Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[C:2]=[S:3].[Na+].N1C=CC=CC=1.[CH3:11][C:12]1([CH3:27])[O:16][C@@H:15]([C:17](Cl)=[N:18]OS(C)(=O)=O)[C:14]([CH3:26])([CH3:25])[O:13]1.[CH2:28]([N:30]1[C:34]([O:35][C:36]2[C:37]([NH2:49])=[N:38][CH:39]=[C:40]([S:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH:41]=2)=[CH:33][CH:32]=[N:31]1)[CH3:29]>CCOC(C)=O.[OH-].[Na+]>[CH2:28]([N:30]1[C:34]([O:35][C:36]2[C:37]([NH:49][C:2]3[S:3][N:18]=[C:17]([C@H:15]4[C:14]([CH3:25])([CH3:26])[O:13][C:12]([CH3:11])([CH3:27])[O:16]4)[N:1]=3)=[N:38][CH:39]=[C:40]([S:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH:41]=2)=[CH:33][CH:32]=[N:31]1)[CH3:29]
Reactant: [N-]=C=S
Reactant: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1N
Reactant: CC1(C)O[C@@H](C(Cl)=NOS(C)(=O)=O)C(C)(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2OC(C)(C)OC2(C)C)ns1
Temperature: 60 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To 30 mL of EtOAc was added sodium isothiocyanate (0.0970 g, 1.20 mmol), pyridine (0.195 ml, 2.39 mmol) and (R)-2,2,5,5-tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (0.342 g, 1.20 mmol). The reaction was heated to 60° C. for 15 minutes. To the mixture was added 3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (0.250 g, 0.798 mmol) and the reaction was stirred overnight at 70° C. The reaction was cooled and diluted with 50 ml EtOAc and 50 ml 1N NaOH. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in-vacuo. The residue was purified over silica gel (50% EtOAc/Hexanes) to afford (S)-N-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine (0.134 g, 0.255 mmol, 32.0% yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](S)=[S:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].S(Cl)([Cl:15])=O>C(OCC)C>[CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[S:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CCCc1ccc(C(=S)S)cc1
Solvent: CCOCC
Product: CCCc1ccc(C(=S)Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 102.1 %

Procedure:
To a 300 ml three neck flask provided with a stirrer, thermometer, cooling tube, and dropping funnel were added 11.1 g (56.7 mmol) of the 4-propyldithiobenzoic acid obtained by the procedures described above and 60 ml of diethyl ether, and 13.5 g (113.4 mmol) of thionyl chloride was added dropwise thereto while being stirred at room temperature in 5 minutes, and further heated to reflux for 8 hours. From the reaction mixture, diethyl ether was distilled off, and unreacted thionyl chloride was distilled off under a reduced pressure to obtain 11.5 g of dark purplish red oily 4-propylthiobenzoic acid chloride.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:32][CH:31]([C:33](O)=[O:34])[CH2:30]2)=[CH:25][CH:24]=1)=[O:21].[CH2:36]1[C:44]2[C:39](=[CH:40]C=CC=2)[CH2:38][N:37]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:38][CH:39]([CH3:40])[CH2:44][CH2:36][NH:37][C:33]([CH:31]1[CH2:30][N:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])=[CH:28][CH:27]=2)[CH2:32]1)=[O:34]
Reactant: O=C(O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-methylbutan-1-amine for 3-phenylpropan-1-amine and 1-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)phenyl)azetidine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.13 (s, 1H), 7.90 (t, J=5.5 Hz, 1H), 7.42 (d, J=4.8 Hz, 1H), 7.34-7.27 (m, 2H), 6.41-6.34 (m, 2H), 4.79-4.73 (m, 4H), 3.94-3.85 (m, 2H), 3.76-3.69 (m, 2H), 3.47-3.36 (m, 1H), 3.13-3.04 (m, 2H), 1.65-1.48 (m, 1H), 1.35-1.24 (m, 2H), 0.87 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 408 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](=[O:14])[CH3:13])=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:15].C(=O)CC.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](=[O:14])[CH:13]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:15]
Reactant: CC(=O)c1ccc2c(c1)SCC(=O)N2C
Reactant: O=Cc1ccccc1
Solvent: CCC=O
Product: CN1C(=O)CSc2cc(C(=O)C=Cc3ccccc3)ccc21

Procedure:
Using the procedure described in Preparation 3, but replacing 3-methyl-6-acetylbenzoxazolin-3-one by 4-methyl-7-acetyl-2,3-dihydro-4H-1,4-benzothiazin-3-one and propionaldehyde by benzaldehyde, the product of the title is obtained.
Reaction SMILES: Cl.N1CCCC1.[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([OH:25])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:28])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:37][CH2:38][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:28])[CH:9]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCCC1
Temperature: 100 °C
Yield: 9.5 %

Procedure:
1-2-Chloroethyl)pyrrolidine hydrochloride (200 mg, 1.2 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (403 mg, 1.26 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (650 mg, 4.7 mmol) in DMF (4 ml). The mixture was heated to 100° C. and further portions of 1-(2-chloroethyl)pyrrolidine hydrochloride (800 mg in total) were added periodically over 4 hours while the reaction mixture was maintained at 100° C. The reaction was then allowed to cool and volatiles were removed by evaporation. The residue was partitioned between methylene chloride and water, separated and the organic phase passed through phase separating paper. Column chromatography eluting with methylene chloride/methanol (95/5) gave 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (50 mg, 10%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]2[CH2:19][O:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:20]=[N+:21]=[N-:22].[Na+].C(OC)=O.CO>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]([OH:18])[CH2:19][N:20]=[N+:21]=[N-:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(CCCCCCCCOCC2CO2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COC=O
Product: [N-]=[N+]=NCC(O)COCCCCCCCCc1ccccc1
Yield: 96.7 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 2.4 g of 8-phenyloctyloxymethyloxirane (prepared as described in Preparation 64), 2.97 g of sodium azide, 20 ml of methyl formate and 80 ml of an 8:1 by volume mixture of methanol and water were used, to give 2.7 g of the title compound having an Rf value of 0.29 (on silica gel thin layer chromatography, using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:27][C:28]1[N:32]=[C:31](Cl)[S:30][N:29]=1>C1COCC1>[C:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:31]3[S:30][N:29]=[C:28]([Cl:27])[N:32]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Reactant: Clc1nsc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3nc(Cl)ns3)CC2)CC1

Procedure:
A solution of tert-butyl 4,4′-bipiperidine-1-carboxylate (537 mg; 2.00 mmol) in dry THF (10 mL) was treated with triethylamine (307 μL; 2.20 mmol). A solution of 3,5-dichloro-1,2,4-thiadiazole (341 mg; 2.20 mmol) in THF (5 mL) was added dropwise at ambient temperature. An immediate precipitate was accompanied by a mild exotherm. The mixture was stirred until it returned to ambient temperature. The mixture was filtered and the filtrate evaporated to afford the title compound.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+]>[Cl-].[Mg+2].[Cl-]>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Mg+2]
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 48 h

Procedure:
The immobilized Escherichia coli prepared in the above (1) (61 g) was packed in a jacketed column (4 cm×8 cm) and incubated at 37° C. for 48 hours to activate the immobilized cells (aspartase activity: 1980 m moles/hr). After activation, 1 M ammonium fumarate solution containing 1 mM magnesium chloride (pH 8.5, 1,000 ml) was passed through the column at 37° C. at the flow rate of 50 ml/hr. The effluent was adjusted to pH 2.8 to precipitate crystals and the crystals were filtered off to give L-aspartic acid (128 g).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[C:8]([CH3:27])=[C:9]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[N:14]=2)[S:10][C:11]=1Br.IC.[Cl-].[NH4+]>C1COCC1>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[C:15]1[N:14]=[C:13]([C:9]2[S:10][C:11]([CH3:1])=[C:7]([Br:6])[C:8]=2[CH3:27])[N:17]([CH3:18])[N:16]=1
Reactant: [Li]CCCC
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)sc(Br)c1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1sc(-c2nc(-c3c(F)cccc3Cl)nn2C)c(C)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
n-Butyllithium (0.7 g, 10.8 mmol) was added dropwise to a solution of 5-(4,5-dibromo-3-methylthien-2-yl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (5 g, 10.8 mmol) in THF (70 mL) at −70° C. and stirred for 1 hour. Iodomethane (1.6 g, 11.29 mmol) was added to the reaction mixture and allowed to warm to 25° C. After adding saturated aq ammonium chloride (10 mL), the organic layer was separated, washed with water, followed by saturated aq sodium chloride (20 mL) and dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed to give the product as a yellow oil (2.0 g, 47%): 1H NMR (CDCl3) δ 2.32 (s, 3H), 2.48 (s, 3H), 3.99 (s, 3H), 7.07-7.13 (m, 1H), 7.28-7.38 (m, 2H); EI/MS 400 m/e (M+); Calcd. for C15H12ClBrFN3S: C, 44.96; H, 3.02; N, 10.49; Found: C, 44.94; H, 3.01; N, 10.29.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:5]([C:6]([OH:8])=O)=[C:4]([O:13][CH3:14])[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:27][NH:28][O:29][CH3:30].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([C:6]([N:28]([O:29][CH3:30])[CH3:27])=[O:8])=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(I)cc(OC)c1C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(I)cc(OC)c1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 4-iodo-2,6-dimethoxybezoic acid (308.0 mg, 1.00 mmol) in methylene chloride (5.0 mL) were added dimethylformamide (0.020 mL, 0.26 mmol) and oxalyl chloride (0.13 mL, 1.5 mmol), and the resulting mixture was stirred for 30 minutes. The reaction mixture was poured into an ice-cold solution of N,O-dimethylhydroxyamine hydrochloride (488.0 mg, 5.00 mmol) and N,N-diisopropylethylamine (1.74 mL, 10.0 mmol) in methylene chloride (5.0 mL). The ice bath was removed, and the mixture was stirred at room temperature for 30 minutes. 0.1 M Hydrochloric acid was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The organic layer was washed with 0.1 M aqueous sodium hydroxide and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Hexane was added to the residue and the resulting precipitate was collected by filtration to yield crude 4-iodo-N,2,6-trimethoxy-N-methylbenzamide as a pale yellow crystalline powder (305.0 mg, yield: approx. 87%).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#N)([F:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.C(=O)=[O:24].CC(O)=O>C1(C)C=CC=CC=1.O>[F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:24])([F:4])[CH3:3]
Reactant: O=C=O
Reactant: CC(F)(F)c1cccc(C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(F)(F)c1cccc(C=O)c1
Temperature: -78 °C

Procedure:
Dissolve 3-(1,1-difluoro-ethyl)-benzonitrile (4.39 g, 26.26 mmol) in toluene (44 mL). Place the reaction under nitrogen, cool to −78° C. in a dry-ice bath, then add diisobutylaluminum hydride (52.5 mmol, 1 M solution in toluene) dropwise over 30 minutes with stirring. Stir the reaction in the dry-ice bath for 30 minutes, then add glacial HOAc (14 mL) dropwise to control foaming, followed by water (100 mL). Stir the reaction mixture overnight at room temperature. Separate the layers; extract the cloudy aqueous with toluene. Wash the toluene extracts with brine, dry the organics over magnesium sulfate, filter, and evaporate to afford 3-(1,1-difluoro-ethyl)-benzaldehyde as a pale yellow oil. (4.0 g, 90%). 1H NMR (400 MHz, CDCl3): δ 10.03 (s, 1H), 8.00 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 1.98-1.89 (m, 3H).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([F:23])=[CH:25][CH:26]=2)[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1ccc(CCBr)cc1
Product: Cc1ccc(N(CCc2ccc(F)cc2)N=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example 36A) and 4-fluorophenethylbromide (1.38 g, 6.8 mmol; Aldrich) to the title compound: MS (DCI/NH3) m/z 409 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20](OCC)(OCC)(OCC)[CH3:21]>CN(C=O)C>[CH3:20][C:21]1[N:6]([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])[C:4](=[O:5])[C:3]2[C:2](=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1cccc(N)c1C(=O)NC1CCC(=O)NC1=O
Solvent: CN(C)C=O
Product: Cc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Yield: 42.4 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (1.00 g, 3.8 mmol) and triethyl orthoacetate (0.9 mL, 4.9 mmol) in DMF (10 mL) was heated to reflux for 1 hour. The mixture was cooled to room temperature. To the solution, Celite (40 mL) was added, and the solvent was removed in vacuo. The solid was loaded on a SIM and purified with ISCO flash gel chromatography (silica gel, CH3OH/CH2Cl2) to give 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (0.46 g, 43% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 2.95 min (96%); mp: 292-294° C.; 1H NMR (DMSO-d6) δ 2.11-2.18 (m, 1H, CHH), 2.55-2.65 (m, 2H, CH2), 2.60 (s, 3H, CH3), 2.69 (s, 3H, CH3), 2.78-2.85 (m, 1H, CHH), 5.19 (dd, J=6, 11 Hz, 1H, NCH), 7.25 (d, J=8 Hz, 1H, Ar), 7.43 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 22.43, 23.32, 30.55, 56.33, 118.69, 124.73, 128.82, 133.72, 139.82, 148.34, 154.58, 161.03, 169.61, 172.60; LCMS: MH=286; Anal. Calcd. for C15H15N3O3+1H2O: C, 59.26; H, 5.68; N, 13.66. Found: C, 59.26; H, 5.68; N, 13.66.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.CCN(C(C)C)C(C)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl.[Cl-].[Na+].O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ncc1N
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Br)ncc1NC(=O)C(C)(C)C
Reaction time: 1 h

Procedure:
6-Bromo-4 methyl-3 pyridinamine (1.03 g, 5.51 mmol) was dissolved in DCM (20 ml) at 0° C. then added Hunig's Base (1.154 ml, 6.61 mmol) followed by pivaloyl chloride (0.745 ml, 6.06 mmol). After stirring for 1 hr, the reaction was not complete. Another equivalent of TEA and pivaloyl chloride were added then stirred for an hour. The reaction was poured into brine and extracted with DCM (2×). The organic layer was separated and dried over Na2SO4, filtered and concentrated. The residue was chromatographed thru a 200 g ISCO redisep column and eluted with 5% MeOH/DCM to yield title compound. LC-MS: M+2=273;
Reaction SMILES: [CH:1]([N:3]1[C:8]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12]CC)=[O:11])=[CH:7][S:6][CH2:5][CH2:4]1)=[O:2].[OH-].[K+]>C(O)C>[CH:1]([N:3]1[C:8]([C:9](=[N:15][O:16][CH3:17])[C:10]([OH:12])=[O:11])=[CH:7][S:6][CH2:5][CH2:4]1)=[O:2]
Reactant: CCOC(=O)C(=NOC)C1=CSCCN1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)C1=CSCCN1C=O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 82 %

Procedure:
To a suspension of thus obtained ethyl 2-(4-formyl-2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer, 4.8 g.) in ethanol (48 ml.) was added 1N aqueous solution of potassium hydroxide (22.3 ml.), and the mixture was stirred at room temperature for 1.25 hours. After removing ethanol from the resultant solution under reduced pressure, water was added to the residue to a total volume of 100 ml., and washed with diethyl ether. The solution was adjusted to pH 1 with 10% hydrochloric acid, and salted out. After the solution was extracted with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether (15 ml.) and the crystals were collected by filtration and washed with diethyl ether to give 2-(4-formyl-2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetic acid (syn isomer, 3.51 g.).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])[CH3:14].[I:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](O)=[O:35].ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[I:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:13][CH3:14])=[O:17])[CH2:19][CH2:20]2)=[CH:29][CH:28]=1)=[O:35]
Reactant: O=C(O)c1ccccc1I
Reactant: CCOC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.096 mol) was added at room temperature to a mixture of 4-(4-aminophenyl)-1-piperazinecarboxylic acid ethyl ester (0.08 mol), 2-iodo benzoic acid (0.096 mol) and 1-hydroxybenzotriazole (HOBT) (0.096 mol) in DCM (500 ml). The mixture was stirred at room temperature overnight. Water was added. The mixture was extracted with DCM. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was taken up in DIPE. The precipitate was filtered off and dried, yielding 39 g of 4-[4-[(2-iodobenzoyl)-amino]phenyl]-1-piperazinecarboxylic acid, ethyl ester (intermediate 27).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1.C(O[Na])(C)(C)C.[CH3:35][C:36]1[CH:41]2C(C)(C)[CH:39]([CH2:40]2)[CH2:38][CH:37]=1>[Cu]Cl.C1(C2C=CC(C3C=CC=CN=3)=NC=2C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC=CC=1>[C:15]1([N:14]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([CH3:35])[CH:37]=2)[C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[CH:9][CH:10]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1=CCC2CC1C2(C)C
Reactant: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Reactant: Cc1cccc(I)c1
Agent: Cl[Cu]
Agent: CC(C)(C)O[Na]
Agent: c1ccc(-c2ccc(-c3ccccn3)nc2-c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(N(c2ccccc2)c2ccc(N(c3ccccc3)c3cccc(C)c3)cc2)c1
Yield: 90.5 %

Procedure:
A mixture of 31.2 g (0.12 mole) of N,N′-diphenyl-N,N′-p-phenylenediamine, 54.5 g (0.25 mole) of m-iodotoluene, 32.6 g (0.34 mole) of t-butoxy sodium, 59.0 mg (0.6 mmole) of copper (I) chloride, 185 mg (0.6 mmole) of 2-(5,6-diphenyl-2-pyridyl)pyridine (A-8) and 87.6 ml of α-pinene was reacted at 125 to 130° C. for 5 hours under a nitrogen gas stream. After completion of the reaction, 66 ml of toluene and 66 ml of water were added to separate the reaction mixture. Toluene was then concentrated under reduced pressure. The residue was crystallized by the addition of 39 ml of ethyl acetate and 253 ml of isopropanol, whereby 47.8 g (yield: 90.5%) of the target compound was obtained as pale yellow crude crystals. The compound was found to have a melting point of 170 to 171° C. and an HPLC content (column: YMC-A-002, UV detector: 310 nm, eluent having a flow rate of 1.1 ml/min) was 99.5%.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:35])([CH3:34])N(C(C)=O)C(=O)C.[Br:36]N1C(=O)CCC1=O>ClCCl>[Br:36][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:35])([CH3:34])[CH3:25])=[O:9]
Reactant: CC(=O)N(C(C)=O)[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 47 %

Procedure:
A clear solution was obtained after refluxing a suspension of 371.8 mg (1.07 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide and 284.7 mg (1.65 mmoles) of N-trimethylsilyldiacetamide in 40 ml of dichloromethane for 5 minutes and it was cooled in an ice-bath and brominated in half an hour with 290.2 mg (1.63 mmoles) of N-bromosuccinimide to obtain a 47% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:15][C:3]=12.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25][C:26]1[N:27]([CH3:42])[C:28]([C:31]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:32]=2[CH:33]=[CH:34][C:35]([CH3:41])=[N:36]3)=[N:29][N:30]=1>>[ClH:20].[CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH2:21][CH2:22][CH2:23][CH2:24][S:25][C:26]3[N:27]([CH3:42])[C:28]([C:31]4[CH:40]=[CH:39][CH:38]=[C:37]5[C:32]=4[CH:33]=[CH:34][C:35]([CH3:41])=[N:36]5)=[N:29][N:30]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[O:15][C:3]=12
Reactant: Cc1ccc2c(-c3nnc(SCCCCCl)n3C)cccc2n1
Reactant: Cc1c2c(cc3nc(C(F)(F)F)oc13)CCNCC2
Product: Cc1ccc2c(-c3nnc(SCCCCN4CCc5cc6nc(C(F)(F)F)oc6c(C)c5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 10-methyl-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (120 mg) and 5-{5-[(4-chlorobutyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (224 mg) and was obtained according as a colourless slightly hygroscopic solid (163 mg).