Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11](=[O:20])[O:12]CC1C=CC=CC=1.CC#N.O.CCN(CC)CC>C(#N)C>[C:1]([NH:8][C@@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11]([OH:12])=[O:20])(=[O:3])[CH3:2]
Reactant: N[C@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N[C@H](CC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of acetic anhydride (85 μ1, 0.90 mmol.) in acetonitrile (1 ml), there is added a solution of commercially available H-D-Asp(OBn)-OH (Senn Chemicals, CH-Dielsdorf) (200 mg, 0.90 mmol.) in a CH3CN.H2O/Et3N (3.5/1.0/0.4 ml) mixture. The reaction mixture is stirred for 18 hours at room temperature. The organic solvent is evaporated and the remaining aqueous phase is cooled down to 0° C., acidified with a 10% aqueous solution of citric acid till pH=3 and extracted with EtOAc (2×). The organic layers are pooled and dried over MgSO4, filtered and evaporated. The -benzyl ester of N-acetyl-D-aspartic acid obtained as a white cristalline solid (192 mg, 81%) is used in the next step with no further purification. (Rf=0.45 in 20/1 CH2Cl2/MeOH containing 2% of acetic acid, phosphomolybdinium compound and U.V. color development agent).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[CH2:26][OH:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35]1([N:41]=[C:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:14][C@H:13]1[CH2:26][O:27][C:42](=[O:43])[NH:41][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](COC(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl(1R,3R,4S)-4-benzyloxycarbonylamino-3-(hydroxymethyl)cyclohexylcarbamate (75 mg) in dichloromethane (1 mL) and N,N-dimethylformamide (0.1 mL) was-treated with triethylamine (3 μL) and phenyl isocyanate (33 μL), and the mixture was and stirred at rt for 18 h. Additional phenyl isocyanate (22 μL) was added and stirring was continued for 96 h. The mixture was concentrated, and the residue was purified by flash column chromatography on silica gel, eluting with 4:6 v/v ethyl acetate/hexane, to provide tert-butyl(1R,3R,4S)-(4-benzyloxycarbonylamino-3-phenylcarbamoyloxymethylcyclohexyl)carbamate as a white glassy foam (85 mg). MS found: (M+H)+=498.3.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([C@H:14]([OH:23])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[Li].O>C1COCC1.O>[OH:23][C@@H:14]([C@@H:4]([CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:3]([OH:24])=[O:2])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.2 %

Procedure:
A solution of (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester (230 mg, 0.69 mmol) and LiOH.H2O (57.5 mg, 1.37 mmol) in a mixture of THF and water (2:1, 6 ml) was stirred at room temperature for 2.5 hrs. The reaction was diluted with water and THF removed under reduced pressure. The pH of the aqueous solution was adjusted to 5 with 1N HCl and extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and evaporated under reduced pressure to give the title compound as white solid (180 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][N:13]([CH3:25])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[H][H]>C(O)C.[Ni]>[CH3:1][S:2]([NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][N:13]([CH3:25])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CN(CCOc1ccc(NS(C)(=O)=O)cc1)CCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CN(CCOc1ccc(NS(C)(=O)=O)cc1)CCc1ccc(N)cc1
Yield: 72.2 %

Procedure:
A solution of 1-(4-methanesulphonamidophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane (0.9 g) in ethanol (100 ml) was stirred for 16 hours at room temperature under three atmospheres of hydrogen in the presence of Raney Nickel ("Nicat 102"--Trade Mark). The reaction mixture was filtered and evaporated to dryness. The resultant solid was crystallised from toluene to give the title compound as yellow crystals, (0.6 g), m.p. 155°-157°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10](O)([CH3:12])[CH3:11]>C(OCC)(=O)C.C(O)(=O)C>[CH:10]([C:4]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:12])[CH3:11]
Reactant: COc1cccc(C)c1C(C)(C)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cccc(C)c1C(C)C
Yield: 98.9 %

Procedure:
A solution of 2-(2-methoxy-6-methylphenyl)-2-propanol (0.50 g, 2.77 mmol) in ethyl acetate-acetic acid (9:1, 10.0 mL) at room temperature was stirred under a H2 atmosphere for 16 h. The mixture was filtered through a Celite plug and the solvent was removed under reduced pressure. The residue was dissolved in hexanes and washed with water. The organic layer was dried MgSO4, filtered and concentrated under reduced pressure to afford 2-iso-propyl-3-methylanisole (0.45 g, 100%) as colorless oil, which was used for the next step without further purification: 1H NMR (300 MHz, DMSO-d6): δ 7.01 (dd, J=12.0 Hz, 11.7 Hz, 1 H), 6.78 (d, J=12.0 Hz, 1 H), 6.70 (d, J=11.7 Hz, 1 H), 3.74 (s, 3 H), 3.28 (m, 1 H), 2.26 (s, 3 H), 1.24 (d, J=10.8 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:9); Rf=0.80.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4](=[O:6])[CH3:5].[CH2:10]1OCOCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:4]([C:3]1([CH3:7])[CH2:8][O:9][CH2:10][O:1][CH2:2]1)(=[O:6])[CH3:5]
Reactant: C1OCOCO1
Reactant: CC(=O)C(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C1(C)COCOC1

Procedure:
A solution of 3,3-bis(hydroxymethyl)-2-butanone (66.1parts) and s-trioxane (27 parts) in toluene (250 parts) containing p-toluenesulfonic acid (1.9 parts) is held under reflux while water of reaction is continuously removed (ca. 0.5 hr) by a Dean-Stark trap. The solution is cooled, neutralized by stirring with solid sodium bicarbonate and filtered Toluene is removed in vacuo and the residue distilled at 50-55° C. and 0.6 mm Hg. Proton NMR and combustion analysis are consistent with those values predicted for the desired product. Combustion Analysis for C7H12O3 --Calculated: C, 58.3%; H, 8.4%. Found: C, 57.9%; H, 8.2%.
Reaction SMILES: [Br:1][C:2]1[C:7](C=O)=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH:14]([O:19][CH3:20])([O:17][CH3:18])OC>CO>[CH3:20][O:19][CH:14]([O:17][CH3:18])[C:7]1[C:2]([Br:1])=[CH:3][C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=1
Reactant: COC(OC)OC
Reactant: COc1cc(Br)c(C=O)cc1OC
Solvent: CO
Product: COc1cc(Br)c(C(OC)OC)cc1OC
Temperature: 25 °C

Procedure:
6-Bromo-3,4-dimethoxybenzaldehyde (470 g) is suspended in methanol (600 ml), and thereto are added trimethyl orthoformate (1025 ml) and IRA-120 (H+-type, 10 g), and the mixture is refluxed for one hour. The mixture is cooled to room temperature, and the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in ether, washed, dried, evaporated to remove the ether, and distilled under reduced pressure to give 6-bromo-3,4-dimethoxybenzaldehyde dimethyl acetal (522 g) as a main distillate (133-138° C./1 Torr).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[CH:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:37]1([CH:43]([O:50][C:51]([C:53]2[N:58]3[C:59](=[O:62])[C@@H:60]([NH2:61])[C@H:57]3[S:56][CH2:55][C:54]=2[CH2:63][O:64][C:65](=[O:67])[NH2:66])=[O:52])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CN1CCOCC1>ClCCl.C(N(CC)CC)C>[C:37]1([CH:43]([O:50][C:51]([C:53]2[N:58]3[C:59](=[O:62])[C@@H:60]([NH:61][C:15](=[O:17])/[C:14](/[C:12]4[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[S:10][CH:11]=4)=[CH:18]\[CH2:19][CH3:20])[C@H:57]3[S:56][CH2:55][C:54]=2[CH2:63][O:64][C:65](=[O:67])[NH2:66])=[O:52])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCC=C(C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: NC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CS(=O)(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(N)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Yield: 86.1 %

Procedure:
To a mixture of 2-(2-t-butoxycarbonylaminothiazol-4-yl)-pentenoic acid (75 mg), triethylamine (0.041 ml), and dichloromethane (3 ml) is added dropwise methanesulfonyl chloride (0.02 ml) at -60° C. with stirring. After stirring at the same temperature for 5 hours, a solution of 7beta-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate salt (153 mg) and N-methylmorpholine (0.05 ml) in dichloromethane (3 ml) is added dropwise to the mixture. After stirring for 3.5 hours, the mixture is quenched with diluted hydrochloric acid. The organic layer is separated, washed with water, dried, and concentrated. The residue is purified by silica gel column chromatography to give 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester (155 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:36][O:37][CH2:38][C:39]2[CH:43]=[CH:42][N:41]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:40]=2)[C:33](O)=[O:34])[N:31]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl.[NH2:71][C@@H:72]1[C:89](=[O:90])[N:74]2[C:75]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])=[C:76]([CH2:80][Br:81])[CH2:77][S:78](=[O:79])[C@H:73]12>C(Cl)(Cl)Cl.C(Cl)Cl>[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:36][O:37][CH2:38][C:39]2[CH:43]=[CH:42][N:41]([C:44]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[N:40]=2)[C:33]([NH:71][C@@H:72]2[C:89](=[O:90])[N:74]3[C:75]([C:82]([O:84][C:85]([CH3:86])([CH3:87])[CH3:88])=[O:83])=[C:76]([CH2:80][Br:81])[CH2:77][S:78](=[O:79])[C@H:73]23)=[O:34])[N:31]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2[C@H](N)C(=O)N12
Reactant: O=C(O)C(=NOCc1ccn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2[C@H](NC(=O)C(=NOCc3ccn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reaction time: 0.5 h
Yield: 87 %

Procedure:
420 mg of phosphorus pentachloride was dissolved in 70 ml of chloroform and the mixture was cooled to -25° to -30° C. 1.51 g of 2-(2-tritylaminothiazol-4-yl)-2-((N-tritylpyrazol-3-yl)methoxyimino)acetic acid was added to the mixture and the resulting mixture was stirred for 30 minutes at the same temperature. 0.5 ml of triethylamine was added to the mixture and, after 3 minutes, a mixture of 810 mg of tertiary butyl 7β-amino-3-bromomethyl-3-cephem-4-carboxylate 1-oxide hydrochloride, 0.28 ml of triethylamine and methylene chloride was added to the mixture. The resulting mixture was stirred for 40 minutes at the same temperature. 50 ml of chloroform cooled in an ice-bath was added to the reaction mixture and the mixture was washed with water, a 3% aqueous solution of sodium bicarbonate and SSC and dried with sodium sulfate and then concentrated to dryness. The residue was purified by silica gel column chromatography using chloroform and nextly a mixture of chloroform and ethyl acetate (4:1 by volume) as an eluent solvent to give 1.92 g of tertiary butyl 7β-(2-(2-tritylaminothiazol-4-yl)-2-((N-tritylpyrazol-3-yl)methoxyimino)acetamido)-3-bromomethyl-3-cephem-4-carboxylate 1-oxide (syn isomer).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21]>CN(C=O)C>[CH2:18]([NH:22][C:23]([O:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CCCCN=C=O
Solvent: CN(C)C=O
Product: CCCCNC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C

Procedure:
The title compound was prepared in DMF using 3,5-di-tert-butyl-4-hydroxybenzaldehyde and n-butyl isocyanate according to the procedure described in Example H. The title compound was isolated in 87.5% yield as a buff solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.Cl>C(O)C.C(OCC)C>[CH2:1]([N:8]1[C:12]([CH2:13][NH2:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nnnn1Cc1ccccc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: CCOCC
Product: NCc1nnnn1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of the solid isolated in Step B (7.88 g, 24.7 mmol) in ethanol (300 mL), hydrazine (1.58 g, 49.3 mmol) was added. The reaction mixture was then refluxed four hours. After cooling down to room temperature, the white solid from the solution was removed by filtration. The filtrate was concentrated. Acetonitrile (50 mL) was added to the residue. The precipitate from the solution was removed by filtration. The filtrate was concentrated to yield a colorless oil which was treated with 1N HCl in diethyl ether to yield C-(1-benzyl-1H-tetrazol-5-yl)-methylamine as a white solid, as its corresponding HCl salt.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18]O)[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[Br:30]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][Br:30])[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCO)[C@H]1Oc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCBr)[C@H]1Oc1ccccc1
Reaction time: 1.17 h
Yield: 88.1 %

Procedure:
To a solution of tert-butyl((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carbamate (700 mg, 1.718 mmol) in CH2Cl2 (17 mL) at 0° C. (icewater bath) were added perbromomethane (627 mg, 1.890 mmol) and triphenylphosphine (541 mg, 2.061 mmol). After 70 min, TLC (2:1 hexanes:acetone) showed incomplete conversion so additional CBr4 and Ph3P (64 mg and 54 mg, respectively) were added and the reaction was stirred for an additional 20 min. The reaction was concentrated and purified by column chromatography on SiO2 (5→20% acetone/hexanes) to provide the title compound as a hard white foam (712 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 7.39-7.27 (m, 2H), 7.03-6.82 (m, 3H), 5.18-4.99 (m, 2H), 4.21 (q, J=8.7 Hz, 2H), 3.44 (ddd, J=10.0, 7.4, 5.0 Hz, 1H), 3.33 (ddd, J=9.9, 8.4, 6.9 Hz, 1H), 2.28 (dt, J=13.0, 6.6 Hz, 1H), 2.10 (dtd, J=12.6, 7.9, 4.5 Hz, 1H), 2.05-1.96 (m, 1H), 1.85-1.73 (m, 2H), 1.73-1.61 (m, 1H), 1.44 (s, 10H), 1.30 (d, J=6.5 Hz, 3H), 1.28-1.20 (m, 1H), 1.20-1.09 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 173.20, 159.18, 154.89, 129.74, 121.33, 115.37, 80.94, 79.95, 74.57, 53.02, 41.18, 34.13, 33.95, 31.54, 28.33, 19.13, 18.29; HRMS-ESI (m/z) ([M+Na]+) calcd for C22H32BrNNaO5, 492.1356; found, 492.1352.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]([F:26])([F:25])[O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24]>>[O:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:17]3([OH:24])[C:16]4[C:20](=[CH:21][CH:22]=[C:14]([O:13][C:12]([F:11])([F:26])[F:25])[CH:15]=4)[NH:19][C:18]3=[O:23])[C:10]=2[O:9][CH2:8]1
Reactant: Brc1cccc2c1OCO2
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Product: O=C1Nc2ccc(OC(F)(F)F)cc2C1(O)c1cccc2c1OCO2
Yield: 46.9 %

Procedure:
With 7.80 g of 4-bromo-1,3-benzodioxol and 2.30 g of 5-trifluoromethoxyisatin as starting materials, 1.65 g of the title compound was obtained by a similar method to Step 21-1.
Reaction SMILES: Cl.C[NH:3][C@H:4]([C:8]([OH:10])=[O:9])[CH:5]([CH3:7])[CH3:6].[CH:11]1C=CC2N(O)N=NC=2C=1.[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([OH:32])=O)[CH:25]=[C:26]([F:28])[CH:27]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>ClCCl>[F:28][C:26]1[CH:25]=[C:24]([CH2:29][C:30]([NH:3][C@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]([CH3:7])[CH3:6])=[O:32])[CH:23]=[C:22]([F:21])[CH:27]=1
Reactant: On1nnc2ccccc21
Reactant: CN[C@H](C(=O)O)C(C)C
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)Cc1cc(F)cc(F)c1)C(C)C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To a solution of methyl-L-valinate hydrochloride (168 mg) in dichloromethane (6 mL) was added HOBt (135 mg), 3,5-difluorophenylacetic acid (172 mg), EDCI (191 mg) and DIEA (0.522 mL). The reaction mixture was stirred for 16 h, diluted with dichloromethane (50 mL), washed with 5% hydrochloric acid (10 mL) and 10% potassium carbonate (10 mL). The organic layer after drying over anhydrous magnesium sulfate and concentration under reduced pressure afforded the title compound (272 mg). 1H NMR (300 MHz, CDCl3) δ 0.87 (d, 1.5H, J=7 Hz), 0.89 (d, 1.5H, J=7 Hz), 2.01 (m, 1H), 3.58 (s, 2H), 3.63 (s, 3H),4.18 (d,d, 1H, J=6 Hz, J=8 Hz), 7.0 (m, 3H), 8.45 (d, 1H, J=8 Hz). MS APCI, m/z=244(M+1). LC/MS: 1.97 min.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][C:5]=1[C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.[NH2:28][NH2:29]>C(O)C>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3](=[O:2])[NH:29][N:28]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)nc1C(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccccc2)c2nc(OCc3ccccc3)ccc12

Procedure:
2-Benzoyl-6-benzyloxynicotinic acid methyl ester (1.14 g) and hydrazine monohydrate (0.40 ml) were stirred together in ethanol (50 ml) at reflux overnight. The reaction was cooled (ice bath) precipitating a solid, which was separated by filtration and washed with diethyl ether. This was 2-benzyloxy-8-phenyl-6H-pyrido[2,3-d]pridazin-5-one (0.845 g). 1H NMR (400 MHz, DMSO) δ5.42 (2H, s), 7.33 (6H, m), 7.50 (3H, m), 7.86 (2H, m), 8.51 (1H, d, J=9.7 Hz), 13.04 (1H, s); MS (ES+) m/e 330 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]=[C:10](Br)Br.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]1[NH:15][CH2:14][CH2:13][N:16]=1
Reactant: NCCN
Reactant: Clc1cccc(Cl)c1C=C(Br)Br
Product: Clc1cccc(Cl)c1CC1=NCCN1

Procedure:
2-(2,6-Dichloro-benzyl)-4,5-dihydro-1H-imidazole was prepared from 1,3-dichloro-2-(2,2-dibromo-vinyl)-benzene and ethylene diamine in analogy to Example 1e): white crystals; MS (ISP): 233.1 (11%), 231.1 (63%) & 229.2 100%) (each [M+H]+).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:28]1([P:34](Cl)(Cl)=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCC.C1CCCCC1>[C:28]1([P:34]2(=[O:35])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: O=P1(c2ccccc2)c2ccccc2CN1c1ccccc1
Temperature: 26 °C
Reaction time: 2 h

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (3.90 g, 0.061 mol) in hexane was added to a solution of tetramethylethylenediamine (1.8 g, 0.0155 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-benzylaniline (5.5 g, 0.03 mol) in 30 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2 hours at 26° C. and then cooled to 0° C. A solution of phenylphosphonic dichloride (6.25 g, 0.032 mol) in 30 ml. of anhydrous cyclohexane was added dropwise to the suspension over a period of 15 minutes and the resulting mixture was stirred for 0.5 hours at 0° C., then for 2.5 hours at 26° C. The reaction was quenched with the rapid addition of 6 ml. of acetic acid. The reaction mixture was concentrated in vacuo and the residue partitioned in methylene chloride and water. The layers were separated and the methylene chloride layer was washed with 5% hydrochloric acid, sodium bicarbonate, then water. The methylene chloride layer was dried over magnesium sulfate, concentrated in vacuo and the resulting residue was slurried in anhydrous diethyl ether and allowed to stand at 0° C. for 40 hours. The slurry was filtered and the resulting yellow precipitate was dissolved in a minimal amount of hot ethyl alcohol. The ethyl alcohol solution was diluted with petroleum ether to yield 1,2-diphenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as white fluffy crystals. A second crop was obtained and the combined product yield was recrystallized from ethanol to yield 1,2-diphenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (3.0 g, 33% yield) as fluffy needles having a melting point of 227°-229° C. and the following analysis:
Reaction SMILES: Cl[CH2:2][S:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[C:8](=[O:21])[CH2:7]1)(=[O:5])=[O:4].[Cl:22][C:23]1[CH:30]=[C:27]([CH:28]=O)[C:26]([OH:31])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[O:31][C:2]([S:3]([N:6]3[CH2:11][CH2:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=4)[C:8](=[O:21])[CH2:7]3)(=[O:5])=[O:4])=[CH:28][C:27]=2[CH:30]=1
Reactant: N#Cc1ccc(CN2CCN(S(=O)(=O)CCl)CC2=O)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)c3cc4cc(Cl)ccc4o3)CC2=O)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 9.2 %

Procedure:
A mixture of 4-chloromethylsulfonyl-1-(4-cyanobenzyl)-2-piperazinone (3.20 g), 5-chlorosalicylaldehyde (2.29 g), potassium carbonate (1.48 g), potassium iodide (1.62 g) and DMF (80 ml) was stirred at 80° C. for 2 days. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) to give colorless crystals of the title compound (384 mg).