Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([C:11]3[N:12]=[CH:13][N:14]4[CH:18]=[CH:17][S:16][C:15]=34)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].C(=O)([O-])O.[Na+].[C:30]([O:36][CH2:37]I)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:21][CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:20])=[C:8]([C:11]3[N:12]=[CH:13][N:14]4[CH:18]=[CH:17][S:16][C:15]=34)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ncn4ccsc34)[C@H](C)[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ncn4ccsc34)[C@H](C)[C@H]12
Temperature: -30 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 27 mg of sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.5 ml of DMF was added 4.0 mg of sodium hydrogen carbonate, and the mixture was cooled to −30° C. under the atmosphere of argon. Pivaloyloxymethyl iodide (30 mg) was added, and the reaction mixture was stirred at −20-−30° C. for 1 hour. The reaction mixture was diluted with 20 ml of ethyl acetate and 10 ml of semi-saturated aqueous saline, and the mixture was stirred and separated. The organic layer was washed with semi-saturated aqueous saline, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to a volume of about 1 ml. It was purified by column chromatography on silica gel (ethyl acetate-ethyl acetate:methanol=97:3), and the solvent was concentrated under reduced pressure to a volume of about 0.5 ml and added dropwise to isopropyl ether. The resulting precipitate was collected by filtration, and desiccated under reduced pressure to give 17 mg of the title compound.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[C:13](C#N)[CH:12]=2)=[CH:7][CH:6]=1.C[CH2:39][N+:40](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:39]#[N:40])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(F)c(C#N)c3)cc2)C(N)=O)CCOCC1
Reactant: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(C#N)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(3′-cyano-4′-fluorobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 22, step (i), 366 mg) in dichloromethane (5 mL) was treated with Burgess' reagent (205 mg) and the mixture was stirred at room temperature for 18 h. The reaction mixture was evaporated to afford the sub-titled compound as a crude mixture (336 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8](=[O:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@@H:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(=O)c1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](O)C[C@H](O)COC(=O)c1ccccc1
Temperature: 50 °C
Yield: 82.3 %

Procedure:
To (S)-6-benzoyloxy-3-oxo-5-hydroxyhexanoic acid tert-butylester (161 mg, 0.50 mmol) and RuBr2(S)-BINAP (4.4 mg, 0.0050 mmol) (BINAP was 2,2′-bisdiphenylphosphino-1,1′-binaphthyl), 2 mL of a methanol-water (10/1) solution was added to completely dissolve the (S)-6-benzoyloxy-3-oxo-5-hydroxyhexanoic acid tert-butylester and RuBr2(S)-BINAP in an argon atmosphere. Hydrogen replacement at −78° C. was performed three times. After the temperature of the resulting mixture had increased to 50° C., the mixture was allowed to react for twenty hours under a hydrogen pressure of 5.0 kg/cm2. After extraction of hydrogen, the mixture was condensed and purified by silica gel column chromatography. As a result, 133.4 mg (82%) of (3S, 5S)-6-benzoyloxy-3,5-dihydroxyhexanoic acid tert-butylester was obtained. The diastereomer ratio determined by high performance liquid chromatography (HPLC) analysis was (3R, 5S):(3S, 5S)=10.4/89.6.
Reaction SMILES: [CH:1]1([N:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][C:8]([C:19]([O:21]C)=[O:20])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].CO.OS(O)(=O)=O>O>[CH:1]1([N:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][C:8]([C:19]([OH:21])=[O:20])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(-c2ccccn2)c(=O)n(C2CCCC2)c1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2ccccn2)c(=O)n(C2CCCC2)c1
Yield: 88.9 %

Procedure:
The pyridone (Step 3, 57 mg, 0.19 mmol) and lithium hydroxide (16 mg, 0.38 mmol) were stirred at room temperature in a solution of 2 mL of MeOH and 0.3 mL of H2O, for 2 h. The reaction mixture was diluted with water and the pH was adjusted to pH ˜2 with concentrated H2SO4. The mixture was extracted 3×20% IPA:CHCl3 and the combined organic fractions were dried over MgSO4 and concentrated. The crude residue was purified to obtain the title compound as a white powder (48 mg, 89%). MS m/z: 285 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](B(O)O)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.[C:19]([O-:22])(=[O:21])[CH3:20].[C:23]([O-:26])(=[O:25])[CH3:24].[C:27]([O-:30])(=[O:29])[CH3:28].C([O-])(=O)C.[Pb+4:35].CCCCCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:19]([O-:22])(=[O:21])[CH3:20].[C:23]([O-:26])(=[O:25])[CH3:24].[C:27]([O-:30])(=[O:29])[CH3:28].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([Pb+3:35])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: [Pb+4]
Reactant: CCc1cc(-c2ccc(Cl)cc2)ccc1B(O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1[Pb+3]
Temperature: 25 °C
Yield: 58.3 %

Procedure:
4′-Chloro-3-ethylbiphen-4-ylboronic acid (4.2 g, 0.016 mol) is added in one portion to a mixture of lead tetraacetate (7.86 g, 0.017 mol) and mercuric acetate (0.25 g, 5 mol %) in chloroform (23 ml) under an atmosphere of nitrogen. The reaction mixture is stirred at ambient temperature until dissolution is complete, and then heated at 40° C. for 4 hours. The reaction mixture is cooled to ambient temperature, filtered through a plug of diatomaceous earth and the filtrate is concentrated under reduced pressure to give an orange solid. Trituration with hexane (50 ml) affords a yellow solid which is dried under high vacuum. This solid is then dissolved in chloroform (100 ml), anhydrous potassium carbonate (26.7 g, 0.19 mol) is added and the suspension is stirred rapidly for 10 minutes. The mixture is filtered through a plug of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give 4′-chloro-3-ethylbiphen-4-yllead triacetate (5.6 g) as a cream solid.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH:4](F)F.[Li]CCCC.[C:14]1([Sn:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[F:1][C:2]([F:8])([F:7])[C:3]#[C:4][Sn:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: FC(F)CC(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: FC(F)(F)C#C[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
The triphenylstannane derivative was prepared using a modified procedure of Brisdon (Chem. Commun. 2002, 2420-2421). Accordingly, 1,1,1,3,3-pentafluoropropane (2.0 g, 14.9 mmol) was condensed into a 500 mL three neck round bottom flask containing ether (20 mL) cooled to −15° C. The mixture was maintained below −10° C. while n-BuLi (2.5 M in hexanes, 16.08 mL, 40.2 mmol) was added. After the reaction was stirred for 10 minutes at −10° C., triphenyl tin chloride (5 g, 13.4 mmol) was added as a solution in ether, maintaining −10° C. The mixture was slowly warmed to room temperature and allowed to stir for an additional 4 hours. An excess of hexanes (300 mL) was added and then the settled mixture was filtered through Celite®. Concentration of the filtered solution in vacuo afforded a pale yellow solid which was purified by column chromatography (SiO2: ether/hexanes, 1:10) affording 5.2 g (78%) of the triphenylstannane derivative as an off white solid.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10]([CH3:18])=[N:9]1)C1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[CH3:18][C:10]1[C:11]([CH2:13][C:14]([F:16])([F:15])[F:17])=[CH:12][NH:8][N:9]=1
Reactant: [H][H]
Reactant: Cc1nn(Cc2ccccc2)cc1CC(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1n[nH]cc1CC(F)(F)F
Yield: 51 %

Procedure:
To a solution of 1-benzyl-3-methyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole (compound 314.5, 700 mg, 2.75 mmol) in methanol (10 mL) was added palladium on carbon (700 mg, 10 wt. %) and HCl (4 M) (3 mL). The reaction mixture was hydrogenated for 48 h at room temperature under 1 atmosphere of hydrogen. The solids were removed via filtration. The filtrate was evaporated under reduced pressure and diluted with 50 mL of water. The pH of the solution was adjusted to 7 with NaOH (2 M). The aqueous phase was extracted with 5×20 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 230 mg (51%) of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH2:9][CH3:10])[N:3]=1.O.[NH2:12][NH2:13]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:12][NH2:13])[N:5]=[C:4]([CH2:9][CH3:10])[N:3]=1
Reactant: NN
Reactant: CCc1nc(Cl)cc(Cl)n1
Solvent: CO
Solvent: O
Product: CCc1nc(Cl)cc(NN)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a stirred, cold (0° C.) solution of 60 g (0.34 mole) of 4,6-dichloro-2-ethylpyrimidine in 500 ml of methanol was added 35 g (0.7 mole) of hydrazine hydrate while maintaining the temperature below 10° C. Stirring was continued for 2 hours after completion of the addition, the temperature being maintained at 0° C. The mixture was allowed to warm to about 20° C. and was stirred for 16 hours. The white solid was collected by filtration and the filtrate was partially evaporated to provide a second crop. The combined solids were washed with water and air dried to provide 51 g (77%) of 4-chloro-2-ethyl-6-hydrazinylpyrimidine, m.p. 147°-150° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:3]=1.[Cl:23]N1C(C)(C)C(=O)N(Cl)C1=O>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: COC(=O)c1cc(N)c(F)c(-c2ccc(Cl)c(OC)c2F)n1
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of methyl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-picolinate (0.5 g, 1.52 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.30 g, 1.52 mmol) in acetonitrile (10 mL) was heated to reflux for 1.5 h. Upon cooling to room temperature, the reaction mixture was concentrated under vacuum and then purified by silica gel chromatography (100% hexane to 100% EtOAc gradient) to give a light brown solid (0.53 g, 100%): mp 169-170.5° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.4 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.15 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.8 (s), 153.1 (d, J=253 Hz), 146.3 (s), 144.5 (d, J=4 Hz), 143.7 (s), 142.8 (dd, J=227, 14 Hz), 136.4 (d, J=13 Hz), 128.6 (d, J=3 Hz), 125.9 (s), 125.5 (d, J=4 Hz), 122.9 (dd, J=14, 4 Hz), 113.0 (d, J=3 Hz), 61.6 (d, J=4 Hz), 52.7 (s). Anal. Calcd for C14H10Cl2F2N2O3: C, 46.30; H, 2.78; N, 7.71. Found: C, 46.60; H, 2.68; N, 7.51.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].C(N(CC)CC)C.Br[C:15]1[C:16]([F:23])=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=1>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)I.CCOC(C)=O>[F:23][C:16]1[C:15]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:21][OH:22]
Reactant: C#C[Si](C)(C)C
Reactant: OCc1cccc(Br)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(CO)c1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere, ethynyl(trimethyl)silane (9.0 ml) was mixed with triethylamine (50 ml), and (3-bromo-2-fluorophenyl)methanol, bis(triphenylphosphine)palladium chloride (II) (1.54 g), and copper iodide (420 mg) were added thereto, followed by stirring at 90° C. overnight. The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {2-fluoro-3-[(trimethylsilyl)ethynyl]phenyl}methanol (4.88 g).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])C>C(=O)([O-])[O-].[K+].[K+].C(#N)C.Cl>[CH2:17]([O:16][C:13]([NH:1][C@H:2]([C:10]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:11])[CH3:3])=[O:15])[C:18]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 39 %

Procedure:
To a solution of L-phenylalanine (0.33 g, 2.0 mmol) in 0.20M potassium carbonate (20 mL) and acetonitrile (30 mL) was added dropwise a solution of N-benzyloxycarbonyl-L-alanine N-carboxyanhydride (0.45 g, 1.8 mmol) in acetonitrile (5 mL) at 0° C. The mixture was stirred 40 min at 0° C. and diluted with ethyl acetate (50 mL) and 1M hydrochloric acid (10 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (2×35 mL). The combined organic fractions were washed with brine (30 mL), 0.5M hydrochloric acid (2×50 mL) and water (2×50 mL), dried (MgSO4) and concentrated. The residue was recrystallized from chloroform/hexane to give 0.26 g (39%) of N-benzyloxycarbonyl-L-alanyl-L-phenylalanine: mp 121°-122° C.; NMR (DMSO-d6) δ 12.71 (s, 1 H), 8.06 (m, 1 H), 7.30 (m, 5 H), 5.01 (s, 2 H), 4.43 (m, 1 H), 4.06 (m, 1 H), 2.99 (m, 2 H), 11.19 (d, 2 H, J=7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15]Cl)[CH:6]=[C:5]2[CH:19]=[O:20].C([O-])(=[O:23])C.[Na+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:23])[CH:6]=[C:5]2[CH:19]=[O:20]
Reactant: CC(C)(CCl)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(CO)Cn1cc(C=O)c2cc(Br)ccc2c1=O

Procedure:
A solution of 6-bromo-2-(3-chloro-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Example 26c, 20 g) in DMSO (140 mL) was treated with sodium acetate (55 g) under nitrogen. The resulting mixture was stirred at 135° C. for 48 h during which more sodium acetate was added after 6 h (55 g), 24 h (55 g) then 30 h (22.5 g).
Reaction SMILES: Cl.NNC(N[N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=N.FC(F)([O:21]C1C=CC(C=NO)=CC=1)C(F)F>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]=[N:7][OH:21])=[CH:10][CH:11]=1
Reactant: ON=Cc1ccc(OC(F)(F)C(F)F)cc1
Reactant: N=C(NN)NN=Cc1ccc(Cl)cc1
Agent: Cl
Product: ON=Cc1ccc(Cl)cc1

Procedure:
Using a similar procedure, 1-amino-3-p{[p-(1,1,2,2-tetrafluoroethoxy)benzylidene]amino}guanidine hydrochloride (white solid, mp 205°-212° C.); 1-amino-3-{p-(trifluoroethoxy)benzylidene]amino}guanidine hydrochloride (white powder; mp 235°-238° C.); and 1-amino-3-(p-chlorobenzylideneamino)guanidine hydrochloride may be prepared. The second products of the reactions, p-(1,1,2,2-tetrafluoroethoxy)benzaldehyde oxime (pinkish white solid, mp 47°-53.5° C.); α,α,α-trifluoro-p-anilaldehyde oxime (off-white solid, mp 46°-49.5° C.) and p-chlorbenzaldehyde oxime may also be isolated from the reactions.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:25](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:25])[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 5-(benzyloxy)-1H-indole-2-carboxylate (5.00 g, 16.93 mmol) and methyl iodide (1.14 mL, 18.28) in 17 mL dimethylformamide was added potassium carbonate (2.57 g, 18.62 mmol). The resulting suspension was stirred for 2 h at 150° C. in a sealed reaction vessel. Solids were filtered and the liquor concentrated to give crude ethyl 5-(benzyloxy)-1-methyl-1H-indole-2-carboxylate. Used without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[S:9](=O)(=[O:12])([OH:11])[OH:10]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:8]=[C:7]([S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccc1Cl
Solvent: Clc1ccccc1Cl
Product: Nc1ccc(S(=O)(=O)O)cc1Cl
Reaction time: 4.3 h

Procedure:
Starting from 293.5 g of 2-chloroaniline, 460 ml of o-dichlorobenzene and 225.5 g of monohydrate, the reaction was performed as in Example 4. After 4.3 hours at 200° C., the mixture was cooled, filtered off with suction and dried. The isolated solid weighed 489.3 g and contained 51.1% of 2-chloroaniline-4-sulphonic acid, based on the use of 2-chloroaniline, with a selectivity of 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([O:19]CC)=[O:18])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:14])[F:15])=[C:11]([C:17]([OH:19])=[O:18])[N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncn(-c2ccc(Cl)cc2)c1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of ethyl 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-imidazole-4-carboxylate (800 mg, 2.51 mmol) in EtOH (20 mL) was added a predissolved solution of sodium hydroxide (1004 mg, 25.1 mmol) in Water (5.00 mL). The reaction was stirred overnight at room temperature. The next day, the reaction was concentrated in vacuo, acidified with dilute HCl and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated to give 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid (400 mg, 1.376 mmol, 54.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.3 (1H, br s), 8.19 (1H, dd), 7.68 (2H, d), 7.72 (2H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]([CH3:22])[CH3:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH:23](=[O:26])[C:24]#[CH:25]>C1COCC1.CC(C)=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[N:9](/[CH:25]=[CH:24]/[CH:23]=[O:26])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1
Reactant: C#CC=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O

Procedure:
A solution of 4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazole (200 mg) and propiolaldehyde (75% solution in toluene, 0.15 ml) in dry THF (15 ml) were heated under reflux, under nitrogen for 24 h. The residue was dissolved in acetone and absorbed onto silica gel before purifying by CC eluting with petroleum ether (b.p. 40°-60°)/ethyl acetate (2:1) to give the title compound (84 mg) as a pale yellow solid, δ(CDCl3), 1.49 (d,J=7 Hz, Me2CH), 3.25 (septet, J=7 Hz, Me2CH), 5.67 (dd,J=15 Hz, 7 Hz,CH=CH.CHO), 6.95 and 7.10-7.60 (t,J=9 Hz and m, CH=CH.CHO and aromatic protons), 9.40 (d, J=7 Hz, CH=CH.CHO).
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:29]([NH2:32])[C:30]#[CH:31]>C1COCC1>[CH2:1]([N:8]1[CH2:9][C:10](=[O:12])[N:32]([CH2:29][C:30]#[CH:31])[C:14](=[O:16])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Reactant: C#CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C#CCN1C(=O)CN(Cc2ccccc2)CC1=O
Yield: 61.9 %

Procedure:
To a suspension of N-benzyliminodiacetic acid (10 mmol) in THF (30 ml), 1,1′-carbonyldiimidazole (22 mmol) is added with stirring. The reaction mixture is refluxed with stirring for 15 minutes. Propargylamine (100 mmol) is added and then reaction mixture is stirred at 90° C. for 1 day. The organic solvent is evaporated and then the residue is dissolved in AcOEt. The organic layer is washed with 2×100 ml 0.1N HCl and then dried over sodium sulfate. The solvent is concentrated under vacuum. The purification of the residue by silica gel column chromatography affords 1.5 g of title compound in 62% yield. Rf=0.24 (n-hexane:AcOEt=3:1)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21]O)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].S(Cl)([Cl:38])=O.CN(C=O)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:38][CH2:21][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[N:23]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:13]([C:9]3[C:7]4=[N:8][C:3]([O:2][CH3:1])=[C:4]([O:34][CH3:35])[CH:5]=[C:6]4[N:11]([CH3:12])[CH:10]=3)=[CH:14][C:15]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CO)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(nc1OC)c(-c1cc3c(CCl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reaction time: 2 h

Procedure:
To a solution of 4.2 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]methanol in 50 cm3 of dichloromethane, at a temperature in the region of 20° C., are added 0.747 cm3 of thionyl chloride and 0.3 cm3 of DMF. The reaction medium is stirred at this same temperature for 2 hours. Ice is added and the reaction medium is then neutralized with saturated sodium hydrogencarbonate solution. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/ethyl acetate 95/05 by volume as eluents), 2.64 g of 3-[4-chloromethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine are obtained with the following characteristics: