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[ CAS No. 864825-81-0 ]

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Product Details of [ 864825-81-0 ]

CAS No. :	864825-81-0	MDL No. :	MFCD07369913
Formula :	C₉H₁₀BrNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ATWMWAQQPBRPCA-UHFFFAOYSA-N
M.W :	228.09	Pubchem ID :	25417812
Synonyms :

Safety of [ 864825-81-0 ]

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 [ 864825-81-0 ]

* 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 [ 864825-81-0 ]
Downstream synthetic route of [ 864825-81-0 ]

[ 864825-81-0 ] Synthesis Path-Upstream 1~1

1
[ 864825-81-0 ]
[ 75344-77-3 ]

Reference： [1] Journal of the American Chemical Society, 1940, vol. 62, p. 2995,3001

[ 864825-81-0 ] Synthesis Path-Downstream 1~16

1
[ 7697-32-7 ]
[ 864825-81-0 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride Behandeln des erhaltenen Saeurechlorids mit wss. Ammoniak;

Reference： [1]Spitzer; Wheland [Journal of the American Chemical Society, 1940, vol. 62, p. 2995,3001]

2
[ 864825-81-0 ]
[ 75344-77-3 ]

Reference： [1]Journal of the American Chemical Society,1940,vol. 62,p. 2995,3001

3
[ 201230-82-2 ]
[ 7697-32-7 ]
[ 864825-81-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	With 1,3-bis-(diphenylphosphino)propane; 1,1,1,3,3,3-hexamethyl-disilazane In methanol at 80℃; for 4.167h;	15.B A mixture of Compound 15b (3.33 g, 10 mmol), PdCl2 (0.053 g, 0.3 mmol), hexamethyldisilazane (HMDS, 8.4 mL, 40 mmol), and dppp (0.12 g, 0.3 mmol) was bubbled with a gaseous CO for 5 min and then stirred in a CO balloon at 80° C. for 4 h. To the reaction mixture was added MeOH (5 mL). The mixture was stirred for 10 min, diluted with 2N H2SO4 (200 mL), and then extracted with EtOAc. The EtOAc extract was washed with saturated aqueous NaHCO3, brine, and then dried over Na2SO4. Filtration and evaporation of the resultant filtrate gave a residue, which was purified by flash column chromatography (eluent: EtOAc) to give Compound 15d (1.60 g, 70%) as a white solid.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2005/203143, 2005, A1 Location in patent: Page/Page column 45

4
[ 55477-80-0 ]
[ 864825-81-0 ]
[ 864825-84-3 ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 110℃; for 24h;	15.E E. (Z)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)acrylic acid methyl ester. A flask charged with Compound 15d (0.46 g, 2.0 mmol), Compound 15f (0.80 g, 4.0 mmol), tri-o-tolylphosphine (0.098 g, 0.32 mmol), DMF (8 mL) was purged with N2 (g) 3 times. After the addition of tris(dibenzylideneacetone)dipalladium (0) (0.074 g, 0.08 mmol) and TEA (0.31 mL, 2.2 mol), the reaction mixture was heated at 110° C. for 24 h. At that time, the reaction was quenched by addition of water, and then extracted with EtOAc. The organic phase was washed with 1 N HCl, saturated aqueous NaHCO3, brine, and dried over MgSO4. The mixture was concentrated to a residue, which was purified by flash column chromatography (eluent: EtOAc:hexane~1:1 to EtOAc only) to give Compound 15g (0.40 g, 57%) as a white solid. 1H NMR (300 MHz, CD3OD): δ 1.36 (9H, s), 2.26 (6H, s), 3.83 (3H, s), 7.10 (1H, s), 7.56 (2H, s); 13C NMR (75 MHz, DMSO-d6): δ 17.6, 25.7, 50.2, 78.7, 124.9, 126.4, 128.3, 131.2, 135.2, 135.5, 152.8, 164.3,169.6; MS (ES+) (relative intensity): 349.1 (38%)(M+1).
	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; triethylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 110℃; for 24h;	1.E A flask charged with compound 1d (0.46 g, 2.0 mmol), compound 1f (0.80 g, 4.0 mmol), tri-o-tolylphosphine (0.098 g, 0.32 mmol) and DMF (8 mL) was purged with N2(g) 3 times. After the addition of tris(dibenzylideneacetone)dipalladium (0) (0.074 g, 0.08 mmol) and TEA (0.31 mL, 2.2 mol), the reaction mixture was heated at 110° C. for 24 h. At that time, the reaction was quenched by addition of water, and then extracted with EtOAc. The organic phase was washed with 1N HCl, saturated aqueous NaHCO3, brine, and dried over MgSO4. The mixture was concentrated to a residue, which was purified by flash column chromatography (eluent: EtOAc:hexane1:1 to EtOAc only) to yield compound 1g as a white solid. 1H NMR (300 MHz, CD3OD): δ 1.36 (9H, s), 2.26 (6H, s), 3.83 (3H, s), 7.10 (1H, s), 7.56 (2H, s); 13C NMR (75 MHz, DMSO-d6): δ 17.6, 25.7, 50.2, 78.7, 124.9, 126.4, 128.3, 131.2, 135.2, 135.5, 152.8, 164.3, 169.6; MS (ES+) (relative intensity): 349.1 (38%)(M+1).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2005/203143, 2005, A1 Location in patent: Page/Page column 45
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2006/211861, 2006, A1 Location in patent: Page/Page column 19; 26-27

5
[ 1379327-07-7 ]
[ 864825-81-0 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia In dichloromethane; water at 50℃; for 2h;	1.C.A Into a suspension of compound 1c in DCM (40 mL) was added SOCl2 (3.1 mL, 42 mmol) and the mixture was heated at reflux for 2 h. Upon removal of the solvent by evaporation, the residue was dissolved in DCM (40 mL) and then ammonium hydroxide (28% NH3 in water, 2.8 mL) was added. The reaction mixture was heated at 50° C. for 2 h and concentrated. The residue was diluted with H2O, extracted with EtOAc, and the organic portion was dried over Na2SO4. After filtration and evaporation, the residue was purified by flash column chramotagraphy (eluent: EtOAc) to yield compound 1d as an off-white solid. 1H NMR (300 MHz, CD3CN): δ 2.45 (6H, s), 5.94 (1H, br s), 6.71 (1H, br s), 7.57 (2H, s) MS(ES+)(relative intensity): 228.0 (100%) (M+1).
	With ammonium hydroxide In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran at 50℃; for 2h;	15.C C. 4-Bromo-3,5-dimethyl-benzamide. A suspension of Compound 15c in DCM (40 mL) was added SOCl2 (3.1 mL, 42 mmol) and the mixture was heated at reflux for 2 h. Upon removal of the solvent by evaporation, the residue was dissolved in DCM (40 mL) and ammonium hydroxide (28% NH3 in water, 2.8 mL) was added. The mixture was heated at 50° C. for 2 h and concentrated. The residue was diluted with H2O, extracted with EtOAc, and the organic portion was dried over Na2SO4. After filtration and evaporation, the residue was purified by flash column chramotagraphy (eluent: EtOAc) to give the Compound 15d (2.90 g, 65% for 2 steps) as an off-white solid. 1H NMR (300 MHz, CD3CN): δ 2.45 (6H, s), 5.94 (1H, br s), 6.71 (1H, br s), 7.57 (2H, s); MS(ES+)(relative intensity): 228.0 (100%) (M+1).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2006/211861, 2006, A1 Location in patent: Page/Page column 26
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2005/203143, 2005, A1 Location in patent: Page/Page column 45

6
[ 864825-79-6 ]
[ 201230-82-2 ]
[ 999-97-3 ]
[ 864825-81-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-bromo-3,5-dimethylphenyl trifluoromethanesulfonate; carbon monoxide; 1,1,1,3,3,3-hexamethyl-disilazane With 1,3-bis-(diphenylphosphino)propane; palladium dichloride at 80℃; for 4.08333h; Stage #2: With methanol for 0.166667h;	1.C.B A mixture of compound 1b (3.33 g, 10 mmol), PdCl2 (0.053 g, 0.3 mmol), hexamethyldisilazane (HMDS, 8.4 mL, 40 mmol), and DPPP (0.12 g, 0.3 mmol) was bubbled with a gaseous CO for 5 min and then stirred in a CO balloon at 80° C. for 4 h. To the reaction mixture was added MeOH (5 mL). The reaction mixture was stirred for 10 min, diluted with 2N H2SO4 (200 mL), and then extracted with EtOAc. The EtOAc extract was washed with saturated aqueous NaHCO3, brine, and then dried over Na2SO4. Filtration and evaporation of the resultant filtrate yielded a residue, which was purified by flash column chromatography (eluent: EtOAc) to yield compound 1d as a white solid.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2006/211861, 2006, A1 Location in patent: Page/Page column 26-27

7
[ 864825-81-0 ]
[ 2032-35-1 ]
[ 1458652-89-5 ]

Yield	Reaction Conditions	Operation in experiment
125 mg	at 150℃; for 0.5h; Sealed tube;	1 Step 1: 2-(4-Bromo-3,5-dimethylphenyl)oxazole Step 1: 2-(4-Bromo-3,5-dimethylphenyl)oxazole In a microwave vial 4-bromo-3,5-dimethylbenzamide (200 mg) is mixed with 2-bromo-1,1-diethoxyethane (1 mL), the vial is sealed and the mixture is heated to 150° C. for 30 minutes. The mixture is diluted with acetonitrile (2 mL) and purified by HPLC on reversed phase to give the title compound. Yield: 125 mg; LC (method 7): tR=1.13 min; Mass spectrum (ESI+): m/z=252 [M+H]+.
125 mg	at 150℃; for 0.5h; Microwave irradiation; Sealed tube;	1 Step 1 : 2-(4-Bromo-3,5-dimethylphenyl)oxazole In a microwave vial 4-bromo-3,5-dimethylbenzamide (200 mg) is mixed with 2-bromo- 1 ,1 -diethoxyethane (1 mL), the vial is sealed and the mixture is heated to 150°C for 30 minutes. The mixture is diluted with acetonitrile (2 mL) and purified by HPLC on reversed phase to give the title compound. Yield: 125 mg; LC (method 7): tR = 1 .13 min; Mass spectrum (ESI+): m/z = 252 [M+H]+.
125 mg	at 150℃; for 0.5h; Microwave irradiation; Sealed tube;	1 Step 1 : 2-(4-Bromo-3,5-dimethylphenyl)oxazole In a microwave vial 4-bromo-3,5-dimethylbenzamide (200 mg) is mixed with 2-bromo- 1 ,1 -diethoxyethane (1 mL), the vial is sealed and the mixture is heated to 150°C for 30 minutes. The mixture is diluted with acetonitrile (2 mL) and purified by HPLC on reversed phase to give the title compound. Yield: 125 mg; LC (method 7): tR = 1 .13 min; Mass spectrum (ESI+): m/z = 252 [M+H]+.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG; SANOFI - US2013/252937, 2013, A1 Location in patent: Paragraph 0486
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG; SANOFI - WO2013/144097, 2013, A1 Location in patent: Page/Page column 89
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG; SANOFI - WO2013/144098, 2013, A1 Location in patent: Page/Page column 143

8
[ 1380389-07-0 ]
[ 864825-81-0 ]
methyl 2-((S)-6-((R)-4-(4-carbamoyl-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21.9 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In N,N-dimethyl-formamide at 80℃; for 5h; Inert atmosphere; Sealed tube;	Methyl 2-((S)-6-((R)-4-(4-carbamoyl-2,6-dimethylphenyl)-2,3-dihvdro-1 H-inden-1 - yloxy)-2,3-dihvdrobenzofuran-3-yl)acetate Methyl 2-((S)-6-((R)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 H- inden-1 -yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (45 mg) and 4-Bromo-3,5- dimethyl-benzamide (34.2 mg) are dissolved in dimethylformamide (1 mL) and purged with argon. [1 ,1 '-Bis(di-tert butylphosphino)-ferrocene]-dichloropalladium-(ll) (6.5 mg) and aqueous Cs2CO3-solution (0.1 mL, 2 Mol/L) are added and the reaction mixture is shaken 5 hours in a sealed vial at 80°C. The reaction mixture is acidified with aqueous trifluoroacetic acid, filtrated and chromatographed by H PLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 21 .9 mg; LC (method 23): tR = 1 .88 min; Mass spectrum (ESI+): m/z = 472 [M+H]+.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG; SANOFI - WO2013/144098, 2013, A1 Location in patent: Page/Page column 250; 251

9
[ 75344-77-3 ]
[ 864825-81-0 ]

Yield	Reaction Conditions	Operation in experiment
	With dihydrogen peroxide; potassium carbonate; In dimethyl sulfoxide; at 0 - 20℃; for 2h;	Step A: 4-bromo-3.5-dimethylbenzamide To a solution of 4-bromo-3, 5- dimethylbenzonitrile (1.0 g, 4.8 mmol) in DMSO (10 ml) at 0 C was added 35% H202 (0.542 mL, 6.19 mmol) and K2C03 (1.32 g, 9.52 mmol). The resulting mixture was stirred at 20 C for2 hours and then poured into water (50 mL). The resulting solid was collected by filtration, then washed with water twice, dried in an oven to give the title compound. ?H NMR (400MHz, CD3OD) oe: 7.62 (s, 2H), 2.46 (s, 6H).

Reference： [1]Patent: WO2015/73342,2015,A1 .Location in patent: Page/Page column 115

10
[ 864825-81-0 ]
3-(4-bromo-3,5-dimethylphenyl)-1H-1,2,4-triazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 12 h / 120 °C 2: acetic acid; hydrazine hydrate / 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/73342, 2015, A1

11
[ 864825-81-0 ]
1-(3-(4-bromo-3,5-dimethylphenyl)-1H-1,2,4-triazol-1-yl)-2-methylpropan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 12 h / 120 °C 2: acetic acid; hydrazine hydrate / 2 h / 0 - 20 °C 3: caesium carbonate / N,N-dimethyl-formamide / 12 h / 50 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/73342, 2015, A1

12
[ 864825-81-0 ]
(5aR,6S,6aS)-tert-butyl 3-((4,6-difluoro-4’-(1-(2-hydroxy-2-methylpropyl)-1H-1,2,4-triazol-3-yl)-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclo-propa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 12 h / 120 °C 2: acetic acid; hydrazine hydrate / 2 h / 0 - 20 °C 3: caesium carbonate / N,N-dimethyl-formamide / 12 h / 50 °C 4: potassium carbonate; chloro(2-dicyclohexylphosphino-2‘,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl)]palladium(II) / tetrahydrofuran; water / 0.5 h / 100 °C / Inert atmosphere; Microwave irradiation

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/73342, 2015, A1

13
[ 864825-81-0 ]
(5aR,6S,6aS)-3-((4,6-difluoro-4’-(1-(2-hydroxy-2-methylpropyl)-1H-1,2,4-triazol-3-yl)-2’,6’-dimethyl-[1,1‘-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclo-penta[1,2-c]pyridine-6-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 12 h / 120 °C 2: acetic acid; hydrazine hydrate / 2 h / 0 - 20 °C 3: caesium carbonate / N,N-dimethyl-formamide / 12 h / 50 °C 4: potassium carbonate; chloro(2-dicyclohexylphosphino-2‘,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl)]palladium(II) / tetrahydrofuran; water / 0.5 h / 100 °C / Inert atmosphere; Microwave irradiation 5: water; lithium hydroxide monohydrate / tetrahydrofuran; methanol / 2 h / 23 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/73342, 2015, A1

14
[ 864825-81-0 ]
[ 4637-24-5 ]
(E)-4-bromo-N-((dimethylamino)methylene)-3,5-dimethylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 120℃; for 12h;	17.B Step B: (E)-4-bromo-N-((dimethylamino)methylene)-3 ,5-dimethylbenzamide Step B: (E)-4-bromo-N-((dimethylamino)methylene)-3 ,5-dimethylbenzamide A mixtureof 4-bromo-3,5-dimethylbenzamide (1.0 g, 4.4 mmol) and dimethylformamide dimethyl acetal (1.76 mL, 13.2 mmol) was heated at 120 °C for 12 hours. Then the reaction mixture was cooled to 20°C and petroleum ether (40 mL) was added. The resulting precipitate was collected by filtration and dried in an oven to afford the title compound, which was used directly in the next step without further purification. ‘H NMR (400MHz, CD3OD) ö: 8.61 (s, 1H), 7.93 (s, 2H), 3.25(d, J= 4.7 Hz, 6H), 2.45 (s, 6H). ESI-MS mlz [M + H]: 283.1

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/73342, 2015, A1 Location in patent: Page/Page column 115

15
[ 864825-81-0 ]
(1S,2S)-2-{5-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ylamino]-pyridin-2-yl}-cyclopropanecarboxylic acid methyl ester [ No CAS ]
C₂₇H₂₆FN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-bromo-3,5-dimethylbenzamide; (1S,2S)-2-{5-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ylamino]-pyridin-2-yl}-cyclopropanecarboxylic acid methyl ester With potassium phosphate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) In 1,4-dioxane; water at 80℃; Inert atmosphere; Stage #2: With trifluoroacetic acid at 20℃;	11 Typical procedure for the synthesis of the Examples compiled in the table below: General procedure: A vial charged with a stir bar, (1S,2S)-2-{5-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ylamino]-pyridin-2-yl}-cyclopropanecarboxylic acid methyl ester (0.064 mmol, 1 equiv.), the coupling partner as bromide, chloride, or iodide (0.076 mmol, 1.2 equiv.), K3PO4 (0.159 mmol, 2.5 equiv.), water (0.4 mL), and 1,4-dioxane (0.5 mL) is purged with Ar for 10 min. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (PdCl2(Amphos)2, 1-5 mol %; alternatively, Pd-PEPPSI-IPent Cl is used as catalyst) is added, and the mixture is shaken at 80° C. overnight. After cooling to room temperature, the mixture is acidified with 50% trifluoroacetic acid and chromatographed (HPLC on reversed phase, acetonitrile/water/trifluoroacetic acid) to afford the title compound as trifluoroacetic acid salt that is optionally transformed into its trifluoroacetic acid free form. (0392) In case the ester group is not fully saponified after the coupling reaction is complete, the reaction mixture is treated with aqueous 4 M NaOH solution at 50° C. until all the ester is hydrolyzed. (0393) The compounds in the following table are obtained from a 90:10 to 97.5:2.5 diastereomeric mixture of (1S,2S)-2-{5-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ylamino]-pyridin-2-yl}-cyclopropanecarboxylic acid methyl ester and (1R,2R)-2-{5-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-ylamino]-pyridin-2-yl}-cyclopropanecarboxylic acid methyl ester, with the former diastereomer prevailing. The minor diastereomer after the coupling is usually not separated by chromatography resulting in a product mixture of comparable diastereomeric ratio to the one of the starting material.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2018/148411, 2018, A1 Location in patent: Paragraph 0390-0393

16
[ 864825-81-0 ]
2-{5-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)indan-1-ylamino]-pyrazin-2-yl}-cyclopropanecarboxylic acid methyl ester [ No CAS ]
C₂₆H₂₅FN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-bromo-3,5-dimethylbenzamide; 2-{5-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)indan-1-ylamino]-pyrazin-2-yl}-cyclopropanecarboxylic acid methyl ester With potassium phosphate In 1,4-dioxane; water at 80℃; Inert atmosphere; Stage #2: With water; sodium hydroxide In methanol at 20℃; Inert atmosphere;	10 Typical procedure for the synthesis of the compoundsin the table below: General procedure: A vial charged with a stir bar, (1S,2S)-2-{ 5-[(R)-7 -fluoro-4-( 4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)indan-1-ylamino ]-pyrazin-2-y I} -cyclopropanecarboxy lieacid methyl ester (0.11 mmol, 1 equiv.), the coupling partneras bromide, chloride, or iodide (0.17 mmol, 1.5 equiv.),K3P04 (0.28 mmol in 0.14 mL water, 2.5 equiv.), and1 ,4-dioxane (1.5 mL) is purged with Ar for 10 min. Bis( ditert-buty I( 4-dimethylaminopheny )phosphine )dichloropalladium(II) (PdCI2 (Amphos)2 , 1-5 mol%; alternatively, PdPEPPSI-IHept Cl is used as catalyst) is added, and themixture is shaken at 80° C. for 2 to 16 h. After cooling toroom temperature, methanol (1.5 mL) and NaOH solution (4mol/L in water, 0.5 mL, 18 equiv.) are added, and themixture is shaken at room temperature overnight. The mixtureis neutralized with 50% trifluoroacetic acid and chromatographed(HPLC; acetonitrile/water/ammonium hydroxide)to afford the title compound as ammonium salt that isoptionally transformed into its free acid form by standardmeans. The Examples in the following table are obtainedfrom a ca. 73:27 diastereomeric mixture of (1S,2S)-2-{ 5-[ (R)-7-fluoro-4-( 4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-indan-1-ylamino ]-pyrazin-2-yl }-cyclopropanecarboxylicacid methyl ester and (1R,2R)-2-{5-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)-indan-1-y amino]-pyrazin-2-y I} -cyclopropanecarboxy lie acidmethyl ester, with the former diastereomer predominant. Theminor diastereomer after the coupling is usually not separatedby chromatography resulting in a product mixture ofcomparable diastereomeric ratio to the one of the startingmaterial.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2018/208560, 2018, A1 Location in patent: Paragraph 0349; 0350; 0351

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4-Bromo-3-methylbenzamide

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3-Bromo-4-methylbenzamide

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
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