Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]2)=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:55]([NH2:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C)C=O.ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]=[C:19]([C:21](=[O:23])[NH:62][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[N:18]=[N:17]2)=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(-n2cc(C(=O)O)nn2)sc1C(=O)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-n2cc(C(=O)NCc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8 %

Procedure:
To a solution of 1-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-1H-1,2,3-triazole-4-carboxylic acid (0.25 g, 0.73 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.12 g, 0.87 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.17 g, 0.87 mmol), N,N-diisopropylethylamine (0.38 mL, 2.19 mmol) and benzylamine (0.095 mL, 0.87 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate (15 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white solid in 8% yield: mp 178-180° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.33 (t, J=6.0 Hz, 1H), 9.24 (s, 1H), 9.02 (t, J=6.0 Hz, 1H), 7.36-7.23 (m, 10H), 4.49-4.46 (m, 4H), 2.63 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 160.1, 158.4, 154.2, 152.4, 143.6, 139.1, 138.9, 128.3, 128.2, 127.3, 127.2, 126.9, 126.8, 125.3, 123.5, 42.8, 42.1, 17.1; MS (ES+) m/z 433.3 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[I:11][C:12]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:13]=1[C:14]#N.C(OCC)(=[O:26])C.Cl>C1(C)C=CC=CC=1.C(Cl)Cl.O.C(O)C>[I:11][C:12]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:26]
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc(C(F)(F)F)cc1I
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(C(F)(F)F)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A 1.0 M solution of diisobutylaluminum hydride in toluene (13 mL, 13 mmol) was added slowly drop-wise to a 0° C. solution of 2-iodo-4-trifluoromethyl-benzonitrile (3.58 g, 12 mmol) in toluene (11 mL). The reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was warmed to room temperature, then stirred at room temperature for 24 hours. The reaction mixture was cooled to 0° C., then ethyl acetate (5 mL), and ethanol (5 mL) were added dropwise to the cold reaction mixture. After stirring at 0° C. for 10 minutes, the reaction mixture was concentrated to give a yellow, oily liquid. The residue was cooled to 0° C. Methylene chloride (10 mL) was added. Water (10 mL) was added slowly drop-wise, then 1.0 N aqueous HCl was added slowly drop-wise. After stirring at 0° C. for 10 minutes, concentrated HCl (1 mL) was added followed by additional methylene chloride (60 mL). The mixture was stirred at 0° C. for 10 minutes, then warmed to room temperature. Stirring at room temperature continued for 105 minutes. The mixture was poured into a separatory funnel, and the organic phase was separated, dried over Na2SO4, filtered, and concentrated to an oily, yellow solid. The crude product was purified using flash chromatography (RediSep® Flash column, 230-400 mesh, 0-3% ethyl acetate in hexanes) to give 1.44 g (40%) of 2-iodo-4-trifluoromethyl-benzaldehyde as a slightly yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 10.11 (s, 1 H), 8.20 (s, 1 H), 7.97 (d, J=8.2 Hz, 1 H), 7.73 (d, J=8.2 Hz, 1 H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:19][C:18]([F:20])([F:21])[C:17]([NH:16][CH2:15][C@@H:12]1[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]1)=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CNC(=O)C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](CNC(=O)C(F)(F)F)CC1
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A solution of 0.53 g of cis-N-(tert-butoxycarbonyl)-4-trifluoroacetylaminomethylcyclohexylamine in methylene chloride was combined with 2 mL of trifluoroacetic acid, and stirred for 2 hours. The reaction solution was basified by addition of a saturated solution of sodium hydrogen carbonate, and then extracted with chloroform. After drying over sodium sulfate, 0.19 g of the desirable compound was obtained as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br>C(Cl)(Cl)Cl.C(OCC)C>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: BrBr
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107 %

Procedure:
4′-Fluoroacetophenone (13.8 g) was dissolved in chloroform (60 mL) and diethyl ether (60 mL), and a solution of bromine (16.0 g) in chloroform (10 mL) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude 2-bromo-1-(4-fluorophenyl)ethanone (23.2 g) as crystals. A solution (20 mL) of ethyl 3-oxobutanoate (11.7 g) in N,N-dimethylformamide was added dropwise to a suspension (50 mL) of sodium hydride (60% in oil, 4.00 g) in N,N-dimethylformamide with stirring under ice-cooling. After stirring at the same temperature for 15 min, a solution (10 mL) of crude 2-bromo-1-(4-fluorophenyl)ethanone (23.2 g) obtained above in N,N-dimethylformamide was added dropwise. The reaction mixture was stirred at room temperature for 2 hr, water was added, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude ethyl 2-acetyl-4-(4-fluorophenyl)-4-oxobutanoate as an oil (yield 23.20 g). Without further purification, the product was stirred with ammonium acetate (11.56 g, 0.15 mol) and acetic acid (100 mL) with heating at 80° C. for 20 hr. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:2). The residue was crystallized from hexane to give the title compound as crystals (yield 13.6 g, from ethyl 3-oxobutanoate, 61%).
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[CH2:6][CH2:5]1.[OH-].[Na+]>C1COCC1>[Cl:14][C:9]1[CH:8]=[C:7]2[C:12](=[C:11]([Cl:13])[CH:10]=1)[CH:4]([NH2:3])[CH2:5][CH2:6]2
Reactant: CON=C1CCc2cc(Cl)cc(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC1CCc2cc(Cl)cc(Cl)c21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of BH3 (0.6 mL, 1M in THF) was added to a solution of 5,7-dichloro-2,3-dihydro-1H-inden-1-one O-methyl oxime (0.31 mmol) in 1 mL THF. The reaction mixture was heated to 60° C. for 3 days. An aq. 1M NaOH solution was added and heating to 60° C. was continued for another 24 h. The solvent was removed under vacuo, the residue was diluted with a sat. aq. NaHCO3 solution and extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[C:14]([C:16]1[N:17]=[CH:18][NH:19][CH:20]=1)[CH3:15])([O-])=O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[C:14]([C:16]1[N:17]=[CH:18][NH:19][CH:20]=1)[CH3:15]
Reactant: CC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1c[nH]cn1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=C1C(=O)Nc2ccc(N)cc21)c1c[nH]cn1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
5-nitro-3-[1-(imidazol-4-yl)ethylidene]indolin-2-one (0.55 g, 2 mmol) was suspended in ethyl acetate (50 mL) and tin chloride (4.6 g, 20 mmol) was added. The resulting reaction mixture was heated overnight to 70° C. The reaction mixture was then cooled to ambient temperature and sodium bicarbonate solution was added. Extraction with ethyl acetate afforded 0.4 g of 5-amino-3-[1-(imidazol-4-yl)ethylidene]indolin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](Cl)[N:3]=1.[NH3:12]>C(O)C>[NH2:12][C:4]1[N:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCO
Product: Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
To a solution of commercially available 2,6-dichloro-5-nitropyridine (20.0 g, 95.3 mmol) in ethanol (300 mL) was added aqueous ammonia (60 mL), and the mixture was stirred at room temperature for 10 hours. The resulting precipitate was filtered, washed with ethanol, and dried in vacuo to give 6-amino-2-chloro-5-nitropyridine (13.8 g, 83%). The compound thus obtained was suspended in an acetic acid solution (130 mL) of 30% hydrogen bromide. The suspension was stirred at 100° C. for 26 hours, cooled to room temperature, and concentrated in vacuo. The resulting residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue thus obtained was recrystallized from ethyl acetate to give the title compound (14.93 g, 86%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C:14]1[C:23](=[O:24])[C:22]([CH2:28][CH2:29][CH3:30])([CH2:25][CH2:26][CH3:27])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[OH:31])=O)(=[O:4])=[O:3].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>[OH-].[K+]>[O:4]=[S:2]1(=[O:3])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:12]([C:14]2[C:23](=[O:24])[C:22]([CH2:28][CH2:29][CH3:30])([CH2:25][CH2:26][CH3:27])[C:21]3[C:16]([C:15]=2[OH:31])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:1]1
Reactant: CCCC1(CCC)C(=O)C(C(=O)Nc2ccccc2S(N)(=O)=O)=C(O)c2ccccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 130 °C
Reaction time: 30 h
Yield: 57.5 %

Procedure:
A suspension of the product of Example 1G (150 mg, 0.34 mmol) in 10% potassium hydroxide solution (9 mL) was stirred at 130° C. for 30 hours, cooled to 25° C., acidified to pH 3 by addition of 1 M citric acid, stirred with ethyl acetate, and filtered through celite®. The organic layer from the filtrate was washed with saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo. The residue was recrystallized from ether-hexane solution to afford the title compound (83 mg, 57%). 1H NMR (300 MHz, CDCl3): δ16.70 (s, 1 H), 14.22 (s, 1 H), 8.26 (d, J=8.09 Hz, 1 H), 7.99 (d, J=8.09 Hz, 1 H), 7.67 (m, 1 H), 7.47 (m, 3 H), 7.29 (m, 2 H), 2.25 (m, 2 H), 1.86 (m, 2 H), 0.89 (m, 2 H), 0.70 (m, 8 H).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1)(=[O:12])[CH3:11]>[Cu]I.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>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:22]#[C:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][S:13][C:10](=[O:12])[CH3:11])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(I)cc1
Reactant: C#Cc1ccc(CSC(C)=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(=O)SCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reaction time: 0.05 h
Yield: 88.3 %

Procedure:
Samples of 4-iodobenzaldehyde (1.18 g, 5.00 mmol), 7 (950 mg, 5.00 mmol), CuI (52 mg, 270 μmol) and Pd(PPh3)2Cl2 (23 mg, 33 μmol) were placed in a Schlenk flask. The flask was evacuated via vacuum pump for 3 min and then the flask was backflushed with argon for 3 min. The process of evacuation and flushing was repeated 3 times. At this point the argon flow rate was increased and the threaded stopcock was removed. Deareated THF (5.0 mL) and DIEA (5.0 mL) were added in succession to the flask by gastight syringe. The threaded stopcock was replaced, the argon flow rate was reduced and the flask was immersed in an oil bath thermostated at 40° C. The reaction was stopped after 40 h. The mixture was then filtered and evaporated. The resulting orange-brown solid was chromatographed (silica, CH2Cl2/hexanes, 2:3, then 1:1, then 3:2) to afford yellowish-white crystals. Recrystallization (ethyl acetate/heptane) gave 1.30 g (88.2%) of white crystals. mp 128–129° C.; 1H NMR δ 2.49 (s, 3H), 4.07 (s, 2H), 7.25, 7.43 (AA′BB′, 2×2H), 7.59, 7.79 (AA′BB′, 2×2H), 9.95 (s, 1H); 13C NMR δ 30.9, 33.9, 89.5, 93.9, 122.1, 129.8, 130.1, 130.2, 132.7, 132.7, 136.1, 139.5, 192.0, 195.4; FAB-MS obsd 294.0717, calcd exact mass 294.0715; Anal. Calcd. for C18H14O2S: C, 73.44; H, 4.79; S, 10.89; Found: C, 73.18; H, 4.82; S, 10.88.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)(=[O:37])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:22][CH:21]([CH3:23])[CH:20]=[C:19]([C:42]1[CH:43]=[C:38]([C:35](=[O:37])[CH3:36])[CH:39]=[CH:40][CH:41]=1)[C:11]1[N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Yield: 56.2 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.0 mmol), 3-acetylphenylboronic acid (2.5 g, 15 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.42 g, 0.6 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated in a microwave at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a saturated aqueous sodium bicarbonate solution (2×50 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (40 g, 10% ethyl acetate/petroleum ether) afforded 1-(3-(3-methyl-1-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)but-1-enyl)phenyl)ethanone (1.5 g, 56.3%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.49 (dd, 1H, J1=4.8 Hz, J2=1.8 Hz), 7.90 (dd, 1H, J1=7.8 Hz, J2=1.5 Hz), 7.81 (dd, 1H, J1=8.1 Hz, J2=1.8 Hz), 7.68-764 (m, 3H), 7.45-7.16 (m, 6H), 6.58 (s, 1H), 6.18 (d, 1H, J=10.2 Hz), 2.67-2.65 (m, 1H), 2.44 (s, 3H), 1.17-1.12 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:11]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+]>O1CCCC1.CN(C)C=O.O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)CC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])nc1
Yield: 35.8 %

Procedure:
To a mixture of 5-bromo-2-nitropyridine (8.66 g, 42.7 mmol) and benzyl ethyl malonate (9.50 g, 42.7 mmol) in tetrahydrofuran (160 ml) and dimethylformamide (40 ml) was added K2CO3 (5.90 g, 42.7 mmol) and stirred under reflux temperature for 20 h. The mixture was diluted with water (1 l) and extracted with ethyl acetate (3×200 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to give 5.26 g of title compound as orange oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:15]([O:17][N:18]([CH3:20])[CH3:19])=[O:16])=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)=[N:4]1.CS([C:25]1[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[N:26]=1)(=O)=O.P(=O)(O)(O)O>CN(C)C=O.C(OCC)(=O)C.O>[NH:3]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:15]([O:17][N:18]([CH3:20])[CH3:19])=[O:16])=[C:10]([O:14][C:25]3[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[N:26]=3)[CH:11]=[CH:12][CH:13]=2)=[N:4]1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CN(C)OC(=O)c1c(O)cccc1-c1cc[nH]n1
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(-c3cc[nH]n3)c2C(=O)ON(C)C)n1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
At 10° C., 0.30 g (0.01 mol) of sodium hydride (80% strength) is added to a solution of 2.47 g (10 mmol) of 3-pyrazolyl-2-(N,N-dimethylaminooxycarbonyl)-phenol in 25 ml of anhydrous dimethylformamide, and the reaction mixture is stirred for 3 hours at 30° C. 2.18 g (0.01 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine is added and the mixture is stirred for 12 hours at room temperature. The reaction mixture is introduced into 500 ml of water to which 2.5 ml of orthophosphoric acid has previously been added. The oil which separates out is taken up in ethyl acetate and dried over sodium sulfate. The greasy residue remaining after evaporation is purified to give a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7](=[O:24])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][C:17]1[C:18](=[O:23])[NH:19][CH:20]=[CH:21][CH:22]=1.[CH:28]1([CH2:31]Cl)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7](=[O:24])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][C:17]1[C:18](=[O:23])[N:19]([CH2:31][CH:28]2[CH2:30][CH2:29]2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(CC1CCCCN1CCc1ccc[nH]c1=O)NCc1cccc(F)c1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC1CCCCN1CCc1cccn(CC2CC2)c1=O)NCc1cccc(F)c1

Procedure:
230 mg of N1-(3-fluorobenzyl)-2-[1-[2-(2-oxo-1,2-dihydro-3-pyridinyl)ethyl]-2-piperidyl]acetamide obtained in Example 198, 0.08 ml of cyclopropylmethyl chloride, 450 mg of potassium carbonate and 5 ml of DMF were stirred at 60° C. for 1 hour. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate. The drying agent was filtered off, and the solvent was evaporated. The residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=1:1, subsequently ethyl acetate), to give 180 mg of a colorless oil.
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][N:27]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.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.[Cu]I>[OH:25][C:26]1[N:27]=[CH:28][C:29]([C:12]#[C:11][C:9]2[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=2)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:30][CH:31]=1
Reactant: Oc1ccc(I)cn1
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(O)nc2)c1)c1ccccc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
A solution of (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]-nicotinamide (150 mg, 0.42 mmol) and 2-hydroxy-5-iodopyridine (105.4 mg, 0.46 mmol) in DMF (2.1 mL) was degassed (vacuum and argon). The resulting solution was treated tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.021 mmol), triethylamine (0.08 mL, 0.55 mmol), and CuI (8 mg, 0.042 mmol). The reaction mixture was then heated to 85° C. and tetrabutylammonium fluoride (1.0 M solution in THF, 0.46 mL, 0.46 mmol) was added dropwise over 10 min. The reaction was allowed to be stirred at 85° C. for 2 hours. The reaction mixture was partitioned between EtOAc and H2O. The organic extracts and associated solid were collected and concentrated. The residue was purified by chromatography (silica gel, gradient elution MeOH—CHCl3: 1:100-1:4). The product containing fractions were collected, concentrated, and the brown solid residue was triturated with a combination of MeOH and EtOAc. The resulting mixture was filtered and the filtrate allowed to stand at room temperature. The solid which precipitated from solution was collected and dried to give the title compound as a white solid (11 mg).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]([OH:31])([CH3:30])[CH2:12][N:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[O:15][C:14]2=[O:29])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>O1CCOCC1>[CH3:30][C:11]1([CH2:12][N:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[O:15][C:14]2=[O:29])[O:31][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC(O)(Cn1cc([N+](=O)[O-])nc1Cl)Cn1nc(-c2ccc(OC(F)(F)F)cc2)oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(Cn2nc(-c3ccc(OC(F)(F)F)cc3)oc2=O)Cn2cc([N+](=O)[O-])nc2O1
Yield: 47.5 %

Procedure:
To a solution of 3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one prepared in Example 516 (3.27 g, 7.05 mmol) in 1,4-dioxane (70 ml), sodium hydride (0.37 g, 9.17 mmol) was added with cooling on ice-bath followed by stirring under reflux for 3 hours. The reaction mixture was concentrated under reduced-pressure. To the solution, water was added with cooling on ice-bath, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=4/1) and recrystallized from acetonitrile-ethanol to afford 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (1.43 g, yield 48%) as a white solid.