Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.[C:20]([C:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)([CH3:25])[CH3:24])([OH:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:1]1[C:5]([CH2:6][NH:7][C:8]2[N:9]=[C:10]([CH3:15])[N:11]=[C:12]([C:28]3[CH:27]=[C:26]([C:23]([CH3:25])([CH3:24])[C:20]([OH:22])=[O:21])[CH:31]=[CH:30][CH:29]=3)[CH:13]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: Cc1nc(Cl)cc(NCc2cc3ccccc3s2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1nc(NCc2cc3ccccc3s2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 15.3 %

Procedure:
Argon is bubbled through a mixture of benzo[b]thiophen-2-ylmethyl-(6-chloro-2-methyl-pyrimidin-4-yl)-amine [247 mg, 0.81 mmol], 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [304 mg, 1.46 mmol, see Example 49(b) step 2], Cs2CO3 (792 mg, 2.43 mmol), and tetrakis(triphenylphosphine)palladium (0) (92 mg, 0.08 mmol) in ethylene glycol dimethyl ether (2.5 mL) and water (0.5 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 6 hours the heating is turned off and the mixture is allowed to cool to ambient temperature upon standing for 24 hours. The mixture is diluted with water (20 mL) and extracted twice with EtOAc (30 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-(3-{6-[(benzo[b]thiophen-2-ylmethyl)-amino]-2-methyl-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [51.6 mg, 14.7%, Example 72] as a solid. LCMS RT=2.27 minutes, MS: 434 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:17])[NH:10]2)[CH3:4].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19].O>CN(C=O)C>[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:17])[N:10]2[CH2:25][C:24]1[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=1)[CH3:4]
Reactant: CCc1cc2[nH]c(=O)ccc2c(CC)n1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(ccc(=O)n2Cc2ccc([N+](=O)[O-])cc2)c(CC)n1
Yield: 61.7 %

Procedure:
Sodium hydride (50% dispersion in oil; 0.2 g) was added to a stirred suspension of 5,7-diethyl-1,6-naphthyridin-2(1H)-one (1.0 g) in DMF (10 ml) under an atmosphere of argon. The mixture was stirred until effervescence ceased and 4-nitrobenzyl bromide (1.1 g) was added. The mixture was then stirred for 16 hours. The mixture was then poured into water (50 ml) and extracted twice with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried (MgSO4) and solvent was removed by evaporation to give an oil. The oil was purified by flash chromatography, eluting with ethyl acetate/dichloromethane (1:4 v/v) to give 5,7-diethyl-1-(4-nitrobenzyl)-1,6-naphthyridin-2(1H)-one (B) as a solid (1.03 g); m.p. 105°-106° C.; NMR (CDCl3): 1.22(t, 3H), 1.36(t, 3H), 2.77(q, 2H), 3.11(q, 2H), 5.57(s, 2H), 6.69(s, 1H), 6.77(d, 1H), 7.38(d, 2H), 8.03(d, 1H), 8.19(d, 2H); mass spectrum (CI, ammonia): 338 (M+H)+ ; microanalysis, found: C, 67.0; H, 5.7; N, 12.4%; C19H19N3O3 requires: C, 67.6; H, 5.7; N, 12.5%.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.CCOC(C)=O>C1COCC1>[S:18]1[CH2:19][CH2:20][N:15]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[CH2:16][CH2:17]1
Reactant: C1CSCCN1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2oc(N3CCSCC3)nc12
Yield: 84.1 %

Procedure:
A solution of methyl 2-chlorobenzoxazole-4-carboxylate (1.0 g, 4.7 mmol) and thiomorpholine (1.4 mL, 14 mmol) in THF (20 mL) was stirred at ambient temperature for 1 h. Then, the reaction mixture was poured into EtOAc (100 mL) and washed with 1N HCl (20 mL), H2O (20 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (silica gel, 5 to 50% EtOAc in hexanes) gave methyl 2-thiomorpholinobenzoxazole-4-carboxylate (1.1 g, 84%) as a yellow solid. 1H NMR and MS consistent.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:21]#[N:22])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:21]([C:4]1[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[N:3]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2C#N)CC1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)nc2C#N)CC1
Temperature: 100 °C
Yield: 69.8 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(5-bromo-3-cyanopyrazin-2-yl)piperazine-1-carboxylate (1.0 g, 2.7 mmol), thiophen-2-ylboronic acid (0.52 g, 4.1 mmol), Pd(PPh3)4 (0.31 g, 0.27 mmol), Cs2CO3 (1.4 g, 4.1 mmol), 1,4-dioxane (20 mL) and water (10 mL). The resulting mixture was heated at 100° C. overnight under N2 atmosphere. Work-up: the reaction mixture was poured into brine (80 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 30% EtOAc in petroleum ether, to afford 700 mg (70%) of the product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][N:14]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C1COCC1>[CH2:27]([N:14]([CH2:13][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:15][CH2:16][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccccc1NC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1NCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a stirred slurry of 11 g of lithium aluminum hydride in 250 ml anhydrous THF under nitrogen was added dropwise a solution of 43.6 g of 2-[bis(phenylmethyl)amino]-N-(2-methoxyphenyl)acetamide in 500 ml anhydrous tetrahydrofuran and stirred overnight at room temperature. After cooling to 0°, the mixture was treated cautiously in succession with 50 ml of water. The granular precipitate was separated by filtration and washed several times with methylene chloride. The filtrate was evaporated to dryness, the residue dissolved in ether and the organic phase extracted with 3N hydrochloric acid. the water phase was made alkaline with 3N sodium hydroxide and the base extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate and evaporated at reduced pressure. The crude syrup (36.9 g) was chromatographed on silica gel column packed in methylene chloride. Elution with methylene chloride provided N,N-dibenzyl-N'-(2-methoxyphenyl)ethylenediamine (22.8 g) in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]O.P(Br)(Br)[Br:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][Br:26]
Reactant: BrP(Br)Br
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Product: Cc1nnc(CBr)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 5, 2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is treated with phosphorus tribromide to give 2',5-dichloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:5]([F:15])[CH:4]=1.Cl.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:27]=[CH:28][C:29]([NH:1][CH2:2][C:3]2[CH:8]=[C:7]([CH3:9])[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:5]([F:15])[CH:4]=2)=[O:30])=[CH:25][CH:26]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)cc1
Reactant: Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: Cl
Product: Cc1cc(CNC(=O)C=Cc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Yield: 96 %

Procedure:
N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, and HCl salt (100 mg, 0.35 mmol) were reacted with 3-(4-t-butyl-phenyl)-acrylic acid following the general procedure to give a white solid (140 mg, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[C:5]2=[O:20].C(OC(=O)C)(=O)C.[CH3:28][N:29]([CH2:31][C:32]1[S:33][CH:34]=[C:35]([CH:37]=O)[N:36]=1)[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>O.[Cl-].[Zn+2].[Cl-]>[CH3:28][N:29]([CH2:31][C:32]1[S:33][CH:34]=[C:35]([CH:37]=[CH:12][C:7]2[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5](=[O:20])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=2)[N:36]=1)[CH3:30]
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1F
Reactant: CN(C)Cc1nc(C=O)cs1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CN(C)Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2ccccc2F)cs1
Temperature: 25 °C
Yield: 30.8 %

Procedure:
Anhydrous zinc chloride (0.106 g, 0.78 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, then dioxane (6 mL) was added. To this mixture was added 6-fluoro-3-(2-fluoro-phenyl)-2-methyl-3H-quinazolin-4-one (0.108 g, 0.39 mmol), acetic anhydride(0.111 mL, 1.18 mmol), and 2-dimethylaminomethylthiazole-4-carboxaldehyde (0.280 g, 1.18 mmol in 4 mL of dioxane). The reaction was refluxed 4 d, cooled to ambient temperature, and diluted with water. Sodium carbonate was added until the mixture was basic. The mixture was repeatedly extracted with chloroform. The combined chloroform layer was washed with aqueous bisulfite, water and brine and finally dried over sodium sulfate and concentrated to leave a dark residue. This residue was triturated with ether, filtered and dried to afford 0.051 g (31%) of 2-[2-(2-dimethylaminomethyl-thiazol-4-yl)-vinyl]-6-fluoro-3-(2-fluoro-phenyl)-3H-quinazolin-4-one as tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:19][C:20]([Si:23]([CH3:33])([CH3:32])[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:22])[CH3:21].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:29][C:28]2[CH:27]=[CH:26][C:25]([O:24][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:32])[CH3:33])=[CH:31][CH:30]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2cc(Cl)ncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
The product from Example 1, Step 3 (20.0 g, 104 mmol) and triethylamine (17.4 mL, 125 mmol) were dissolved in THF (200 mL) and a solution of 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}aniline (25.0 g, 113 mmol) in THF (50 mL) was added and the mixture was allowed to stir at rt overnight. The reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated to give the title compound (37.5 g, 95%) as a yellow oil. MS (ES+) m/e 381 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16]C)=[O:15])[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([OH:16])=[O:15])[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2cccc3cccnc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cccc3cccnc23)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
820 mg (3.11 mmol) of methyl 3-(quinolin-8-yl)benzoate was dissolved in 8.2 mL of THF, and a 1N aqueous sodium hydroxide solution (4.7 mL) was added thereto at room temperature. The mixture was stirred at 60° C. for 1.5 hours. Thereafter, the organic solvent was distilled off under reduced pressure, H2O was added to the resulting residue, and then dissolution was conducted. Thereafter, 1N hydrochloric acid was added to the resultant at 0° C., and the pH was adjusted to 4. The precipitated solids were collected by filtration and dried, thereby giving 711 mg of 3-(quinolin-8-yl)benzoic acid (yield: 92%).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]([OH:20])[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[C:13]([NH:12][CH2:11][CH:10]([O:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Yield: 61.9 %

Procedure:
To a solution of N,N′-di-Boc-2-hydroxy-1,3-diaminopropane (13.19 g, 45.4 mmol) and triethylamine (1.5 eq, 9.5 ml, 68.1 mmol) in dry 50 ml CH2Cl2 was added dropwise a solution of methanesulfonyl chloride (1.5 eq, 5.25 ml, 68 mmol) in dry 15 ml CH2Cl2 over a period of 1 h at 0° C. with stirring under nitrogen. After the addition, the reaction was stirred overnight at room temperature. Water was slowly added to quench the reaction; the organic layer was separated and then washed with water (5×15 ml) and dried over Na2SO4 and evaporated to give white solid. Recrystallization from hot acetone and cyclohexane gave 10.36 g (62%) white solid. M.p.=127° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[C:17]([CH3:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[CH3:10][C:11]1[C:17]([CH3:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:12]=1[NH:13][C:2]1[N:7]=[C:6]([NH:13][C:12]2[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([CH3:18])[C:11]=2[CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Cc1c(N)ccc(O)c1C
Reactant: Fc1cnc(Cl)nc1Cl
Product: Cc1c(O)ccc(Nc2ncc(F)c(Nc3ccc(O)c(C)c3C)n2)c1C

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 2,3-dimethyl-4-hydroxyaniline gave N2,N4-bis-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 19.07 min.; purity: 99%; MS (m/e): 369 (MH+); 1H NMR (DMSO-d6): δ 9.21 (1H, s), 8.99 (1H, s), 8.63 (1H, s), 7.92 (1H, s), 7.84 (1H, d, J=3.6 Hz), 6.94 (1H, d, J=8.5 Hz), 6.85 (1H, d, J=8.5 Hz), 6.70 (1H, d, J=8.5 Hz), 6.58 (1H, d, J=8.5 Hz), 2.12 (3H, s), 2.06 (3H, s), 2.02 (3H, s), 1.94 (3H, s).
Reaction SMILES: CN(CCN(C)C)C.[F:9][S:10]([F:23])([F:22])([F:21])([F:20])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl.O>C1COCC1.[Li]C(CC)C.C1CCCCC1>[Cl:24][C:13]1[CH:12]=[C:11]([S:10]([F:20])([F:21])([F:22])([F:23])[F:9])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1Cl
Temperature: -90 °C
Reaction time: 2 h

Procedure:
20.0 ml of TMEDA were dissolved in 150 ml of THF (anhydrous) and, at a temperature between −80° C. and −90° C., 93.0 ml of a 1.25M solution of sec-BuLi in cyclohexane were added. Then, at a temperature between −87° C. and −93° C., a solution of 4-pentafluorosulfanylbenzoic acid (example 2a) in 50 ml of THF (anhydrous) was added dropwise over the course of 35 minutes, After stirring at −90° C. for 2 hours, 38.2 g of 1,1,1,2,2,2-hexachloroethane in 60 ml of THF (anhydrous) were added dropwise at −90° C. The mixture was allowed to warm to −70° C., and then 100 ml of water were added dropwise. The solvent was removed in vacuo, and the residue was chromatographed on silica gel with DIP/2% HOAc. 5.0 g of the desired product were obtained as a partly crystallizing oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[Cl:27][C:25]1[CH:24]=[C:23]([S:28]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:29])=[O:30])[CH:22]=[C:21]([Cl:20])[CH:26]=1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 3,5-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[N:21][CH:22]=1)=[CH:13][C:12]([C:36]1[CH:41]=[C:40]([F:42])[C:39]([OH:43])=[C:38]([Cl:44])[CH:37]=1)=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>>[Cl:44][C:38]1[CH:37]=[C:36]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[C:15]3[NH:16][C:17]2[CH:22]=[N:21][C:20]([N:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[CH:19][CH:18]=2)[CH:41]=[C:40]([F:42])[C:39]=1[OH:43]
Reactant: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCNCC2)nc1
Yield: 52.1 %

Procedure:
Following general procedure A-2, tert-butyl 4-{5-[3-butyryl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)quinolin-4-ylamino]pyridin-2-yl}piperazine-1-carboxylate (0.144 mmol) was reacted with TFA (2 mL) to afford the desired product (39 mg, 51% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.29 (s, 1H), 8.29 (d, J=2.7 Hz, 1H), 8.20 (dd, J=8.8, 2.0 Hz, 1H), 8.03-7.95 (m, 2H), 7.74 (dd, J=8.8, 2.7 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 7.11-7.02 (m, 2H), 3.94 (t, J=5.3 Hz, 4H), 3.37 (t, J=5.3 Hz, 4H), 3.19 (t, J=7.2 Hz, 2H), 1.87-1.76 (m, 2H), 1.11-1.04 (t, J=7.2 Hz, 3H); ESI MS m/z 520 [C28H27ClFN5O2+H]+; HPLC>99% (AUC), tR=10.99 min.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][NH:8]/[C:9](/[NH:20][C:21]2[NH:25][N:24]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:22]=2)=[N:10]/[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1COCC1>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][NH:8]/[C:9](/[NH:20][C:21]1[NH:25][N:24]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:22]=1)=[N:10]/[C:11](=[O:19])[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1
Reactant: CC1(C)OCC(CN/C(=N/C(=O)c2ccc(F)cc2)Nc2cc(C(F)(F)F)n[nH]2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/N=C(/NCC(O)CO)Nc1cc(C(F)(F)F)n[nH]1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of (Z)—N-((((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)amino)((3-(trifluoromethyl)-1H-pyrazol-5-yl)amino)methylene)-4-fluorobenzamide (300 mg) in THF (7 mL) was added para-toluenesulfonic acid (p-TsOH) (133 mg, 1 equiv). The reaction mixture was shaken at room temperature overnight. The solution was then treated with triethylamine (100 μL), concentrated onto silica gel, and purified by silica chromatography (3:1 hexanes:EtOAc to EtOAc) to provide the title compound (115 mg (91% purity), 42% yield). MS (EI+) m/z: 389.93, 411.89; HPLC (Method B): 5.19 min
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[O:39]([C:46]1[C:51]([O:52][CH2:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][N:59]=[CH:58][C:57]=2[OH:62])=[CH:50][CH:49]=[CH:48][N:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1>[O:39]([C:46]1[C:51]([O:52][CH2:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][N:59]=[CH:58][C:57]=2[O:62][CH2:4][CH2:3][O:2][CH3:1])=[CH:50][CH:49]=[CH:48][N:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COCCO
Reactant: Oc1cnccc1CCCOc1cccnc1Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1cnccc1CCCOc1cccnc1Oc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-Methoxyethanol (0.08 g, 0.93 mmol) and triphenylphosphine (0.32 g, 1.2 mmol) are dissolved in THF (20 ml), and thereto are successively added with stirring diisopropyl azodicarboxylate (0.17 g, 0.93 mmol) and 2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.20 g, 0.62 mmol) obtained in Example 30 under ice-cooling. The mixture is further stirred at 60° C. for one hour, and the reaction solution is concentrated under reduced pressure. To the residue is added ethyl acetate (50 ml), and the mixture is extracted with a 10% aqueous hydrochloric acid solution (50 ml×2). The pH value of the aqueous layer is adjusted to pH 12 with potassium carbonate, and the mixture is extracted with ethyl acetate (50 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/methanol) to give 2-phenoxy-3-[3-(3-methoxyethoxypyridin-4-yl)propoxy]pyridine, which is further treated with fumaric acid to give the title compound (0.12 g), m.p. 120-123° C. (recrystallized from diethyl ether).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[NH4+:19].[NH4+]>C(#N)C.N>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:19])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Reactant: [NH4+]
Agent: N
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of (4-nitrophenyl)methanesulfonyl chloride (4 g, 17 mmol) in acetonitrile (100 mL) was added a solution of ammonium carbonate (3 g, 31.3 mmol) in ammonia (50 mL). The reaction mixture was stirred for 1 h, and TLC indicated the starting material consumed completely. The organic solvent was removed under reduced pressure. Addition of water (10 mL) led to precipitate formation. The solid was collected, washed with water (2×5 mL), and dried to give (4-nitrophenyl)methanesulfonamide (3.4 g, 93%) as a white solid. MS (ES+) C7H8N2O4S requires: 216, found: 217 [M+H]+.