Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[N:24][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=5)=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([C:7]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4([NH2:36])[CH2:35][CH2:34][CH2:33]4)=[CH:30][CH:31]=3)=[N:24][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=5)=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccccn3)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccccn3)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 65.1 %

Procedure:
Tert-butyl (1-(4-(8-phenyl-1-(pyridin-2-yl)-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.026 mmol) was dissolved in dichloromethane (1 ml); TFA (0.5 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure. The resulting residue was purified via preparative HPLC to give the desired product as a white solid (8 mg, 64% yield). LCMS (Method D) RT=0.825 min, M+H+=474. 1H NMR (500 MHz, d6-DMSO): 8.79 (1H, d), 8.44 (1H, bs), 8.13 (1H, s), 8.11-8.05 (1H, m), 7.62-7.59 (1H, m), 7.41 (2H, s), 7.42-7.38 (2H, d), 7.25-7.27 (3H, m), 7.10 (2H, m), 5.71 (2H, s), 2.60-2.51 (4H, m), 2.27-2.19 (1H, m), 1.88-1.76 (1H, m).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:2]([OH:1])[C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: OC[C@@H](O)C(O)[C@H](O)CO

Procedure:
Using the above described procedure of Example 1, glucose (Example 2) was cleanly decarbonylated by one equivalent of chlorotris(triphenylphosphine)rhodium to yield arabinitol (88%) in about 4 hours. Similarly, arabinose (Example 3) yielded erythritol (84%). Glyceraldehyde (Example 4), which has a higher free aldehyde content (ca. 2% in aqueous solution at room temperature), yielded ethylene glycol (95%) in just 30 minutes under the same conditions. Similar results were observed with glycol aldehyde, which yielded methanol (83%) and glucoheptose which yielded glucitol (88%) (Example 5). A practical demonstration of the utility of this reaction is provided by the one-step conversion of commercially available 2-deoxyribose (Example 6) into the much less accessible 1-deoxyerythritol (30 min., >90%). This is particularly significant in that the best known synthesis of 1-deoxyerythritol requires seven steps from glucose [Chaby, R., et al., Tetrahedron, 27:3197-3205 (1971)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.P(Cl)(Cl)([Cl:22])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:22])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2[nH]1
Product: Clc1cccc(-c2cc(Cl)nc3ccc(Br)cc23)c1
Yield: 100 %

Procedure:
A mixture of intermediate (4) (0.16 mol) in phosphoryl chloride (500 ml) was stirred and refluxed for one night. The mixture was evaporated till dryness, the residue was taken up in ice and water, alkalized with NH4OH and extracted with DCM. The organic layer was decanted, dried (MgSO4), filtered off and evaporated, yielding 56 g (100%) 6-bromo-2-chloro-4-(3-chlorophenyl)quinoline, mp. 125° C. (intermediate 5).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][OH:16])([CH3:14])[CH2:6][CH2:5]2.[H-].[Na+].[CH3:20][O:21][CH2:22]Cl>CN(C)C=O.C1C=CC=CC=1>[CH3:20][O:21][CH2:22][O:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][OH:16])([CH3:14])[CH2:6][CH2:5]2
Reactant: COCCl
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CO)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COCOc1c(C)c(C)c2c(c1C)CCC(C)(CO)O2
Temperature: 0 °C

Procedure:
16.1 g of 6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethanol were dissolved in 70 ml of dry dimethylformamide. 3.0 g of a 50% w/w suspension of sodium hydride in oil (which had been washed with cyclohexane 3 times) were added gradually to the resulting solution at 5°-10° C., with stirring and under a nitrogen stream. The mixture was reacted for 1 hour at room temperature, and then the solution was ice-cooled to 3°-5° C., and 5.5 g of chloromethyl methyl ether dissolved in 40 ml of dry benzene were added dropwise. After the whole of this had been added, the solution was reacted for 1 hour at room temperature. The reaction mixture was then poured into ice-water and extracted with cyclohexane. The extract was washed four times with a 5% w/v aqueous solution of sodium hydroxide, and then with water. It was then dried and the solvent was distilled off under reduced pressure, giving the desired 6-(methoxymethoxy)-2,5,7,8-tetramethylchroman-2-ylmethanol. On thin layer chromatography, the Rf value was 0.45 [silica gel; developing solvent:benzene:ethyl acetate=4:1 by volume].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:17]=[O:18])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:17][OH:18])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
2-Chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-8-carbaldehyde (3.8 g, 11 mmol) in MeOH (22 mL) was treated with sodium tetrahydroborate (0.817 g, 22 mmol), and stirred at room temperature for 1 hour. The reaction was quenched with water and extracted with EtOAc. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The crude material was purified with isco with 0-80% EtOAc/hexane to give the pure (2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)methanol (3.4 g, 89% yield). LC/MS (ESI+): m/z 354 (M+H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: CN1CCN(CCN)CC1
Solvent: C1COCCO1
Product: CN1CCN(CCNC(=O)Nc2cc(CN3C(=O)N(c4ccc(C(C)(C)C)cc4)C(=O)C3(C)C)ccn2)CC1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 48 μl of 1-(2-aminoethyl)-4-methylpiperazine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica, eluting with a gradient (100/0 to 75/25 by volume) of dichloromethane and methanol/aqueous ammonia (6/1 by volume) to give 75 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-[2-(4-methylpiperazin-1-yl)ethyl]urea, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH3:2].[CH3:16][C:17]1[C:18](OS(C(F)(F)F)(=O)=O)=[C:19]([CH2:38]/[CH:39]=[C:40](\[CH3:48])/[CH:41]([CH3:47])[CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:20]([O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[C:21]2[C:25]=1[CH2:24][O:23][C:22]2=[O:26]>>[CH2:1]([C:18]1[C:17]([CH3:16])=[C:25]2[C:21]([C:22](=[O:26])[O:23][CH2:24]2)=[C:20]([O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:19]=1[CH2:38]/[CH:39]=[C:40](\[CH3:48])/[CH:41]([CH3:47])[CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH3:2]
Reactant: CCCC[Sn](CC)(CCCC)CCCC
Reactant: COC(=O)CC(C)/C(C)=C/Cc1c(OS(=O)(=O)C(F)(F)F)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Product: CCc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)C(C)CC(=O)OC)C(=O)OC2

Procedure:
By following the procedure of part A and substituting vinyltributyltin with ethyltributyltin, and substituting methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate with methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5yl)-3,4-dimethyl-4-hexenoate, there is obtained methyl (E) 6-(1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-3,4-dimethyl-4-hexenoate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:24](O)=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH:22]=[CH2:23])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:35]1.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.[OH-].[Na+]>CN(C=O)C>[C:43]([O:42][C:41]([NH:40][C@H:36]1[CH2:37][CH2:38][CH2:39][N:34]([C:33]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[NH:27][C:24]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([CH:22]=[CH2:23])=[CH:18][CH:19]=3)[N:14]=2)=[O:25])[CH2:35]1)=[O:47])([CH3:44])([CH3:46])[CH3:45]
Reactant: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
3-{[(Benzyloxy)carbonyl]amino}-7-vinylquinoline-2-carboxylic acid (0.55 g, 1.6 mmol) was mixed with tert-butyl [(3S)-1-(3-aminopyridin-4-yl)piperidin-3-yl]carbamate (0.46 g, 1.6 mmol), DMF (4.0 mL), HATU (1.2 g, 3.2 mmol) and DIPEA (1.1 mL, 6.3 mmol). The reaction mixture was stirred at room temperature for 16 h. Aq. NaOH (1 M, 20 mL) was then added to the reaction mixture. A precipitate formed, which was collected by vacuum filtration to give the sub-title compound (0.52 g, 53%) as light yellow powder. LCMS calc. for C35H39N6O5 (M+H)+: m/z=623.2. Found: 623.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[O:11][C:10](=[O:15])[CH2:9]2)[CH:7]=1.[NH3:19]>O1CCCC1.CO>[NH2:19][C:10](=[O:15])[CH2:9][CH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:16]([O-:18])=[O:17])[CH2:13][C:12]([OH:11])=[O:14]
Reactant: N
Reactant: O=C1CC(c2cc(Cl)ccc2[N+](=O)[O-])CC(=O)O1
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)CC(CC(=O)O)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
Adapting literature known protocols (Ji, et al., Tetrahedron Lett., 2009, 50(45), 6166-6168; and Hoekstra, et al., Org. Proc. Dev. Dev., 1997, 1(1), 26-38), 5-amino-3-(5-chloro-2-nitro-phenyl)-5-oxo-pentanoic acid (18d) is prepared from 4-(5-chloro-2-nitro-phenyl)tetrahydropyran-2,6-dione (18a) (2.70 g, 10.0 mmol) in tetrahydrofuran (THF) (20 mL) with a concentrated solution of ammonia (NH3) in methanol (MeOH) (˜7.0 M; about 100 mL) at room temperature for about 14 hours. The reaction course is followed by TLC and/or LC/MS till completion. The reaction mixture is concentrated to dryness under reduced pressure using a rotary evaporator. The residue is triturated with ethyl acetate (EtOAc) (2×). The solids remaining after titruation are acidified at a temperature of about 0° C. (ice bath) with 1.0 M hydrochloric acid. Aqueous work-up yields the title compound (18d). The crude material may either be used directly in the next step or may be further purified by silica gel column chromatography using methanol (MeOH), dichloromethane (DCM), and hexane mixtures or by re-crystallization.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:14]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([I:25])=[C:21]([O:26][CH3:27])[CH:20]=4)[N:16]=[N:15]3)[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>C1COCC1.O>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:14]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([I:25])=[C:21]([O:26][CH3:27])[CH:20]=4)[N:16]=[N:15]3)[C:11](=[O:13])[N:12]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1cc(-c2cn(C3CCc4c(F)cccc4NC3=O)nn2)ccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)ccc1I
Temperature: 25 °C
Yield: 90.9 %

Procedure:
6-Fluoro-3-[4-(4-iodo-3-methoxy-phenyl)-1,2,3-triazol-1-yl]-1,3,4,5-tetrahydro-1-benzazepin-2-one (20 g, 41.8 mmol) was suspended in THF and stirred at room temperature. Cesium carbonate (24.53 g, 75 mmol) was added, followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (14.56 g, 62.7 mmol). The mixture was heated to gentle reflux for 2 h. The reaction was diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic fractions were dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel, gradient to 100% EtOAc/hexanes. 6-Fluoro-3-[4-(4-iodo-3-methoxy-phenyl)-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoro-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (21.3 g) was obtained as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([F:19])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.IC.[C:24]([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([F:19])=[CH:14][CH:15]=3)[N:10]([CH3:24])[C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cccc1-n1c(=O)[nH]c2cc(F)ccc2c1=O
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)c2ccc(F)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
A mixture of 3-(3-bromo-2-methylphenyl)-7-fluoroquinazoline-2,4(1H,3H)-dione (2.70 g, 7.73 mmol), iodomethane (0.580 mL, 9.28 mmol) and Cs2CO3 (3.78 g, 11.6 mmol) in THF (20 mL) was stirred at room temperature for 3 h. The mixture was filtered and the filtrate was diluted with DCM and washed with water. The aqueous phase was extracted with DCM, and the combined organic phases were dried and concentrated to give 3-(3-bromo-2-methylphenyl)-7-fluoro-1-methylquinazoline-2,4(1H,3H)-dione (2.85 g), used without further purification. Mass spectrum m/z 363, 365 (M+H)+, 385, 387 (M+Na)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)Oc1cc[nH]c(=O)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccnc(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
A 0.77 g quantity of 4-acetoxy-2-pyridone was suspended in 30 ml of dioxane. To the suspension were added 2.09 ml of triethylamine and 0.58 ml of benzoyl chloride and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography using, as an eluent, chloroform, giving 0.95 g of the title compound in a yield of 73%.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([CH3:24])[CH2:11][N:12]1[C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:23])(C(C)(C)C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCCC.CCOC(C)=O>[F:22][C:20]1[CH:19]=[CH:18][C:17]2[N:12]([CH2:11][C@H:10]([CH3:24])[CH2:9][OH:8])[C:13](=[O:23])[CH2:14][O:15][C:16]=2[CH:21]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2cc(F)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](CO)CN1C(=O)COc2cc(F)ccc21
Yield: 100.4 %

Procedure:
The compound (S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methyl-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (111MF14) (3.79 g, 10.7 mmol) and tetrabutylammonium fluoride monohydrate (3.99 g, 14.3 mmol) were mixed according to GP8. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF18) (2.57 g, 100%). 1H NMR (CDCl3) δ 6.99-6.95 (m, 1H), 7.77-7.72 (m, 2H), 4.63 (m, 2H), 4.23-4.16 (m, 1H), 3.58-3.40 (m, 3H), 2.86 (s, 1H), 2.05-1.97 (m, 1H), 1.04 (d, J=6.8 Hz, 3H); 13C NMR (CDCl3) 164.6, 159.2 (d, J=244.5 Hz), 146.4 (d, J=11.6 Hz), 124.9 (d, J=3.1 Hz), 115.9 (d, J=9.6 Hz), 109.4 (d, J=22.7 Hz), 105.3 (d, J=26.1 Hz), 67.5, 63.8, 43.8, 34.0, 15.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:34][CH2:35][CH2:36][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(2-aminoethyl)morpholine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white rigid foam: 1H NMR (CDCl3) δ 10.39 (1H, br m), 8.55 (1H, s), 7.15 (3H, m), 7.02 (2H, t, J=9 Hz), 4.85 (2H, s), 4.12 (2H, s), 3.98 (4H, br), 3.88 (2H, q, J=6 Hz), 3.72 (2H, br), 3.54 (2H, t, J=7 Hz), 3.45 (2H, t, J=7 Hz), 3.35 (2H, t, J=6 Hz), 2.92 (2H, br), 2.06 (2H, m, J=7 Hz), 1.90 (2H, m, J=7 Hz); HRMS calcd for C28H32FN5O5+H+: 538.2466. Found: 538.2460.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH2:17])[C:7]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:8])([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH2:17])[C:7]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)=[O:8]
Reactant: Nc1ccc(C(=O)c2nccs2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)c2nccs2)cc1N

Procedure:
A suspension of 20 g. (0.082 mol) of 2-(3-nitro-4-aminobenzoyl)thiazole in 1 liter of tetrahydrofuran containing 5 g. of 5% palladium on carbon was reduced with hydrogen under a pressure of 3 atmospheres. The resulting mixture was filtered and concentrated in vacuo to yield 2-(3,4-diaminobenzoyl) thiazole as unstable red needles, mp. 125°-127° C. (dec.) (acetone-water).
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:26]#[N:27])=[N:13][N:14]2[CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=1.CO>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:26](=[NH:6])[NH2:27])=[N:13][N:14]2[CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])=[CH:10][CH:9]=1
Reactant: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2cc(Cl)ccc12
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CO
Product: N=C(N)c1nn(CCC(F)(F)C(F)(F)F)c2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Trimethylaluminum (2.0M in toluene, 23.17 mL, 46.3 mmol) was added dropwise to a suspension of ammonium chloride (2.49 g, 46.5 mmol) in 69 mL toluene cooled to 0° C. The solution was then stirred at room temperature for 3 hours. This solution was then added to the intermediate from Step D (3.0 g, 9.27 mmol) and then heated at 110° C. for 6 hours. The solution was then cooled to room temperature and carefully poured to silica gel (ca 150 mL) and methanol (ca 250 mL). After stirring for 1.5 hours the suspension was filtered and the filtrate concentrated to give the indicated product which was used in the next step without further purification. 1H NMR (400 MHz, CH3 CN-d3): selected peaks δ 8.26 (d, J=8.7 Hz, 1H); 7.70 (d, J=1.7 Hz, 1H); 7.24 (dd, J=8.7, 1.8 Hz, 1H); 4.67 (t, J=7.1 Hz, 2H); 3.01-2.78 (m, 2H). m/z=341.1 (M+H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:15](OCC)(OCC)OCC>>[N:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH:6]=[CH:5][N:4]3[CH:15]=[N:2][N:1]=[C:3]3[CH:8]=2)=[CH:10][CH:11]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1cc(-c2ccncc2)ccn1
Product: c1cc(-c2ccn3cnnc3c2)ccn1

Procedure:
A 1.0 g portion of 2-hydrazino-4,4'-bipyridine and 50 ml of triethyl orthoformate was refluxed 18 hours, then chilled and the crystals collected. These crystals were dissolved in acetone-ethyl acetate, treated with activated carbon, filtered and the filtrate concentrated while hexane was added. Cooling gave the desired product as white crystals, mp 194°-196° C.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32]([CH2:31][N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:29])=[O:5])[C:9]=2[CH3:28])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:27])=[O:26])=[O:33])[CH3:36]
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN1C(c2c(C)n(CC(=O)O)c3ccccc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and ethyl bromoacetate. MS: ESI (negative): 441 (M−H).