Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[ClH:25]>CN(C)P(N(C)C)(N(C)C)=O.CO.CCOCC>[ClH:25].[C:18]1([CH2:17][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[OH:11])[CH2:4][CH2:3][CH2:2]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc2c1NCCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Oc1cccc2c1N(Cc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2.00 g (13.4 mmol) of 1,2,3,4-tetrahydro-8-quinolinol (see Example 7A), 1.69 g (20.0 mmol, 1.5 eq.) of finely powdered sodium bicarbonate and 1.75 ml (14.7 mmol, 1.1 eq.) of benzyl bromide in 40 ml of hexamethylphosphoramide was stirred for 24 hours at room temperature under argon. The following work-up was carried out under conditions of minimum air exposure. Solvents and solutions were bubbled with nitrogen prior to use. The reaction mixture was diluted with 300 ml of 1:1 ether:petroleum ether and washed with five 100 ml portions of water and 100 ml of brine, dried over sodium sulfate and evaporated to obtain a tan solid. The solid was immediately dissolved in 10 ml of methanol, treated with 10 ml of hydrogen chloride-saturated methanol and diluted with 200 ml of ether. The precipitate was filtered, washed with ether, and dried under vacuum for 20 hours to afford 3.19 g of the title compound as an ivory solid; melting point 192°-194° C. (decomposition from 175° C.). 1H NMR indicated that this material contained 0.16 equivalents of methanol.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[N:5]1[CH:9]=[CH:8][N:7]2[CH2:10][CH2:11][C:12](=[O:13])[C:6]=12>C1COCC1>[C:1]([C:12]1([OH:13])[C:6]2=[N:5][CH:9]=[CH:8][N:7]2[CH2:10][CH2:11]1)#[CH:2]
Reactant: O=C1CCn2ccnc21
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC1(O)CCn2ccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethynylmagnesium bromide (0.5M in THF, 14.6 mL, 7.3 mmol) at 0° C. was added 5H,6H-pyrrolo[1,2-a]imidazol-7-one (900 mg, 4.86 mmol) in THF (10 mL) slowly. The reaction mixture was allowed to warm to RT and stirred for 1 hr. The reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL) and the organics were removed in vacuo. The product was extracted into EtOAc (10 mL×2) and the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (Biotage), eluting with 3-10% methanol in DCM afforded the title product; 1H NMR (500 MHz, CDCl3) delta 2.55 (1H, s), 2.96 (1H, ddd, J=13.24, 7.57, 4.26 Hz), 3.03-3.12 (1H, m), 3.16-3.22 (1H, m), 4.01 (1H, ddd, J=10.56, 8.12, 4.33 Hz), 4.15 (1H, ddd, J=10.52, 7.29, 6.62 Hz), 6.84 (1H, d, J=1.10 Hz), 7.11 (1H, d, J=0.79 Hz); LC-MS: m/z=+136.9 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[CH:9][C:8]2=[O:22])([O:3]C)=[O:2].[O:23]1[CH:25]([CH2:26][CH3:27])[CH2:24]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:24][CH:25]([OH:23])[CH2:26][CH3:27])=[CH:9][C:8]2=[O:22])([OH:3])=[O:2]
Reactant: COC(=O)c1ccc2oc(-c3ccccc3O)cc(=O)c2c1
Reactant: CCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(O)COc1ccccc1-c1cc(=O)c2cc(C(=O)O)ccc2o1
Yield: 39.3 %

Procedure:
A mixture consisting of 6-carbomethoxy-2'-hydroxy-flavone (10 g), obtained according to the method described in Example 2, and 1,2-epoxy-butane (6 g) and benzyl-trimethylammonium hydroxide (0.5 ml) in dioxane (40 ml) was kept at reflux temperature for 48 hours. After cooling, dilution with water, and extraction with ethylacetate, the organic phase was washed with potassium carbonate 5% and water. The solution was evaporated to dryness, and the resulting product was treated with the stoichiometric quantity of a solution of potassium hydroxide 1% in ethanol 95% at reflux temperature for an hour. After acidification with acetic acid, concentration under vacuum, dilution with water, filtration and double crystallisation from ethanol, 6-carboxy-2'-(2-hydroxy-butoxy)-flavone (4.7 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:23][CH3:24])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][O:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[O:9]2)=[CH:4][C:3]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[C:27]=1[F:35].[H-].[Na+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH2:38]([O:16][C@H:11]1[C@H:12]([O:15][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([O:14][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C@@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[C:27]=3[F:35])[CH:4]=2)([O:23][CH3:24])[O:9][C@@H:10]1[CH2:17][O:18][Si:19]([CH3:21])([CH3:22])[CH3:20])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 210.4 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-methoxy-6-(trimethylsilyloxymethyl)tetrahydropyran-3,4,5-triol 2h (1.63 g, 2.84 mmol) was dissolved in 30 mL DMF and cooled to 0° C., followed by addition of 60% NaH (570 mg, 14.2 mmol). Then the reaction mixture was warmed to room temperature and stirred for 45 minutes. Thereafter, benzyl bromide (1.7 mL, 14.2 mmol) was added before the reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure after 5 mL methanol were added. After 150 mL ethyl acetate and 50 mL water were added into the residue, the resulting residue was partitioned and the organic extract was washed with water (50 mL), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]trimethyl-silane 21 (2.4 g, yellow grease), with yield: 100%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH3:12]OC(OC)N(C)C.N1CCCC1.O>CN(C=O)C.[Zn].C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:12][NH:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCNC1
Solvent: O
Product: Brc1ccc2cc[nH]c2c1
Temperature: 110 °C
Yield: 39.1 %

Procedure:
To a mixture solution of 4-bromo-2-nitrotoluene (2.00 g, 9.26 mmol) and dimethylformamide-dimethylacetal (3.68 mL, 27.8 mmol) in DMF (20 mL), pyrrolidine (1.16 mL, 13.9 mmol) was added at room temperature. After stirring at 110° C. for an hour, the mixture was cooled to room temperature and then water was added. After extracting 3 times with ether, the collected organic layer was dried with anhydrous magnesium sulfate and the concentrated. The resulting residue was subjected to the next reaction without purification. After adding 80% acetic acid aqueous solution (60 mL), the mixture was heated to 85° C. While adding zinc powder (5.27 g, 80.6 mmol) in small amounts, the mixture was stirred at 85° C. for 2 hours. After cooling to room temperature and filtering, followed by addition of water, the filtrate was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (silica gel, EA:Hx=1:20). The target compound (710 mg) was obtained as violet solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1)[CH3:2].[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[CH2:1]([NH:3][C:4]1[C:9]([CH:10]=[CH:24][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][N:7]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1)[CH3:2]
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCNc1nc(Nc2ccccc2)ncc1C=CC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a room temperature solution of 4-ethylamino-2-phenylamino-pyrimidine-5-carboxaldehyde (320 mg, 1.32 mmol) in 12 mL of tetrahydrofuran was added (carbethoxymethylene)triphenylphosphorane (720 mg, 2.07 mmol). The reaction mixture was heated at reflux for 7 hours then stirred at room temperature overnight. An additional amount of (carbethoxymethylene)triphenylphosphorane (300 mg, 0.86 mmol) was added, and the reaction mixture was heated at reflux for an additional 8 hours then stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography, eluting with 1:2 ethyl acetate:hexane, to provide 357 mg (86%) of ethyl 3-(4-ethylamino-2-phenylamino-pyrimidin-5-yl)acrylate, mp 125-126° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C@@H:19]([OH:21])[CH3:20])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:24][N:25]1[C:29]([CH3:30])=[C:28]([C:31](O)=[O:32])[C:27](=[O:34])[N:26]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[OH:21][C@@H:19]([CH3:20])[CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31]([C:28]4[C:27](=[O:34])[N:26]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:25]([CH3:24])[C:29]=4[CH3:30])=[O:32])=[CH:23][CH:22]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][CH:14]=1
Reactant: C[C@H](O)COc1ccc2c(Oc3ccc(N)cc3)ccnc2c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC[C@H](C)O)ccc34)cc2)c(=O)n(-c2ccccc2)n1C
Yield: 33 %

Procedure:
The title compound was prepared according to the procedure described in Example 11 by using (S)-1-((4-(4-aminophenoxy)quinolin-7-yl)oxy)propan-2-ol (3.24 g, 10.5 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.55 g, 11.0 mmol), EDCI (2.4 g, 12.5 mmol) and HOAT (0.28 g, 2.1 mmol) in DCM (21 mL). The crude product was purified by a column chromatography on silica gel (EtOAc) to afford the title compound as a yellow solid (1.82 g, 33.2%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].[NH2:16]C(N)=O>O>[NH2:16][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Reactant: NC(N)=O
Solvent: O
Product: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Temperature: 150 °C
Yield: 92.5 %

Procedure:
A mixture of 5-chloro-6-nitroisoindoline-1,3-dione (28.0 g, 0.123 mol) and urea (73.8 g, 1.23 mol) was stirred and heated to 150° C. under argon for 6 h. After cooled to rt, the solid was suspended in hot water (100 mL, 80° C.), filtered, washed with hot water (3×50 mL) and dried under vacuum to give a yellow solid product, 23.56 g, 92.5% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:2]1([NH:1][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=S(=O)(Nc1ccccc1)c1ccccc1
Yield: 68 %

Procedure:
The title compound was synthesized by triturating aniline (0.5 g, 5.36 mmol), powdered sodium bicarbonate (0.9 g, 1.07 mmol) and benzene sulfonyl chloride (0.95 g, 5.36 mmol) for 10 min at rt. Then reaction mixture was stirred with water at 60° C. for 30 minutes, filtered, washed with water and dried to gave 17 (0.85 g, 68%). Product was purified by FCC by using eluent as in 15 to give 17 as white flakes (0.79 g), mp: 107-109° C. (lit33A 110° C.); IR (CHCl3) 3256, 1599, 1331, 1162, cm−1; 1H NMR (500 MHz, DMSOD6) δ 6.4 (br, 1H, NH), and 7.04-7.77 (m, 10H, aromatic). HRMS calcd 256.04027 (C12H11NO2S.Na+), found 256.04016.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[N:12]([C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1CCCC(=O)O1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=O)CCCC(=O)O)OCO3

Procedure:
By using the product of Example 26 as starting material and performing the acylation according to Example 14 with glutaric acid anhydride, finally recrystallizing the raw product from ethanol the pure aimed product was obtained, m.p.: 148°-150° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33]O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[C:5]([N+:16]([O-:18])=[O:17])=[C:6]([O:8][CH2:33][CH2:32][CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: OCCCCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Nc1nc(OCCCCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, 4-phenyl-1-butanol and DBU in DME. ES-MS ni/e (%): 355 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:21][C:20]([F:23])([F:22])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][C:27]=2[C:32]([F:35])([F:33])[F:34])[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:19][C:20]([F:22])([F:23])[CH2:21]1)=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CC(F)(F)C1
Reactant: Fc1ccc(S)c(C(F)(F)F)c1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(F)cc2C(F)(F)F)C[C@H]1C(=O)N1CC(F)(F)C1

Procedure:
The title compound was prepared in analogy to Example 68/69, step 8, using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (Example 117, step 3) and 4-fluoro-2-trifluoromethyl-benzenethiol (Intermediate 2). Light yellow oil. MS (EI): 456.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2C=C(C(O)C)[O:10][N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C=C(C(=O)C)ON=2)=CC=1.FC1C=CC(C=O)=CC=1.Cl.NO>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[N:9][OH:10])=[CH:4][CH:3]=1
Reactant: CC(O)c1cc(-c2ccc(F)cc2)no1
Agent: CC(=O)c1cc(-c2ccc(F)cc2)no1
Agent: Cl
Agent: NO
Product: ON=Cc1ccc(F)cc1

Procedure:
In a further embodiment, 1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanol and 1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanone are prepared according to the methodology and reagents of Scheme 12B. 4-Fluoro-benzaldehyde is reacted with hydroxylamine hydrochloride to provide 4-fluorobenzaldehyde oxime. In one embodiment, the reaction is performed in methanol and sodium carbonate. In another embodiment, the reaction is performed at about room temperature for about 4 hours. The isoxazole ring is then generated by reacting this intermediate with 3-hydroxy-butyne and NCS (about 1.2 equivalents) to provide 1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanol. In one embodiment, this cyclization is performed in dichloromethane at about 40° C. 1-(3-(4-Fluorophenyl)isoxazol-5-yl)ethanol is then oxidized to 14344-fluorophenyl)-isoxazol-5-yl)ethanone using Dess-Martin periodinane. In one embodiment, the reaction is performed in dichloromethane. In another embodiment, the reaction is performed at room temperature for about 16 hours.
Reaction SMILES: C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1P(C(C)(C)C)C(C)(C)C.Br[C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34]([N+:39]([O-:41])=[O:40])=[CH:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:48]([O:52][C:53]([N:55]1[CH2:59][CH2:58][CH2:57][C@H:56]1[CH2:60][OH:61])=[O:54])([CH3:51])([CH3:50])[CH3:49]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:48]([O:52][C:53]([N:55]1[CH2:59][CH2:58][CH2:57][C@H:56]1[CH2:60][O:61][C:31]1[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([O:37][CH3:38])[N:36]=1)=[O:54])([CH3:51])([CH3:50])[CH3:49]
Reactant: COc1nc(Br)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: COc1nc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.3 %

Procedure:
To a mixture of Pd(OAc)2 (0.08 g, 0.34 mmol) and [1,1′]binaphthalen-2-yl-di-tert-butyl-phosphane (0.14 g, 0.34 mmol) in toluene (10 ml) was added 6-bromo-2-methoxy-3-nitropyridine(1.0 g, 4.29 mmol), Cs2CO3 (3.5 g, 10.73 mmol), and (S)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.73 g, 8.58 mmol). The mixture was stirred under nitrogen at room temperature for 24 h. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel chromatography with dichloromethane/ethyl acetate/methanol (10:0:0; 9:0.5:0.5; 7:1.5:1.5; 0:5:5) as eluent to provide 0.11 g (7.5%) of the product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Hg](C#N)C#N.[C:16]([O:19][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:23][S:22][C@@H:21]1Br)(=[O:18])[CH3:17]>>[C:16]([O:19][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:23][S:22][C@H:21]1[S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc([N+](=O)[O-])cc2)SC[C@H]1OC(C)=O
Yield: 66 %

Procedure:
If the procedure described in Preparation I is followed starting from 6 g (38.10-3 mol) of 4-nitrobenzenethiol, 10.7 g (42.10-3 mol) of mercuric cyanide, Hg(CN)2, and 15.1 g (42.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 10.8 g (yield: 66%) of the expected product are obtained.
Reaction SMILES: [CH3:1]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI.[C:14]([O:18][C:19]([NH:21][C:22]1[C:23]([F:48])=[CH:24][C:25]([F:47])=[C:26]([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:40])=[C:35]([F:39])[C:36]=3[CH3:38])[C:31](=[O:41])[C:30]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:29]2)[CH:27]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O.C(OCC)(=O)C>[C:14]([O:18][C:19]([N:21]([C:22]1[C:23]([F:48])=[CH:24][C:25]([F:47])=[C:26]([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:40])=[C:35]([F:39])[C:36]=3[CH3:38])[C:31](=[O:41])[C:30]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:29]2)[CH:27]=1)[CH3:1])=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(C)c(F)c(F)cc2c1=O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2cc(N(C)C(=O)OC(C)(C)C)c(F)cc2F)c2c(C)c(F)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (4 ml), potassium carbonate (0.6 g) and methyl iodide (0.6 g) were added to ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.0 g), and the mixture was stirred overnight at 60° C. Ethyl acetate and water were added to the reaction mixture to collect an organic layer. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. Ethanol was added to the residue, and solids deposited were collected to obtain the title compound (410 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCO.[ClH:30]>[Fe].O>[ClH:30].[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([S:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=3)=[CH:14][CH:13]=2)=[O:26])=[CH:18][CH:19]=1
Reactant: Nc1cc(Sc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc2)ccn1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)Nc2ccc(Sc3ccnc(N)c3)cc2)cc1
Reaction time: 8 h
Yield: 93 %

Procedure:
Nitro compound 10 (0.83 g, 2.07 mmol) was suspended in 2:1 EtOH:H2O (100 mL) and the resulting suspension brought to reflux. To this mixture was sequentially added Fe dust (0.54 g, 9.59 mmol) and c.HCl (2 mL), and the resulting dark orange suspension was refluxed for 1 h. After this time, the resulting yellow suspension was filtered hot through a pad of Celite, and the solvent removed under reduced pressure. The residue was re-suspended on H2O, to which was added a quantity of Celite, and the resulting suspension was stirred overnight. After this time, the suspension was filtered through a pad of Celite, and solvent was removed under reduced pressure to afford crude amine 11 as an amorphous off-white solid (0.65 g, 93%), which was used without further purification. 1H NMR [(CD3)2SO]: δ 9.98 (s, 1H, ArC(O)NHAr), 7.91 (ddd, J=9.40, 4.48, 2.58 Hz, 2H, ArH), 7.72 (m, 3H, ArH), 7.48 (ddd, J=9.37, 4.39, 2.55 Hz, 2H, ArH), 6.61 (d, J=7.85 Hz, 2H, ArH), 6.18 (dd, J=5.46, 1.68 Hz, 1H, ArH), 5.82 (d, J=1.36 Hz, 1H, ArH), 6.01 (br s, 2H, ArNH2), 5.82 (br s, 2H, ArNH2); HRMS: Calc. for C18H17N4OS (MH+) m/z 337.1123, found 337.1126.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:21])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[NH:18][C:17](=[O:20])[CH2:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9](=[O:21])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[N:18]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:17](=[O:20])[CH2:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C1Cc2cccc(CC(=O)OCc3ccccc3)c2N1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2C(=O)Cc3cccc(CC(=O)OCc4ccccc4)c32)cc1
Temperature: 70 °C

Procedure:
A solution of 28.1 g (0.1 mole) 2,3-dihydro-2-oxo-1H-indole-7-acetic acid phenylmethyl ester in 400 ml of toluene is treated with 17.1 g (0.1 mole) of 4-methoxybenzoyl chloride. The mixture is heated at 70° C. with stirring and a solution of 10.2 g (0.1 mole) of triethylamine in 100 ml of toluene is added dropwise.