Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][NH:9][C:8](=[O:11])[CH2:7]1.Br[C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=2[CH:23]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cu](I)I.CO.ClCCl>[CH3:1][O:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][N:9]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=3[CH:23]=2)[C:8](=[O:11])[CH2:7]1
Reactant: O=C1COc2ccc(Br)cc2N1
Reactant: COCOC[C@@H]1CNC(=O)C1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COCOC[C@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Temperature: 100 °C
Reaction time: 42 h
Yield: 39.9 %

Procedure:
Copper iodide (1.50 g, 7.85 mmol) was added at room temperature to a suspension of (4S)-4-[(methoxymethoxy)methyl]pyrrolidin-2-one (3.00 g, 18.8 mmol), 6-bromo-2H-1,4-benzoxazin-3(4H)-one (3.58 g, 15.7 mmol) and N,N′-dimethylethylenediamine (0.84 ml, 7.85 mmol) and potassium carbonate (6.51 g, 47.1 mmol) in toluene (60 ml) and the mixture was heated to 100° C. The mixture was stirred at the same temperature for 42 hours and dichloromethane (100 ml) and methanol (10 ml) were then added thereto to dilute the reaction solution, and the insoluble material was removed by filtration. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 1.92 g (40%) of the title compound in the form of a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
2,5-Dibromopyridine (7.1 g, 30 mmol), morpholine (1.74 mL, 20 mmol), cesium carbonate (9.1 g, 28 mmol), tris(dibenzylideneacetone)dipalladium(0) (183 mg, 0.2 mmol), and racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (374 mg, 0.6 mmol) in toluene (20 mL) was heated at 120° C. for 24 hours. After cooling to room temperature, the mixture was filtered through Celite™ and the Celite™ pad was washed with chloroform. The solution was concentrated in vacuo and was purified by silica gel chromatography (200:1 chloroform-methanol) to give 2.9 g (60% yield) of the title compound. 13C NMR (100 MHz, CDCl3) d 158.3, 148.7, 140.0, 108.4, 66.8, 45.7; MS (AP/Cl) 243.0, 245.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1OS(C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(-c2ccccc2)nc1N1CCCCC1
Temperature: 80 °C
Yield: 96 %

Procedure:
To a solution of the above-prepared 2-phenyl-4-trifluoromethanesulfonyloxy-thiazole-5-carboxylic acid ethyl ester (0.75 mmol) in toluene (5 mL) was added piperidine (4.5 mmol). The reaction mixture was heated to 80° C. for 2 hours. The mixture was then diluted in ethyl acetate, washed successively with water and brine, and dried over MgSO4. Silica gel chromatography of the crude mixture provided title compound (96%) as a yellowish oil.
Reaction SMILES: [CH:1]1([OH:4])[CH2:3][CH2:2]1.[H-].[Na+].F[C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([O:4][C:8]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:3][CH2:2]1
Reactant: OC1CC1
Reactant: N#Cc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1ccc(F)cc1OC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution cyclopropanol (1.9 g, 29 mmol) in 20 mL dioxane was added dropwise to a 0° C. solution of Sodium hydride (60% dispersion in mineral oil, 1.04 g, 26 mmol) in 80 mL dioxane. The reaction mixture was allowed to warm to room temperature, 2,4-difluorobenzonitrile (3.48 g, 25 mmol) was added portionwise, and reaction temperature raised to 95° C. The reaction solution was cooled to room temperature after stirring for 18 hours, diluted with ethyl acetate, washed twice with water and twice with brine, dried over MgSO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (0-10% EtOAc/hexanes) afforded 2-cyclopropoxy-4-fluorobenzonitrile. 1H-NMR (400 MHz, Chloroform-d) δ 7.52 (dd, J=8.6, 6.2 Hz, 1H), 7.05 (dd, J=10.5, 2.3 Hz, 1H), 6.73 (td, J=8.2, 2.3 Hz, 1H), 3.87-3.76 (m, 1H), 0.87 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[CH:3]=1.C1C(=O)N([Br:30])C(=O)C1>>[Br:30][C:3]1[C:4](=[O:22])[O:5][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][C:2]=1[OH:1]
Reactant: O=C1C=C(O)CC(CCc2ccccc2)(c2ccccc2)O1
Reactant: O=C1CCC(=O)N1Br
Product: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br

Procedure:
The title compound was prepared as described in General Method 3 using 2.0 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in Example X) and 2.0 mmol of NBS. 1H NMR (DMSO-d6) δ 2.16-2.58 (m, 4 H), 3.30 (m, 2 H), 7.04-7.60 (m, 10 H).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([N:18]1[CH2:23][CH2:22][CH:21](Br)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CN(C)C=O>[C:11]([N:18]1[CH2:19][CH2:20][CH:21]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:23]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(SCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
To benzyl mercaptan (17 ml, 152 mmol)in dimethylformamide at 0° C. under nitrogen was added sodium hydride (80% dispersion in mineral oil, 4.38 g, 152 mmol) the solution was stirred at room temperature for 15 minutes then cooled to 0° C. prior to adding N-Boc-(4-bromo)piperidine (10.8 g, 38 mmol). The mixture was stirred for 14 h at room temperature then poured into water (50 ml), extracted with diethyl ether (2×100 ml), the organic layers combined, dried (MgSO4), filtered, evaporated, and the crude product purified by flash column chromatography using 10% ethyl acetate in hexane to yield the product as a pale yellow oil (2.86 g); δH (CDCl3) 1.46 (9H, s, t-Bu), 1.51 and 1.87 (4H, m, 3,5-piperidinyl CH2), 2.85 and 3.91 (4H, m, 2,6-piperidinyl CH2), 2.69 (1H, m, 4-piperidinyl H), 3.77 (2H, s, SCH2), and 7.24-7.32 (5H, m, ArH).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.[Cl:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[C:17]([I:18])=[CH:16][N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[N:14]=1>C1COCC1>[Cl:8][C:9]1[N:10]=[C:11]([O:7][CH:3]2[CH2:6][CH2:5][CH2:4]2)[C:12]2[C:17]([I:18])=[CH:16][N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=2[N:14]=1
Reactant: OC1CCC1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCC3)nc(Cl)nc21
Temperature: 30 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of sodium hydride (2 equiv, 60% in mineral oil) in dry THF (0.44 M) under nitrogen atmosphere was added a solution of cyclobutanol (1.05 equiv) in dry THF (1.4 M) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes before 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)-methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv) in dry THF (0.33 M) was added and the resulting reaction mixture was stirred at 30° C. for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution. The organic solvent was removed under reduced pressure and the resulting aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure. The crude obtained was purified by flash column chromatography on silica gel (5% ethyl acetate in petroleum ether) to afford the title compound (95% yield) as a white solid. MS (ESI) m/z 479.2 [M+1]+.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:17][OH:18])[CH2:10][C@@H:11]([C:13]([F:16])([F:15])[F:14])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:31][Cr](O[Cr]([O-])(=O)=O)(=O)=O.CN(C=O)C>C(OCC)(=O)C.O>[C:1]([NH:8][C@@H:9]([C:17]([OH:31])=[O:18])[CH2:10][C@@H:11]([C:13]([F:16])([F:15])[F:14])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: C[C@@H](C[C@H](CO)NC(=O)OC(C)(C)C)C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A mixture of (2S,4R)-, (2R,4S)-N-Boc-5,5,5-trifluoroleucinol (330 mg, 1.23 mmol), PDC (4.62 g, 12.3 mmol), and dry DMF (2.5 mL) was stirred at room temperature under argon for 4 h, then diluted with 50 mL of ethyl acetate and 50 mL of water. The organic layer was washed with 30 mL of 1N HCl and 2×30 mL of water, dried over MgSO4, and concentrated to give 198 mg of (2S,4R)-, (2R,4S)-N-Boc-5,5,5-trifluoroleucine as a pale-brownish oil (60%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:12]3[N:13]=[CH:14][C:9]([N:4]4[CH2:5][CH2:6][N:2]([CH3:1])[C:3]4=[O:7])=[CH:10][CH:11]=3)=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cn3)CC2)c(C)c1
Yield: 62.3 %

Procedure:
Using 1-methyl-2-imidazolidinone (53 mg) and (5-bromopyridin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 134 and by the reaction and treatment in the same manner as in Example 1, the title compound (130 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]1([C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)O)[OH:28].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:23][C:22]([F:24])([F:25])[O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:28][C:27]3[CH:29]=[CH:31][CH:32]=[CH:33][C:34]=3[O:26]2)=[CH:20][CH:19]=1
Reactant: Oc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: FC(F)(F)Oc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Yield: 71.2 %

Procedure:
A solution of 4-(4-trifluoromethoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 247) (373 mg, 1.0 mmol), catechol (440 mg, 4.0 mmol) and p-TsOH.H2O (380 mg, 2.0 mmol) in xylene (10 mL) was heated at reflux under a Dean-Stark trap for 44 hours. Standard work-up and purification gave 4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a white solid (260 mg, 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
1-(4Nitrophenyl)piperazine (2.79 g, 13.5 mmol) was dissolved in dichloromethane (100 ml). Triethylamine (2.25 ml, 16.2 mmol) was added and the reaction was cooled to 0° C. Methanesulfonyl chloride (1.15 ml, 14.9 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. Saturated sodium bicarbonate was added and the reaction was extracted (×3) with dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to give 4-(4-nitrophenyl)-1-methylsulfonylpiperazine as a yellow solid (3.83 g, quantitative yield). GC/MS (EI, M+) m/z=285.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[Na].[H-].[Na+].[CH2:26]([O:28][C:29](=[O:34])[CH2:30][C:31](Br)=[O:32])[CH3:27]>CN(C)P(=O)(N(C)C)N(C)C.C(OCC)C.CCCCCC>[CH2:26]([O:28][C:29](=[O:34])[CH:30]([S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)[CH:31]=[O:32])[CH3:27]
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)CC(=O)Br
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C(C=O)Sc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.3 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and converted into the sodium salt under nitrogen with sodium hydride (0.5 g of a 50% strength suspension in mineral oil, de-oiled with hexane). The product is allowed to warm to room temperature, 2.0 g of 2-bromoformylacetic acid ethyl ester are added dropwise and the mixture is stirred at 25° for 1 hour, poured into 750 ml of ice-water and taken up in diethyl ether. The ethereal phase is washed with water, dried over magnesium sulphate and concentrated to dryness by evaporation. 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-2-formylacetic acid ethyl ester is obtained, which can be used without further purification.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[C:11]([CH2:17]CO)[C:12]([O:14][CH2:15]C)=[O:13])[CH:7]=[CH:8][CH:9]=1>O.C(O)C.C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[C:6](/[C:10](=[C:11]2\[C:12](=[O:13])[O:14][CH2:15][CH2:17]\2)/[C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CCO)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2cccc(F)c2)cc1
Yield: 15.5 %

Procedure:
3.3 g of sodium hydroxide dissolved in 10 ml of water are added to a solution of 29.3 g of ethyl 3-(3-fluorophenyl)-3-(4-methanesulfonylphenyl)-2-(2-hydroxyethyl)-2-propenoate, prepared in Example 12, in 50 ml of ethanol and the mixture is refluxed for 2 hours. After evaporation to dryness, the residue is taken up with water, acidified with 1N hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give an oily residue. The oil is solubilized in 150 ml of toluene, and 10 mg of paratoluenesulfonic acid are added. The mixture is refluxed and the water formed is removed with a Dean-Stark apparatus. After cooling, the mixture is washed with water, the organic phase is dried over magnesium sulfate and evaporated under vacuum and the residue is chromatographed on silica in t-butyl methyl ether to give 4 g of (Z)-3-[1-(3-fluorophenyl)-1-(4-methanesulfonylphenyl)methylidene]dihydrofuran-2-one (2nd product eluted) in the form of crystals melting at 153°-154° C.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2].[F:28][C:29]([F:46])([F:45])[O:30][C:31]1[CH:44]=[CH:43][C:34]([O:35][C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O1CCCC1>[N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][CH2:23][CH:24]([NH:42][C:39]4[CH:40]=[CH:41][C:36]([O:35][C:34]5[CH:43]=[CH:44][C:31]([O:30][C:29]([F:28])([F:45])[F:46])=[CH:32][CH:33]=5)=[CH:37][CH:38]=4)[CH2:25][CH2:26]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2]
Reactant: Nc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: O=C1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(Nc4ccc(Oc5ccc(OC(F)(F)F)cc5)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.2 %

Procedure:
1-[4-((R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-one (700 mg) and 4-(4-trifluoromethoxyphenoxy)phenylamine (557 mg) were suspended in 1,2-dichloroethane (20 ml) and tetrahydrofuran (20 ml). Sodium triacetoxyborohydride (558 mg) and acetic acid (0.13 ml) were added to the suspension, and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the remaining water layer was ice-cooled. A 20% sodium carbonate aqueous solution was added thereto, followed by extraction with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (methylene chloride:methanol=100:1→methylene chloride:methanol=40:1) and recrystallized from isopropyl alcohol-isopropyl ether to afford the title compound as a yellow solid (226 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([NH2:28])[C:9]([F:27])=[C:10]([N:14]3[CH2:18][CH2:17][CH:16]([NH:19]C(OC(C)(C)C)=O)[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:29])[C:5]([C:30]([OH:32])=[O:31])=[CH:4]1)[CH3:2].[ClH:33]>C(O)(=O)C>[ClH:33].[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([NH2:28])[C:9]([F:27])=[C:10]([N:14]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:29])[C:5]([C:30]([OH:32])=[O:31])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(N)c(F)c(N3CCC(NC(=O)OC(C)(C)C)C3)c(F)c21
Agent: Cl
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2c(N)c(F)c(N3CCC(N)C3)c(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A near solution of 4.5 g (10 mmole) of 1-ethyl-5-amino-6,8-difluoro-7-[3-(t-butoxycarbonylamino)-1-pyrrolidinyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 10 ml of 6.0M hydrochloric acid and 100 ml of glacial acetic acid is heated at 60° C. for four hours and then stirred at room temperature for 18 hours. The solvent is removed in vacuo, the residue triturated with ethanol/ether (1:1), filtered, washed with ether, and dried in vacuo to give the title compound.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[F:12])=[O:4].CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[S:22]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]([F:1])[F:13])=[C:6]([F:12])[CH:7]=1)(=[O:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(c1ccc(O)cc1F)C(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(OS(=O)(=O)C(F)(F)F)cc1F)C(F)F

Procedure:
To 2,2-difluoro-1-(2-fluoro-4-hydroxyphenyl)ethanone (39.0 g, 0.2 mol) and Et3N (20.7 g, 0.2 mol) in CH2Cl2 at 0° C. was added Tf2O (58 g, 0.2 mol) dropwise while keeping the temperature at 0° C. The ice-salt bath was removed, and when the temperature rose to 25° C., a solution of saturated NaHCO3 was added. The aqueous phase was extracted with CH2Cl2 and the combined extracts were dried over MgSO4, and concentrated, and the residue was purified by column chromatography (PE/EA 10:1) to afford 4-(difluoroacetyl)-3-fluorophenyl trifluoromethanesulfonate as an brown oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.P([Cl:30])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[C:6]1([N:5]=[C:3]([Cl:30])[C:2]([F:13])([F:12])[F:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Nc1ccccc1)C(F)(F)F
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)C(Cl)=Nc1ccccc1
Temperature: 82 °C
Yield: 81.2 %

Procedure:
Seven grams (37.0 mmol) of 2,2,2-trifluoro-N-phenylacetamide, 19.84 g (74.0 mol) of diphenyl chlorophosphate, 7.44 g (74.0 mmol) of triethylamine, and 28 ml of acetonitrile were introduced into a 100 ml flask and reacted for 15 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 28 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 6.24 g of N-phenyl-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 81.2%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncsc1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncsc1CCOS(C)(=O)=O
Temperature: 25 °C
Yield: 66.9 %

Procedure:
2-(4-methylthiazol-5-yl)ethanol (5.01 g) was dissolved in dichloromethane (100 ml) and to the solution was added triethylamine (5.06 g), followed by adjusting the temperature of reactor to 0° C. To the obtained solution was added dropwise methanesulfonyl chloride (4.58 g), and the mixture was stirred for 21. hours while allowed to warm up to room temperature. The reaction solution was washed with water, concentrated under reduced pressure, and then purified by column-chromatography (hexane/ethyl acetate=1/3) to yield 5-(2-methylsulfonyloxyethyl)-4-methylthiazole (5.18 g, 67%) as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:10][CH:9]=[C:8]([I:11])[C:6]=2[N:7]=1.[OH-].[Na+].I[CH3:15].O>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]([CH3:15])[CH:9]=[C:8]([I:11])[C:6]=2[N:7]=1
Reactant: CI
Reactant: Clc1ncc2[nH]cc(I)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cn1cc(I)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a suspension of 2-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (1 g, 3.57 mmol, 1.0 eq.) and NaOH (0.430 mg, 10.73 mmol, 3.0 eq.) in DCM (28 ml) was added iodomethane (0.66 g, 4.6 mmol, 1.3 eq.) and tetrabutylammonium bromide (0.116 g, 0.36 mmol, 0.1 eq.). The reaction mixture was stirred at room temperature overnight. Water was poured in and the aqueous layer extracted with ethyl acetate (2 times). The combined organic layers were then dried over Na2SO4. After filtration and evaporation the yellow residue was triturated with a mixture of ethyl acetate/petroleum spirit (1:2) to give the product as a white solid (0.73 g, 70%). 1H NMR (DMSO, 300 MHz): 8.99 (s, 1H), 8.17 (s, 1H), 3.94 (s, 3H); LRMS (EI): m/z calcd for [M+H]+ 293.93 found 294.1.