[ CAS No. 1012880-11-3 ]

Name: 1012880-11-3|2-Fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline|95%
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Product Details of [ 1012880-11-3 ]

CAS No. :	1012880-11-3	MDL No. :	MFCD22494866
Formula :	C₁₃H₁₉BFNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	251.10 g/mol	Pubchem ID :	-
Synonyms :

Safety of [ 1012880-11-3 ]

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

Application In Synthesis of [ 1012880-11-3 ]

Upstream synthesis route of [ 1012880-11-3 ]
Downstream synthetic route of [ 1012880-11-3 ]

[ 1012880-11-3 ] Synthesis Path-Upstream 1~3

1
[ 1012880-11-3 ]
[ 30564-98-8 ]
[ 1885-14-9 ]
[ 1454682-74-6 ]

Yield	Reaction Conditions	Operation in experiment
54.9 g	Stage #1: With sodium hydrogencarbonate In tetrahydrofuran at 0 - 60℃; Inert atmosphere Stage #2: With triethylamine In toluene at 90℃;	Method B: To 4 necked round bottom flask equipped with mechanical agitation, thermometer and N₂ inlet is added 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (40g, 0.159 mol), THF (600 ml) and NaHC0₃ (16.0g, 0.19 mol, 1.20eq). The mixture is cooled to 0~5°C and phenyl chloroformate (26.14g, 0.167 mol, 1.05eq) is added dropwise. The reaction mixture is warmed to 60°C and stirred until the content of 2-fluoro-4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline < 2percent. The mixture is filtered and the solid (salt) is washed with THF (120 ml). The filtrate is concentrated to 65~80ml. To the residue, toluene (720 ml), 3,3-dimethylbutan-l-amine (HC1 salt, 26.14g, 0.19 mol, 1.2eq) and TEA (20.87g, 0.21 mol, 1.3eq) are added. The resulting mixture is heated to 90°C and stirred until the content of intermediate < 2percent. The mixture is cooled to 15~20°C, stirred for 2hrs and filtered. The solid is washed with toluene (120 ml), H₂0 (2 x 400 ml) and dried under high vacuum to afford title compound as a white solid. ( 54.9g, 91.3percent yield and 99percent purity detected by UV absorption at 210 nm);1H NMR (400 MHz, d6-DMSO): δ 8.34 (d, J = 9.1 Hz, 1H), 8.08 (s, 1H), 6.98 (d, J = 12.3 Hz, 1H), 6.41 (s, 1H), 3.08 (s, 2H), 2.38 (s, 3H), 1.36 (m, 14H), 0.90 (s, 9H);¹³C NMR (500MHz, d6-DMSO): δ 21.12,24.65,29.37,29.58, 35.65,43.50,83.25, 104.32116.09, 125.02, 128.19, 138.71, (152.40,154.34) ,154.81; ¹⁹F NMR (400 MHz, d6-DMSO): δ 136.34

Reference： [1] Patent: WO2013/134243, 2013, A1, . Location in patent: Page/Page column 14-15

2
[ 1012880-11-3 ]
[ 1454682-74-6 ]

Reference： [1] Patent: WO2013/134243, 2013, A1,
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179

3
[ 1012880-11-3 ]
[ 1454682-72-4 ]

Reference： [1] Patent: WO2013/134243, 2013, A1,
[2] Patent: WO2013/134243, 2013, A1,
[3] Patent: WO2013/134243, 2013, A1,
[4] Patent: WO2013/134243, 2013, A1,
[5] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
[6] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
[7] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179
[8] Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179

[ 1012880-11-3 ] Synthesis Path-Downstream 1~26

1
[ 1012880-11-3 ]
[ 1454682-74-6 ]

Reference： [1]Patent: WO2013/134243,2013,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 4165 - 4179
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 4165 - 4179

2
[ 1012880-11-3 ]
[ 1454682-72-4 ]

Reference： [1]Patent: WO2013/134243,2013,A1
[2]Patent: WO2013/134243,2013,A1
[3]Patent: WO2013/134243,2013,A1
[4]Patent: WO2013/134243,2013,A1
[5]Journal of Medicinal Chemistry,2015,vol. 58,p. 4165 - 4179
[6]Journal of Medicinal Chemistry,2015,vol. 58,p. 4165 - 4179
[7]Journal of Medicinal Chemistry,2015,vol. 58,p. 4165 - 4179
[8]Journal of Medicinal Chemistry,2015,vol. 58,p. 4165 - 4179

3
[ 57933-83-2 ]
[ 1012880-11-3 ]
[ 1454682-73-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydrogencarbonate In water; ethyl acetate at 20℃; for 6h;
	With sodium hydrogencarbonate In water; ethyl acetate at 20℃; for 6h;	3 Preparation 3 Prop-l-en-2-yl 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenylcarbamate Add 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (5.0 g, 19.91 mmol) and isopropenyl chloroformate (2.40 mL, 21.90 mmol) in EtOAc (60 mL) and saturated aqueous NaHC03 (60 mL) and stir at RT for 6 h. Separate the layers, extract the aqueous layer with EtOAc (2x), wash the combined organics with brine, dry over Na2S04 and concentrate to obtain the title compound. Use for the next reaction without further purification (assuming 100% yield). MS (m/z): 336.2 (M+l).
	With sodium hydrogencarbonate In ethyl acetate at 20℃; for 6h;	31 Synthesis of prop-1-en-2-yl 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate Combine 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (5.0 g, 19.91 mmol) and isopropenyl chloro formate (2.40 mL, 21.90 mmol) in EtOAc (60 mL) and saturated NaHC03 (60 mL) and stir at RT for 6 h. Separate the layers, extract the aqueous layer with EtOAc (2x), wash the combined organics with brine, dry over Na2S04 and concentrate to obtain the title compound. Use for the next reaction without further purification (assuming 100% yield). MS (m/z): 336.2 (M+ H+).

Reference： [1]Henry, James R.; Kaufman, Michael D.; Peng, Sheng-Bin; Ahn, Yu Mi; Caldwell, Timothy M.; Vogeti, Lakshminarayana; Telikepalli, Hanumaiah; Lu, Wei-Ping; Hood, Molly M.; Rutkoski, Thomas J.; Smith, Bryan D.; Vogeti, Subha; Miller, David; Wise, Scott C.; Chun, Lawrence; Zhang, Xiaoyi; Zhang, Youyan; Kays, Lisa; Hipskind, Philip A.; Wrobleski, Aaron D.; Lobb, Karen L.; Clay, Julia M.; Cohen, Jeffrey D.; Walgren, Jennie L.; McCann, Denis; Patel, Phenil; Clawson, David K.; Guo, Sherry; Manglicmot, Danalyn; Groshong, Chris; Logan, Cheyenne; Starling, James J.; Flynn, Daniel L. [Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179]
[2]Current Patent Assignee: ELI LILLY & CO; DECIPHERA PHARMACEUTICALS LLC - WO2013/134243, 2013, A1 Location in patent: Page/Page column 12-13
[3]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC; ELI LILLY & CO - WO2013/134298, 2013, A1 Location in patent: Page/Page column 44

4
[ 1012880-11-3 ]
[ 30564-98-8 ]
[ 1885-14-9 ]
[ 1454682-74-6 ]

Yield	Reaction Conditions	Operation in experiment
54.9 g		Method B: To 4 necked round bottom flask equipped with mechanical agitation, thermometer and N2 inlet is added 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (40g, 0.159 mol), THF (600 ml) and NaHC03 (16.0g, 0.19 mol, 1.20eq). The mixture is cooled to 0~5C and phenyl chloroformate (26.14g, 0.167 mol, 1.05eq) is added dropwise. The reaction mixture is warmed to 60C and stirred until the content of 2-fluoro-4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline < 2%. The mixture is filtered and the solid (salt) is washed with THF (120 ml). The filtrate is concentrated to 65~80ml. To the residue, toluene (720 ml), 3,3-dimethylbutan-l-amine (HC1 salt, 26.14g, 0.19 mol, 1.2eq) and TEA (20.87g, 0.21 mol, 1.3eq) are added. The resulting mixture is heated to 90C and stirred until the content of intermediate < 2%. The mixture is cooled to 15~20C, stirred for 2hrs and filtered. The solid is washed with toluene (120 ml), H20 (2 x 400 ml) and dried under high vacuum to afford title compound as a white solid. ( 54.9g, 91.3% yield and 99% purity detected by UV absorption at 210 nm);1H NMR (400 MHz, d6-DMSO): delta 8.34 (d, J = 9.1 Hz, 1H), 8.08 (s, 1H), 6.98 (d, J = 12.3 Hz, 1H), 6.41 (s, 1H), 3.08 (s, 2H), 2.38 (s, 3H), 1.36 (m, 14H), 0.90 (s, 9H);13C NMR (500MHz, d6-DMSO): delta 21.12,24.65,29.37,29.58, 35.65,43.50,83.25, 104.32116.09, 125.02, 128.19, 138.71, (152.40,154.34) ,154.81; 19F NMR (400 MHz, d6-DMSO): delta 136.34

Reference： [1]Patent: WO2013/134243,2013,A1 .Location in patent: Page/Page column 14-15

5
[ 945244-29-1 ]
[ 73183-34-3 ]
[ 1012880-11-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃;Inert atmosphere;	Combine <strong>[945244-29-1]5-bromo-2-fluoro-4-methylaniline</strong> (3.1 g, 15.2 mmol), bis(pinacolato)diboron (4.24 g, 16.7 mmol), and potassium acetate (4.47 g, 45.6 mmol) in dioxane (40 mL) and sparge with argon. Add [l,l'-bis(diphenylphosphino)ferrocene]- dichloropalladium(II)-dichloromethane complex (0.620 g, 0.760 mmol), sparge again with argon and heat at 100C overnight. Filter the reaction mixture and concentrate in vacuo. Purify by silica gel chromatography (EtOAc/hexanes) to give the title compound (3.24 g, 85%). MS (m/z): 252.1 (M+ H+).
74%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In Isopropyl acetate; at 50℃;Inert atmosphere; Reflux;	Method B: To 4 necked round bottom flask, equipped with mechanical agitation, thermometer, and N2 inlet is added 5-bromo-2-fiuoro-4-methylaniline (200g, 0.98 mol), CH3COOK (192g, 1.95 mol, 2.0eq), bis(pinacolato)diboron (248g, 0.98 mol,1.0eq) and IPAC (3L). After degassing with N2 for 30 min, the mixture is warmed to 50C and Pd(dppf)Cl2 (8g, 4wt%) is added. The reaction mixture is heated under reflux for at least lOh until the content of starting material <2% (GC). The mixture is cooled to 20~30C, filtered through a pad of Celite and rinsed with IPAC (1L). The filtrate is concentrated to 400~500ml remaining. The residue is mixed with n-Heptane (700ml), filtered through a Si02 pad and eluted with IPAC/n-Heptane(l/5 first, ~2L, and then 2/5, ~3L ). The filtrate is concentrated to 350~400ml. n-Heptane (300ml) is added and the mixture is again concentrated to 350~400ml. The residue (suspension) is cooled to -10- -20C and filtered after stirring for 2- 5 h. The crude product is dissolved in MeOH (200 ml) at 30-40 C, then slowly add H20 (600 ml) dropwise in 0.5~lh. The suspension is cooled to 20-30 C and filtered after stirring for 1-2 h .The solid is dried under high vacuum to afford the title compound as off- white solid (183g, 74% yield and 99% purity detected by UV absorption at 210 nm; 1H NMR (400 MHz, CDC13): delta 7.42 (d, J = 10.2 Hz, 1H), 7.01 (d, J = 12.4 Hz, 1H), 3.76 (s, 2H), 2.64 (s, 3H), 1.55 (s, 12H); 13C NMR(500MHz,CDC13): delta 20.66, 20.67, 24.40, 82.93, 116.20, 124.37, 130.64, 135.02, (151.93, 153.37);19F NMR (400 MHz,CDC13): delta 145.72

Reference： [1]Patent: WO2013/134298,2013,A1 .Location in patent: Page/Page column 43
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 4165 - 4179
[3]Patent: WO2013/134243,2013,A1 .Location in patent: Page/Page column 11-12

6
[ 452-63-1 ]
[ 1012880-11-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sulfuric acid; potassium nitrate / -10 - 20 °C / Cooling with ice; Inert atmosphere 2: iron; hydrogenchloride / ethyl acetate; water / 20 - 30 °C / Inert atmosphere 3: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / Isopropyl acetate / 50 °C / Inert atmosphere; Reflux
	Multi-step reaction with 3 steps 1: nitric acid; sulfuric acid / -5 - 20 °C 2: hydrogen / ethanol / 2062.71 Torr 3: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 100 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: nitric acid; sulfuric acid / 0.83 h / -5 - 20 °C 2: hydrogen / ethanol / 2062.71 Torr 3: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: ELI LILLY & CO; DECIPHERA PHARMACEUTICALS LLC - WO2013/134243, 2013, A1
[2]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC; ELI LILLY & CO - WO2013/134298, 2013, A1
[3]Henry, James R.; Kaufman, Michael D.; Peng, Sheng-Bin; Ahn, Yu Mi; Caldwell, Timothy M.; Vogeti, Lakshminarayana; Telikepalli, Hanumaiah; Lu, Wei-Ping; Hood, Molly M.; Rutkoski, Thomas J.; Smith, Bryan D.; Vogeti, Subha; Miller, David; Wise, Scott C.; Chun, Lawrence; Zhang, Xiaoyi; Zhang, Youyan; Kays, Lisa; Hipskind, Philip A.; Wrobleski, Aaron D.; Lobb, Karen L.; Clay, Julia M.; Cohen, Jeffrey D.; Walgren, Jennie L.; McCann, Denis; Patel, Phenil; Clawson, David K.; Guo, Sherry; Manglicmot, Danalyn; Groshong, Chris; Logan, Cheyenne; Starling, James J.; Flynn, Daniel L. [Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179]

7
[ 170098-98-3 ]
[ 1012880-11-3 ]

Reference： [1]Patent: WO2013/134243,2013,A1
[2]Patent: WO2013/134298,2013,A1
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 4165 - 4179

8
[ 1012880-11-3 ]
[ 1455035-96-7 ]
[ 1455035-98-9 ]

Yield	Reaction Conditions	Operation in experiment
61%	With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 60℃; for 1h; Inert atmosphere;	38 Synthesis of 5 -(7-chloro-2 -methyl[1,6]naphthyridin-3-yl)-2-fluoro-4-methylaniline. Sparge a mixture of 7-chloro-2-methyl-l,6-naphthyridin-3-yl trifluoromethanesulfonate (2.250 g, 6.89 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.729 g, 6.89 mmol) in dioxane (32 mL) with argon, add a solution of K2CO3 (2.86 g, 20.66 mmol) in H20 (16 mL) followed by Pd(PPh3)4 (252 mg, 0.689 mmol) and heat at 60°C for 1 h. Cool to RT, add EtOAc, wash successively with H20, satd. NaHC03, then brine, dry over Na2S04, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (1.277 g, 61%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (d, J = 0.8 Hz, 1 H), 8.28 (s, 1 H), 8.00 (s, 1 H), 7.00 (d, J = 12.4 Hz, 1 H), 6.59 (d, J = 9.3 Hz, 1 H), 5.08 (s, 2 H), 2.42 (s, 3 H), 1.85 (s, 3 H); MS (ESI) m/z: 302.1(M+H+).
61%	With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In lithium hydroxide monohydrate at 60℃; for 1h; Inert atmosphere;
41%	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 80℃; for 1h; Inert atmosphere;	D7 Example D1: 2,4-difluoro-5-(isoquinolin-7-yl)aniline General procedure: A solution of 7-chloro-2-methyl-1,6-naphthyridin-3-yl trifluoromethanesulfonate (B27, 3.0 g, 9.2 mmol), 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (A6, 2.2 g, 9.2 mmol) and K2CO3 (3.81 g, 28 mmol) in 1,4-dioxane (15 mL) and water (2.5 mL) was degassed with Ar for 5 min. PdCl2(dppf) (0.34 g, 0.46 mmol) was added and the reaction mixture was heated at 80 C for 1 h. The reaction mixture was cooled to rt and then the solution was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the crude was purified by silica gel column chromatography (0 to 100% EtOAc/hexanes) to afford 3-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)- 2-fluoroaniline (2.0 g, 76% yield) as a brown solid.1H NMR (500 MHz, DMSO-d6): δ 9.27 (s, 1H), 8.45 (s, 1H), 8.02 (s, 1H), 7.03 (t, J = 7.7 Hz, 1H), 6.90 (t, J = 8.3 Hz, 1H), 6.56 (t, J = 6.9 Hz, 1H), 5.35 (s, 2H); MS (ESI) m/z: 288.0 (M+H+).

Reference： [1]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC; ELI LILLY & CO - WO2013/134298, 2013, A1 Location in patent: Page/Page column 46
[2]Henry, James R.; Kaufman, Michael D.; Peng, Sheng-Bin; Ahn, Yu Mi; Caldwell, Timothy M.; Vogeti, Lakshminarayana; Telikepalli, Hanumaiah; Lu, Wei-Ping; Hood, Molly M.; Rutkoski, Thomas J.; Smith, Bryan D.; Vogeti, Subha; Miller, David; Wise, Scott C.; Chun, Lawrence; Zhang, Xiaoyi; Zhang, Youyan; Kays, Lisa; Hipskind, Philip A.; Wrobleski, Aaron D.; Lobb, Karen L.; Clay, Julia M.; Cohen, Jeffrey D.; Walgren, Jennie L.; McCann, Denis; Patel, Phenil; Clawson, David K.; Guo, Sherry; Manglicmot, Danalyn; Groshong, Chris; Logan, Cheyenne; Starling, James J.; Flynn, Daniel L. [Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179]
[3]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - WO2022/109001, 2022, A1 Location in patent: Paragraph 0294-0295

9
[ 1012880-11-3 ]
[ 1384080-06-1 ]
[ 1455036-05-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water at 75℃; for 8h; Inert atmosphere;	42 Synthesis of 5-(7-chloro[1,6]naphthyridin-3-yl)-2-fluoro-4-methylaniline Sparge a solution of 3-bromo-7-chloro-l,6-naphthyridine (0.5 g, 2.053 mmol) and 2-fiuoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.516 g, 2.053 mmol) in dioxane (15 mL) with Ar, add a solution of K2CO3 (0.568 g, 4.11 mmol) in H20 (3 mL), followed by Pd(PPh3)4 (0.237 g, 0.205 mmol), heat at 75°C for 8 h, then cool to RT. Add H20, extract with EtO Ac (2x), wash the combined organics with brine, dry over Na2S04, concentrate to dryness and purify via silica gel chromatography (EtO Ac/Hex) to afford the title compound (470 mg, 80%) as an off-white solid. MS(ESI) m/z: 288.1 (M+H+).

Reference： [1]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC; ELI LILLY & CO - WO2013/134298, 2013, A1 Location in patent: Page/Page column 48

10
[ 1012880-11-3 ]
1-(5-(2-amino-7-methylpyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)-3-(3,3-dimethylbutyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / water; ethyl acetate / 6 h / 20 °C 2.1: phenyl chloroformate; sodium hydrogencarbonate / tetrahydrofuran / 0 - 60 °C / Inert atmosphere 2.2: 2 h / 20 - 90 °C 3.1: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane; water / 100 °C / Inert atmosphere 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C 4.2: 20 °C
	Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / water; ethyl acetate / 6 h / 20 °C 2.1: 1-Methylpyrrolidine / 1,4-dioxane / 75 °C 3.1: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane; water / 100 °C / Inert atmosphere 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C 4.2: 20 °C

Reference： [1]Henry, James R.; Kaufman, Michael D.; Peng, Sheng-Bin; Ahn, Yu Mi; Caldwell, Timothy M.; Vogeti, Lakshminarayana; Telikepalli, Hanumaiah; Lu, Wei-Ping; Hood, Molly M.; Rutkoski, Thomas J.; Smith, Bryan D.; Vogeti, Subha; Miller, David; Wise, Scott C.; Chun, Lawrence; Zhang, Xiaoyi; Zhang, Youyan; Kays, Lisa; Hipskind, Philip A.; Wrobleski, Aaron D.; Lobb, Karen L.; Clay, Julia M.; Cohen, Jeffrey D.; Walgren, Jennie L.; McCann, Denis; Patel, Phenil; Clawson, David K.; Guo, Sherry; Manglicmot, Danalyn; Groshong, Chris; Logan, Cheyenne; Starling, James J.; Flynn, Daniel L. [Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179]
[2]Henry, James R.; Kaufman, Michael D.; Peng, Sheng-Bin; Ahn, Yu Mi; Caldwell, Timothy M.; Vogeti, Lakshminarayana; Telikepalli, Hanumaiah; Lu, Wei-Ping; Hood, Molly M.; Rutkoski, Thomas J.; Smith, Bryan D.; Vogeti, Subha; Miller, David; Wise, Scott C.; Chun, Lawrence; Zhang, Xiaoyi; Zhang, Youyan; Kays, Lisa; Hipskind, Philip A.; Wrobleski, Aaron D.; Lobb, Karen L.; Clay, Julia M.; Cohen, Jeffrey D.; Walgren, Jennie L.; McCann, Denis; Patel, Phenil; Clawson, David K.; Guo, Sherry; Manglicmot, Danalyn; Groshong, Chris; Logan, Cheyenne; Starling, James J.; Flynn, Daniel L. [Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179]

11
[ 1012880-11-3 ]
1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate / water; ethyl acetate / 6 h / 20 °C 2.1: phenyl chloroformate; sodium hydrogencarbonate / tetrahydrofuran / 0 - 60 °C / Inert atmosphere 2.2: 2 h / 20 - 90 °C 3.1: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane; water / 100 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / water; ethyl acetate / 6 h / 20 °C 2: 1-Methylpyrrolidine / 1,4-dioxane / 75 °C 3: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane; water / 100 °C / Inert atmosphere

Reference： [1]Henry, James R.; Kaufman, Michael D.; Peng, Sheng-Bin; Ahn, Yu Mi; Caldwell, Timothy M.; Vogeti, Lakshminarayana; Telikepalli, Hanumaiah; Lu, Wei-Ping; Hood, Molly M.; Rutkoski, Thomas J.; Smith, Bryan D.; Vogeti, Subha; Miller, David; Wise, Scott C.; Chun, Lawrence; Zhang, Xiaoyi; Zhang, Youyan; Kays, Lisa; Hipskind, Philip A.; Wrobleski, Aaron D.; Lobb, Karen L.; Clay, Julia M.; Cohen, Jeffrey D.; Walgren, Jennie L.; McCann, Denis; Patel, Phenil; Clawson, David K.; Guo, Sherry; Manglicmot, Danalyn; Groshong, Chris; Logan, Cheyenne; Starling, James J.; Flynn, Daniel L. [Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179]
[2]Henry, James R.; Kaufman, Michael D.; Peng, Sheng-Bin; Ahn, Yu Mi; Caldwell, Timothy M.; Vogeti, Lakshminarayana; Telikepalli, Hanumaiah; Lu, Wei-Ping; Hood, Molly M.; Rutkoski, Thomas J.; Smith, Bryan D.; Vogeti, Subha; Miller, David; Wise, Scott C.; Chun, Lawrence; Zhang, Xiaoyi; Zhang, Youyan; Kays, Lisa; Hipskind, Philip A.; Wrobleski, Aaron D.; Lobb, Karen L.; Clay, Julia M.; Cohen, Jeffrey D.; Walgren, Jennie L.; McCann, Denis; Patel, Phenil; Clawson, David K.; Guo, Sherry; Manglicmot, Danalyn; Groshong, Chris; Logan, Cheyenne; Starling, James J.; Flynn, Daniel L. [Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4165 - 4179]

12
[ 1012880-11-3 ]
6-bromo-N-[(4-methoxyphenyl)methyl]-N-methylpyrido[2,3-d]pyrimidin-2-amine [ No CAS ]
6-(5-amino-4-fluoro-2-methylphenyl)-N-(4-methoxybenzyl)-N-methylpyrido[2,3-d]pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water at 60℃; for 3h;

13
[ 1012880-11-3 ]
[ 1454682-76-8 ]
2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.8%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium carbonate In tetrahydrofuran; water at 70℃; for 2h; Inert atmosphere;	86.I Step I, 2-Fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6- yl)aniline To a stirred solution of 7-m ethyl -2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl tnfluoromethane sulfonate (1.0 g, 2.95 mmol, 1.0 equiv.) (Henry et. al. J. Med. Chem. 2015, 58 (10), 4165-4179) in THF (25 mL, 25 vol. equiv.) was added 2-fluoro-4-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (888 mg, 3.54 mmol, 1.0 equiv.) (Henry et. al. J. Med. Chem. 2015, 58 (10), 4165-4179), potassium carbonate (1.22 g, 8.84 mmol, 3.0 equiv.), water (2 mL, 2 vol. equiv.) and PdCl2(dppf).DCM adduct (241 mg, 0.295 mmol, 0.1 equiv.). The reaction mixture was degassed three times with alternating vacuum and nitrogen. The resulting reaction mixture was heated at 70°C for 2.0 h. The progress of the reaction was monitored by TLC (70% EtOAc in -hexane) to ensure completion of the reaction. The reaction mixture was filtered through a Celite pad, rinsed with EtOAc. Water (50 mL) was added to the filtrate and the product was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water and brine (60 mL), dried (Na2S04), and concentrated. The residue was purified on Si02 cartridge (80 g) using a gradient of EtOAc in hexanes (10-70%) to afford the title compound (563 mg, 60.8%) as a yellow solid. The product was triturated with ether (10 mL) and hexanes (25 mL) to afford the title compound. Rf = 0.48 (70% EtOAc in hexanes). MR (400 MHz, CDCb) 5 9.11 (s, 1H), 7.86 (s, 1H), 6.96 (d, J = 11.7 Hz, 1H), 6.58 (d, J = 8.9 Hz, 1H), 3.71 (s, 2H), 2.77 (s, 3H), 2.55 (s, 3H), 1.94 (s, 3H). 19F NMR (376 MHz, CDCb) δ - 135.85 (dd, J = 11.7, 9.0 Hz). LRMS (m/z) calculated for Ci6Hi5FN4S, 314.10; found 336.90 (M+Na)+, 314.96 (M+H)+.

Reference： [1]Current Patent Assignee: ZAMBONI CHEM SOLUTIONS - WO2018/200981, 2018, A1 Location in patent: Paragraph 0209; 0421-0422

14
[ 1012880-11-3 ]
4-(5-bromo-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-3-yl)morpholine [ No CAS ]
2-fluoro-4-methyl-5-(5-morpholino-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-3-yl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,4-dioxane; water at 80℃; for 16h;	3 Step 3: 2-fluoro-4-methyl-5-[5-(morpholin-4-yl)-6-[2-(oxan-2-yloxy)ethoxylpyridin-3-yllaniline To a solution of 4-[5-bromo-2-[2-(oxan-2-yloxy)ethoxy]pyridin-3-yl]morpholine (550.00 mg, 1.42 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (534.93 mg, 2.13 mmol) in 1,4-dioxane (0.5 mL) and ThO (0.1 mL) were added NaiCCb (301.05 mg, 2.84 mmol) and l, l-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (463.91 mg, 0.57 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (1-10%). The fractions contained desired product were combined and concentrated to afford 2-fluoro-4- methyl-5-[5-(morpholin-4-yl)-6-[2-(oxan-2-yloxy)ethoxy]pyridin-3-yl]aniline (580 mg, 95%) as a yellow solid. MS ESI calculated for C23H30FN3O4[M + H]+, 432.22; found 432.30.1H-NMR (400 MHz, -DMSO) d 7.63 (d, J= 2.0 Hz, 1H), 7.05 (d, J= 2.0 Hz, 1H), 6.93 (d, J= 12.4 Hz, 1H), 6.65 (d, J= 9.6 Hz, 1H), 4.96 (s, 2H), 4.48 - 4.44 (m, 2H), 3.92 (s, 1H), 3.82 - 3.68 (m, 6H), 3.50 - 3.46 (m, 1H), 3.10 - 3.06 (m, 4H), 2.08 (s, 3H), 1.73 - 1.58 (m, 2H), 1.57 - 1.45 (m, 5H).

Reference： [1]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2020/198058, 2020, A1 Location in patent: Paragraph 00204; 00206

15
[ 1012880-11-3 ]
4-(5-bromo-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)morpholine [ No CAS ]
2-fluoro-4-methyl-5-(5-morpholino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,4-dioxane; water at 80℃; for 3h;	2 Step 2: 2-fluoro-4-methyl-5-(5-morpholino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)aniline To a solution of 4-[5-bromo-2-(oxan-4-yloxy)pyridin-3-yl]morpholine (940.00 mg, 2.74 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (894.05 mg, 3.56 mmol) in dioxane (15.00 mL) and H2O (3.00 mL) were added NaiCCL (580.55 mg, 5.48 mmol) and 1, 1- bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (223.66 mg, 0.27 mmol). The reaction mixture was degassed with nitrogen for three times and stirred at 80 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 10% MeOH in CH2CI2. The fractionscontained desired product were combined and concentrated to afford 2-fluoro-4-methyl-5-[5- (morpholin-4-yl)-6-(oxan-4-yloxy)pyridin-3-yl]aniline (0.86 g, 81%) as an off-white solid. MS ESI calculated for C21H26FN3O3[M + H]+, 388.20; found 388.20.1H-NMR (400 MHz, /6-DMSO) d 7.62 (d, J= 2.0 Hz, 1H), 7.04 (d, J= 2.0 Hz, 1H), 6.91 (d, J= 12.4 Hz, 1H), 6.63 (d, J= 9.2 Hz, 1H), 5.31- 5.30 (m, 1H), 4.96 (brs, 2H), 3.89 - 3.79 (m, 2H), 3.75 - 3.73 (m, 4H), 3.58 - 3.53 (m, 2H), 3.07 - 3.05 (m, 4H), 2.11 - 1.95 (m, 5H), 1.72 - 1.65 (m, 2H).

Reference： [1]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2020/198058, 2020, A1 Location in patent: Paragraph 00208

16
[ 1012880-11-3 ]
4-[4-iodo-6-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]morpholine [ No CAS ]
2-fluoro-4-methyl-5-(2-morpholino-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,4-dioxane; water at 80℃; for 1h;	3 Step 3 : 2-fluoro-4-methyl-5-(2-morpholino-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-4-yl)aniline To a solution of 4-[4-iodo-6-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]morpholine (5.75 g, 13.24mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (3.66 g, 14.56 mmol) in dioxane (170 mL) and water (40 mL) were added NaiCCb (4.21 g, 39.72 mmol) and 1,1- bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.08 g, 1.32 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 80 °C. The resulting mixture was diluted with water (100 mL) and extracted with EA (3 x 150 mL). The combined organic layers was washed with brine (3 x 100 mL), dried over anhydrous NaiSCL and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 40% EA in PE. The fractions contained desired product were combined and concentrated to afford 2-fluoro-4-methyl-5-[2-(morpholin-4-yl)-6-[2- (oxan-2-yloxy)ethoxy]pyridin-4-yl]aniline (4.4 g, 77%) as a yellow oil. MS ESI calculated for C23H30FN3O4[M + H]+, 432.22; found 432.25. H-NMR (300 MHz, CDCb) d 6.87 (d, 7= 11.7 Hz, 1H), 6.65 (d, J= 9.0 Hz, 1H), 6.11 - 6.07 (m, 2H), 4.70 (t, J= 3.6 Hz, 1H), 4.54 - 4.41 (m, 2H),4.11 - 4.02 (m, 1H), 3.94 - 3.77 (m, 6H), 3.54 - 3.47 (m, 5H), 2.14 (s, 3H), 1.89 - 1.43 (m, 6H).

Reference： [1]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2020/198058, 2020, A1 Location in patent: Paragraph 00212; 00339

17
[ 32315-10-9 ]
[ 1189485-03-7 ]
[ 1012880-11-3 ]
N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrrolidine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.928 g	Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 3-(trifluoromethyl)pyrrolidine hydrochloride In tetrahydrofuran at 20℃;	1 Intermediate 2: A-[2-fluoro-4-methyl-5-t4,4,5,5-tetramethyl-l,3.,2-dioxaborolan-2- yl)nhenyll-3-itrifluoromethyl)nyrrolidine-l-carboxamide To a stirred solution of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)aniline (800 mg, 3.19 mmol) and ditri chi orom ethyl carbonate (378.16 mg, 1.27 mmol) in THF (40 mL) was added DIEA (2.63 mL, 20.37 mmol) dropwise at 0 °C. After stirring for 0.5 h, 3-(trifluoromethyl)pyrrolidine hydrochloride (559.37 mg, 3.19 mmol) in THF (1 mL) was added to the reaction mixture. The reaction mixture was stirred for 0.5 h at ambient temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 33% EA in PE. The fractions contained desired product were concentrated to afford /V-[2-fluoro-4-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)pyrrolidine-l-carboxamide (0.928 g, 64%) as an off-white solid. MS ESI calculated for C19H25BF4N2O3 [M + H]+, 417.19, found 417.15. NMR (400 MHz, CDCb) d 8.34 (d, J= 9.2 Hz, 1H), 6.86 (d, J = 12.0 Hz, 1H), 6.17 (s, 1H), 3.81 - 3.53 (m, 4H), 3.06 - 2.96 (m, 1H), 2.47 (s, 3H), 2.32 - 2.16 (m, 2H), 1.31 (s, 12H).

Reference： [1]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2020/227020, 2020, A1 Location in patent: Paragraph 00122; 00131

18
[ 32315-10-9 ]
[ 1012880-11-3 ]
2-(tert-butyl)morpholine hydrochloride [ No CAS ]
2-(tert-butyl)-N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 2-(tert-butyl)morpholine hydrochloride In tetrahydrofuran at 0℃; for 1h;	22.1; 23.1 Step 1: To a solution of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (400 mg, 1.59 mmol) and DIEA (1.0 g, 7.75 mmol) in THF (20 mL) was added a solution of BTC (191 mg, 0.64 mmol) in THF (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then 2-(tert-butyl)morpholine hydrochloride (344 mg, 1.91 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for lh. The reaction mixture was concentrated. The residue was purified by FCC (PE:EA = 2: 1) to afford 2-(tert-butyl)-N-(2-fluoro-4- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxamide (460 mg, 62%). MS Calcd.: 420, MS Found: 421 ([M+H]+).

Reference： [1]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2020/227020, 2020, A1 Location in patent: Paragraph 00158

19
[ 32315-10-9 ]
[ 1012880-11-3 ]
2-(2,2,2-trifluoroethyl)morpholine hydrochloride [ No CAS ]
N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(2,2,2-trifluoroethyl)morpholine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 2-(2,2,2-trifluoroethyl)morpholine hydrochloride In tetrahydrofuran at 0℃; for 1h;	25.1; 26.1 Step 1: To a solution of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (251 mg, 1.00 mmol) and DIEA (646 mg, 5.00 mmol) in THF (20 mL) was added a solution of BTC (119 mg, 0.40 mmol) in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then 2-(2,2,2-trifluoroethyl)morpholine hydrochloride (308 mg, 1.50 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for lh. The reaction mixture was concentrated. The residue was purified by FCC (PE:EA = 2: 1) to afford N-(4-methyl-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-(2,2,2-trifluoroethyl)morpholine-4- carboxamide (286 mg, 64%).MS Calcd. : 428, MS Found: 429 ([M+H]+).

Reference： [1]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2020/227020, 2020, A1 Location in patent: Paragraph 00164

20
[ 1012880-11-3 ]
[ 1454682-77-9 ]
6-(5-amino-4-fluoro-2-methylphenyl)-N,7-dimethylpyrido[2,3-d]pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 70℃; for 16h; Inert atmosphere;	3.1 Step 1: To a solution of 7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6- yltrifluoromethanesulfonate (1.5 g, 4.9 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxab orolan-2-yl)aniline (1.6 g, 6.3 mmol) and CS2CO3 (3.2 g, 9.7 mmol) in dioxane (30 mL) and water (5 mL) was added Pd(dppf)Cl2 (356 mg, 0.5 mmol) under N2, and the mixture was stirred at 70 °C for 16 h. The mixture was cooled down to RT diluted with water (100 mL) and extracted with DCM (100 mL3). The combined organic layers were washed with LbO (100 mL2) and brine (200 mL), dried over NaiSCL, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=10: 1 to PE:EA=2: 1) to afford 6-(5-amino-4-fluoro-2-methylphenyl)-N, 7-dim ethylpyrido[2,3-d]pyrimidin-2-amine (1.0 g, 72%). MS Calcd.: 297, MS Found: 298 ([M+H]+).

Reference： [1]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2020/227020, 2020, A1 Location in patent: Paragraph 00144

21
[ 32315-10-9 ]
[ 1012880-11-3 ]
(3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride [ No CAS ]
(3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride In tetrahydrofuran at 20℃; for 3h; Inert atmosphere;	76.76B Preparation 76B: (3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide A mixture of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.00 g, 7.965 mmol, 1.00 equiv), DIEA (5.15 g, 0.040 mmol, 5 equiv) and Triphosgene (0.95 g, 0.003 mmol, 0.4 equiv) in THF (19 mL) was stirred for 30 min at room temperature under nitrogen atmosphere. To the above mixture was added (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride (1.51 g, 0.008 mmol, 1.00 equiv). The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc/EtOH (4/3/1) to afford (3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3.2 g, 75%) as an off-white solid. MS ESI calculated for C20H27BF4N2O3[M + H]+, 431.21, found 431.25.1H NMR (400 MHz, Chloroform-d) δ 8.38 (d, J = 9.3 Hz, 1H), 6.88 (dd, J = 12.3, 0.8 Hz, 1H), 6.20 (d, J = 3.2 Hz, 1H), 3.83 (dd, J = 9.9, 7.5 Hz, 1H), 3.67-3.63 (m, 1H), 3.46 (td, J = 9.7, 6.8 Hz, 1H), 3.13 (t, J = 9.5 Hz, 1H), 2.66-2.51 (m, 1H), 2.46 (s, 3H), 2.35-2.17 (m, 3H), 1.78-1.74 (m, 1H), 1.33 (s, 12H). [00545]
75%	Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride In tetrahydrofuran at 20℃; for 3h; Inert atmosphere;	70.1 Preparation 70A: (3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide A mixture of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.00 g, 7.965 mmol, 1.00 equiv), DIEA (5.15 g, 0.040 mmol, 5 equiv) and triphosgene (0.95 g, 0.003 mmol, 0.4 equiv) in tetrahydrofuran (19 mL) was stirred for 30 min at room temperature under nitrogen atmosphere. To the above mixture was added (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride (1.51 g, 0.008 mmol, 1.00 equiv). The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc/EtOH (4/3/1) to afford (3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3.2 g, 75%) as an off-white solid. MS ESI calculated for C20H27BF4N2O3 [M + H]+, 431.21, found 431.25.1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 9.3 Hz, 1H), 6.88 (dd, J = 12.3, 0.8 Hz, 1H), 6.20 (d, J = 3.2 Hz, 1H), 3.83 (dd, J = 9.9, 7.5 Hz, 1H), 3.67-3.63 (m, 1H), 3.46 (td, J = 9.7, 6.8 Hz, 1H), 3.13 (t, J = 9.5 Hz, 1H), 2.66-2.51 (m, 1H), 2.46 (s, 3H), 2.35-2.17 (m, 3H), 1.78-1.74 (m, 1H), 1.33 (s, 12H).
75%	Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride In tetrahydrofuran at 20℃; for 3h; Inert atmosphere;	70.1 Preparation 70A: (3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide A mixture of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.00 g, 7.965 mmol, 1.00 equiv), DIEA (5.15 g, 0.040 mmol, 5 equiv) and triphosgene (0.95 g, 0.003 mmol, 0.4 equiv) in tetrahydrofuran (19 mL) was stirred for 30 min at room temperature under nitrogen atmosphere. To the above mixture was added (3S)-3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride (1.51 g, 0.008 mmol, 1.00 equiv). The resulting mixture was stirred for additional 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc/EtOH (4/3/1) to afford (3S)-N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (3.2 g, 75%) as an off-white solid. MS ESI calculated for C20H27BF4N2O3 [M + H]+, 431.21, found 431.25.1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 9.3 Hz, 1H), 6.88 (dd, J = 12.3, 0.8 Hz, 1H), 6.20 (d, J = 3.2 Hz, 1H), 3.83 (dd, J = 9.9, 7.5 Hz, 1H), 3.67-3.63 (m, 1H), 3.46 (td, J = 9.7, 6.8 Hz, 1H), 3.13 (t, J = 9.5 Hz, 1H), 2.66-2.51 (m, 1H), 2.46 (s, 3H), 2.35-2.17 (m, 3H), 1.78-1.74 (m, 1H), 1.33 (s, 12H).

Reference： [1]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2021/81375, 2021, A1 Location in patent: Paragraph 00540; 00543-00544
[2]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2022/60996, 2022, A1 Location in patent: Paragraph 00426-00428
[3]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2022/60996, 2022, A1 Location in patent: Paragraph 00426-00428

22
[ 1012880-11-3 ]
(2R)-2-[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino}propan-1-ol [ No CAS ]
(2R)-2-[4-(5-amino-4-fluoro-2-methylphenyl)-6-(morpholin-4-yl)pyridin-2-yl]amino}propan-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,4-dioxane; water at 80℃; for 1h; Inert atmosphere;	77.77A Preparation 77A: (2R)-2-[[4-(5-amino-4-fluoro-2-methylphenyl)-6-(morpholin-4-yl)pyridin-2- yl]amino]propan-1-ol To a stirred solution of (2R)-2-[[4-iodo-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol (200 mg, 0.551 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (138 mg, 0.551 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) were added Na2CO3(175 mg, 1.652 mmol) and Pd(dppf)Cl2CH2Cl2(45 mg, 0.055 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc/EtOH(6/3/1) to afford (2R)-2-[[4-(5-amino-4-fluoro- 2-methylphenyl)-6-(morpholin-4-yl)pyridin-2-yl]amino]propan-1-ol (140 mg, 38%) as an off- white solid. MS ESI calculated for C19H25FN4O2[M + H]+, 361.20, found 361.15.1H NMR (300 MHz, chloroform-d) δ 6.88 (d, J = 11.9 Hz, 1H), 6.64 (d, J = 9.2 Hz, 1H), 5.81 (d, J = 14.5 Hz, 2H), 4.08 (s, 1H), 3.88-3.73 (m, 5H), 3.68-3.53 (m, 3H), 3.49 (s, 4H), 2.17 (s, 3H), 1.25 (d, J = 6.7 Hz, 3H).19F NMR (282 MHz, chloroform-d) δ -136.65.

Reference： [1]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2021/81375, 2021, A1 Location in patent: Paragraph 00547-00549

23
[ 1012880-11-3 ]
isopropyl (6-bromo-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate [ No CAS ]
isopropyl (6-(5-amino-4-fluoro-2-methylphenyl)-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.8%	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; Cs₂CO₃ In 1,4-dioxane; water monomer at 90℃; for 16h; Inert atmosphere;	175.2 Step 2: Synthesis of isopropyl (6-(5-amino-4-fluoro-2-methylphenyl)-8,9- dihydroimidazo[1',2' : l,6]pyrido[2,3-d]pyrimidin-2-yl)carbamate A mixture of isopropyl (6-bromo-8,9-dihydroimidazo[1',2' : l,6]pyrido[2,3- d]pyrimidin-2-yl)carbamate (25 mg, 0.071 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)aniline (22 mg, 0.085 mmol), CS2CO3 (69 mg, 0.213 mmol), and Pd(dppf)C12 (5 mg, 0.007 mmol) in dioxane (5 mL) and H2O (0.5 mL) was degassed, charged with N2 three times and stirred at 90 °C for 16h under N2.The reaction mixture was concentrated in vacuum and purified by column chromatography on silica gel (DCM/MeOH=15/l) to give isopropyl (6-(5-amino-4-fluoro-2-methylphenyl)-8,9-dihydroimidazo[1',2' : l,6]pyrido[2,3- d]pyrimidin-2-yl)carbamate (23 mg, 81.8% yield) as brown solid. LCMS (M+H+) m/z: 397.3.

Reference： [1]Current Patent Assignee: ABM THERAPEUTICS - WO2022/32071, 2022, A1 Location in patent: Paragraph 1042; 1044-1045

24
[ 1012880-11-3 ]
4-[4-chloro-6-(1-methylpyrazol-4-yl)pyridin-2-yl]morpholine [ No CAS ]
2-fluoro-4-methyl-5-[2-(1-methylpyrazol-4-yl)-6-(morpholin-4-yl)pyridin-4-yl]aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With tripotassium phosphate tribasic; chloro‐(2‐dicyclohexylphosphino‐2′,4′,6′‐triisopropyl‐1,1′‐biphenyl)‐2‐(2′‐amino‐1,1′‐biphenyl)palladium(II) In tetrahydrofuran; water monomer at 80℃; for 2h; Inert atmosphere;	67.2; 74.2 Preparation 67B: 2-fluoro-4-methyl-5-[2-(1-methylpyrazol-4-yl)-6-(morpholin-4-yl)pyridin-4- yl]aniline A mixture of 4-[4-chloro-6-(1-methylpyrazol-4-yl)pyridin-2-yl]morpholine (1 g, 3.588 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.99 g, 3.947 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) (2nd Generation XPhos precatalyst) (280 mg, 0.359 mmol) and potassium phosphate (1.52 g, 7.176 mmol) in tetrahydrofuran (10 mL) and H2O (1 mL) was stirred for 2 h at 80 oC under nitrogen atmosphere. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (1/1) to afford 2-fluoro-4-methyl-5-[2-(1- methylpyrazol-4-yl)-6-(morpholin-4-yl)pyridin-4-yl]aniline (707 mg, 51%) as a light brown solid. MS ESI calculated for C20H22FN5O [M + H]+, 368.18, found 368.30. 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.89 (s, 1H), 6.92 (d, J = 12.0 Hz, 1H), 6.81-6.80 (m, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 3.97 (s, 3H), 3.89-3.86 (m, 4H), 3.61-3.59 (m, 4H), 2.18 (s, 3H).19F NMR (376 MHz, CDCl3) δ -136.37 (1F).
51%	With tripotassium phosphate tribasic; chloro‐(2‐dicyclohexylphosphino‐2′,4′,6′‐triisopropyl‐1,1′‐biphenyl)‐2‐(2′‐amino‐1,1′‐biphenyl)palladium(II) In tetrahydrofuran; water monomer at 80℃; for 2h; Inert atmosphere;	67.2; 74.2 Preparation 67B: 2-fluoro-4-methyl-5-[2-(1-methylpyrazol-4-yl)-6-(morpholin-4-yl)pyridin-4- yl]aniline A mixture of 4-[4-chloro-6-(1-methylpyrazol-4-yl)pyridin-2-yl]morpholine (1 g, 3.588 mmol), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.99 g, 3.947 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) (2nd Generation XPhos precatalyst) (280 mg, 0.359 mmol) and potassium phosphate (1.52 g, 7.176 mmol) in tetrahydrofuran (10 mL) and H2O (1 mL) was stirred for 2 h at 80 oC under nitrogen atmosphere. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (1/1) to afford 2-fluoro-4-methyl-5-[2-(1- methylpyrazol-4-yl)-6-(morpholin-4-yl)pyridin-4-yl]aniline (707 mg, 51%) as a light brown solid. MS ESI calculated for C20H22FN5O [M + H]+, 368.18, found 368.30. 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.89 (s, 1H), 6.92 (d, J = 12.0 Hz, 1H), 6.81-6.80 (m, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 3.97 (s, 3H), 3.89-3.86 (m, 4H), 3.61-3.59 (m, 4H), 2.18 (s, 3H).19F NMR (376 MHz, CDCl3) δ -136.37 (1F).

Reference： [1]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2022/60996, 2022, A1 Location in patent: Paragraph 00412; 00415-00416; 00445; 00448-00449
[2]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2022/60996, 2022, A1 Location in patent: Paragraph 00412; 00415-00416; 00445; 00448-00449

25
[ 32315-10-9 ]
[ 1012880-11-3 ]
3-(trifluoromethyl)-2,5-dihydro-1H-pyrrole hydrochloride [ No CAS ]
N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.76%	Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 3-(trifluoromethyl)-2,5-dihydro-1H-pyrrole hydrochloride In tetrahydrofuran at 20℃; for 2h;	69.1 Preparation 69A: N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]- 3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide A mixture of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (700 mg, 2.788 mmol), DIEA (1.8 g, 13.940 mmol)and triphosgene (331 mg, 1.115 mmol) in tetrahydrofuran (67 mL) was stirred for 30 min at room temperature. To this was added 3- (trifluoromethyl)-2,5-dihydro-1H-pyrrole hydrochloride (611.52 mg, 4.461 mmol,) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc/EtOH (4:3:1) to afford N-[2- fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)-2,5- dihydropyrrole-1-carboxamide (794 mg, 68.76%) as an off-white solid. MS ESI calculated for C19H23BF4N2O3 [M + H]+, 415.17, found 415.30.1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 12.4 Hz, 1H), 6.44 (s, 1H), 6.17 (s, 1H), 4.48 (s, 4H), 2.50 (s, 3H), 1.34 (s, 12H).
68.76%	Stage #1: bis(trichloromethyl) carbonate; 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 3-(trifluoromethyl)-2,5-dihydro-1H-pyrrole hydrochloride In tetrahydrofuran at 20℃; for 2h;	69.1 Preparation 69A: N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]- 3-(trifluoromethyl)-2,5-dihydropyrrole-1-carboxamide A mixture of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (700 mg, 2.788 mmol), DIEA (1.8 g, 13.940 mmol)and triphosgene (331 mg, 1.115 mmol) in tetrahydrofuran (67 mL) was stirred for 30 min at room temperature. To this was added 3- (trifluoromethyl)-2,5-dihydro-1H-pyrrole hydrochloride (611.52 mg, 4.461 mmol,) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc/EtOH (4:3:1) to afford N-[2- fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(trifluoromethyl)-2,5- dihydropyrrole-1-carboxamide (794 mg, 68.76%) as an off-white solid. MS ESI calculated for C19H23BF4N2O3 [M + H]+, 415.17, found 415.30.1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 12.4 Hz, 1H), 6.44 (s, 1H), 6.17 (s, 1H), 4.48 (s, 4H), 2.50 (s, 3H), 1.34 (s, 12H).

Reference： [1]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2022/60996, 2022, A1 Location in patent: Paragraph 00421-00423
[2]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2022/60996, 2022, A1 Location in patent: Paragraph 00421-00423

26
[ 16133-25-8 ]
[ 1012880-11-3 ]
N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-3-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	In dichloromethane at 0 - 20℃;	G1 Example G1: N-(6-bromoquinazolin-2-yl)acetamide A solution of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (A1, 0.2 g, 0.80 mmol) in DCM (3 mL) was cooled to 0 C. Pyridine-3-sulfonyl chloride (0.14 g, 0.80 mmol) was added portion-wise and the reaction mixture was slowly warmed to rt overnight. [0320] The solvent was removed under reduced pressure and the crude was purified by silica gel column chromatogrphy (0 to 10% DCM/MeOH) to obtain N-(2-fluoro-4-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine-3-sulfonamide (0.30 g, 98% yield) as a white solid.1H NMR (500 MHz, DMSO-d6): δ 10.2 (s, 1H), 8.80 (m, 2H), 8.03 (d, J = 8.2 Hz,1H), 7.62 (m, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 11.6 Hz, 1H), 2.41 (s, 3H), 1.29 (s, 12H); MS (ESI) m/z: 393.2 (M+H+).

Reference： [1]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - WO2022/109001, 2022, A1 Location in patent: Paragraph 0319-0320

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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

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

[ CAS No. 1012880-11-3 ]

Quality Control of [ 1012880-11-3 ]

Related Doc. of [ 1012880-11-3 ]

Product Details of [ 1012880-11-3 ]

Safety of [ 1012880-11-3 ]

Application In Synthesis of [ 1012880-11-3 ]

[ 1012880-11-3 ] Synthesis Path-Upstream 1~3

[ 1012880-11-3 ] Synthesis Path-Downstream 1~26

Related Functional Groups of [ 1012880-11-3 ]

Organoboron

Organoboron

Esters

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1012880-11-3 ]