Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18](=[O:21])([OH:20])[OH:19].N>C(O)C>[CH:1]([N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18](=[O:19])([OH:21])[OH:20])[OH:11])=[O:3]
Reactant: O=P(O)(O)CCCCCNO
Reactant: O=CO
Agent: N
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: O=CN(O)CCCCCP(=O)(O)O
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Formic acid (1.19 g.) was added dropwise to acetic anhydride (1.33 g.) at ambient temperature with stirring. After the stirring was continued at the same temperature for 30 minutes, 5(N-hydroxyamino)pentylphosphonic acid (1.83 g.) was added to the mixture. The reaction mixture was stirred at ambient temperature for an hour and 45 minutes, and then concentrated under reduced pressure to give an oily residue. The residue was dissolved in ethanol (30 ml) and to the solution was added dropwise conc. aqueous ammonia (2 ml.) to give crystals. After the mixture containing crystals was stirred at ambient temperature for an hour, the crystals were separated by filtration and dried to give crystalline monoammonium salt of 5-(N-formyl-N-hydroxyamino)pentylphosphonic acid (2.10 g.). A part (1.8 g.) of the crystals was dissolved in water (6 ml.) to give insoluble materials, which were removed by filtration and washed with water. The filtrate and the washing were combined and ethanol (30 ml.) was added thereto under heating at 60° C. to give purified crystals (1.62 g) of the same compound as mentioned above. M.p. 170°-175° C. (dec.).
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[OH:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11]>O1CCCC1>[CH3:1][O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: CN(C)C=O
Reactant: COC(=O)C(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl formamide (100 ml) and tetrahydrofuran (300 ml) were placed in a 1000 ml three-neck round-bottom flask equipped with a thermometer, a mechanical stirrer, and a dropping funnel. An 80% dispersion of sodium hydride in oil (19.80 g, 0.66 mol) was added to form a gray suspension. The suspension was cooled in an ice-water bath. Methyl hydroxyisobutyrate (70.8 g, 0.60 mol) was dissolved in tetrahydrofuran (50 ml) and added slowly to the cooled sodium hydride suspension while the temperature was held below 15° C. The resulting suspension was stirred for one hour. Methyl iodide (freshly distilled, 108.75 g, 0.75 mol) in tetrahydrofuran (25 ml) was slowly added to the cooled suspension. The addition took 1.5 hours, during which the temperature was held below 15° C. The suspension was stirred and allowed to warm to room temperature for 15 hours. The suspension was poured into ethyl acetate (300 ml) and water (300 ml). The clear layers were separated and the aqueous phase was extracted with ethyl acetate (300 ml). The combined organic layers were decolorized with water (200 ml) containing sodium bisulfite (10 g). The organic phase was separated and dried over magnesium sulfate. The solvent was mostly removed by rotary evaporation (25 mm Hg, 30° C.). The resulting solution was distilled at atmospheric pressure and the product collected at 137°-146° C. The product was contaminated with DMF, but by NMR the yield of product was 48.8 g (61%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[C:4]([Br:9])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1c(Br)cc(Br)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2c(Br)cc(Br)cc2Br)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2,4,6-tribromophenol (3.8 g), 4-fluoronitrobenzene (1:6 g), cesium carbonate (3.7 g) in dimethylformamide (8 mL) was heated at reflux until the starting materials were consumed. The reaction was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate and washed with sodium hydroxide (2 N), hydrochloric acid (2 N) and brine. Concentration of the organic phase gave 1,3,5-tribromo-4-(4-nitrophenoxy)benzene in quantitative yield. The crude product was used directly in the next step.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10]Cl)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1.O>[C:24]([O:23][C:21]([NH:20][C@@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:9]1[O:8][CH2:10]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](CCl)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
To a magnetically stirred solution of 2(S)-t-butyldimetylsilyloxy-3(R)-(t-butyloxycarbonyl)amino-1-chloro-4-phenylbutane (30.0 mg, 0.073 mmol) in THF (0.5 mL) was added a 1 M solution of TBAF in THF (0.11 mL, 0.109 mmol) at 0° C. After 10 min, stirring was continued at room temperature for 40 min. The reaction mixture was treated with sat NH4Cl (0.5 mL), diluted with water (2 mL), and extracted with EtOAc (3 mL×3). The combined organic layers were washed with brine (3 mL), dried over anhyd magnesium sulfate, filtered, and concentrated. The residue was dissolved with MeOH (0.5 mL) and treated with KOH at 0° C. Stirring was continued at room temperature for 2 h. Solvent was removed under reduced pressure, diluted with water (2 mL), and extracted with EtOAc (3 mL×3). The combined organic layers were washed with brine (3 mL), dried over anhydrous magnesium sulfate, filtered, concentrated and column-chromatographed (10% EtOAc in n-Hex) to provide 3(S)-(t-butyloxycarbonyl)amino-1,2(S)-epoxy-4-phenylbutane (14.4 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[CH:23][N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[CH:23][N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(Cl)cc5)cn4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2ccc(Cl)cc2)cn1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Ethyl 6-chloro-7-(4-(5-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (30 mg, 0.053 mmol) was diluted with THF (500 μL) followed by the addition of NaOH (266 μl, 0.27 mmol) and ethanol (200 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 0.5N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the desired compound (27 mg, 0.050 mmol, 95% yield). MS (ESI)=535.1 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]3([CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:9][N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[C:5]2=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F-].[Cs+].[CH2:42]([Sn](CCCC)(CCCC)C=C)[CH2:43]CC>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:42]([C:2]1[N:7]=[C:6]2[C:8]3([CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH2:9][N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[C:5]2=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH2:43]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2nc(Br)c(N3CCOCC3)cc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: C=Cc1nc2c(cc1N1CCOCC1)N(c1c(C)c(-c3ccccn3)nc3cc(F)ccc13)CC21CCOCC1
Temperature: 120 °C

Procedure:
To a stirred solution of 5′-bromo-1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (140 mg, 0.237 mmol) in 1,4-dioxane (4 mL) was added bis(tri-tert-butylphosphine)palladium (0) (12.12 mg, 0.024 mmol), cesium fluoride (36 mg, 0.237 mmol) and tri-n-butyl(vinyl)tin (90 μL, 0.285 mmol) and the reaction was heated at 120° C. for 3 h in the microwave. After this time the reaction was partitioned between EtOAc (50 mL) and water (15 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. The crude reaction was purified by column chromatography on silica gel (DCM to DCM:MeOH:—NH4OH (9:1:0.4), 1:0 to 2:1 as eluent) to give 5′-ethenyl-1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.66-8.80 (1H, m), 7.85-7.96 (3H, m), 7.73 (1H, dd, J=9.3, 6.0 Hz), 7.42 (1H, ddd, J=6.8, 4.8, 2.1 Hz), 7.23-7.30 (1H, m), 7.09 (1H, dd, J=17.2, 10.8 Hz), 6.30 (1H, dd, J=17.3, 2.6 Hz), 5.96 (1H, s), 5.18-5.36 (1H, m), 4.23-4.32 (2H, m), 3.93-4.03 (2H, m), 3.77 (4H, t, J=4.6 Hz), 3.61-3.69 (2H, m), 2.68-2.80 (4H, m), 2.27-2.47 (5H, m), 1.77-1.90 (2H, m). Mass Spectrum (ESI) m/e=538.2 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][Mg]Cl)=[CH:18][CH:17]=1>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:20][C:19]2[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(C[Mg]Cl)cc1
Reactant: CON(C)C(=O)c1ccc(I)cc1
Product: COc1ccc(CC(=O)c2ccc(I)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
4-Iodo-N-methoxy-N-methylbenzamide (3.4 g, 11.7 mmol) was added dropwise over 5 min (internal temperature kept below 5° C.) to a vigorously stirring solution of (4-methoxybenzyl)magnesium chloride (52 mL, 0.25M in 2-MeTHF, 13 mmol) at 0° C. under N2. After 10 min, a white precipitate was observed. After 5 hours of vigorous stirring at 0° C., the reaction was quenched with 1N HCl (50 mL). When the internal temperature returned to 0° C., the reaction was filtered, and the filter cake was washed with ethyl acetate (50 mL) (Note #1). The filter cake was dried under vacuum to give 2.7 g of 1-(4-iodophenyl)-2-(4-methoxyphenyl)ethanone as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.92 (d, 2H), 7.78 (d, 2H), 7.16 (d, 2H), 6.87 (d, 2H), 4.28 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[NH2:27][C:25](=[O:26])[CH2:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N+:13]([O-:36])=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]=23)=[CH:23][CH:22]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Solvent: ClC(Cl)Cl
Product: NC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)[n+]([O-])c3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
To a solution of 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide (0.070 g, 0.18 mmol) in chloroform (20 mL) at rt was added MCPBA (77%, 0.062 g, 0.28 mmol). The mixture stirred at rt for 16 h and then purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.017 g, 23%) as a white solid. MW=393.87. 1H NMR (DMSO-d6, 500 MHz) δ 9.52 (s, 1H), 7.76-7.73 (m, 1H), 7.64-7.60 (m, 1H), 7.59-7.52 (m, 2H), 7.47 (s, 1H), 7.36-7.26 (m, 4H), 6.88 (s, 1H), 6.83 (s, 1H), 3.38 (s, 2H), 3.19 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.25 (quin, J=7.5 Hz, 2H); APCI MS m/z 394 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Ba+2].[CH3:9][CH:10]1[CH:14]([C:15]([O:17][CH3:18])=[O:16])[C:13](=O)[CH:12]([CH3:20])[S:11]1>C(O)C>[OH:3][N:2]=[C:13]1[CH:12]([CH3:20])[S:11][CH:10]([CH3:9])[CH:14]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1C(=O)C(C)SC1C
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Product: COC(=O)C1C(=NO)C(C)SC1C

Procedure:
Hydroxylamine hydrochloride, 145 g (2.09 mol), and barium carbonate (J. T. Baker Chemical Company), 219.2 g (1.11 mol), are added to a solution of 89.3 g (0.474 mol) of tetrahydro-2,5-dimethyl-4-oxo-3-thiophenecarboxylic acid, methyl ester (Example C) in 1 L of absolute ethanol. The suspension is stirred and refluxed for sixteen hours, cooled, filtered through Supercell Hyflo® (Johns-Manville), the filtrate evaporated and the residue dissolved in 500 ml of diethyl ether. The diethyl ether solution is washed with 500 ml of water (2 times). The diethyl ether layer is separated, dried over anhydrous Na2SO4 and evaporated to give 83.7 g of tetrahydro-4-(hydroxyimino)-2,5-dimethyl-3-thiophenecarboxylic acid, methyl ester as an orange liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[C:5]([CH3:19])[N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>CC#N>[C:35]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)=[C:5]([CH3:19])[N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1c(Oc2ccc(Cl)cc2)c2c(N)cccc2n1CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1cccc2c1c(Oc1ccc(Cl)cc1)c(C)n2CC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of the product from example 3 step (iv) (70 mg) in MeCN (1 ml) was added triethylamine (50 μl) and acetyl chloride (17 μl) and the reaction stirred at 50° C. for 3 h. The residue was partitioned between diethylether/water, the organics were separated, washed with aq potassium hydrogensulfate solution, brine, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-30% ethylacetate/iso-hexane.
Reaction SMILES: FC1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])C=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6].[F:31][C:32]([F:47])([F:46])[C:33]1C=C(C=C(C(F)(F)F)[N:41]=1)C(O)=O>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:7]([CH3:8])[C:5](=[O:6])[C:4]2[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:41]=[C:33]([C:32]([F:47])([F:46])[F:31])[CH:3]=2)=[C:16]([O:22][CH3:23])[CH:17]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate) and 2,6-bis(trifluoromethyl) isonicotinic acid (Key Organics Ltd.) after a reaction time of 22 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (73%). MS (ESI): m/z=474.11 [M+H]+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([C@H:27]3[CH2:31][CH2:30][NH:29][CH2:28]3)[C:11]2=[O:32])[CH:7]=[CH:8][CH:9]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([C@H:27]3[CH2:31][CH2:30][N:29]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:28]3)[C:11]2=[O:32])[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n([C@H]3CCNC3)c12
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n([C@H]3CCN(S(C)(=O)=O)C3)c12

Procedure:
3-(3-Chloro-phenyl)-1-((S)-1-methanesulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (27 mg) was prepared according to general procedure H from (S)-3-(3-chloro-phenyl)-7-methoxy-1-pyrrolidin-3-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (42 mg, 0.1 mmol) and methanesulfonyl chloride. LCMS: m/z 501 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(O)=[O:2].Cl.[C:24]1([CH2:30][O:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:24]1([CH2:30][O:31][NH:32][C:1]([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[CH:8][CH:9]=2)=[O:2])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: NOCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NOCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
A mixture of 4-(4-carboxyphenyl)-1-piperazinecarboxylic acid, 1-(1,1-dimethylethyl) ester (0.032 mol), O-(phenylmethyl)-hydroxylamine hydrochloride (0.064 mol), DMAP (0.03 mol) in DCM p.a. (250 ml) and TEA (14 ml) was stirred at room temperature. DIC (0.064 mol) was added. The reaction mixture was stirred at room temperature for 8 hours, then washed with water, HCl (0.5N) and water. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/MeOH 98/2). The desired fractions were collected and the solvent was evaporated, yielding 13.7 g of 4-[4-[[(phenylmethoxy)amino]carbonyl]phenyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (interm. 4).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11][C:12]1[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:13]=1[NH:14][S:15]([CH3:18])(=[O:17])=[O:16]>CO>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11][C:12]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:13]=1[NH:14][S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Nc1ccc(C=O)cc1Sc1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CO)cc1Sc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
Sodium borohydride (0.11 g) was added portionwise to a solution of 2'-(2,4-difluorophenylthio)-4'-formylmethanesulfonanilide (1 g) in methanol (10 ml) at 10° C. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and water successively, dried, and concentrated to dryness. The residue was recrystallized from ethanol to give colorless crystals of 2'-(2,4-difluorophenylthio)-4'-(hydroxymethyl)methanesulfonanilide (0.74 g).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]=[O:22]>>[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][C@@H:21]([OH:22])[C@@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: COCCOCC=O
Product: COCCOC[C@@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with (2-methoxyethoxy)acetaldehyde. 13C-NMR (CDCl3, 100 MHz): δ 175.01, 151.02, 142.18, 127.91, 125.30, 124.77, 116.15, 109.76, 73.23, 71.86, 70.73, 70.64, 58.88, 41.63, 11.88.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([CH3:9])=[N:6][C:5]2=[C:10]([C:12]([OH:14])=O)[CH:11]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Cl:46][C:47]1[C:48]([CH3:54])=[C:49]([CH:51]=[CH:52][CH:53]=1)[NH2:50]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([CH3:9])=[N:6][C:5]2=[C:10]([C:12]([NH:50][C:49]2[CH:51]=[CH:52][CH:53]=[C:47]([Cl:46])[C:48]=2[CH3:54])=[O:14])[CH:11]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: Cc1nc2c(C(=O)O)cc(Br)cc2o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(Br)cc2o1
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-2-methyl-1,3-benzoxazole-4-carboxylic acid (136 mg) in DMF (2 mL), were added HBTU (242 mg) and triethylamine (110 μL). To the mixture was added 3-chloro-2-methylaniline (76 μL) and it was stirred at room temperature over night. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on silica gel column chromatography to obtain the titled compound (53 mg) as white powder.
Reaction SMILES: O[C:2]1C=CC(C=O)=C[C:3]=1OC.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]>>[CH2:2]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])[CH3:3]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: COc1cc(C=O)ccc1O
Product: CCOc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
This example was according to Example 1, except that 4-hydroxy-3-methoxybenzaldehyde was replaced by 68.5 g 4-hydroxy-3-nitro-benzaldehyde (0.41 mol) to obtain 68.7 g 4-ethoxy-3-nitrobenzaldehyde in a yield of 86%. 1H-NMR (ppm) δ: 9.96 (1H, s; —CHO); 7.73 (1H, m; 2-ArH); 7.58 (1H, m; 6-ArH); 7.33 (1H, m; 5-ArH); 4.15 (2H, q; —CH2); 3.82 (3H, s; —OCH3); 1.53 (3H, t; —CH3). MS (m/Z): 195 (M+).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[CH:6]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:11][CH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[CH:6]=1
Reactant: Cc1cc(C(F)(F)F)co1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1coc(CBr)c1
Yield: 60.1 %

Procedure:
6 g of the product of Stage D were refluxed for 1 and a half hours in 50 ml of carbon tetrachloride in the presence of 7.2 g of N-bromosuccinimide and 0.3 g of azobisisobutyronitrile and the mixture was allowed to return to room temperature and was filtered. The solvent was evaporated and the residue was chromatographed on silica (eluent: 98/2 ether/isopropyl ether) to obtain 5.5 g of the expected product.