Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][N:14]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:6][C:5]2[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:18])=[CH:15][N:14]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1cc(N)cc(OC)c1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: COc1cc(NC(=O)c2ccc(Cl)nc2)cc(OC)c1

Procedure:
6-Chloro-N-(3,5-dimethoxy-phenyl)-nicotinamide was prepared from 3,5-dimethoxy aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C14H13N2O3Cl [M+H]+: 293.0688. Found: 293.0687.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:23]C(OC(Cl)=O)C>ClCCl>[ClH:23].[S:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=[C:14]1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: c1ccc(CN2CCN(c3cc4ccccc4s3)CC2)cc1
Solvent: ClCCl
Product: Cl
Product: c1ccc2sc(N3CCNCC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-4-(benzothiophen-2-yl)piperazine (1.5 g, 4.9 mmol) in anhydrous dichloromethane (20 ml) at 0° C. under nitrogen was added 1-chloroethylchloroformate (0.68 ml, 6.37 mmol). The mixture was allowed to warm to room temperature, stirred for 1 h and concentrated in vacuo. The crude residue was dissolved in methanol (10 ml) and heated to reflux for 30 minutes, left to cool and the title compound collected by filtration (0.6 g), m.p. 240° C. (dec.).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[N:15]([S:16]([N:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[N:14]=[CH:13][CH:12]=1)[CH3:10]>O1CCCC1>[Br:1][C:12]1[CH:13]=[N:14][N:15]([S:16]([N:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[C:11]=1[CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccnn1S(=O)(=O)N(C)C
Solvent: C1CCOC1
Product: CCc1c(Br)cnn1S(=O)(=O)N(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
1-Bromopyrrolidine-2,5-dione (20.8 g) was added to a stirring solution (300 mL) of 5-ethyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide (19.8 g) in tetrahydrofuran at room temperature. The reaction system was heated to 50° C., stirred for 2 hr and concentrated under reduced pressure. The residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (26.2 g) as a yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[N:14][C:15]([N+:18]([O-])=O)=[CH:16][CH:17]=2)[CH2:8]1>CO.[Pd]>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[N:14][CH:13]=2)[CH2:8]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc([N+](=O)[O-])nc2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc(N)nc2)C1
Yield: 92.8 %

Procedure:
To a solution of (2S,3′S)-2-methyl-1′-(6-nitro-pyridin-3-yl)-[1,3′]bipyrrolidinyl (0.11 g, 0.398 mmol) in methanol (30 mL) in a 250 mL parr bottle was added 5% Pd/C (0.03 g). The reaction mixture was allowed to shake under a hydrogen atmosphere (55 psi) at room temperature for 3 hours. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to afford 0.091 g (93%) of title compound.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1.C(OCC)(=O)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH:22]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:10][CH:11]=2)=[CH:25][CH:24]=1)=[O:23]
Reactant: Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 34.3 %

Procedure:
6.75 g (64 mmole) triethylamine was added to 5 g (14,6 mmole) 4-[2-(4-aminophenyl)ethoxy]benzaldehyde x HCl (containing some ethyl acetate) in dichloromethane. 3.65 g (32 mmole) methanesulfonyl chloride was slowly added at 0° C., and the mixture was stirred over the weekend. A yellow precipitate was filtered off and the filtrate was washed with water. The organic phase was dried (sodium sulfate), filtered and the solvent was evaporated. The residue contained some triethylamine and therefore it was dissolved in dichloromethane and washed with 2 M hydrochloric acid and brine, dried and filtered and the solvent was evaporated to give 1.6 g (yield 34%) of N-{4-[2-(4-formylphenoxy)ethyl]phenyl}methanesulfonamide as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:21][C:15]=3[N:14]=2)[C:4]=1[CH3:29].ClC1C=C(C=CC=1)C(OO)=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH2:11][S:12]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])=[CH:21][C:15]=3[N:14]=2)=[O:35])[C:4]=1[CH3:29]
Reactant: COc1cnc(CSc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c(C)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cnc(CS(=O)c2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c(C)c1OC

Procedure:
0.8 g of a pale yellow oil is obtained by the procedure described in Example 2 by oxidation of 0.99 g of 2-[(4,5-dimethoxy-3-methyl-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole with 12 ml of a 0.2M solution of m-chloroperoxybenzoic acid in methylene chloride at -40° C. for a reaction time of 1.5 hours. Recrystallization twice from methylene chloride/diisopropyl ether gives 0.30 g (34% of theory) of the title compound in the form of colorless crystals of m.p. 125° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[C-:12]#[N:13].[K+]>CN(C)C=O.O.[Na+].[Cl-]>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:12]#[N:13])[CH:5]=[N:4][C:3]=1[CH2:10][CH3:11]
Reactant: [C-]#N
Reactant: CCc1ncc(CCl)cc1Cl
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ncc(CC#N)cc1Cl
Reaction time: 4 h
Yield: 90.2 %

Procedure:
A solution of 3-chloro-5-chloromethyl-2-ethyl-pyridine (4.03 g, 21 mmol) in dimethylformamide (26 mL, 0.8 M) is cooled to 0° C. and treated with a solution of potassium cyanide (1.48 g, 22.7 mmol) in water (10 mL). After 4 h, the solution is diluted with 50% aq NaCl and extracted with ethyl acetate. The organic extracts are washed with sat'd aq lithium chloride and purified by MPLC (30-90% ethyl acetate in heptane) to give 5-chloro-6-ethyl-pyridin-3-yl-acetonitrile as a light brown oil (3.42 g, 90%): Rf 0.29 (30% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.38 (br s, 1 H), 7.67 (br s, 1 H), 3.74 (s, 2 H), 2.97 (q, J=7.5 Hz, 2 H), 1.30 (t, J=7.5 Hz, 3 H) ESI-LCMS m/z calcd for C9H9ClN2: 180.0; found 181.0 (M+1)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:10]2[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[O:26])[CH:16]=3)[N:11]=2)[CH:6]=[CH:7][C:8]=1[OH:9])=O.[NH2:37]OS(O)(=O)=O.CO>O>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27][CH2:28][C:29]5[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=5)=[O:26])[CH:16]=4)[N:11]=3)=[CH:4][C:3]=2[CH:1]=[N:37]1
Reactant: NOS(=O)(=O)O
Reactant: COc1ccc(COC(=O)c2ccc3nc(-c4ccc(O)c(C=O)c4)c(N(C)C(C)C)nc3c2)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(COC(=O)c2ccc3nc(-c4ccc5oncc5c4)c(N(C)C(C)C)nc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
To a solution of (4-methoxyphenyl)methyl 2-(3-formyl-4-hydroxyphenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (190 mg, 0.39 mmol) in water (5 mL) was added aminooxysulfonic acid (83 mg, 0.48 mmol) and methanol (5 mL). The resulting solution was stirred overnight at 25° C. Then the reaction was quenched by the addition of water (200 mL) and extracted with ethyl acetate (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1% to 5% ethyl acetate in petroleum to afford (4-methoxyphenyl)methyl 2-(1,2-benzoxazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a yellow solid (50 mg, 26%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([CH3:15])([CH3:14])[CH3:13].[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17].N#N>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:12]([NH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1C#C[Si](C)(C)C
Temperature: 70 °C
Yield: 15.7 %

Procedure:
To a solution of (2-bromo-4-nitro-phenyl)-tert-butyl-amine (0.6 g, 2.2 mmol) in Et3N (10 mL) was added Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), CuI (20.9 mg, 0.1 mmol) and ethynyl-trimethyl-silane (0.32 g, 3.3 mmol) successively under N2 protection. The reaction mixture was heated at 70° C. overnight. The solvent was removed under vacuum and the residue was washed with EtOAc (10 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to afford tert-butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine (100 mg, 16%). 1H-NMR (CDCl3, 400 MHz) δ 8.20 (d, J=2.4, Hz, 1H), 8.04 (dd, J=2.4, 9.2 Hz, 1H), 6.79 (d, J=9.6 Hz, 1H), 5.62 (brs, 1H), 1.41 (s, 9H), 0.28 (s, 9H).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C.[Cu]I.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:9]1([C:15]#[C:16][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccncc1
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: C(#Cc1ccncc1)c1ccccc1
Yield: 31.1 %

Procedure:
A mixture of 4-bromopyridine hydrochloride (9.75 g, 50 mmol), phenylacetylene (11 ml, 10.2 g; 100 mmol), copper (I) iodide (50 mg) and bis(triphenylphosphino)palladium (II) chloride (200 mg) in dry triethylamine (60 ml) was stirred under reflux for 16 h, the cooled reaction mixture filtered, and the filtrate evaporated. The residual black oil was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium carbonate (2×50 ml) and HCl (1M, 4×25 ml). The acidic washings were extracted with ethyl acetate (2×25 ml) and then basified (5M NaOH). The resulting suspension was extracted with dichloromethane (4×25 ml), the combined organic layers washed with water (25 ml), dried (MgSO4), evaporated, and the residue chromatographed on silica gel, eluting with 7:3 ethyl acetate/60°-80° petrol to give the product as a buff solid (2.79 g, 31%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[C:12]([Cl:19])=[C:13]([CH2:17]Br)[CH:14]=[CH:15][CH:16]=1)=[O:10]>CS(C)=O>[Cl:19][C:12]1[C:11]([C:9](=[O:10])[C:5]2[S:4][CH:8]=[CH:7][CH:6]=2)=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:17][C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=C(c1cccs1)c1cccc(CBr)c1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1cccc(C(=O)c2cccs2)c1Cl
Reaction time: 2 h

Procedure:
To a stirred and hot solution of 7.35 parts of sodium cyanide in 50 parts of dimethyl sulfoxide is added dropwise a solution of 15.2 parts of α-bromo-2-chloro-m-tolyl 2-thienyl ketone in 25 parts of dimethyl sulfoxide at 60° C. Upon completion, stirring is continued for 2 hours at 60° C. The reaction mixture is poured onto water and the product is extracted three times with 240 parts of ether. The combined ether phases are washed three times with 100 parts of water, dried, filtered and evaporated. The residue is boiled four times in 80 parts of diisopropylether and the latter is each time decanted, yielding 2-[2-chloro-3-(2-thenoyl)phenyl]acetonitrile as a residue which solidifies on standing.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:20][C:19]2[C@H:14]([CH2:15][CH2:16][C:17](=[O:21])[CH:18]=2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:22])[CH2:7][CH2:6]1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([O:22][C@H:8]1[CH2:7][CH2:6][C@H:5]2[C@H:4]3[C@H:13]([CH2:12][CH2:11][C@:9]12[CH3:10])[C@@H:14]1[C:19](=[CH:18][C:17](=[O:21])[CH2:16][CH2:15]1)[CH2:20][C@H:3]3[CH2:1][CH3:2])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Solvent: O
Solvent: c1ccncc1
Product: CC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
i)—A solution of (7α,17β)-7-ethyl-17-hydroxyestr-4-en-3-one (Example 1, 2.0 g) in dry pyridine (15 ml) was treated with acetic anhydride (1.86 ml) and the reaction mixture was stirred at room temperature for 6.5 h; additional acetic anhydride (1.86 ml) was added after 3 h. The mixture was cooled to 0° C.; water was added and stirring was continued for 30 min. The product was extracted into ethyl acetate; the combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure, to give (7α,17β)-17-(acetyloxy)-7-ethylestr-4-en-3-one (2.15 g). The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].[Br:11][CH:12](Br)[CH3:13]>>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:13][CH2:12][Br:11])[CH:2]=[CH2:3]
Reactant: CC(Br)Br
Reactant: C=CCc1ccccc1O
Product: C=CCc1ccccc1OCCBr
Yield: 17.9 %

Procedure:
Using the procedure described in Example I step A and starting from 43.5 g o-allylphenol and 140 g dibromoethane, 35 g of crude product are produced which after distillation under reduced pressure give 14 g of pure compound. The latter boils at 150°-154° under 18-20 mm Hg.
Reaction SMILES: [Na][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].O1CCCC1.[O-]S(C(F)(F)[F:29])(=O)=O.[O-]S(C(F)(F)F)(=O)=O.F[N+]12CC[N+](F)(CC1)CC2>C(#N)C.C(OCC)C>[F:29][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C([Na])(C(=O)OCC)c1ccccc1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[N+]12CC[N+](F)(CC1)CC2
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(F)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Yield: 65 %

Procedure:
A cold (-10° C.) solution of diethyl sodio(phenyl)-malonate in anhydrous tetrahydrofuran [prepared in conventional fashion from sodium hydride (2.5 mmol) and diethyl phenylmalonate (0.5 g, 2.1 mmol) in THF (15 cm3)] was added slowly to a cold (-10° C.) stirred solution of 1,4-difluoro-1,4-diazoniabicyclo[2.2.2]octane bistriflate (0.95 g, 2.12 mmol) in dry acetonitrile (50 cm3) under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and then diluted with diethyl ether (100 cm3). The mixture was then washed with 0.5M oxalic acid (30 cm3), 10% aqueous potassium hydrogen carbonate (30 cm3), and saturated brine (30 cm3) (in that order), dried (MgSO4), filtered, and the filtrate evaporated under reduced pressure to provide diethyl fluoro(phenyl)-malonate (65% yield) with correct NMR parameters.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C@H:3]([N:30]1[CH2:34][CH2:33][C@H:32]([NH:35]C(=O)OC(C)(C)C)[CH2:31]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[ClH:45]>ClCCl.C(#N)C>[ClH:45].[ClH:45].[F:44][C:2]([F:1])([F:43])[C@H:3]([N:30]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: COCCCOc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Product: COCCCOc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 169.1 %

Procedure:
To a solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-8-(3-methoxypropoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.12 g, 0.19 mmol) in dichloromethane (1 mL) was added hydrochloric acid (5-6M in 2-propanol; 6.5 mL, 0.19 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the solid obtained was suspended in acetonitrile (3 mL) and stirred at ambient temperature for 5 minutes. The solid formed was collected by vacuum filtration to give the title compound (0.095 g, 80%). FIA-MS APCI (+) m/z 519 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:28]=[CH:27][C:10]([C:11]([C:13](=[CH:19][NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14](OCC)=[O:15])=[O:12])=[C:9](F)[CH:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].[NH3:32]>O1CCOCC1>[C:21]1([N:20]2[C:27]3[C:10](=[CH:9][CH:8]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:28]=3)[C:11](=[O:12])[C:13]([C:14]([NH2:32])=[O:15])=[CH:19]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N
Reactant: CCOC(=O)C(=CNc1ccccc1)C(=O)c1ccc(-c2ccncc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)c1cn(-c2ccccc2)c2cc(-c3ccncc3)ccc2c1=O

Procedure:
Novel quinolones (see Examples 1, 2, 3, 4, 5, 6 and 7) of this invention may be prepared by a mild ring closure reaction of ethyl 2-[4-(4-pyridyl)-2-fluoro-benzoyl]-3-phenylamino-propenoate (Formula 3) with sodium hydride in dioxane followed by treatment of the propeonate with ammonia to afford the desired 1,4-dihydro-1-phenyl-7-(4-pyridyl)-4-oxo-3-quinolinecarboxamide (Formula 5) as shown in Scheme 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]([C:13](O)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:31][C:32]1([OH:45])[CH2:36][CH2:35][N:34]([CH:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])[CH2:33]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:12][C:8]1[NH:9][C:10]([CH3:11])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:13]([O:45][C:32]1([CH3:31])[CH2:36][CH2:35][N:34]([CH:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])[CH2:33]1)=[O:14]
Reactant: CC(c1ccccc1)N1CCC(C)(O)C1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC2(C)CCN(C(C)c3ccccc3)C2)[C@H]1c1cccc([N+](=O)[O-])c1
Yield: 48 %

Procedure:
According to Example 15, (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was synthesized. To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (2.9 g, 8.73 mmol) in dichloromethane was added 0.1 mL DMF. To the mixture was slowly added oxalyl chloride (2.2 g, 17.33 mmol) dropwisely in an ice bath. The reaction was conducted at 25° C. until the completion of reaction. The resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (20 mL), 3-methyl-1-phenylethylpyrrolidin-3-ol (1 g, 4.87 mmol) and DIPEA (1.56 g, 12.1 mmol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25° C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether:ethyl acetate=78:1 (volumetric ratio)) to produce (4S)-3-(3-methyl-1-phenylethylpyrrolidin-3-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.21 g) in a yield of 48%.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:12]=[C:13]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH:14](O)[C:15]([O:17][CH3:18])=[O:16]>ClCCl>[F:10][C:11]1[CH:12]=[C:13]([CH:14]([F:7])[C:15]([O:17][CH3:18])=[O:16])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: COC(=O)C(O)c1cc(F)cc(F)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(F)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.3 g of N-ethyl-N-(trifluoro-λ4-sulfanyl)-1-ethanamine are added dropwise at 20° C. to 2 g of methyl 3,5-difluoromandelate, obtained in step 2.1, in solution in 25 ml of dichloromethane, and the mixture is stirred for 18 hours at room temperature. The reaction medium is taken up in dichloromethane and washed with water, with a saturated aqueous sodium hydrogen carbonate solution, and then with a hydrochloric acid solution (0.5 N). The organic phase is dried over anhydrous sodium sulfate and concentrated to give 1.9 g of oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([OH:13])[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C(N(CC)C(C)C)(C)C.[CH3:27][O:28][CH2:29]Cl.[O:31]1[CH2:35]CC[CH2:32]1>>[OH:1][C:2]1[C:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH2:27][O:28][CH3:29])[CH:5]=[C:4]([O:14][CH2:32][O:31][CH3:35])[C:3]=1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)c1c(O)cc(O)c(CC=C(C)C)c1O
Reactant: C1CCOC1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(OCOC)c(C(C)=O)c(O)c1CC=C(C)C
Reaction time: 1 h

Procedure:
Then, 30.0 g of 2',4',6'-trihydroxy-3'-(3-methyl- 2-butenyl)acetophenone was dissolved in tetrahydrofuran and 131.7 ml of N,N-diisopropylethylamine was added to the solution, and the mixture was stirred for 1 hour. Then, 48.0 ml of chloromethyl methyl ether was dropped into the mixture and the mixture was stirred for 3 hours. The mixture was extracted with dimethyl ether, and the organic layer was washed with water, dried with anhydrous sodium sulfate and concentrated under reduced pressure. Crystallization from ethyl acetate gave 21.5 g of 2'-hydroxy-4',6'-bis(methoxymethoxy)-3'-(3-methyl-2-butenyl)acetophenone.