Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl:19][C:20]1[CH:25]=[C:24](/[C:26](/[C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:42][CH2:41]3)=[C:36]([O:43][CH3:44])[N:35]=2)=[CH:27]\[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=[CH:22][C:21]=1[OH:45].O>CN(C)C=O>[Si:12]([O:11][CH2:10][CH2:9][CH2:8][O:45][C:21]1[CH:22]=[CH:23][C:24](/[C:26](/[C:34]2[N:35]=[C:36]([O:43][CH3:44])[C:37]([CH:40]3[CH2:41][CH2:42]3)=[CH:38][CH:39]=2)=[CH:27]\[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:25][C:20]=1[Cl:19])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: COc1nc(/C(=C/C2CCOCC2)c2ccc(O)c(Cl)c2)ccc1C1CC1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(/C(=C/C2CCOCC2)c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c2)ccc1C1CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Potassium carbonate (214 mg) and (3-bromopropoxy)(tert-butyl)dimethylsilane (240 μL) were added to a solution of 2-chloro-4-[(E)-1-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethenyl]phenol obtained in Example 1-53(2) (200 mg) in N,N-dimethylformamide (4 mL), and the mixture was stirred at 65° C. for 1.5 hours and at room temperature overnight. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 6-{(E)-1-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-3-chlorophenyl]-2-(tetrahydro-2H-pyran-4-yl)ethenyl}-3-cyclopropyl-2-methoxypyridine as a colorless oil (245 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.Cl[CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1>>[NH2:22][C:20]1[CH:19]=[CH:18][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:31][CH2:30]4)=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCCl)CC1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
T1 was prepared from 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol and tert-butyl 4-(3-chloropropyl)piperazine-1-carboxylate following the general procedure reported in Preparative Example 54 Step 1-2. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.38 (s, 9H), 1.96 (m, 2H), 2.23 (m, 4H), 2.47 (m, 2H), 3.30 (m, 4H), 3.92 (s, 3H), 4.17 (t, J=6.3 Hz, 2H), 5.46 (br s, 2H), 6.37 (d, J=5.2 Hz, 1H), 6.45 (dd, J=8.9 Hz, J=1.8 Hz, 1H), 6.54 (dd, J=13.1 Hz, J=2.4 Hz, 1H), 7.05 (t, J=8.9 Hz, 1H), 7.35 (s, 1H), 7.49 (s, 1H), 8.42 (d, J=5.2 Hz, 1H). MS (ES) C29H35FN4O5 requires: 526. Found: 527 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])(=O)=O)=CC=1.O[C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14]([NH:13][CH2:12][CH2:11][O:10][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCNC(=O)OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCNC(=O)OCc2ccccc2)cc1
Reaction time: 24 h
Yield: 88.6 %

Procedure:
A mixture of 35 g of 2-(N-benzyloxycarbonylamino)ethyl p-toluenesulfonate, 13 g of 4'-hydroxyacetophenone and 55 g of anhydrous potassium carbonate in 450 ml of dry acetone was refluxed with stirring for 24 hrs under argon atmosphere. After cooling, the insoluble material was removed by filtration and the filtrate was evaporated. The residue was diluted with ethyl acetate, washed with water, 1% NaOH and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give a solid, which was recrystallized from hexane-benzene to give 26.5 g of 4'-(2-(N-benzyloxycarbonylamino)ethoxy)-acetophenone as white needles.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH:10]=[CH:9]1>>[C:2]1([NH:1][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccccc1
Product: O=C(O)/C=C\C(=O)Nc1ccccc1

Procedure:
Aniline (1 mol) and maleic anhydride (1.0 mol) were subjected to an addition reaction at 20 to 30° C. for 2.5 hours to give N-phenylmaleamidic acid. Then, the resulting N-phenylmaleamidic acid was neutralized with sodium hydroxide under cooling to give an N-phenylmaleamidic acid sodium salt.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:19]=[CH:18][C:11]2[CH:12]=[C:13]([C:15]([OH:17])=O)[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]([F:35])([F:34])[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[NH2:23].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl>CN(C)C=O>[F:20][C:21]([F:34])([F:35])[CH:22]([NH:23][C:15]([C:13]1[O:14][C:10]2[CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:19]=[CH:18][C:11]=2[CH:12]=1)=[O:17])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=1
Reactant: CC(C)(C)OC(=O)c1ccc2cc(C(=O)O)oc2c1
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 6-(tert-butoxycarbonyl)-1-benzofuran-2-carboxylic acid (350 mg, 1.33 mmol) and 2,2,2-trifluoro-1-[3-trifluoromethylphenyl]ethanamine (357 mg, 1.46 mmol) in N,N-dimethylformamide (5 ml) was admixed with 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (304 mg, 1.46 mmol) and stirred in a closed vessel at 50° C. overnight. The cooled reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with sat. sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. This leaves 453 mg as a mixture of the tert-butyl ester and of the free acid, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[C:16]1([CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O-]S([O-])(=O)=O.[Mg+2].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O.C1COCC1.CC(N(C)C)=O>[CH3:12][C:11]1[NH:10][N:9]=[CH:8][C:7]=1[C:5]1[S:4][C:3]2[C:13](=[O:14])[NH:15][C:25]3([CH2:24][CH2:23][CH:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:27][CH2:26]3)[NH:1][C:2]=2[CH:6]=1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCC(c3ccccc3)CC1)N2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl) thiophene-2-carboxamide (111 mg, 0.50 mmol), 4-phenylcyclohexanone (261 mg, 1.50 mmol), MgSO4 (120 mg, 1.00 mmol), CSA (11.61 mg, 0.050 mmol) and DMA (3 mL) was stirred at 80° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and 2:1 EtOAc/THF. The precipitate was collected by filtration and washed with water and EtOAc to give the title compound (28.7 mg, 15%, single isomer on cyclohexane, absolute structure not determined) as gray solid:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([OH:21])=[O:20])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:30][N:31]([CH3:42])[C:32]1[CH:41]=[CH:40][C:35]2[C:36]([CH3:39])=[CH:37][O:38][C:34]=2[CH:33]=1.[OH-].[Na+]>C(OC(=O)C)(=O)C>[CH3:42][N:31]([CH3:30])[C:32]1[CH:41]=[CH:40][C:35]2[C:36]([CH3:39])=[C:37]([C:11]3([C:10]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:2]=4[CH3:1])[C:13]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:19](=[O:21])[O:20]3)[O:38][C:34]=2[CH:33]=1
Reactant: CCCCCCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: Cc1coc2cc(N(C)C)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCn1c(C)c(C2(c3oc4cc(N(C)C)ccc4c3C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 40 °C
Yield: 66.3 %

Procedure:
3.5 g of (2-methyl-1-n-octylindol-3-yl)-(2-carboxyphenyl)ketone and 1.6 g of 6-dimethylamino-3-methylbenzofuran are suspended in 45 ml of acetic anhydride and heated to 40° C. After 2 hours the reaction product is poured onto ice, basified with concentrated sodium hydroxide solution and filtered off. The crude product is recrystallized from toluene/methanol to give 3.25 g of the 3-(6-dimethylamino-3-methyl-benzofuran-2-yl)-3-(2-methyl-1-n-octylindol-3-yl)-phthalide compound of the formula ##STR28## having a melting point of 157°-158° C. The phthalide compound gives a green colour on acid-modified silica gel.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[C:10]([O:12]CC)=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C(S(CC(CC1C=CC=CC=1)C(OCC)=O)(=O)=O)(C)(C)C.S(=CC(C(OCC)=O)C(OCC)=O)=O>>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[C:10]([OH:12])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H](Cc1cccs1)CS(=O)(=O)C(C)(C)C
Agent: CCOC(=O)C(C=S=O)C(=O)OCC
Agent: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1cccs1)C(=O)O

Procedure:
This compound is prepared in a manner analogous to Example 1(d) by the enzymatic hydrolysis of ethyl (S)-α-[(tert-butylsulphonyl)methyl]-2-thiophenepropionate which, in turn, is prepared analogously to the synthesis, described in EPA 0236734, of ethyl (RS)-α-[(tert-butylsulphonyl)methyl]hydrocinnamate from diethyl 2-thionylmethylmalonate (P. Cagniant et al., Bull. Soc. Chim. Fr. 1954, 1349). MS: 318 (M)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1([CH3:22])[C:16]2=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=[C:15]2[O:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:12]1([CH3:22])[C:16]2[C:17]([O:21][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC1(C)COc2cccc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)COc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Yield: 67.4 %

Procedure:
In a large microwave vial, 2-chloro-5-nitropyridine (386 mg, 2.436 mmol) was dissolved in 4 ml of dimethylformamide. 3,3-dimethyl-2,3-dihydro-1-benzofuran-4-ol (Intermediate 57, 400 mg) and potassium carbonate (2.02 g, 14.62 mmol) were added. The reaction mixture was heated under microwave irradiation during 30 minutes at 110 C (Biotage Initiator). The reaction mixture was filtered. The filtrated solid was washed with dichloromethane (30 ml). The volatiles were evaporated under vacuum. The residue was purified by silica gel chromatography (Companion instrument, 120 g cartridge) with cyclohexane as eluent to afford the title compound (470 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:35][NH2:36]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4cccc(F)c4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3cccc(F)c3)c2O1

Procedure:
The title compound was prepared (0.058 g, 74%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[F:12][C@@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:12][C@@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: CCCCCC[C@H](F)CO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCC[C@H](F)COc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
0.1 mol of methyl 4-hydroxybenzoate, 0.1 mol of (S)-2-fluoro-1-octanol and 0.12 mol of triphenylphosphine are dissolved in 250 ml of tetrahydrofuran, and 0.12 mol of diethyl azodicarboxylate is added dropwise with stirring and ice cooling. The mixture is allowed to warm to room temperature, and is then stirred for a further 8 hours. The solvent is then distilled, and the methyl 4-(2-fluorooctyloxy)benzoate is purified by column chromatography. Saponification using aqueous/alcoholic potassium hydroxide solution gives (S)-4-(2-fluorooctyloxy)benzoic acid.
Reaction SMILES: CC([O-])(C)C.[Li+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[N:12][C:13]=1Cl.[F:19][CH2:20][CH2:21][OH:22].Cl>CN(C=O)C.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[N:12][C:13]=1[O:22][CH2:21][CH2:20][F:19]
Reactant: COC(=O)c1ccc(Br)c(Cl)n1
Reactant: OCCF
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Br)c(OCCF)n1
Temperature: 70 °C
Reaction time: 6 h
Yield: 11.9 %

Procedure:
Lithium 2-methylpropan-2-olate (4.17 mL, 9.18 mmol) was added within 30 minutes at ambient temperature to a solution of methyl 5-bromo-6-chloro-pyridine-2-carboxylate (CAN 1214353-79-3, 1 g, 3.99 mmol) and 2-fluoroethanol (CAN 371-62-0, 332 mg, 300 μL, 5.19 mmol) in DMF (6.67 mL). The reaction mixture was heated to 70° C. and stirred for 6 h. After cooling to ambient temperature, water (5 mL) and 2N HCl (5 mL) were added. The mixture was poured onto ice/brine (50 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with ice/brine (50 mL), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash-chromatography (50 g SiO2, heptane/0-30% EtOAc in 120 min.) to give the title compound (132 mg, 12%) as light brown solid, MS (ESI) m/e=278.0 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1OC(=O)[S:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:23]>ClC1C=CC=CC=1Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:18][N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1oc(-c2ccc(Cl)cc2OCc2ccccc2)ns1
Reactant: CCOC(=O)C#N
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2OCc2ccccc2)ns1
Temperature: 150 °C
Yield: 11.4 %

Procedure:
To a solution of 5-(2-(benzyloxy)-4-chlorophenyl)-1,3,4-oxathiazol-2-one (0.15 g, 0.47 mmol) in 1,2-dichlorobenzene (1 ml) was added ethyl cyanoformate (185 μL, 1.88 mmol). The resulting reaction mixture was refluxed for 3 h at 150° C. After the completion of the reaction (TLC monitoring), the reaction mass was as such (direct loading) purified through flash chromatography (100-200 M silica, 2% EtOAc-Hexane) to get the desired product (0.02 g, 12%). MS: 375.18 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)[NH2:20])=[CH:24][CH:23]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Product: NN(Cc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
reacting the 4-(quinolin-2-ylmethoxy)phenylhydrazine product of step (4) with p-chlorobenzyl chloride, tetrabutylammonium bromide and diisopropyl ethyl amine to yield 1-(p-chlorobenzyl)-1-[4(quinolin-2-yl-methoxy)phenyl]hydrazine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:22])=[C:15]([CH2:18][S:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.C1C=CC=CC=1>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15]([CH2:18][S:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: 10 °C
Yield: 40.7 %

Procedure:
The mixture of benzhydryl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-methylthiomethyl-3-cephem-4-carboxylate (3.3 g), trifluoroacetic acid (10 ml) and anisole (10 ml) in methylene chloride (10 ml) was stirred at 10° C. for an hour. After benzene (50 ml) was added to the reaction mixture, the trifluoroacetic acid therein was azeotropically removed under reduced pressure. The remained aqueous solution was poured into a mixture of ethyl acetate (100 ml) and water (100 ml), followed by adjusting to pH 7.5 with sodium bicarbonate. After separating out the aqueous solution, the organic solvent was removed therefrom by evaporation completely under reduced pressure, followed by adjusting to pH 3.0 with 10% hydrochloric acid. The precipitated solid was collected by filtration and then dried to give 7-[2-(2-aminothiazol-4-yl)acetamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (0.95 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:36][CH2:37][OH:38]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]([CH2:36][CH2:37][OH:38])[CH2:7]1)=[O:5])[CH3:2]
Reactant: OCCBr
Reactant: CCOC(=O)C1CNCCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Solvent: ClCCl
Product: CCOC(=O)C1CN(CCO)CCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a solution of 0.6 g (1.24 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid ethyl ester (see Example 31, Step 1) in CH2Cl2 (10 mL) and TEA (0.313 mL, 3.1 mmol) at 0° C. was added 2-bromoethanol (0.1 mL, 1.36 mmol). The resulting reaction mixture was allowed to warm to 25° C. over 19 h. The reaction was then diluted with CH2Cl2 (50 mL) and washed with 1N HCl (5 mL) and saturated aqueous sodium chloride (30 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by Biotage Flash 40S chromatography, eluting with 2:1 ethyl acetate-hexanes, to provide 1-(2-hydroxy-ethyl)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid ethyl ester as a white solid (0.6 g, 92%). MS: 528 (M+H)+
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32]C1C=CC(C#N)=C(O)C=1.C(O)(=O)C(O)=O.[Cl:48][C:49]1[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[C:51]([O:57][C@@H:58]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:59][CH2:60][CH2:61]NC)[CH:50]=1>O1CCCC1.C1(C)C=CC=CC=1>[Cl:48][C:49]1[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[C:51]([O:57][C@@H:58]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:59][CH2:60][CH2:61][Cl:32])[CH:50]=1
Reactant: CNCCC[C@@H](Oc1cc(Cl)ccc1C#N)c1ccccc1
Reactant: N#Cc1ccc(Cl)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Cl)cc1O[C@H](CCCCl)c1ccccc1
Yield: 197.8 %

Procedure:
Diethyl azodicarboxylate (1.86 g) was added dropwise to a solution of triphenylphosphine (2.81 g), 4-chloro-2-hydroxybenzonitrile (1.49 g) and the product from step (a) (1.79 g) in tetrahydrofuran (5 ml) and toluene (60 ml) at 0° C. and stirred at 0° C. for 4hand at 20° C. for 18 h. The solvent was removed in vacuo and the residue was purified by chromatography on silica eluting with hexane-diethyl ether (4:1) to give the title compound as a colourless oil (2.80 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:35]1[CH:36]=[CH:37][C:38](=[O:42])[N:39]([CH3:41])[CH:40]=1>>[CH3:1][O:2][CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:35]3[CH:36]=[CH:37][C:38](=[O:42])[N:39]([CH3:41])[CH:40]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: COC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Reactant: Cn1cc(Br)ccc1=O
Product: COC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-6-(methoxymethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 76. Mass spectrum (ESI+): m/z=433 [M+H]+
Reaction SMILES: O[C@@H:2]1[CH2:7][C@@H:6]([O:8][CH3:9])[CH2:5][N:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.CCOC(C)=O.CN(C=O)C>[N:32]([C@H:2]1[CH2:7][C@@H:6]([O:8][CH3:9])[CH2:5][N:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:3]1)=[N+:33]=[N-:34]
Reactant: CO[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CO[C@@H]1C[C@H](N=[N+]=[N-])CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of (3R,5R)-benzyl 3-hydroxy-5-methoxypiperidine-1-carboxylate (1 eq) in 40 mL of dichloromethane was added triethyl amine (3 eq) and methanesulfonyl chloride (1.5 eq) at 0° C. The reaction mixture was allowed to stir at room temperature for 2 hours. The crude mixture was diluted with 150 mL of EtOAc, washed with sat. aq. sodium bicarbonate, brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to give the intermediate, which was dissolved in 15 mL of DMF. Sodium azide (3.3 eq) was added and the resulting suspension was stirred at 80° C. overnight. The reaction mixture was diluted with 150 mL of EtOAc, washed with water, brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:2) to yield (3S,5R)-benzyl 3-azido-5-methoxypiperidine-1-carboxylate (95%). LC/MS (m/z): 263.2 (MH+-28).