Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:19]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nc[nH]n1
Reactant: O=Cc1ccccn1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2ccccn2)nc2nc[nH]n12

Procedure:
Compound 4 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2-pyridinecarbaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12]C)=[O:11])[CH:7]=1.[CH3:21][O:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O>CCOCC>[Cl:1][C:2]1[C:3]([O:20][CH2:25][CH2:24][CH2:23][O:22][CH3:21])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: CCCCC(CC(=O)OC)c1cc(Cl)c(O)cc1OC
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Product: CCCCC(CC(=O)O)c1cc(Cl)c(OCCCOC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using methyl 3-(5-chloro-4-hydroxy-2-methoxyphenyl)heptanoate (prepared as described in Preparation 56B) and 3-methoxy-1-tosyloxypropane, the corresponding ether derivative was obtained. Hydrolysis of this derivative and subsequent treatment of the reaction mixture were conducted in a similar manner to that described in Preparation 7 to give the title compound as a viscous substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:68]=[CH:67][C:39]([O:40][CH2:41][C@H:42]([NH:47][C:48]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:27][C:4]1[N:3]=[C:2]([C:36]2[CH:68]=[CH:67][C:39]([O:40][CH2:41][C@H:42]([NH:47][C:48]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=2)[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=1
Reactant: Nc1nc(Cl)cc(OC(c2ccc(-c3cccc(F)c3)cc2)C(F)(F)F)n1
Reactant: COC(=O)[C@H](COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)[C@H](COc1ccc(-c2cc(OC(c3ccc(-c4cccc(F)c4)cc3)C(F)(F)F)nc(N)n2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
4-chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine (80 mg, 0.20 mmol), (S)-methyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-(tritylamino)propanoate (113 mg, 0.20 mmol), dichlorobis(triphenylphosphine)palladium (2 mg, 0.03 mmol), and Na2CO3 (42 mg, 0.40 mmol) were added to a mixture of ethanol (5 mL) and water (5 mL) in a round-bottom flask. The flask was heated to reflux for 8 hours. The reaction mixture was cooled and solvent was removed. The residue was purified by chromatography to get (2S)-methyl 3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenoxy)-2-(tritylamino)propanoate, which was deprotected by TFA and LiOH respectively to afford 50 mg of (2S)-2-amino-3-(4-(2-amino-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenoxy)propanoic acid as the HCl salt. 1H NMR (300 MHz, CD3OD): δ 7.95 (m, 2H), 7.71 (s, 3H), 7.61 (m, 2H), 7.48 (m, 2H), 7.26 (m, 1H), 7.11 (m, 1H), 7.01 (s, 1H), 6.78 (m, 1H), 4.65 (m, 1H), 4.40-4.55 (m, 3H); M+1=543.
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:20])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:20][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1CCCN1[C@H]1CC[C@@H](O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCN1[C@H]1CC[C@H](F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one in CH2Cl2 at −30° C., add 786 mL of DAST dropwise. Allow the resulting mixture to warm up to room temp and let stand for 1 h. To the solution, add 10 mL of 5% aq NaHCO3 and allow to stand at room temp for 1 h. Extract the aqueous layer by CH2Cl2 twice (2×10 mL) and then dry the organic layer over Na2SO4, filter and concentrate. Purify the crude material by chromatography to yield the title compound: mass spectrum (m/z): 186 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].[Br:16]Br.S([O-])([O-])(=O)=O.[Na+].[Na+]>[Fe]>[CH:1]([C:4]1[CH:9]=[C:8]([Br:16])[CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: BrBr
Agent: [Fe]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC(C)c1cc(Br)cc(C(C)C)c1N=C=O
Temperature: 120 °C

Procedure:
0.5 g of anhydrous iron-III chloride is added to 203 g of 2,6-diisopropyl-phenyl isocyanate and 162 g of bromine are added dropwise at 20° C. The mixture is then slowly warmed to 120° C until the evolution of gas has ceased. 3.0 g of anhydrous sodium sulfate are then added and the mixture is fractionated in vacuo.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]1([O-:22])[C:16]([Cl:17])=[C:15]([Cl:18])[C:14]([Cl:19])=[C:13]([Cl:20])[C:12]=1[Cl:21].[Na+].O.C(O)C>C(O)C>[Cl:17][C:16]1[C:15]([Cl:18])=[C:14]([Cl:19])[C:13]([Cl:20])=[C:12]([Cl:21])[C:11]=1[O:22][CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCC=Cc1ccccc1
Reactant: [O-]c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1c(Cl)c(Cl)c(OCC=Cc2ccccc2)c(Cl)c1Cl
Yield: 85 %

Procedure:
In a 500 ml four necked flask equipped with a stirrer, a thermometer and a nitrogen gas inlet, chloromethylstyrene (m/p=60/40) (25 g, 0.161 mole) was dissolved in ethanol (50 ml) at room temperature. A solution of sodium pentachlorophenate (hereinafter abbreviated as Na-PCP) (49 g. 0.170 mole) in a mixed solvent of water/ethanol (1/1, 250 ml) was gradually added dropwise thereto and, after completion of addition, the mixture was reacted at 50° C. for 1 hour. The mixture was cooled and the resulting precipitate was filtered off. The filtrate was concentrated with a rotary evaporator. Then, n-hexane (250 ml) and distilled water (100 ml) were added to the concentrated solution and the mixture was shaken. The aqueous layer was removed and additional distilled water (100 ml) was added. This procedure was repeated to remove unreacted Na-PCP. The hexane layer was evaporated with a rotary evaporator. Then, the solid residue was recrystallized from acetone to obtain (2, 3, 4, 5, 6-pentachlorophenyloxy)methylstyrene of the formula [Ia] as white needle crystals, m.p. 113°-115° C., yield 85%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:20])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[C-:21]#[N:22].[K+].C(Cl)Cl>CN(C)C=O>[Cl:19][C:14]1[CH:13]=[C:12]([S:11][C:5]2[N:4]([CH3:20])[C:3]([CH2:2][C:21]#[N:22])=[N:7][C:6]=2[CH:8]([CH3:10])[CH3:9])[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: [C-]#N
Reactant: CC(C)c1nc(CCl)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1nc(CC#N)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 72.5 °C
Yield: 52.5 %

Procedure:
In 13.6 ml of dry dimethylformamide was dissolved 4.75 g (13.6 mmol)of 2-chloromethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (28a)and 1.0 g of potassium cyanide (97.5%), and the mixture was stirred with heating at 70 to 75° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and to the residue, water was added. The mixture was extracted with diethyl ether, and the organic layer was washed with water 3 times and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:9 to 4)to obtain 2.43 g of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]acetonitrile (Compound I-80a)(yield 53%). mp 103-105° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li:10]CCCC.[S:15](=[O:17])=[O:16]>C1COCC1.CCCCCC>[Li+:10].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:15]([O-:17])=[O:16]
Reactant: [Li]CCCC
Reactant: c1ccc2occc2c1
Reactant: O=S=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S([O-])c1cc2ccccc2o1
Product: [Li+]
Temperature: -40 °C
Reaction time: 0.58 h

Procedure:
To a solution of benzofuran (10 mmol) in dry THF (15 mL) at −40° C., n-BuLi (2.5 M in hexanes; 4.4 mL; 11 mmol) was added dropwise. The reaction mixture was stirred at −40° C. for 30-40 min. Sulfur dioxide gas was passed into the reaction mixture, keeping the tip of the needle just above the reaction mixture, for about 5-10 min. A white precipitate was formed. The reaction mixture was then brought to RT and the stirring was continued for 1 h, then the mixture was diluted with hexane (20 mL) to give benzofuran-2-sulfinic acid lithium salt as a white precipitate. The solid was filtered and dried in vacuo to afford the salt.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:15]([NH:22][CH2:23][CH2:24]Br)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CC#N.C(Cl)Cl>[C:18]([O:17][C:15](=[O:16])[NH:22][CH2:23][CH2:24][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCn1cc([N+](=O)[O-])cn1
Temperature: 80 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (2.50 g, 21.45 mmol) in MeCN (30 mL), Cs2CO3 (8.39 g, 25.74 mmol) and 2-(boc-amino)ethyl bromide (5.45 g, 23.59 mmol) was added. The resulting mixture was refluxed (80° C.) for 1.5 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo. The residue was partitionned between water and EtOAc, the org. layer was separated and the aq. layer was extracted with EtOAc (1×). The combined org. layers were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification was performed by FC (EtOAc/hept 7:3 to EtOAc/MeOH 9:1) to obtain tert-butyl(2-(4-nitro-1H-pyrazol-1-yl)ethyl)carbamate as a slightly yellow solid which was used without further purification in the next step. LC-MS conditions A: tR=0.72 min, [M+H]+=257.08.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:8](O)=[N:9][C:10]([CH3:14])=[N:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:8]1[C:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)=[C:12]([CH3:13])[N:11]=[C:10]([CH3:14])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(C)c(Cc2ccc(F)cc2)c(O)n1
Product: Cc1nc(C)c(Cc2ccc(F)cc2)c(Cl)n1
Yield: 67 %

Procedure:
A solution of 5-(4-fluorobenzyl)-2,6-dimethylpyrimidin-4-ol (730 mg, 3.14 mmol) in phosphorus oxychloride (10 mL) was stirred at 60° C. for 90 min. The reaction mixture was concentrated and ethyl acetate (50 mL) was added to the residue. The organic solution was washed with saturated sodium bicarbonate (50 mL), water (50 mL), and brine (50 mL), dried over sodium sulfate, filtered and concentrated. Column chromatography of the residue on silica (5-40% ethyl acetate in hexanes) afforded 4-chloro-5-(4-fluorobenzyl)-2,6-dimethylpyrimidine (527 mg, 67% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3): 7.21 (m, 2H), 6.98 (m, 2H), 4.12 (s, 2H), 2.67 (s, 3H), 2.45 (s, 3H); MS (EI) for C13H12ClFN2: 250 (M+).
Reaction SMILES: ClC1C=C2C(=CC=1)NC(C)=C2.CC([CH2:15][CH2:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=C.ClC1NC2C(C=1)=CC=CC=2.[C:36](=[O:38])=[O:37]>>[C:36]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH2:16][CH3:15])=[CH:25]2)([OH:38])=[O:37]
Reactant: C=C(C)CCc1cc2ccccc2[nH]1
Reactant: O=C=O
Agent: Cc1cc2cc(Cl)ccc2[nH]1
Agent: Clc1cc2ccccc2[nH]1
Product: CCc1cc2cc(C(=O)O)ccc2[nH]1

Procedure:
This synthesis could start with 5-chloro-2-methylindole, which could be alkylated with methyl indole (see 28a). The product chloroindole could then be converted to its Grignard species and exposed to carbon dioxide to finish the synthesis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([Cl:16])[CH:8]=1)[CH3:2].[Cl-].[NH4+]>C(O)C.C1COCC1.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:13][C:12]2=[CH:11][N:10]=[C:9]([Cl:16])[CH:8]=[C:7]2[CH:6]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Cl)ncc2[nH]1

Procedure:
3-(2-Chloro-5-nitropyridin-4-yl)-2-oxopropionic acid ethyl ester (Preparation 16, 3.0 g, 11.0 mmol) was dissolved in ethanol (100 mL) and THF (50 mL). Iron powder (3.7 g, 66.0 mmol) and saturated ammonium chloride solution (50 mL) were added and the mixture heated under reflux for 2 h. The mixture was cooled, filtered through celite and washed several times with ethyl acetate. The organic layers were combined, washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a brown solid. δH (CD3OD): 1.42 (3H, t), 4.44 (2H, q), 7.15 (1H, s), 7.70 (1H, s), 8.59 (1H, s); m/z (ES+)=225 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CI.[C:24]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][N:18]1[N:17]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[O:20][C:19]1=[O:21]
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)oc1=O
Temperature: 0 °C
Yield: 90.4 %

Procedure:
5-[1-(4-Nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.16 g, 4 mmol) on reacting with CH3I (0.68g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at 27° C. for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-methyl-5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6a, 1.10 g, 91%). Nitro compound (6a, 1.21 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7b, 960 mg, 88%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylamino propyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7b, 0.27 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8b, 351 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=O)[CH:13]=[N:14][CH:15]=2)=[CH:4][CH:3]=1.[ClH:18].[O:19]([NH2:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>>[ClH:18].[CH3:20][O:19][N:21]=[CH:16][C:12]1[CH:13]=[N:14][CH:15]=[C:10]([C:9]#[C:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:11]=1
Reactant: O=Cc1cncc(C#Cc2ccc(F)cc2)c1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CON=Cc1cncc(C#Cc2ccc(F)cc2)c1
Yield: 64 %

Procedure:
Prepare essentially as described in EXAMPLE 6 using 5-(4-fluorophenylethynyl)-pyridine-3-carbaldehyde, (prepared essentially as described in EXAMPLE 99), (150 mg, 0.64 mmol), methoxylamine hydrochloride (430 mg, 5.15 mmol) and potassium carbonate to give the title compound (120 mg, 64%).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25]O)[CH2:23][S:24][C@H:19]23)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[SH:39][C:40]1[N:44]([CH3:45])[N:43]=[N:42][N:41]=1.CNC(N1C2C(=CC=CC=2)C(=O)C1=O)=O>C(#N)C>[C:8]1([CH2:14][C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25][S:39][C:40]4[N:44]([CH3:45])[N:43]=[N:42][N:41]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cn1nnnc1S
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Agent: CNC(=O)N1C(=O)C(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
In acetonitrile (14 ml) is dissolved 7β-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (900 mg), followed by the addition of triethylamine (200 mg), 5-mercapto-1-methyl-1H-tetrazole (464 mg) and N-(methylcarbamoyl)isatin (916 mg). The mixture is stirred at 30° C. overnight. The solvent is then distilled off and the residue is dissolved by the addition of water and ethyl acetate. After separation, the water layer is taken, rinsed once with ethyl acetate and rendered acidic with hydrochloric acid. Following the addition of ethyl acetate, the mixture is stirred for 30 minutes. After separation , the organic layer is taken and rinsed with an aqueous solution of sodium chloride. It is extracted with an aqueous solution of sodium hdyrogen carbonate. The water layer is purified by column chromatography on Sephadex LH-20 . The fractions rich in the contemplated compound are pooled, concentrated, rendered acidic with phosphoric acid and extracted with ethyl acetate. After drying, the extract is concentrated, followed by addition of ether to the residue. The procedure provides 7β-phenylacetamido-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The NMR spectrum of this product is in good agreement with that of the compound obtained in Example 6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:25]([O:32][C:33]1[O:37][C:36]([CH2:38]O)=[C:35](C)[CH:34]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[C:41]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:16]2[N:17]([CH:38]([CH3:41])[C:36]3[O:37][C:33]([O:32][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:26])[CH3:27])=[CH:34][CH:35]=3)[C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)oc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CC(c1ccc(O[Si](C)(C)C(C)(C)C)o1)n1c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
According to the method of P. G. McDougal, et al., J. Org. Chem., 5, 3388-3390 (1986), combine hexane washed sodium hydride (20 mmol) and tetrahydrofuran (40 mL). Slowly add 2,5-furandimethanol (20 mmol). After gas evolution ceases, add t-butyldimethylsilyl chloride (20 mmol) and stir vigorously. After about 1 hour, pour the reaction mixture into diethyl ether and extract with a saturated aqueous solution of sodium carbonate, water, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give 5-(t-butyldimethylsilyloxy)methyl-2-hydroxymethylfuran. Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (10 mmol), 5-(t-butyldimethylsilyloxy)-methyl-2-hydroxymethylfuran (10 mmol), and triphenylphosphine (10 mmol) in tetrahydrofuran (100 mL). Add diethyl azodicarboxylate (10 mmol). After 18 hours, evaporate the reaction mixture in vacuo to give a residue. Partition the residue between ethyl acetate and water. Separate the organic layer and extract with water and brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel to give 1-(t-butoxycarbonyl)-4-(1-(5-(t-butyldimethylsilyloxy)-methylfur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>ClCCl.C(O)(=O)C.O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]([N+:6]([O-:9])=[O:7])=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCCCN2CCOCC2)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OC)c(OCCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 161.8 %

Procedure:
Concentrated sulphuric acid (110 ml) and concentrated nitric acid (19.0 ml, 0.289 mol) were added cautiously, over a 50 minute period, to a two-phase system containing a stirred solution of ethyl 3-methoxy-4-(3-morpholinopropoxy)benzoate (76.5 g, 0.237 mol) in dichloromethane (600 ml), acetic acid (300 ml) and water (70 ml) at 5° C. The reaction was allowed to warm to ambient temperature over 18 hours, the aqueous phase was separated, and the aqueous phase was taken to pH 9 by addition of 40% aqueous sodium hydroxide solution (775 ml). Extraction of the aqueous phase with dichloromethane (3×600 ml) and subsequent solvent evaporation in vacuo yielded ethyl 3-methoxy-4-(3-morpholinopropoxy)-6-nitrobenzoate (141.3 g, 86% yield) as a yellow gum:
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]2[CH:10]=[C:9]([CH2:11]Cl)[N:8]=[C:5]2[S:6][CH:7]=1.[CH:13]1[CH:18]=[CH:17][C:16]([O-:19])=[CH:15][CH:14]=1.[Na+]>C1COCC1>[CH3:2][C:3]1[N:4]2[CH:10]=[C:9]([CH2:11][O:19][C:16]3[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=3)[N:8]=[C:5]2[S:6][CH:7]=1
Reactant: [O-]c1ccccc1
Reactant: Cc1csc2nc(CCl)cn12
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1csc2nc(COc3ccccc3)cn12
Yield: 107.4 %

Procedure:
3.4 g of 3-methyl-6-chloromethyl-imidazo-(2,1-b)thiazole hydrochloride, prepared as described in Example 27, is introduced with stirring into a cooled solution of 3.5 g of sodium phenate in 100 ml of THF. After about 1 hour the sodium chloride which precipitates is filtered off, the solvent is evaporated and acidic water is added to the residue. The aqueous solution is extracted, at pH 3-6, with chloroform. The pH is then raised to 7-7.5 and the aqueous solution is again extracted with chloroform. This extract is dried and the solvent is then evaporated to yield 4 g of 3-methyl-6-phenoxymethyl-imidazo-(2,1-b)thiazole; m.p. 190°-192° (methyl-ethyl-ketone).