Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1.[CH:15](=O)[C:16]([CH3:18])=[O:17]>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:13][N:14]=[CH:15][C:16](=[O:17])[CH3:18])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)C=O
Reactant: COc1cccc(NN)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(NN=CC(C)=O)c1
Reaction time: 48 h
Yield: 33.7 %

Procedure:
Acetic acid (1.7 mL) was added to a solution of 3-methoxyphenylhydrazine (3.0 g, 17 mmol) in water (35 mL). This mixture was then added dropwise to a solution of pyruvaldehyde (3.1 g, 2.8 mL, 17 mmol) in water (45 ml) over 15 minutes. The mixture was stirred for two days and solids were removed by filtration and washed with water to obtain 2-oxopropanal (3-methoxyphenyl)hydrazone as a black solid (1.1 g, 33%).
Reaction SMILES: [C:1]1([C:7]2[O:23][C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH:15][C@@H:16]4[CH2:21][CH2:20][CH2:19][C@H:18]([OH:22])[CH2:17]4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[C:26]([O:30][C:31](=[O:34])[CH2:32]Br)([CH3:29])([CH3:28])[CH3:27].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C1COCC1>[C:26]([O:30][C:31](=[O:34])[CH2:32][O:22][C@H:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([NH:15][C:14]2[C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:23][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:17]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O[C@H]1CCC[C@@H](Nc2ncnc3oc(-c4ccccc4)cc23)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](Nc2ncnc3oc(-c4ccccc4)cc23)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
At 40° C., add approx. 0.06 mmol of tetrabutylammonium hydrogensulphate and a solution of 200 mg (0.646 mmol) of (+/−)-cis-3-[(6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclohexanol in 0.5 ml of toluene and 0.1 ml of THF to a mixture of 517 mg of 50% sodium hydroxide solution (6.5 mmol) and 0.5 ml of toluene. Admix the resulting mixture with 0.19 ml (1.29 mmol) of bromoacetic acid tert-butyl ester with vigorous stirring and heat it to 70° C. After 2 h, cool the mixture and add it to water. Extract three times with dichloromethane, wash the combined organic phases with saturated sodium chloride solution and concentrate under reduced pressure. After preparative RP-HPLC (eluent: acetonitrile/water), 152 mg (55.5% of theory) of the target product are isolated from the crude product.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32]>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])[C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
The title compound is prepared following the procedures of Daisley, R. W.; Hanbali, J. R. Synth. Commun., 763, (1981) as follows. Dibenzyl malonate (3.47 mL, 13.9 mmol) is added dropwise to a stirred mixture of 60% oil dispersion of sodium hydride (556 g, 13.9 mmol) in toluene (20 mL). After 1 hr, the mixture is treated with a solution of 4-chloro-3-nitropyridine (2.0 g, 12.6 mmol) in toluene (10 mL) and then heated at reflux for 2 hr. After cooling to room temperature, the reaction is concentrated and the residue is treated with 1M aq hydrochloric acid (6 mL) and extracted with ethyl acetate. The combined extract is washed with saline, dried, filtered and concentrated. The residue is purified by chromatography eluting with pentane-20% ethyl acetate. Product containing fractions are combined and concentrated to give 2-(3-nitropyridin-4-yl)malonic acid dibenzyl ester (1.72 g, 33.6% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(O)(=O)C>O>[C:24]([NH:1][C:2]1[C:3]([C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:26])[CH3:25]
Reactant: CCCCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1cc(C(=O)O)cc(NC(C)=O)c1C(=O)c1ccccc1
Reaction time: 20 h

Procedure:
A mixture of 5-amino-4-benzoyl-3-n-butoxybenzoic acid (0.8 g), acetic anhydride (0.8 ml) and acetic acid (8.0 ml) is heated on a steam-bath for 1 hour. After cooling, the resulting solution is poured into water (about 20 ml) and the mixture is left at room temperature for about 20 hours. The resulting precipitate is collected by filtration and washed with water. After drying and recrystallization twice from aqueous ethanol, 5-acetamido-4-benzoyl-3-n-butoxybenzoic acid is obtained with a melting point of 177°-178° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]([OH:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][C:13](=[O:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC(=O)C1
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (1.05 g, 2.83 mmol) from Examples 88, 89, 148 in DCM (35 mL) at 0° C. was added (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (2.40 g, 5.66 mmol). The mixture was stirred overnight, quenched with brine (40 mL) and DCM (30 mL), and extracted with DCM (100 mL×3), and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (5% to 50%) as eluting solvents to afford tert-butyl 4-(6-bromopyridin-2-yl)-6-oxo-1,4-diazepane-1-carboxylate as a yellow oil (846 mg, 81%). MS (ESI) m/z: 370 [M+H]+.
Reaction SMILES: CC(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:10]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:9]=1)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:23]([O:22][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OC(C)(C)C)cc(OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(OCc2ccccc2)c1
Yield: 88.5 %

Procedure:
A solution of 28 g of 3-(octadecyloxy)-5-(phenylmethoxy)phenylcarbamic acid dimethylethyl ester and 76 ml of trifluoroacetic acid in 700 ml of methylene chloride was kept at room temperature for 2 hours. The solution was concentrated at reduced pressure and the residue was extracted with methylene chloride. The extract was washed with NaHCO3 solution, dried and concentrated to a solid which was dissolved in 1000 ml of ether. The solution was treated with 21 ml of 3N HCl in ethanol. The hydrochloride salt which precipitated was filtered and treated with excess NaHCO3 to liberate the free base which was extracted with methylene chloride. The dried extract was concentrated at reduced pressure to give 20.4 g (89% yield, mp 57°-59°) of 3-(octadecyloxy)-5-(phenylmethoxy)benzenamine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[S:11]1[CH:15]=[C:14]([S:16][C:17]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:18]=2[C:19]([NH:21][CH3:22])=O)[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2.[OH-].[Na+]>C(OCC)C.C1COCC1.O>[S:11]1[CH:15]=[C:14]([S:16][C:17]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:18]=2[CH2:19][NH:21][CH3:22])[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2
Reactant: CNC(=O)c1cc(C)ccc1Sc1csc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNCc1cc(C)ccc1Sc1csc2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (250 g, 6.6 mmol) is suspended in dry diethyl ether (50 mL) and cooled to 0° C. Aluminum chloride (295 mg, 2.2 mmol) dissolved in dry diethyl ether (50 mL) is added dropwise at 0-5° C. The cooling bath is removed and the mixture is stirred at ambient temperature for 1 hour. The resulting aluminum hydride reagent solution is cooled to 0° C. followed by dropwise addition of of 2-(benzo[b]thiophen-3-ylsulfanyl)-5,N-dimethyl-benzamide (327 mg, 2.0 mmol) in 10 mL dry THF. After complete addition the solution is allowed to heat to ambient temperature and stirring is continued for 16 hours. The mixture is cooled to 10° C. followed by slow dropwise addition of water (0.5 mL) followed by 2M sodium hydroxide (0.5 mL) and water (2.5 mL) to quench excessive reducing agent. The mixture is filtered and concentrated in vacuo. The remanence is redissolved in ethyl acetate (100 mL), dried (MgSO4) and concentrated in vacuo. The product is purified by preparative HPLC or by silica gel chromatography eluting with ethyl acetate-triethyl amine to furnish the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH2:29][C:30]3[CH:38]=[CH:37][C:33]4[O:34][CH2:35][O:36][C:32]=4[CH:31]=3)[CH2:12][C:13]3[N:14]([CH2:25][CH2:26][CH2:27][CH3:28])[C:15](I)=[N:16][C:17]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1B(O)O>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH2:29][C:30]3[CH:38]=[CH:37][C:33]4[O:34][CH2:35][O:36][C:32]=4[CH:31]=3)[CH2:12][C:13]3[N:14]([CH2:25][CH2:26][CH2:27][CH3:28])[C:15]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=4[CH3:45])=[N:16][C:17]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccccc1B(O)O
Reactant: CCCCn1c(I)nc(-c2ccccc2)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCn1c(-c2ccccc2C)nc(-c2ccccc2)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Temperature: 100 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-iodo-5-phenyl-3H-imidazol-4-ylmethyl)-amine (62 mg, 0.1 mmol) and Pd(PPh3)4 (6 mg) in 1 ml of toluene is added aqueous sodium carbonate (0.4 ml of 2.0 N) and 2-methylphenyl boronic acid (18 mg, 0.13 mmol, 1.3 eq.) in 0.3 ml of ethanol under nitrogen, the resulting mixture is stirred at 100° C. for 8 h. After being cooled to room temperature, the reaction mixture is diluted with 10 ml of ethyl acetate, washed with water and brine and dried over sodium sulfate. Concentration and purification by flash chromatography affords 43 mg of bis-benzo[1,3]dioxol-5-ylmethyl(3-butyl-5-phenyl-2-o-tolyl-3H-imidazol-4-ylmethyl)-amine 1H NMR (400 MHz, CDCl3) δ 7.70 (2H, d, J=7.2 Hz), 7.43˜7.24 (7H, m), 6.77˜6.67 (6H, m), 5.94 (4H, s) 3.87 (2H, t, J=7.6 Hz), 3.78 (2H, s), 3.37 (4H, s), 2.20 (3H,s), 1.17 (2H, m), 0.88 (2H, m), 0.63 (3H, t, J=7.2 Hz); MS (+VE) m/z 588 (M+1).
Reaction SMILES: [CH2:1]([NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[K+]>C(OCC)C>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:2][CH2:1][N:9]=2)=[CH:12][CH:13]=1
Reactant: O=C(NCCc1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: FC(F)(F)c1ccc(C2=NCCc3ccccc32)cc1
Temperature: 165 °C
Reaction time: 0.08 h

Procedure:
To a 100-mL round-bottomed flask was added N-phenethyl-4-(trifluoromethyl)benzamide (5.0 g, 17 mmol), phosphoric pentoxide (0.526 mL, 8.52 mmol), and polyphosphoric acid (60.0 g). The reaction mixture was heated to 165° C. for 2 h. Then, the hot solution was carefully poured into ice/water and a solution of KOH (20%, 40 mL) was added to break up the oil. The mixture was stirred at RT for 5 min and an additional amount of KOH solution was added until pH 7. Ethyl ether (250 mL) was added and the mixture was stirred at RT for 15 min. The organic layer was collected and the aqueous layer was extracted with EtOAc (2×200 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give the title compound as orange oil, which was used in the next step without further purification. MS (ESI, positive ion) m/z: 276 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]([O:16][C@@H:17]([C@H:19]2[CH2:23][N:22]([C@@H:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH3:25])[C:21](=[O:34])[CH2:20]2)[CH3:18])[C:10]2[N:11]([N:13]=[CH:14][CH:15]=2)[CH:12]=1.CN([CH:38]=[O:39])C>>[Br:6][C:7]1[CH:8]=[C:9]([O:16][C@@H:17]([C@@H:19]2[CH2:20][C:21](=[O:34])[N:22]([C@@H:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[CH3:25])[CH2:23]2)[CH3:18])[C:10]2[N:11]([N:13]=[CH:14][C:15]=2[CH:38]=[O:39])[CH:12]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4nccc34)CC2=O)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(C=O)c34)CC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an appropriate sized microwave vial, DMF (7.22 mL, 93.0 mmol) was added and cooled to 0° C. Phosphorus oxychloride (0.346 mL, 3.72 mmol) was slowly added and the resulting solution was stirred at room temperature for 1 h. A solution of (R)-4-((R)-1-((6-bromopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.01 (851 mg, 1.86 mmol) in DMF (3.0 mL) was then added and the solution was stirred at room temperature for 3 h. The reaction was cooled to room temperature and was slowly quenched with a saturated aqueous solution of sodium bicarbonate and the resulting mixture was stirred for 1 h at room temperature. The reaction was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to isolate 6-bromo-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbaldehyde without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:21])([F:20])[C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:11][O:10]1.C([O-])([O-])=O.[K+].[K+].FC(F)(F)S(O[CH2:34][C:35]([F:38])([F:37])[F:36])(=O)=O>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:20])([F:21])[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:17][N:18]=2)[CH2:11][O:10]1
Reactant: Oc1ccc(C(F)(F)C2(c3ccc(F)cc3F)CO2)nc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(C2(C(F)(F)c3ccc(OCC(F)(F)F)cn3)CO2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a magnetically stirred mixture of 6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-ol (600 mg, 2.005 mmol) and K2CO3 (305 mg, 2.206 mmol) in acetone (6.76 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (558 mg, 2.406 mmol) in a 20 mL vial under an atmosphere of air. The reaction mixture was stirred at 25° C. for 16 h. As the reaction progressed the reaction mixture became a cloudy beige suspension. The reaction was quenched with MeOH (2 mL) and then volatiles were removed under a gentle stream of N2. The resulting residue was partitioned with water and CH2Cl2 and the organic layer was removed. The aqueous layer was washed CH2Cl2 (2×) and combined organic layers were dried by passing through a phase separator. Volatiles were removed under a gentle stream of N2 and the crude orange oil was carried on without further purification (779 mg, 97%): 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=2.9 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.38 (dd, J=14.7, 8.2 Hz, 1H), 7.28 (d, J=2.9 Hz, 1H), 6.88-6.80 (m, 1H), 6.78-6.71 (m, 1H), 4.44 (q, J=7.9 Hz, 2H), 3.43 (d, J=5.1 Hz, 1H), 3.00-2.95 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −73.75 (s, 3F), −107.01 (dd, J=257.0, 8.5 Hz, 1F), −107.55-−108.43 (m, 2F), −109.41 (q, J=8.5 Hz, 1F). ESIMS m/z 382 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CC(C)=O>[Cl:25][CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2
Reactant: COc1cc2c(cc1O)CCCC2=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1OCCCCl)CCCC2=O
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A mixture of 6-hydroxy-7-methoxy-1-tetralone (J. Org. Chem., 1985, 50, 4937) (1.5 g, 7.8 mmol), K2CO3 (1.7 g, 12.3 mmol), and acetone (30 ml) was stirred at reflux under nitrogen for 45 minutes. The reaction was cooled to ambient temperature and a solution of 1-bromo-3-chloropropane (1.9 g, 12.1 mmol) dissolved in 8 ml acetone was dripped into the mixture. After total addition, the reaction was heated to reflux and stirred under nitrogen for 21 hours. The reaction was cooled to ambient temperature and filtered. The filter cake was washed well with acetone and the filtrate was concentrated to yield 2.0 g 6-(3-chloropropoxy)-7-methoxy-1-tetralone as an amber oil.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4](Cl)=[CH:3][CH:2]=1.[NH2:9][CH:10]([C:21]([OH:23])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1>>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([NH:9][CH:10]([C:21]([OH:23])=[O:22])[CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[CH:3][CH:2]=1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Cc1ccc(Cl)cc1
Product: Cc1ccc(NC(Cc2c[nH]c3ccccc23)C(=O)O)cc1
Yield: 82 %

Procedure:
The same procedure is used as in Example 1, p-toluyl chloride and DL-tryptophane being used. Yield 82%. Melting point 217.5° to 218.5° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.S1C=CN=C1C(O)(C#C)C.[CH3:35][C:36]1[O:40][N:39]=[C:38]([C:41]([OH:45])([C:43]#[CH:44])[CH3:42])[CH:37]=1>>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:44]#[C:43][C:41]([C:38]4[CH:37]=[C:36]([CH3:35])[O:40][N:39]=4)([OH:45])[CH3:42])[CH:10]=3)[C:6]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(-n2nc(C(=O)N3CCCC3)c3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: C#CC(C)(O)c1nccs1
Product: Cc1cc(C(C)(O)C#Cc2ccc3c(C(=O)N4CCCC4)nn(-c4ccnc(N)n4)c3c2)no1

Procedure:
The title compound was prepared by procedure described in Example 62-c, by substituting 1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide with 4-{6-bromo-3-[(pyrrolidin-1-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol with 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol in Step 3: 1H NMR (500 MHz, DMSO) delta 1.84-1.93 (5H, m), 1.93-1.98 (2H, m), 2.42 (3H, s), 3.60 (2H, t, J=6.86 Hz), 3.99 (2H, t, J=6.78 Hz), 6.41 (1H, s), 6.57 (1H, s), 7.13 (1H, d, J=5.36 Hz), 7.15 (2H, br. s.), 7.44 (1H, dd, J=8.43, 1.18 Hz), 8.22 (1H, d, J=8.35 Hz), 8.36 (1H, d, J=5.52 Hz), 8.94 (1H, s); LC-MS: m/z=+458.45 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=1.C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C.Cl>CCCCCC.C1COCC1>[CH:4]1[C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=[CH:2][C:3]=1[B:20]([OH:23])[OH:21]
Reactant: COB(OC)OC
Reactant: Brc1ccc2c(c1)oc1ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2oc3ccccc3c2c1
Temperature: -80 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
In a 300 mL three-neck flask was put 3.6 g (14 mmol) of 3-bromodibenzofuran. The air in the flask was replaced with nitrogen. To this mixture was added 70 mL of THF, and this solution was cooled to −80° C. Then, 10 mL (16 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped into this solution with a syringe. After that, this solution was stirred at the same temperature for 2 hours. Then, 3.4 mL (30 mmol) of trimethyl borate was added to this solution, and the mixture was stirred for 4 days while its temperature was returned to room temperature. After that, about 30 mL of diluted hydrochloric acid (1.0 mol/L) was added to this solution, followed by stirring for 1 hour. Then, the aqueous layer of this mixture was extracted with ethyl acetate, and the ethyl acetate solution and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The resulting filtrate was concentrated to give a solid. The solid was washed with hexane, whereby 0.70 g of a white powder was obtained in 27% yield, which was the substance to be produced.
Reaction SMILES: [OH-:1].[Na+:2].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1>C(O)C.O>[OH2:11].[OH2:1].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH3:27])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([O-:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1.[Na+:2]
Reactant: [OH-]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1

Procedure:
20% Aqueous solution of sodium hydroxide was added to a suspension of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 15 g.) in a mixture of ethanol (8 ml.) and water (8 ml.) at room temperature to make a solution of pH 7.5. After filtration and washing, the filtrate and washings were combined (which contained 18.3 ml. of water) and added dropwise to ethanol (46 ml.) at 20° to 25° C. under stirring and stirred at the same temperature for 30 minutes. Ethanol (28 ml.) was added dropwise to the mixture over 30 minutes, and stirred at the same temperature for 2 hours. The precipitates were collected by filtration, washed with ethanol (20 ml.) and dried in vacuo at room temperature to give plates of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate dihydrate (syn isomer, 13.5 g.), mp 260° C. (dec.).