Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:19]([O:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25](F)[C:24]=1[N+:32]([O-:34])=[O:33])[CH:20]=[CH2:21]>C1COCC1>[CH2:19]([O:22][C:23]1[C:24]([N+:32]([O-:34])=[O:33])=[C:25]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[C:26]([F:30])=[C:27]([F:29])[CH:28]=1)[CH:20]=[CH2:21]
Reactant: Nc1ccc(I)cc1
Reactant: C=CCOc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a solution of 4-iodophenylamine (0.940 g, 4.3 mmol) in THF (50 mL) was dropwise added LHMDS solution (5.6 mL, 5.6 mmol, 1 M in THF) at −78° C. After stirring for 1 h at −78° C., a solution of 1-allyloxy-3,4,5-trifluoro-2-nitro-benzene (1.1 g, 4.7 mmol) in THF (10 mL) was added dropwise into the reaction mixture, which was stirred at −78° C. for 1 h and at room temperature for 16 h. The progress of reaction was monitored by 1H NMR. After completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue obtained was triturated with hexane to yield (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(4-iodo-phenyl)-amine as an orange solid (1.1 g). 1H-NMR (400 MHz, CDCl3): δ 4.54 (2H, d, J=4.8), 5.24 (1H, s), 5.32 (1H, d, J=10.8), 5.42 (1H, d, J=17.2), 6.06-6.02 (1H, m), 6.45 (2H, d, J=8.4), 6.57-6.62 (1H, m), 7.47 (2H, d, J=8.4).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C1COCC1.CC(O)C>[CH:9]1([NH:8][C:6]2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[CH:22][CH:23]=3)[N:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3ncc([N+](=O)[O-])c(NC4CCCC4)n3)cc2)CC1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To a solution of 0.97 g (4 mmol) of 2-chloro-4-(cyclopentylamino)-5-nitropyrimidine in 50 mL THF at −78° C. is added a solution of 0.91 g (4.8 mmol) of 1-(4-aminophenyl)-4-methylpiperazine in 50 mL of 2-propanol, and the resulting mixture is allowed to warm slowly to room temperature. After acidification with acetic acid, the solvents were removed under vacuum, and the residue is dissolved in water. After being washed with EtOAc, the aqueous solution is basified with aqueous ammonia, and the product is extracted into EtOAc and dried, to give 1.15 g (77%) of the title compound: mp (MeOH) 204–206° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=2)[C:3]1=[O:14]
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Reactant: Cc1ncccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncccc1N1CC(C(=O)OC(C)(C)C)N(C)C1=O
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3.00 mmol) (prepared as described in step (iii) of Example 13) and 3-bromo-2-methylpyridine (515 mg, 3.00 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.49 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give 1,1-dimethylethyl 3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (738 mg, 85%). LC/MS [M+H]+=292. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (738 mg, 2.53 mmol) in TFA/DCM (1:2, 12 ml) was stirred at room temperature for 6 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give crude 3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜2.5 mmol) which was used in the next step.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15].[OH-].[Na+].O.[ClH:20]>CO>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH3:15])=[C:4]([CH:9]=1)[C:3]([Cl:20])=[O:2])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)c1cc(C(C)(C)C)ccc1OC
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(C)(C)C)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.8 g of 5-(tert-butyl)-2-methoxybenzoic acid methyl ester in MeOH (30 mL) was added 50% NaOH-water solution (1 mL). The resulting solution was stirred at room temperature for 3 hr. After the reaction was complete, the pH was adjusted to pH=2–3 using 1M HCl. The reaction mixture was collected by extraction with ethylacetate and water three times. The organic layer was dried over anhydrous magnesium sulfate (MgSO4) and evaporated under reduced pressure. After recrystallization, the final product yielded 3.4 g (96%). Without further purification a solution of 3.4 g of 5-(tert-butyl)-2-methoxybenzoic acid in 20 mL CH2Cl2 was slowly treated with SOCl2 (1.2 eq). The resulting solution was stirred at room temperature for 2 hr. The reaction mixture was evaporated under reduced pressure and dried in a vacuum oven overnight to yield 3.4 g (91.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Clc1ccc(CNc2ccc(Br)cn2)cc1

Procedure:
To 2-Amino-5-bromopyridine (15, 6.10 g, 0.0352 mol) in toluene (90.0 mL) were added 4-chlorobenzaldehyde (40, 5.00 g, 0.0356 mol), trifluoroacetic acid (8.0 mL, 0.10 mol) and triethylsilane (16.5 mL, 0.103 mol). The reaction was heated to reflux for 48 hours. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude residue was crystallized with ethyl acetate to give compound (41, 6.8 g, 65.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH:14]([NH2:20])[CH2:13]2>C1(C)C=CC=CC=1.C1COCC1>[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH:14]([NH:20][C:10]([NH:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)=[O:11])[CH2:13]2
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: NC1CN2CCC1CC2
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)NC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dichlorophenyl isocyanate (1.88 g, 10 mmol) in toluene (20 ml) was added at 0° to 1-azabicyclo[2.2.2]octan-3-amine (3-aminoquinuclidine) (1.26 g, 10 mmol) in THF (40 ml). The mixture was stirred at room temperature overnight and evaporated to dryness. The residue was partitioned between ether and dilute hydrochloric acid. The aqueous phase was basified with potassium carbonate and extracted with ethyl acetate. The dried (Na2SO4)ethyl acetate phase was evaporated and the residue (1.64 g) converted to the 1:1 oxalate, quarter hydrate, mp 208°-209° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:18])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].C(N(CC)CC)C.[F:26][C:27]([F:35])([F:34])[C:28]([F:33])([F:32])[C:29](O)=[O:30]>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:18])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:29](=[O:30])[C:28]([F:33])([F:32])[C:27]([F:35])([F:34])[F:26]
Reactant: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Reactant: O=C(O)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2cccc3n(CCCCNC(=O)C(F)(F)C(F)(F)F)c(=O)c1n23
Temperature: 25 °C

Procedure:
To a solution of 2.44 g (10.0 mmol) of 3-methyl-1-[4-(amino)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one and 1.81 ml (13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, while stirring at room temperature, 2.31 g (12.0 mmol) of ethyl ester of pentafluoropropionic acid. The mixture was stirred for 14 hours at the same temperature. The solvent was distilled off. To the residue was added methylene chloride. The mixture was washed with water, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:ethyl acetate), and recrystallized from ethyl acetate—hexane to afford 1.53 g (39.1%, a colorless crystals) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH:11]([CH2:13][CH3:14])[C:10]([CH:17]3[CH2:19][CH2:18]3)([C:15]#[N:16])[C:9]2=[O:20])[CH:5]=[CH:4][N:3]=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][CH3:14])[C@@:10]([CH:17]3[CH2:19][CH2:18]3)([C:15]#[N:16])[C:9]2=[O:20])[CH:5]=[CH:4][N:3]=1
Reactant: CCC1CN(c2ccnc(Cl)n2)C(=O)C1(C#N)C1CC1
Solvent: CC(C)O
Solvent: CCCCCC
Product: CC[C@H]1CN(c2ccnc(Cl)n2)C(=O)[C@@]1(C#N)C1CC1
Yield: 38.5 %

Procedure:
To a mixture of 3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (3.7 g) obtained in Step B of Example 376, 2,4-dichloropyrimidine (3.1 g), cesium carbonate (13 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.71 g) in tetrahydrofuran (55 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.38 g), and the mixture was stirred overnight at 85° C. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (3SR,4RS)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.3 g) and (3SR,4SR)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.6 g). (3SR,4RS)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.3 g) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=700/300) to give (3S,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (500 mg) having a shorter retention time and (3R,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (510 mg) having a longer retention time. (3SR,4SR)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.6 g) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=700/300) to give (3S,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (560 mg) having a shorter retention time and (3R,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (600 mg) having a longer retention time.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[OH-].[Na+].O.C(OCC)C>CO>[NH2:12][C:5]1[C:6]([CH3:11])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cc(Cl)nc(C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: Cc1nc(Cl)cc(C(=O)O)c1N
Temperature: 25 °C
Yield: 95.7 %

Procedure:
3-Amino-6-chloro-2-methylisonicotinic acid methyl ester (100 mg) was dissolved in methanol (2 mL) and 2N aqueous sodium hydroxide solution (2 mL) was added. The reaction mixture was stirred under reflux for 2.5 hours. After cooling to room temperature, water and diethyl ether were added, the layers were separated and the aqueous layer was washed with diethyl ether. The aqueous layer was acidified by addition of 2N hydrochloric acid and the formed precipitate was 3× extracted with MTB-ether. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum to afford 89 mg of the title compound of the formula
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[O:32][CH3:31])[CH3:2]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: COc1ccccc1B(O)O
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccccc2OC)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 2-methoxyphenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C22H22NO4 (M+H): 364.1544. Found 364.1537
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([NH:23][C@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][C:26]([OH:28])=O)=[O:22])=[N:15]1.[NH3:36]>C(Cl)Cl.CN(C=O)C>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([NH:23][C@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][C:26]([NH2:36])=[O:28])=[O:22])=[N:15]1
Reactant: N
Reactant: COc1cc(C(=O)N[C@@H](CC(=O)O)c2ccccc2C)nn1-c1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@@H](CC(N)=O)c2ccccc2C)nn1-c1ccccc1F
Reaction time: 16 h
Yield: 34 %

Procedure:
DMF (1.8 mg, 25 μmol) and oxalyl chloride (160 mg, 1.26 mmol) were added to a solution of (S)-3-{[1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carbonyl]-amino}-3-(2-methyl-phenyl)-propionic acid (500 mg, 1.26 mmol) in DCM (5 ml) at room temperature. After 16 h at room temperature a 33% aqueous solution of ammonia (649 mg, 12.6 mmol) was added and the mixture was stirred for further 16 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 170 mg (34%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:10][C:3]1[C:2]([O:1][CH3:11])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(O)cccc1C#N
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc(C#N)c1C

Procedure:
A mixture of 3-hydroxy-2-methylbenzonitrile [23.38 g described by S. Gabriel and A. Thieme, Ber., 52, 1079 (1919)] anhydrous potassium carbonate (26.7 g) and methyl iodide (16.43 ml) in acetone (255 ml) is refluxed for 4 hr, cooled and filtered. The filtrate is evaporated and dissolved in dichloromethane. The solution is washed with water, dried and evaporated. The residue is chromatographed on silica gel using dichloromethane-hexane(1:1) and the eluates are evaporated and crystallized from hexane to obtain 2-methyl-3-methoxybenzonitrile: (II: R1 =2-Me and Y=CN): mp 47°-48° C.; ir 2,220, 1,265 and 1,100 cm-1 ; and nmr (CDCl3) δ2.42 (s, 3H), 3.85 (s, 3H) and 7.15 (m, 3H).
Reaction SMILES: [O-]CC.[Na+].[Na].[CH:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[C:16]([O:18][CH2:19][CH2:20][O:12][C:11]1[CH:6]=[C:7]([CH3:13])[CH:8]=[CH:9][CH:10]=1)(=[O:17])[CH3:15]
Reactant: Cc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(=O)OCCOc1cccc(C)c1
Yield: 59.4 %

Procedure:
To a solution of sodium ethoxide prepared from 25 g (1.1 mol) sodium metal in 800 ml ethanol was added 108 g (1.0 mol) m-cresol. After warming at reflux for 1.5 hr, 167 g (1.0 mol) ethyl bromoacetate was added dropwise as reflux continued. After 5.5 hr reflux, the reaction mixture was cooled and NaBr removed by filtration. The filtrate was concentrated to 200 ml volume and extracted with 3 × 300 ml ether. The combined ether layers were washed with pH 10.5 NaOH solution, saturated NaCl solution and were dried over anhydrous MgSO4. The ether was removed under reduced pressure and the residual yellow oil distilled at 105°/1 mm Hg to give 115.3 g m-tolyloxyethyl acetate.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.C(O)CCC>[CH3:9][N:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Ic1ccccc1
Reactant: CNCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: OCCO
Product: CN(Cc1ccccc1)c1ccccc1
Yield: 74 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (425 mg, 2.00 mmol), N-methylbenzylamine (155 μL, 1.20 mmol), iodobenzene (112 μL, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 1-butanol (1.0 mL) at 90° C. Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rf=0.5) afforded N-methyl-N-phenylbenzylamine (146 mg, 74% isolated yield) as colorless liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron 1999, 55, 12829-12842.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.[C:26](OC(=N)N(C(C)C)C(C)C)([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([O:22][C:21]([C:5]1[N:4]2[C:24](=[O:25])[CH:2]([NH2:1])[C@H:3]2[S:8][CH2:7][C:6]=1[CH:9]([S:15][C:16]1[NH:17][N:18]=[N:19][N:20]=1)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:23])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Reactant: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(C(CCC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12

Procedure:
To a suspension of 19.3 g. (0.05 mol.) of 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 500 ml. of dry methylene chloride is added in one portion 30.0 g. (0.15 mol.) of O-t-butyldiisopropylpseudourea in 50 ml. of methylene chloride and the mixture is stirred at ambient temperature for 24 hours. The precipitate is removed by filtration and the filtrate is evaporated to give a residue which is taken up in 200 ml. of benzene and filtered again. The filtrate is extracted with three 100 ml. portions of cold 1N hydrochloric acid. The aqueous extracts are layered with ethyl acetate and the pH is adjusted to 7.5 by addition of solid sodium bicarbonate. The organic layer is separated and the aqueous phase is extracted with two 150 ml. portions of ethyl acetate. The combined extracts are dried (MgSO4), filtered and evaporated to dryness to give 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:9][C:10]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[ClH:27].[Cl:28][C:29]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:30]=1[NH2:31].Cl>C(O)(C)C>[ClH:1].[ClH:28].[ClH:27].[Cl:28][C:29]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:30]=1[NH:31][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:9][C:10]=2[N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[N:5]=[CH:4][N:3]=1
Reactant: CN1CCN(c2cc(OCCN3CCCC3)cc3ncnc(Cl)c23)CC1
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OCCN4CCCC4)cc(N4CCN(C)CC4)c23)c1

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.11 g) was reacted with 2-chloro-5-methoxyaniline hydrochloride (0.064 g) in the presence of a 6M solution of hydrogen chloride in isopropanol (0.05 ml) to give the title compound, as a trihydrochloride salt (0.092 g), a portion of which was converted into the free base using an analogous procedure to that described in Example 3. The free base gave the following characterising data: NMR Spectrum: (CDCl3) 1.8–1.9 (m, 4H), 2.32 (s, 3H), 2.48 (m, 2H), 2.65 (br s, 4H), 2.82 (d, 2H), 2.98 (m, 4H), 3.2 (d, 2H), 3.82 (s, 3H), 4.25 (m, 2H), 6.65 (m, 1H), 6.95 (m, 1H), 7.3 (d, 1H), 8.02 (d, 1H), 8.52 (s, 1H); Mass Spectrum: M+H+ 497 and 499.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>C(OCC)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][C:12]([Cl:18])=[O:14]
Reactant: O=C(O)CCCc1ccc(Cl)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)CCCc1ccc(Cl)cc1Cl

Procedure:
By the method of Example 1, Step B, 9.79 g (0.042 mole) of 4-(2,4-dichlorophenyl)butanoic acid and 5.8 g (0.050 mole) of oxalyl chloride are reacted in 75 mL of diethyl ether and two drops of N,N-dimethylformamide, yielding 4-(2,4-dichlorophenyl)butanoic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl>[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[S:3][C:4]3[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=3[N:6]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Yield: 54 %

Procedure:
and 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (1.0 g, 3.8 mmol), 4-(chloromethyl) benzoyl chloride (810 mg, 4.2 mmol) and pyridine (0.36 ml, 4.5 mmol) are reacted in dichloromethane (20 ml) for 18 h. The reaction is quenched with water (25 ml) and brought to pH 8.0 with sodium carbonate. The mixture is extracted with dichloromethane and the combined organic layers are dried and evapoarted to dryness. Flash chromatography (silica, eluent methylene chloride containing 2.5% methanol) affords the product as white crystalls in 54% yield. MS: m/e=418 (M+H+).