Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([Cl:5])(=O)C.[CH2:6]([O:13][C:14]([N:16]([CH:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C>CO>[ClH:5].[CH2:6]([O:13][C:14]([N:16]([CH:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]1)[CH2:17][CH2:18][CH3:19])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN(C(=O)OCc1ccccc1)C1CCNCC1
Reaction time: 0.17 h

Procedure:
To a solution of 2.4 mmol of HCl in 2 mL of methanol (prepared by the addition of 0.17 mL of acetyl chloride at 0° C. and stirring for 10 min) was added 90 mg of 4-(N-(benzyloxycarbonyl)-N-(prop-1-yl)amino)-1-t-butoxycarbonylpiperidine. The mixture was stirred at rt for 16 h at which time the reaction was complete by TLC (20% ethyl acetate in hexanes) and was evaporated to dryness in vacuo to afford 75 mg of the title compound as the hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([OH:21])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(#N)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:19])[CH3:20])[N:11]=[C:10]([O:21][S:33]([CH3:32])(=[O:35])=[O:34])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(OS(C)(=O)=O)nc1C(C)C
Temperature: 2.5 °C
Yield: 89.2 %

Procedure:
In a 100 mL-volume glass flask were placed 10.0 g (34.4 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 5.22 g (58.5 mmol.) of triethylamine, and 34 mL of acetonitrile. The mixture in the flask was chilled to 0-5° C. in an ice bath. To the chilled mixture was slowly added 5.12 g (44.7 mmol.) of methanesulfonyl chloride, and the resulting mixture was subjected to reaction at 20-25° C. for 2 hours. After the reaction was complete, to the reaction mixture was added 60 mL of water. The aqueous reaction mixture was extracted with toluene and the toluene portion was separated. The toluene portion was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The dried mixture was filtered and concentrated under reduced pressure. The residue was crystallized from methanol, to give 11.3 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine as a colorless crystalline product having the below-mentioned characteristics. The yield was 89% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[CH3:5][C@H:6]1[CH2:11][CH2:10][NH:9][C@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1>CCO>[CH3:5][C@H:6]1[CH2:11][CH2:10][NH:9][C@H:8]([C:12]([O:14][CH2:1][CH3:2])=[O:13])[CH2:7]1
Reactant: CC(=O)Cl
Reactant: C[C@H]1CCN[C@H](C(=O)O)C1
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@@H](C)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of dry EtOH (65 mL) and acetyl chloride (6.52 mL added dropwise at 0° C.) was added (2S, 4S)-4-methyl pipecolic acid (2.8 g, 19.6 mmol at room temperature. The reaction was stirred at room temperature for 16 hrs and then concentrated in vacuo to give the title compound, (3.01 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:8]1=[O:25].C([Sn](CCCC)(CCCC)[C:36]([O:38]CC)=[CH2:37])CCC>C1(C)C=CC=CC=1.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>[C:36]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[C:8](=[O:25])[N:7]([CH2:6][C:5]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:16]2=[O:17])(=[O:38])[CH3:37]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(Cn2c(=O)c3cc(I)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2c(=O)c3cc(C(C)=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 130 °C
Reaction time: 48 h

Procedure:
A mixture of 1 g of 3-(3,4-dimethoxybenzyl)-6-iodo-1-(tetrahydro-2H-pyran-4-yl)-quinazoline-2,4(1H,3H)-dione, 1.3 ml of tributyl(1-ethoxyvinyl)tin and 0.04 g of Pd(PPh3)4 in 20 ml of toluene is heated for 1 hour at 130° C. and then stirred for 48 hours at room temperature. The solvent is evaporated off under reduced pressure. The residue is taken up in EtOAc and washed four times with 4N HCl and then with water. The organic phase is dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (80/20, v/v) to give 0.84 g of the expected product.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:10]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[NH:12][C:11]1=[O:20].CCOC(C)=O>C1COCC1.O>[Cl:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:20])[C:10]2([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)COC1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21
Reaction time: 0.17 h
Yield: 36 %

Procedure:
Under nitrogen atmosphere, to a solution of 12.9 g of methyl glycolate in THF (250 ml), under room temperature, was added 3.43 g of NaH, and the reaction mixture was stirred for 10 minutes at the same temperature. Under room temperature, 22.0 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one was added to the reaction solution and the reaction mixture was stirred for 10 minutes. To the reaction solution was added EtOAc and water and the mixture was stirred for 5 minutes. Liquid separation was performed, the aqueous layer was extracted with EtOAc, the combined organic layer was washed with 1 mol/L hydrochloric acid and saturated brine, then, was dried over MgSO4, the drying agent was separated by filtration, then, the solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc) to obtain 9.30 g of an orange solid. The obtained solid was crystallized from Et2O to obtain 8.18 g of the title compound (pale yellow crystal).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.S(Cl)([Cl:27])=O>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:27])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ncnc2cc(OCc3ccccc3)ccc12
Yield: 89 %

Procedure:
A mixture of 7-benzyloxy-3,4-dihydroquinazolin-4-one (1 g, 43.6 mmol) and DMF (1 ml) in thionyl chloride (100 ml) was heated at reflux for 1.5 hours. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene. The residue was partitioned between methylene chloride and water and saturated aqueous sodium hydrogen carbonate was added until the aqueous layer was at about pH9. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated to give 7-benzyloxy-4-chloroquinazoline (10.5 g, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=O)[NH:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:15].[N:20]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[O:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(#N)C>ClC1C=CC=CC=1Cl>[ClH:15].[N:20]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[O:30][CH2:31][CH2:32][CH2:33][NH:34][C:6]2[C:5]3[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=3[S:8](=[O:10])(=[O:9])[N:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1NS(=O)(=O)c2cc(Br)ccc21
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC#N
Solvent: Clc1ccccc1Cl
Product: Cl
Product: O=S1(=O)N=C(NCCCOc2cccc(CN3CCCCC3)c2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4.00 g (15 mmol) 6-bromo-1,2-benzisothiazol-3(2H)-one 1,1-dioxide and 3.57 g (17 mmol) phosphorus pentachloride in 5 ml o-dichlorobenzene is heated from ambient temperature to 160° C. over one hour and is held at that temperature for one additional hour. Upon cooling, liquids are removed in vacuo and the residual 6-bromo-3-chlorobenzisothiazole 1,1-dioxide is suspended in acetonitrile and added portionwise to a solution of 3.7 g (15 mmol) 3-[3-[(1-piperidinyl)methyl]phenoxy]propylamine in refluxing acetonitrile. Heating at reflux is continued for one hour after completion of the addition, after which the reaction mixture is cooled to room temperature. The solution is decanted away from a small quantity of gum and the solvent is removed on a rotoevaporator. The resulting oil is dissolved in absolute ethanol, from which the title compound precipitates. m.p. 217°-220° C. IR (KBr) 1625, 1290, 1165, 1150 cm-1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][N:20]4[CH:24]=[N:23][CH:22]=[N:21]4)[C:16](=[O:25])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(O)C>N1C=CC=CC=1>[C:26]([O:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:25])[C:17]([CH2:19][N:20]4[CH:24]=[N:23][CH:22]=[N:21]4)=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=3)[CH:9]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c(Cn2cncn2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(=O)c(Cn3cncn3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
10-bromo-2-hydroxy-5-(1H-1,2,4-triazole-1-ylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (30 mg) obtained in Example 96 was suspended in pyridine (0.8 ml), and acetic anhydride (0.021 ml) was added, and the mixture was stirred at room temperature for 3 hours. After adding dropwise a small amount of ethanol to the reaction mixture, the solvent was evaporated under reduced pressure. The residue was washed with ethanol and ether in succession to obtain the title compound (24 mg, 72%).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[NH:7])[N:4]([CH3:6])[CH3:5].[CH:9]([OH:11])=[O:10]>CCOCC>[CH:9]([O-:11])=[O:10].[CH3:1][N:2]([CH3:8])[C:3](=[NH2+:7])[N:4]([CH3:6])[CH3:5]
Reactant: O=CO
Reactant: CN(C)C(=N)N(C)C
Solvent: CCOCC
Product: CN(C)C(=[NH2+])N(C)C
Product: O=C[O-]

Procedure:
Tetramethylguanidine (22 g., 0.19 mole) was dissolved in anhydrous ether (100 ml.) and to this solution at 0° was added a solution of anhydrous formic acid (7.1 ml., 0.198 mole) in anhydrous ether (40 ml.). The resulting salt crystallized. It was collected, washed with ether, dried in high vacuum and recrystallized from chloroform-ether.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH3:16])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[C:17](=[O:19])=[O:18].Cl>CCCCCC.O1CCCC1>[CH3:15][O:14][C:12]1[CH:11]=[C:10]([CH3:16])[CH:9]=[C:8]([O:7][CH3:6])[C:13]=1[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: COc1cc(C)cc(OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C)cc(OC)c1C(=O)O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
104 ml of 1.6M n-butyllithium solution in hexane are added to 200 ml of tetrahydrofuran, followed by dropwise addition of 25 ml of 3,5-dimethoxytoluene, at a temperature between 0° and 5° C. The reaction medium is stirred at 5° C. for 1 h 30, followed by introduction of excess gaseous CO2 over 30 minutes. The mixture is introduced into 200 ml of aqueous 0.5N HCl solution and the aqueous phase is extracted with ethyl acetate. The residue is concentrated and chromatographied on a silica column (eluent: dichloromethane/methanol - 93/7).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][O:11][CH3:12].[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:23])[CH:15]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:10]([O:11][CH3:12])[CH3:9])=[O:19])=[C:16]([CH3:23])[CH:15]=1
Reactant: Cc1cc(Br)ccc1C(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc(Br)cc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.3 ml, 10.04 mmol) is added to a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (0.45 g, 4.6 mmol) in toluene (15 ml). After 30 minutes at RT the solution is cooled to 0° C. and a solution of 4-bromo-2-methylbenzoyl chloride (0.977 g, 4.81 mmol) in toluene (5 ml) is slowly added. The reaction is stirred at RT for 2 h at 0° C. and then diluted with ethyl acetate. The mixture is washed with 0.1M aq. HCl solution followed by brine. The organic extract is separated, dried over (MgSO4) and concentrated in vacuo to afford a colourless oil. Purification by chromatography on silica, eluting with ethyl acetate:iso-hexane (1:1) yields the title product as a colourless oil. MS m/z 258.0 [M+H]+1H NMR (400 MHz, CDCl3) δ 2.32 (3H, s), 3.0 (3H, br s), 3.50 (3H, br s), 7.15 (1H, d), 7.35 (1H, d), 7.37 (1H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([O:18][C:19]2[C:20]([CH3:26])=[N:21][C:22](Cl)=[CH:23][CH:24]=2)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[CH3:31][O-:32].[K+]>O.CC(OC)(C)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([O:18][C:19]2[C:20]([CH3:26])=[N:21][C:22]([O:32][CH3:31])=[CH:23][CH:24]=2)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(Cl)ccc1O[C@@H](CC(C)C)[C@H]1CCN(Cc2ccccc2)C1
Reactant: C[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: COc1ccc(O[C@@H](CC(C)C)[C@H]2CCN(Cc3ccccc3)C2)c(C)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a 200 mL RB flask equipped with a magnetic stir bar and N2 inlet was charged with (S)-1-benzyl-3-((S)-1-(6-chloro-2-methyl-3-pyridyloxy)-3-methylbutyl)-pyrrolidine (5.46 g, 14.65 mmoles) and DMSO (30 mL). Add potassium methoxide (4.11 g, 58.61 mmoles) in one portion with stirring. Stir the reaction mixture in an oil bath at 100° C. for 1 hour. Dilute with H2O (60 mL) and MTBE (60 mL). Separate the layers and wash organic layer with H2O (2×30 mL), followed by brine (30 mL), and then dry over Na2SO4. Filter and concentrate the crude material (in toluene). Load onto silica (225 g, wet with toluene), and elute with the following: hexanes (2×500 mL), 50% MTBE/hexanes (6×500 mL). Concentrate the appropriate fractions to give (S)-1-benzyl-3-((S)-1-(6-methoxy-2-methyl-3-pyridyloxy)-3-methylbutyl)-pyrrolidine. (4.32 g, 11.72 mmoles, 80% yield) as a yellow/orange oil. 1H NMR (300 MHz, CDCl3) δ 7.34-7.2 (m, 5H), 7.10 (d, 1H, J=8.79 Hz), 6.49 (d, 1H, J=8.79), 4.17-4.07 (m, 1H), 3.88 (s, 3H), 3.68-3.50 (m, 2H), 2.78-2.67 (m, 2H), 2.61-2.48 (m, 1H), 2.48-2.38 (m, 1H), 2.37 (s, 3H), 2.33-2.24 (m, 1H), 2.00-1.50 (m, 5H), 1.44-1.30 (m, 1H), 0.885 (at, 6H, Ja=7.03 Hz, Jb=6.44 Hz). LC/MS=369.3 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CCOCC.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>[C:11]1([C:2]2[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: CN(C)c1ccnc(I)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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CN(C)c1ccnc(-c2ccccc2)c1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
A mixture of 2-iodo-4-dimethylaminopyridine (3.3 g, 13.3 mmol), phenylboronic acid (2.5 g, 20 mmol) and K2CO3 (8.3 g, 60 mmol) in toluene (60 ml) and water (10 ml) were degased with nitrogen for 15 minutes. Pd(PPh3)4 (800 mg, 0.66 mmol) was added and the resulting mixture was heated to 90° C. for 48 hours under nitrogen. After being cooled to room temperature, the aqueous phase was separated and extracted with EtOAc (3×100 ml). The combined organic fractions were washed with brine, dried over MgSO4, filtered and evaporated to afford a brown oil. The following oil was dissolved in Et2O and extracted with 10% HCl solution (3×50 ml). The combined aqueous fractions were washed with Et2O (2×100 ml) and neutralized with concentrated NaOH solution. The resulting mixture was extracted with EtOAc (4×100 ml), the combined organic fractions were washed with brine (50 ml), dried over MgSO4, filtered and evaporated to dryness. The obtained residue was then purified by column chromatography (SiO2, CH2Cl2/MeOH, 97/3) to afford 1.2 g (46%) of the titled compound as a colorless oil, which solidify upon standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:39])[C:37]#[CH:38].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:39][CH2:36][C:37]#[CH:38])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: C#CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C#CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1F
Yield: 86.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (150 mg) was dissolved in chloroform (10 ml) and triethylamine (2 ml), and a solution of triphosgene (156 mg) in dichloromethane was added to the solution. The mixture was heated under reflux for 10 min. Next, propargylamine (53 mg) was added, and the mixture was heated under reflux for additional 30 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to give 164 mg (yield 87%) of the title compound.
Reaction SMILES: Cl.[CH:2]12[NH:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH2:6][CH2:5][CH2:4][CH2:3]2.C(N(CC)CC)C.[CH3:19][S:20](Cl)=[O:21]>C(OCC)C>[CH3:19][S:20]([N:11]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:21]
Reactant: CS(=O)Cl
Reactant: C1CCC2CCCC(C1)N2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)N1C2CCCCC1CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A mixture of 10-azabicyclo[4.3.1]decane hydrochloride (10 mg, 0.057 mmol) in anhydrous diethyl ether (1 mL) was cooled in an ice bath. The reaction mixture was treated with triethylamine (0.1 mL, 0.72 mmol) and methanesulfinyl chloride (10 mg, 0.1 mmol). The reaction vial was sealed and placed in a −40° C. freezer overnight. The reaction mixture was warmed to room temp, diluted with ether (2 mL), washed with water (2×1 mL), sat. aq. KCl (1×2 mL), dried (MgSO4) and concentrated in vacuo. Flash chromatography (SiO2, ethyl acetate eluant) afforded the product as an oil (8.1 mg, 71%): 1H NMR (CDCl3, 600 MHz, δ) 4.02 (br quin, 1H, J=4 Hz, C1- or C9-H), 3.84 (br quin, 1H, J=4 Hz, C1- or C9-H), 2.55 (s, 3H, C1′H), 1.88-1.72 (m, 5H), 1.65-1.48 (m, 9H); ESIMS m/z 224.1 (89, MNa+), 202.1 (base, MH+); ESIHRMS m/z 202.1260 (calculated for C10H20NOS 202.1260).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[CH:18]1([CH3:30])[CH2:23][CH2:22][CH:21]([CH:24]([CH3:26])[CH3:25])[CH:20]([C:27](Cl)=[O:28])[CH2:19]1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH:6][C:27]([CH:20]1[CH2:19][CH:18]([CH3:30])[CH2:23][CH2:22][CH:21]1[CH:24]([CH3:26])[CH3:25])=[O:28]
Reactant: NCCc1ccccc1Br
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCC(C(C)C)C(C(=O)NCCc2ccccc2Br)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A 100 mL round bottom flask equipped with a stir bar was charged with CH2Cl2 (30 mL), 2-bromo-phenethylamine (1.0 g, 5.00 mmol) and triethylamine (684 μl, 5.05 mmol). The reaction solution was treated with menthoyl chloride (1.02 g, 5.05 mmol) in one portion and stirred at ambient temperature for 30 minutes. The reaction was diluted with CH2Cl2 (50 mL) and washed with water (3×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a thick oil (1.8 g). Product was used for next step without purification.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C2C=CC=NC=2N=C1.[CH3:28][O-:29].[Na+].[Na]>CN(P(N(C)C)(N(C)C)=O)C.O.CO>[Cl:8][C:6]1[CH:7]=[C:2]([O:29][CH3:28])[C:3]2[N:4]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:5]=1
Reactant: Clc1ccc(-c2cn3cc(Cl)cc(Br)c3n2)cc1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Agent: c1cnc2nc[nH]c2c1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Product: COc1cc(Cl)cn2cc(-c3ccc(Cl)cc3)nc12
Reaction time: 0.5 h

Procedure:
10 g (29.4 mmol) of 8-bromo-6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine, the preparation of which compound is described in the patent application filed this day entitled: Derives d'imidazopyridines, leur preparation et leur application en therapeutique (Imidazopyridine derivatives, their preparation and their application in therapy) by the Applicant, dissolved in 60 ml of hexamethylphosphorotriamide, are added to a solution of sodium methylate prepared using 2.03 g of sodium and 15 ml of methanol, the reaction mixture is brought to 60° C. for 2 h 30 min., water is added, the mixture is extracted with CH2Cl2, the organic phase is washed with water, dried over MgSO4 and filtered, and the filtrate is concentrated under reduced pressure. The evaporation residue is recrystallized in an ethyl acetate/hexane mixture. M.p. 150°-151° C.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][S:29][CH2:30][CH:31]=[CH2:32])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][S:29][CH2:30][CH:31]=[CH2:32])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCSCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CCSCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 84.8 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2-allylthioethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (1.19 g.), tetrahydrofuran (7.5 g.) and methanol (22.5 ml.) were treated in a similar manner to that of Example 1-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-allylthioethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.), powder.