Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5](=[O:14])[CH:4]=1.[H][H]>C(OC(=O)C)(=O)C.[Pd]>[CH3:1][N:2]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:6](=[O:13])[CH3:7])=[C:5]([O:14][C:5](=[O:14])[CH3:4])[CH:4]=1
Reactant: [H][H]
Reactant: CN(C1=CC(=O)C(=O)c2ccccc21)C1CCCCC1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc(N(C)C2CCCCC2)c2ccccc2c1OC(C)=O

Procedure:
A suspension of 3.5 g of 4-(N-methylcyclohexylamino)-1,2-naphthoquinone in 50 ml of acetic anhydride is hydrogenated at 45 lbs pressure and room temperature using 1.2 g of 10% palladium on carbon as catalyst. After uptake of hydrogen ceases and the red color of the solution is discharged (5 hours) the catalyst is removed by filtration. The acetic anhydride is evaporated under reduced pressure at 60° C. and the residue is taken up in toluene, treated with charcoal and filtered. The toluene solution is evaporated under reduced pressure and the product crystallized from 1:1 hexane-diethyl ether (100 ml) to afford 4-(N-methylcyclohexylamino)-1,2-diacetoxynaphthalene, the compound of formula II wherein NR1R2 represents N-methylcyclohexylamino, R3 represents hydrogen, and R4 and R5 represent acetyl, m.p. 103°-105° C.; hydrochloride salt, m.p. 165°-167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]([N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)=[O:23])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)O)cc2)=C(C)C1=O
Reactant: C1CSCCN1
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCCC(=O)N3CCSCC3)cc2)=C(C)C1=O
Yield: 24.3 %

Procedure:
4-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (50 mg, 0.14 mmol) obtained in Example 26 and thiomorpholine (0.016 ml, 0.15 mmol) were used, a method similar to that described in Example 24 was employed to obtain the title compound (15 mg, 0.034 mmol, yield 24%).
Reaction SMILES: COC1C=CC(C[N:8]([C@@H:12]([C@H:27]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:28]2[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[CH2:13][CH2:14][C:15](=O)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)C(=O)[O-])=CC=1.FC(F)(F)C(O)=O>ClCCl>[Si:36]([O:35][C@@H:27]([C@H:12]1[CH2:13][CH2:14][C:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:8]1)[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[N:30][CH:29]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38]
Reactant: COc1ccc(CN(C(=O)[O-])[C@H](CCC(=O)Cc2ccc([N+](=O)[O-])cc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)O[C@H](c1ccc(Cl)nc1)[C@H]1CCC(Cc2ccc([N+](=O)[O-])cc2)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a stirred solution of 18 g (28 mmol) of 4-methoxybenzyl[(1R)-1-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(6-chloropyridin-3-yl)methyl]-5-(4-nitrophenyl)-4-oxopentyl]carbamate from Step B in 75 mL of anhydrous dichloromethane was added 75 ml of trifluoroacetic acid. The resulting mixture was stirred at ambient temperature for 2 h during which time the reaction became dark red in color. All volatiles were removed in vacuo and the residue dissolved in 300 mL of dichloromethane. The solution was washed with a saturated aqueous sodium bicarbonate solution (2×100 mL), brine (100 ml) and then dried over magnesium sulfate and filtered. All volatiles were evaporated in vacuo to afford the title compound as a dark red gum (13 g, >99%) that was used immediately without further purification. LC-MS: m/z (ES) 460.4 (MH)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](Cl)=[O:48])=[CH:42][CH:41]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:32]([O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:21][C:18]2[C:17]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:10][CH:11]=3)=[CH:20][N:19]=2)=[O:48])=[CH:44][CH:45]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cccc4ccccc34)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cccc3ccccc23)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 55.9 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(naphthalen-1-yl)pyrazin-2-amine (7d) (500 mg, 1.17 mmol) and 4-(dimethylamino)pyridine (15.3 mg, 125 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) at 0° C. and the mixture was heated with stirring at 50° C. for 16 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11d (442 mg, 653 μmol, 55.9%) as a yellow foamy solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.13 (s, 6H), 0.19 (s, 6H), 0.91 (s, 9H), 0.92 (s, 9H), 3.24 (s, 2H), 6.54-6.60 (AA′BB′, 2H), 6.65-6.72 (AA′BB′, 2H), 6.91-6.98 (AA′BB′, 2H), 7.36-7.54 (m, 4H), 7.61-7.69 (m, 1H), 7.87-8.08 (m, 4H, includes AA′BB′), 9.09 (s, 1H), 10.27 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.90, 17.94, 25.48 (3C), 25.55 (3C), 119.4 (2C), 120.4 (2C), 125.0, 125.4, 125.7, 126.2, 126.8, 128.0, 128.15, 128.21 (2C), 128.6, 128.9 (2C), 129.9, 130.7, 133.4, 134.8, 138.2, 144.4, 147.9, 148.3, 153.5, 156.7, 169.3 (one carbon at the benzyl position was unobservable due to overlapping with the septet peak of DMSO); IR (KBr, cm−1) 492, 538, 675, 718, 779, 806, 839, 914, 1007, 1080, 1115, 1169, 1260, 1362, 1420, 1441, 1472, 1510, 1605, 1670, 2857, 2886, 2930, 2955, 3046, 3223; HRMS (ESI+) m/z 698.3205 ([M+Na]+, C40H49N3NaO3Si2+ requires 698.3205).
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([CH3:35])[C:32]([NH2:34])=[O:33])=[N:6][C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[N:8][CH:9]=1.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Cl:3][C:4]1[C:5]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([CH3:35])[C:32]([NH2:34])=[O:33])=[N:6][C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:36])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[N:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)nc2)ncc1Cl
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C)CC3)nc2)ncc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.5 %

Procedure:
Formaldehyde (31.2 μL, 0.419 mmol, 37 wt % in H2O) was added to a suspension of 2-(2-(2-(5-chloro-2-((6-(piperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)propanamide 37 (39.0 mg, 0.084 mmol) in MeOH (2.0 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (178 mg, 0.839 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 2.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (10 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (20 mL) and brine (15 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting solid was suspended in DCM (20 mL) and cyclohexane (30 mL). The solid was filtered to give the title compound 38 (34 mg, 84%). LCMS-C: rt 4.19 min; m/z 479.2 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:23]([OH:25])=[O:24])=[C:5]([C:7]2[C:17]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:16]=3[O:15][C:14]3[C:8]=2[CH:9]=[CH:10][C:11]([CH:13]=3)=[O:12])[CH:6]=1.S(=O)(=O)(O)O.[C:31](=O)(O)[O-].[Na+]>CO>[CH3:31][O:24][C:23]([C:4]1[C:5]([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([OH:12])=[CH:13][C:14]=3[O:15][C:16]3[C:17]=2[CH:18]=[CH:19][C:20]([CH:21]=3)=[O:22])=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:25]
Reactant: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 120 °C
Yield: 88.2 %

Procedure:
Fluorescein (10 g; 30 mmol) was dispersed in methanol (30 mL) and concentrated sulfuric acid was added slowly. After the addition was complete the mixture was stirred with heating at 120° C. for 14 hours. After cooling the mixture, sodium bicarbonate was added to neutralize the mixture to give a solid. The crude product was filtered and washed with 2% sodium bicarbonate (200 mL), with water (4×) and with 1% acetic acid to give the fluorescein methyl ester (9.2 g, 26.4 mmol, 88.2% yield), m.p. 260-261° C. Step 8B. The fluorescein methyl ester (8 g, 23.1 mmol) and potassium carbonate (9.6 g, 69.3 mmol) were dissolved in dimethylformamide (50 mL) at 90° C. and to the solution was added toluenesulfonyl chloride (6.6 g, 34.7 mmol) slowly for 30 minutes. The mixture was then further stirred with heating at 110° C. for 5 hours. The mixture, after being cooled to room temperature, was poured into water (1L) to give a precipitate which was collected by filtration and washed with water to give the product(10 g, 20 mmol, 86.5% yield). Step 8c. The toluenesulfonyl fluorescein ester (2 g, 4 mmol) and indoline (1.4 g, 12 mmol) were dissolved in N-methylpyrollidinone (100 mL) and the solution was stirred with heating at 95° C. for 17 hours. After being cooled to room temperature the mixture was poured into water (600 mL) to form a precipitate. The precipitate was filtered, washed with water and dried to give the ester (1.7 g, 3.9 mmol, 96.8% yield). The desired dye was obtained by basic hydrolysis of the ester using the following method: the dye and aqueous sodium hydroxide (3 eq.) were dissolved in methanol and stirred with heating at 60° C. for 1 hour until TLC showed complete conversion. The crude product was purified by column chromatography (5% methanol in methylene chloride) to give the desired product. (1.35 g, 3.1 mmol, 78% yield) The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [CH2:1](Br)[CH2:2][OH:3].[K].[CH3:6][S:7][C:8]1[C:13]([F:14])=[CH:12][NH:11][C:10](=[O:15])[N:9]=1>CN(C)C=O>[OH:3][CH2:2][CH2:1][N:11]1[CH:12]=[C:13]([F:14])[C:8]([S:7][CH3:6])=[N:9][C:10]1=[O:15]
Reactant: CSc1nc(=O)[nH]cc1F
Reactant: OCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CSc1nc(=O)n(CCO)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
Ethylene bromohydrin (0.023 mol) was added to a solution of the potassium salt of 4-methylthio-5-fluoropyrimid-2-one (0.015 mol) in dimethylformamide (65 ml) and the reaction mixture was stirred at room temperature for 24 h before evaporation at reduced pressure (1 mm Hg). The residue was extracted with chloroform, the solution was washed with aqueous 2 N NaOH, with water and was dried (MgSO4) before evaporation. The solid residue was recrystallized from acetone; yield 77%, m.p. 161°-162° C. (Found: C, 41.36; H, 4.62. Calc. for C7H9FN2O2S: C, 41.17; H, 4.44).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C:14]([O:16]CC)=[O:15].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)CC(Cc1cccc(OC)c1OC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(CC(CC(=O)O)c2ccccc2)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
Ethyl 4-(2',3'-dimethoxyphenyl)-3-phenylbutyrate (40.3 g, 123 mmol), from Step 3, was dissolved in 400 mL of methanol and 62 mL of 3M aqueous sodium hydroxide solution was added in one portion. The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated and the residue was partitioned between 300 mL of diethyl ether and 200 mL of water. The layers were separated and the aqueous layer was adjusted to pH 6 with 6M aqueous hydrochloric acid solution and extracted with 3×200 mL of diethyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, faltered and concentrated in vacuo to give 37 g (100% yield) of the title compound as a colorless oil. The 1H NMR spectrum was identical to the spectrum reported for the product of Step 5 of Method A, Example 1.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[F:10][C:11]1[C:19]([F:20])=[C:18]([F:21])[C:17]([N+:6]([O-:9])=[O:7])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Temperature: 0 °C
Yield: 92 %

Procedure:
A 3 liter three neck round bottom flask is charged with 125 mL H2SO4. Fuming nitric acid is added (8.4 mL, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1 (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 minutes at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice water mixture and extracted with diethyl ether (3×600 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 minutes after which time it is filtered to give 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (−) m/z 220 (M−1) detected.
Reaction SMILES: [I-].[CH:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[O:16]CC(C)(C)[N+]=1C)([CH3:4])[CH3:3].[OH-:23].[Na+].Cl>CO>[CH:2]([C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[C:15]([OH:16])=[O:23])([CH3:3])[CH3:4]
Reactant: [OH-]
Reactant: CC(C)c1cc(C(F)(F)F)ccc1C1=[N+](C)C(C)(C)CO1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 75 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a solution of 2-(2-isopropyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-ium iodide (step 2) (1.26 g, 2.949 mmol) in 12 ml methanol were added 5N NaOH solution (11.8 ml, 58.98 mmol). The mixture was stirred in a 75° C. oil bath for 3 hours. The solution was cooled in an ice bath and acidified to pH 1 with a 5N HCl solution. The methanol was removed in vacuo. The suspension was stirred in an ice bath. The solid was filtered, washed with water and dried in vacuo to provide 618 mg (90%) of the title compound as a white solid. MS (m/e): 231.1 (M−H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[Li][CH2:11][CH2:12][CH2:13][CH3:14].O>CCOCC>[Br:9][C:4]1[CH:3]=[C:2]([C:12]2[CH2:13][C:14]3[C:6]([CH:11]=2)=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH:7]=[C:6]([Br:8])[CH:5]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Brc1cc(Br)cc(C2=Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 12.6 g (40.0 mmol) of 1,3,5-tribromobenzene in 400 ml of ether, 160 ml (40.0 mmol) of 0.25 M nBuLi in hexanes was added for 1 h at −80° C. The mixture was stirred for 1.5 h at this temperature, and then a solution of 5.29 g (40.0 mmol) of indanone-2 in 200 ml of ether was added dropwise over 1 hour while vigorously stirring. The reaction mixture was allowed to warm to room temperature and it was stirred at this temperature for 24 h. Then, 100 ml of water was added. The organic layer was separated; the aqueous layer was extracted with 3×50 ml of dichloromethane. The combined organic layers were dried over Na2SO4 and then evaporated to dryness. The residue was dissolved in 250 ml of toluene, and 0.75 g of p-TosOH was added. The resulting solution was refluxed for 1 hours using a Dean-Stark trap to remove the water formed. Next, the mixture was evaporated to dryness, and the product was isolated by flash-chromatography on Silica Gel 60 (d 50 mm, 1 400 mm, eluent: hexanes). Yield 8.54 g (61%) of white powder.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH3:14][C:15]1[N:20]=[C:19]([SH:21])[N:18]=[C:17]([OH:22])[CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[ClH:2].[CH3:14][C:15]1[N:20]=[C:19]([S:21][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[N:18]=[C:17]([OH:22])[CH:16]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2ccc3ccccc3n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A mixture of 2-(chloromethyl)quinoline hydrochloride (1.0 g, 4.67 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (0.46 g, 3.26 mmol) and K2CO3 (1.28 g, 9.34 mmol) in DMF (25 mL) was stirred overnight at room temperature. The solvent was filtered and evaporated to provide the crude product. Water was added to the crude reaction mixture to precipitate the product, which was then filtered and washed with water and ether to provide the titled product as a beige solid (0.68 g, 52% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.09 (s, 3H), 2.31 (s, 3H), 4.95 (s, 2H), 6.04 (bs, 1H), 7.87 (t, J=7.8, 15.0 Hz, 1H), 8.08 (m, 2H), 8.26 (d, J=8.1 Hz, 1H), 8.48 (d, J=8.2 Hz, 1H), 9.00 (d, J=8.2 Hz, 1H); M+283.3.
Reaction SMILES: [F:1][CH:2]([F:18])[S:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)=O.FC1C=C2C(C(=O)C(SCF)=CN2C)=CC=1>>[F:18][CH:2]([F:1])[S:3][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1
Reactant: Cn1cc(S(=O)C(F)F)c(=O)c2ccc(F)cc21
Agent: Cn1cc(SCF)c(=O)c2ccc(F)cc21
Product: Cn1cc(SC(F)F)c(=O)c2ccc(F)cc21

Procedure:
In one embodiment, the present invention contemplates methods of synthesis of difluoroflosequinan (3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone). In one embodiment, a second fluorine atom is introduced onto a side chain of 7-fluoro-3-fluoromethylthio-1-methyl-4-quinolone, to produce 3-difluoromethylthio-7-fluoro-1-methyl-4-quinolone, which is subsequently oxidized to produce 3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. In one embodiment, the method comprises: a) providing (i) 7-fluoro-3-fluoromethylthio-1-methyl-4-quinolone, (ii) SELECTFLUOR and (iii) triethylamine and b) reacting said 7-fluoro-3-fluoromethylthio-1-methyl-4-quinolone, SELECTFLUOR and triethylamine in a solvent under conditions such that 3-difluoromethylthio-7-fluoro-1-methyl-4-quinolone is produced and c) further reacting said 3-difluoromethylthio-7-fluoro-1-methyl-4-quinolone with m-chloroperbenzoic acid (MCPBA) in a solvent under conditions such that 3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is produced. In some embodiments, the solvent in step b) is acetronitrile. In some embodiments, the solvent in step c) is dichloromethane (DCM)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([S:19]([N:22](CC1C=CC(OC)=CC=1OC)[C:23]1[S:27][N:26]=[CH:25][N:24]=1)(=[O:21])=[O:20])=[CH:14]2.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:53]2[CH:54]=[N:55][N:56](C(OC(C)(C)C)=O)[CH:57]=2)O1.Cl.C(Cl)Cl.C(O)(C(F)(F)F)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([S:19]([NH:22][C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:20])=[O:21])=[CH:14]3)=[C:2]([C:53]2[CH:54]=[N:55][NH:56][CH:57]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4Br)cccc3c2)c(OC)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(Cl)cc3-c3cn[nH]c3)cccc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A pressure vessel was charged with 5-(2-bromo-4-chlorophenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (0.8 g, 1.268 mmol), potassium carbonate (1.227 g, 8.88 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.748 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.147 g, 0.127 mmol), dioxane (8.45 mL) and water (4.23 mL). The reaction was heated in a microwave at 100° C. for 30 min. The reaction mixture was cooled to room temperature and 2N HCl (10 mL) was then added dropwise to neutralize the base. The aqueous layer was then washed with DCM (three times). The organic layers were combined and dried over sodium sulfate, filtered over a layer of diatomaceous Earth® (diatomaceous earth) and concentrated under a vacuum to provide a yellow oil. To this oil was added DCM (12.68 mL, 1.268 mmol) and TFA (0.488 mL, 6.34 mmol). The resulting mixture was stirred for 1 h at rt. LC/MS indicated that the dimethoxybenzyl (DMB)-protected intermediate remained. The mixture was then heated to 50° C. for 1 h. LC/MS indicated that the desired product (M+H=467.8) was generated. The mixture was concentrated, diluted with DCM (3 mL) and purified by reverse phase HPLC using a Phenomenex Gemini 5 μm, C18, 110 Å, 150×30 mm column eluting with a mixture of 0.1% TFA in acetonitrile/water. The fractions containing product were dried to provide a white solid. 5-(4-chloro-2-(1H-pyrazol-4-yl)phenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (0.165 g, 0.352 mmol). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.08 (s, 2H) 2.54 (s, 1H) 7.02 (br. s., 2H) 7.30 (d, J=8.23 Hz, 1H) 7.40-7.47 (m, 2H) 7.56 (d, J=7.05 Hz, 1H) 7.65 (dd, J=8.87, 1.92 Hz, 1H) 7.69-7.76 (m, 1H) 7.79 (d, J=2.14 Hz, 1H) 8.26 (d, J=8.23 Hz, 1H) 8.44 (s, 1H) 8.53 (d, J=1.71 Hz, 1H); m/z (ESI) 467.8 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10](F)[CH:9]=1)([F:7])[F:6].O>CO>[CH3:1][O:2][C:10]1[CH:9]=[C:8]([C:5]([F:7])([F:6])[F:4])[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: C[O-]
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1C=O

Procedure:
A solution of sodium methoxide (25% wt in methanol, 50 ml) was added to a solution of (4-(1,1,1-trifluoromethyl)-2-fluoro-benzaldehyde (5.0 g) in methanol (50 ml) and the mixture heated under reflux for 2 h. Water (200 ml) was added and the mixture extracted with ethyl acetate. The organics were dried and evaporated under reduced pressure to give a residue that was purified by chromatography on silica eluting with isohexane/diethylether 3:1, yield 3.18 g.