885520-70-7|4-Bromo-6-fluoro-1H-indole| Ambeed

Structure of 885520-70-7

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Quality Control of [ 885520-70-7 ] Purity: 95% SDS Specification

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Product Details of [ 885520-70-7 ]

CAS No. :	885520-70-7
Formula :	C₈H₅BrFN
M.W :	214.03
SMILES Code :	FC1=CC2=C(C(Br)=C1)C=CN2
MDL No. :	MFCD08272203
InChI Key :	DMOWKZSCECYXSE-UHFFFAOYSA-N
Pubchem ID :	24728173

Safety of [ 885520-70-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 885520-70-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	9
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	45.96
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	15.79 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.91
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.84
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.49
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.73
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.62
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.92

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.56
Solubility	0.0587 mg/ml ; 0.000274 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.83
Solubility	0.317 mg/ml ; 0.00148 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.42
Solubility	0.00812 mg/ml ; 0.0000379 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.59 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.85

Application In Synthesis of [ 885520-70-7 ]

* 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 [ 885520-70-7 ]
Downstream synthetic route of [ 885520-70-7 ]

[ 885520-70-7 ] Synthesis Path-Upstream 1~7

1
[ 1093066-65-9 ]
[ 885520-70-7 ]

Yield	Reaction Conditions	Operation in experiment
37%	With hydrazine In tetrahydrofuran; methanol; water at 20℃; for 5 h;	To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney.(R).-Nickel (suspension in H₂0, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0 ⁰C and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was evaporated to dryness and the resulting residue to give the title compound as pale oil (2.57 g, 37 percent). NMR δ_H (300 MHz, CDCl₃) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.1, IH), 7.12 (dd, J = 2.1, 9.1, IH), 7.20-7.25 (m, IH) and 8.25 (s, IH).
37%	With hydrazine In tetrahydrofuran; methanol; water at 0 - 20℃; for 5 h;	Reference Example 44-Bromo-6-fluoro-lH-indoleTo a solution of l-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) was added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100 °C. The mixture was cooled to RT and evaporated to dryness to give l-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-l -methyl vinyl]- pyrrolidine as a dark red residue (10.0 g, theoretical yield). To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney.(R).-Nickel (suspension in H₂O, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0 ⁰C and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was evaporated to dryness and the resulting residue to give the title compound as pale oil (2.57 g, 37 percent).NMR δ_H (300 MHz, CDCl₃) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.1, IH), 7.12 (dd, J = 2.1, 9.1, IH), 7.20-7.25 (m, IH) and 8.25 (s, IH).

References: [1] Patent: WO2008/152387, 2008, A1, . Location in patent: Page/Page column 34.
[2] Patent: WO2009/53716, 2009, A1, . Location in patent: Page/Page column 56.
[3] Patent: WO2008/152394, 2008, A1, . Location in patent: Page/Page column 39.
[4] Patent: WO2008/152390, 2008, A1, . Location in patent: Page/Page column 54-55.

2
[ 4637-24-5 ]
[ 502496-33-5 ]
[ 885520-70-7 ]

Yield	Reaction Conditions	Operation in experiment
39%	Stage #1: at 20℃; Heating / reflux Stage #2: With iron; acetic acid In N,N-dimethyl-formamide for 0.666667 h; Heating / reflux Stage #3: With water; sodium carbonate In dichloromethane	Intermediate 35; 4-Bromo-6-fluoro-lH-indole; l-Bromo-5-fluoro-2-methyl-3-nitrobenzene (2.00 g, 8.55 mmol) and(dimethoxymethyl)dimethylamine (5.66 mL, 42.7 mmol) in dry DMF (20 mL) was refiuxed under N₂ for 8 h, then rt. over night. The mixture was diluted with DCM and extracted 5 times with water. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was dissolved in AcOH (10 mL) and added drop wise to a boiling mixture of Fe(s, fine powder) in AcOH (10 mL). The mixture was refiuxed for 40 min., partitioned between DCM and saturated aq. Na₂CO₃/brine (the mixture was filtered through celite before phase separation). The water layer was extracted once more with DCM. The organic layers were combined, dried and concentrated. Purification was performed by flash column chromatography (DCM/hexane 1:3) and afforded the title compound (660 mg, 39percent) as a yellow oil. MS (ESI+) for C₈H₅BrFN m/z 214 (M+H)⁺.
27%	Stage #1: With pyrrolidine In 1,4-dioxane at 20 - 100℃; for 18 h; Stage #2: With iron; acetic acid In 1,4-dioxane for 1 h; Reflux	Example 41 N4-(5-Cyclobutyl- 1 H-pyrazol-3-yl)-N2-((6-fluoro- 1 H-indol-4-yl)methyl)pyrimidine-2,4-diamine Formate (1-88) step 1 : To a solution of l-bromo-5-fluoro-2-methyl-3-nitrobenzene (4.69 g, 20 mmol) in 1,4-dioxane (25 mL) at RT was slowly added DMF dimethylacetal (13.3 mL) and pyrrolidine (1.7 mL). The solution was heated at 100 °C for 18 h, then concentrated in vacuo to give a dark residue. To the residue was added HOAc (30 mL) and iron powder (11 g, 200 mmol) then the mixture was heated to reflux for 1 h, cooled to RT, neutralized by addition of 50percent aq. NaOH and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried (MgSO i), filtered and concentrated in vacuo. The residue was purified by Si02 chromatography eluting with an EtO Ac/petroleum ether gradient (5 to 30percent EtOAc) to afford 1.16 g (27percent) of 4-bromo-6-fluoro-lH-indole (224) -as brown solid: MS (ESI) m/z = 213.9 [M+l] +.

References: [1] Patent: WO2008/3703, 2008, A1, . Location in patent: Page/Page column 91.
[2] Patent: WO2013/26914, 2013, A1, . Location in patent: Page/Page column 158.

3
[ 1181566-93-7 ]
[ 885520-70-7 ]

References: [1] Patent: WO2009/103710, 2009, A1, . Location in patent: Page/Page column 21.

4
[ 1354219-92-3 ]
[ 885520-70-7 ]

Yield	Reaction Conditions	Operation in experiment
800 mg	at 110℃; for 1.5 h;	An acetic acid (20 ml) solution containing the deep brown oily matter obtained in the 2nd step was added to amixture of iron powder (3.61 g) and acetic acid (20 ml) at 110°C for 30 minutes. The resulting mixture was stirred for 1hour and then diluted with ethyl acetate. Insoluble matter was removed by filtration with Celite, the filtrate was washedwith water and 1M hydrochloric acid (x3). The obtained organic layer was poured into a saturated aqueous sodiumhydrogen carbonate solution to separate the organic layer, and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. Thereafter, activated carbon was added and insoluble matter wasremoved by filtration with Celite. The solvent was distilled away under reduced pressure, and light brown oily matter of4-bromo-6-fluoro-1H-indole (880 mg) was thus obtained.MS (ESI m/z): 214, 216 (M+H)RT (min): 1.561H-NMR (DMSO-d6, 300MHz) δ:11.53 (br, 1H), 7.46 (t, 1H, J = 3.0Hz), 7.24 (dd, 1H, J = 5.6, 3.0 Hz), 7.19 (dd, 1H, J =9.2, 2.0Hz), 6.39 (d, 1H, J = 2.0Hz)

References: [1] Patent: EP2589592, 2018, B1, . Location in patent: Paragraph 0755; 0758.
[2] Patent: WO2007/122410, 2007, A1, . Location in patent: Page/Page column 67.

5
[ 502496-33-5 ]
[ 885520-70-7 ]

References: [1] Patent: EP2589592, 2018, B1, .
[2] Patent: WO2007/122410, 2007, A1, .
[3] Patent: WO2007/122410, 2007, A1, .
[4] Patent: WO2008/152394, 2008, A1, .
[5] Patent: WO2008/152390, 2008, A1, .
[6] Patent: WO2009/103710, 2009, A1, .

6
[ 446-10-6 ]
[ 885520-70-7 ]

7
[ 1057369-11-5 ]
[ 885520-70-7 ]

References: [1] Patent: WO2007/122410, 2007, A1, . Location in patent: Page/Page column 105.

[ 885520-70-7 ] Synthesis Path-Downstream 1~35

1
[ 1057369-11-5 ]
[ 885520-70-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine;Raney- Nickel; In tetrahydrofuran; methanol; water; for 24h;Product distribution / selectivity;	To a solution of crude l-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-vinyl]- pyrrolidine (2.74 g) in tetrahydrofuran (25 ml) and methanol (25 ml) was added Raney nickel, 50% slurry in water, active catalyst (5.0 ml) followed by careful addition of hydrazine monohydrate (0.63 ml). After stirring for 24 hours the reaction mixture was filtered through celite and the filtrate reduced in vacuo. The residue was purified by flash chromatography to give 4-bromo-6-fluoro-l H-indole (0.80 g).

References: [1]Patent: WO2007/122410,2007,A1 .Location in patent: Page/Page column 105.

2
[ 1354219-92-3 ]
[ 885520-70-7 ]

Yield	Reaction Conditions	Operation in experiment
800 mg	With iron; acetic acid; at 110℃; for 1.5h;	An acetic acid (20 ml) solution containing the deep brown oily matter obtained in the 2nd step was added to amixture of iron powder (3.61 g) and acetic acid (20 ml) at 110°C for 30 minutes. The resulting mixture was stirred for 1hour and then diluted with ethyl acetate. Insoluble matter was removed by filtration with Celite, the filtrate was washedwith water and 1M hydrochloric acid (x3). The obtained organic layer was poured into a saturated aqueous sodiumhydrogen carbonate solution to separate the organic layer, and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. Thereafter, activated carbon was added and insoluble matter wasremoved by filtration with Celite. The solvent was distilled away under reduced pressure, and light brown oily matter of4-bromo-6-fluoro-1H-indole (880 mg) was thus obtained.MS (ESI m/z): 214, 216 (M+H)RT (min): 1.561H-NMR (DMSO-d6, 300MHz) delta:11.53 (br, 1H), 7.46 (t, 1H, J = 3.0Hz), 7.24 (dd, 1H, J = 5.6, 3.0 Hz), 7.19 (dd, 1H, J =9.2, 2.0Hz), 6.39 (d, 1H, J = 2.0Hz)
	With hydrazine;Raney.(R).- Nickel; In tetrahydrofuran; methanol; water; at 0 - 20℃; for 0.666667h;Product distribution / selectivity;	Reference Example 14; 4-Bromo-6-fluoro-ll?~indoIe; Prepared according to the method used in the preparation of 4-bromo-lT- indole-6-sulfonic acid dimethylamide using l-bromo-5-fluoro-2-methyl-3-nitro- benzene in place of 3-bromo-4-iV,N-trimethyl-5-nitro-benzenesulfonamide. The title compound was obtained as a white solid (6.06 g, 33 percent).NMR deltaH (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.I5 IH), 7.12 (dd, J = 2.1, 9.1, IH)5 7.20-7.25 (m, IH) and 8.25 (s, IH).

References: [1]Patent: EP2589592,2018,B1 .Location in patent: Paragraph 0755; 0758.
[2]Patent: WO2007/122410,2007,A1 .Location in patent: Page/Page column 67.

3
[ 4637-24-5 ]
[ 502496-33-5 ]
[ 885520-70-7 ]

Yield	Reaction Conditions	Operation in experiment
39%		Intermediate 35; 4-Bromo-6-fluoro-lH-indole; l-Bromo-5-fluoro-2-methyl-3-nitrobenzene (2.00 g, 8.55 mmol) and(dimethoxymethyl)dimethylamine (5.66 mL, 42.7 mmol) in dry DMF (20 mL) was refiuxed under N2 for 8 h, then rt. over night. The mixture was diluted with DCM and extracted 5 times with water. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was dissolved in AcOH (10 mL) and added drop wise to a boiling mixture of Fe(s, fine powder) in AcOH (10 mL). The mixture was refiuxed for 40 min., partitioned between DCM and saturated aq. Na2CO3/brine (the mixture was filtered through celite before phase separation). The water layer was extracted once more with DCM. The organic layers were combined, dried and concentrated. Purification was performed by flash column chromatography (DCM/hexane 1:3) and afforded the title compound (660 mg, 39percent) as a yellow oil. MS (ESI+) for C8H5BrFN m/z 214 (M+H)+.
27%		Example 41 N4-(5-Cyclobutyl- 1 H-pyrazol-3-yl)-N2-((6-fluoro- 1 H-indol-4-yl)methyl)pyrimidine-2,4-diamine Formate (1-88) step 1 : To a solution of l-bromo-5-fluoro-2-methyl-3-nitrobenzene (4.69 g, 20 mmol) in 1,4-dioxane (25 mL) at RT was slowly added DMF dimethylacetal (13.3 mL) and pyrrolidine (1.7 mL). The solution was heated at 100 °C for 18 h, then concentrated in vacuo to give a dark residue. To the residue was added HOAc (30 mL) and iron powder (11 g, 200 mmol) then the mixture was heated to reflux for 1 h, cooled to RT, neutralized by addition of 50percent aq. NaOH and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried (MgSO i), filtered and concentrated in vacuo. The residue was purified by Si02 chromatography eluting with an EtO Ac/petroleum ether gradient (5 to 30percent EtOAc) to afford 1.16 g (27percent) of 4-bromo-6-fluoro-lH-indole (224) -as brown solid: MS (ESI) m/z = 213.9 [M+l] +.

References: [1]Patent: WO2008/3703,2008,A1 .Location in patent: Page/Page column 91.
[2]Patent: WO2013/26914,2013,A1 .Location in patent: Page/Page column 158.

4
[ 885520-70-7 ]
[ 98-09-9 ]
[ 1001394-95-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate; In dichloromethane; water; for 1h;	Intermediate 36; 4-Bromo-6-fluoro-l-(phenylsulfonyl)-lH-indole; Aq. 4 M NaOH (5 mL) was added to a stirring mixture of 4-bromo-6-fluoro-lH-indole (500 mg, 2.34 mmol; Intermediate 35), benzenesulfonyl chloride (329 muL g, 2.57 mmol) and tetrabutylammonium hydrogen sulfate (78 mg, 0.23 mmol) in DCM (30 mL). The reaction mixture was stirred Ih, combined with an earlier batch of this intermediate (followed this experimental and starting with 4-bromo-6-fluoro-lH-indole, 152 mg, 0.71 mmol; Intermediate 35), washed twice with water, dried and concentrated. The product <n="93"/>(1.08 g, 100percent) was obtained as a beige solid. MS (ESI+) for Ci4H9BrFNO2S m/z 354 (M+H)+.
79%	With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 4h;Inert atmosphere;	To a solution of 4-bromo-6-fluoro-indole (2 g, 9.38 mmol) in anhydrous tetrahydrofuran (30 mL) cooled in an ice bath was added sodium hydride (0.452 g, 11.3 mmol, 60percent in mineral oil). The reaction mixture was stirred under nitrogen for 10 min before benzenesulfonyl chloride (1.44 mL, 11.3 mmol) was added. The black solution was allowed to warm to room temperature over 4 h. TLC and LCMS indicated completion of the reaction. Saturated aqueous ammonium chloride solution was added slowly, and the resulting solution was extracted with ethyl acetate (2*). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude solid was triturated with ethanol. The resulting beige solid was collected by filtration to give 4-bromo-6-fluoro-1-(phenylsulfonyl)-1H-indole (2.6 g, 79percent yield).

References: [1]Patent: WO2008/3703,2008,A1 .Location in patent: Page/Page column 91-92.
[2]Patent: US2017/240525,2017,A1 .Location in patent: Paragraph 0626.

6
[ 885520-70-7 ]
[ 73183-34-3 ]
[ 955978-85-5 ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 18h;	To a solution of 4-bromo-6-fluoro-lH-indole (6.0 g, 25.53 mmol) and bis(pinacolato)diboron (9.7 g, 38.19 mmol) in anhydrous DMSO (120 mL) were added KOAc (7.5 g, 76.41 mmol) and [l,r-bis(diphenylphosphine)ferrocene]-dichloropalladium (1.0 g, 1.22 mmol). The mixture was heated at 80 °C for 18 h. The reaction mixture was cooled to RT and partioned between EtOAc and H2O. The organic layer was isolated, washed successively with H2O and brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide the title compound as a white solid (4.6 g, 61 percent). <n="41"/>^NMR deltaH (300 MHz, CDCl3) 1.39 (s, 12H), 7.02 (m, IH), 7.14-7.19 (m, IH), 7.20-7.26 (m, IH), 7.38 (dd, J = 2.4, 9.9, IH) and 8.16 (s, IH).
61%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 18h;	To a solution of 4-bromo-6-fluoro-lH-indole (6.0 g, 25.53 mmol) and bis(pinacolato)diboron (9.7 g, 38.19 mmol) in anhydrous DMSO (120 mL) were added KOAc (7.5 g, 76.41 mmol) and [l,r-bis(diphenylphosphine)ferrocene]-dichloropalladium (1.0 g, 1.22 mmol). The mixture was heated at 80 °C for 18 h. The reaction mixture was cooled to RT and partioned between EtOAc and H2O. The organic layer was washed successively with H2O and brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide the title compound as a white solid (4.6 g, 61 percent).NMR deltaH (300 MHz, CDCl3) 1.39 (s, 12H), 7.02 (m, IH), 7.14-7.19 (m, IH), 7.20-7.26 (m, IH), 7.38 (dd, J = 2.4, 9.9, IH) and 8.16 (s, IH).
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 100℃; for 16h;	To a stirring mixture of 4-bromo-6-fluoro-lH-indole (6.76 g, 31.5 mmol), bis(pinacolato)diboron (12.8 g, 94.7 mmol) and potassium acetate (9.3 g, 94.7 mmol) in methyl sulfoxide (100 mL) was added l,r-bis(diphenylphosphine)ferrocene- dichloropalladium (1.29 g, 5 mol percent). The reaction mixture was flushed out with nitrogen and heated to 100 0C for 16 hours. The mixture was partitioned between ethyl acetate and water and the organic layer washed with brine, dried over MgSO4 and evaporated down. The crude product was purified by column chromatography followed by triturating to yield the title compound (7.87 g). deltaH(400MHz, CDCl3) 1.41 (s, 12H)5 7.04 (m, IH), 7.16 (dd, IH), 7.26 (t, IH)5 7.40 (dd, IH)5 8.14 (br S5 IH).

With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 100℃; for 16h;

Reference Example 56-FIuoro-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indoleTo a stirring mixture of 4-bromo-6-fluoro-lH-indole (6.76 g, 31.5 mmol), bis(pinacolato)diboron (12.8 g, 94.7 mmol) and potassium acetate (9.3 g, 94.7 mmol) in methyl sulfoxide (100 mL) was added l,l'-bis(diphenylphosphine)ferrocene- dichloropalladium (1.29 g, 5 mol percent). The reaction mixture was flushed out with nitrogen and heated to 100 0C for 16 hours. The mixture was partitioned between ethyl acetate and water and the organic layer washed with brine, dried over MgSO4 and evaporated down. The crude <n="58"/>product was purified by column chromatography followed by triturating to yield the title compound (7.87 g). deltaH(400MHz, CDCl3) 1.41 (s, 12H), 7.04 (m, IH), 7.16 (dd, IH), 7.26 (t, IH), 7.40 (dd, IH), 8.14 (br s, IH).

References: [1]Patent: WO2008/152394,2008,A1 .Location in patent: Page/Page column 39-40.
[2]Patent: WO2008/152390,2008,A1 .Location in patent: Page/Page column 55.
[3]Patent: WO2008/152387,2008,A1 .Location in patent: Page/Page column 34.
[4]Patent: WO2009/53716,2009,A1 .Location in patent: Page/Page column 56-57.

7
[ 1093066-65-9 ]
[ 885520-70-7 ]

Yield	Reaction Conditions	Operation in experiment
37%	With hydrazine;nickel; In tetrahydrofuran; methanol; water; at 20℃; for 5h;	To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney.(R).-Nickel (suspension in H20, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0 0C and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was evaporated to dryness and the resulting residue to give the title compound as pale oil (2.57 g, 37 percent). NMR deltaH (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.1, IH), 7.12 (dd, J = 2.1, 9.1, IH), 7.20-7.25 (m, IH) and 8.25 (s, IH).
37%	With hydrazine;Raney.(R).-Nickel; In tetrahydrofuran; methanol; water; at 0 - 20℃; for 5h;	Reference Example 44-Bromo-6-fluoro-lH-indoleTo a solution of l-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) was added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100 °C. The mixture was cooled to RT and evaporated to dryness to give l-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-l -methyl vinyl]- pyrrolidine as a dark red residue (10.0 g, theoretical yield). To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney.(R).-Nickel (suspension in H2O, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0 0C and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was evaporated to dryness and the resulting residue to give the title compound as pale oil (2.57 g, 37 percent).NMR deltaH (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.1, IH), 7.12 (dd, J = 2.1, 9.1, IH), 7.20-7.25 (m, IH) and 8.25 (s, IH).
	With pyrrolidine; nickel; hydrazine; In tetrahydrofuran; methanol; sulfuric acid; at 20℃; for 5h;	To a solution of l-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) were added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100 0C for 3 h. The mixture was cooled to RT and concetrated in vacuo to give l-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-l -methyl vinyl]- pyrrolidine as a dark red residue. To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney.(R).-Nickel (suspension in H2O, 15 mL) in MeOHrTHF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0 0C and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide the title compound as a pale oil (2.57 g, 37 percent). NMR deltaH (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.1, IH), 7.12 (dd, J = 2.1, 9.1, IH), 7.20-7.25 (m, IH) and 8.25 (s, IH).

With pyrrolidine; nickel; hydrazine; In water; at 20℃; for 5h;

To a solution of l-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) were added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100 °C for 3 h. The mixture was cooled to RT and concetrated in vacuo to give l-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-l -methyl vinyl]- pyrrolidine as a dark red residue. To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney.(R).-Nickel (suspension in H20, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0 °C and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was concentrated in vacuo and the resulting residue was purified by <n="56"/>column chromatography (silica gel, pentane:EtOAc 75:25) to provide the title compound as a pale oil (2.57 g, 37 percent).NMR deltaH (300 MHz, CDCl3) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.1, IH), 7.12 (dd, J = 2.1, 9.1, IH), 7.20-7.25 (m, IH) and 8.25 (s, IH).

References: [1]Patent: WO2008/152387,2008,A1 .Location in patent: Page/Page column 34.
[2]Patent: WO2009/53716,2009,A1 .Location in patent: Page/Page column 56.
[3]Patent: WO2008/152394,2008,A1 .Location in patent: Page/Page column 39.
[4]Patent: WO2008/152390,2008,A1 .Location in patent: Page/Page column 54-55.

8
[ 885520-70-7 ]
[ 146631-00-7 ]
[ 1181566-98-2 ]

Yield	Reaction Conditions	Operation in experiment
	With oxygen; triethylamine;copper diacetate; In dichloromethane; at 20℃; for 16h;	Description 19. 4-bromo-6-fluoro-1-{4-[(phenylmethyl)oxy]phenyl}-1H-indole A mixture of 4-bromo-6-fluoro-1 H-indole (D16),(200 mg, 0.935 mmol), 4- benzyloxyphenylboronic acid (426 mg, 1.87 mmol), copper (II) acetate (332 mg, 1.87 mmol) and triethylamine (0.26 ml_, 188 mg, 1.87 mmol) in dichloromethane (5 ml.) was stirred in air at room temperature for 16 hours. The mixture was filtered through celite, concentrated and purified by chromatography on silica gel (elution with 0-20percent ethyl acetate in hexanes) to give the tite compound as a pink solid (D19), (205 mg). LC-MS: MH+ = 396/398 (C21H15BrFNO = 395/397)

References: [1]Patent: WO2009/103710,2009,A1 .Location in patent: Page/Page column 23.

9
[ 885520-70-7 ]
4-benzyloxy-3-fluorophenylboronic acid [ No CAS ]
[ 1181566-95-9 ]

Yield	Reaction Conditions	Operation in experiment
	With oxygen; triethylamine;copper diacetate; In dichloromethane; at 20℃; for 72h;Molecular sieve;	Description 17. 4-Bromo-6-fluoro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H- indole (D17) <n="24"/> To a solution of 4-bromo-6-fluoro-1 /-/-indole (D16) (580 mg, 2.71 mmol) in dichloromethane (20 mL) was added {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (1.33 g, 5.42 mmol), copper (II) acetate (984 mg, 5.42 mmol), triethylamine (0.755 mL, 5.42 mmol) and powdered 4A molecular sieves (2 g, 2.71 mmol). The mixture was stirred at room temperature in the presence of air for 3 days. The reaction was filtered through a pad of celite and washed with dichloromethane. The organic solution was washed with water and then the aqueous phase re-extracted with dichloromethane. The combined organic phases were dried over magnesium sulphate, filtered and concentrated. The product was partially purified by silica gel chromatography eluting with 5-20percent ethyl acetate in hexane to yield the title compound (D17), (980 mg). LC-MS: MH+ = 414, 415 (C2iH14BrF2NO = 413, 415)

References: [1]Patent: WO2009/103710,2009,A1 .Location in patent: Page/Page column 21; 22.

10
[ 1181566-93-7 ]
[ 885520-70-7 ]

Yield	Reaction Conditions	Operation in experiment
		Description 16. 4-Bromo-6-fluoro-1H-indole (D16) To a solution of crude[(E)-2-(2-bromo-4-fluoro-6-nitrophenyl)ethenyl]dimethylamine (D15) (6.07 g, 21.0 mmol) in acetic acid (200 ml.) and water (50.0 ml.) at 750C was added zinc powder (15.11 g, 231 mmol) portionwise over 1 hour. The mixture was heated to 850C and stirred for 4 hours. After cooling to room temperature, the reaction mixture was neutralised by the addition of 50percent aqueous sodium hydroxide solution. The product was extracted into diethyl ether. After separation of the layers, the aqueous phase was re-extracted with diethyl ether. The combined organic layers were dried over magnesium sulphate, filtered and concentrated. The product was partially purified by silica gel chromatography eluting with 5-30percent ethyl acetate in hexane. Purer fractions were combined to give the title compound (D16), (580 mg). LC-MS: [M-H]" = 212, 214 (C8H5BrFN = 213, 215)

References: [1]Patent: WO2009/103710,2009,A1 .Location in patent: Page/Page column 21.

11
[ 885520-70-7 ]
[ 98-74-8 ]
[ 1198438-04-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of 4-bromo-6-fluoro-1 H-indole (2 g) in DMF (5 ml) was added sodium hydride (60 percent in mineral oil) (0.448 g). The reaction was stirred at 20 °C for 10 min. 4- Nitrobenzenesulfonyl chloride (2.278 g) was added and the reaction was stirred at 20 °C for 1 h. The mixture was poured onto water (100 ml), and extracted with DCM (50 ml) which was separated by hydrophobic frit. Purification by silica (2 x 100 g) on Flashmaster II using a gradient of DCM and cyclohexane gave the title compound as a pale yellow solid, 1.54g.LCMS (Method B); Rt = 1.39 min.
	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 0.166667h;	To a mixture of 4-bromo-6-fluoro-1 H-indole (2 g) in DMF (5 ml) was added sodium hydride (60percent in mineral oil) (0.448 g). The reaction was stirred at RT for 10 min. 4- Nitrobenzenesulfonyl chloride (2.278 g) was added and the reaction was stirred at RT for 1 h. The mixture was poured onto water (100 ml), and extracted with DCM (50 ml) which was separated by hydrophobic frit. Purification by silica (2 x 100 g) on Flashmaster II using a gradient of DCM and cyclohexane gave the title compound as a pale yellow solid, 1 .54 g.LCMS (Method B); Rt = 1 .39 min, MH+ = 400.
1.54 g		4-Bromo-6-fluoro-1-[(4-nitrophenyl)sulfonyl]-1H-indole To a mixture of <strong>[885520-70-7]4-bromo-6-fluoro-1H-indole</strong> (2 g) in DMF (5 ml) was added sodium hydride (60percent in mineral oil) (0.448 g). The reaction was stirred at 20° C. for 10 min. 4-Nitrobenzenesulfonyl chloride (2.278 g) was added and the reaction was stirred at 20° C. for 1 h. The mixture was poured onto water (100 ml), and extracted with DCM (50 ml) which was separated by hydrophobic frit. Purification by silica (2*100 g) on Flashmaster II using a gradient of DCM and cyclohexane gave the title compound as a pale yellow solid, 1.54 g. LCMS (Method E); R=1 .39 mm.

Intermediate 111 4-Bromo-6-fluoro-1 -[(4-nitrophenyl)sulfonyl]-1 H-indole <n="142"/> Sodium hydride (299 mg, 7.48 mmol) was added to a stirred solution of 4-bromo-6-fluoro- 1H-indole (800 mg, 3.74 mmol) in DMF (20 ml) that had been cooled in an ice bath to 0 0C and placed under nitrogen. The mixture was stirred for 5 mins before 4- nitrobenzenesulfonyl chloride (911 mg, 4.1 1 mmol) was added. The mixture was stirred at 0 0C for 1 hour. The resultant orange/brown solution was poured into stirring water (40 ml). The mixture was rapidly stirred for 30 mins. The resulting brown suspension was collected by filtration, washed with water and dried in a vacuum oven at 5O0C overnight to give a pale brown solid, which was purified by Flashmaster II, on a silica cartridge (100g) using a gradient of ethylacetate and cyclohexane to afford the title compound as a white solid. LCMS (Method C): R1 = 3.61 mins, MH+ = 400.

References: [1]Patent: WO2011/67364,2011,A1 .Location in patent: Page/Page column 81-82.
[2]Patent: WO2011/67365,2011,A1 .Location in patent: Page/Page column 79.
[3]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 152.
[4]Patent: WO2009/147188,2009,A1 .Location in patent: Page/Page column 139-140.

12
[ 885520-70-7 ]
[ 1198437-63-6 ]
C₂₇H₂₇FN₆O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;chloro(di-2-norbornylphosphino)(2'-dimethylamino-1,1'-biphenyl-2-yl)palladium(II); In 1,4-dioxane; water; at 120℃; for 0.166667h;Microwave irradiation;	Example 129N-[6-(6-Fluoro-1 H-indol-4-yl)-1 H-indazol-4-yl]-1 -(1 -methylethyl)-1 H-pyrazole-5- carboxamide A microwave vial was charged with Solvias catalyst (8mg), tripotassium phosphate (90mg) and 4-bromo-6-fluoro-1 H-indole (available from Sinova, 33mg). 1 -(1 -Methylethyl)- N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1 ,3,2-dioxaborinan-2-yl)-2H- indazol-4-yl]-1 H-pyrazole-5-carboxamide (70mg) in 1 ,4-dioxane (0.5ml) was added followed by water (0.1 ml). The mixture was heated under microwave irradiation at 1200C for 10min. The mixture was passed through a silica cartridge which had been preconditioned with methanol, washed through with methanol, then dried under a stream of nitrogen. The residue was subjected to a DCM/water wash and then dried under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1 :1 , v/v) and purified by MDAP (method A). Appropriate fractions were evaporated under a stream of nitrogen. The residues were dissolved in a minimum amount of methanol, a few drops of 2M HCI (aq) were added and the reactions were left to stand briefly at room temperature. The reactions were combined then passed through an aminopropyl cartridge preconditioned with methanol and dried. Purification was carried out using the following system: Column: Supelco ABZ+ Plus, 5 mum, 100x21.2mm i.d. Solvent A: 0.1percent formic acid in water <n="205"/>Solvent B: 1 percent formic acid in watepiacetonitrile (5:95, v/v) Flow rate: 20 ml/min. Gradient: 35 - 70percent B over 12min.The appropriate fraction was dried under a stream of nitrogen to give title compound, 7mg.LC/MS (method B) LOOmin m/z 404 [MH+].

References: [1]Patent: WO2009/147188,2009,A1 .Location in patent: Page/Page column 202-203.

13
[ 885520-70-7 ]
[ 1198437-65-8 ]
C₂₅H₂₂FN₅O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;chloro(di-2-norbornylphosphino)(2'-dimethylamino-1,1'-biphenyl-2-yl)palladium(II); In 1,4-dioxane; water; at 120℃; for 0.416667h;Microwave irradiation;	Example 89N-[6-(6-Fluoro-1 H-indol-4-yl)-1 H-indazol-4-yl]-2-methyl-1 ,3-thiazole-4-carboxamide A microwave vial was charged with Solvias catalyst (15mg), tripotassium phosphate (116mg), 4-bromo-6-fluoro-1 H-indole (available from Sinova, 32mg), 1-(1-methylethyl)-N- [2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1 ,3,2-dioxaborinan-2-yl)-2H-indazol-4- yl]-1 H-pyrazole-5-carboxamide (66mg), 1 ,4-dioxane (0.5ml) and water (0.1 ml). The reaction mixture was heated under microwave irradiation for a total of 25min at 1200C. The mixture was passed through a silica cartridge pre-conditioned with methanol, washing with methanol, then dried. The residue was separated between DCM and water and the organic layer was passed through a hydrophobic frit and dried. The residue was dissolved in DMSO:methanol (1 ml, 1 :1 , v/v) and purified by MDAP (Method H). Appropriate fractions were dried, redissolved in methanol and a few drops of 2M HCI (aq) were added. The reaction was left to stir for 30min. The reaction was passed through an aminopropyl cartridge, preconditioned with methanol, washing with methanol, then dried under a stream of nitrogen to give title compound, 11 mg. LC/MS (Method D) LOOmin m/z 392 [MH+].

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7381 - 7399.
[2]Patent: WO2009/147188,2009,A1 .Location in patent: Page/Page column 183.

14
[ 885520-70-7 ]
[ 1198438-06-0 ]

References: [1]Patent: WO2011/67364,2011,A1 .
[2]Patent: US9326987,2016,B2 .
[3]Patent: WO2009/147188,2009,A1 .

15
[ 885520-70-7 ]
[ 1198439-08-5 ]

References: [1]Patent: WO2011/67364,2011,A1 .
[2]Patent: WO2011/67365,2011,A1 .
[3]Patent: US9326987,2016,B2 .

16
[ 885520-70-7 ]
[ 1310556-45-6 ]

References: [1]Patent: WO2011/67364,2011,A1 .
[2]Patent: US9326987,2016,B2 .

17
[ 885520-70-7 ]
[ 1309785-09-8 ]

References: [1]Patent: WO2011/67365,2011,A1 .

18
zinc cyanide [ No CAS ]
[ 885520-70-7 ]
[ 1082040-44-5 ]

Yield	Reaction Conditions	Operation in experiment
68%	With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); zinc; In 1-methyl-pyrrolidin-2-one; at 140℃; for 18h;Inert atmosphere;	step 2: To a solution of 224 (1.16 g, 5.42 mmol) in NMP (8.5 mL) under argon atmosphere was added Zn(CN)2 (634 mg, 5.42 mmol), zinc powder (70 mg, 1.1 mmol), Pd2(dba)3 (743 mg, 0.81 mmol) and dppf (900 mg, 1.62 mmol). The reaction was stirred at 140 °C for 18 h, cooled and partitioned between EtOAc (200 mL) and H20 (50 mL). The organic layer was separated, washed with brine, dried (MgSO i), filtered and concentrated to dryness in vacuo. The residue was purified by S1O2 chromatography eluting with 15percent EtO Ac/petroleum ether to afford 588 mg (68percent) of 6-fluoro- lH-indole-4-carbonitrile (226) as yellow solid (588 mg, 68percent): MS (ESI) m/z = 161.1 [M+l] +.

References: [1]Patent: WO2013/26914,2013,A1 .Location in patent: Page/Page column 159.

19
[ 885520-70-7 ]
[ 1422057-38-2 ]

References: [1]Patent: WO2013/26914,2013,A1 .

20
[ 885520-70-7 ]
[ 1425929-76-5 ]

References: [1]Patent: WO2013/26914,2013,A1 .

21
[ 885520-70-7 ]
[ 1101818-09-0 ]
[ 1233338-98-1 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 2125 - 2138.

22
[ 885520-70-7 ]
C₁₆H₂₂ClN₃O₅S [ No CAS ]
[ 73183-34-3 ]
C₂₄H₂₇FN₄O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30 mg		A mixture of 4-bromo-6-fluoro-1 H-indole (32 mg, 0.149 mmol), £>/s(pinacolato)diboron (79 mg, 0.309 mmol), KOAc (36 mg, 0.371 mmol) and PdCI2(dppf) (20 mg, 0.025 mmol) in dioxane (1.3 mL) was heated in a sealed tube at 100°C for 3 h. On cooling, intermediate 2-XI (50 mg, 0.124 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol) and Na2C03 2M (0.25 mL) were added. The reaction mixture was heated at 100°C for 20h. On cooling, the mixture was purified by flash column chromatography (5percent to 20percent EtOAc in DCM) and triturated with Et20 to give final compound 33 as a white solid (30 mg). LC-MS1 , tR= 4.95 min, MS: 503.2 [M+H]+ 1 H NMR (300 MHz, DMSO) delta 1 1.32 (s, 1 H), 7.74 (d, J = 1 1.4 Hz, 1 H), 7.45 (s, 1 H), 7.30 (d, J = 9.4 Hz, 1 H), 7.23 (s, 1 H), 4.26 (s, 2H), 4.05-3.71 (m, 8H), 3.52 (m, 1 H), 3.56-3.09 (m, 4H), 2.86 (s, 3H), 2.27-1.96 (m, 4H).

References: [1]Patent: WO2014/140644,2014,A1 .Location in patent: Page/Page column 65.

23
[ 885520-70-7 ]
C₁₂H₁₆ClN₃O₃ [ No CAS ]
C₂₀H₂₁FN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12 mg		A mixture of <strong>[885520-70-7]4-bromo-6-fluoro-1H-indole</strong> (36 mg, 0.168 mmol), bis(pinacolato)diboron (90 mg, 0.350 mmol), potassium acetate (41 mg, 0.420 mmol) and PdCI2(dppf) (23 mg, 0.028 mmol) in dioxane (1 mL) was heated in a sealed tube at 100°C for 3 h. On cooling, intermediate XL (40 mg, 0.140 mmol) in dioxane (1 mL), tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) and Na2C032M (0.21 mL) were added. The reaction mixture was heated at 100°C for 19h. On cooling, the mixture was purified by flash column chromatography, first (5percent to 10percent EtOAc in DCM) and second by prep-HPLC to give the final product Example 45 as a white solid (12 mg). LC-MS1 , tR= 4.04 min. MS: 385.2 [M+H]+ 1 H NMR (300 MHz, DMSO) delta 1 1.30 (s, 1 H), 7.79 (d, J = 1 1.4 Hz, 1 H), 7.44 (s, 1 H), 7.26 (d, J = 15.4 Hz, 2H), 5.34 (s, 1 H), 4.47 (dd, J = 27.0, 10.9 Hz, 2H), 4.05 (d, J = 8.2 Hz, 1 H), 3.93 (t, J = 10.1 Hz, 2H), 3.72 (s, 1 H), 3.58 (s, 1 H), 3.20 (dd, J = 24.7, 13.8 Hz, 3H), 1.52 (s, 7H).

References: [1]Patent: WO2014/140644,2014,A1 .Location in patent: Page/Page column 77-78.

24
[ 885520-70-7 ]
C₃₄H₂₃FN₆O₇S₂ [ No CAS ]

References: [1]Patent: US9326987,2016,B2 .

25
[ 885520-70-7 ]
4-bromo-6-fluoro-1H-indoline-2,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With cerium(III) chloride; 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione; In water; acetonitrile; at 85℃; for 4h;	An acetonitrile/water (9:1) suspension (500 ml) of <strong>[885520-70-7]4-bromo-6-fluoro-1H-indole</strong> (5.0 g, 23.4 mmol), cerium chloride (1.1 g, 0.23 mmol) and 2-iodoxybenzoic acid (16.4 g, 58.5 mmol) was stirred at 85° C. for 4 hours. To the reaction mixture, ethyl acetate and water were added for extraction and the organic layer was dried, then concentrated under reduced pressure. The resulting residue was purified by neutral, OH-form silica gel column chromatography (hexane/ethyl acetate). The titled compound was obtained as a brown solid in an amount of 2.0 g (yield: 35percent). (ESI neg.) m/z: 242 (M-H)-

References: [1]Patent: US2016/159814,2016,A1 .Location in patent: Page/Page column 31.

26
[ 885520-70-7 ]
4-bromo-3,3,6-trifluoro-1,3-dihydro-2H-indol-2-one [ No CAS ]

References: [1]Patent: US2016/159814,2016,A1 .

27
[ 885520-70-7 ]
2-(5-[3-(6-fluoro-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]methyl}-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl]amino}pyridin-2-yl)-2-methylpropanenitrile [ No CAS ]