Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=O.[O-:18][N+:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[C:21]([C@H:29]([NH2:31])[CH3:30])[CH:20]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([NH:31][C@@H:29]([C:21]1[CH:20]=[N+:19]([O-:18])[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:22]=1)[CH3:30])=[O:16]
Reactant: O=C(O)c1cncc(-c2ccc(F)cc2F)c1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)c1cncc(-c2ccc(F)cc2F)c1)c1ccc(C(F)(F)F)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(2,4-difluorophenyl)nicotinic acid (40.0 mg, 0.15 mmol) in DMF (0.7 mL) were added hydrochloride salt of (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (49.3 mg, 0.18 mmol), EDC (33.9 mg, 0.18 mmol), HOBT (22.6 mg, 0.15 mmol) and triethylamine (0.10 mL, 0.74 mmol). The mixture was stirred at ambient temperature for 18 h. Purification by reverse chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title product, which was converted to hydrochloride salt using 2.0 M HCl in ether (47 mg). HRMS 424.1086. 1H NMR (400 MHz, CD3OD): δ 9.22 (s, 1H); 9.15 (s, 1H); 9.00 (s, 1H); 8.52 (s, 1H); 7.92 (d, J=8.4 Hz, 1H); 7.83-7.73 (m, 1H); 7.70 (d, J=8.4 Hz, 1H); 7.31-7.21 (m, 2H); 5.33-5.25 (m, 1H); 1.67 (d, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])[CH:5]=[O:6].Br[CH2:15][CH2:16][Cl:17].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13])[CH:5]=[O:6]
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OCCCl)c1
Temperature: 55 °C
Reaction time: 15 h
Yield: 84.9 %

Procedure:
A mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde (77 g, 409 mmol), 1-bromo-2-chloroethane (176 g, 1.23 mol) and Cs2CO3 (146 g, 449 mmol) in DMF (2 L) was stirred at 70° C. for 3 h and at 55° C. for 15 h. The mixture was cooled to room temperature and partitioned between ethyl acetate (1 L) and water (2 L). The aqueous layer was extracted with ethyl acetate (2×) and the combined organics were washed with water, dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 4:1 to 7:3) provided the 3-(2-Chloro)ethoxy-4-difluoromethoxybenzaldehyde compound (87 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:19]=[CH:20][C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[BH4-].[Na+]>C(O)C>[OH:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19][NH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C=CC(=O)CCCCC
Reactant: CCOC(=O)CCCCCCC(N)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)CCNC(CCCCCCC(=O)OCC)C(=O)OCC
Reaction time: 3 h

Procedure:
Diethyl 2-aminononanedioate (10.40 g) and oct-1-en-3-one (5.04 g) were mixed slowly at 0° C., with stirring, and set aside at room temperature for 3 h., giving diethyl 2-(3-oxoctylamino) nonanedioate as a colourless oil, 2.3(4H, multiplet, --CH2 --CO2Et and NCH2CH2CO--), 3.16(1H, triplet, EtO2C--CHR--N), 4.11(2H, quartet, --O--CH2 --CH3), 4.17(2H, quartet, --O--CH2 --CH3). A stirred solution of this ketone (13.5 g) in absolute ethanol (140 ml) was treated dropwise at 0° C. with sodium borohydride (665 ml) in absolute ethanol (70 ml), then kept for 31/2 h. at room temperature, and concentrated at 40° C. in vacuo. The residue dissolved in water, was brought to pH 5 with N hydrochloric acid and extracted throughly with chloroform, the extract was washed with water, dried, and evaporated, giving diethyl 2-(3-hydroxyoctylamino)nonanedioate as a colourless oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([OH:35])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[CH3:36][N:37]=[C:38]=[O:39].C(OCC)(=O)C.CCCCCC>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([O:35][C:38](=[O:39])[NH:37][CH3:36])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][C:20]([CH3:23])([CH3:24])[CH2:21][O:22]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CN=C=O
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CNC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
In 5 ml of toluene was dissolved 49.0 mg (0.1 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregna-5-en-3β-yl acetate, followed by addition of one drop of pyridine. Then, 0.1 ml (1.7 mmoles) of methyl isocyanate was added at a temperature of 0° C. and the mixture was stirred at a temperature of 60° C. for 30 minutes. The reaction mixture thus obtained was cooled to room temperature, poured in ice-water, and extracted 3 times with 20 ml portions of methylene chloride. The extracts are pooled, washed successively with water and aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eluent:ethyl acetate-hexane=1:10, v/v) to recover 35 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-(N-methylcarbamoyloxy)pregn-5-en-3β-yl acetate (yield: 65%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH:25](O)([CH3:27])[CH3:26]>>[C:1]1([C:7]2[O:8][C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[C:10]([CH2:12][C:13]([O:15][CH:25]([CH3:27])[CH3:26])=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)O
Reactant: O=C(O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Yield: 43 %

Procedure:
2 g of 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetic acid, 3 g of thionyl chloride and 30 ml of isopropanol are treated in the same manner as described in Example 13. One g of isopropyl 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetate is obtained. Yield: 43%
Reaction SMILES: C(S)[C@@H](O)[C@H](O)CS.[C:9]([O-:14])(=[O:13])[C:10]([CH3:12])=[O:11].[O:15]=[CH:16][C@H:17]([C@H:19]([C@@H:21]([C@@H:23]([CH2:25][OH:26])[OH:24])[OH:22])[OH:20])[OH:18].OC(C1(O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](NC(C)=O)[C@@H](O)C1)O)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[C:9]([OH:14])(=[O:13])[C:10]([CH2:12][C@H:25]([C@@H:23]([C@@H:21]([C@H:19]([C@H:17]([CH2:16][OH:15])[OH:18])[OH:20])[OH:22])[OH:24])[OH:26])=[O:11]
Reactant: CC(=O)C(=O)[O-]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Product: O=C(O)C(=O)C[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 37 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
To a 10 mL potassium phosphate buffer (0.1M, pH 7.5) were added 10 mM DTT, 0.5M pyruvate, 0.1M D-mannose and 1.5 mg NeuAc aldolase. The reaction mixture was shaken at 37° C. for three days. The reaction mixture was chromatographed with a Dowex-1 (HCO3-) resin, eluted with zero to 1M ammonium bicarbonate gradient. The fractions containing KDN were pooled and lyophilized three times repeatedly to remove the volatile salt to give a 78 percent yield of KDN. The physical data of the product were are consistent with the reported.
Reaction SMILES: N1C2C=CC=CC=2N=N1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:26]2[CH:30]=[CH:29][N:28]([CH2:31][C@@H:32]([NH:34][C:35]([C:37]3[N:38]=[CH:39][NH:40][CH:41]=3)=[O:36])[CH3:33])[N:27]=2)[CH:21]=[CH:22][C:23]=1[C:24]#[N:25].CC([O-])(C)C.[K+]>[Cu]I.O.CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:26]2[CH:30]=[CH:29][N:28]([CH2:31][C@@H:32]([NH:34][C:35]([C:37]3[N:38]=[CH:39][N:40]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)[CH:41]=3)=[O:36])[CH3:33])[N:27]=2)[CH:21]=[CH:22][C:23]=1[C:24]#[N:25]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]cn1
Reactant: Brc1ccccn1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(-c2ccccn2)cn1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A microwave oven reaction tube was charged with CuI (5.5 mg, 0.028 mmol), 1H-benzotriazole (6.7 mg, 0.056 mmol), DMSO (1 ml), 2-bromopyridine (0.054 ml, 89 mg, 0.566 mmol), (S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide (200 mg, 0.564 mmol) and KOt-Bu (89 mg, 0.789 mmol). The reaction mixture was stirred for 30 min at 150° C. in a microwave oven. Then the mixture was cooled to RT, water was added and the product was extracted into ethyl acetate. The combined organic layers were washed with water and dried. After evaporation of the solvent the residue was purified by flash chromatography on silica gel using CH2Cl2-MeOH as a gradient eluent (100:0-99:1). Trituration in diethyl ether provided the desired product. 1H NMR (400 MHz, CDCl3): 1.26 (3H, d), 4.29 (1H, distorted dd), 4.45 (1H, distorted dd), 4.61 (1H, m), 6.62 (1H, d), 7.32 (1H, dd), 7.38 (1H, d), 7.50 (1H, d), 7.66 (1H, d), 7.81 (1H, dd), 7.88 (1H, td), 8.00 (1H, m), 8.18 (2H, m), 8.42 (1H, s), 8.53 (1H, d).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH4+].[F-:16].N([O-])=O.[Na+]>>[F:16][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [F-]
Reactant: Cc1ccc(-c2ccccc2)c(N)c1
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1ccc(-c2ccccc2)c(F)c1
Reaction time: 0.67 h

Procedure:
To a cold (ice-salt bath) solution of 21.3 g (0.115 mol) of 2-amino-4-methyl biphenyl (prepared in Example 2) and 6.5 g (0.11 mol) of NH4F.HF and 75 g of 70% HF (2.6 mol) was portion-wise added 8.9 g (0.13 mol) of NaNO2 so that the temperature of the reaction mixture did not rise above 5°. This addition took approximately 40 minutes. The reaction mixture was allowed to stir at 0° for 15 minutes thereafter, and then the cooling bath was removed and stirring continued. The temperature rose to 15° after 20 minutes and then to 60° over a subsequent 25 minute period during which time nitrogen was evolved. The reaction mixture was cooled in an ice bath and extracted three times with petroleum ether. This organic extract was washed successfully with water, aqueous NaHCO3, and H2O and then dried over MgSO4 which, after concentration left 18.8 g of dark red liquid. Subsequent analysis of this material by gas chromatography showed the fluoride compound present at about 90% by weight and about 6% by weight of the corresponding hydroxy compound. A solution of the crude product in petroleum ether was passed through a short column of silica gel. Removal of the solvent at reduced pressure left 16.6 g of pure 2-fluoro-4-methylbiphenyl (78%) as a colorless liquid.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[OH:18][C:19]1[CH:28]=[CH:27][C:22]2[C:23](=[O:26])[CH2:24][O:25][C:21]=2[CH:20]=1.O>CN(C=O)C>[C:1]([Si:5]([CH3:7])([CH3:6])[O:18][C:19]1[CH:28]=[CH:27][C:22]2[C:23](=[O:26])[CH2:24][O:25][C:21]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1COc2cc(O)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a solution of tert-butyl-chloro-dimethyl-silane (12.6 g, 83.9 mmol) in DMF (120 mL) was added DIEA (18.4 g, 24.9 mL, 142.7 mmol) and the mixture was stirred (rt, 0.5 h). The reaction mixture was treated with 6-hydroxy-benzofuran-3-one (12.0 g, 79.9 mmol) and stirred (rt, 0.25 h). The reaction mixture was treated with water (100 mL) to form a solid. The solid was filtered to afford the title compound as a yellow solid (20.4 g, 98%). MS (ESI): mass calcd. for C14H20O3Si, 264.1; m/z found, 265.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.55 (d, J=8.4, 1H), 6.57 (dd, J=8.5, 2.0, 1H), 6.51 (d, J=1.9, 1H), 4.60 (s, 2H), 0.99 (s, 9H), 0.26 (s, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][O:5][CH:6]=1.[CH:7]([C:9]1[CH:10]=[C:11](OB(O)O)[CH:12]=[CH:13][CH:14]=1)=[O:8].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1(C)C=CC=CC=1.CCO.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:5]1[CH:6]=[C:2]([C:13]2[CH:14]=[C:9]([CH:10]=[CH:11][CH:12]=2)[CH:7]=[O:8])[CH:3]=[N:4]1
Reactant: Ic1cnoc1
Reactant: O=Cc1cccc(OB(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: O=Cc1cccc(-c2cnoc2)c1
Temperature: 80 °C
Yield: 1.4 %

Procedure:
To a mixture of 4-iodoisoxazole (1 g, 5.13 mmol), 3-formylphenylboric acid (923 mg, 6.15 mmol) and sodium carbonate in DME/H2O/Toluene/EtOH (15 mL, 3/1/10/6, V/V) was added Pd(PPh3)4 (200 mg). The mixture was purged with N2 for 30 min and heated to 80° C. for 3 h. The reaction mixture was cooled followed by a standard aqueous/EtOAc workup and purified by prep-TLC (EA:PE=1:5) to give Intermediate 46 (12 mg, 1.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH:13]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([NH2:18])[CH2:16][NH2:17].C1C(=O)N(Br)C(=O)C1>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[NH:17][CH2:16][CH2:15][N:18]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NCCN
Reactant: O=CCCCc1ccc([N+](=O)[O-])cc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCC2=NCCN2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
The mixture of 4-(4-Nitrophenyl)butanal (64) (0.28 g, 1.45 mmol) and ethylene diamine (0.1 mL, 1.59 mmol) in dry dichloromethane (10 mL) was stirred at 0° C. for 30 min under argon. NBS (0.26 g, 1.59 mmol) was added to the mixture and the resulting solution was stirred overnight at 21° C. Reaction was quenched by the addition of saturated NaHCO3 solution. The mixture was extracted with dichloromethane. The organic layer was dried over MgSO4, and evaporated in vacuo. The residue was purified by flash column chromatography (ethanol:ethyl acetate:triethylamine, 1:1:0.2) to give 2-(3-(4-Nitrophenyl)propyl)-4,5-dihydro-1H-imidazole (62) (0.26 g, 76%): 1H NMR δ 8.14 (d, 2H, J=8.7 Hz) 7.35 (d, 2H, J=8.7 Hz) 3.59 (s, 4H), 2.79 (t, 2H, J=7.7 Hz) 2.26 (t, 2H, J=7.4 Hz) 1.96-2.05 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][C:34]2[NH:38][CH:37]=[N:36][N:35]=2)[CH2:28]1>>[O:18]=[C:17]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:22]([CH2:23][CH2:24][CH3:25])[N:35]2[N:36]=[CH:37][N:38]=[C:34]2[N:33]1[CH:29]1[CH2:30][CH2:31][CH2:32][O:27][CH2:28]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: c1nnc(NC2CCCOC2)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCCOC2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.37 g) and N-(tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-amine (0.088 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.15 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([O:25][C:24]([F:23])([F:34])[F:35])[CH:27]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (495 mg) in DMF (5 mL) was added potassium carbonate powder (763 mg) and 3-(trifluoromethoxy)benzyl bromide (1.41 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:18])[CH2:4][CH2:3]1.[N+:19]([O-])([OH:21])=[O:20]>OS(O)(=O)=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:18])[CH2:4][CH2:3]1
Reactant: CN1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CN1CCC(N2C(=O)CCc3cc([N+](=O)[O-])ccc32)CC1
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A solution of 1-(1-methylpiperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (305 mg, 1.25 mmol) in conc. H2SO4 (4 mL) was treated with fuming HNO3 (53 μL, 1.25 mmol) at −5 to −10° C. (ice/MeOH) and the resulting solution was stirred for 30 min. at the same temperature. The reaction was quenched with the addition of crushed ice, and then basified with 1 N NaOH, and the product was extracted into CH2Cl2 (2×50 mL). The combined CH2Cl2 layer was dried (Na2SO4), filtered, and the solvent was evaporated. The crude was triturated with hexanes to afford the title compound (320 mg, 88.4%) as a solid. 1H-NMR (CDCl3) δ 8.10-8.05 (m, 2H), 7.33 (d, J=8.7 Hz, 1H), 4.50-4.39 (m, 1H), 3.01-2.90 (m, 4H), 2.67-2.54 (m, 4H), 2.33 (s, 3H), 2.15-2.08 (m, 2H), 1.74-1.70 (m, 2H). MS (ESI): 290.2 (M+1, 100%).
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[N+:9](/[CH:12]=[CH:13]/[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)([O-])=O.C[O-].[Na+].C(OC(=O)C)C.CCCCCC>CO.N>[CH3:7][O:6][C:4]([C:3]1[C:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:12][NH:9][C:2]=1[CH3:8])=[O:5]
Reactant: O=[N+]([O-])/C=C/c1cccc2ccccc12
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: N
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1c(-c2cccc3ccccc23)c[nH]c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
0.69 g(5.9 mmol) of methyl 3-oxobutanoate and 1.08 g(5.9 mmol) of 1-[(E)-2-nitroethenyl]naphthalene were added to 2.37 ml of 0.5M sodium methoxide in methanol, and the resulting mixture was stirred for 2 hours at 0° C. The reaction solution was diluted with 10 ml of cold methanol, through which ammonia gas was passed. Reaction was carried out for 12 hours at 0° C. under stirring. After reaction was completed, the solvent was removed under reduced pressure and the residue was subjected to column chromatography(eluent: ethylacetate/hexane=90/10, v/v; ethylacetate/hexane=70/30, v/v) to give 936 mg(3.53 mmol, Yield 59%) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:14]([O:16]CC)=[O:15])[CH:10]=[N:11]2)=[CH:6][CH:5]=1.[OH-].[Na+]>CCO>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:14]([OH:16])=[O:15])[CH:10]=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2cc(C(=O)O)cnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7-methoxy-3-ethoxycarbonylquinoline hydrochloride (Step C, 1.45 g, 5.4 mmol) in EtOH (24 mL) was added at RT 2N NaOH (8 mL, 16 mmol). The reaction was stirred at RT overnight. After concentration under vacuum, the mixture was acidified with 1N HCl. The resulting solid was filtered off, washed with water and dried over P2O5 to give 7-methoxy-3-carboxyquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25](=[O:34])[C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])=[O:23])=[CH:17][N:16]=2)[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:35](Cl)(=[O:39])[C:36](Cl)=[O:37]>ClCCCl>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[C:25]([N:24]1[C:36](=[O:37])[C:35](=[O:39])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:10]([F:12])([F:11])[F:13])=[N:16][CH:17]=2)[C:22]1=[O:23])=[O:34]
Reactant: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(OC(c2ccc(Cl)c(Cl)c2)C(F)(F)F)nc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C1C(=O)N(c2ccc(OC(c3ccc(Cl)c(Cl)c3)C(F)(F)F)nc2)C(=O)N1C(=O)c1c(F)cccc1F
Yield: 73.1 %

Procedure:
To a stirred solution of N-[[[2-[1-(3,4-dichlorophenyl)-2,2,2-trifluoroethoxy]pyridin-5-yl]amino]carbonyl]2,6-difluorobenzamide (1.0 g, 0.002 mole) in 1,2-dichloroethane (10 ml) was added oxalyl chloride (0.24 g, 0.0020 mole). This mixture was heated at reflux for five days. Additional oxalyl chloride (0.24 g) was added, and refluxing was continued for one more day. The solvent was removed from the reaction mixture by distillation under reduced pressure, leaving an oil. This oil was purified by column chromatography on silica gel, elution with toluene: ethyl acetate (9:1), yielding 0.84 g of 1-[(2,6-difluorophenyl)carbonyl]-3-[2-[1-(3,4-dichlorphenyl)2,2,2-trifluoroethoxy]pyridin-5-yl]imidazolidinetrione as a solid (mp 160° C.). The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C@@:13]([NH:24][S@@](C(C)(C)C)=O)([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:14][CH:15]=[CH2:16])[CH3:9])=[CH:4][CH:3]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C@:13]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)([NH2:24])[CH2:14][CH:15]=[CH2:16])[CH3:9])=[CH:4][CH:3]=1
Reactant: C=CC[C@](CCN[C@@H](C)c1ccc(Br)cc1)(N[S@](=O)C(C)(C)C)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CC[C@@](N)(CCN[C@@H](C)c1ccc(Br)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A mixture of (R)—N—((R)-1-((S)-1-(4-bromophenyl)ethylamino)-3-(4-fluorophenyl)hex-5-en-3-yl)-2-methylpropane-2-sulfinamide (16 g, 32.2 mmol) in 4M HCl in dioxane (100 mL, 400 mmol) was stirred for 1 h at 0° C. The mixture was concentrated to give the residue, which was treated with saturated Na2CO3 solution. The resulting mixture was extracted with EtOAc, and the combined organic layers was concentrated to afford (R)—N1—((S)-1-(4-bromophenyl)ethyl)-3-(4-fluorophenyl)hex-5-ene-1,3-diamine (12 g, 100%), which was used for the next step without purification.