Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[OH:20])[N:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O[C:43](=O)[C:44]([CH2:48][CH3:49])([CH3:47])[CH2:45][CH3:46])C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:43][C:44]([CH2:48][CH3:49])([CH3:47])[CH2:45][CH3:46])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Br)ccc2O)n1
Reactant: CCOC(=O)C(C)(CC)CC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)n(Cc2cc(Br)ccc2OCC(C)(CC)CC)n1
Temperature: 100 °C

Procedure:
A solution of 1-(5-bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester, 6 (0.20 g, 0.60 mmol), triphenylphosphine (0.31 g, 1.2 mmol), ditert-butylazodicarboxylate (0.27 g, 1.2 mmol) and 2-ethyl-2-methyl-butan-1-ol 20 (0.13 g, 1.2 mmol) in a mixture of THF (8 mL) was heated at 100° C. in an Emrys microwave reactor for 20 minutes. The volatiles were removed in vacuo and the crude product was purified on silica to yield 1-[5-bromo-2-(2-ethyl-2-methyl-butoxy)-benzyl]-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester, 22.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:14])C>CC(C)=O>[C:1]([C:5]1[CH:10]=[C:9]([OH:14])[C:8](=[CH:7][CH:6]=1)[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OO
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(O)c(O)c1
Yield: 50 %

Procedure:
A five-neck flask having a volume of 500 ml and provided with a stirrer, a reflux condenser, a sampling tube, a test specimen inlet and a thermometer was charged with 75.1g (0.5 mol) of paratert.-butyl phenol and 20 ml of acetone as a solvent. The flask was placed in a constant temperture bath ketp at 60°C. Into the flask contents, 3.80g (0.05 mol) of peracetic acid in the form of about 35 weight% acetone solution was added through a micro-feeder over 12 minutes. Within 60 minutes after the start of the addition of peracid, the reaction solution was analyzed by gas chromatography. Consequently, it was found that the conversion of para-tert.-butyl phenol was 5.1%, that 4-tert.-butyl pyrocatechol was formed in a yield of 50% based on the converted butyl phenol and that the conversion of the peracetic acid was 95.2%.
Reaction SMILES: [C:1](=[O:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[O:2][CH:3](Cl)[CH3:4].[C:17]([OH:20])(=[O:19])[CH3:18]>>[C:1](=[O:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[O:2][CH:3]([O:20][C:17](=[O:19])[CH3:18])[CH3:4]
Reactant: CC(Cl)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O
Product: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 10.0 g of product from Example 317 in 250 ml of acetic acid is added 15.0 g mercuric acetate. The mixture is stirred at room temperature for 22 hours, concentrated in vacuo, and purified by chromatography (Silica gel: methylene chloride -5% methyl alcohol/methylene chloride) to give 7.5 g of the desired product.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:35])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:34])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:34][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:35])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.1 %

Procedure:
Lithium hydroxide monohydrate (0.046 g, 1.1 mmol) was added to a stirred solution of {6-chloro-3-methyl-4-[4-(piperidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.130 g, 0.27 mmol) in a 3:1 mixture of THF—H2O mixture (15 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-chloro-3-methyl-4-[4-(piperidine-1-sulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.125 g, 99%) as a solid. 1H NMR (DMSO-d6) δ: 12.51 (br. s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.88-7.95 (m, 3H), 7.53 (d, J=8.3 Hz, 2H), 7.50 (dd, J=8.8, 1.5 Hz, 1H), 7.01 (s, 1H), 3.87 (s, 2H), 3.02 (t, J=4.9 Hz, 4H), 2.08 (s, 3H), 1.59 (br. s, 4H), 1.33-1.49 (m, 2H). MS calcd. for C24H25ClNO4S [(M+H)+] 458, obsd. 458.4.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:30][CH2:26][CH2:27][CH2:28][CH3:29])=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: CCCCN
Product: CCCCNC(=O)C(C)(C)COc1cccc2nc(C)c(C(=O)OCC)c(N)c12

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and n-butylamine as a pale-yellow solid (91%). 1H NMR (400 MHz, DMSO-d6) δ 0.74 (t, J=8.0 Hz, 3H), 1.15-1.20 (m, 2H), 1.27 (s, 6H), 1.32-1.38 (m, 5H), 2.57 (s, 3H), 3.06-3.11 (q, J=8.0 Hz, 2H), 4.14 (s, 2H), 4.35 (q, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 8.10 (s, 2H). MS 402 (MH+).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:16][CH3:17])[O:14][CH3:15])=[CH:9][N:8]=1.CN([CH:21]=[O:22])C>CCCCCC.C1COCC1.O>[CH3:15][O:14][CH:13]([O:16][CH3:17])[C:10]1[CH:11]=[CH:12][C:7]([CH:21]=[O:22])=[N:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: COC(OC)c1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COC(OC)c1ccc(C=O)nc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 53.7 %

Procedure:
A solution of 2.5 M BuLi in hexane (7.6 ml) was added drop-wise, under a N2 atmosphere, to a solution of 2-bromo-5-dimethoxymethyl-pyridine (3.66 g, 15.84 mmol) in THF (60 ml) at −70° C. After 15 minutes, DMF (1.82 ml, 23.5 mmol) was added drop-wise and the mixture was stirred for 30 minutes at −70° C. and then allowed to reach room temperature. The reaction was diluted with H2O and extracted with DCM. The organic phase was dried over Na2SO4 and evaporated to dryness in vacuo. The crude product was purified by flash chromatography (petroleum ether: AcOEt 7:3) to obtain 1.54 g of 5-dimethoxymethyl-pyridine-2-carbaldehyde as a yellow oil.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][N:5]=1.[C-:10]#[N:11].[Na+]>CS(C)=O>[CH3:9][N:8]1[C:4]([CH2:3][C:10]#[N:11])=[N:5][CH:6]=[N:7]1
Reactant: [C-]#N
Reactant: Cn1ncnc1CCl
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1ncnc1CC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
A solution of 5-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (1.5 g, 11.45 mmol) in dimethylsulfoxide (30 mL) was added to a stirred suspension of sodium cyanide (3.366 g, 68.70 mmol) in dimethylsulfoxide (20 mL), and the reaction mixture was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated. The resulting crude product was purified via column chromatography (100-200 mesh silica gel, 10-12% ethyl acetate in petroleum ether) to afford 2-(1-methyl-1H-1,2,4-triazol-5-yl)acetonitrile (1.2 g). MS (ES+APCI) (M+H) 123.2.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:12]=2)[C:7]([CH3:19])=[N:6]1.[OH-].[K+:26]>C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]([O-:18])=[O:17])[CH:12]=2)[C:7]([CH3:19])=[N:6]1.[K+:26]
Reactant: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CCC(=O)O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CCC(=O)[O-])ccc12

Procedure:
To a solution of the compound [122](24 mg) in ethanol (2.0 mL) was added an aqueous solution of 1N-potassium hydroxide (65 μL) at room temperature, and the solution was concentrated under reduced pressure to give the titled compound (27 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([CH:35](O)[CH3:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:36])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1ccccc1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CC(Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccccc1

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and 1-phenyl-ethanol. MS (ESI) m/z 484.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[CH:7][C:6]=1[NH2:21])=O.C(O)(=O)C.[CH:26](N)=[NH:27]>COCCO.[OH-].[Na+]>[F:18][C:17]([F:20])([F:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:7]=[C:6]2[C:5]([C:3](=[O:2])[NH:27][CH:26]=[N:21]2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1N
Reactant: N=CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: COCCO
Product: O=c1[nH]cnc2cc(-c3ccccc3C(F)(F)F)ccc12

Procedure:
Heat a solution of 3-amino-2′-trifluoromethyl-biphenyl-4-carboxylic-acid methyl ester (5.0 g, 0.0169 mol) and formamidine acetate (2.8 g, 0.0203 mol) in 2-methoxyethanol at reflux for 8 hours. Cool the mixture and concentrate under reduced pressure to give a dark oil. Dissolve the residue in 10% NaOH and wash the aqueous with ether (3×). Bring the aqueous layer to pH 4 using 12N HCl to produce a milky solution. Extract the solution with EtOAc, wash the EtOAc with brine, dry (Na2SO4) and concentrate under reduced pressure to give 7-(2-Trifluoromethyl-phenyl)-3H-quinazolin-4-one as a beige solid.
Reaction SMILES: C[OH:2].[C:3]([N:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1)(=[O:5])[CH3:4].[O:11]1[CH2:15]CC[CH2:12]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>[CH3:12][O:11][C:15](=[O:2])[C@@H:7]1[CH2:8][CH2:9][CH2:10][N:6]1[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)N1C=CCC1
Reactant: CO
Reactant: C1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)[C@@H]1CCCN1C(C)=O
Temperature: 100 °C
Reaction time: 26 h
Yield: 42.8 %

Procedure:
A 70 mL stainless steel high pressure reactor having a Pyrex glass liner and a magnetic stir bar was charged with 5 mL of tetrahydrofuran, 0.5 mmol of n-pendadecane internal standard, 0.5 mmol of CH3OH, 35.1 mg of (PPh3)2PdCl2, and 56.6 mg of N-acetyl-2-pyrroline. The reactor was pressurized to 1000 psi with CO at room temperature, and the reaction mixture was stirred at 100° C. for 26 hours. Thereafter, the reactor was cooled to room temperature and vented to atmospheric pressure. The product mixture was analyzed by gas chromatography, and the analysis indicated 98.4% conversion of N-acetyl-2-pyrroline and 42.8% yield of N-acetylproline methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][CH3:11])[N:4]=1.N12CCN(CC1)CC2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[S:28]([N:31]=[C:32]=[O:33])(=[O:30])=[O:29]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]([CH3:11])[C:32]([NH:31][S:28]([C:22]2[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])(=[O:29])=[O:30])=[O:33])[N:4]=1
Reactant: O=C=NS(=O)(=O)c1c(Cl)cccc1Cl
Reactant: CNc1nc(C)cc(OC)n1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1cc(C)nc(N(C)C(=O)NS(=O)(=O)c2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.9 %

Procedure:
To 0.8 g of 4-methoxy-6-methyl-2-methylaminopyrimidine in 25 ml of dry acetonitrile containing a few crystals of 1,4-diazabicyclo[2.2.2]octane was added 1.3 g of 2,6-dichlorobenzenesulfonyl isocyanate. The mixture was stirred at ambient temperature for 16 hours and the resultant solution was evaporated leaving a white solid. Trituration with 1-chlorobutane followed by filtration afforded 0.5 g of N-[N-(4-methoxy-6-methylpyrmidine-2-yl)-N-methylaminocarbonyl]-2,6-dichlorobenzenesulfonamide melting at 170°-171°. Infrared absorption peaks were observed at 1700 cm-1, 1600 cm-1, and 1570 cm-1.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH2:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[O-:20][C:21]#[N:22].[K+].O.C(OCC)C>Cl>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH:16][C:21]([NH2:22])=[O:20])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:18][CH3:19]
Reactant: N#C[O-]
Reactant: CCCN(CCC)C1CCc2cccc(CN)c2C1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCCN(CCC)C1CCc2cccc(CNC(N)=O)c2C1

Procedure:
2.6 g (10 mmol) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were dissolved in 22 ml of 1N hydrochloric acid under nitrogen. A solution of 0.81 g (10 mmol) of potassium cyanate and 6 ml of water was subsequently added dropwise at a maximum of +25° C., and the batch was allowed to react for 4 h at room temperature. 20 ml of diethyl ether were then added. The aqueous phase was separated off and adjusted to pH 9 using 1N sodium hydroxide solution. The precipitated reaction product was filtered off under suction and dried at +40° C. in vacuo. The product was purified by recrystallization from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:16])[N:13]=[C:12](OC)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:18].[CH3:19][OH:20]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:16])[CH2:9][O:10][CH2:11][C:12]([NH2:18])=[N:13]2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][C:8]1[NH:13][O:20][CH:19]=[CH:3][CH:4]=1
Reactant: [NH4+]
Reactant: COC1=NC(C)(c2cccc(Br)c2)COC1
Reactant: CO
Agent: [Cl-]
Product: CC1(c2cccc(Br)c2)COCC(N)=N1
Product: NC1=CC=CON1
Temperature: 100 °C

Procedure:
A dried pressure tube was charged with a dispersion of (RS)-3-(3-bromo-phenyl)-5-methoxy-3-methyl-3,6-dihydro-2H[1,4]oxazine (3.91 g, 14 mmol) and ammonium chloride (4.42 g, 83 mmol) in methanol (140 ml). The tube was sealed and heated at 100° C. overnight. After cooling, the reaction mixture was evaporated to dryness. The crude product was purified on an Isolute flash NH2 column using a gradient of dichloromethane/methanol=100/0 to 75/25 as the eluent. The (RS)-5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as a light yellow foam (2.71 g, 73% of theory). MS (ISP): m/z=269.2 [M+H]+, 271.1 [M+2+H]+.
Reaction SMILES: [C:1]([O:5][C:6](/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[C:30]2[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[NH:26][CH2:25][C:24]=2[CH:23]=[N:22]1>ClCCl.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])/[CH:8]=[CH:9]/[C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:26]2[CH2:25][C:24]3[CH:23]=[N:22][N:21]([CH3:20])[C:30]=3[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]2=3)=[O:16])=[CH:12][C:11]=1[CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: Cc1cc(C(=O)O)ccc1/C=C/C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1/C=C/C(=O)OC(C)(C)C
Yield: 82 %

Procedure:
4-((E)-2-tert-Butoxycarbonyl-vinyl)-3-methyl-benzoic acid from Example E45.1 (1.1 g, 4.2 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (720 mg, 3.6 mmol) were dissolved in dichloromethane (50 ml) and triethylamine (0.75 ml). DMAP (4.45 g, 3.6 mmol) and WSCD (1.36 g, 7.1 mmol) were added and the mixture was heated at re-flux for 2 days. The solution was diluted with di-chloromethane, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (1.35 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11](O)=[O:12])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])(=[O:17])=[O:16])[CH:3]=1.[CH3:26][CH2:27][N:28]=[C:29]=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.CNCC>CN(C=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([N:28]([CH2:27][CH3:26])[CH3:29])=[O:12])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])(=[O:17])=[O:16])[CH:3]=1
Reactant: O=C(O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Reactant: CCN=C=NCCCN(C)C
Agent: CCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C)C(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoic acid (297 mg, 0.70 mmol) in DMF (2 ml) was added EDC.HCl (148 mg, 0.77 mmol), HOBT.H2O (104 mg, 0.77 mmol), and N-methylethanamine (0.30 ml, 3.5 mmol). The reaction was stirred at room temperature for 16 hours, diluted with 1M HCl, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-40% EtOAc in hexane) to yield the title compound (269 mg, 83%) as a mixture of amide bond cis-trans isomers.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O

Procedure:
Reaction of potassium benzylpenicillin with α-chlorodiethylcarbonate in organic solvents or in an aqueous solution of 70% dioxane in the presence of sodium bicarbonate. The 1-ethoxycarbonyloxyethyl ester of benzylpenicillin which is obtained is subjected to the reaction of removing the phenylacetic chain, via the iminochlorideimino-ether, in order to obtain the 1-ethoxycarbonyloxyethyl ester of the 6-aminopenicillanic acid, which is isolated as the hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10]([O:11][CH:12]=[C:13]3[CH2:15][O:14]3)=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:16][CH:17]1[CH2:20][N:19]([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18]1>O1CCOCC1.C(O)C>[CH:21]([N:19]1[CH2:20][CH:17]([NH:16][CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:10]2[C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)[CH2:18]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Cc1nc2cccc(OC=C3CO3)c2s1
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nc2cccc(OCC(O)CNC3CN(C(c4ccccc4)c4ccccc4)C3)c2s1

Procedure:
The title compound was prepared according to Method A from 2-methyl-7-(oxiranyl-2-ylmethoxy)benzothiazole and 3-amino-1-benzhydrylazetidine with dioxane/ethanol (1:1) as the solvent. mp 55° C.; LSIMS m/z 460. The 3-amino-1-benzhydrylazetidine was prepared as described in Preparation 96.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])C.C(N(CC)CC)C.[Cl:12][C:13]([Cl:20])=[CH:14][CH2:15][CH2:16][C:17](Cl)=O.C([O:23]CC)C>>[Cl:12][C:13]([Cl:20])=[CH:14][CH:15]1[C:2]([CH3:4])([CH3:1])[CH2:17][C:16]1=[O:23]
Reactant: CCOCC
Reactant: C=C(C)C
Reactant: O=C(Cl)CCC=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)C1C=C(Cl)Cl
Temperature: 120 °C
Reaction time: 2 h

Procedure:
84 g (1.5 mols) of isobutylene and 10.0 g (0.099 mol) of triethylamine are heated in an autoclave to 120° C. A solution of 17.35 g (0.1 mol) of 4,4-dichlorobut-3-enecarboxylic acid chloride in 35 ml of diethyl ether is then injected in the course of 30 minutes, and the reaction mixture is stirred at 120° C. for 2 hours. After cooling, the reaction mixture is triturated with diethyl ether. Solid constituents are filtered off, and the filtrate is subsequently washed with 1 N sulphuric acid (2×30 ml) as well as with 1% sodium bicarbonate solution (3×50 ml). After drying over sodium sulphate, concentration by evaporation is performed, and the residue is distilled in a bulb tube to yield 2-(2',2'-dichlorovinyl)-3,3-dimethylcyclobutanone as colourless oil; b.p. 100°-110° C./0.5 Torr.
Reaction SMILES: BrC(Br)=O.[C:5]1([S:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:13](Cl)(=[O:15])[CH3:14]>>[CH3:14][C:13]([C:8]1[CH:9]=[CH:10][C:5]([S:11][CH3:12])=[CH:6][CH:7]=1)=[O:15]
Reactant: CSc1ccccc1
Reactant: CC(=O)Cl
Agent: O=C(Br)Br
Product: CSc1ccc(C(C)=O)cc1

Procedure:
The synthesis of bromoketone 2 begins with the Friedel-Crafts reaction between thioanisole and acetyl chloride, to give 4-(methylthio)acetophenone 3 herein referred to as ketosulfide 3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O[N:19]1[C:23]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN>C(#N)C>[CH3:23][NH:19][C:14]([C:11]1[S:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:13][CH:12]=1)=[O:16]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)s1
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a heterogeneous mixture of 2-(tert-butoxycarbonylamino)thiazole-5-carboxylic acid (1.0 g, 4.1 mmol), 1-hydroxybenzotriazole hydrate (0.63 g, 4.1 mmol), N,N-diisopropylethylamine (4.3 mL, 24 mmol), methylamine hydrochloride (0.83 g, 12 mmol) in anhydrous acetonitrile (20 mL), was added WSCDI (2.4 g, 12 mmol) at room temperature under a nitrogen atmosphere and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. To the residue was added saturated aqueous sodium bicarbonate solution (20 mL), ethyl acetate (6 mL), and heptane (2 mL). The solid that separates out was filtered, washed with water (2×2 mL) and diethyl ether (2×4 mL), and dried to give tert-butyl 5-(methylcarbamoyl)thiazol-2-ylcarbamate (0.77 g, 73% yield) as a white solid. MS found: (M+H)+=258; 1H NMR (400 MHz, methanol-d4) δ ppm 7.83 (s, 1H), 2.87 (s, 3H), 1.55 (s, 9H).