Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](OC)([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH:4]=[O:5].[CH3:15]O>>[CH3:15][O:5][CH2:4][CH2:3][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: COC(C=O)(OC)c1ccc(O)cc1
Reactant: CO
Product: COCCc1ccc(O)cc1
Yield: 47 %

Procedure:
The procedure of Example 2 was repeated with a solution of 2.00 g (10.2) mmol) 4-hydroxyphenylglyoxal dimethyl acetal in 10 g methanol containing 0.37 g (10.2 mmol) hydrogen chloride and a 0.20 g dry 10% Pd/C catalyst being reacted with hydrogen gas pressurized at 50 psig at 25° C. A 47% yield of 4-(2'-methoxyethyl)phenol was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)(=[NH:4])=[O:3].[H-].[Na+].CCCCCC.Cl[CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23]>CN(C)C=O.O>[CH2:20]([N:21]([CH2:24][CH3:25])[CH2:22][CH2:23][N:4]=[S:2]([CH3:1])([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:3])[CH3:19]
Reactant: CCN(CC)CCCl
Reactant: CS(=N)(=O)c1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCN=S(C)(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
A solution of S-methyl-S-(thien-3-yl)sulfoximine (Maybridge, 2.56 g, 15.9 mmol) in dimethylformamide (15 mL) was added dropwise to a slurry of sodium hydride (0.76 g, 19.0 mmol, 60% oil dispersion, washed (3×8 mL) hexane) in dimethylformamide (10 mL) at 0° C. The solution was allowed to warm to ambient temperature and was stirred at ambient temperature for 0.5 h. The resulting mixture was cooled to 0° C. and a solution of 1-chloro-2-diethylaminoethane (2.14 g, 15.9 mmol) in dimethylformamide (15 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 15 h. Water (1 mL) was added and the reaction mixture was concentrated in vacuo. The residue was partitioned between water (25 mL) and methylene chloride (25 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (2×25 mL). The combined organic extracts were washed (saturated sodium chloride), dried (MgSO4), and concentrated in vacuo to afford 3.9 g of residue. The residue was chromatographed (flash, SiO2, 9:1:0 to 9:1:1 methylene chloride/methanol/concentrated ammonium hydroxide) to give an oil that was partitioned between water (15 mL) and methylene chloride (15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The oil partially solidified on standing.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(=O)(O)O.[C:17]([OH:30])(=[O:29])/[CH:18]=[CH:19]/[C:20]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:22]([OH:23])[CH:21]=1.[C:31]1([CH:38]=[CH:37][CH:36]=[C:34](O)[CH:33]=1)[OH:32]>O1CCOCC1>[OH:32][C:31]1[CH:38]=[C:37]2[C:36]([C@@H:19]([C:20]3[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:22]([OH:23])[CH:21]=3)[CH2:18][C:17](=[O:30])[O:29]2)=[CH:34][CH:33]=1
Reactant: Oc1cccc(O)c1
Reactant: COc1ccc(/C=C/C(=O)O)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: COc1ccc([C@H]2CC(=O)Oc3cc(O)ccc32)cc1O

Procedure:
0.5 g para-toluenesulfonic acid and 1.5 ml concentrated sulfuric acid were added to a mixture of 50 mmol isoferulic acid and 75 mmol resorcinol in 75 ml of 1,4-dioxane and heated under reflux for 14 hours. As the reaction was not completed at this time point according to LC-MS, a further 1.5 ml of concentrated sulfuric acid was added and the mixture was heated for a further 10 hours. Then a large part of the solvent was removed in a rotary evaporator and the product mixture was taken up in 200 ml ethyl acetate. The organic phase was washed twice with 50 ml demineralized water and 5% sodium bicarbonate solution each time and once with saturated sodium chloride solution. The organic phase was then dried over sodium sulfate and after removing the solvent, the product was purified by silica-gel column chromatography (solvent: ethyl acetate/hexane 4:5), recrystallized from a solvent mixture of diethyl ether/pentane (1:6) and the resultant product was dried at 60° C. in a vacuum drying cabinet.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12](Br)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].[OH:15][CH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:16][OH:15])[CH:22]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: OCc1cccc(B(O)O)c1
Reactant: CC(C)c1cc(Br)c2ncccc2c1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)c1cc(-c2cccc(CO)c2)c2ncccc2c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 6-isopropyl-8-Bromoquinoline (11.1 g, 44.4 mmol) (described in International Patent Publication WO 94/22852), 3-(hydroxymethyl)phenylboronic acid (8.70 g, 57.2 mmol), Na2CO3 (2M, 71 mL, 142 mmol) and Pd(PPh3)4 (2.51 mg, 2.17 mmol) in 280 mL of DME was stirred at 80° C. for 5 h. The resulting mixture was cooled to r.t., diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex/EtOAc, 1/1) and stirring in CH2Cl2/hexane (1/9) yielded 6-Isopropyl-8-[3-(hydroxymethyl)phenyl]quinoline as a white solid.
Reaction SMILES: Cl.Br[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[CH2:11][NH:12][CH3:13])=[CH:5][CH:4]=1.C(N(CC)CC)C.[H][H].Cl>[Pd].C(O)C>[CH3:13][NH:12][CH2:11][C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[CH2:8][CH2:7][C:6]1[CH:18]=[CH:19][CH:3]=[CH:4][CH:5]=1
Reactant: [H][H]
Reactant: CNCc1ccccc1CCc1ccc(Br)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CNCc1ccccc1CCc1ccccc1

Procedure:
A solution of 2.0 g. (0.00657 mole) of 2-(4-bromo-phenethyl)-N-methylbenzylamine hydrochloride in 200 ml. of absolute ethanol -- 1 ml. of triethylamine is shaken with hydrogen at atmospheric pressure and 25° C. over 400 mg. of 10% palladium on carbon until hydrogen uptake ceases. The catalyst is removed by filtration, the filtrate evaporated to dryness under reduced pressure, and the residue partitioned between aqueous sodium hydroxide and 1:1 ether-benzene. Evaporation of solvents from the washed and dried organic extract leaves the product as the residual oil. The oily base is converted to the hydrochloride salt by treating a solution in absolute ethanol with a slight excess of ethanolic hydrogen chloride. Dilution with absolute ether precipitates the hydrochloride as white crystals, m.p. 204°-206° C. After repeated recrystallizations from absolute ethanol-absolute ether, an analytical sample melts at 205°-206° C.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][CH:4]=[C:3]([CH:9]=[O:10])[CH:2]=1.NCC1C=CC=CN=1.[H][H]>[Pd].CO>[OH:10][CH2:9][C:3]1[CH:2]=[CH:1][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C=O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: NCc1ccccn1
Solvent: CO
Product: O=Cc1ccc(CO)cc1
Yield: 78 %

Procedure:
Terephthaldicarboxaldehyde (30.02 g, 224 mmol), methanol (200 mL), palladium on activated carbon, (10%, 3.02 g) and 2-(aminomethyl)pyridine (2.3 mL, 22 mol, 0.01 mol equiv) were combined in a hydrogenation vessel and the reaction mixture was shaken on a Parr hydrogenator for 2.5 hours at 40 psi of hydrogen. The mixture was filtered through celite, the cake washed with methanol and the solvent from the eluent removed in vacuo. Purification of the crude product by column chromatography on silica gel (EtOAc/Hexanes, 1:1) afforded the title compound (23.8 g, 78%) as a white solid. 1H NMR (CDCl3) δ 4.80 (s, 2H), 7.53 (d, 2H, J=9 Hz), 7.87 (d, 2H, J=9 Hz), 10.00 (s, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH:22]=O)[CH:18]=[CH:17]2.C([O:26][C:27](=O)[C:28](=[O:35])[CH2:29][C:30]([CH:32]1[CH2:34][CH2:33]1)=[O:31])C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:22]([C:19]4[CH:18]=[CH:17][C:16]5[C:21](=[C:12]([OH:11])[CH:13]=[CH:14][CH:15]=5)[N:20]=4)[C:29]([C:30]([CH:32]4[CH2:34][CH2:33]4)=[O:31])=[C:28]([OH:35])[C:27]3=[O:26])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: O=Cc1ccc2cccc(O)c2n1
Reactant: Nc1ccc2[nH]cnc2c1
Solvent: CCO
Product: O=C(C1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc2cccc(O)c2n1)C1CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and 8-Hydroxy-quinoline-2-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3 4-Cyclopropyl-2,4-dioxo-butyric acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6](=[O:27])[C:7](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]=[N+:14]=[N-:15])#[N:2].[NH2:28]/[C:29](/[CH3:35])=[CH:30]\[C:31]([O:33][CH3:34])=[O:32]>CCO>[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8]1[NH:28][C:29]([CH3:35])=[C:30]([C:31]([O:33][CH3:34])=[O:32])[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:7]=1[C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:27])=[N+:14]=[N-:15]
Reactant: COC(=O)/C=C(/C)N
Reactant: N#CCCOC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)CCCCN=[N+]=[N-]
Solvent: CCO
Product: COC(=O)C1=C(C)NC(CCCCN=[N+]=[N-])=C(C(=O)OCCC#N)C1c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 7-azido-2-[(4-nitrophenyl)methylene]-3-oxoheptanoic acid 2-cyanoethyl ester (2.87 g, 7.73 mmol) and methyl 3-aminocrotonate (0.900 g, 7.73 mmol) in 50 ml of EtOH was refluxed for 48 hrs. After the EtOH was removed in vacuo, the residue was dissolved in 150 ml of CHCl3, washed with water (2×100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, the product was purified by chromatography (SiO2, CHCl3:MeOH=95:5). 2-(4-Azidobutyl)-3-(2-cyanoethoxy)carbonyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(4-nitrophenyl)pyridine was obtain as a yellow oil (2.43 g, 67% yield).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][S:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=3)[N:13]=2)[CH2:2][CH2:3]1)(=[O:23])=[O:24]
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: CS(=O)(=O)c1ccccc1C=O
Product: CS(=O)(=O)c1ccccc1CN1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-methylsulfonylbenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-methylsulfonylphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][CH2:8][NH:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:6])[CH3:3].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C1C=CC=CC=1>[CH2:2]([O:4][C:5]([CH2:7][CH2:8][N:9]([CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:23](=[O:24])[CH2:22][Cl:21])=[O:6])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)CCNC(C(=O)OCC)C(=O)OCC
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(=O)CCN(C(=O)CCl)C(C(=O)OCC)C(=O)OCC
Reaction time: 5 h
Yield: 86 %

Procedure:
To a suspension of 14 g. (0.045 moles) of diethyl N-(2-ethoxycarbonylethyl)-amino-malonate hydrochloride prepared according to Example 1b) in 150 ml. of dry benzene 5.65 g. (4 ml., 0.05 moles) of chloroacetyl chloride are added with stirring. The mixture is boiled for 5 hours. The solution is evaporated in vacuo, the evaporation residue is triturated with 50 ml. of hexane, hexane is decanted and the same procedure is repeated two more times. The oily product is dried over sodium hydroxide in a vacuum desiccator. 13.6 g. (86%) of the named compound are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CNc1nc(C#N)nc2ccc(OCc3ccncc3)cc12

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.23 mmol), 4-chloromethyl-pyridine hydrochloride (0.35 mmol) and cesium carbonate (2.3 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 203-205° C., Rf=0.2 (CH2Cl2/MeOH=15:1) is obtained. 1H-NMR (CDCl3): 1.0 (m, 9H), 3.55 (m, 2H), 5.2 (m, 2H), 5.8 (broad m, 1H), 7.05 (m, 1H), 7.4 (m, 2H), 7.55 (d, 1H), 7.85 (d, 1H), 8.65 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.[CH2:16]([Mg][Cl:21])[CH2:17][CH2:18][CH3:19]>CCOCC>[ClH:21].[ClH:21].[CH2:16]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCC[Mg]Cl
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Solvent: CCOCC
Product: CCCCc1cncc(OC[C@@H]2CCCN2C)c1
Product: Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a 1.08 g (4 mmol) sample of 5-bromo-3-((1-methyl-2-(S)-pyrrolidinyl)-methoxy)pyridine, prepared as in Example 56a above, dissolved in 40 mL of dry ether and cooled to 0° C. was added 6.0 mL of n-butylmagnesium chloride and 13.0 mg of Ni(dppp)Cl, and the reaction mixture was stirred for 5 hours at room temperature. The reaction was quenched by addition of satd NH4Cl, and the mixture was extracted with chloroform. The solvent was dried over MgSO4 and removed under vacuum, and the residue was purified of a column of silica gel, eluting with 100:1.25:0.025 chloroform:methanol:ammonium hydroxide. The product was converted into the title compound by treatment with HCl in ether according to Example 14c. MS (DCI/NH3) m/e: 259 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 8.28 (d, J=3.0 Hz, 1H), 8.24 (s, 1H), 7.80 (m, 1H), 4.58 (dd, J=11.0, 3.0 Hz, 1H), 4.42 (dd, J=11.4, 5.5 Hz, 1H), 3.96 (m, 1H), 3.77 (m, 1H), 3.32-3.23 (m, 1H), 3.05 (s, 3H), 2.78 (t, J=7.3, 2H), 2.43-2.38 (m, 1H), 2,26-2.06 (m, 3H), 1.70-1.60 (m, 2H), 1.40-1.27 (m, 2H), 0.91 (t, J=7.4 Hz, 3H). Anal. Calc. for C15H24N2O·2 HCl·0.2 ether: C, 56.46; H, 8.40; N, 8.33; Found C, 56.85; H, 8.73; N, 7.99. [α]25D =-7.30° (methanol).
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18](O)=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:43][C:44]([C:47]([O:49][CH3:50])=[O:48])([CH3:46])[CH3:45].Cl.CN1CCOCC1>C(Cl)Cl.CN(C=O)C>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([NH:43][C:44]([C:47]([O:49][CH3:50])=[O:48])([CH3:46])[CH3:45])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: COC(=O)C(C)(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.4 %

Procedure:
A solution containing about 1.5 g of Boc-Tyr(OBn)-OH (5) in 10 ml of dry CH2Cl2 was treated at 0° C. with about 417 mg of DCC. The mixture was stirred at 0° C. for about 5 minutes and treated with a solution containing about 620 mg of Aib-OMe hydrochloride (6) and about 490 mg of NMM in 2 ml of dry DMF. After stirring at 22° C. for about 12 hours, the reaction mixture was extracted with a saturated aqueous solution of NH4Cl. The organic layer was dried over Na2SO4, evaporated to dryness, and the residue chromatographed on SiO2 (EtOAc/hexanes 3:7) to yield about 900 mg of compound 7.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16]Cl)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:36].[Na+].[CH:38]([NH:40][C:41]1[N:45]([CH3:46])[N:44]=[CH:43][CH:42]=1)=[O:39].O>CC(C)=O.C(OCC)(=O)C>[I-:36].[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][N+:44]3[N:45]([CH3:46])[C:41]([NH:40][CH:38]=[O:39])=[CH:42][CH:43]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nccc1NC=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cn1c(NC=O)cc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Reaction time: 40 h
Yield: 98.3 %

Procedure:
To a mixture of benzhydryl 7β-tert-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylate (15 g) and sodium iodide (4.37 g) in acetone (15 ml) was added 5-formamido-1-methylpyrazole (15 g) at ambient temperature. After being stirred for 40 hours at the same temperature, the mixture was poured into a mixture of water and ethyl acetate. The organic layer was separated and washed with water, aqueous sodium chloride solution, and dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 7β-tert-butoxycarbonylamino-3-(3-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (20.95 g).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Cl:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>CC(C)=O>[Cl-:5].[CH2:10]([O:9][C:7]([CH2:6][S:3][C:2]([NH2:4])=[NH2+:1])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(N)=S
Reactant: O=C(CCl)OCc1ccccc1
Solvent: CC(C)=O
Product: NC(=[NH2+])SCC(=O)OCc1ccccc1
Product: [Cl-]
Temperature: 25 °C
Yield: 90 %

Procedure:
7.6 g (0.1 mol) of thiourea were dissolved in 50 ml of acetone. 18.5 g (0.1 mol) of benzyl chloroacetate were added dropwise and the mixture was heated at the boil for two hours. After cooling down to room temperature, the precipitated product was filtered off and washed with diethyl ether. Drying left 23.5 g (corresponding to a yield of 90%) of the title compound in the form of colorless crystals. The product was more than 99% pure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[O:5][CH2:6][CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10].ClCCl.CO>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[O:5][CH2:6][CH2:7][N:8]([CH2:9][CH3:10])[CH2:11][CH3:12]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])c(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(CC)CCOc1ccc(N)c(Cl)c1

Procedure:
Prepared analogously to Example 3.1.b. from [2-(3-chloro-4-nitrophenoxy)ethyl]diethylamine in ethyl acetate. Yield: 1.05 g (95.4% of theory); C12H19ClN2O (M=242.75); calc.: molecular ion peak (M+H)+: 243/245; found: molecular ion peak (M+H)+: 243/245; Rf value: 0.41 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(O)C>O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(F)c(O)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(F)c(OCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Charge methyl 4-fluoro-3-hydroxybenzoate (519 mg, 3.05 mmol), 4-(bromomethyl)-1-fluorobenzene (577 mg, 3.05 mmol), K2CO3 (843 mg, 6.10 mmol) and ethanol (10 mL) to a flask. The mixture was then stirred at room temperature overnight. Water was added to the reaction mixture at 0° C., filtered, and the solid dried and purified by flash column chromatograph to give 571 mg of the title compound (67%). 1H NMR (400 MHz, CDCl3): δ 3.90 (3H, s), 5.13 (2H, s), 7.06-7.15 (3H, m), 7.41-7.45 (2H, m), 7.63-7.67 (1H, m), 7.71 (1H, dd, J=2.0 Hz, 8.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[CH3:16][C:17](N=C([O-])N(C(C)C)C(C)C)([CH3:19])[CH3:18]>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][C:17]([CH3:19])([CH3:18])[CH3:16])=[O:14]
Reactant: Cc1c(CC(=O)O)ccc2c1COC2=O
Reactant: CC(C)N(C([O-])=NC(C)(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(CC(=O)OC(C)(C)C)ccc2c1COC2=O
Temperature: 25 °C

Procedure:
To a solution of (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetic acid (100 mg, 0.48 mmol) in anhydrous DCM (10 mL) was added 1,1-dimethylethyl-N,N-bis(1-methylethyl)imidocarbamate (485 mg, 2.50 mmol) dropwise at 0° C. under N2. Then the mixture was stirred at r.t. over night. The mixture was filtered and the filtrate was washed with 2N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give 1,1-dimethylethyl (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetate. 1H-NMR (400 MHz, CDCl3) δ 6 ppm 7.70 (d, J=7.8 Hz, 1H), 7.38 (d, J=7.0 Hz, 1H), 5.25 (s, 2H), 3.67 (s, 3H), 2.27 (s, 3H), 1.44 (s, 9H).