Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8](/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CCCCC/C(=C\C=C\C(=O)O)c1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.6 %

Procedure:
As in Example 115, (E,E)-5-(3-fluorophenyl)-2,4-decadienoic acid (3.55 g) and 4-nitrophenol (2.33 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.81 g) and the mixture was stirred at room temperature for 3 days. After the usual work up. crystallization of the crude ester from hexane gave 3.51 g of (E,E)-5-(3-fluorophenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 46°-47° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][N:33]([CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]4[CH:51]=[CH:50][CH:49]=[C:48]5[C:43]=4[CH:44]=[CH:45][CH:46]=[N:47]5)[CH2:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCNC2)C1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCN(C[C@@H](O)COc3cccc4ncccc34)C2)C1
Temperature: 25 °C
Yield: 67 %

Procedure:
1-(Piperidine-3-carbonyl)-piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (79) (243.4 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 17 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (230 mg) as a white solid. ESMS:MH+ 691.6
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[O:10]C=[C:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2.[N+](C1C=C(C)[N+]([O-])=CC=1)([O-])=O.[K+].[Br-]>>[CH2:1]([S:8][C:15]1[CH:14]=[C:13]([CH3:12])[N+:9]([O-:10])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: c1ccc2nocc2c1
Agent: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Br-]
Agent: [K+]
Product: Cc1cc(SCc2ccccc2)cc[n+]1[O-]
Temperature: 0 °C
Yield: 30 %

Procedure:
Mineral oil was removed from potassium hydride (0.11M; 35 wt. % dispersion in mineral oil) by several washings with petroleum ether (5×50 ml). The remaining petroleum ether was removed under vacuum. To this dry solid, 350 ml of anhydrous THF was added cautiously. The well stirred suspension was cooled to 0° C. To this mixture, 14.1 ml (0.12 mol) of benzylmercaptan was added dropwise over a period of 30 minutes. The resultant milky white mixture was warmed to room temperature and allowed to stir for an additional 30 minutes. The mixture was then cooled to -30° C., and 15 41 g (0.1 mol) of 4-nitro 2-picoline-N-oxide was added portionwise. The mixture became dark orange-brown in color. Once warmed to room temperature, the mixture was refluxed for one hour. At this time, the reaction was cooled to 0° C. and quenched with 50 ml of water. The pH of the mixture was adjusted to approximately 6 with 2M HCl, and extracted with dichloromethane (3×300 ml). The combined organic layers were dried (anhydrous Na2SO4), and the solvent was removed under reduced pressure. The crude residue was chromatographed on flash silica gel with MeOH/CH2Cl2 (Gradient: 3:97, 4:96, 5:95). The pure product was isolated (6.94 g; 30% yield) as a tan solid: M.P. 98°-99° C.; IR (KBr) 3063, 3028, 1612, 1466, 1236, 831, 715, 675 cm-1 ; 1H NMR (CDCl3) δ 2.45 (s, 3H), 4.16 (s, 2H), 6.97 (dd, 1H, J=6.8, 2.7 Hz), 7.07 (d, 1H, J=2.7 Hz), 7.32 (m, 5H), 8.09 (d, 1H, J=6.8 Hz). Anal. Calcd. for C13H13NOS: C, 67.50; H, 5.66; N, 6.05; S, 13.86. Found: C, 67.51; H, 5.69; N, 6.08; S, 13.77.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[F:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: CC(C(=O)O)C(=O)NCc1cccc(F)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CC(C(=O)NCc1cccc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=473.2 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(3-fluoro-benzyl)-malonamic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.COC(=O)[O-].[Mg+2].COC(=O)[O-].Br[CH2:24][C:25]#[N:26]>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH2:9][CH2:24][C:25]#[N:26])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: N#CCBr
Agent: COC(=O)[O-]
Agent: Cl
Agent: [Mg+2]
Product: N#CCCC(=O)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
A solution of 1-(5-chloro-2-hydroxy-phenyl)-ethanone (1.0 g, 5.86 mmol) and magnesium methylcarbonate (13 mL, 32.5 mmol, 2.5 M solution in DMF) was stirred at 120° C. for 3 hours. The mixture was cooled to ambient temperature followed by the addition of bromoacetonitrile (1.22 mL, 17.6 mmol). The resulting solution was stirred at 90° C. for 3 hours. The reaction was cooled to ambient temperature then slowly poured into 1 M hydrochloric acid (200 mL). This was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated. Flash chromatography on silica gel gave the title compound (0.72 g).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:29]2[N:38]=[CH:37][C:36]3[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:35]=3)[C:30]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[CH2:26][CH2:25][CH2:24][N:22]3[N:23]=2)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=1)(=O)C.[OH-].[Li+].O>C1COCC1.C(O)(C)C.O>[C:39]([C:34]1[CH:35]=[C:36]2[C:31](=[C:32]([F:43])[CH:33]=1)[C:30](=[O:44])[N:29]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:20]=[C:21]5[CH2:26][CH2:25][CH2:24][N:22]5[N:23]=4)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:38]=[CH:37]2)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCC4)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CCC3)c1=O
Reaction time: 2.5 h
Yield: 33.7 %

Procedure:
To a solution of 162d (50 mg, 0.080 mmol) in THF/i-propanol/water (1/1/0.5 ml) was added lithium hydroxide (19 mg, 0.80 mmol) at room temperature. After the reaction was stirred for 2.5 h, LCMS indicated the reaction was complete. Then the mixture was poured into water (15 mL) and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was purified by reverse-phase prep-HPLC (A: 1% NH4HCO3/water, B: acetonitrile) to afford 162 (15 mg, 33.3%) as white solid. MS-ESI: [M+H]+ 556.3. 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J=5.0 Hz, 1H), 8.32 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.55-7.47 (m, 4H), 7.26 (s, 1H), 5.74 (s, 1H), 4.47 (d, J=4.0 Hz, 2H), 4.07 (t, J=2.0 Hz, 2H), 3.70 (s, 3H), 2.87 (t, J=6.5 Hz, 2H), 2.55-2.52 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]([NH:23]NC3C=CC=CC=3)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl.[CH3:32][N:33]([CH3:40])[CH2:34]/[CH:35]=[CH:36]/[C:37](Cl)=[O:38].C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]([NH:23][C:2]3[CH:3]=[C:4]([NH:16][C:37](=[O:38])/[CH:36]=[CH:35]/[CH2:34][N:33]([CH3:40])[CH3:32])[CH:5]=[CH:6][CH:7]=3)[CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Nc2cc(NNc3ccccc3)ncn2)ccc1OCc1ccccn1
Reactant: CN(C)C/C=C/C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CN(C)C/C=C/C(=O)Nc1cccc(Nc2cc(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncn2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 6.4 %

Procedure:
3-{[6-(3-chloro-4-(2-pyridyl)methoxyphenylamino)-pyrimidin-4-ylamino]phenylamine (IR-9) was dissolved in N-methylpyrrolidinone (1.2 mL) and added dropwise over 10 minutes to the ice-cold solution of (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride in acetonitrile. The reaction was stirred in an ice bath for 2 hr. To the mixture was added sodium bicarbonate to pH greater than 9. The oil that formed was extracted with EtOAc (3×25 mL). A portion of the material was insoluble and set aside. The organic layer was dried (MgSO4) filtered and evaporated to a dark red oil. Both oils contained substantial amount of product as shown by TLC: SiO2CHCl3:MeOH/NH4OH (8:1) 19:1. The oils were combined and purified by flash column chromatography silica gel (25×300 mm) eluted first with 5% methanol/ammonium hydroxide 8/1 to remove non-polar impurities followed by 10% methanol/ammonium hydroxide 8/1 to elute 59 mg of product. The sample was further purified by a second flash column chromatography silica gel (25×250 mm) eluted with 10% methanol/ammonium hydroxide 8/1 to give the title compound (16.3 mg, 0.03 mmol, 6.4% yield). MS (ES+) 530 (M+): 552, (M+Na); 1H NMR (DMSO-d6, 500 MHz) δ (ppm): 10.04 (s, 1H), 9.19 (s, 1H), 9.14 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 7.88 (s, 2H), 7.57 (s, 1H), 7.36 (d, 1H, J=7.4 Hz), 7.29 (d, 2H, J=7.8 Hz), 7.22 (d, 2H, J=7.9 Hz), 7.18 (m, 2H), 6.74 (m, 1H), 6.30 (d, 1H, J=15 Hz) 6.10 (s, 1H), 5.24 (s, 2H), 3.06 (s, 2H), 2.18 (s, 6H) ppm; HPLC: tR=5.15 min, 97.5% (YMC-Pack ODS-A 4.6×100 mm, 80% water/20% acetonitrile to 5% water/95% acetonitrile over 5.5 min, hold to 9 min.).
Reaction SMILES: [ClH:1].Cl.[Br:3][C:4]1[CH:5]=[C:6]([CH:12]([C:21]([CH2:25][CH3:26])([OH:24])[CH2:22][CH3:23])[CH2:13][N:14]2[CH2:19][CH2:18][N:17](C)[CH2:16][CH2:15]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].BrC1C=C(C(C(CC)(O)CC)C(N2CCN(C(OC(C)(C)C)=O)CC2)=O)C=CC=1OC.Cl>>[ClH:1].[ClH:1].[Br:3][C:4]1[CH:5]=[C:6]([CH:12]([C:21]([CH2:22][CH3:23])([OH:24])[CH2:25][CH3:26])[CH2:13][N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCC(O)(CC)C(CN1CCN(C)CC1)c1ccc(OC)c(Br)c1
Agent: CCC(O)(CC)C(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c1ccc(OC)c(Br)c1
Agent: Cl
Product: CCC(O)(CC)C(CN1CCNCC1)c1ccc(OC)c(Br)c1

Procedure:
In an analogous manner to Example 1, step 2 2-(3-bromo-4-methoxyphenyl)-3-ethyl-1-(4-methylpiperazin-1-yl)pentan-3-ol dihydrochloride was prepared from tert-butyl 4-[2-(3-bromo-4-methoxyphenyl)-3-ethyl-3-hydroxypentanoyl]piperazine-1-carboxylate. MS m/z 385/387 ([M+H]+); HRMS: calcd for C18H29BrN2O2.2.00 HCl, 456.0946; found (ESI), 385.1494.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=1.C1C(=O)N([Br:22])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>CC#N>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([O:10][CH3:11])[C:9]=1[Br:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(OC)cc(OC)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(OC)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
3,5-Dimethoxy-benzoic acid methyl ester (4.0 g) was dissolved in MeCN (28 mL), and NBS (4.4 g ) was added at 0° C. After stirring at room temperature for 3 hours, saturated Na2SO3 (15 mL) was added. The mixture was evaporated under vacuum and extracted with ether (1×, 500 mL). After the solvent was removed, the crude material was subjected to silica gel chromatography using effluent of 10-40% ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 2-bromo-3,5-dimethoxy-benzoic acid methyl ester (5.2 g, 93%) as a clear oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.CC(C)([O-])C.[K+].Cl[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.O>CN(C)C=O>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH:5]=1
Reactant: Clc1cnccn1
Reactant: COC(OC)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1cccc(Oc2cnccn2)c1
Temperature: 60 °C

Procedure:
A solution of 168 mg of 3-hydroxybenzaldehyde dimethyl acetal in 10 ml of anyhydrous dimethylformamide was stirred under nitrogen and 220 mg of potassium tert-butoxide were added. The mixture was heated at 60° C. for 1 hour, then cooled to room temperature and 115 mg of 2-chloropyrazine were added in portions. The mixture was then heated at 160° C. for 18 hours. After cooling 15 ml of water were added and the product was extracted with 50 ml of ethyl acetate. The extract was washed with 25 ml of 1M sodium hydroxide solution and 25 ml of brine and then dried over anhydrous magnesium sulphate. After filtration and evaporation of the filtrate the residual yellow oil was purified by column chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution to give 3-(2-pyrazinyloxy)-benzaldehyde dimethyl acetal as a yellow oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]3[N:25]=[CH:26][C:27]4[C:32]5[CH:33]=[CH:34][N:35]=[CH:36][C:31]=5[N:30]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:28]=4[N:29]=3)=[N:21][CH:22]=2)[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>C1COCC1.CO.Cl>[CH:37]1([N:30]2[C:28]3[N:29]=[C:24]([NH:23][C:20]4[N:21]=[CH:22][C:17]([N:14]5[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][OH:8])[CH2:12][CH2:13]5)=[CH:18][CH:19]=4)[N:25]=[CH:26][C:27]=3[C:32]3[CH:33]=[CH:34][N:35]=[CH:36][C:31]2=3)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: OCCN1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
Compound 296 (85.0 mg, 148 μmol) was dissolved in dry THF (3 mL).). Tetrabutylammonium fluoride, 1.0M in THF (1.00 mL, 1.00 mmol) was added and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo and silica gel chromatography (gradient elution hexanes+2.5%/0-100% ethyl acetate+2.5% TEA, then ethyl acetate+2.5% TEA/0-5% methanol) afforded a yellow solid. This residue was taken up in methanol (3 mL) and 1M ethanolic HCl (1 mL). Diethyl ether (20 mL) was added to precipitate the product, which was filtered and dried in vacuo to give compound 295 as a yellow solid (54 mg, 79%). 1H NMR (500 MHz, DMSO-d6) δ 10.75-10.97 (m, 2 H) 9.70 (s, 2 H) 9.47 (s, 1 H) 8.74 (d, J=3.67 Hz, 2 H) 8.16 (d, J=2.45 Hz, 1 H) 7.99-8.10 (m, 1 H) 7.84-7.99 (m, 1 H) 5.30-5.52 (m, 1 H) 3.81-3.96 (m, 4 H) 3.62-3.72 (m, 2 H) 3.20-3.36 (m, 6 H) 2.39-2.49 (m, 2 H) 2.02-2.20 (m, 4 H) 0.88 (d, J=6.85 Hz, 2 H) ppm.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:35]/[O:36][C:37]([C:40]([OH:42])=[O:41])([CH3:39])[CH3:38])/[C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][N+:19]4[N:20]([CH2:27][CH2:28][OH:29])[C:21]([NH2:26])=[C:22]([CH2:24][NH2:25])[CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[S:43](=[O:47])(=[O:46])([OH:45])[OH:44].C(#N)C>O>[S:43]([O-:47])([OH:46])(=[O:45])=[O:44].[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:35]/[O:36][C:37]([C:40]([OH:42])=[O:41])([CH3:39])[CH3:38])/[C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([OH:32])=[O:31])=[C:15]([CH2:18][N+:19]4[N:20]([CH2:27][CH2:28][OH:29])[C:21]([NH2:26])=[C:22]([CH2:24][NH2:25])[CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(CN)c(N)n3CCO)CS[C@H]12)c1nsc(N)n1)C(=O)O
Reactant: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(C[n+]3cc(CN)c(N)n3CCO)CS[C@H]12)c1nsc(N)n1)C(=O)O
Product: O=S(=O)([O-])O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7β-[(Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-aminomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (5.0 g) was dissolved in water (100 ml), and 2.0 M sulfuric acid (4.0 ml) was added to the solution. The mixture was freeze-dried to give crude 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-aminomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate hydrogensulfate (5.18 g) as an amorphous solid. The amorphous solid (1.0 g) was dissolved in water (1.0 ml). To the solution was added acetonitrile (5.0 ml) dropwise. After stirring at room temperature for 2 hours, white crystals precipitated. The precipitated crystals were collected by filtration on a glass filter, washed with a small amount of water/acetonitrile (1:5) and dried under reduced pressure to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-aminomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate hydrogensulfate (880 mg) as white crystals. 1H-NMR(D2O) δ1.61(6H, s), 3.20 and 3.53 (2H, ABq, J=18.0 Hz), 3.87 (2H, t, J=4.6 Hz), 4.09 (2H, s), 4.38 (2H, t, J=4.6 Hz), 5.16 (2H, s), 5.28 (1H, d, J=4.8 Hz), 5.88 (1H, d, J=4.8 Hz), 8.10 (1H, s)
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]([C:11]([NH:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:32].C([O-])([O-])=O.[K+].[K+].CO.C(Cl)Cl>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[O:32][C:2]1[C:3]2[S:10][C:9]([C:11]([NH:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: O=C(NCCN1CCOCC1)c1cc2ncnc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(NCCN1CCOCC1)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 120 °C
Yield: 91 %

Procedure:
To a stirred solution of compound 23 (458 mg, 1.40 mmol) in Ph2O (6 mL) was added 2-fluoro-4-nitrophenol (242 mg, 1.54 mmol). The reaction mixture was heated at 120° C. for 2.5 hours, treated with K2CO3 (80 mg, 0.56 mmol) and heated at the same temperature for additional 18 hours. After cooling, the reaction mixture was purified by flash chromatography on a silica gel column (eluents EtOAc-hexane 5:95, 1:1, then MeOH-DCM, 5:95 and 1:9), to afford the title compound 24 (570 mg, 91% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ(ppm): 9.09 (t, J=5.6 Hz, 1H), 8.77 (s, 1H), 8.41 (dd, J=2.4 and 10.4 Hz, 1H), 8.30 (s, 1H), 8.22 (dd, J=2.4 and 8.8 Hz, 1H), 7.88 (t, J=8.8 Hz, 1H), 3.60-3.52 (m, 4H), 3.45 (q, J=6.8 Hz, 2H), 2.50 (q, J=6.8 Hz, 2H), 2.46-2.40 (m, 4H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13](N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([O-])=O.[Na+].[CH:21](=[O:27])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1>O.Cl>[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([C:25]2[O:26][C:22]([CH:21]=[O:27])=[CH:23][CH:24]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=Cc1ccco1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(-c2ccc(OCc3ccccc3)cc2)o1
Reaction time: 0.75 h

Procedure:
A mixture of 236 g (1.0 mole) of p-benzyloxyaniline hydrochloride in 1.5 l of water and 230 ml of conc. HCl was warmed on a steam bath for 11/2 hours. No solution was effected. The mixture was then cooled down to 0°-5° and a solution of 76 g (1.1 mole) of sodium nitrite in 500 ml of water was added in about 1 hour while keeping the temperature at 4°-7°. The mixture was allowed to stir further for an additional 45 minutes while the temperature gradually rose to 10°. Furfural (192 g, 2 moles) and 55 g of cupric chloride dihydrate in a minimum amount of water was added and the mixture was allowed to stir at ambient temperature overnight. Solid started to separate after 2 days of stirring. The solid was collected, washed well with water. The filtrate and the water washings were combined and allowed to stir for an additional 4 days while more solid separated. The dark gummy solids were combined, triturated with ether, filtered and air dried. Repeated recrystallizations from hot cyclohexane gave 48.5 g (17.5%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH:9]([C:8]2[C:4]([CH2:3][O:2][CH3:1])=[N:5][N:6]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[CH:7]=2)[OH:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COCc1nn(-c2cccc(OC)c2)cc1C=O
Solvent: C1CCOC1
Product: COCc1nn(-c2cccc(OC)c2)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution (5 mL) of 3-(methoxymethyl)-1-(3-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (0.30 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (2.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.40 g, quantitative) as a pale-yellow oil.