Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([OH:23])[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O[C@H:25]([C@H:27]1[CH2:31][N:30]([C@@H](C2C=CC=CC=2)C)[C:29](=[O:40])[CH2:28]1)[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15]([O:23][C@@H:25]([C@H:27]3[CH2:31][NH:30][C:29](=[O:40])[CH2:28]3)[CH3:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2cc(O)c3cccnc3c2)cc(OC)c1OC
Reactant: C[C@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3cccnc3c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.3 %

Procedure:
80 mg of 7-(3,4,5-Trimethoxyphenyl)quinolin-5-ol, 62 mg of (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one and 142 mg of triphenylphosphine was dissolved in 5 mL of DCM. 125.5 mg of DBAD was added and the mixture stirred for 6 h at room temperature. The mixture was diluted with DCM and extracted with 1N NaOH and water. The organic phase was concentrated in vacuo and purified via flash chromatography (10 SiO2; cyclohexane→cyclohexane:ethylacetate:MeOH 58:40:2). Product containing fractions were concentrated, dissolved in 1.5 mL of TFA and heated 75 min at 150° C. in the microwave. The mixture was purified with HPLC (XbridgeC18, MeOH/water, TFA) to yield after lyophilisation 21 mg of Example 2 as solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([NH2:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][C:21]=1[Cl:33])[CH:17]=[CH2:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(OC(C)(C)C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:15])[NH:32][C@H:27]([C:28]([O:30][CH3:31])=[O:29])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:16][CH:17]=[CH2:18])=[C:21]([Cl:33])[CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCOc1ccc(C[C@H](N)C(=O)OC)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)(C)OC=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(C[C@H](NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(=O)OC)cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a 25 mL round-bottomed flask, (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (279 mg, 1.3 mmol, Eq: 1.00) and (S)-methyl 3-(4-(allyloxy)-3-chlorophenyl)-2-aminopropanoate (350 mg, 1.3 mmol, Eq: 1.00) were combined with DMF (6 mL) to give a colorless solution. HATU (986 mg, 2.59 mmol, Eq: 2.00) and Hunig's base (335 mg, 453 μL, 2.59 mmol, Eq: 2.00) were added. The reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was poured into saturated aqueous NaHCO3 solution and extracted with DCM (2×). The organic layers were combined, washed with water (3×) and brine (1×). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, n-heptane/AcOEt 3/1, 2/1) to yield a yellow oil (570 mg; 94%). m/z=467.2 [M+H]+; 367.1 [M+H-Boc]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:21](=[O:23])[CH3:22].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[C:11]([CH:21]([OH:23])[CH3:22])=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Fc1cccc2ccc(Cl)nc12
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1cc2cccc(F)c2nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
2-Chloro-8-fluoroquinoline (5.00 g, 27.5 mmol) was dissolved in THF (60 mL) and cooled to −78° C. To this solution was added freshly prepared and titrated lithium diisopropylamide (1M solution in THF, 30 mL, 30 mmol, 1.1 eq) over 5 min. The reaction was allowed to stir at −78° C. for 20 min, after which time acetaldehyde (2.3 mL, 41.3 mmol, 1.5 eq.) was added via syringe over 30 seconds (exothermic). After 30 min at −78° C., the reaction was quenched with 50% saturated NH4Cl solution and diluted with EtOAc. The layers were separated and washed with brine, dried over MgSO4, and filtered. The crude reaction mixture was deposited on 30 g of silica gel and passed through a plug of 60 g of silica gel, eluted with 8:2 hexanes:EtOAc. Fractions containing product and a closely (second) eluting regioisomer were collected. The fractions were concentrated and the crude solid was slurried in 140 mL of 9:1 hexanes:EtOAc at reflux for 30 min. After cooling to rt, the solid was filtered and washed with a small amount of cold 9:1 hexanes:EtOAc to afford pure 1-(2-chloro-8-fluoroquinolin-3-yl)ethanol (3.1 g, 13.7 mmol, 50% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (br s, 1H), 7.64 (td, J=7.8, 5.1 Hz, 1H), 7.41 (ddd, J=10.2, 7.4, 1.2 Hz, 1H), 5.39 (qdd, J=6.3, 3.9, 0.8 Hz, 1H), 2.22 (d, J=3.9 Hz, 1H), 1.62 (d, J=6.3 Hz, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][C:13]1[N:17]([CH3:18])[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:25])[C:14]=1[CH:26]([CH3:28])[CH3:27]>CN(C=O)C.O.CCOC(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]2[N:17]([CH3:18])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](=[O:25])[C:14]=2[CH:26]([CH3:28])[CH3:27])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)c1c(CBr)n(C)n(-c2ccccc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1c(COc2ccc(Cl)cc2)n(C)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.3 %

Procedure:
To a suspension of sodium hydride (0.023 g of a 50% dispersion in mineral oil) in DMF (2 mL) at 0° C. was added 4-chlorophenol (0.042 g). To this was added a solution of 5-bromomethyl-4-isopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one (0.10 g) in DMF (1 mL) and the reaction mixture was allowed to stir at ambient temperature for 18 hours. The reaction was then diluted with water and EtOAc. The phases were separated and the aqueous was extracted with further EtOAc. The combined organic phases were washed with further brine and dried with sodium sulfate. Filtration and evaporation of the volatiles in vacuo and purification of the residue via ISCO Combiflash chromatography (using EtOAc/heptane) afforded the 5-(4-chloro-phenoxymethyl)-4-isopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one (0.020 g) as a light yellow solid. MS (ESI+): 357.1 [M+H]+).
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:15]1[CH:19]=[CH:18]N=C1)(N1C=CN=C1)=[S:9].C(Cl)Cl.NC1C=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=1>C(OCC)(=O)C>[N:15]([C:19]1[CH:18]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=1)=[C:8]=[S:9]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(N=C=S)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Triethylamine (55.8 μL, 0.4 mmol) and thiocarbonyldiimidazole (46.3 mg, 0.26 mmol) were added to a methylene chloride solution (0.4 mL) of 4-amino-2-nitrobenzoic acid (36.4 mg, 0.2 mmol) at room temperature, followed by stirring at room temperature for 10 minutes. The reaction mixture was dissolved in ethyl acetate and washed with 1 M hydrochloric acid, the organic layer was separated, and then the organic layer was dried over magnesium sulfate. Thereafter, filtration and concentration under reduced pressure to dryness were carried out to obtain 4-isothiocyanato-2-nitrobenzoic acid as a colorless solid (40 mg, yield: 89%, HPLC purity: 96.4%)
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15]([CH2:17][O:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.Cl[C:45]([O:47][CH3:48])=[O:46]>C(Cl)Cl>[CH2:1]([O:13][CH2:14][CH:15]([CH2:17][O:18][C:19]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[O:16][C:45]([O:47][CH3:48])=[O:46])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)OC
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of (rac)-1-O-dodecyl-3-O-trityl-glycerol (16.0 g) and dry pyridine (7.54 g) in dry methylenechloride (200 ml) was added, dropwise over 20 minutes, a solution of methyl chloroformate (5.70 g) in dry methylene chloride (40 ml) at 5° C. After 3 hours, the solution was allowed to stand for 17 hours at ambient temperature, and then washed with aqueous hydrochloric acid and water, dried, and evaporated. The residue was purified by column chromatography on silica gel (240 g, elution by chloroform) to yield 17.33 g of (rac)-1-O-dodecyl-2-O-methoxycarbonyl-3-O-trityl-glycerol as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Cl:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[C:23](Cl)[N:22]=1.C(N(CC)CC)C>CN1CCCC1=O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([F:29])([F:30])[F:28])=[C:21]([Cl:20])[N:22]=2)[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ccc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 120 °C

Procedure:
Add bis(4-methoxybenzyl)amine (35.7 g, 138.9 mmol) in 20 mL of N-methylpyrrolidone to a solution of 2,6-dichloro-3-trifluoromethylpyridine (20 g, 92.6 mmol) and triethylamine (19.4 mL, 138.9 mmol) in 100 mL of N-methylpyrrolidone. Raise the temperature to 120° C., and stir the reaction for 14 hours. Quench the reaction mixture by the addition of water (80 mL), followed by extraction with EtOAc (3×70 mL). Wash the combined organic extracts with water (2×70 mL) and brine (70 mL), and dry over anhydrous Na2SO4. Filter the dried extract and concentrate under vacuum to afford the crude product, which is purified by column chromatography to give a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, 1H, J=8.4 Hz), 7.15 (m, 4H), 6.85 (m, 4H), 6.31 (d, 1H, J=8.8 Hz), 4.70 (s, 4H), 3.80 (s, 6H). Mass spec. (436.99, M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=O)[CH2:9][CH2:8]2.Cl.Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(C(C)C)CC)(C)C.Cl.C([BH3-])#N.C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:25]1[CH2:26][CH2:27][N:22]([C:17]3[N:16]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:23][CH2:24]1)[CH2:9][CH2:8]2
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: COc1cccc2c1CC(=O)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC(N1CCN(c3ncccn3)CC1)CC2
Yield: 30.8 %

Procedure:
8-Methoxy-2-tetralone (3.5 g, 20 mmole), 1-(2-pyrimidinyl) piperazine dihydrochloride (4.6 g, 20 mmole), 0.38 g of p-toluenesulfonic acid and 3.48 ml of diisopropylethylamine were combined in 200 ml of toluene and the mixture refluxed under N2 for three days with water removal via a Dean-Stark trap. After the reaction had cooled, 10.5 ml of 4 N isopropanolic HCl was added, followed in portions by 5.93 g of tetra-n-butyl ammonium cyanoborohydride. The mixture was refluxed under N2 for one hour and the solvent removed in vacuum. The residue was redissolved in 300 ml of CHCl3, washed with saturated NaHCO3 solution, dried over MgSO4, filtered, and evaporated in vacuum. The crude product was column chromatographed on 75 g of silica gel employing chloroform as the eluent and the relevant fractions were combined and concentrated in vacuum. The crude title compound was crystallized from 50 ml of isopropanol with addition of 4 N isopropanolic HCl to obtain 2.0 g of the title compound as the monohydrochloride. A second crystallization from isopropanol gave 1.3 g of monohydrochloride, m.p. 273°-276° C. (d).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[O:30]1[C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=[N:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:35]([C:34]2[O:30][N:31]=[CH:32][CH:33]=2)=[O:36])=[C:4]([F:20])[C:5]=1[O:10][C:11]1[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1ccno1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3ccno3)c2F)c1
Reaction time: 8 h
Yield: 46.2 %

Procedure:
In a 1 dram vial, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 5-isoxazolecarboxylic acid (9.09 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.015 g, 46%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 8.65 (br. s., 1H), 8.57 (d, 1H), 7.63 (t, 1H), 7.46-7.53 (m, 1H), 7.41-7.46 (m, 1H), 7.35-7.41 (m, 2H), 6.99 (d, 1H), 4.69 (d, 2H). LCMS m/z 405.9 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:25])[C:13]4[C:17]([CH:18]=3)=[N:16][N:15](C3CCCCO3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56](O)=[O:57])[CH:51]=1.CCN(C(C)C)C(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([NH:25][C:56]([C:52]4[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=4)=[O:57])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccnc1
Temperature: 25 °C
Reaction time: 67.5 h
Yield: 41.5 %

Procedure:
A mixture of 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (50 mg, 0.15 mmol), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (63 mg, 0.17 mmol) and 3-pyridinecarboxylic acid (20 mg, 0.16 mmol) was treated with DMF (2 ml) and DIPEA (0.052 ml). The reaction was stirred at room temperature for approximately 67.5 hours, then the solvent was removed in vacuo and the residue dissolved in methanol (3 ml). This was treated with macroporous p-toluenesulfonic acid resin (loading 1.43 mmol/g, 316 mg, 0.45 mmol), stirred for approximately 2 hours and then overnight, then treated with ammonia solution (0.88, 0.30 ml). The mixture was stirred for 5 mins, then the resin was filtered and the filtrate evaporated (blown down). The residue was purified by Mass Directed Automated Preparative HPLC (Method B). One fraction was evaporated to give the title compound (22 mg) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]1.[CH3:18][C:19]1[N:24]=[C:23]([SH:25])[N:22]=[C:21]([OH:26])[CH:20]=1.C(N(CC)CC)C>C(O)C>[Cl:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]2)[C:3]=1[CH2:2][S:25][C:23]1[N:22]=[C:21]([OH:26])[CH:20]=[C:19]([CH3:18])[N:24]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCN1CCN(c2cccc(Cl)c2CBr)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN1CCN(c2cccc(Cl)c2CSc2nc(C)cc(O)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
A mixture of 1-[2-(bromomethyl)-3-chlorophenyl]-4-ethylpiperazine (24.8 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (2.35 g, 16.5 mmol), and triethylamine (17 mL, 124 mmol) in absolute ethanol (300 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was recovered and evaporated. The solid residue was treated with water (500 mL). The mixture was extracted with DCM (3×200 mL) and EtOAc (1×200 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-20% MeOH/DCM and 0-15% MeOH/DCM), affording 2-({[2-chloro-6-(4-ethylpiperazin-1-yl)phenyl]methyl}sulfanyl)-6-methylpyrimidin-4-ol (505 mg, 5% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.00 (t, 3H, J=7.2 Hz), 2.24 (s, 3H), 2.85 (m, 2H), 2.50 (m, 4H), 2.87 (m, 4H), 4.67 (s, 2H), 6.02 (s, 1H), 7.22 (m, 2H), 7.32 (t, 1H, J=8.0 Hz); M+ 379.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=[N:8][CH:9]=1.F[C:17]1[CH:22]=[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])[C:20]([F:36])=[CH:19][C:18]=1[N+:37]([O-:39])=[O:38].[Cl-].[NH4+]>CN(C)C=O>[F:36][C:20]1[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:22][C:17]([O:3][C:4]2[C:5]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=[N:8][CH:9]=2)=[C:18]([N+:37]([O-:39])=[O:38])[CH:19]=1
Reactant: COC(=O)COc1ncncc1O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ncncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a mixture of 42 mg of Sodium hydride and N,N-dimethylformamide, 0.184 g of 5-hydroxy-4-(methoxycarbonyl)methoxypyrimidine was added and stirred at room temperature for 1 hour. Then 0.35 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene was added to the mixture, and stirred for 2 hours at room temperature, then for 1 hour at 50° C. The mixture was poured into saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.448 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-(methoxycarbonyl)methoxypyrimidine.
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([NH2:18])[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:22][NH2:23]>CCO>[NH2:18][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][C:15]=1[F:17])[O:10][CH2:9][C:8]1[N:7]2[CH:5]([CH3:6])[C:4](=[O:20])[NH:22][N:23]=1
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2cc(F)c(N)cc21
Solvent: O
Solvent: CCO
Product: CC1C(=O)NN=C2COc3cc(F)c(N)cc3N21
Temperature: 90 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of 2-(6-amino-7-fluoro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.400 g, 1.34 mmol) in EtOH (15 mL) was added hydrazine hydrate (98%, 0.430 g, 13.4 mmol) and the reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was cooled to ambient temperature then concentrated in vacuo and the residue was purified by column on silica gel (basified by treatment with triethyl amine, eluting with 10-20% MeOH in DCM) to give 6-amino-7-fluoro-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a light yellow solid (0.316 g, 94%). 1H NMR (DMSO-d6, 400 MHz): δ 10.73 (s, 1H), 6.78 (d, J=11.6 Hz, 1H), 6.62 (d, J=8.8 Hz 1H), 4.84 (brs, 2H), 4.44-4.53 (m, 3H), 1.29 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH2:54][C:55](O)=[O:56])=[CH:46]1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:55](=[O:56])[CH2:54][C:47]3[C:48]4[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:45]([CH3:44])[CH:46]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1cc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c2ccccc21
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 1-methyl-3-indoleacetic acid (0.5 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 5:95) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(1-methyl-1H-indol-3-yl)-acetamide (0.8 g, 83%) as a yellow solid: mp 231-233° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.53 min. (98%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.54-2.63 (m, 2H), 2.83-2.91 (m, 1H), 3.62 (s, 2H), 3.73 (s, 3H), 4.70 (d, J=5.9 Hz, 2H), 5.10-5.16 (dd, J=5.2 and 12.7 Hz, 1H), 6.99-7.04 (dd, J=7.1 and 7.9 Hz, 1H), 7.12-7.17 (dd, J=7.1 and 7.9 Hz, 1H), 7.21 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.54-7.79 (m, 4H), 8.47 (t, J=5.9 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 32.23, 32.34, 37.86, 48.83, 107.82, 109.50, 118.39, 118.78, 121.07, 121.79, 127.06, 127.47, 128.27, 131.46, 133.19, 134.54, 136.53, 139.38, 166.91, 167.45, 169.77, 171.15, 172.71; Anal. Calcd. for C25H22N4O5: C, 65.49; H, 4.84; N, 12.22. Found: C, 65.11; H, 4.54; N, 12.05.