Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[C:32]([OH:37])=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.Br[CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:46][C:2]([F:1])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:43])([F:42])[F:44])[CH:40]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: Oc1ccccc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2′-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-ol (150 mg) is dissolved in N,N-dimethylformamide (3 ml) and thereto are added ethyl 4-bromobutyrate (50 μl) and potassium carbonate (47 mg), and the mixture is stirred at room temperature for 2 hours and at 80° C. for 2 hours. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-(2′-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-yloxy)-butyrate (163 mg). MS (m/z): 771 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][N:38]([C:41](Cl)=[O:42])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][N:11]([C:41]([N:38]2[CH2:37][CH2:36][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:40][CH2:39]2)=[O:42])[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccccc1
Yield: 75.8 %

Procedure:
To a solution of rac-[(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (0.76 g, 2.46 mmol) in CH2Cl2 (10 ml) was added ethyl-diisopropyl-amine (0.51 ml, 2.95 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (0.61 g, 2.7 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/Hx 1:1) afforded 0.87 g (70%) of the title compound as a white solid. ES-MS m/e: 501.4 (M+H+).
Reaction SMILES: [CH:1](=[N:8][NH:9][C:10]1[N:11]=[N:12][C:13]([Cl:21])=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C>C(O)(=O)C>[Cl:21][C:13]1[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:15][C:10]2[N:11]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:8][N:9]=2)[N:12]=1
Reactant: Clc1nnc(NN=Cc2ccccc2)cc1N1CCCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: Clc1nn2c(-c3ccccc3)nnc2cc1N1CCCC1

Procedure:
A slurry of N-benzylidene-N′-[6-chloro-5-(pyrrolidin-1-yl)pyridazin-3-yl]hydrazine (14 g, 0.046 mol) and lead(IV) acetate (24 g, 0.055 mol) in acetic acid (300 ml) was stirred at 60° C. under nitrogen overnight. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with 0-10% methanol in ethyl acetate. The title compound was isolated as a yellow solid (4.1 g, 30%). 1H NMR (250 MHz, CDCl3) δ2.05 (4H, m), 3.56 (4H, m), 7.05 (1H, s), 7.51 (3H, m), 8.42 (2H, m). MS (ES+) m/e 300 [MH]+, 302 [MH]+.
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].[NH2:9][C:10]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:11][C:12](=[S:14])[NH2:13].II>CCOCC.O>[NH2:13][C:12]1[S:14][N:9]=[C:10]([CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1
Reactant: NC(=S)C=C(N)COCc1ccccc1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: Nc1cc(COCc2ccccc2)ns1

Procedure:
In a stream of argon, 182 ml of dry methanol, 191 ml of dry ether and 38.5 g (0.279 mole) of potassium carbonate were added to 31.0 g (0.140 mole) of 3-amino-4-benzyloxy-2-butenethioamide obtained in Referential Example 4, and under heating and reflux, a solution of 26.6 g (0.209 mole) of iodine in dry ether 191 ml was added droopwise to the mixture. Then, the mixture was refluxed for 1.5 hours, and 130 ml of dry ether containing 17.7 g (0.140 mole) of iodine was added dropwise under reflux. After cooling, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water, an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting 5-amino-3-benzyloxymethyl isothiazole was subjected to silica gel column chromatography, and the column was eluted with chloroform/methanol (500/2) to give 25.5 g (83.0%) of a brown oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]([NH:14][S:15]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23]C)=[O:22])(=[O:17])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([O:5][C:6](=[O:28])[CH:7]([NH:14][S:15]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([OH:23])=[O:22])(=[O:17])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)C(NS(=O)(=O)c1cccc(C(=O)O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
To a stirring solution of methyl 3-[(2-tert-butoxy-2-oxo-1-phenylethyl)-sulfamoyl]benzoate (2.2 g, 5.4 mmol) in tetrahydrofuran (33.7 mL) and methanol (33.7 mL) was added 1.0 N aqueous lithium hydroxide (13.5 mL, 13.5 mmol) in one portion. The reaction mixture was stirred for 18 hours at ambient temperature, after which time the mixture was concentrated under reduced pressure. The resulting crude was partitioned between ethyl acetate (20 mL) and water (40 mL); the resulting aqueous was acidified with concentrated sulphuric acid (c. 1.0 mL) and washed with ethyl acetate (2×20 mL). The organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound as a white solid (1.21 g, 57%).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH3:24][N:25]([CH3:34])[C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][CH:27]=1>>[CH3:24][N:25]([CH3:34])[C:26]1[CH:31]=[CH:30][C:29]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])=[CH:28][CH:27]=1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Reactant: CN(C)c1ccc([Mg]Br)cc1
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3ccc(N(C)C)cc3)ccc2o1

Procedure:
The product from Example 71E and 4-(dimethylamino)phenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.44 (d, 3H), 1.73 (m, 1H), 1.80 (m, 2H), 2.15 (m, 2H), 2.35 (m, 1H), 3.18 (s, 6H), 3.50 (m, 2H), 3.55 (m, 1H), 3.80 (m, 2H), 6.80 (dd, 2H), 6.85 (s, 1H), 7.56 (dd, 1H), 7.65 (dd, 1H), 7.75 (dd, 2H), 7.95 (d, 1H); MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NC3CC3)cc2n1
Yield: 48 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (64 mg, 0.2 mmol) was converted, using cyclopropylamine instead of aminomethylcyclopropane, to the title compound (35 mg, 48%) which was obtained as a yellow solid. MS: m/e=359.3 [M+H]+.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]2[N:16]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:15]=[CH:14][CH:13]=2)=[C:8]([CH3:25])[N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:6]1=O.O.FC(F)(F)C(O)=O.[OH-].[Na+]>O1CCCC1>[CH3:25][C:8]1[N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:6][N:5]([CH2:4][CH:3]=[O:2])[C:10](=[O:11])[C:9]=1[C:12]1[N:16]([C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)[N:15]=[CH:14][CH:13]=1
Reactant: COC(Cn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(c2ccnn2-c2ccc(C#N)cc2)C(=O)N(CC=O)CN1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 102.7 %

Procedure:
To a solution of 4-[5-[3-(2,2-dimethoxyethyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 7) (10.0 mg) in tetrahydrofuran (0.5 ml)/water (0.1 mL) was added trifluoroacetic acid (40 μl) and the resulting mixture was stirred at 100° C. for three hours. The reaction mixture was neutralized with aqueous sodium hydroxide solution, and thereto was added water and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford 4-[5-[6-methyl-4-oxo-3-(2-oxoethyl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (9.1 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([OH:9])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.[Br:27][C:28]1[CH:33]=[CH:32][C:31](O)=[C:30]([N+:35]([O-:37])=[O:36])[C:29]=1F>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([O:9][C:31]2[CH:32]=[CH:33][C:28]([Br:27])=[CH:29][C:30]=2[N+:35]([O-:37])=[O:36])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(O)CC1
Reactant: O=[N+]([O-])c1c(O)ccc(Br)c1F
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Oc2ccc(Br)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
To a stirred solution of ethyl-1-hydroxycyclopropane carboxylate (2.93 g, 20.5 mmol) in THF (50 mL) was added sodium hydride (60% in mineral oil, 981 mg, 24.5 mmol) under argon atmosphere. After 10 min, 15-crown-5 (0.2 mL) followed by 4-bromo-2-nitro-fluorophenol (4.5 g, 20.5 mmol) were added. The reaction mixture was stirred at room temperature overnight then quenched by the addition of methanol (1.5 mL) and diluted with ethyl acetate. The mixture was washed with brine, and the organic layer was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give 1-(4-bromo-2-nitro-phenoxy)-cyclopropanecarboxylic acid ethyl ester (3.51 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17]([CH3:19])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:26])[CH2:23]CS.C1CCN2C(=NCCC2)CC1>C1COCC1.C(OCC)(=O)C.CCCCCC>[CH3:20][O:21][C:22](=[O:26])[CH2:23][CH2:19][S:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: COC(=O)CCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CCSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 1 h
Yield: 58.1 %

Procedure:
To a solution of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (50 mg, 0.18 mmol) in THF (0.9 mL) was added methyl-3-mercaptopropionate (40 μL, 0.36 mmol) followed by DBU (60 μL, 0.40 mmol). The solution was stirred for 1 h, diluted with 25% ethyl acetate/hexane and passed through a plug of SiO2 washing with 50% ethyl acetate/hexane. The filtrate was concentrated, and the resulting solids triturated with 20% ethyl acetate/hexane to afford 35.1 mg (58% yield) of the titled product as a white solid. ESI-MS m/z 336 (MH+), 334 (M−H)−.
Reaction SMILES: C([O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=[O:10])=[C:7](Br)[CH:6]=1)(=O)C.[CH:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:4][C:5]1[CH:6]=[C:7]([C:22]2[CH:23]=[CH:24][C:19]([CH:16]([CH3:18])[CH3:17])=[CH:20][CH:21]=2)[C:8]([CH:9]=[O:10])=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COc1cc(C=O)c(Br)cc1OC(C)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(-c2ccc(C(C)C)cc2)cc1O
Temperature: 80 °C
Yield: 72 %

Procedure:
To a mixture of (273 mg, 1 mmol) of 4-Acetoxy-2-bromo-5-methoxybenzaldehyde, (164 mg, 1 mmol) of 4-isopropylphenylboronic acid and 276 mg (2 mmol) of K2CO3 in 5 mL of DMF and 1 mL of H2O was added 73.1 mg (0.1 mmol) of Pd(dppf)Cl2. The mixture was heated at 80° C. overnight. After the removal of the catalyst via filtration, the mixture was repartitioned between EtOAc and H2O. Aqueous layer was extracted 3 times with EtOAc and organic layers were combined and dried over Na2SO4. After the removal of the solvent, the residue was chromatographed to give 362 mg of 5-Hydroxy-4′-isopropyl-4-methoxy-biphenyl-2-carbaldehyde (72%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:8][CH2:9][C:10](=O)[NH:11][C:12]=2[N:13]=1)([O-:3])=[O:2]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:8][CH2:9][CH:10]=[N:11][C:12]=2[N:13]=1)([O-:3])=[O:2]
Reactant: O=C1COc2ccc([N+](=O)[O-])nc2N1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(n1)N=CCO2

Procedure:
6-Nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (500 mg) was refluxed with boron hydride methyl sulfide complex (1 mL) in THF (10 mL) for 30 min to give 6-nitro-2H-pyrido[3,2-b]-1,4-oxazine. In a manner analogous to the preparation of 5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine, 6-nitro-2H-pyrido[3,2-b]-1,4-oxazine was reduced and reacted with 2,4-dichloro-5-fluoropyrimidine (500 mg) and 3-methylaminocarbonylmethyleneoxyaniline (500 mg) to give 5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-6-yl]-2,4-pyrimidinediamine as a gray solid. 1H NMR (CD3OD): δ 2.81 (s, 3H), 3.48 (t, J=4.5 Hz, 2H), 4.14 (t, J=4.5 Hz, 2H), 4.44 (s, 2H), 6.60 (ddd, J=1.5 and 2.7 and 7.5 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.14 (d, J=3.0 Hz, 1H), 7.17 (t, J=7.8 Hz, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.42 (t, J=2.1 Hz, 1H), 7.92 (d, J=3.3 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ−168.20; LCMS: ret. time: 25.49 min.; purity: 97.56%; MS (m/e): 426.23 (MH+).
Reaction SMILES: [C:1](=[O:3])=[O:2].[K].[CH3:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[C:8]([CH3:20])[C:7]=1[CH2:21][CH:22]1[C:26](=O)O[CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:23]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].CI>C1(C)C=CC=CC=1.C1COCC1>[CH3:20][C:8]1[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:11]=[C:6]([CH3:5])[C:7]=1[CH2:21][C:22]1([CH3:26])[C:1](=[O:3])[O:2][CH:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:23]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1CC1C(=O)OC(c2ccccc2)N1C(=O)OCc1ccccc1
Reactant: O=C=O
Agent: [K]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(OCc2ccccc2)cc(C)c1CC1(C)C(=O)OC(c2ccccc2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 500 ml round bottom flask fitted with a magnetic stirrer, thermometer, dropping funnel, and y-tube (connected to an N2 inlet and a drying tube outlet) was charged with dry THF (150 ml), which was cooled (dry ice bath) to -60°. A solution of potassium hexamethyldislazane in toluene (0.653M, 21.0 ml, Callery Chemical Company, Callery, Pa.) was added all at once. The solution was cooled back to -70°, and a solution of the title compound of Example 53 (5.5 g, 10.6 mmol) in THF (100 ml) was added dropwise rapidly, keeping the reaction temperature at or below -62°. The mixture was then stirred in the cold bath for 30 min, and the cold bath was then removed. Stirring at room temperature for another 30 min elevated the reaction tempature to -12°. The reaction mixture was then re-immersed in the cold bath, and the temperature returned to -70°. Methyl iodide (1.05 ml, 2.40 g, 16.9 mmol) was added al at once, and after another 10 min the cold bath was removed. The reaction mixture was permitted to warm to room temperature, and 3 hr after removal of the cold bath the mixture was partitioned between a mixture of H2 0 (200 ml), 0.5N KHSO4 (50 ml), saturated brine (200 ml) and ether (200 ml). The aqueous phase was washed with ether, the organic fractions were combined, dried (MgSO4), filtered, and stripped to an oil. The oil was applied to silica gel column chromatography on using ethyl acetate-hexane eluent, giving the title compound. NMR: α methyl group at ∫2.71 A, 3 protons.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[C:20]([CH3:22])[N:19]=[C:18](Cl)[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:24][CH3:25])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>[Pd].CN(C=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:17]=[CH:18][N:19]=[C:20]([CH3:22])[CH:21]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:24][CH3:25])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(-c3cc(C)nc(Cl)c3)nc(=O)c1-2
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccnc(C)c3)nc(=O)c1-2
Temperature: 60 °C
Reaction time: 6.5 h
Yield: 82.5 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(2-chloro-6-methyl-4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one (1.3 g, 3.6 mmol), DMF (75 ml), triethylamine (1.0 ml, 7.2 mmol) and 10% palladium on carbon (0.13 g) was placed on a parr hydrogenator at 50 psi and heated via an external heating jacket to 60° C. for 2 hours, then at 70° C. for 6.5 hours. Additional catalyst was added and the mixture was placed back on the parr hydrogenator for 4 hours at 70° C. The mixture was filtered through a celite plug while hot, and the filtrate was concentrated in vacuo. Water was added to the residue and a white solid was collected by filtration to afford 0.96 g (82%) of 1-cyclopentyl-3-ethyl-6-(2-methyl-4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one as a white powder, m.p. 258°-259° C. when recrystallized from DMF/acetonitrile.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[C:38]([O:39][CH3:40])=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[C:26]([F:41])[CH:25]=1.C(O)(C(F)(F)F)=O>>[F:41][C:26]1[CH:25]=[C:24]([NH:23][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)[C:38]([O:39][CH3:40])=[CH:37][C:27]=1[CH2:28][P:29](=[O:36])([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35]
Reactant: CCOP(=O)(Cc1cc(OC)c(N)cc1F)OCC
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1F)OCC
Yield: 54 %

Procedure:
A solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A, 75.0 mg, 0.227 mmol) and diethyl (4-amino-2-fluoro-5-methoxybenzyl)phosphonate (Compound 130A, 79.0 mg, 0.271 mmol) in TFE (1.1 mL) was charged with TFA (77.3 mg, 0.678 mmol). The reaction mixture was irradiated on the microwave at 105° C. for 30 min. The reaction mixture was concentrated under reduced pressure to yield a yellow oil. The reaction was purified by silica gel chromatography on the combi-flash Rf system using EtOAc/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid, 71.3 mg (54% yield). 1H NMR (DMSO-d6, 400 MHz): δ=1.20 (t, J=7.07 Hz, 6 H), 2.77 (d, J=4.55 Hz, 3 H), 3.16-3.25 (m, 2 H), 3.79 (s, 3 H), 3.95-4.04 (m, 4 H), 7.01 (d, J=5.05 Hz, 1 H), 7.10-7.17 (m, 1 H), 7.42 (t, J=7.58 Hz, 1 H), 7.70 (d, J=7.58 Hz, 2 H), 8.40 (br. s., 1 H), 8.44 (s, 1 H), 8.67 (s, 1 H), 8.73 (d, J=3.79 Hz, 1 H), 11.41 (s, 1 H). MS (ES+): m/z 586.19 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(Cc2ccc(F)cc2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 85.9 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.2 g) is alkylated using 1-bromomethyl-4-fluoro-benzene (0.88 g; 4.66 mmol) and K2CO3 (1.8 g; 13 mmol) at RT for 18 h. After aqueous work-up the crude material is de-acetylated using hydrochloric acid (60 ml; 6 N) at reflux. After aqueous work-up 5-amino-1-(4-fluoro-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.29 g) is obtained and used without further purification.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:17]CN[CH2:14][CH2:13]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1.FC1C(F)=CC2C3C(C(=O)N(C4C=CC=CC=4)N=3)=CNC=2C=1.[CH3:50][N:51]([CH3:58])[CH:52]1CCNC[CH2:53]1>>[CH3:50][N:51]([CH3:58])[CH:52]1[CH2:14][CH2:13][N:12]([C:11]2[C:2]([F:1])=[CH:3][C:4]3[C:5]4[C:6]([C:18](=[O:27])[N:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:20]=4)=[CH:7][NH:8][C:9]=3[CH:10]=2)[CH2:17][CH2:53]1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Reactant: CN(C)C1CCNCC1
Agent: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1
Product: CN(C)C1CCN(c2cc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3cc2F)CC1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27a and 4-dimethylaminopiperidine. 1H-NMR (DMSO-d6) δ (ppm): 1.56 (2H, brm), 1.89 (2H, brm), 2.22 (6H, s), 2.74 (2H, brm), 3.13 (1H, brm), 3.52 (2H, brm), 7.10 (1H, m), 7.22 (1H, d, J=7.96 Hz), 7.40 (2H, t, J=7.42 Hz), 7.76 (2H, d, J=2.91 Hz), 8.20 (2H, m), 8.64 (1H, s). m/z 406.4 (MH+).