Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C(OC([N:22]1[CH2:26][CH2:25][C@H:24]([NH2:27])[C@@H:23]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=O)C1C=CC=CC=1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=[O:37])C.[Na+].[BrH:49]>C(Cl)Cl.C(O)(=O)C>[BrH:49].[BrH:49].[Cl:34][C:30]1[CH:29]=[C:28]([C@H:23]2[C@@H:24]([NH:27][CH2:11][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[O:37][CH3:35])[CH2:25][CH2:26][NH:22]2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N[C@H]1CCN(C(=O)OCc2ccccc2)[C@H]1c1cccc(Cl)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1CN[C@H]1CCN[C@H]1c1cccc(Cl)c1
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of cis-3-amino-2-(3-chloro-phenyl)-pyrrolidine-1-carboxylic acid benzyl ester p-toluenesulfonate (0.32 mmol), obtained from preparatory example 7,2-methoxy-benzaldehyde (0.034 g, 0.34 mmol), and sodium triacetoxyborohydride (0.082 g, 0.38 mmol) was stirred in 3 mL of methylene chloride at rt for 16 h. The reaction was washed 1× with 1M NaOH, dried through cotton, and concentrated to give an oil. The oil was dissolved in acetic acid (1 mL) and a solution of 30% hydrogen bromide in acetic acid (0.302 g, 1.12 mmol) was added. The solution was stirred for 16 h and the resultant solids were collected, washed with ether, and concentrated under vacuum. Trituration with hot isopropanol provided 0.082 g (50%) of title compound. 1H NMR (2HBr, CD3OD) δ 7.72 (s, 1H), 7.63-7.59 (m, 3H), 7.44-7.40 (t, J=7.89 Hz, 1H), 7.31-7.29 (d, J=7.48 Hz, 1H), 7.04-7.02 (d, J=8.31 Hz, 1H), 6.99-6.96 (t, J=7.48 Hz, 1H), 5.25-5.23 (d, J=7.47 Hz, 1H), 4.39-4.33 (q, J=7.47 Hz, 1H), 4.26-4.23 (d, J=12.86 Hz, 1H), 4.13-4.10 (d, J=12.86 Hz, 1H), 3.93-3.87 (ddd, J=12.0, 9.55, 3.74 Hz, 1H), 3.81 (s, 3H), 3.59-3.51 (m, 1H), 2.81-2.74 (m,1H), 2.66-2.58 (m, 1H). MS APCI: [M+H]+=317.3
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(C)c1ccc(CBr)cc1
Yield: 97 %

Procedure:
A solution of methyl 2-(4-methylphenyl)-2-methylpropionate (58.5 g), N-bromosuccinimide (54.2 g), benzoyl peroxide (1.2 g) and carbon tetrachloride (300 ml) was refluxed for 40 min. After being cooled, the reaction mixture was filtrated. The filtrate was washed with an aqueous sodium sulfite solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give methyl 2-(4-bromomethylphenyl)-2-methylpropionate (80.0 g) as a pale-brown oil. To a solution of this oil in dimethylformamide (500 ml) was added sodium azide (21.14 g) and the mixture was stirred at 80° C. for 40 min. The reaction mixture was poured into water (1000 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; hexane,hexane:ethyl acetate=20:1) to give the title compound (48.1 g) as a pale-yellow oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH:18]([N:21](C(OCC4C=CC=CC=4)=O)[C:22]([NH:24]C(OCC4C=CC=CC=4)=O)=[NH:23])[CH2:17][CH2:16]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH:18]([NH:21][C:22]([NH2:24])=[NH:23])[CH2:17][CH2:16]3)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: N=C(NC(=O)OCc1ccccc1)N(C(=O)OCc1ccccc1)C1CCC(CCN2CCN(c3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: N=C(N)NC1CCC(CCN2CCN(c3ccccc3)CC2)CC1
Yield: 0.1 %

Procedure:
Trans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]cyclohexyl-N,N'-dicarbobenzyloxyguanidine (2.77 g, 4.63 mol) was hydrogenolyzed in MeOH (250 mL) under 48 psi hydrogen pressure in the presence of 20% palladium on carbon catalyst (0.25 g). Filtration of the reaction mixture, evaporation of the filtrate, and recrystallization of the residue from isopropanol (i-PrOH)-Et2O yielded 1.39 g (91%) of the product; mp 140-170° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:6]#[N:7])[CH3:2].[H-].[Na+].[C:14]([N:19]=[C:20]=[S:21])([CH2:17][CH3:18])([CH3:16])[CH3:15].C(OCC)C>CN(C=O)C.Cl.O>[CH2:1]([C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:10]=1[NH:11][C:20]([NH:19][C:14]([CH3:16])([CH3:15])[CH2:17][CH3:18])=[S:21])[CH3:2]
Reactant: CCc1cc(C#N)ccc1N
Reactant: CCC(C)(C)N=C=S
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(C#N)ccc1NC(=S)NC(C)(C)CC
Temperature: 70 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 3-ethyl-4-aminobenzonitrile (1.35 g, 9.29 mmol) in DMF (10 mL) at room temperature was added sodium hydride (0.28 g, 80%, 9.29 mmol). The mixture was heated to 70° C. for 40 minutes and was then cooled to room temperature. A solution of tert-amyl isothiocyanate (1.0 g, 7.74 mmol) in DMF (1 mL) was added by syringe and the reaction was stirred at 70° C. overnight. The cooled reaction mixture was diluted with 2N HCl and water and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to afford an oil. The crude product was taken up in a minimal amount of diethyl ether and the solution was made turbid by adding petroleum ether. Sonication resulted in the formation of a precipitate which was collected by filtration to afford 1.2 g (56%) of 1-(2-ethyl-4-cyanophenyl)-3-(1,1-dimethyl-propyl)-thiourea as an off-white solid which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26](OC)=O)[C:5]2[C:6](=O)[CH:7]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][N:20]=3)[CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[NH:9][C:10]=2[CH:11]=1.[OH2:30].[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH:7]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][N:20]=3)[C:6]3=[N:31][NH:32][C:26](=[O:30])[C:4]([CH:3]=1)=[C:5]23
Reactant: O
Reactant: COC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: CO
Product: Cn1ncnc1C1c2n[nH]c(=O)c3cc(F)cc(c23)NC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
Methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (5) (150 g, 0.38 mol, 1.0 eq.) and methanol (1.7 L) were charged into a 3 L 3-neck flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet/outlet. The resulted suspension was stirred at room temperature for 15 minutes. Hydrazine hydrate (85% of purity, 78.1 g, 1.33 mol, 3.5 eq.) was charged dropwise into the above reaction mixture within 30 minutes at ambient temperature. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by HPLC, showing about 2% of compound (5) left. The obtained slurry was filtered. The wet cake was suspended in methanol (2 L) and stirred at room temperature for 3 hours. The above slurry was filtered, and the wet cake was washed with methanol (0.5 L). The wet cake was then dried in vacuum at 45-55° C. for 12 hours. This afforded the title compound as a pale yellow solid (112 g, yield: 78.1%, purity: 95.98% by HPLC). LC-MS (ESI) m/z: 381 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.66 (s, 3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, J1=2.4, J2=11.2 Hz, 1H), 7.06-7.09 (dd, J1=2.4, J2=8.8 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51 (m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:3]=1.[NH2:24][CH2:25][C:26]([N:28]([CH:30]1[CH2:32][CH2:31]1)[CH3:29])=[O:27].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH:30]1([N:28]([CH3:29])[C:26](=[O:27])[CH2:25][NH:24][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:3]=2)[CH2:32][CH2:31]1
Reactant: CN(C(=O)CN)C1CC1
Reactant: FC(F)(F)c1ccc(-c2nc(Cl)cc(-c3ccccc3)n2)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C(=O)CNc1cc(-c2ccccc2)nc(-c2ccc(C(F)(F)F)cc2)n1)C1CC1
Temperature: 150 °C
Yield: 89 %

Procedure:
A mixture of 4-chloro-6-phenyl-2-(4-trifluoromethylphenyl)-pyrimidine (15 g), 2-amino-N-cyclopropyl-N-methylacetamide (10 g) and triethylamine (5.4 g) is heated at 150° C. under reflux for 2 hours. To the reaction mixture are added water and chloroform, and the chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform), and recrystallized from ethanol to give the desired compound (17 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([F:12])[C:3]=1F.[CH2:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([F:12])[C:3]=1[N:19]1[CH2:20][CH2:21][N:16]([CH2:14][CH3:15])[CH2:17][CH2:18]1
Reactant: Nc1c([N+](=O)[O-])cc(Cl)c(F)c1F
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN1CCN(c2c(Cl)cc([N+](=O)[O-])c(N)c2F)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
To a solution of 768 mg of 4-chloro-2,3-difluoro-6-nitroaniline (which was prepared by the method described in WO 98/56761 or WO 98/35977) and 629 mg of 1-ethylpiperazine in 5 ml of dimethylsulfoxide, 1.00 g of potassium carbonate was added, followed by 2 hours' stirring at 50° C. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried on anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (chloroform/methanol=50/1) to provide 704 mg of the title compounds.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:16]=[CH:17][CH:18]=1.ICCCCCCOCCC#CC1C=C(N2C(=O)CNC2=O)C=CC=1.[CH2:51]([NH:58][CH2:59][C@@H:60]([C:62]1[CH:73]=[CH:72][C:65]2[O:66][C:67]([CH3:71])([CH3:70])[O:68][CH2:69][C:64]=2[CH:63]=1)[OH:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(#N)C.C(N(C(C)C)CC)(C)C>[CH2:51]([N:58]([CH2:59][C@@H:60]([C:62]1[CH:73]=[CH:72][C:65]2[O:66][C:67]([CH3:70])([CH3:71])[O:68][CH2:69][C:64]=2[CH:63]=1)[OH:61])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:16]=[CH:17][CH:18]=1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCc3ccccc3)ccc2O1
Reactant: O=C1CNC(=O)N1c1cccc(C#CCCOCCCCCCBr)c1
Agent: O=C1CNC(=O)N1c1cccc(C#CCCOCCCCCCI)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCC#Cc3cccc(N4C(=O)CNC4=O)c3)Cc3ccccc3)ccc2O1
Temperature: 50 °C

Procedure:
A solution of 3-(3-{4-[(6-bromohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione and 3-(3-{4-[(6-iodohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione (3:1, 23.98 g) in acetonitrile (240 ml) and diisopropylethylamine (20 ml) was treated with (1R)-2-(benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (18.22 g) and the mixture was heated to 50° C. for 5 days. The solvent was removed under reduced pressure, the residue was diluted with EtOAc (250 ml) and washed with water. The aqueous phase was re-extracted with EtOAc (75 ml) and the combined organic solutions were washed with brine, dried (MgSO4), and evaporated. The residue was purified by chromatography on flash silica gel eluting with dichloromethane-EtOAc (1:1) to give the title compound (17.25 g) LCMS RT=2.80 min
Reaction SMILES: O[CH2:2][C:3]1[NH:12][C:6]2=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=[C:5]2[N:4]=1.S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[ClH:11].[Cl:11][C:8]1[N:7]=[C:6]2[NH:12][C:3]([CH2:2][Cl:15])=[N:4][C:5]2=[CH:10][CH:9]=1
Reactant: OCc1nc2ccc(Cl)nc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCc1nc2ccc(Cl)nc2[nH]1
Yield: 103.1 %

Procedure:
1.0 g 2-Hydroxymethyl-5-chloro-3H-imidazo[4,5-b]pyridine (5.45 mmol) was suspended in chloroform (10.0 ml) and treated with 3.3 ml thionyl chloride (45 mmol) for 4 h at reflux. The mixture was evaporated and the residue triturated with methanol. After concentration the residue was stirred over night in ether and the suspension was then filtered. The residue on the filter was dried to yield 0.67 g 5-chloro-2-chloromethyl-3H-imidazo[4,5-b]pyridine hydrochloride as a brown solid; M.p.: 218–220° C., (dec.). 14.5 ml Triethyl amine (104.0 mmol), 1.67 g sulfur (52.0 mmol) and 0.65 g 5-chloro-2-chloromethyl-3H-imidazo[4,5-b]pyridine hydrochloride (26.0 mmol) were dissolved in DMF (15 ml) and stirred at ambient temperature for 2 h. After cooling to 0° C., 1.6 ml MeI (26.0 mmol) were added and stirring at ambient temperature was continued for 1 h. Then water (100 ml) was added and the mixture extracted 3 times with ethyl acetate (150 ml). The combined organic phase were filtered over dicalit® and concentrated. The residue was dissolved in ethanol (100 ml) and treated with 5.4 g 2-methoxy-5-morpholin-4-yl-phenylamine (26 mmol) for 16 h at reflux. Upon cooling to ambient temperature a precipitate formed, which was isolated and dried in vacuo. 2 g 5-chloro-3H-imidazo[4,5-b]pyridine-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (19%) was obtained as a red solid; MS (ISP): m/e=404 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[O:35]1[CH2:39][CH2:38][C@@H:37]([NH2:40])[CH2:36]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:40][C@@H:37]4[CH2:38][CH2:39][O:35][CH2:36]4)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCOC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: O=C(N[C@@H]1CCOC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (3R)-tetrahydro-3-furanamine using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54-1.65 (m, 4 H), 1.88 (d, J=8.42 Hz, 1 H), 2.04 (t, J=5.69 Hz, 2 H), 2.23-2.32 (m, 1 H), 3.25-3.30 (m, 2 H), 3.45-3.54 (m, 2 H), 3.65 (dd, J=9.16, 2.84 Hz, 1 H), 3.72-3.88 (m, 3 H), 4.17 (s, 2 H), 4.39 (t, J=7.16 Hz, 2 H), 4.55 (s, 1 H), 7.11-7.17 (m, 2 H), 7.38-7.43 (m, 2 H), 8.23 (s, 1 H), 8.58 (d, J=1.47 Hz, 1 H), 10.50 (d, J=7.16 Hz, 1 H), 16.83 (s, 1 H); ES+ MS: 509 (M+H+).
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: Cc1ccccc1C1=COCCN1C(=O)OC(C)(C)C
Yield: 57 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and o-tolylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (57% yield); 1H-NMR (d6-DMSO) 0.97 (9H, s), 2.15 (3H, s), 3.69 (2H, t), 4.14 (2H, t), 6.06 (1H, s), 7.10-7.15 (4H, m); MS ES(+) 220.0 (M+-tBu). IR λmax=1694, 1365, 1165 cm−1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:22][O:23][CH2:24][O:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29]([C:33]2[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=2)=[CH:28][C:27]=1[CH3:42].C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH2:18]([CH:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:39]([C:36]2[CH:37]=[CH:38][C:33]([C:29]3[CH:30]=[C:31]([CH3:32])[C:26]([O:25][CH2:24][O:23][CH3:22])=[C:27]([CH3:42])[CH:28]=3)=[CH:34][CH:35]=2)=[O:40])=[CH:6][CH:7]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][CH3:21]
Reactant: COCOc1c(C)cc(-c2ccc(C(=O)O)cc2)cc1C
Reactant: CCCCC(Cc1ccc(OCCN)cc1)C(=O)OCC
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cc(C)c(OCOC)c(C)c3)cc2)cc1)C(=O)OCC
Yield: 1068.4 %

Procedure:
In a similar manner to that described in Example 5, a reaction was carried out using ethyl 3-[4-(2-aminoethoxy)phenyl]-2-butylpropionate (880 mg), which is the product of Reference example 6, 4′-methoxymethoxy-3′,5′-dimethylbiphenyl-4-carboxylic acid (859 mg), which is the product of reference example 17(b), and carbonyldiimidazole (577 mg) and the reaction mixture was treated to afford the desired compound (1 18 g) as colorless crystals.
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[N:2].FC(F)(F)C(O)=O.[CH2:22]([N:29]([CH2:33][Si](C)(C)C)[CH2:30]OC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:22]([N:29]1[CH2:30][C@@H:3]([C:1]#[N:2])[C@H:4]([C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:33]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)c1ccccc1C=CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1C#N

Procedure:
In a 50 mL round bottom flask were combined methyl 2-(2-cyanovinyl)benzoate (Example 1A, 11.03 g, 58.9 mmol) trifluoroacetic acid (0.045 mL, 0.589 mmol) and dichloromethane (100 mL). N-Benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (64.8 mmol) was added as a solution in dichloromethane (100 mL) dropwise over 15 minutes while stirring under argon. The reaction was stirred at room temperature for 20 hours, then quenched with aqueous sodium bicarbonate and extracted with dichloromethane. The organic washes were combined and washed with brine, dried over Na2SO4, filtered, and the solvent was removed in vacuo to provide the crude product. The mixture of isomers was added to a silica gel column and was eluted with ethyl acetate/hexanes (gradient 0-20%, 40 minutes) to provide the title compound as the faster eluting (less polar) isomer. 1H NMR (500 MHz, CDCl3) δ ppm 2.82 (dd, 1H, J=9.09 Hz, J=7.81 Hz), 2.88 (dd, 1H, J=9.74 Hz, J=4.27 Hz), 2.99-3.03 (m, 1H), 3.05-3.09 (m, 1H), 3.29 (t, 1H, J=8.37 Hz), 3.71 (m, 2H), 3.94 (s, 3H), 4.51 (ddd, 1H, J=8.29 Hz, J=6.36 Hz, J=4.35 Hz), 7.25-7.40 (m, 6H), 7.50 (dt, 1H, J=7.65 Hz, J=1.45 Hz), 7.62 (d, 1H, J=7.24 Hz), 7.81 (dd, 1H, J=7.89 Hz, J=1.29 Hz); MS (DCI+) m/z 321.2 [M+H]+.
Reaction SMILES: [N:1]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([CH3:12])[NH:6][C:5]1=[O:13])=[N+:2]=[N-:3].I[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[H-].[Na+]>>[C:19]([O:18][C:16]([CH2:15][N:6]1[CH:7]([CH3:12])[CH2:8][CH2:9][CH2:10][CH2:11][CH:4]([N:1]=[N+:2]=[N-:3])[C:5]1=[O:13])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CI
Reactant: CC1CCCCC(N=[N+]=[N-])C(=O)N1
Agent: [H-]
Agent: [Na+]
Product: CC1CCCCC(N=[N+]=[N-])C(=O)N1CC(=O)OC(C)(C)C

Procedure:
React 5.65 g of this azide with 7.9 g t-butyl iodoacetate and 0.82 g sodium hydride as described in Example 1 to obtain 1-t-butoxycarbonylmethyl-3-azido-8-methylperhydroazocin-2-one, which can be purified by chromatography over silica gel. NMR (CCl4, TMS): δ 1.0-2.2 (m); δ 1.3 (d); δ 1.45 (s); δ 3.45 (d, J=16h3); δ 3.95 (d, J-16h3); δ 4.3-5.1 (m).
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[CH:22]1([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[OH:35][C:36]1[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][C:39]([CH:40]=O)=[CH:38][C:37]=1[C:48]([CH3:51])([CH3:50])[CH3:49].C(OC(C)C)(C)C>CO.C(Cl)(Cl)Cl>[OH:35][C:36]1[C:43]([C:44]([CH3:46])([CH3:45])[CH3:47])=[CH:42][C:39]([CH:40]=[N:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([O-:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]4[N:15]([CH3:16])[N:14]=[N:13][N:12]=4)[CH2:7][S:8][C@H:3]23)=[CH:38][C:37]=1[C:48]([CH3:51])([CH3:50])[CH3:49].[CH:29]1([NH2+:28][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CC(C)OC(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](N=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)[C@H]2SC1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a suspension of 3.28g of 7β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid in 60 ml of methanol was added 1.81g of dicyclohexylamine and stirred for 1 hour, and then 2.40g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde, 20 ml of chloroform and 5g of molecular sieve 3A were added to the mixture and stirring was continued for further 5 hours. After filtration of the reaction mixture, the filtrate was concentrated to dryness under reduced pressure. The residue was extracted with chloroform-isopropylether (1:1) and the extract was condensed under reduced pressure and then diluted with a large excess of isopropylether. A precipitate thus produced was collected by filtration to give 7.04g of dicyclohexylammonium 7β-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate. To a solution of 1.45g of this compound in 20 ml of methanol was dropwise added at -15° C a solution of 475 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 4 ml of methanol. After stirring for 10 minutes at the same temperature, 100 mg of 2,6-di-tert.-butyl-p-cresol was added to the mixture and stirred for another 10 minutes at 0° C. After adding 0.56 ml of triethylamine the reaction mixture was condensed to about 10 ml under reduced pressure, diluted with 50 ml of chloroform, washed four times with the same volume of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was extracted with a mixture of chloroform-ether (3:7). The extract was condensed and subsequently added a large excess of n-hexane to deposit a precipitate, which was collected by filtration giving 926 mg of the desired product as a yellow powder.