Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)#N.C[Mg+].[Br-].C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[OH:20][CH:17]1[CH2:18][CH2:19][N:14]([C:3]2([CH3:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)N1CCC(C#N)(N2CCC(O)CC2)CC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C)(N2CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
To a stirred solution of ethyl 4-cyano-4-(4-hydroxy-1-piperidyl)piperidine-1-carboxylate (2.45 g, 8.69 mmol) in THF (20 mL) was added a 1.4 M solution of MeMgBr in toluene/THF (18.6 mL, 26.1 mmol) at 0° C., and the mixture was stirred at room temperature for 12 h. The reaction was then quenched with saturated aqueous ammonium chloride, and the mixture was extracted with dichloromethane (2×25 mL). The combined extracts were concentrated in vacuo to afford the title compound (1.54 g, 65%), which was used in the next step without further purification. MS (M+1): 271.26.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:21][C:22]3[S:23][CH:24]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:26]=3)[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=2)=[C:5]([CH3:33])[O:4][N:3]=1.[Li+].[OH-].Cl.O>C1COCC1.CO.O>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([NH:21][C:22]3[S:23][CH:24]=[C:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:26]=3)[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=2)=[C:5]([CH3:33])[O:4][N:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2c(C)noc2C)cc1)Nc1nc(-c2ccccc2)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1COc1ccc(C[C@H](Nc2nc(-c3ccccc3)cs2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The crude product from Step B was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added, and the mixture extracted with ethyl acetate. The solvent was evaporated.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][C:24]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[O:23][C:22]2=[O:31])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][C:24]3([CH2:26][CH2:27][N:28]([C:2]4[N:3]=[N:4][C:5]([C:8]5[O:12][N:11]=[C:10]([CH3:13])[N:9]=5)=[CH:6][CH:7]=4)[CH2:29][CH2:30]3)[O:23][C:22]2=[O:31])=[CH:17][CH:16]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: O=C1OC2(CCNCC2)CN1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)CN(c3ccc(F)cc3)C(=O)O4)nn2)n1

Procedure:
The object product (24 mg, 58%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (20 mg) obtained in Example 43(2), 3-(4-fluorophenyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (25 mg) obtained in Example 30(3) and potassium carbonate (15 mg).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[K+].[Cl:24][C:25]([O:27][CH3:28])=[O:26].C(Cl)Cl>CC(C)=O>[ClH:24].[C:25](=[O:26])([O:27][CH3:28])[O:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)Cl
Reactant: Cc1cccc(O)c1CNc1cccn2c(C)c(C)nc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)Oc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.7 %

Procedure:
A mixture of 8-(2-hydroxy-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.068 g, 0.24 mmol) sodium carbonate (0.12 g, 1.1 mmol), and potassium hydroxide (0.019 g, 0.34 mmol) in acetone (12 ml) was stirred for 15 min in room temperature in a nitrogen atmosphere. Methyl chloroformate (0.023 g, 0.24 mmol) was added and the reaction mixture was stirred for 70 min. Methylene chloride was added and the mixture was filtred and the filtrate was evaporated under reduced pressure. The residue was solved in methylene chloride, washed with saturated sodium bicarbonate and water and the organic layer was separated, dried and evaporated under reduced pressure. The residue was purified by by column chromatography on silica gel using methylene chloride:methanol (100:5) as eluent and treated with HCl/diethyl ether to give 0.025 g (28%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=3)=[CH:13][C:8]=2[C:9]([O:11]C)=[O:10])[CH:4]=[N:3]1.[OH-].[Li+].Cl>C(O)(C)C.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=3)=[CH:13][C:8]=2[C:9]([OH:11])=[O:10])[CH:4]=[N:3]1
Reactant: COC(=O)c1cc(-c2cncc(C)c2)ccc1-c1cnn(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1cncc(-c2ccc(-c3cnn(C)c3)c(C(=O)O)c2)c1
Temperature: 80 °C

Procedure:
To a mixture of methyl 2-(1-methyl-1H-pyrazol-4-yl)-5-(5-methylpyridin-3-yl)benzoate (2-4, 0.216 g, 0.703 mmol, 1.0 equiv) in isopropanol/water (3:1, 4 mL) was added 1M lithium hydroxide solution (0.773 mL, 0.773 mmol, 1.1 equiv) and the reaction was heated to 80° C. for 15 minutes in the microwave. The reaction mixture was cooled and the pH was adjusted to ˜7 by the addition of 1N HCl. The reaction mixture was concentrated and the solids azeotroped from toluene to afford the product as a solid. ESI+ MS [M+H]+ C12H15N3O2: 308.02 found, 308.36 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>ClCCl>[C:31]([NH:35][S:19]([CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[CH2:12][CH2:13]1)(=[O:21])=[O:20])([CH3:34])([CH3:33])[CH3:32]
Reactant: O=S(=O)(Cl)CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 54.6 %

Procedure:
To a stirred solution of [4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexyl]-ethanesulfonyl chloride (60 mg, 0.12 mmol) (Example 105) in dichloromethane (5 mL) was added tert-butylamine (0.065 mL, 0.62 mmol), the mixture stirred at ambient temperature for 45 minutes, then evaporated. The residue was taken up in ethyl acetate (20 mL) and washed with 2N aqueous hydrochloric acid (20 mL) and brine (100 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica eluting with diethyl ether:dichloromethane:iso-hexane 1:1:2 to afford the desired product (35 mg). MS (ES+) 556 ([MNa]+).
Reaction SMILES: C[N:2]([P+]([O:11]N1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[OH:28][CH:29]1[O:37][C@H:36]([CH2:38][OH:39])[C@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]1[NH2:31]>CN(C=O)C.C(N(CC)CC)C>[O:28]=[CH:29][C@@H:30]([C@H:32]([C@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])[OH:11].[NH2:31][C@H:30]([C:29]([OH:37])=[O:28])[CH2:32][CH2:34][CH2:36][CH2:38][NH2:2]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NCCCC[C@H](N)C(=O)O
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
To a 250 ml round bottom flash, charged with 10.0 g (0.041 mole) of N ε-(tert-butoxy carbonyl) L-lysine 27, commercially available from BACHEM Bioscience Inc. (subsidiary of BACHEM Switzerland, 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia, Pa., 19406, USA), and 100 ml of methanol is added 10.0 g (0.07 mole) of ethyl trifluoroacetate followed by 20.0 ml (0.144 mole) of triethylamine. The mixture is stirred at 20–30° C. for 20 hours and then concentrated via rotary evaporation. The residue is diluted with 50 ml of diethyl ether and then filtered. The filtrate is then washed with 3×30 ml aliquots of 1N aqueous HCL, 20 ml of deionized water, and finally with 20 ml of deionized water. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is distilled under vacuum to yield product 28 in good yield. N ε-(tert-butoxy carbonyl) N1-α-trifluoroacetyl L-lysine is reacted with tri-o-acetyl tet-Gal-NAC1-a-S-Pentylamine in the presence of a BOP reagent. The activated carboxylic acid reacts with the clustered galactosamine in DMF and Triethylamine to afford galactose cluster lysine adduct 29 in good yield. The N α-trifluoroacetyl protection of the lysine is removed to afford Primary α-amino lysine-galactose cluster 29a in moderate yield.
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:19]3[C:20](O)=[CH:21][C:22]4[O:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]=4[CH:29]=3)([CH2:17][OH:18])[C:9]2=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[C:32]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:17][O:18][C:20]4[CH:21]=[C:22]5[C:23](=[CH:29][C:19]3=4)[C:24]([CH3:27])([CH3:28])[CH2:25][O:26]5)[C:9]2=[O:31])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1(C)COc2cc(O)c(C3(CO)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE1, and making non-critical variations using 1-(diphenylmethyl)-3-(6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained: mp 190-192° C.; 1H NMR (300 MHz, CDCl3) δ 7.40-7.26 (m, 10H), 7.19-7.15 (m, 1H), 7.07-6.93 (m, 3H), 6.55-6.51 (m, 1H), 6.38 (s, 1H), 6.20 (s, 1H), 4.98 (d, 1H), 4.71 (d, 1H), 4.17 (s, 2H), 1.17 (s, 3H), 1.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.1, 161.1, 161.0, 141.8, 137.9, 137.2, 132.8, 130.0, 128.6, 128.5, 128.4, 128.2, 128.0, 127.8, 123.9, 123.1, 120.8, 116.1, 112.1, 93.4, 85.4, 80.4, 58.7, 57.4, 41.3, 27.7, 27.6; MS (ES+) m/z 474.5 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(CC)C(C)C)(C)C.[CH3:46][N:47]([CH3:63])[CH:48]1[CH2:52][CH2:51][N:50]([C:53]2[CH:62]=[CH:61][C:56]([C:57]([NH:59][NH2:60])=[O:58])=[CH:55][CH:54]=2)[CH2:49]1>O.CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:60][NH:59][C:57](=[O:58])[C:56]2[CH:55]=[CH:54][C:53]([N:50]3[CH2:51][CH2:52][CH:48]([N:47]([CH3:46])[CH3:63])[CH2:49]3)=[CH:62][CH:61]=2)=[O:12])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: CN(C)C1CCN(c2ccc(C(=O)NN)cc2)C1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(C(=O)NNC(=O)c2ccc(N3CCC(N(C)C)C3)cc2)cc1
Reaction time: 0.17 h

Procedure:
A mixture of 4-butoxybenzoic acid (156 mg) and DMF (10 ml) was mixed with TOTU (264 mg) and N,N-diisopropylethylamine (104 mg). After 10 minutes, 4-(3-dimethylaminopyrrolidin-1-yl)benzohydrazide (200 mg) was added. After one hour, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The product with the molecular weight of 424.55 (C24H32N4O3) was obtained in this way; MS (ESI): 425 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][NH:7][C:8](=[O:22])[NH:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[C:12]([S:17]([OH:20])(=[O:19])=[O:18])[C:11]=1[OH:21])[C:3]([OH:5])=[O:4].[H][H]>O.CO.[Pd]>[NH2:1][C@@H:2]([CH2:6][NH:7][C:8](=[O:22])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:17]([OH:20])(=[O:18])=[O:19])[C:11]=1[OH:21])[C:3]([OH:5])=[O:4]
Reactant: [H][H]
Reactant: N[C@@H](CNC(=O)Nc1cc(Cl)cc(S(=O)(=O)O)c1O)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: N[C@@H](CNC(=O)Nc1cccc(S(=O)(=O)O)c1O)C(=O)O

Procedure:
The compound obtained in Example 6 was dissolved in water and methanol, to which a catalyst amount of Pd/C was added, and the resultant was stirred for three days in a hydrogen atmosphere. After filtrating the catalyst, the solvent was distilled away, and the resultant was purified using purification step A to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])[CH3:2].C(N(CC)CC)C.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>C(Cl)Cl>[CH2:20]([O:19][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[C:9]=1[O:17][CH3:18])[S:35]([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36])[CH3:21]
Reactant: CCOC(CNCc1ccc2c(c1OC)OCO2)OCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
59.46 g (0.2 mol) of N-(2-methoxy-3,4-methylenedioxybenzyl)aminoacetaldehyde diethylacetal (1) and 28.45 ml (0.204 mol) of triethylamine were dissolved in 100 ml of methylene chloride, to which 38.8 g (0.204 mol) of p-toluenesulfonyl chloride in 80 ml of methylene chloride was added dropwise at 15°-30° C. for 25 minutes. After stirring at room temperature for 30 minutes, 150 ml of water was added to the reaction mixture, which was stirred followed by liquid separation and then being washed with 100 ml of water. After drying the methylene chloride layer over anhydrous magnesium sulfate, the solvent was distilled off under vacuum to obtain 90.3 g of N-(2-methoxy-3,4-methylenedioxybenzyl)-N-(p-toluenesulfonyl)aminoacetaldehyde diethylacetal (2) as an oil. Yield 100%. IR and NMR spectra of the resultant product are listed below. ##STR26##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)=[CH:3][CH:2]=1.O.[N:18]#[C:19][Br:20]>C(#N)C>[BrH:20].[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[NH:15][C:19]([NH2:18])=[N:16][C:11]=3[CH:10]=2)=[CH:3][CH:2]=1
Reactant: N#CBr
Reactant: Nc1ccc(OCc2ccncc2)cc1N
Solvent: CC#N
Solvent: O
Product: Br
Product: Nc1nc2cc(OCc3ccncc3)ccc2[nH]1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
4-(Pyridin-4-ylmethoxy)benzene-1,2-diamine (21.4 mmoles, 0.460 g, 1 equivalent) was dissolved in acetonitrile (10 ml) and water (5 ml) and cooled to 0-5° C. (ice-water). Cyanogen bromide (0.226 g, 21.4 mmoles, 1 equivalent) was added in one lot and the reaction mixture was allowed to go to room temperature and stirred for 16 hours. The reaction mixture was then evaporated under reduced pressure to 0.4571 g of 5-(pyridin-4-ylmethoxy)-1H-benzo[d]imidazol-2-amine hydrobromide (yield: 86%) which was used directly in the next reaction without any further reaction. 1H-NMR (400 MHz, DMSO-d6) 12.60 (br s, 1H), 8.56 (s, 2H), 7.58 (m, 1H), 8.23 (br s, 3h), 7.57 (m, 1H), 7.40 (m, 1H), 5.28 (s, 2H). (MS (EI): 241 (MH+).
Reaction SMILES: C[C:2]([CH3:10])([C:7]([O-:9])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH2:13](C(N)CC)C>CS(C)=O>[CH3:6][O:5][C:3](=[O:4])[CH:2]([CH3:10])[C:7]([O:9][CH3:13])=[O:8]
Reactant: CCC(N)CC
Reactant: COC(=O)C(C)(C)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of methyl dimethylmalonate (260 mg) and 60% sodium hydride in oil (70 mg) in 4 ml of DMSO was stirred at room temperature for 10 min. A solution of 3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine (200 mg) in 2 ml of DMSO was added. The mixture was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give the crude material which was purified through silica gel using hexane to 10% ethyl acetate in hexane as eluent to give 137 mg of 2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]methyl]-2-methyl-malonic acid dimethyl ester as a white solid. 1H NMR (CDCl3) δ 6.83(s,2H), 6.01(s,1H), 5.00(m,1H), 3.70(s,6H), 3.40(s,2H), 3.25(m,1H), 2.27(s,3H), 2.12(s,3H), 2.05(s,6H), 1.5-1.7(m,4H), 1.48(s,3H), 0.94(t,6H)ppm.
Reaction SMILES: CO[C:3]1([C:18]([OH:20])=O)[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=[CH:8][CH:4]1[C:5]([OH:7])=O.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1.[C:31](O)(=[O:33])C>>[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][N:30]2[C:18](=[O:20])[C:3]3[C:4](=[CH:8][CH:9]=[C:10]([O:33][CH3:31])[C:11]=3[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]2=[O:7])=[CH:24][CH:23]=1
Reactant: CCCCCOC1=CC=CC(C(=O)O)C1(OC)C(=O)O
Reactant: NCCc1ccc(O)cc1
Reactant: CC(=O)O
Product: CCCCCOc1c(OC)ccc2c1C(=O)N(CCc1ccc(O)cc1)C2=O
Temperature: 25 °C
Yield: 31.8 %

Procedure:
2-Methoxy-3-pentyloxyphthalic acid (155 mg, 0.55 mmol, 1 eq) and 2-(4-hydroxyphenyl)ethylamine (101.6 mg, 0.74 mmol, 1.4 eq) were dissolved in acetic acid (10 ml), and the solution was refluxed under heating for 2 hours. The mixture was cooled to room temperature and extracted twice with ethyl acetate (40 ml). The organic layers were combined, washed with a 1N aqueous hydrochloric acid solution (40 ml) and further with saturated brine (40 ml), and dried over anhydrous sodium sulfate. The drying agent was Eltered off, and the filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel (n-hexane/ethyl acetate=4/1) to give 2-[2-(4-hydroxyphenyl)ethyl]-5-methoxy-4-pentyloxyisoindole-1,3-dione (67 mg, 31.8%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>O>[CH3:18][O:19][CH2:20][CH2:21][O:22][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: COCCO
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCOc1cnc(C(=O)O)cn1
Temperature: 95 °C
Reaction time: 4.5 h

Procedure:
A solution of methyl 5-chloropyrazine-2-carboxylate (2.0 g, 11.63 mmol) in 2-methoxyethanol (20 mL) was treated with solid potassium carbonate (4.8 g, 34.8 mmol). The mixture was heated at 95° C. and was stirred at this temperature for 4.5 h. The mixture was dissolved in water (20 mL) and extracted with diethyl ether. The aqueous layer was neutralized with a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-methoxyethoxypyrazine-2-carboxylic acid as a pale yellow solid powder: (1.89 g, 82.2%).
Reaction SMILES: [Mg].BrCC.Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.CON(C)[C:23]([C:25]1[O:29][N:28]=[C:27]([CH3:30])[CH:26]=1)=[O:24]>O.C1COCC1>[CH3:30][C:27]1[CH:26]=[C:25]([C:23]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[O:24])[O:29][N:28]=1
Reactant: CON(C)C(=O)c1cc(C)no1
Reactant: Brc1ccccc1COC1CCCCO1
Agent: [Mg]
Solvent: O
Solvent: CCBr
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2ccccc2COC2CCCCO2)on1
Temperature: 55 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
Magnesium (0.73 g, 0.03 mol) and bromoethane (0.2 ml) were added to a mixture of 1-bromo-2-(2-tetrahydro-pyranyloxymethyl)benzene (5.42 g, 0.02 mol) and THF (50 ml) under an atmosphere of nitrogen gas, and the resulting mixture was stirred at 50 to 60° C. for 1 hour to prepare Grignard reagent. The Grignard reagent was added dropwise to a mixture of N-methoxy-3, N-dimethyl-5-isoxazolcarboxamide (3.40 g, 0.02 mol) and THF (40 ml). The mixture was stirred at −60° C. to room temperature for 1 hour, water (200 ml) was added, and the mixture was extracted with ether (200 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2-tetrahydropyranyloxymethyl)phenyl 3-methylisoxazol-5-yl ketone (4.09 g, yield: 67.9%) as a colorless oil.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[C:11]([O:15][C:16]([CH2:18][O:19][N:20]=[C:21]([C:52]1[N:53]=[CH:54][S:55][CH:56]=1)[C:22]([NH:24][CH:25]1[C:50](=[O:51])[N:27]2[C:28]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:29]([CH2:32]Cl)[CH2:30][S:31][C@H:26]12)=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[C:11]([O:15][C:16]([CH2:18][O:19][N:20]=[C:21]([C:52]1[N:53]=[CH:54][S:55][CH:56]=1)[C:22]([NH:24][CH:25]1[C:50](=[O:51])[N:27]2[C:28]([C:34]([O:36][CH:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[O:35])=[C:29]([CH2:32][S:1][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[N:9][N:10]=4)[N:7]=3)[CH2:30][S:31][C@H:26]12)=[O:23])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1cscn1
Reactant: Sc1ccc2nncn2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3ccc4nncn4n3)CS[C@H]12)c1cscn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.5 %

Procedure:
6-Mercapto-1,2,4-triazolo[4,3-b]pyridazine (4.7 g) was added to a stirred suspension of benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (5.0 g) and sodium iodide (4.6 g) in N,N-dimethylformamide (35 ml) and the mixture was stirred for 2 hours at ambient temperature. To the reaction mixture was added a mixture of ethyl acetate and water and then the resultant mixture was adjusted to pH 7.5 with 20% aqueous solution of sodium carbonate. The separated organic layer was washed with saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The crude product obtained by concentration of organic layer was purified by silica gel column chromatography using ethyl acetate as an eluate. The fractions containing the object compound were evaporated to give benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (1.2 g).