Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12](N(OC)C)=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1.[C:35]([Mg]Cl)#[CH:36]>O1CCCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12](=[O:13])[C:35]#[CH:36])[CH:18]=[CH:19][C:20]=2[CH3:21])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[N:26]=1
Reactant: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C(F)(F)F)n3)c(Cl)c2=O)c1
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C(F)(F)F)n3)c(Cl)c2=O)c1

Procedure:
To a solution of 3-[5-chloro-2-methyl-6-oxo-4-(6-trifluoromethyl-pyridin-2-ylmethoxy)-6H-pyrimidin-1-yl]-N-methoxy-4,N-dimethyl-benzamide from Step B (53 mg, 0.11 mmol) in tetrahydrofuran (1.5 mL), cooled using an ice water bath, was added ethynylmagnesium chloride, 0.5M in tetrahydrofuran, (0.3 mL, 0.15 mmol) in a drop-wise manner. Additional Grignard reagent was added as necessary to ensure full product formation. After thirty minutes, the reaction was quenched into ice cold water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated. The crude material was used without additional purification.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: C1CC(N2CCOCC2)CCN1

Procedure:
41.59 g (0.16 Mol) 4-[1-(phenylmethyl)-4-piperidinyl]-morpholine (N) are dissolved in 400 mL methanol, combined with 5.2 g palladium on activated charcoal (10%) and hydrogenated for 18 hours at ambient temperature with 50 psi hydrogen. The catalyst is filtered off and the filtrate is evaporated down. A colourless oil remains, which crystallises after a short time.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].S(Cl)([Cl:12])(=O)=O>C(Cl)Cl>[Cl:12][C:2]1([CH3:1])[C:6](=[CH2:7])[O:5][C:4](=[O:8])[O:3]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1oc(=O)oc1C
Solvent: ClCCl
Product: C=C1OC(=O)OC1(C)Cl
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of 50 g of 4,5-dimethyl-1,3-dioxolene-2-one (IV)(Synthesized by the method described in Tetrahedron Letters, 1701-1704 (1972)) in 350 ml of methylene chloride was added 65 g of sulfuryl chloride dropwise over 1 hour at 40°-42° C. The mixture was stirred for one hour at the same temperature and then evaporated in vacuo to remove the solvent. The resulting residue was distilled in vacuo to obtain 42.1 g (65% of theory) of 4-chloro-4-methyl-5-methylene-1,3-dioxolane-2-one (III) as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][C@H:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:21]([O:23][CH3:24])=[O:22])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.O1CCOCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH2:19][C@H:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:21]([O:23][CH3:24])=[O:22])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCOCC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(O)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
0.4 g of palladium on carbon at 10% is added to a solution of 4 g (9.2 mmol) of methyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-morpholin-4-ylpropanoate (prepared as described in example 7.3) in 200 ml of methanol and 20 ml of dioxane degassed beforehand with nitrogen. The reaction mixture is stirred for one hour at ambient temperature under atmospheric hydrogen pressure. After filtration through celite and concentration of the filtrate under vacuum, the residue obtained is purified by chromatography on silica gel, elution being carried out with a 60/40 ethyl acetate/heptane mixture. 2.6 g (81%) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-morpholin-4-ylpropanoate are obtained in the form of a white solid.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[NH:23][S:24]([C:27]1[C:32]2=[N:33][S:34][N:35]=[C:31]2[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.C1COCC1.[Li+].[OH-].Cl>O>[N:35]1[S:34][N:33]=[C:32]2[C:27]([S:24]([NH:23][C:17]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=3[C:15]([NH:14][C@@H:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=3)[C:3]([OH:37])=[O:2])=[O:36])(=[O:25])=[O:26])=[CH:28][CH:29]=[CH:30][C:31]=12
Reactant: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid methyl ester (0.81 mmol), THF (10 mL), and LiOH (2 M in water, 5 mL) was stirred vigorously overnight at rt. The mixture was poured into water, acidified to pH 1 with conc. HCl, and extracted with EtOAc (4×). The combined organic layers were dried (Na2SO4) and concentrated to provide the desired acid as a tan solid. The acid was purified by preparative reverse phase HPLC to provide 0.44 g (94%, 2 steps) of the acid as a white solid. HPLC: RT=10.08 min. MS (ESI−): mass calcd. for C22H15Cl3N4S5O2, 583.95; m/z found, 583 [M−H]−. 1H NMR (400 MHz, CD3OD): 8.34 (dd, J=7.0, 1.0, 1H), 8.25 (dd, J=8.8, 1.0, 1H), 7.77 (dd, J=8.8, 7.0, 1H), 7.66 (d, J=2.0, 1H), 7.45-7.37 (m, 3H), 7.18 (dd, J=8.2, 2.0, 1H), 6.99 (dd, J=8.5, 2.1, 1H), 4.75 (dd, J=9.3, 5.2, 1H), 3.28 (dd, J=14.0, 5.1, 1H), 3.03 (dd, J=14.0, 9.4, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.N12CCN(CC1)CC2.[C:20](#[N:23])[CH:21]=[CH2:22]>C(OCC)(=O)C>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:21]([C:20]#[N:23])[CH2:22][O:1]2)=[CH:6][CH:7]=1
Reactant: C=CC#N
Reactant: COc1ccc(C=O)c(O)c1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)OCC(C#N)=C2
Yield: 72.3 %

Procedure:
To 2-hydroxy-4-methoxy-benzaldehyde (10.0 g, 65.72 mmol) and DABCO (1,4-diazabicyclo[2.2.2]octane) (1.84 g, 16.43 mmol) was added acrylonitrile (17.44 g, 328.62 mmol). The reaction mixture was refluxed for 20 h. The reaction mixture was diluted with ethyl acetate and the resulting rheum was separated. The organic phase was washed with a 1 molar solution of NaOH and then with a 1 molar solution of HCl. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give the crude product (8.89 g, 72% yield).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)#[N:25]>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:30][C:29]1[CH:32]=[CH:33][C:26]([C:24]#[N:25])=[CH:27][CH:28]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: COC=Cc1ccc(C#N)cc1
Reaction time: 1 h

Procedure:
A suspension of 37.2 g of methoxymethyl-triphenylphosphonium chloride in 250 ml of t-butyl methyl ether is treated at room temperature while gassing with argon with 13.4 g of potassium t-butylate and stirred for 1 hour. Subsequently, the reaction mixture is treated at about 20° C. with a mixture of 9.49 g of 4-cyanobenzaldehyde and 100 ml of t-butyl methyl ether and stirred for a further 1 hour. Thereafter, the reaction mixture is partitioned in diethyl ether/water. The aqueous phase is extracted several times with diethyl ether. The organic phases are washed with water, dried over magnesium sulfate, filtered and evaporated. Chromatographic purification of the resulting crude product on silica gel with petroleum ether and toluene/hexane (vol. 3:1) gives 4-(2-methoxyvinyl)benzonitrile.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:16]1[C:17]2[CH:26]=[CH:25][N:24]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[CH3:35])[C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[N:21]=1>CN(C=O)C.O>[C:28]1([CH3:35])[CH:29]=[C:30]([CH3:34])[CH:31]=[C:32]([CH3:33])[C:27]=1[N:24]1[C:18]2[C:19](=[O:23])[N:20]([CH3:22])[N:21]=[C:16]([O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=3)[C:17]=2[CH:26]=[CH:25]1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(C)c(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(-n2ccc3c(OCc4ccc(C(F)(F)F)cc4)nn(C)c(=O)c32)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a solution of 4-(trifluoromethyl)benzyl alcohol (0.062 ml, 0.45 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 18 mg, 0.45 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-mesityl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (45.3 mg, 0.15 mmol). The mixture was stirred at 60° C. for 1 hour, then diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 16 mg (24%) of the title compound as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[C:15]([S-:17])#[N:16].[K+].BrBr>CC(O)=O>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]2[N:13]=[C:15]([NH2:16])[S:17][C:11]=2[CH:12]=1)[CH3:6])[CH3:2]
Reactant: N#C[S-]
Reactant: CCOC(=O)C(C)c1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3 (3.13 g, 1 mmol) in CH3COOH (15 ml) was cooled to −5□ in iced bath. A mixture KSCN (6.36 g, 4.04 mmol) in CH3COOH (15 ml) added to the flask that contained 4 and CH3COOH at −5° in iced bath. A solution of bromine (0.80 ml) in CH3COOH (10 ml) is added dropwise to a stirred mixture of 4, KSCN and CH3COOH at −5° in iced bath. The reaction mixture is stirred for 1 h at room temperature. The mixture is extracted with ethyl acetate. The extracts are washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH:33](=O)[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+]>ClC(Cl)C.CO>[CH2:33]([N:16]1[CH2:15][CH2:14][N:13]([C:6]2[C:5]([CH3:19])=[C:4]([NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:26]=3)[C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[N:7]=2)[CH2:18][CH2:17]1)[CH3:34]
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: CCN1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)CC1
Reaction time: 8 h

Procedure:
The 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)-quinolin-4-amine (50 mg, 0.11 mmol) was dissolved in a mixture of dichloroethane (1.3 mL) and MeOH (0.63 mL). The acetaldehyde (6.4 μL, 0.11 mmol) and sodium triacetoxyborohydride (72 mg, 0.34 mmol) were added and the mixture was stirred overnight. A small amount (50 mg) of sodium cyanoborohydride was added to drive the reaction to completion. The reaction was quenched with satd sodium bicarbonate solution and extracted with EtOAc. The organic layer was then dried over magnesium sulfate and the filtrate was cond. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini™ column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 95% over 20 min to provide 2-(4-ethylpiperazin-1-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. The salt was then free based by eluting through an SCX column with 0 to 2M ammonia in MeOH to give the desired product as the free base. TFA salt: 1H NMR (CDCl3) δ ppm 7.86 (2H, dd, J=4.3, 2.2 Hz), 7.61 (1H, d, J=9.2 Hz), 7.36-7.43 (1H, m), 7.20 (1H, t, J=2.0 Hz), 6.89 (1H, ddd, J=13.4, 8.5, 2.3 Hz), 4.24 (2H, d, J=14.7 Hz), 3.86-3.95 (4H, m), 3.77 (2H, t, J=13.2 Hz), 3.63 (2H, d, J=12.3 Hz), 3.26-3.38 (4H, m), 3.15 (4H, q, J=7.2 Hz), 2.13 (3H, s), 1.39 (3H, t, J=7.3 Hz). Mass Spectrum (ESI) m/e=469.3 (M+1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[C:2]1=[O:12].FC(F)(F)S([O-])(=O)=O.[F:21][C:22]([I+]C1C=CC=CC=1)([F:27])[C:23]([F:26])([F:25])[F:24].CN(C)C=O>C(OCC)(=O)C>[F:21][C:22]([F:27])([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2](=[O:12])[NH:1]2)[C:23]([F:26])([F:25])[F:24]
Reactant: O=c1[nH]c2ccccc2[nH]c1=O
Reactant: FC(F)(F)C(F)(F)[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2ccc(C(F)(F)C(F)(F)F)cc2[nH]c1=O
Temperature: 45 °C
Reaction time: 8 h
Yield: 5.8 %

Procedure:
A mixture of 0.5 g of 2(1H), 3(4H)-quinoxalinedione, 1.60 g of pentafluoroethylphenyliodonium trifluoromethanesulfonate and 10 ml of dimethylformamide was stirred overnight on an oil bath at 45° C. Ethyl acetate was then added to the reaction mixture and the unreacted 2(1H), 3(4H)-quinoxalinedione was removed by filtration (recovery of the starting material: 0.13 g). Water was added to the filtrate and, after rendering the mixture neutral, the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off. A small amount of methylene chloride was added to the residue and the precipitated crystals were collected by filtration to obtain 0.05 g of 6-pentafluoroethyl-2(1H), 3(4H)-quinoxalinedione as colorless crystals. Yield 6% (conversion yield, 8%). Melting Point (after recrystallized from acetonitrile): 317°-320° C. (with decomposition).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:13]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:29](=[O:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:3]1.N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>C1COCC1>[C:42]([NH:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)=[O:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:29](=[O:35])[C:30]([N:32]([CH3:33])[CH3:34])=[O:31])=[CH:3]1)(=[O:44])[CH3:43]
Reactant: COc1cc2c(cc1C(=O)N1CCC(Cc3ccc(F)cc3)CC1)c(C(=O)C(=O)N(C)C)cn2N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2c(cc1C(=O)N1CCC(Cc3ccc(F)cc3)CC1)c(C(=O)C(=O)N(C)C)cn2NC(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.3 %

Procedure:
To the suspension of 2-{1-Amino-5-[4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-N,N-dimethyl-2-oxo-acetamide (100 mg, 0.21 mmol) in anhydrous THF (3 mL) was added pyridine (60 uL, 0.63 mmol) and acetyl chloride (45 uL, 0.63 mmol) at 0° C. The mixture became clear and was stirred continually at RT for 72 h. The reaction mixture was evaporated in vacuo. The crude material was added water and it was extracted with CH2Cl2. The organic extract was dried (Na2SO4), filtered, and concentrated. The residue was purified by radial chromatography with 0-3% MeOH/CHCl3 to give 30 mg (28%) of the desired product. M+H+(523).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:27][CH:28]=3)[C:10](=[O:22])[NH:11]2)[C:6]([OH:35])=[C:5]1[C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(N4CCOCC4)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)C1=C(O)C2=CC(c3ccc(N4CCOCC4)cc3)C(=O)NC2=CN1Cc1ccccc1
Temperature: 25 °C
Yield: 129.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(4-morpholin-4-yl-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (44 mg, 0.093 mmol), β-alanine (666 mg, 7.5 mmol) and NaOMe solution (11 mL, 5.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 32 mg of the title compound. MS: (+) m/z 529.34 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Solvent: CCCCO
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(Nc2nc(Cl)nc3c2ncn3C2CCSC2)cc1
Reaction time: 30 h

Procedure:
The operation is carried out as in Stage 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 100 mg of ethyl 4-aminobenzoate in place of the benzylamine and the reaction medium is taken to a temperature of approximately 80 to 85° C. for 30 hours, left to return to ambient temperature, diluted with 3 ml of isopropanol, placed for approximately one hour at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying under vacuum at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 202 mg of expected product is thus obtained in the form of white-cream crystals.
Reaction SMILES: [CH:1]1[C:16]2[C:17]3[C:4]([C:5](=O)[O:6][C:7](=[O:18])[C:8]=3[CH:9]=[C:10]3[C:15]=2[O:14][CH2:13][O:12][CH2:11]3)=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22].O>N1C=CC=CC=1>[OH:22][N:21]1[C:5](=[O:6])[C:4]2=[CH:3][CH:2]=[CH:1][C:16]3[C:17]2=[C:8]([CH:9]=[C:10]2[C:15]=3[O:14][CH2:13][O:12][CH2:11]2)[C:7]1=[O:18]
Reactant: NO
Reactant: O=C1OC(=O)c2cc3c(c4cccc1c24)OCOC3
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2cccc3c4c(cc(c23)C(=O)N1O)COCO4
Yield: 57.9 %

Procedure:
To a solution of 310 mg (1.21 mmol) of 8H-5,9,11-trioxabenzo[de]anthracene-4,6-dione (from Example T3) in 4 mL pyridine was added 260 mg (3.74 mmol) of hydroxylamine hydrochloride and the reaction mixture refluxed for 2 hours and poured into 50 mL water while hot. The precipitate was isolated, washed with water, and dried to yield 190 mg of the title compound, mp 314-315° C.
Reaction SMILES: CO[N:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH3:15])=[C:11]([Cl:14])[CH:12]=2)[O:7][CH2:6][CH2:5]1.CON=C1C2C(=CC=C(C)C=2)OCC1>>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[CH3:15])[O:7][CH2:6][CH2:5][CH:4]2[NH2:3]
Reactant: CON=C1CCOc2cc(C)c(Cl)cc21
Agent: CON=C1CCOc2ccc(C)cc21
Product: Cc1cc2c(cc1Cl)C(N)CCO2

Procedure:
The title compound was prepared using the procedure as described in Example 7B, substituting the product of Example 13A for the product of Example 7A. 1H NMR (300 MHz, CDCl3) δ 7.27 (s, 1H), 6.68 (s, 1H), 4.15-4.29 (m, 2H), 3.98 (m, 1H), 2.29 (s, 3H), 2.07-2.17 (m, 1H), 1.75-1.85 (m, 1H). MS (DCI) m/e 198 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[C:20]3[CH:28]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:65]([NH2:69])([CH3:68])([CH3:67])[CH3:66]>CN(C=O)C>[C:65]([NH:69][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([NH:18][C:19]3[C:20]4[CH:28]=[C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:26]=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:17][C:2]=2[CH3:1])[CH:6]=1)([CH3:68])([CH3:67])[CH3:66]
Reactant: CC(C)(C)N
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)NC(C)(C)C)c1
Yield: 35.2 %

Procedure:
A solution of 3-[2-Methyl-4-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-benzoic acid (72 mg, 0.16 mmol), HATU (93 mg, 0.24 mmol), NEt3 (50 mg, 0.48 mmol), and tert-butyl amine (24 mg, 0.33 mmol) in DMF (1.5 mL) was shaken at 60° C. for 12 h. The reaction was concentrated and purified by preparative HPLC to give a yellow solid (28 mg, 35%). LRMS: 497.3 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.65 (s, 1H), δ 8.81 (s, 1H), δ 8.36 (s, 1H), δ 7.77-7.81 (m, 3H), δ 7.54 (d, J=7.78, 1H), δ 7.42 (t, J=7.78, 1H), δ 7.34-7.35 (m, 1H), δ 7.14 (s, 1H), δ 7.00-7.069 (m, 2H), δ 3.50-3.54 (m, 4H), δ 2.21 (s, 3H), δ 2.00-2.09 (m, 4H), δ 1.37 (s, 9H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][CH3:3].[Br:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13](Cl)[S:14][C:10]=2[CH:9]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([CH:2]([CH3:3])[C:1]([O:5][CH3:6])=[O:4])[S:14][C:10]=2[CH:9]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: CCC(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)c1nc2ccc(Br)cc2s1
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a solution of methyl propionate (0.088 mL, 0.89 mmol) and 6-bromo-2-chlorobenzo[d]thiazole (221 mg, 0.89 mmol) in degassed toluene (5 mL) at brine/ice bath temperature was slowly added 1.0 M NaHMDS in THF (2.22 mL, 2.22 mmol). After the addition was complete, the reaction was stirred for 10 min. The mixture was then quenched with satd. NH4Cl (15 mL) then extracted with EtOAc (2×20 mL). The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexane to give Compound R3a (198 mg, 0.66 mmol, 74% yield) as a yellow solid. LCMS=1.0 min using analytical method (M), 302.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=1.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.7, 1.9 Hz, 1H), 4.30 (q, J=7.3 Hz, 1H), 3.78 (s, 3H), 1.75 (d, J=7.3 Hz, 3H).