellow foam. LC/MS Rt 2.71 min m/z 249 [MH+]. Method A
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 115℃; for 18h;	Intermediate 46-(1 H-lndol-4-yl)-1 H-indazol-4-amine 6-Bromo-1 H-indazol-4-amine (10 g, available from Sinova Inc.) and 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole (16.05g, available from Frontier Scientific, Europe Ltd) were dissolved in 1 ,4-dioxane (60ml) and water (60ml). 2M sodium carbonate (70.7ml) and Pd(dppf)CI2-DCM adduct (1.93g) were added and the mixture was heated at 115C for 18 hr. The reaction mixture was diluted with dichloromethane (200ml) and the organic and aqueous layers were separated by hydrophobic frit. The aqueous layer was extracted with further quantities of dichloromethane (2 x 200ml), using a hydrophobic frit to separate the layers. The organic layers were combined and silica (8Og) was added. The solvent was removed in vacuo to give a crude material that was purified by chromatography on silica gel (75Og cartridge, Flashmaster II) eluting with 0-100% ethyl acetate in cyclohexane over 60 minutes. The oil was dried in vacuo on a drying rack overnight. The resultant yellow foam was dissolved in dichloromethane (3 x 400ml), removing the solvent in vacuo after each dissolution. Ethyl acetate (50ml) was then added and the solvent was removed in vacuo. The solid obtained was dried in a vacuum oven to afford the title compound (12.8g) as a yellow foam. LCMS (Method A) m/z 249 [MH+], R1 2.71 mins.

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7381 - 7399
[2]Patent: WO2011/67364,2011,A1 .Location in patent: Page/Page column 66-67
[3]Patent: WO2011/67365,2011,A1 .Location in patent: Page/Page column 72-73
[4]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 138
[5]Patent: WO2009/147190,2009,A1 .Location in patent: Page/Page column 73
[6]Patent: WO2009/147188,2009,A1 .Location in patent: Page/Page column 101
[7]Patent: WO2009/147189,2009,A1 .Location in patent: Page/Page column 59

16
[ 1198437-71-6 ]
[ 388116-27-6 ]
[ 1198437-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;bis[1,2-bis(diphenylphosphino)ferrocene]-palladium(0); In 1,4-dioxane; water; at 100℃; for 0.166667h;microwave;	6-Bromo-1 -(phenylsulfonyl)-1 /-/-indazol-4-amine (3 g), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-indole (2.278 g), Pd(dppf)CI2 (0.623 g) and sodium carbonate (2.71 g) were divided between 2 microwave vials and dissolved in 1 ,4-dioxane (16 ml) and water (16 ml) to give 8 ml of each solvent in each vial. The vials were heated in the microwave at 100 C for 10 min. The mixtures were combined and filtered through Celite, washing with ethyl acetate. The resulting mixture was partitioned between water (100 ml) and ethyl acetate (100 ml) and the layers separated. The aq layer was extracted with further ethyl acetate (2 x 50 ml) and the organic extracts were combined, passed through a hydrophobic frit and the solvent removed in vacuo to give a brown solid which was pre- adsorbed onto silica and added to the top of a 100 g silica SPE cartridge. This was eluted with 0-100 % ethyl acetate:cyclohexane over 60 min on the FlashMaster II. The product- containing fractions were combined and the solvent was removed in vacuo to afford the title compound as orange crystals which were dried on a high vacuum line for 1 hour. LCMS (Method B): Rt = 1 .1 1 min, MH+ = 389.
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 0.166667h;microwave;	6-Bromo-1 -(phenylsulfonyl)-1 H-indazol-4-amine (3 g), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-indole (2.278 g), Pd(dppf)CI2 (0.623 g) and sodium carbonate (2.71 g) were divided between 2 microwave vials and dissolved in 1 ,4-dioxane (16 ml) and water (16 ml) to give 8 ml of each solvent in each vial. The vials were heated in the microwave at 100 C for 10 min. The mixtures were combined and filtered through Celite, washing with EtOAc. The resulting mixture was partitioned between water (100 ml) and EtOAc (100 ml) and the layers separated. The aqueous layer was extracted with further EtOAc (2 x 50 ml) and the organic extracts were combined, passed through a hydrophobic frit and the solvent removed in vacuo to give a brown solid which was pre- adsorbed onto silica and added to the top of a 100 g silica SPE cartridge. This was eluted with 0 - 100 % EtOAc:cyclohexane over 60 min on the FlashMaster II. The product- containing fractions were combined and the solvent was removed in vacuo to afford the title compound as orange crystals which were dried on a high vacuum line for 1 h.LCMS (Method B): Rt = 1 .1 1 min, MH+ = 388.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 0.166667h;Microwave irradiation;	6-(1H-Indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-amine 6-Bromo-1-(phenylsulfonyl)-1H-indazol-4-amine (3 g), <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (2.278 g), Pd(dppf)Cl2 (0.623 g) and sodium carbonate (2.71 g) were divided between 2 microwave vials and dissolved in 1,4-dioxane (16 ml) and water (16 ml) to give 8 ml of each solvent in each vial. The vials were heated in the microwave at 100 C. for 10 min. The mixtures were combined and filtered through Celite, washing with ethyl acetate. The resulting mixture was partitioned between water (100 ml) and ethyl acetate (100 ml) and the layers separated. The aq layer was extracted with further ethyl acetate (2*50 ml) and the organic extracts were combined, passed through a hydrophobic frit and the solvent removed in vacuo to give a brown solid which was pre-adsorbed onto silica and added to the top of a 100 g silica SPE cartridge. This was eluted with 0-100% ethyl acetate:cyclohexane over 60 min on the FlashMaster II. The product-containing fractions were combined and the solvent was removed in vacuo to afford the title compound as orange crystals which were dried on a high vacuum line for 1 hour. LCMS (Method E): R=1 .11 mi MH=389.

	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 110℃; for 0.25h;Microwave irradiation;	6-Bromo-1-(phenylsulfonyl)-1 H-indazol-4-amine (3 g, 8.52 mmol), 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1H-indole (2.28 g, 9.37 mmol), Pd(dppf)CI2 (0.623 g, 0.852 mmol) and sodium carbonate (2.71 g, 25.6 mmol) were divided equally between 2 x microwave vials and each dissolved in 1 ,4-dioxane (8 ml.) and water (8 ml_). The vials were heated in the microwave at 1 10 0C for 15 min, then allowed to cool. The mixtures were combined and filtered through Celite, washing with EtOAc. The resulting mixture was partitioned between water (100 ml) and EtOAc (100 ml) and the layers separated. The aqueous layer was extracted with further EtOAc (2 x 50 ml) and the organic extracts were combined and the solvent removed in vacuo. The residue (4.6 g) was pre-adsorbed onto silica, which was added to the top of 2 x 100 g silica SPE cartridges. These were eluted with 0-100% EtOAc/cyclohexane over 60 minutes on the FlashMaster II. The product-containing fractions were combined and the solvent was removed in vacuo to afford the title compound as an orange solid (920mg). LCMS (Method C) R1 = 1.04 min, MH+=389
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 0.166667h;Microwave irradiation;	Intermediate 1056-(1 H-lndol-4-yl)-1 -(phenylsulfonyl)-i H-indazol-4-amine 6-Bromo-1-(phenylsulfonyl)-1 H-indazol-4-amine (3 g, 8.52 mmol), 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-indole (2.278 g, 9.37 mmol), Pd(dppf)CI2 (0.623 g, 0.852 mmol) and sodium carbonate (2.71 g, 25.6 mmol) were divided between 2 x microwave vials and dissolved in 1 ,4-dioxane (16 ml.) and water (16 ml_); 8 ml of each solvent in each vial. The vials were heated in the microwave at 100 0C for 10 min. The mixtures were combined and filtered through Celite, washing with EtOAc. The resulting mixture was partitioned between water (100 ml) and EtOAc (100 ml) and the layers separated. The aqueous layer was extracted with further EtOAc (2 x 50 ml) and the organic extracts were combined, passed through a hydrophobic frit and the solvent removed in vacuo to give a brown solid which was pre-adsorbed onto silica and added to the top of a 10O g silica SPE cartridge. This was eluted with 0-100% EtOAc/cyclohexane over 60 minutes on the FlashMaster II. The product-containing fractions were combined and the solvent was removed in vacuo to afford the title compound as orange crystals which were dried on a high vacuum line for 1 hour.LCMS (Method D): R1 = 1.11 mins, MH+ = 388.

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7381 - 7399
[2]Patent: WO2011/67364,2011,A1 .Location in patent: Page/Page column 68-69
[3]Patent: WO2011/67365,2011,A1 .Location in patent: Page/Page column 65
[4]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 139; 140
[5]Patent: WO2009/147190,2009,A1 .Location in patent: Page/Page column 84
[6]Patent: WO2009/147188,2009,A1 .Location in patent: Page/Page column 136

17
[ 1198437-04-5 ]
[ 388116-27-6 ]
[ 1198437-06-7 ]

Yield	Reaction Conditions	Operation in experiment
	With water; sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 150℃; for 0.25h;microwave;	To a solution of 6-bromo-3-fluoro-1 H-indazol-4-amine (0.25 g) in 1 ,4-dioxane (5 ml) was added 4-(4,4.5.5-tetramethyl-1 .3,2-dioxaborolan-2-yl)-1 H-indole (0.317 g), Pd(dppf)CI2 (0.04 g) followed by water (3.33 ml) and 2 M sodium carbonate (aq) (1 .63 ml). The reaction vessel was sealed and heated in a microwave at 150 C for 15 min. The sample was loaded onto a 5 g Silica cartridge and eluted with methanol (4 column volumes). The fractions were combined and evaporated to dryness to give a brown solid. A portion of this solid (0.2 g) was purified by MDAP (method A). The appropriate fraction was collected, evaporated to dryness, azeotroped with methanol (1 x 5 ml) then left under vacuum to give the title compound as a beige solid, 39 mg.LCMS (method A); Rt = 2.22 min, MH+ = 267.
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 150℃; for 0.25h;Microwave irradiation;	To 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole (24mg) and 1 ,1 '- bis(diphenylphosphino)ferrocenedichloropalladium(ll) (3mg) at 200C in a microwave vial was added a solution of 6-bromo-3-fluoro-1 H-indazol-4-amine (19mg) in 1 ,4-dioxane (0.75ml) followed by water (0.5ml) and aqueous sodium carbonate (2M, 0.124ml). The reaction vessel was sealed and heated under microwave irradiation at 1500C for 15min. After cooling, the black solution was loaded onto a 500mg silica cartridge which was then <n="85"/>eluted with methanol (4 column volumes). The eluant was blown to dryness, re-dissolved in methanol (3ml), filtered and blown to dryness to give the title compound (67mg) as a brown film.LC/MS Rt 2.99min m/z 267 [MH+]. Method A
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 150℃; for 0.25h;Microwave irradiation;	Intermediate 463-Fluoro-6-(1H-indol-4-yl)-1H-indazol-4-amine <n="110"/> To 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole (24mg) and 1 ,1 '- bis(diphenylphosphino)ferrocenedichloropalladium(ll) (3mg) at 200C in a microwave vial was added a solution of 6-bromo-3-fluoro-1 H-indazol-4-amine (19mg) in 1 ,4-dioxane (0.75ml) followed by water (0.5ml) and aqueous sodium carbonate (2M, 0.124ml). The reaction vessel was sealed and heated under microwave irradiation at 1500C for 15min. After cooling, the black solution was loaded onto a 500mg silica cartridge which was then eluted with methanol (4 column volumes). The eluant was blown to dryness, re-dissolved in methanol (3ml), filtered and blown to dryness to give the title compound (67mg) as a brown film. LC/MS R1 2.99min m/z 267 [MH+]. Method A

Reference： [1]Patent: WO2011/67365,2011,A1 .Location in patent: Page/Page column 77
[2]Patent: WO2009/147190,2009,A1 .Location in patent: Page/Page column 82-83
[3]Patent: WO2009/147188,2009,A1 .Location in patent: Page/Page column 107-108

18
[ 160199-54-2 ]
[ 388116-27-6 ]
[ 1225037-77-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 90℃; for 15.5h;Reflux; Inert atmosphere;	Example P48; 2-(1H-indol-4-yl)-4-morpholinobenzofuro[3,2-d]pyrimidine:Argon gas was bubbled through a mixture of 2-chloro-4-morpholinobenzofuro[3,2- djpyrimidine (ASA75) (80 mg, 0.276 mmol, 1.0 eq) and lndole-4-boronic acid pinacol ester (MW 243) (267 mg, 1.10 mmol, 4.0 eq) in 1 ,2 dimethoxyethan and 2 M Na2CO3 (3:1) (6 ml_) for 5 min. dichloro 1 ,1'-bis(diphenylphosphino)ferrocene-palladium(ll) dichloromethane complex (MW 732) (5.05 mg, 0.00690 mmol, 0.025 eq) was added and the reaction mixture was heated to reflux (90 0C) for 15 h 30 min, cooled and dilluted with EtOAc (20 mL). The organic solution was washed with a mixture of H2O:Na2CO3:NH4OH (cone. 32 % in water) = 5:4:1 (9 mL), then NH4CI (sat.) and brine (2x), dried over Na2CO3, filtered and concentrated. Purification by silica gel chromatography (gradient from 100 % hexane in EtOAc to 50 % hexane) gave a yellowish solid (89.0 mg, 87 %).Analytical data:1H-NMR (400 MHz, DMSO): delta 11.26 (s, 1H), 8.20-8.17 (m, 2H), 7.76 (d, 3JHH = 8.4Hz, 1H), 7.66 (dt, 3Jm = 6.0 Hz, LambdaJm = 1.3 Hz, 1H), 7.55-7.53 (m, 2H), 7.50-7.47 (m,2H), 7.22 (t, 3JHH =7.8 Hz, 1 H), 4.08 (t, 3JHH = 5.1 Hz, 4H), 3.81 (t, 3JHH = 5.0 Hz, 4H).13C-NMR (100 MHz, DMSO): delta 161.2, 156.6, 149.3, 148.9, 138.0, 134.3, 131.1 ,130.5, 127.2, 126.9, 124.8, 123.0, 122.2, 121.5, 121.3, 114.2, 113.5, 104.4, 66.9,46.3.MS-ESI (MeOH, 70 eV): calculated for C22H18N4O2 [M+H]+ (371); found 372.

Reference： [1]Patent: WO2010/52569,2010,A2 .Location in patent: Page/Page column 246

19
[ 1245465-34-2 ]
[ 388116-27-6 ]
[ 1245465-92-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwaves;	To a solution of 9-({5-[6-bromo-1-(phenylsulfonyl)-1 H-indazol-4-yl]-1 ,3,4-oxadiazol-2- yl}methyl)-6-oxa-9-azaspiro[4.5]decane (100 mg, 0.179 mmol) in 1 ,4 dioxane (2.5 ml) and water (0.25 ml) was added 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole (56.6 mg, 0.233 mmol, available from Frontier Scientific Europe), 1 ,1'- bis(diphenylphosphino)ferrocene palladium dichloride (26.2 mg, 0.036 mmol) and potassium phosphate tribasic (1 14 mg, 0.537 mmol). The mixture was heated under microwave irradiation at 100 0C for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The residue was dissolved in DMSO (2ml) and purified by Mass Directed Automated Preparative HPLC. The appropriate fractions were blown down under a stream of nitrogen to give a yellow solid. The solid was dissolved in 1 ,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 3 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the residue was freeze dried from 1 ,4-dioxane/water (1 :1 , 2 ml) overnight to give the title compound as a cream solid (21 mg). LCMS (Method A): Rt 0.93 mins, MH+ 455.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwave irradiation;	Example 48 9-({5-[6-(1H-Indol-4-yl)-1H-indazol-4-yl]-1,3,4-oxadiazol-2-yl}methyl)-6-oxa-9-azaspiro[4.5]decane To a solution of 9-({5-[6-bromo-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3,4-oxadiazol-2-yl}methyl)-6-oxa-9-azaspiro[4.5]decane (100 mg, 0.179 mmol) in 1,4 dioxane (2.5 ml) and water (0.25 ml) was added <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (56.6 mg, 0.233 mmol, available from Frontier Scientific Europe), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (26.2 mg, 0.036 mmol) and potassium phosphate tribasic (114 mg, 0.537 mmol). The mixture was heated under microwave irradiation at 100 C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The residue was dissolved in DMSO (2 ml) and purified by Mass Directed Automated Preparative HPLC. The appropriate fractions were blown down under a stream of nitrogen to give a yellow solid. The solid was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 3 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the residue was freeze dried from 1,4-dioxane/water (1:1, 2 ml) overnight to give the title compound as a cream solid (21 mg).

Reference： [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 153; 154
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 196; 197

20
[ 1245464-65-6 ]
[ 388116-27-6 ]
[ 1245464-67-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 0.5h;Microwaves;	A stirred mixture of 6-bromo-1-[(4-methylphenyl)sulfonyl]-4-[5-(4-morpholinylmethyl)- 1 ,3,4-oxadiazol-2-yl]-1 H-indazole (75 mg, 0.145 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-indole (52.8 mg, 0.217 mmol), 1 ,1 '-bis(diphenylphosphino)- ferrocene palladium dichloride (5.29mg, 7.23 mumol) and tripotassium phosphate (92 mg, 0.434 mmol) in 1 ,4-dioxane (2 ml) and water (0.2 ml) was heated at 1000C in the microwave (Biotage initiator) for 30mins. The mixture was poured into water (40ml) and extracted into ethyl acetate (2x30ml). The combined extracts were washed with water (30ml), dried (frit) and evaporated. The residual solid was purified on a silica (5g) cartridge using ether and ethyl acetate/ether (2:1 ) as the eluent. The appropriate fractions were evaporated to dryness to give the title compound as a cream coloured solid (24mg).LCMS (Method B): Rt 2.85mins, MH+ 555.
24 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 0.5h;Microwave irradiation;	6-(1H-Indol-4-yl)-1-[(4-methylphenyl)sulfonyl]-4-[5-(4-morpholinylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazole A stirred mixture of 6-bromo-1-[(4-methylphenyl)sulfonyl]-4-[5-(4-morpholinylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazole (75 mg, 0.145 mmol), <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (52.8 mg, 0.217 mmol), 1,1'-bis(diphenylphosphino)-ferrocene palladium dichloride (5.29 mg, 7.23 mumol) and tripotassium phosphate (92 mg, 0.434 mmol) in 1,4-dioxane (2 ml) and water (0.2 ml) was heated at 100 C. in the microwave (Biotage initiator) for 30 mins. The mixture was poured into water (40 ml) and extracted into ethyl acetate (2*30 ml). The combined extracts were washed with water (30 ml), dried (frit) and evaporated. The residual solid was purified on a silica (5 g) cartridge using ether and ethyl acetate/ether (2:1) as the eluent. The appropriate fractions were evaporated to dryness to give the title compound as a cream coloured solid (24 mg).LCMS (Method B): Rt 2.85 mins, MH 555.

Reference： [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 86; 87
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 85

21
[ 1245464-56-5 ]
[ 388116-27-6 ]
[ 1245465-23-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80℃; for 1h;	To a suspension of 6-bromo-1-[(4-methylphenyl)sulfonyl]-1 H-indazole-4-carbonitrile in 1 ,4-dioxane (100 ml) was added 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole (4.79 g, 10.72 mmol, available from Frontier Scientific Europe), 1 ,1 '- bis(diphenylphosphino)ferrocene palladium dichloride (2.061 g, 2.82 mmol) and potassium phosphate tribasic (8.97 g, 42.3 mmol). Water (20 ml) was added and the reaction mixture heated to 8O0C for 1 h. The solvent was removed and the residue partitioned between water (50 ml) and ethyl acetate (100 ml). The layers were filtered and the filtrate partitioned and concentrated, then purified by column chromatography, on a silica cartridge (300 g), eluting with a gradient of cyclohexane and ethyl acetate to give the title compound as a pale yellow solid (2.5 g). LCMS (Method B): Rt 3.39 mins, MH+ 413.
2.5 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 80℃; for 1h;	6-(1H-Indol-4-yl)-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carbonitrile To a suspension of 6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carbonitrile in 1,4-dioxane (100 ml) was added <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (4.79 g, 10.72 mmol, available from Frontier Scientific Europe), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (2.061 g, 2.82 mmol) and potassium phosphate tribasic (8.97 g, 42.3 mmol). Water (20 ml) was added and the reaction mixture heated to 80 C. for 1 h. The solvent was removed and the residue partitioned between water (50 ml) and ethyl acetate (100 ml). The layers were filtered and the filtrate partitioned and concentrated, then purified by column chromatography, on a silica cartridge (300 g), eluting with a gradient of cyclohexane and ethyl acetate to give the title compound as a pale yellow solid (2.5 g)._LCMS (Method B): Rt 3.39 mins, MH+ 413.

Reference： [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 106; 107
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 103

22
[ 1245465-15-9 ]
[ 388116-27-6 ]
[ 1245463-87-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 110℃; for 0.25h;Microwaves;	6-Bromo-4-(5-[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1 ,3,4-oxadiazol-2-yl)-1- methyl-1 H-indazole (50 mg, 0.123 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-indole (32.9 mg, 0.135 mmol), sodium carbonate (39.1 mg, 0.369 mmol) and 1 ,1- bis(diphenylphosphino)ferrocene palladium dichloride) (9.00 mg, 0.012 mmol) were added to a microwave vial and dissolved in 1 ,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 1 1O0C for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified by silica (20 g) cartridge using a gradient of ethyl acetate and cyclohexane to give the tjt\|e compound as a white solid (5.5 mg).LCMS (Method A): Rt 0.89 min, MH+ 443.
5.5 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 0.25h;Microwave irradiation;	Example 23 4-(5-[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-6-(1H-indol-4-yl)-1-methyl-1H-indazole 6-Bromo-4-(5-[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-methyl-1H-indazole (50 mg, 0.123 mmol), <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (32.9 mg, 0.135 mmol), sodium carbonate (39.1 mg, 0.369 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride) (9.00 mg, 0.012 mmol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110 C. for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified by silica (20 g) cartridge using a gradient of ethyl acetate and cyclohexane to give the title compound as a white solid (5.5 mg). LCMS (Method A): Rt 0.89 mi MH+ 443.

Reference： [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 136; 137
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 181

23
[ 1245465-19-3 ]
[ 388116-27-6 ]
[ 1245463-89-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 110℃; for 0.25h;Microwaves;	6-Bromo-1-methyl-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1 ,3,4-oxadiazol-2-yl)-1 H- indazole (45 mg, 0.107 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole (26.1 mg, 0.107 mmol), sodium carbonate (34.1 mg, 0.322 mmol) and 1 ,1- bis(diphenylphosphino)ferrocene palladium dichloride (7.85 mg, 10.73 mumol) were added to a microwave vial and dissolved in 1 ,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 1 1O0C for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified firstly by silica (20 g) cartridge using a gradient of ethyl acetate and cyclohexane then by Mass Directed Automated Preparative HPLC (Method B). The solvent was evaporated under a stream of nitrogen to give the title compound as a white solid (20 mg). LCMS (Method A): Rt 0.63 min, MH+456.
20 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 0.25h;Microwave irradiation;	Example 24 6-(1H-Indol-4-yl)-1-methyl-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1H-indazole 6-Bromo-1-methyl-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1H-indazole (45 mg, 0.107 mmol), <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (26.1 mg, 0.107 mmol), sodium carbonate (34.1 mg, 0.322 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (7.85 mg, 10.73 mumol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110 C. for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified firstly by silica (20 g) cartridge using a gradient of ethyl acetate and cyclohexane then by Mass Directed Automated Preparative HPLC (Method B). The solvent was evaporated under a stream of nitrogen to give the title compound as a white solid (20 mg). LCMS (Method A): Rt 0.63 mi MH+ 456.

Reference： [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 137
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 181; 182

24
[ 1245465-20-6 ]
[ 388116-27-6 ]
[ 1245465-94-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwaves;	To a solution of 6-bromo-4-{5-[(2,2-dimethyl-4-morpholinyl)methyl]-1 ,3,4-oxadiazol-2-yl}-1- (phenylsulfonyl)-I H-indazole (176 mg, 0.298 mmol) in dioxane (2.5 ml) and water (0.25 ml) was added 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole (102 mg, 0.420 mmol, available from Frontier Scientific Europe), 1 ,1 '-bis(diphenylphosphino)ferrocene palladium dichloride (43.5 mg, 0.060 mmol) and potassium phosphate tribasic (198 mg, 0.933 mmol). The mixture was heated under microwave irradiation at 100 0C for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The crude residue was dissolved in DMSO (2 ml) and purified by Mass Directed Automated Preparative HPLC. The product-containing fractions were blown down under a stream of nitrogen to give a yellow solid. The protected compound was dissolved in 1 ,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 3 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen to give a brown solid (31 mg) that was dissolved in DMSO (750mul_) and purified by Mass Directed Automated Preparative HPLC. The solvent was removed under a stream of nitrogen. The appropriate fraction was blown down under a stream of nitrogen to give the title compound as a pale yellow gum (2.4 mg). LCMS (Method A): Rt 0.86 mins, MH+ 429.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwave irradiation;	Example 49 4-{5-[(2,2-Dimethyl-4-morpholinyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(1H-indol-4-yl)-1H-indazole To a solution of 6-bromo-4-{5-[(2,2-dimethyl-4-morpholinyl)methyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazole (176 mg, 0.298 mmol) in dioxane (2.5 ml) and water (0.25 ml) was added <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (102 mg, 0.420 mmol, available from Frontier Scientific Europe), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (43.5 mg, 0.060 mmol) and potassium phosphate tribasic (198 mg, 0.933 mmol). The mixture was heated under microwave irradiation at 100 C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The crude residue was dissolved in DMSO (2 ml) and purified by Mass Directed Automated Preparative HPLC. The product-containing fractions were blown down under a stream of nitrogen to give a yellow solid. The protected compound was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 3 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen to give a brown solid (31 mg) that was dissolved in DMSO (750 muL) and purified by Mass Directed Automated Preparative HPLC. The solvent was removed under a stream of nitrogen. The appropriate fraction was blown down under a stream of nitrogen to give the title compound as a pale yellow gum (2.4 mg).LCMS (Method A): Rt 0.86 mins, MH+ 429.

Reference： [1]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 154; 155
[2]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 197; 198

25
[ 1245465-29-5 ]
[ 388116-27-6 ]
[ 1245464-12-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 150℃; for 0.25h;Microwaves;	6-Bromo-4-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 -[(4-methylphenyl)sulfonyl]-1 H-indazole (70 mg, 0.162 mmol) was dissolved in 1 ,4-dioxane (1.2 ml) and 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-indole (47.1 mg, 0.194 mmol, available from Frontier Scientific Europe), 1 ,1 '-bis(diphenylphosphino)ferrocenedichloropalladium(ll) (5.91 mg, 8.08 mumol), water (0.8 ml) and 2M aqueous sodium bicarbonate (0.242 ml, 0.485 mmol) were added. The reaction mixture was heated under microwave irradiation at 15O0C for 15 mins. The solution was loaded onto a silica cartridge (0.5 g) and eluted with methanol. The eluant was concentrated, the residue dissolved in methanol and absorbed onto Florisil. This was placed on top of a silica cartridge (10 g) and eluted with 25-50% ethyl acetate/cyclohexane. Appropriate fractions were evaporated to give the title compound as a yellow solid (27 mg). LCMS (Method B): Rt 2.22 mins, MH+ 316.
27 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 150℃; for 0.25h;Microwave irradiation;	Example 38 6-(1H-Indol-4-yl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indazole 6-Bromo-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[(4-methylphenyl)sulfonyl]-1H-indazole (70 mg, 0.162 mmol) was dissolved in 1,4-dioxane (1.2 ml) and <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (47.1 mg, 0.194 mmol, available from Frontier Scientific Europe), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (5.91 mg, 8.08 mumol), water (0.8 ml) and 2M aqueous sodium bicarbonate (0.242 ml, 0.485 mmol) were added. The reaction mixture was heated under microwave irradiation at 150 C. for 15 mins. The solution was loaded onto a silica cartridge (0.5 g) and eluted with methanol. The eluant was concentrated, the residue dissolved in methanol and absorbed onto Florisil. This was placed on top of a silica cartridge (10 g) and eluted with 25-50% ethyl acetate/cyclohexane. Appropriate fractions were evaporated to give the title compound as a yellow solid (27 mg).LCMS (Method B): Rt 2.22 mins, MH+ 316.

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7381 - 7399
[2]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 146
[3]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 190

26
[ 1245464-68-9 ]
[ 388116-27-6 ]
[ 1245464-69-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 60℃; for 1h;	To a solution of 6-bromo-1-(phenylsulfonyl)-1 H-indazole-4-carbonitrile (5 g,13.80 mmol) in 1 ,4-dioxane (50 ml) and water (20 ml) was added 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-indole (4.03 g, 16.57 mmol), 1 ,1'-bis(diphenylphosphino)ferrocene palladium dichloride (1.010 g, 1.380 mmol) and potassium phosphate tribasic (8.79 g, 41.4 mmol). The mixture was heated at 600C for 1 h, cooled and evaporated in vacuo. The residue was partitioned between water (50ml) and dichloromethane (100ml). The suspended solid was collected and the organics were separated by hydrophobic frit and concentrated to approx 50ml. The precipitated solid was collected as a beige solid (1.93g) and the filtrate purified by silica (30Og) cartridge using a gradient of ethyl acetate and cyclohexane, to give the title compound as a pale yellow solid (0.91 g). The solid collected during partitioning was purified by pre-absorbing onto florisil and purification by silica (100g) cartridge on Flashmaster Il using a gradient of dichloromethane and ethyl acetate to give a further quantity of the title compound as a pale yellow solid (0.45g). LCMS (Method A): Rt 1.24mins, MH+399.
1.36 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 60℃; for 1h;	6-(1H-Indol-4-yl)-1-(phenylsulfonyl)-1H-indazole-4-carbonitrile To a solution of 6-bromo-1-(phenylsulfonyl)-1H-indazole-4-carbonitrile (5 g, 13.80 mmol) in 1,4-dioxane (50 ml) and water (20 ml) was added <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (4.03 g, 16.57 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (1.010 g, 1.380 mmol) and potassium phosphate tribasic (8.79 g, 41.4 mmol). The mixture was heated at 60 C. for 1 h, cooled and evaporated in vacuo. The residue was partitioned between water (50 ml) and dichloromethane (100 ml). The suspended solid was collected and the organics were separated by hydrophobic frit and concentrated to approx 50 ml. The precipitated solid was collected as a beige solid (1.93 g) and the filtrate purified by silica (300 g) cartridge using a gradient of ethyl acetate and cyclohexane, to give the title compound as a pale yellow solid (0.91 g). The solid collected during partitioning was purified by pre-absorbing onto florisil and purification by silica (100 g) cartridge on Flashmaster 11 using a gradient of dichloromethane and ethyl acetate to give a further quantity of the title compound as a pale yellow solid (0.45 g).LCMS (Method A): Rt 1.24 mins, MH+ 399.

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7381 - 7399
[2]Patent: WO2010/102958,2010,A1 .Location in patent: Page/Page column 87; 88
[3]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 86

27
[ 1254036-86-6 ]
[ 388116-27-6 ]
[ 1254036-71-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate In 1,4-dioxane; water at 100 - 140℃; for 1.5h; microwave irradiation;	1 Example 16-(1 H-lndol-4-yl)-4-(5-[4-(1 -methylethyl)-1 -piperazinyl]methyl}-1 ,3-oxazol-2-yl)-1 H- indazoleMethod A6-Chloro-4-(5-[4-(1-methylethyl)-1 -piperazinyl]methyl}-1 ,3-oxazol-2-yl)-1 -(phenylsulfonyl)- 1 H-indazole (97 mg, 0.194 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- indole (61.3 mg, 0.252 mmol, available from Frontier Scientific Europe), chloro[2'- (dimethylamino)-2-biphenylyl]palladium-(1 R,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4R)- bicyclo[2.2.1]hept-2-yl]phosphane (10.87 mg, 0.019 mmol) and potassium phosphate tribasic (124 mg, 0.582 mmol) were dissolved in 1 ,4-dioxane (1 ml) and water (0.1 ml) and heated in a Biotage Initiator microwave at 100°C for 30 min. Additional 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxabotolan-2-yl)-1 H-indole (61 .3 mg, 0.252 mmol) and chloro[2'- (dimethylamino)-2-biphenylyl]palladium-(1 R,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4R)- bicyclo[2.2.1]hept-2-yl]phosphane (5 mg) were added and the reaction heated at 1 10°C for 30 min, then 140°C for 30 min. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with 0-25% methanol in dichloromethane. The appropriate fractions were combined and concentrated to give a brown solid which was dissolved in MeOH:DMSO (1 ml, 1 :1 , v/v) and purified by MDAP (method A). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (30 mg). LCMS (Method A): Rt 0.57 mins, MH+ 441 .
30 mg	With potassium phosphate; chloro-[2’-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane In 1,4-dioxane; water at 100 - 140℃; for 1.5h; Microwave irradiation;	1.A 6-(1H-Indol-4-yl)-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole 6-Chloro-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (97 mg, 0.194 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (61.3 mg, 0.252 mmol, available from Frontier Scientific Europe), chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (10.87 mg, 0.019 mmol) and potassium phosphate tribasic (124 mg, 0.582 mmol) were dissolved in 1,4-dioxane (1 ml) and water (0.1 ml) and heated in a Biotage Initiator microwave at 100° C. for 30 min. Additional 4-(4,4,5,5-tetramethyl-1,3,2-dioxabotolan-2-yl)-1H-indole (61.3 mg, 0.252 mmol) and chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (5 mg) were added and the reaction heated at 110° C. for 30 min, then 140° C. for 30 min. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with 0-25% methanol in dichloromethane. The appropriate fractions were combined and concentrated to give a brown solid which was dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (method A). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (30 mg).LCMS (Method A): Rt 0.57 mins, MH+ 441.
30 mg	With potassium phosphate; chloro(di-norbonylphosphino)(2’-dimethylamino-1,1’-biphenyl-2-yl)palladium(II) In 1,4-dioxane; water at 100 - 140℃; for 1.5h; Microwave irradiation;	68 6-(1H-Indol-4-yl)-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole Example 68 6-(1H-Indol-4-yl)-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole Method A 6-Chloro-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (97 mg, 0.194 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (61.3 mg, 0.252 mmol, available from Frontier Scientific Europe), chloro[2'-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (10.87 mg, 0.019 mmol) and potassium phosphate tribasic (124 mg, 0.582 mmol) were dissolved in 1,4-dioxane (1 ml) and water (0.1 ml) and heated in a Biotage Initiator microwave at 100° C. for 30 min. Additional 4-(4,4,5,5-tetramethyl-1,3,2-dioxabotolan-2-yl)-1H-indole (61.3 mg, 0.252 mmol) and chloro[2'-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (5 mg) were added and the reaction heated at 110° C. for 30 min, then 140° C. for 30 min. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with 0-25% methanol in dichloromethane. The appropriate fractions were combined and concentrated to give a brown solid which was dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (method H). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (30 mg).LCMS (Method A): Rt 0.57 mins, MH 441.

	With potassium phosphate; water In 1,4-dioxane at 100 - 140℃; for 1.5h; Microwave irradiation;	6.A Method A6-Chloro-4-(5-[4-(1-methylethyl)-1-piperazinyl]methyl}-1 ,3-oxazol-2-yl)-1-(phenylsulfonyl)- 1H-indazole (97 mg, 0.194 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- indole (61.3 mg, 0.252 mmol, available from Frontier Scientific Europe), chloro[2'- (dimethylamino)-2-biphenylyl]palladium-(1 R,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4R)- bicyclo[2.2.1]hept-2-yl]phosphane (10.87 mg, 0.019 mmol) and potassium phosphate tribasic (124 mg, 0.582 mmol) were dissolved in 1 ,4-dioxane (1 ml) and water (0.1 ml) and heated in a Biotage Initiator microwave at 1000C for 30 min. Additional 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxabotolan-2-yl)-1 H-indole (61.3 mg, 0.252 mmol) and chloro[2'- (dimethylamino)-2-biphenylyl]palladium-(1 R,4S)-bicyclo[2.2.1]hept-2-yl[(1 S,4R)- bicyclo[2.2.1]hept-2-yl]phosphane (5 mg) were added and the reaction heated at 1 1O0C for 30 min, then 14O0C for 30 min. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with 0-25% methanol in dichloromethane. The appropriate fractions were combined and concentrated to give a brown solid which was dissolved in MeOH:DMSO (1 ml, 1 :1 , v/v) and purified by MDAP (method A). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (30 mg).LCMS (Method A): Rt 0.57 mins, MH+ 441.
	Multi-step reaction with 2 steps 1: palladium diacetate; tricyclohexylphosphine; potassium hydrogenfluoride; potassium phosphate / isopropyl alcohol; water / 80 °C 2: cetyltrimethylammonim bromide; potassium hydroxide; pentan-3-one / 2-methyltetrahydrofuran / 80 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/55846, 2012, A1 Location in patent: Page/Page column 57-58
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2013/203772, 2013, A1 Location in patent: Paragraph 0331; 0332
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - US9326987, 2016, B2 Location in patent: Page/Page column 214
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2010/125082, 2010, A1 Location in patent: Page/Page column 86-87
[5]Bream, Robert N.; Clark, Hugh; Edney, Dean; Harsanyi, Antal; Hayler, John; Ironmonger, Alan; Mc Cleary, Nadine; Phillips, Natalie; Priestley, Catherine; Roberts, Alastair; Rushworth, Philip; Szeto, Peter; Webb, Michael R.; Wheelhouse, Katherine [Organic Process Research and Development, 2021, vol. 25, # 3, p. 529 - 540]

28
[ 946121-78-4 ]
[ 388116-27-6 ]
[ 1198154-51-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In tetrahydrofuran; water at 80℃; for 4h;	70.a a) Synthesis of 7-(1H-indol-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine To 3 ml of tetrahydrofuran (THF)/0.5 ml of distilled water, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (80.0 mg, 0.37 mmol), 4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolane-2-yl)-1H-indole (109 mg, 0.45 mmol), potassium carbonate (103 mg, 0.74 mmol) and tetrakis triphenylphosphine palladium (172 mg, 0.15 mmol) were added and stirred at 80° C. for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluding with a solvent of dichloromethane:methanol=40:1. The fractions containing the product were collected and evaporated to obtain 7-(1H-indol-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as white solid (130 mg). 1H-NMR (CDCl3, 300 MHz); δ=8.41 (br s, 1H), 7.96 (d, J=1.9 Hz, 1H), 7.39 (m, 1H), 7.27-7.25 (m, 2H), 7.19 (d, J=2.3 Hz, 1H), 7.11 (dd, J=7.3 Hz, 1.4 Hz, 1H), 6.69 (m, 1H), 4.47 (m, 2H), 3.91 (br s, 1H), 3.47 (m, 2H). MS (ESI): 252.1 (M++1).

Reference： [1]Current Patent Assignee: JW PHARMACEUTICAL CO LTD - US2011/28467, 2011, A1 Location in patent: Page/Page column 41

29
[ 41825-73-4 ]
[ 388116-27-6 ]
[ 1335243-03-2 ]

Yield	Reaction Conditions	Operation in experiment
58%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In water; N,N-dimethyl-formamide at 80℃; for 4h; Inert atmosphere;

Reference： [1]Cheng, Dao-Juan; Wu, Hai-Bian; Tian, Shi-Kai [Organic Letters, 2011, vol. 13, # 20, p. 5636 - 5639]

30
[ 771-14-2 ]
[ 388116-27-6 ]
[ 1335243-05-4 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5636 - 5639

31
[ 771-14-2 ]
[ 388116-27-6 ]
[ 1335242-73-3 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5636 - 5639

32
[ 175278-17-8 ]
[ 388116-27-6 ]
[ 1335243-01-0 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5636 - 5639

33
[ 175278-17-8 ]
[ 388116-27-6 ]
[ 1335242-71-1 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 5636 - 5639

34
[ 388116-27-6 ]
[ 1254036-71-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium carbonate / isopropyl alcohol; water / 20 °C / Inert atmosphere 1.2: 20 - 90 °C 2.1: cetyltrimethylammonim bromide; potassium hydroxide; water / tetrahydrofuran / 17 h / 20 °C / Inert atmosphere; Reflux
	Multi-step reaction with 2 steps 1: sodium hydrogencarbonate; 2’-(dimethylamino)-2-biphenylyl-palladium(II)chloride dinorbornylphosphine complex / water; isopropyl alcohol / 20 - 90 °C / Inert atmosphere 2: potassium hydroxide; cetyltrimethylammonim bromide / tetrahydrofuran; water / 17 h / Inert atmosphere; Reflux
	Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / water; isopropyl alcohol / 20 °C / Inert atmosphere 1.2: 2 h / 90 °C / Inert atmosphere 2.1: potassium hydroxide; cetyltrimethylammonim bromide / water; tetrahydrofuran / 17 h / Inert atmosphere; Reflux

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/55846, 2012, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2013/203772, 2013, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - US9326987, 2016, B2

35
[ 1268474-50-5 ]
[ 76-05-1 ]
[ 388116-27-6 ]
2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24.3%		To a 2 mL microwave vial were added 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x1, 200 mg, 0.831 mmol), <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (303 mg, 1.247 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium (II) (34.2 mg, 0.042 mmol). After the vial was sealed, dioxane (3.3 mL) and aqueous saturated NaHCO3 (0.83 mL) were added, and the mixture was degassed by bubbling nitrogen through a syringe needle for 10 minutes. The mixture was then heated in a microwave to 120 C. for 60 minutes. Combined organic layers were dried over MgSO4, filtered, and concentrated. DMF (1 mL) was added and the mixture was filtered by syringe filter. The crude product was purified by preparatory HPLC using a 10-25% gradient of CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). Lyophilization of the collected fractions gave a racemic mixture of the title compounds (TFA salt) (65 mg, 24.3%). 1H NMR (DMSO-d6) delta 3.18 (td, J=12.6, 3.3 Hz, 1H), 3.55-3.71 (m, 2H), 4.04 (dd, J=11.6, 3.3 Hz, 1H), 4.19 (dd, J=11.4, 3.8 Hz, 1H), 4.50 (d, J=8.1 Hz, 1H), 4.63 (d, J=12.6 Hz, 1H), 7.18-7.27 (m, 2H), 7.51 (br s, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.84 (s, 1H), 7.88 (d, J=7.3 Hz, 1H), 11.07 (br s, 1H), 11.41 (br s, 1H). ESI-MS m/z [M+H]+ calc'd for C17H15N5O2, 322.12. found 322.3.

Reference： [1]Patent: US2012/220575,2012,A1 .Location in patent: Page/Page column 82

36
[ 1394070-48-4 ]
[ 76-05-1 ]
[ 388116-27-6 ]
2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12.6%		Example 2 2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine A mixture of 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 308 mg, 1.359 mmol), <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (330 mg, 1.359 mmol) and PdCl2(dppf) (49.7 mg, 0.068 mmol) were partially dissolved in dioxane (8 mL) and aqueous saturated NaHCO3 (1.6 mL). The resulting brown suspension was heated in a microwave on high absorbance at 120 C. for 2 hours. The reaction mixture was subsequently diluted with ethyl acetate and washed with brine (3*15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by LC/MS using a gradient of 20-35% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to give a TFA salt of the title compound as an off-white solid (52.6 mg, 12.6%). 1H NMR (400 MHz, DMSO-d6) delta 3.04 (dd, J=11.87, 8.34 Hz, 1H), 3.28 (t, J=11.12 Hz, 2H), 3.44-3.67 (m, 2H), 3.78-3.91 (m, 1H), 3.97-4.16 (m, 2H), 4.72 (d, J=12.13 Hz, 1H), 6.66-6.82 (br s, 1H), 6.99 (d, J=2.02 Hz, 1H), 7.29 (t, J=7.71 Hz, 1H), 7.49-7.74 (m, 4H), 11.58 (br s, 1H). ESI-MS m/z [M+H]+ calc'd for C17H17N5O, 308.14. found 308.3.

Reference： [1]Patent: US2012/220575,2012,A1 .Location in patent: Page/Page column 41

37
[ 1394070-51-9 ]
[ 76-05-1 ]
[ 388116-27-6 ]
5-(cyclopropylmethyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%		Example 3 5-(cyclopropylmethyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine A mixture of 2-chloro-5-(cyclopropylmethyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x5, 100 mg, 0.356 mmol), <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (173 mg, 0.712 mmol) and PdCl2(dppf) (13.03 mg, 0.018 mmol) were partially dissolved in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). The resulting tan suspension was heated to 100 C. and stirred for 18 hours. The reaction mixture was subsequently diluted with ethyl acetate and washed with aqueous saturated NaHCO3 (210 mL) and brine (210 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by LC/MS using a gradient of 20-40% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to give a TFA salt of the title compound as a yellow solid (47 mg, 37%). 1H NMR (400 MHz, DMSO-d6) delta 0.22-0.63 (m, 4H), 1.01-1.13 (m, 1H), 2.9-3.24 (m, 4H), 3.52-3.61 (m, 3H), 3.84-3.97 (m, 1H), 4.00-4.17 (m, 2 H), 4.66-4.80 (m, 1H), 6.96-7.06 (m, 1H), 7.21-7.36 (m, 1H), 7.64 (d, J=1.77 Hz, 4H), 11.27-11.66 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C21H23N5O, 362.19. found 362.4.

Reference： [1]Patent: US2012/220575,2012,A1 .Location in patent: Page/Page column 41

38
[ 1394070-52-0 ]
[ 76-05-1 ]
[ 388116-27-6 ]
5-(2-chloro-4-(methylsulfonyl)benzyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%		Example 5 5-(2-chloro-4-(methylsulfonyl)benzyl)-2-(1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine A mixture of 2-chloro-5-(2-chloro-4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x6, 143 mg, 0.333 mmol), <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (162 mg, 0.666 mmol) and PdCl2(dppf) (12.19 mg, 0.017 mmol) were partially dissolved in dioxane (1.4 mL) and aqueous saturated NaHCO3 (0.3 mL). The resulting tan suspension was heated in a microwave on high absorbance at 100 C. for 2 hours. The reaction mixture was subsequently diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3*15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by LC/MS using a gradient of 20-45% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to give a TFA salt of the title compound as a pale yellow solid (31 mg, 18%). 1H NMR (400 MHz, DMSO-d6) delta 3.61-3.67 (m, 8H), 3.95-4.04 (m, 2H), 4.08-4.18 (m, 1H), 4.62-4.84 (m, 3H), 6.99-7.06 (m, 1H), 7.27 (s, 1H), 7.46-7.75 (m, 5H), 7.86 (d, J=1.77 Hz, 1H), 8.08 (d, J=1.77 Hz, 1H), 11.33-11.73 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C25H24ClN5O3S, 510.13. found 510.4.

Reference： [1]Patent: US2012/220575,2012,A1 .Location in patent: Page/Page column 42

39
[ 1394070-91-7 ]
[ 76-05-1 ]
[ 388116-27-6 ]
5-(6-chloro-2,3-dihydro-1H-inden-1-yl)-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18.6%		Example 146 5-(6-chloro-2,3-dihydro-1H-inden-1-yl)-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one 2-Chloro-5-(6-chloro-2,3-dihydro-1H-inden-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x41, 90 mg, 0.230 mmol), <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (112 mg, 0.460 mmol) and PdCl2(dppf) (8.42 mg, 0.012 mmol) were suspended in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). The resulting brown suspension was heated to 100 C. and stirred overnight. The reaction mixture was subsequently diluted with EtOAc and washed with aqueous saturated NH4Cl (3*5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give crude product, which was taken up in DMSO (1.5 mL) and purified by LC/MS using a gradient of 35-60% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to give a TFA salt of the title compound as a bright yellow solid (20.2 mg, 18.6%). 1H NMR (400 MHz, DMSO-d6) delta 2.42-2.49 (m, 2H), 2.93-3.24 (m, 4H), 3.60-3.72 (m, 2H), 3.98-4.15 (m, 1H), 4.15-4.35 (m, 1H), 4.43-4.66 (m, 2H), 7.12-7.49 (m, 7H), 7.50-7.59 (m, 1H), 7.89-7.98 (m, 1 H), 11.27-11.36 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C26H22ClN5O2, 472.15. found 472.5.

Reference： [1]Patent: US2012/220575,2012,A1 .Location in patent: Page/Page column 81

40
[ 1394070-89-3 ]
[ 388116-27-6 ]
[ 1394074-24-8 ]

Yield	Reaction Conditions	Operation in experiment
32%	With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 18h;	Example 145 5-benzyl-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one 5-Benzyl-2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x39, 200 mg, 0.605 mmol), <strong>[388116-27-6]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> (294 mg, 1.209 mmol), and PdCl2(dppf) (22.12 mg, 0.030 mmol) was suspended in dioxane (3 mL) and aqueous saturated NaHCO3 (0.6 mL). The resulting brown suspension was heated to 100 C. for 18 hours, then diluted with ethyl acetate and washed with aqueous saturated NH4Cl (35 mL) and brine (35 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give crude product, which was loaded onto an ISCO silica gel cartridge (12 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a white solid (80 mg, 32%). 1H NMR (400 MHz, DMSO-d6) delta 3.06-3.19 (m, 1H), 3.58-3.74 (m, 2H), 4.01-4.12 (m, 1H), 4.25-4.34 (m, 1H), 4.49-4.63 (m, 2H), 5.12-5.31 (m, 2H), 7.11-7.18 (m, 1H), 7.24-7.40 (m, 6H), 7.40-7.44 (m, 1H), 7.46-7.51 (m, 1H), 7.99-8.03 (m, 1H), 8.04-8.07 (m, 1H), 11.20-11.26 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C24H21N5O2, 412.17. found 412.4.

Reference： [1]Patent: US2012/220575,2012,A1 .Location in patent: Page/Page column 81

41
C₁₄H₁₅ClN₄ [ No CAS ]
[ 388116-27-6 ]
C₂₂H₂₁N₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; at 100℃; for 0.75h;Inert atmosphere; Microwave irradiation;	A solution of intermediate (1) (0.2 g, 0.73 mmol) and l-H-<strong>[388116-27-6]indole-4-boronic acid pinacol ester</strong> (0.407 g, 1.67 mmol) in potassium carbonate solution 2M (0.73 mL) and DME (3 mL) was purged with nitrogen for 5 minutes then tetrakis (triphenylphosphine) palladium (0.084 g , 0.073 mmol) was added portionwise .The mixture was heated at 100C using a single mode microwave (Biotage initiator60) with a power output ranging from 0 to 400 W for 45 minutes. Water and EtOAc were added. The organic layer was extracted, dried over MgS04, filtered and evaporated to give 0.6 g of crude product. Purification was carried out by preparative LC (stationary phase: irregular 15-40muiotaeta 30g Merck), mobile phase: 0.5% NH40H, 95% CH2C12, 5% MeOH). Pure fractions were collected and evaporated to give 0.16 g of residue. The residue was crystallized from DIPE, filtered off and dried under vacuum at 60C affording compound (74) as a white powder (0.142 g, 55%). FontWeight="Bold" FontSize="10" Eta NuMuKappa (500 MHz, DMSO-d6) delta 11.08 (br. s., 1H), 8.30 (dd, J= 1.1, 4.6 Hz, 1H), 8.09 (d, J= 6.3 Hz, 2H), 7.50 (dd, J= 1.1, 8.2 Hz, 1H), 7.42 (d, J= 7.0 Hz, 1H), 7.38 (d, J= 7.0 Hz, 1H), 7.28 - 7.35 (m, 2H), 7.16 (t, J= 7.0 Hz, 1H), 6.71 (d, J= 6.3 Hz, 2H), 6.35 (br. s., 1H), 2.99 - 3.08 (m, 4H), 2.81 - 2.89 (m, 4H)

Reference： [1]Patent: WO2015/14836,2015,A1 .Location in patent: Page/Page column 25; 26

42
[ 1090388-79-6 ]
[ 388116-27-6 ]
[ 1671073-62-3 ]

Yield	Reaction Conditions	Operation in experiment
39%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,4-dioxane; water at 80℃; for 0.16h; Inert atmosphere;

Reference： [1]Auberson, Yves P.; Troxler, Thomas; Zhang, Xuechun; Yang, Charles R.; Feuerbach, Dominik; Liu, Yu-Chih; Lagu, Bharat; Perrone, Mark; Lei, Lijun; Shen, Xiaoxia; Zhang, Dushan; Wang, Chunxiu; Wang, Tie-Lin; Briner, Karin; Bock, Mark G. [ChemMedChem, 2015, vol. 10, # 2, p. 266 - 275]

43
[ 1268241-81-1 ]
[ 388116-27-6 ]
[ 1268241-94-6 ]

Yield	Reaction Conditions	Operation in experiment
66%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 102℃; for 1h;	vii. 4 -(1 H-Indol-4 -yl) -6-(morpholin -4 -yl) -8-oxa -3,5,10-triazatricyclo[7. 4.0. 7]trideca -1 (9),2, 4,6,10, 12-hexaene - 12-carbaldehyde To 4-chloro-6-(morpholin-4-yl)-8-oxa-3,5,1 0-triazatricyclo[7.4.0.02?7]trideca- I (9),2(7),3,5, 10,1 2-hexaene-1 2-carbaldehyde (1 64.4g, 0.52mo1, I eq) was added <strong>[388116-27-6]indole-4-boronic acid pinacol ester</strong> (376.Og, I .55mo1, 3eq), PdCI2(PPh3)2 (72.Og, 0.lOmol, 2eq) and sodium carbonate (110.2g, 1.O4mol, 2eq) in dioxane (16.4L) Iwater (5.8L). Reaction mixture was refluxed for lh. It was then cooled to 60-70C. Water (9.8L), brine (4.9L) and EtOAc (9.5L) were added. The phases were separated and the aqueous phase extracted with EtOAc (3 x 9.5L) at 60-65C. The combined organics were dried over MgSO4, filtered and stripped. The resulting solid was slurried in CH2CI2 (4.75L) for 30mins, filtered, washed withCH2CI2 (3 x 238mL) and pulled dry. Further drying in a vacuum oven at 40C yielded Intermediate X as a yellow solid (135.7g, 66%).1H NMR (300MHz, CDCI3) oH. 11.27 (br. 5, IH), 10.26 (5, IH), 9.16 (d, J=2.3Hz, IH), 9.11 (d, J=2.3Hz, IH), 8.18 (d, J=7.5Hz, IH), 7.58-7.67 (m, 2H), 7.49 (t, J=2.8Hz, IH), 7.23 (t, J=7.7Hz, IH), 4.08-4.16 (m, 4H), 3.83-3.90 (m, 4H).MS (ESj 432.0 (100%, [M+MeOH+H]j.
66%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 102℃; for 1h;	To 4-chloro-6-(morpholin-4-yl)-8-oxa-3,5, 1 0-triazatricyclo[7.4.0.02?7]trideca- 1(9)2(7)3,5,10,1 2-hexaene-1 2-carbaldehyde (1 64.4g, 0.S2mol, 1 eq) was added <strong>[388116-27-6]indole-4-boronic acid pinacol ester</strong> (376.Og, 1 .SSmol, 3eq), PdCI2(PPh3)2 (72.Og, 0.lOmol, 2eq) and sodium carbonate (110.2g, 1.O4mol, 2eq) in dioxane (16.4L)Iwater (5.8L). Reaction mixture was refluxed for lh. It was then cooled to 60-70C. Water (9.8L), brine (4.9L) and EtOAc (9.SL) were added. The phases were separated and the aqueous phase extracted with EtOAc (3 x 9.SL) at 60-65C. The combined organics were dried over Mg504, filtered and stripped. The resulting solid was slurried in CH2CI2 (4.75L) for 30mins, filtered, washed withCH2CI2 (3 x 238mL) and pulled dry. Further drying in a vacuum oven at 40C yielded Intermediate X as a yellow solid (135.7g, 66%).1H NMR (300MHz, ODd3) oH. 11.27 (br. s, 1H), 10.26 (s, 1H), 9.16 (d, J=2.3Hz,1H), 9.11 (d, J=2.3Hz, 1H), 8.18 (d, J=7.5Hz, 1H), 7.58-7.67 (m, 2H), 7.49 (t,J=2.8Hz, 1H), 7.23 (t, J=7.7Hz, 1H), 4.08-4.16 (m, 4H), 3.83-3.90 (m, 4H).MS (ESj 432.0 (100%, [M+MeOH+H]j.
66%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 102℃; for 1h;	To 4-chloro-6-(morpholin-4-yl)-8-oxa-3,5, 10-triazatricyclo[7.4.0.02, 7]trideca- 1 (9),2(7),3,5, 10, 12-hexaene-12-carbaldehyde (164.4g, 0.52mol, 1 eq) was added <strong>[388116-27-6]indole-4-boronic acid pinacol ester</strong> (376. Og, 1 .55mol, 3eq), PdCI2(PPh3)2 (72. Og, O. I Omol, 2eq) and sodium carbonate (1 10.2g, 1 .04mol, 2eq) in dioxane (16.4L) / water (5.8L). Reaction mixture was refluxed for 1 h. It was then cooled to 60- 70C. Water (9.8L), brine (4.9L) and EtOAc (9.5L) were added. The phases were separated and the aqueous phase extracted with EtOAc (3 x 9.5L) at 60-65C. The combined organics were dried over MgS04, filtered and stripped. The resulting solid was slurried in CH2CI2 (4.75L) for 30mins, filtered, washed with CH2CI2 (3 x 238ml_) and pulled dry. Further drying in a vacuum oven at 40C yielded Intermediate X as a yellow solid (135.7g, 66%). 1 H NMR (300MHz, CDCI3) deltaEta: 1 1 .27 (br. s, 1 H), 10.26 (s, 1 H), 9.16 (d, J=2.3Hz, 1 H), 9.1 1 (d, J=2.3Hz, 1 H), 8.18 (d, J=7.5Hz, 1 H), 7.58-7.67 (m, 2H), 7.49 (t, J=2.8Hz, 1 H), 7.23 (t, J=7.7Hz, 1 H), 4.08-4.16 (m, 4H), 3.83-3.90 (m, 4H). MS (ES+) 432.0 (100%, [M+MeOH+H]+).

66%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; for 1h;Reflux;	To Intermediate 6 (164.4 g, 0.52 mol, 1 eq) was added <strong>[388116-27-6]indole-4-boronic acid pinacol ester</strong> (376.0 g, 1.55 mol, 3 eq), PdCI2(PPh3)2 (72.0 g, 0.10 mol, 0.2 eq) and sodium carbonate (110.2 g, 1.04 mol, 2 eq) in dioxane (16.4 L) /water (5.8L). The reaction mixture was refluxed for 1 h. It was then cooled to 60-70C. Water (9.8 L), brine (4.9 L) and EtOAc (9.5 L) were added. The phases wereseparated and the aqueous phase extracted with EtOAc (3 x 9.5 L) at 60-65C. The combined organics were dried over MgSO4, filtered and stripped. The resulting solid was slurried in CH2CI2 (4.8 L) for 30 mins, filtered, washed with CH2CI2 (3 x 238 mL) and pulled dry. Further drying in a vacuum oven at 40C yielded Intermediate 7 as a yellow solid (135.7 g, 66%).1H NMR (300MHz, CDCI3) oH. 11.27 (br 5, 1H), 10.26 (5, 1H), 9.16 (d, J=2.3Hz,1H), 9.11 (d, J=2.3Hz, 1H), 8.18 (d, J=7.5Hz, 1H), 7.58-7.67 (m, 2H), 7.49 (t, J=2.8Hz, 1H), 7.23 (t, J=7.7Hz, 1H), 4.08-4.16 (m, 4H), 3.83-3.90 (m, 4H).MS (ESj 432.0 (100%, [M+MeOH+H]j.
66%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; for 1h;Reflux;	vii. 4-(1H-lndol-4-yl)-6-(morpholin-4-yl)-8-oxa-3,5, 10- triazatricyclo[7.4.0.02 ]trideca-1(9),2,4,6, 10, 12 -hexaene -12 -carbaldehyde To 4-chloro-6-(morpholin-4-yl)-8-oxa-3,5, 10-triazatricyclo[7.4.0.02, 7]trideca- 1 (9),2(7),3,5, 10, 12-hexaene-12-carbaldehyde (164.4g, 0.52mol, 1 eq) was added <strong>[388116-27-6]indole-4-boronic acid pinacol ester</strong> (376. Og, 1 .55mol, 3eq), PdCI2(PPh3)2 (72. Og, O. I Omol, 2eq) and sodium carbonate (1 10.2g, 1 .04mol, 2eq) in dioxane (16.4L) / water (5.8L). Reaction mixture was refluxed for 1 h. It was then cooled to 60- 70C. Water (9.8L), brine (4.9L) and EtOAc (9.5L) were added. The phases were separated and the aqueous phase extracted with EtOAc (3 x 9.5L) at 60-65C. The combined organics were dried over MgS04, filtered and stripped. The resulting solid was slurried in CH2CI2 (4.75L) for 30mins, filtered, washed with CH2CI2 (3 x 238ml_) and pulled dry. Further drying in a vacuum oven at 40C yielded Intermediate X as a yellow solid (135.7g, 66%). 1H NMR (300MHz, CDCI3) deltaEta: 11.27 (br. s, 1H), 10.26 (s, 1H), 9.16 (d, J=2.3Hz, 1H), 9.11 (d, J=2.3Hz, 1H), 8.18 (d, J=7.5Hz, 1H), 7.58-7.67 (m, 2H), 7.49 (t, J=2.8Hz, 1H), 7.23 (t, J=7.7Hz, 1H), 4.08-4.16 (m, 4H), 3.83-3.90 (m, 4H). MS (ES+) 432.0 (100%, [M+MeOH+H]+).

Reference： [1]Patent: WO2015/121657,2015,A1 .Location in patent: Page/Page column 17; 20; 21
[2]Patent: WO2017/29518,2017,A1 .Location in patent: Page/Page column 23; 26; 27
[3]Patent: WO2017/29514,2017,A1 .Location in patent: Page/Page column 30; 33-34
[4]Patent: WO2017/29521,2017,A1 .Location in patent: Page/Page column 28
[5]Patent: WO2017/29517,2017,A1 .Location in patent: Page/Page column 30-31

44
[ 41102-25-4 ]
[ 388116-27-6 ]
C₁₄H₇BrClN₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; dichloromethane; water; at 80℃;Inert atmosphere;	10113] To a reaction flask were added purchased compound4-c (1.0 g, 4.11 mmol), compound 1-c (1.06 g, 3.74 mmol),PdCl2(dppf)CH2C12 (137 mg, 0.187 mmol), 2 N sodium carbonate aqueous solution (5.6 mE) and 1, 4-dioxane (25 mE). The reaction solution was stirred under nitrogen atmosphere at 80 C. overnight. The reaction mixture was concentrated and then dissolved with ethyl acetate, afier fllteration through celite, the organic phase was sequentially washed with water, saturated brine, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifled by silica gel preparation plate chromatography (developing system: dichloromethane/petroleum ether=:4/1), to yield compound 4-b (658 mg, 52%).Synthesis of Compound 4-a

Reference： [1]Patent: US2016/214994,2016,A1 .Location in patent: Paragraph 0111; 0113

45
[ 24241-18-7 ]
[ 388116-27-6 ]
C₁₂H₉BrN₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With palladium diacetate; sodium hydrogencarbonate; triphenylphosphine; In tetrahydrofuran; water; at 90℃;Inert atmosphere;	A mixture of compound 12-g (1 g, 3.35 mmol), compound 12-h (1.05 g, 4.11 mmol), triphenylphosphine (0.21 g, 0.80 mmol), palladium acetate (0.09 g, 0.40 mmol), THF (50 mE) and saturated aqueous solution of sodium bicarbonate (5 mE) was stirred overnight at 90 C. under nitrogen gas atmosphere. The reaction solution was diluted with THF,filtrated through celite, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. The residue was separated and purified with silica colunm chromatograph (elution system: dichloromethane/methanol=10/1) to give compound 12-f (0.68 g, 60%). LC-MS (ESI): mlz=289.0 (M+H).

Reference： [1]Patent: US2016/244432,2016,A1 .Location in patent: Paragraph 0253; 0254

46
4-[4-chloro-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.027]trideca1(13),2,4,6,9,11-hexaen-12-yl]methyl}-1-imino-1λ6-thiomorpholin-1-one [ No CAS ]
[ 388116-27-6 ]
1-imino-4-[4-(1H-indol-4-yl)-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.02’7]trideca-1(13)2,4,6,9,11-hexaen-12-yl]methyl}-1λ6-thiomorpholin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; water; toluene; at 120℃; for 1h;Inert atmosphere; Microwave irradiation;	Intermediate 10 (0.044 g, 0.1 mmol), 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-indole (0.029 g, 0.12 mmol), PdCI2(PPh3)2 (0.007 g, 0.01 mmol) and sodiumcarbonate (0.032 g, 0.3 mmol) were placed in a microwave vial. Ethanol (1 mL), toluene (1.6 mL) and water (0.5 mL) were added and the reaction mixture was degassed, placed under an argon atmosphere and heated in a microwave to 12000 for 1 h. Upon cooling to rt the reaction mixture was poured into water (20 ml) and extracted twice with CH2CI2 (20 mL). The combined organic fractionswere dried over MgSO4, filtered and the solvent removed by evaporation in vacuo. Purification by flash silica column chromatography, 5% MeOH/ CH2CI2 elution, gave Example G in 54% yield (0.028 g).1H NMR (300MHz, DMSO-d5) oH. 11.27 (br 5, 1H), 8.64 (dd, J=8.29, 2.07 Hz, 2H), 8.19 (d, J=7.35 Hz, 2H), 7.47-7.48 (m, 3H), 7.23 (t, J=7.72 Hz, 1H), 4.02-4.20 (m, 4H), 3.92 (5, 2H), 3.81-3.96 (m, 4H), 3.62 (brs, 1H), 2.82-3.06 (m, 8H). MS (ESj 518.2 (100%, [M+H]j.

Reference： [1]Patent: WO2017/29521,2017,A1 .Location in patent: Page/Page column 73

47
4-chloro-6-(morpholin-4-yl)-1 2-[(1 S,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02.7]trideca-1⁽¹³⁾,2,4,6,9,11-hexane [ No CAS ]
[ 388116-27-6 ]
4-(1H-indol-4-yI)-6-(morpholin-4-yI)-12-[(1S,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02’7]trideca-1(13)2,4,6,9,11-hexaene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; water; toluene; at 120℃; for 1h;Inert atmosphere; Microwave irradiation;	Intermediate 23 (0.042 g, 0.1 mmol), 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-indole (0.049 g, 0.2 mmol), PdCI2(PPh3)2 (0.007 g, 0.01 mmol) and sodium carbonate (0.032 g, 0.3 mmol) were placed in a microwave vial. Ethanol (1 mL),toluene (1.6 mL) and water (0.5 mL) were added and the reaction mixture was degassed, placed under an argon atmosphere and heated in a microwave to 12000 for 1 h. Upon cooling to rt, the reaction mixture was poured into water (20 mL) and extracted twice with CH2CI2 (20 mL). The combined organic fractions were dried over MgSO4, filtered and the solvent removed by evaporation invacuo. Purification by flash silica column chromatography, EtOAc elution,followed by recrystallization form EtOH gave Example J (0.037 g, 74%).1H NMR (300MHz, DMSO-d5) oH. 11.27 (br 5, 1H), 8.61 (5, 2H), 8.18 (d, J=7.4Hz, 1H), 7.46-7.57 (m, 3H), 7.23 (t, J=7.7 Hz, 1H), 4.13 (br d, J=4.3 Hz, 4H),3.97 (5, 2 H), 3.87 (br 5, 4H), 3.78 (br 5, 1 H), 3.52 (br 5, 1H), 3.13 (br d, J=9.4Hz, 2H), 2.74-2.89 (m, 2H), 2.15-2.26 (m, 1H), 1.72 (brd, J=10.2 Hz, 1H). MS (ESj 499.1 (100%, [M+H]j.

Reference： [1]Patent: WO2017/29521,2017,A1 .Location in patent: Page/Page column 76

48
(1S,4S)-5-[4-chloro-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.027]trideca-1(13),2,4,6,9,11-hexaen-12-yl]methyl}-2λ6-thia-5-azabicyclo[2.2.1]heptane-2,2-dione [ No CAS ]
[ 388116-27-6 ]
(1S,4S)-5-[4-(1H-indol-4-yl)-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.02’7]trideca-1(13)2,4,6,9,11-hexaen-12-yl]methyl}-2λ6-thia-5-azabicyclo[2.2.1]heptane-2,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; water; toluene; at 120℃; for 1h;Inert atmosphere; Microwave irradiation;	Intermediate 26 (0.045 g, 0.1 mmol), 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-indole (0.049 g, 0.2 mmol), PdCI2(PPh3)2 (0.007 g, 0.01 mmol) and sodium carbonate (0.032 g, 0.3 mmol) were placed in a microwave vial. Ethanol (1 mL),toluene (1.6 mL and water (0.5 mL) were added and the reaction mixture was degassed, placed under an argon atmosphere and heated in a microwave to 12000 for 1 h. Upon cooling to rt, the reaction mixture was poured into water (20 mL) and extracted twice with CH2CI2 (20 mL). The combined organic fractions were dried over MgSO4, filtered and the solvent removed by evaporation invacuo. Purification by flash silica column chromatography, 5% MeOH/CH2CI2 elution, a further column, 10% MeOH/EtOAc elution followed by recrystallization form EtOAc gave Example K in 60% yield (0.032 g).1H NMR (300MHz, DMSO-d5) oH. 11.27 (br 5, 1H), 8.64 (5, 2H), 8.19 (d, J=7.5 Hz, 1H), 7.52 (m, 3H), 7.23 (t, J=7.7 Hz, 1H), 4.13 (m, 4H), 4.03 (5, 2H), 3.87 (m,4H), 3.78 (m, 2H), 3.39 (m, 1H), 3.17 (m,1H), 3.05 (m, 2H), 2.35 (m, 2H). MS (ESj 530.2 (100%, [M+H]j.

Reference： [1]Patent: WO2017/29521,2017,A1 .Location in patent: Page/Page column 77

49
(1S,2R,4S)-5-[4-chloro-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.027]trideca1⁽¹³⁾,2,4,6,9,11-hexaen-12-yl]methyl}-2-thia-5-azabicyclo[2.2.1]heptan-2-ium-2-olate [ No CAS ]
[ 388116-27-6 ]
(1S,2R,4S)-5-[4-(1H-indol-4-yl)-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.02’7]trideca-1(13)2,4,6,9,11-hexaen-12-yl]methyl}-2-thia-5-azabicyclo[2.2.1]heptan-2-ium-2-olate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; water; toluene; at 120℃; for 1h;Inert atmosphere; Microwave irradiation;	Intermediate 29 (0.043 g, 0.1 mmol), 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-indole (0.049 g, 0.2 mmol), PdCI2(PPh3)2 (0.007 g, 0.01 mmol) and sodium carbonate (0.032 g, 0.3 mmol) were placed in a microwave vial. Ethanol (1 mL),toluene (1.6 mL) and water (0.5 mL) were added and the reaction mixture was degassed, placed under an argon atmosphere and heated in a microwave to 12000 for 1 h. Upon cooling to rt the reaction mixture was poured into water (20 mL) and extracted twice with CH2CI2 (20 mL). The combined organic fractions were dried over MgSO4, filtered and the solvent removed by evaporation invacuo. Purification by flash silica column chromatography, 5% MeOH/CH2CI2 elution, a further column, 20% MeOH/EtOAc elution, followed by a further column, 10% MeOH/CH2CI2 elution, gave Example L in 85% yield (0.044 g).1H NMR (300MHz, DMSO-d5) oH. 11.27 (brs, 1H), 8.58 (brs, 2H), 8.18 (d, J=7.5 Hz, 1H), 7.47-7.57 (m, 3H), 7.23 (t, J=7.4 Hz, 1H), 4.13 (br 5, 4H), 3.60 - 3.90(m, 9 H), 3.00 (br dd, J=11.9, 5.3 Hz, 1H), 2.26 (br s, 2H), 2.15 (br d, J=13.56 Hz, 1H), 1.75 (brd, J=11.87 Hz, 1H).MS (ESj 515.1 (100%, [M+H]j.

Reference： [1]Patent: WO2017/29521,2017,A1 .Location in patent: Page/Page column 78

50
4-chloro-6-(morpholin-4-yl)-8-thia-3,5,10-triazatricyclo[7.4.0.0^2,7]trideca-1⁽⁹⁾,2⁽⁷⁾,3,5,10,12-hexaene-12-carbaldehyde [ No CAS ]
[ 388116-27-6 ]
4-(1H-indol-4-yl)-6-(morpholin-4-yl)-8-thia-3,5,10-triazatricyclo[7.4.0.02’7]trideca-1(9),2(7),3,5,10,12-hexaene-12-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; toluene; at 80℃; for 1h;	Intermediate 35(2 g, 5.9mmol, leq.) was taken in dioxane (60 mL), toluene (20mL) and aqueous 2M Na2003 (30 mL) and indole-4-boronic acid pinacolester (2g, 8.2 mmol, 1 .4 eq.), PdCI2(PPh3)2 (1 g, 1 .42 mmol, 0.24 eq.) were added to it.The reaction mixture was heated to 80C for 1 h and completion of the reactionwas confirmed by TLC. The reaction mixture was cooled to 70C water (50 mL) and ethyl acetate (700 mL) was added. The organics were separated the aqueous re-extracted with ethyl acetate (2 x 700 mL) at 60 C. The combined organics were evaporated and residue was triturated with dichloromethane (50mL) to give Intermediate 36. Some product was left suspended in the aqueous layer. The aqueous layer was filtered and the residue was washed with dichloromethane (5OmL). The solids (from ethyl acetate and water) were mixed together and triturated with dichloromethane (2OmL) to yield 1.8g (74%) of Intermediate 36.1H NMR (400 MHz, DMSO-d5) oe: 10.24 (5, 1H), 9.27 (brs, 1H), 9.12 (brs, 1H),8.27 (d, J=7.6Hz, 1H), 7.6-7.55 (m, 3H), 7.25 (t, J=7.6Hz, 1H), 7.25 (t, J=7.6Hz, 1H), 3.95-4.10 (m, 4H), 3.78-3.90 (m, 4H).MS (ESj 416 (100%, [M+H]j.

Reference： [1]Patent: WO2017/29521,2017,A1 .Location in patent: Page/Page column 47; 48

51
[ 689260-53-5 ]
[ 388116-27-6 ]
C₁₆H₁₆BrN [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; toluene; for 8h;Inert atmosphere; Reflux;	the obtained 38-6-a (3.92 g, 20 mmol), Bis(pinacolato)diboron (6.22 g, 24 mmol), 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.49 g, 0.6 mmol), potassium acetate (5.90 g, 60 mmol) and 79 ml of toluene were reacted under reflux for 16 hours.After cooling, 26 ml of water was added and stirred for 30 minutes, the organic phase was separated, filtered through a short bed of celite, soon afterwards the organic solvent was evaporated off, and the obtained crude product was recrystallized from heptane / toluene; Under argon atmosphere, the obtained solid 38-6-b (3.65g, 15mmol), 38-6-c (4.45g, 14.3mmol), Tetrakis(triphenylphosphine)palladium (0·35 g, 0.3 mmol), toluene (43 ml), aqueous sodium carbonate (2M, 21 ml) was added to the flask and refluxed for 8 hours.After cooling to room temperature, it was extracted with toluene, and the organic phase was washed with brine, and then dried, and then purified by column chromatography to obtain bromide 38-6-d; Tri-tert-butylphosphine (4.4 mL of a 1.0 M solution in toluene, 1.48 g, 0.05 mmol), palladium acetate (0.4 g, 1.83 mmol) and sodium tert-butoxide (52.7 g, 549 mmol) were added to a solution of 38-6-d (22.04 g, 73.42 mmol) and bromobenzene (11.53 g, 73.42 mmol) in degassed toluene (500 mL) and the mixture was Heat under reflux for 2 hours. This reaction mixture was cooled to room temperature, diluted with toluene and filterated through celite. This filtrate was diluted with water and extracted with toluene, and the organic phases were combined and evaporated in vacuo. This residue was filtered through silica gel (heptane / dichloromethane) and crystallised from isopropyl alcohol to give compound 38-6-e;the obtained 38-6-a (3.92 g, 20 mmol), Bis(pinacolato)diboron (6.22 g, 24 mmol), 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.49 g, 0.6 mmol), potassium acetate (5.90 g, 60 mmol) and 79 ml of toluene were reacted under reflux for 16 hours.After cooling, 26 ml of water was added and stirred for 30 minutes, the organic phase was separated, filtered through a short bed of celite, soon afterwards the organic solvent was evaporated off, and the obtained crude product was recrystallized from heptane / toluene to obtain compound 38-6.

Reference： [1]Patent: CN108530336,2018,A .Location in patent: Paragraph 0101; 0103; 0106; 0107

52
[ 104597-98-0 ]
[ 388116-27-6 ]
methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)propanoate [ No CAS ]
C₂₆H₃₁BN₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 45% 2: 41%	With scandium tris(trifluoromethanesulfonate) In dichloromethane at 20℃; Overall yield = 91 %; Overall yield = 5.32 g;

Reference： [1]Bartoccini, Francesca; Venturi, Silvia; Retini, Michele; Mari, Michele; Piersanti, Giovanni [Journal of Organic Chemistry, 2019, vol. 84, # 12, p. 8027 - 8034]

53
[ 577-19-5 ]
[ 388116-27-6 ]
[ 845866-98-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 120℃; for 4h;Inert atmosphere;	Under a nitrogen stream (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (104.2 g, 428.4 mmol) 1-bromo-2-nitrobenzene (103.9 g, 514.2 mmol), Pd (PPh3) 4 (24.8 g, 21.4 mmol), K 2 CO 3 (118.4 g, 856.9 mmol), 1,4-Dioxane 1000 ml, 200 ml of H 2 O were mixed and stirred at 120 C for 4 hours. After the reaction was completed, the reaction mixture was extracted with methylene chloride, added with MgSO 4 and filtered. The solvent was removed from the obtained organic layer, and the residue was purified by column chromatography (Hexane: EA = 6: 1 (v / v)) to obtain 4- (2-nitrophenyl) -1H-indole (86.8 g, yield 85%).

Reference： [1]Patent: KR2019/71245,2019,A .Location in patent: Paragraph 0157; 0163-0167

54
[ 59214-70-9 ]
[ 388116-27-6 ]
4-(benzofuran-3-yl)-1H-indole [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 8158 - 8163

55
C₂₄H₂₆BrN₅O₃S [ No CAS ]
[ 388116-27-6 ]
[ 1364802-72-1 ]

Yield	Reaction Conditions	Operation in experiment
98.6%	With tetrakis(triphenylphosphine) palladium(0); sodium acetate; In N,N-dimethyl-formamide; at 150℃; for 10h;Inert atmosphere;	Put compound XVII (45 g, 82.7 mmol, 1.0 eq.) Into a 1 L four-necked flask,Adding 4- (4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl) -1H-indole (24.12g, 99.24mol, 1.2eq.),Sodium acetate (20.35 g, 248.1 mmol, 3.0 eq.), Tetrakis (triphenylphosphine) palladium (95.56 g, 82.7 mmol, 1.0 eq.),500 mL of N, N dimethylformamide was added.Protected under N2, heated to 150 C for 10h,Filtration, EA extraction (500 mL * 2), combined organic phases, washed with saturated brine,It was dried over anhydrous sodium sulfate, and recrystallized after evaporation to obtain 47.3 g of compound I as a pale yellow solid with a yield of 98.6%.

Reference： [1]Patent: CN104086538,2016,B .Location in patent: Paragraph 0041; 0060-0063; 0082-0085; 0104-0107; 0121-0123

56
6-(benzyloxy)-5-bromo-N-phenylpyridin-3-amine [ No CAS ]
[ 388116-27-6 ]
6-(benzyloxy)-5-(1H-indol-4-yl)-N-phenylpyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; for 16h;Inert atmosphere; Reflux;	General procedure: To a solution under argonof brominated derivative in 1,4-dioxane (0.1-0.6 mmol,1 eq., 0.1M)were added the boronic acid or boronic ester (1.5 eq.) and a 2 MNa2CO3 aqueous solution (5 eq.). The mixture was degassed withargon for 10 min before the addition of PdCl2(PPh3)2 (0.05 eq.). Thesolution was refluxed overnight. Ethyl acetate was added and theresulting mixture was washed with water. The organic phase wasdried over MgSO4 and filtered. After evaporation under reducedpressure, the crude was purified by column chromatography.

Reference： [1]European Journal of Medicinal Chemistry,2019

57
methyl (S)-4-(2-chloro-5-fluoropyrimidin-4-yl)-3-methylmorpholine-3-carboxylate [ No CAS ]
[ 388116-27-6 ]
methyl (S)-4-(5-fluoro-2-(1H-indol-4-yl)pyrimidin-4-yl)-3-methylmorpholine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium dihydrogenphosphate; In 1,4-dioxane; water; at 90℃; for 18h;	A 2 L round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged with (k)-methyl 4-(2-chloro-5-fluoropyrimidin-4-yl)-3-methylmorpholine-3- carboxylate (93 g, 321 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l7/-indole (82 g, 337 mmol), PdCl2(dppf) (7.05 g, 9.63 mmol), and potassium phosphate (76 g, 803 mmol) in dioxane (535 mL) and water (535 mL). The reaction mixture was stirred at 90C for 18 hours and then cooled to 23C. The contents of the flask were filtered through Celite and the Celite was rinsed with EtOAc, which was combined with the filtrate. The filtrate was further diluted with EtOAc, washed with saturated aqueous NaHC03, saturated aqueous NH4Q, and brine, and then dried over MgS04. The product-containing mixture was filtered and the solvent removed in vacuo. The residue was treated with diethyl ether (200 mL) and concentrated in vacuo. The diethyl ether wash was repeated three times and concentrated in vacuo to give the title compound as a brown solid (119 g,100%). NMR (400 MHz, DMSO-7e) d ppm 1.70 (s, 3 H), 3.51 (s, 3 H), 3.54 - 3.63 (m, 1 H), 3.70 - 3.76 (m, 1 H), 3.78 - 3.88 (m, 2 H), 3.91 - 4.02 (m, 2 H), 7.19 (t, .7=7.71 Hz, 1 H), 7.37 (d, 7=2.02 Hz, 1 H), 7.44 (t, 7=2.78 Hz, 1 H), 7.54 (d, 7=7.83 Hz, 1 H),7.86 (d, 7=7.07 Hz, 1 H), 8.60 (d, 7=5.81 Hz, 1 H), 11.28 (br s, 1 H). ESI-MS m/z [M + H]+371.3.

Reference： [1]Patent: WO2020/76728,2020,A1 .Location in patent: Page/Page column 0174-0175

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H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 388116-27-6 ] {[proInfo.proName]}

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[ 388116-27-6 ] Synthesis Path-Upstream 1~7

[ 388116-27-6 ] Synthesis Path-Downstream 1~57

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Organoboron

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[ 388116-27-6 ]

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[ 388116-27-6 ]