[ CAS No. 1300031-57-5 ]

Name: 1300031-57-5|4-Chloro-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinoline-3-carboxamide|97%
Brand: Ambeed
SKU: A485090
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Product Details of [ 1300031-57-5 ]

CAS No. :	1300031-57-5	MDL No. :	MFCD30607317
Formula :	C₁₆H₁₄ClN₃O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FLBUVOLGZFTRNG-UHFFFAOYSA-N
M.W :	331.75 g/mol	Pubchem ID :	57465581
Synonyms :

Calculated chemistry of [ 1300031-57-5 ]

Physicochemical Properties

Num. heavy atoms :	23
Num. arom. heavy atoms :	15
Fraction Csp3 :	0.19
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	86.77
TPSA :	91.24 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.52 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.24
Log Po/w (XLOGP3) :	2.54
Log Po/w (WLOGP) :	3.27
Log Po/w (MLOGP) :	1.45
Log Po/w (SILICOS-IT) :	3.67
Consensus Log Po/w :	2.63

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.78
Solubility :	0.0548 mg/ml ; 0.000165 mol/l
Class :	Soluble
Log S (Ali) :	-4.1
Solubility :	0.0262 mg/ml ; 0.0000789 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.14
Solubility :	0.00024 mg/ml ; 0.000000724 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.84

Safety of [ 1300031-57-5 ]

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 [ 1300031-57-5 ]

* 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 [ 1300031-57-5 ]
Downstream synthetic route of [ 1300031-57-5 ]

[ 1300031-57-5 ] Synthesis Path-Upstream 1~2

1
[ 1300031-57-5 ]
[ 1300031-49-5 ]

Reference： [1] Patent: US2012/232074, 2012, A1,
[2] Patent: WO2011/54846, 2011, A1,

2
[ 1300031-57-5 ]
[ 27854-90-6 ]
[ 1300031-49-5 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2963 - 2967

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Yield	Reaction Conditions	Operation in experiment
72%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃;	4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (50 g, 151 mmol,) and <strong>[27854-90-6][(1R)-1-(2-pyridinyl)ethyl]amine</strong> (35.3g, 181 mmol, NetChem) were dissolved in N-methyl-2-pyrrolidone (NMP, 250 mL). DIPEA (79 mL, 452 mmol) was added, the solution was heated at 120C overnight, cooled and diluted with ethyl acetate (1 L). The solution was washed with water (2 x 1 L), brine (500 mL), dried (sodium sulphate) and the solvent evaporated to give a dark brown gum. The aqueous washings were extracted with DCM (2 x 600 mL). The combined extracts were washed with a mixture of saturated brine (300 mL) and water (1 L) giving a dense emulsion which took around 2h to separate. The organic layer was dried (sodium sulphate) and evaporated to leave a brown liquid. This liquid was dissolved in ethyl acetate (200 mL), washed with water (2 x 200 mL), dried (sodium sulphate) and evaporated to give a brown gum. This material was combined with the previous brown gum, dissolved in DCM (150 mL) and loaded onto a silica column (750 g), which was eluted with a 2M ammonia in methanol / DCM gradient (0-12%) to give, after evaporation of the solvents in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1R)-1-(2-pyridinyl)ethyl]amino}-3-quinolinecarboxamide as beige foam (45.1 g, 72% yield). 1H-NMR (400MHz, CDCl3): d 9.44 (1H, d), 8.71 (1H, s), 8.62 (1H, d), 7.74 (1H, m), 7.68 (1H, s), 7.65 (1H, d), 7.34 (1H, s), 7.23 (1H, m), 6.06 (2H, b), 5.36 (1H, m), 3.51(3H, s), 2.32 (3H, s), 2.17 (3H, s), 1.73 (3H, d, partially obscured by water). LCMS (Method HpH): MH+ 418, Rt 0.87 min.
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃;Product distribution / selectivity;	Intermediate 55: 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1 R)-1 -(2- pyridinyl)ethyl]amino}-3-quinolinecarboxamide; 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 50g, 151 mmol,) and [(1 R)-1 -(2-pyridinyl)ethyl]amine (35.3g, 181 mmol, NetChem) were dissolved in N-methyl-2-pyrrolidone (NMP, 250ml). DIPEA (79ml, 452 mmol) was added, the solution was heated at 120C overnight, cooled and diluted with ethyl acetate (11). The solution was washed with water (2 x 11), brine (500ml), dried (sodium sulphate) and the solvent evaporated to give a dark brown gum. The aqueous washings were extracted with DCM (2 x 600ml). The combined extracts were washed with a mixture of saturated brine (300ml) and water (11) giving a dense emulsion which took around 2h to separate. The organic layer was dried (sodium sulphate) and evaporated to leave a brown liquid. This liquid was dissolved in ethyl acetate (200ml), washed with water (2 x 200ml), dried (sodium sulphate) and evaporated to give a brown gum. This material was combined with the previous brown gum, dissolved in DCM (150ml) and loaded onto a silica column (750g), which was eluted with a 2M ammonia in methanol / DCM gradient (0-12%) to give, after evaporation of the solvents in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1 R)-1 -(2- pyridinyl)ethyl]amino}-3-quinolinecarboxamide as beige foam (45.1 g). Used in the subsequent step (Example 36) without further purification.1 H NMR CDCI3: deltaEta 9.44(11-1, d), 8.71 (1 H, s), 8.62(1 H, d), 7.74(1 H, m), 7.68(1 H, s), 7.65(1 H, d), 7.34(11-1, s), 7.23(1 H, m), 6.06(2H, b), 5.36(1 H, m), 3.51 (3H, s), 2.32(3H, s), 2.17(3H, s), 1.73(31-1, d, partially obscured by water).The mixed fractions from the column were collected and evaporated to give a brown gum. This was dissolved in DCM (20ml) loaded onto a silica column (330g) and eluted with an 2M ammonia in methanol / DCM gradient (0-10%) to give after evaporation of solvents 7- (3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1 R)-1 -(2-pyridinyl)ethyl]amino}-3- quinolinecarboxamide as beige gum (3.4g).1 H NMR CDCI3: deltaEta 9.44(11-1, d), 8.71 (11-1, s), 8.62(11-1, d), 7.74(11-1, m), 7.68(1 H, s), 7.65(1 H, d), 7.34(11-1, s), 7.23(1 H, m), 6.07(2H, b), 5.36(1 H, m), 3.51 (3H, s), 2.32(3H, s), 2.17(31-1, s), 1.73(31-1, d, partially obscured by water).LCMS (Method HpH): MH+ 418, Rt 0.87min.
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃;Product distribution / selectivity;	Intermediate 55: 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1R)-1-(2-pyridinyl)ethyl]amino}-3-quinolinecarboxamide 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 50 g, 151 mmol,) and <strong>[27854-90-6][(1R)-1-(2-pyridinyl)ethyl]amine</strong> (35.3 g, 181 mmol, NetChem) were dissolved in N-methyl-2-pyrrolidone (NMP, 250 ml). DIPEA (79 ml, 452 mmol) was added, the solution was heated at 120 C. overnight, cooled and diluted with ethyl acetate (1 l). The solution was washed with water (21 l), brine (500 ml), dried (sodium sulphate) and the solvent evaporated to give a dark brown gum. The aqueous washings were extracted with DCM (2600 ml). The combined extracts were washed with a mixture of saturated brine (300 ml) and water (1 l) giving a dense emulsion which took around 2 h to separate. The organic layer was dried (sodium sulphate) and evaporated to leave a brown liquid. This liquid was dissolved in ethyl acetate (200 ml), washed with water (2*200 ml), dried (sodium sulphate) and evaporated to give a brown gum. This material was combined with the previous brown gum, dissolved in DCM (150 ml) and loaded onto a silica column (750 g), which was eluted with a 2M ammonia in methanol/DCM gradient (0-12%) to give, after evaporation of the solvents in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1R)-1-(2-pyridinyl)ethyl]amino}-3-quinolinecarboxamide as beige foam (45.1 g). Used in the subsequent step (Example 36) without further purification. 1H NMR CDCl3: deltaH 9.44 (1H, d), 8.71 (1H, s), 8.62 (1H, d), 7.74 (1H, m), 7.68 (1H, s), 7.65 (1H, d), 7.34 (1H, s), 7.23 (1H, m), 6.06 (2H, b), 5.36 (1H, m), 3.51 (3H, s), 2.32 (3H, s), 2.17 (3H, s), 1.73 (3H, d, partially obscured by water).

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile at 110℃; for 4h;	10 Example 10: 7-(3,5-dimethyl-4-isoxazolyl)-8-(methoxy)-1 -(2-pyridinylmethyl)-1 ,3- dihydro-2H imidazo[4,5-c]quinoli -2-one; The mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxamide (for a preparation see Intermediate 40, 6g, 18mmol) was reacted with 2- aminomethylpyridine (2.5eq, 4.23g, 45mmol) in CH3CN (100ml) was stirred at 1 10°C for 4h. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic layer was dried over Na2S04 and concentrated to dryness to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-4-[(2-pyridinylmethyl)amino]-3-quinoline carboxamide (5.84g) which was used in the next step without purification.An excess of [bis(trifluoroacetoxy)iodo]benzene (19.35g, 45mmol) was added to a solution of the previous carboxamide intermediate (5.84g, 15mmol). The mixture was stirred at 50°C for 12h and then concentrated. The residue was partitioned between DCM and water, the organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/ MeOH, 95:5), then triturated with diethylether to give the title compound as a beige powder (3.9g, 53.7%).LC-HRMS ES+ exact mass calculated for C22H19N503: 402.1566 MH+. Found 402.1574, Rt = 2.14min. (APCI -MS) m/z 402.10 MH+, Rt 2.39min.
	Heating;
	In acetonitrile at 110℃; for 4h;	10 Example 10 7-(3,5-dimethyl-4-isoxazolyl)-8-(methoxy)-1-(2-pyridinylmethyl)-1,3-dihydro-2H imidazo[4,5-c]quinolin-2-one The mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxamide (for a preparation see Intermediate 40, 6 g, 18 mmol) was reacted with 2-aminomethylpyridine (2.5 eq, 4.23 g, 45 mmol) in CH3CN (100 ml) was stirred at 110° C. for 4 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic layer was dried over Na2SO4 and concentrated to dryness to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-4-[(2-pyridinylmethyl)amino]-3-quinoline carboxamide (5.84 g) which was used in the next step without purification.

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile for 4h; Heating;	49 Example 49: 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1 -(3-pyridinylmethyl)-1 ,3- dihydro-2H-imidazo[4,5-c]quinolin-2-one; A solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see intermediate 56, 332mg,) and (3-pyridinylmethyl)amine (2.5 equiv in acetonitrile was heated for 4h. The reaction mixture was then concentrated to dryness and hydrolyzed with water. The mixture extracted with DCM and the organic was dried over Na2S04, filtered and concentrated to dryness to give the crude intermediate. The residue was partially dissolved in acetonitrile (30ml) and bis(trifluoroacetoxy)iodo]benzene (800 mg) was added. The resulting mixture was stirred at room temperature for 24h. The reaction mixture was then concentrated to dryness and hydrolysed with water. The mixture was extracted with DCM and the organic dried over Na2S04, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, eluting with DCM / methanol (95 / 5). The purified residue was taken-up in diethyl ether to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1 -(3-pyridinylmethyl)-1 ,3-dihydro-2/-/- imidazo[4,5-c]quinolin-2-one (70mg) as a brown powder.LC-HRMS: ES+ exact mass calculated for C22H20N5O3 402.1566 MH+, found: 402.1576, Rt 1.96min.
	In acetonitrile for 4h; Heating;	49 A solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see intermediate 56, 332 mg,) and (3-pyridinylmethyl)amine (2.5 equiv in acetonitrile was heated for 4 h. The reaction mixture was then concentrated to dryness and hydrolyzed with water. The mixture extracted with DCM and the organic was dried over Na2SO4, filtered and concentrated to dryness to give the crude intermediate.

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-Aminomethylthiophene; 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide In acetonitrile at 80℃; for 24h; Shlenk sealed tube; Stage #2: With sodium hydrogencarbonate In water; acetonitrile	Intermediate 68: -iS.S-dimethyl^-isoxazolylJ-G-imethyloxyJ-yS^^-thienylmethyl)- 3,4-quinolinediamine; To a magnetically stirred solution 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3- quinolinecarboxamide (for a preparation see Intermediate 56, 1.5g) in acetonitrile (10ml) in a Shlenk tube was added (2-thienylmethyl)amine (1 .53g). The Shlenk tube was sealed and the reaction mixture heated at 80°C for 24h. The water was added to the reaction followed by an aqueous saturated solution of sodium hydrogen carbonate. The mixture was extracted with DCM and the organic phase dried over Na2S04, filtered and concentrated to dryness. The resulting crude compound was purified by chromatography on silica gel (25g) eluting with DCM / methanol (95:5) to give 7-(3,5-dimethyl-4- isoxazolyl)-6-(methyloxy)-/V4-(2-thienylmethyl)-3,4-quinolinediamine (1 .493g) as a cream coloured powder. LC/MS: MH+ 409.12, [M-H]" 407.17, Rt 2.70min
	In acetonitrile at 80℃; for 24h; Sealed tube;	Intermediate 68: 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-N4-(2-thienylmethyl)-3,4-quinolinediamine Intermediate 68: 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-N4-(2-thienylmethyl)-3,4-quinolinediamine To a magnetically stirred solution 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 1.5 g) in acetonitrile (10 ml) in a Shlenk tube was added (2-thienylmethyl)amine (1.53 g). The Shlenk tube was sealed and the reaction mixture heated at 80° C. for 24 h. The water was added to the reaction followed by an aqueous saturated solution of sodium hydrogen carbonate. The mixture was extracted with DCM and the organic phase dried over Na2SO4, filtered and concentrated to dryness. The resulting crude compound was purified by chromatography on silica gel (25 g) eluting with DCM/methanol (95:5) to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-N4-(2-thienylmethyl)-3,4-quinolinediamine (1.493 g) as a cream coloured powder. LC/MS: MH+409.12, [M-H]- 407.17, Rt 2.70 min

[ CAS No. 1300031-57-5 ]

Quality Control of [ 1300031-57-5 ]

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Product Details of [ 1300031-57-5 ]

Calculated chemistry of [ 1300031-57-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1300031-57-5 ]

Application In Synthesis of [ 1300031-57-5 ]

[ 1300031-57-5 ] Synthesis Path-Upstream 1~2

[ 1300031-57-5 ] Synthesis Path-Downstream 1~58

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Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: caesium carbonate / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere 2: palladium on activated charcoal; hydrogen; sodium sulfite / ethanol; ethyl acetate / 24 h 3: 1 h / 130 °C 4: diphenylether / 0.75 h / 255 °C 5: sodium hydroxide / ethanol / Reflux 6: trichlorophosphate / 4 h / Heating 7: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice
	Multi-step reaction with 6 steps 1.1: barium hydroxide octahydrate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,2-dimethoxyethane; water / 20 h / 80 °C 2.1: hydrogen / palladium 10% on activated carbon / ethanol / 4 h 2.2: 20 h 3.1: 1 h / 130 °C 4.1: diphenylether / 0.75 h / 255 °C 5.1: sodium hydroxide; water / ethanol / Reflux 5.2: 0.17 h / pH 4 6.1: trichlorophosphate / 20 °C / Heating 6.2: 0.5 h / Cooling with ice
	Multi-step reaction with 6 steps 1.1: caesium carbonate / 1,2-dimethoxyethane; water / 0.17 h / Inert atmosphere 1.2: 4 h / 90 °C / Inert atmosphere 2.1: hydrogen / 5%-palladium/activated carbon / ethyl acetate; ethanol; water / 24 h 3.1: 1 h / 130 °C 4.1: diphenylether / 0.33 h / Reflux 5.1: sodium hydroxide; water / ethanol; water / Reflux 5.2: 40 °C / pH 4 6.1: trichlorophosphate / 4 h / 20 °C / Heating 6.2: 0.5 h / Cooling with ice

	Multi-step reaction with 7 steps 1: caesium carbonate; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere 2: 5%-palladium/activated carbon; hydrogen / ethanol; water; ethyl acetate / 24 h 3: 1 h / 130 °C 4: diphenylether / 0.5 h / Reflux 5: sodium hydroxide; ethanol / Reflux 6: trichlorophosphate / 4 h / Heating 7: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice
	Multi-step reaction with 6 steps 1.1: barium hydroxide octahydrate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,2-dimethoxyethane; water / 16 h / 80 °C 2.1: hydrogen; acetic acid / palladium 10% on activated carbon / ethanol / 24 h 3.1: 1 h / 130 °C 4.1: diphenylether / 0.75 h / 255 °C 5.1: ethanol; sodium hydroxide / Reflux 5.2: pH 4 6.1: trichlorophosphate / N,N-dimethyl-formamide / 5 h / Reflux 6.2: 1 h / 0 - 5 °C
	Multi-step reaction with 6 steps 1.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; barium hydroxide octahydrate / water; 1,2-dimethoxyethane / 16 h / 80 °C 2.1: iron; ammonium chloride / ethanol; water / 2 h / 80 °C 3.1: 0.5 h / 130 °C 4.1: diphenylether / 0.25 h / 280 °C / Microwave irradiation 5.1: sodium hydroxide; ethanol / 17 h / 80 °C 6.1: trichlorophosphate / 2 h / 100 °C 6.2: 0.5 h / 0 °C

Yield	Reaction Conditions	Operation in experiment
		Example 47: 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1 -(2-pyrimidinylmethyl)-1 ,3- dihydro-2H-imidazo[4,5-c]quinolin-2-one; In a 100ml flask a mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3- quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg) and (2- pyrimidinylmethyl)amine (273mg) in acetonitrile was heated at 100C for 2h. The reaction mixture was hydrolyzed with a solution of sodium hydrogen carbonate, extracted with DCM and the organic dried over Na2S04, filtered and concentrated to dryness to give 350mg of crude intermediate. The residue was dissolved in acetonitrile (15ml), bis(trifluoroacetoxy)iodo]benzene (0.5g) was added and the reaction mixture was stirred for 3h at room temperature. The reaction mixture was washed with water, extracted with DCM and the organic dried over Na2S04, filtered and concentrated to dryness. The resulting crude compound was purified by chromatography on silica gel eluting with DCM / methanol (95:5) and the resulting residue was recrystallised from acetonitrile and dried in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1 -(2-pyrimidinylmethyl)-1 ,3- dihydro-2H-imidazo[4,5-c]quinolin-2-one (70mg) as a beige powder.LC-HRMS: ES+ exact mass calculated for C2iH19N603 403.1519 MH+, found: 403.1516, Rt 2.04min.
	In acetonitrile; at 100℃; for 2h;	In a 100 ml flask a mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg) and (2-pyrimidinylmethyl)amine (273 mg) in acetonitrile was heated at 100 C. for 2 h. The reaction mixture was hydrolyzed with a solution of sodium hydrogen carbonate, extracted with DCM and the organic dried over Na2SO4, filtered and concentrated to dryness to give 350 mg of crude intermediate.

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-methylfurfurylamine; 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide In 1,4-dioxane Reflux; Stage #2: With sodium hydrogencarbonate In dichloromethane	Intermediate 72: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-2-furanyl)methyl]amino}- 6-(methyloxy)-3-quinolinecarboxamide; A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 200mg,) and [(5-methyl-2-furanyl)methyl]amine (200mg) in 1 ,4-dioxane was heated to reflux overnight. The reaction mixture was evaporated to dryness and the residue was taken-up in DCM and washed with a saturated solution of sodium hydrogen carbonate. The organic was dried over Na2S04, filtered and concentrated. The residue was purified by chromatography to give 7-(3,5- dimethyl-4-isoxazolyl)-4-[(5-methyl-2-furanyl)methyl]amino}-6-(methyloxy)-3- quinolinecarboxamide (177 mg) as a beige powder.LC/MS: Rt 2.75, MH+ 406.99, [M-H]" 405.05
	In 1,4-dioxane Reflux;	Intermediate 72: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-2-furanyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide Intermediate 72: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-2-furanyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 200 mg,) and [(5-methyl-2-furanyl)methyl]amine (200 mg) in 1,4-dioxane was heated to reflux overnight. The reaction mixture was evaporated to dryness and the residue was taken-up in DCM and washed with a saturated solution of sodium hydrogen carbonate. The organic was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography to give 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-2-furanyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide (177 mg) as a beige powder. LC/MS: Rt 2.75, MH+406.99, [M-H]- 405.05

Yield	Reaction Conditions	Operation in experiment
	In butan-1-ol at 110℃; for 4h;	Intermediate 67: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-3- isoxazolyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide; A solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg) and [(5-methyl-3-isoxazolyl)methyl]amine (2.5 eq) in butanol (20ml) was heated to 1 10°C for 4h. The reaction mixture was evaporated to dryness and hydrolysed with water. The mixture was extracted with DCM and the organic dried over Na2S04, filtered and concentrated to dryness (280mg). Used without purification in the subsequent reaction (Example 52).
	In butan-1-ol at 110℃; for 4h;	Intermediate 67: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-3-isoxazolyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide Intermediate 67: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-3-isoxazolyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide A solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg) and [(5-methyl-3-isoxazolyl)methyl]amine (2.5 eq) in butanol (20 ml) was heated to 110° C. for 4 h. The reaction mixture was evaporated to dryness and hydrolysed with water. The mixture was extracted with DCM and the organic dried over Na2SO4, filtered and concentrated to dryness (280 mg). Used without purification in the subsequent reaction (Example 52).

Yield	Reaction Conditions	Operation in experiment
		Example 48: 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1 -(2-pyrazinylmethyl)-1 ,3- dihydro-2H-imidazo[4,5-c]quinolin-2-one; In a 100ml flask a mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3- quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg,) and (2- pyrazinylmethyl)amine (2.5 eq) in acetonitrile was heated at 100C for 2h. The reaction mixture was hydrolyzed with a solution of sodium hydrogen carbonate, extracted with DCM and the organic dried over Na2S04, filtered and concentrated to dryness to give the crude intermediate. The residue was dissolved in acetonitrile (15ml), bis(trifluoroacetoxy)iodo]benzene (0.5g) was added and the reaction mixture was stirred for 3h at room temperature. The reaction mixture was washed with water, extracted with DCM and the organic were dried over Na2S04, filtered and concentrated to dryness. The resulting crude compound was purified by chromatography on silica gel eluting with DCM / methanol (95:5) and the resulting residue was recrystallised from acetonitrile and dried in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1 -(2-pyrimidinylmethyl)-1 ,3- dihydro-2H-imidazo[4,5-c]quinolin-2-one (100mg) as a beige powder.LC-HRMS: ES+ exact mass calculated for C2i H19N603 403.1519 MH+, found: 403.1550, Rt 2.06min.
	In acetonitrile; at 100℃; for 2h;	In a 100 ml flask a mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg,) and (2-pyrazinylmethyl)amine (2.5 eq) in acetonitrile was heated at 100 C. for 2 h. The reaction mixture was hydrolyzed with a solution of sodium hydrogen carbonate, extracted with DCM and the organic dried over Na2SO4, filtered and concentrated to dryness to give the crude intermediate.

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: palladium on activated charcoal; hydrogen; sodium sulfite / ethanol; ethyl acetate / 24 h 2: 1 h / 130 °C 3: diphenylether / 0.75 h / 255 °C 4: sodium hydroxide / ethanol / Reflux 5: trichlorophosphate / 4 h / Heating 6: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice
	Multi-step reaction with 5 steps 1.1: hydrogen / palladium 10% on activated carbon / ethanol / 4 h 1.2: 20 h 2.1: 1 h / 130 °C 3.1: diphenylether / 0.75 h / 255 °C 4.1: sodium hydroxide; water / ethanol / Reflux 4.2: 0.17 h / pH 4 5.1: trichlorophosphate / 20 °C / Heating 5.2: 0.5 h / Cooling with ice
	Multi-step reaction with 5 steps 1.1: hydrogen / 5%-palladium/activated carbon / ethyl acetate; ethanol; water / 24 h 2.1: 1 h / 130 °C 3.1: diphenylether / 0.33 h / Reflux 4.1: sodium hydroxide; water / ethanol; water / Reflux 4.2: 40 °C / pH 4 5.1: trichlorophosphate / 4 h / 20 °C / Heating 5.2: 0.5 h / Cooling with ice

	Multi-step reaction with 6 steps 1: 5%-palladium/activated carbon; hydrogen / ethanol; water; ethyl acetate / 24 h 2: 1 h / 130 °C 3: diphenylether / 0.5 h / Reflux 4: sodium hydroxide; ethanol / Reflux 5: trichlorophosphate / 4 h / Heating 6: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice
	Multi-step reaction with 5 steps 1.1: hydrogen; acetic acid / palladium 10% on activated carbon / ethanol / 24 h 2.1: 1 h / 130 °C 3.1: diphenylether / 0.75 h / 255 °C 4.1: ethanol; sodium hydroxide / Reflux 4.2: pH 4 5.1: trichlorophosphate / N,N-dimethyl-formamide / 5 h / Reflux 5.2: 1 h / 0 - 5 °C
	Multi-step reaction with 5 steps 1.1: iron; ammonium chloride / ethanol; water / 2 h / 80 °C 2.1: 0.5 h / 130 °C 3.1: diphenylether / 0.25 h / 280 °C / Microwave irradiation 4.1: sodium hydroxide; ethanol / 17 h / 80 °C 5.1: trichlorophosphate / 2 h / 100 °C 5.2: 0.5 h / 0 °C

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 1 h / 130 °C 2: diphenylether / 0.75 h / 255 °C 3: sodium hydroxide / ethanol / Reflux 4: trichlorophosphate / 4 h / Heating 5: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice
	Multi-step reaction with 4 steps 1.1: 1 h / 130 °C 2.1: diphenylether / 0.75 h / 255 °C 3.1: sodium hydroxide; water / ethanol / Reflux 3.2: 0.17 h / pH 4 4.1: trichlorophosphate / 20 °C / Heating 4.2: 0.5 h / Cooling with ice
	Multi-step reaction with 4 steps 1.1: 1 h / 130 °C 2.1: diphenylether / 0.33 h / Reflux 3.1: sodium hydroxide; water / ethanol; water / Reflux 3.2: 40 °C / pH 4 4.1: trichlorophosphate / 4 h / 20 °C / Heating 4.2: 0.5 h / Cooling with ice

	Multi-step reaction with 5 steps 1: 1 h / 130 °C 2: diphenylether / 0.5 h / Reflux 3: sodium hydroxide; ethanol / Reflux 4: trichlorophosphate / 4 h / Heating 5: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice
	Multi-step reaction with 4 steps 1.1: 1 h / 130 °C 2.1: diphenylether / 0.75 h / 255 °C 3.1: ethanol; sodium hydroxide / Reflux 3.2: pH 4 4.1: trichlorophosphate / N,N-dimethyl-formamide / 5 h / Reflux 4.2: 1 h / 0 - 5 °C
	Multi-step reaction with 4 steps 1.1: 0.5 h / 130 °C 2.1: diphenylether / 0.25 h / 280 °C / Microwave irradiation 3.1: sodium hydroxide; ethanol / 17 h / 80 °C 4.1: trichlorophosphate / 2 h / 100 °C 4.2: 0.5 h / 0 °C

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: diphenylether / 0.75 h / 255 °C 2: sodium hydroxide / ethanol / Reflux 3: trichlorophosphate / 4 h / Heating 4: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice
	Multi-step reaction with 3 steps 1.1: diphenylether / 0.75 h / 255 °C 2.1: sodium hydroxide; water / ethanol / Reflux 2.2: 0.17 h / pH 4 3.1: trichlorophosphate / 20 °C / Heating 3.2: 0.5 h / Cooling with ice
	Multi-step reaction with 3 steps 1.1: diphenylether / 0.33 h / Reflux 2.1: sodium hydroxide; water / ethanol; water / Reflux 2.2: 40 °C / pH 4 3.1: trichlorophosphate / 4 h / 20 °C / Heating 3.2: 0.5 h / Cooling with ice

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydroxide; water / ethanol; water / Reflux 1.2: 40 °C / pH 4 2.1: trichlorophosphate / 4 h / 20 °C / Heating 2.2: 0.5 h / Cooling with ice
	Multi-step reaction with 3 steps 1: sodium hydroxide; ethanol / Reflux 2: trichlorophosphate / 4 h / Heating 3: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice
	Multi-step reaction with 2 steps 1.1: ethanol; sodium hydroxide / Reflux 1.2: pH 4 2.1: trichlorophosphate / N,N-dimethyl-formamide / 5 h / Reflux 2.2: 1 h / 0 - 5 °C

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-6-(methyloxy)-3-quinolinecarboxylic acid With trichlorophosphate at 20℃; for 4h; Heating; Stage #2: With ammonium hydroxide In tetrahydrofuran for 0.5h; Cooling with ice;	Intermediate 94-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-oxo-1 ,4-dihydro-3-quinolinecarboxylic acid (for a preparation see Intermediate 5) (36g, 1 15 mmol) was heated in POCI3 (33ml, 354 mmol) for 4h, then allowed to cool to room temperature and stood overnight. The mixture was evaporated on a rotary evaporator, then the brown residue was azeotroped to dryness with toluene (2 x 300ml) and the resulting dark brown gum dissolved in THF (300ml) and added dropwise to concentrated ammonium hydroxide solution (100ml, 0.880), cooling in an ice bath. The mixture was stirred for 30min, then evaporated to half volume, diluted with water (100ml) and the resulting dark brown solid collected by filtration, washed with water (100ml) and dried in vacuum oven at 50°C for three days to give 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (33.2g, 100 mmol, 87 % yield) as brown solid. LCMS (formate) Rt 0.80 min, MH+ 332
64.7%	Stage #1: 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-6-(methyloxy)-3-quinolinecarboxylic acid With trichlorophosphate for 5h; Reflux; Stage #2: With ammonia In water at 0 - 5℃; for 1h;	Intermediate 40: 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3- quinolinecarboxamide; A mixture of intermediate 10 (27.7 g, 0.079 mol) and 10 drops of anhydrous DMF in POCI3 (250ml) was refluxed for 5h. Then, the mixture was concentrated to dryness under vacuum. The residue was treated twice with 100ml of toluene and evaporated to dryness to remove the last traces of POCI3. The dry foam obtained is added portionwise to an aqueous solution of ammonia (25%, 300ml) cooled to 0/5°C with an ice bath. After the end of the addition, the vigourous stirring was maintained for 1 h at this temperature. Then, the brown solid material was filtered off and washed respectively with water (3 x 200ml), diisopropyl ether (2 x 200ml) and pentane (100ml) to give after drying the crude product. This material was purified by a flash chromatography on silica gel (eluant = CH2CI2/MeOH, 95/5) to give the title compound (16.8 g, 64.7%).1H NMR (300 MHz, CDCI3, ppm) δ : 8.96 (s, 1 H), 7.86 (s, 1 H), 7.54 (s, 1 H), 3.95(s, 3H), 2.30 (s, 3H), 2.15 (s,3H).
64.7%	Stage #1: 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-6-(methyloxy)-3-quinolinecarboxylic acid With N,N-dimethyl-formamide; trichlorophosphate for 5h; Reflux; Stage #2: With ammonia In water at 0 - 5℃; for 1h;	Intermediate 40: 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxamide Intermediate 40: 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxamide A mixture of intermediate 10 (27.7 g, 0.079 mol) and 10 drops of anhydrous DMF in POCl3 (250 ml) was refluxed for 5 h. Then, the mixture was concentrated to dryness under vacuum. The residue was treated twice with 100 ml of toluene and evaporated to dryness to remove the last traces of POCl3. The dry foam obtained is added portionwise to an aqueous solution of ammonia (25%, 300 ml) cooled to 0/5° C. with an ice bath. After the end of the addition, the vigourous stirring was maintained for 1 h at this temperature. Then, the brown solid material was filtered off and washed respectively with water (3200 ml), diisopropyl ether (2200 ml) and pentane (100 ml) to give after drying the crude product. This material was purified by a flash chromatography on silica gel (eluant =CH2Cl2/MeOH, 95/5) to give the title compound (16.8 g, 64.7%). 1H NMR (300 MHz, CDCl3, ppm) δ: 8.96 (s, 1H), 7.86 (s, 1H), 7.54 (s, 1H), 3.95 (s, 3H), 2.30 (s, 3H), 2.15 (s, 3H).

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Heating 2: bis-[(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C
	Multi-step reaction with 2 steps 1: acetonitrile / 4 h / 110 °C 2: [bis-(trifluoroacetoxy)iodo]benzene / 12 h / 50 °C

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 120 °C 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 120 °C 2: [bis(acetoxy)iodo]benzene; potassium hydroxide / methanol / Cooling with ice
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 150 °C 2: potassium hydroxide; [bis(acetoxy)iodo]benzene / methanol / 1 h / 0 °C

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 120 °C 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C 3: 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine polymer bound / N,N-dimethyl-formamide / 20 °C
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 120 °C 2: [bis(acetoxy)iodo]benzene; potassium hydroxide / methanol / Cooling with ice 3: oxygen / N,N-dimethyl-formamide / 20 °C

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 4 h / 120 °C 2.1: potassium hydroxide / methanol / 0.17 h / 0 °C 2.2: 2 h
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 4 h / 120 °C 2: [bis(acetoxy)iodo]benzene; potassium hydroxide / methanol / Cooling with ice

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: butan-1-ol / 4 h / 110 °C 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 12 h / 50 °C
	Multi-step reaction with 2 steps 1: butan-1-ol / 4 h / 110 °C 2: bis-[(trifluoroacetoxy)iodo]benzene / acetonitrile / 12 h / 50 °C

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1,4-dioxane / Reflux 2: bis-[(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C
	Multi-step reaction with 2 steps 1: 1,4-dioxane / Reflux 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 4h;	Intermediate 62: 7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[1 -(1 -methyl-1 H- pyrazol-4-yl)ethyl]amino}-3- uinolinecarboxamide; 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 200mg, 0.603 mmol) and [1 -(1 -methyl-1 /-/-pyrazol-4- yl)ethyl]amine (1 13mg) were heated in a mixture of DIPEA (0.326ml, 1 .869 mmol) and N- Methyl-2-pyrrolidone (NMP) (15ml) at 120°C for 4h. The reaction mixture was cooled to room temperature, diluted with water (300ml) and extracted with ethyl acetate (2 x 200ml). The combined organics were washed with water (300ml) and brine (200ml), dried (sodium sulphate) and evaporated. The resulting gum was dissolved in DCM (3ml) loaded onto a loaded onto a silica cartridge (100g), which was then eluted with a 2M methanolic ammonia / DCM gradient (0-12%) to give, after evaporation of the product containing fractions in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[1 -(1 -methyl-1 H-pyrazol- 4-yl)ethyl]amino}-3-quinolinecarboxamide (1 10mg).LCMS (Method Formate): MH+ 421 , Rt 0.62min
	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 4h;	Intermediate 62: 7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[1-(1-methyl-1H-pyrazol-4-yl)ethyl]amino}-3-quinolinecarboxamide Intermediate 62: 7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[1-(1-methyl-1H-pyrazol-4-yl)ethyl]amino}-3-quinolinecarboxamide 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 200 mg, 0.603 mmol) and [1-(1-methyl-1H-pyrazol-4-yl)ethyl]amine (113 mg) were heated in a mixture of DIPEA (0.326 ml, 1.869 mmol) and N-Methyl-2-pyrrolidone (NMP) (15 ml) at 120° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with water (300 ml) and extracted with ethyl acetate (2*200 ml). The combined organics were washed with water (300 ml) and brine (200 ml), dried (sodium sulphate) and evaporated. The resulting gum was dissolved in DCM (3 ml) loaded onto a loaded onto a silica cartridge (100 g), which was then eluted with a 2M methanolic ammonia/DCM gradient (0-12%) to give, after evaporation of the product containing fractions in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[1-(1-methyl-1H-pyrazol-4-yl)ethyl]amino}-3-quinolinecarboxamide (110 mg). LCMS (Method Formate): MH+421, Rt 0.62 min

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile Reflux;	Intermediate 65: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(2,4-dimethyl-1 ,3-thiazol-5- yl)methyl]amino}-6-(methylox -3-quinolinecarboxamide; To a solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3- quinolinecarboxamide (for a preparation see Intermediate 56, 0.5g,) in acetonitrile (50ml) was added a solution of [(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]amine (0.64g, dihydrochloride available from Matrix Scientific) in acetonitrile (10ml). The reaction mixture was heated at reflux for 3h, whereupon another portion of amine (0.5g) was added. The reaction mixture was refluxed overnight and was then poured into water. The mixture phase was extracted with DCM and the organic dried over Na2S04 and concentrated to dryness to give a yellow sticky solid. The latter was recrystallised in acetonitrile to give 7- (3,5-dimethyl-4-isoxazolyl)-4-[(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)- 3-quinolinecarboxamide (0.33g) as white crystals.LC/MS: MH+ 438.06, [M-H]" 436.13
	In acetonitrile Reflux;	Intermediate 65: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide Intermediate 65: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide To a solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 0.5 g,) in acetonitrile (50 ml) was added a solution of [(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amine (0.64 g, dihydrochloride available from Matrix Scientific) in acetonitrile (10 ml). The reaction mixture was heated at reflux for 3 h, whereupon another portion of amine (0.5 g) was added. The reaction mixture was refluxed overnight and was then poured into water. The mixture phase was extracted with DCM and the organic dried over Na2SO4 and concentrated to dryness to give a yellow sticky solid. The latter was recrystallised in acetonitrile to give 7-(3,5-dimethyl-4-isoxazolyl)-4-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide (0.33 g) as white crystals. LC/MS: MH+438.06, [M-H]- 436.13

Yield	Reaction Conditions	Operation in experiment
66.82%	Stage #1: 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid With trichlorophosphate at 100℃; for 2h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 0℃; for 0.5h;	1B.6 Step 6: Synthesis of 4-chloro-7-(3,5-dimethyl-l,2-oxazol-4-yl)-6-methoxyquinoline-3- carboxamide Into a 100 mL flask was added 7-(3,5-dimethyl-l,2-oxazol-4-yl)-6-methoxy-4-oxo-lH- quinoline-3 -carboxylic acid (1.50 g, 4.77 mmol, 1.00 equiv), phosphorus oxychloride (20.00 mL), the reaction was stirred at 100 degrees C for 2 h. The reaction was concentrated, the residue azeotroped with toluene (2x10 mL), the resulting dark brown gum was dissolved in THF (20.00 mL), added dropwise to NH3.H2O (20.00 mL) at 0 degrees C. The reaction was stirred at 0 degrees C for 30 mins, the reaction was concentrated to half volume, diluted with water (10 mL) and the resulting dark brown solid collected by fdtration. The solid was washed with water (10 mL) and dried under vacuum. This resulted in 4-chloro-7- (3,5-dimethyl-l,2-oxazol-4-yl)-6-methoxyquinoline-3-carboxamide (1.20 g,66.82%) as black solid. LC/MS: mass calcd. For C16H14CIN3O3: 331.07, found: 332.10 [M+H]+.
	Multi-step reaction with 2 steps 1: trichlorophosphate / 4 h / Heating 2: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice
	Stage #1: 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid With trichlorophosphate at 20℃; Heating; Stage #2: With ammonium hydroxide In tetrahydrofuran for 0.5h; Cooling with ice;	Intermediate 56: 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide Intermediate 56: 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide 7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (for a preparation see intermediate 57, 54 g, 172 mmol) was heated in phosphorous oxychloride (80 ml, 859 mmol) for 4 h, then allowed to cool to room temperature and to stand overnight. The mixture was reduced to dryness in vacuo and the brown residue azeotroped with toluene (2*300 ml). The resulting dark brown gum was dissolved in THF (300 ml) with heating and sonication and the resulting solution added dropwise to ammonium hydroxide (33% w/w, 500 ml) with ice bath cooling. The mixture was stirred for 30 min, then concentrated to half volume, diluted with water (100 ml) and the resulting dark brown solid collected by filtration. The solid was washed with water (100 ml) and dried under vacuum at 50° C. for 3 days to give 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide as brown solid (50.8 g). 1H NMR D6-DMSO: δH 8.75 (1H, s), 8.19 (1H, bs), 8.01 (1H, s), 7.98 (1H, bs), 7.62 (1H, s), 4.00 (3H, s), 2.34 (3H, s), 2.14 (3H, s).

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 18h;	Intermediate 107-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1 R)-1 -phenylethyl]amino}-3- quinolinecarboxamide 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 9) (3.33g, 10.04 mmol) was dissolved in NMP (10ml) and DI PEA (1.8ml, 10 mmol) and [(1 R)-1-phenylethyl]amine (1 .58 g, 13.05 mmol) were added, then the solution was heated at 120°C for 18h, then cooled to room temperature, diluted with water (100ml) and extracted with EtOAc (2 x 100ml). The organic layer was washed with water (2 x 100ml), dried with sodium sulphate and evaporated in vacuo to give a brown gum. This was dissolved in DCM 20ml) and loaded onto a 100g silica cartridge, then eluted with MeOH/DCM (0-10%) and product-containing fractions evaporated in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1 R)-1-phenylethyl]amino}-3- quinolinecarboxamide (3.5g, 8.40 mmol, 84 % yield) as a beige solid. LCMS (formate) Rt 0.84 min, MH+ 417
84%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 18h;	10 Intermediate 10 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1R)-1-phenylethyl]amino}-3-quinolinecarboxamide 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 9) (3.33 g, 10.04 mmol) was dissolved in NMP (10 ml) and DIPEA (1.8 ml, 10 mmol) and [(1R)-1-phenylethyl]amine (1.58 g, 13.05 mmol) were added, then the solution was heated at 120° C. for 18 h, then cooled to room temperature, diluted with water (100 ml) and extracted with EtOAc (2×100 ml). The organic layer was washed with water (2×100 ml), dried with sodium sulphate and evaporated in vacuo to give a brown gum. This was dissolved in DCM 20 ml) and loaded onto a 100 g silica cartridge, then eluted with MeOH/DCM (0-10%) and product-containing fractions evaporated in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1R)-1-phenylethyl]amino}-3-quinolinecarboxamide (3.5 g, 8.40 mmol, 84% yield) as a beige solid. LCMS (formate) Rt 0.84 min, MH+ 417

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 2h;
54.1%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 3h;	Intermediate 137-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]-3-quinolinecarboxamide4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 9) (1.890 g, 5.70 mmol) was dissolved in NMP (5ml), DIPEA (2.487 ml, 14.24 mmol) was added followed by (tetrahydro-2H-pyran-4- yl)methanamine (0.82g, 7.12 mmol) and the mixture was heated at 120°C for 3h, then cooled and the brown solution loaded onto a 70g SCX-2 cartridge, the column washed with methanol (200ml) and then eluted with 2M methanolic ammonia (100ml) and methanol (100ml). The eluant was evaporated in vacuo to give a brown solid. This was triturated with EtOAc (30ml) and the solid collected by filtration to give 7-(3,5-dimethyl-4- isoxazolyl)-6-(methyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3- quinolinecarboxamide (1.58g, 3.85 mmol, 54.1 % yield) as brown solid. LCMS (formate) Rt 0.64, MH+ 41 1
54.1%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 3h;	13 Intermediate 13 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-quinolinecarboxamide 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 9) (1.890 g, 5.70 mmol) was dissolved in NMP (5 ml), DIPEA (2.487 ml, 14.24 mmol) was added followed by (tetrahydro-2H-pyran-4-yl)methanamine (0.82 g, 7.12 mmol) and the mixture was heated at 120° C. for 3 h, then cooled and the brown solution loaded onto a 70 g SCX-2 cartridge, the column washed with methanol (200 ml) and then eluted with 2M methanolic ammonia (100 ml) and methanol (100 ml). The eluant was evaporated in vacuo to give a brown solid. This was triturated with EtOAc (30 ml) and the solid collected by filtration to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-quinolinecarboxamide (1.58 g, 3.85 mmol, 54.1% yield) as brown solid. LCMS (formate) Rt 0.64, MH+ 411

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h 3.1: phosphorus pentachloride; trichlorophosphate / 5 h / 120 °C
	Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h 3.1: trichlorophosphate / 72 h / 100 °C

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h 3.1: phosphorus pentachloride; trichlorophosphate / 5 h / 120 °C 4.1: 1-methyl-pyrrolidin-2-one / 0.5 h / 150 °C
	Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h 3.1: trichlorophosphate / 72 h / 100 °C 4.1: 1-methyl-pyrrolidin-2-one / 0.5 h / 150 °C

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetonitrile / 4 h / 110 °C 2: bis-[(trifluoroacetoxy)iodo]benzene / 12 h / 50 °C
	Multi-step reaction with 2 steps 1: [bis(acetoxy)iodo]benzene; potassium hydroxide / acetonitrile / 4 h / Reflux 2: bis-[(trifluoroacetoxy)iodo]benzene / acetonitrile / 12 h / 20 - 50 °C

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