Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([Cl:23])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:28]([O:30]P(CC1C=CC(N)=C(OCC)C=1)(=O)OCC)[CH3:29].ClC1N=C(Cl)C(C(F)(F)F)=CN=1>>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([Cl:23])[C:20]([C:24]([F:26])([F:25])[F:27])=[CH:19][N:18]=2)=[C:14]([O:30][CH2:28][CH3:29])[CH:15]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CCOc1cc(CP(=O)(OCC)OCC)ccc1N
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Product: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1

Procedure:
The title compound was prepared according to the procedure for diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using diethyl(4-amino-3-ethoxybenzyl)phosphonate and 2,4-dichloro-5-trifluoromethylpyrimidine. The crude material was purified on an ISCO CombiFlash®Rf 4X Organic Purification System eluting with 1:1 EtOAc-DCM/MeOH (100:0→95:5)] affording a mixture of both regioisomers. The product was further purified by MDP to afford 514 mg (30%) of the desired regioisomer. 1H NMR (400 MHz, MeOD) δ 8.62 (s, 1H), 8.02 (d, J=8.08 Hz, 1H), 7.03 (t, J=2.15 Hz, 1H), 6.92 (td, J=2.34, 8.21 Hz, 1H), 4.04-4.22 (m, 6H), 3.28 (s, 1H), 3.23 (s, 1H), 1.41 (t, J=6.95 Hz, 3H), 1.27 (t, J=7.07 Hz, 7H). MS (ES+): m/z 468.07/470.09 (100/90) [MH+]. HPLC: tR=1.66 min (Micromass TOF: polar—3 min).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11].NC1C=CC=CC=1C1C=CC=CC=1.C(#N)CC#N.O.[NH2:39][NH2:40]>>[NH2:11][C:10]1[C:9](=[N:8][NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12]([NH2:13])=[N:40][N:39]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccccc1-c1ccccc1
Agent: Nc1ccccc1-c1ccccc1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 61 %

Procedure:
This compound was prepared using 123 mg (0.5 mmol) of 2-[(biphenyl-2-yl)hydrazono]-malononitrile, which was derived from 2-aminobiphenyl (169 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube immediately after the addition of the hydrazine hydrate then the solution cleared. Very little solid remained after heating the reaction at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 85 mg (61%) of the title compound as an orange solid.
Reaction SMILES: [OH:1][CH:2]1[CH:8]2[CH:6]([O:7]2)[CH2:5][N:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[N-:14]=[N+:15]=[N-:16].[Na+].[NH4+].[Cl-]>COCCO>[N:14]([CH:8]1[CH:2]([OH:1])[CH2:3][N:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH:6]1[OH:7])=[N+:15]=[N-:16]
Reactant: CCOC(=O)N1CC(O)C2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: COCCO
Product: CCOC(=O)N1CC(O)C(N=[N+]=[N-])C(O)C1
Temperature: 125 °C
Yield: 26 %

Procedure:
To a solution of Compound 239G (2.0 g, 10.7 mmol) in 2-methoxyethanol (40 mL) was added NaN3 (3.5 g, 53.4 mmol) and NH4Cl (2.3 g, 42.72 mmol). The reaction mixture was heated at 125° C. overnight. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was taken into EtOAc (50 mL), washed with water (10 mL×2) and dried over anhydrous Na2SO4. Concentration in vacuo followed by flash chromatography (hexane-EtOAc: 1:1 to 1:2) on silica gel afforded 0.64 g of 239I (higher Rf) as a crystalline material. The stereochemistry was confirmed by a single x-ray crystallographic determination.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1C(C)CCCN1.[NH2:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][N:15]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:13]=[C:14]1[CH:19]([OH:20])[CH2:18][CH2:17][CH2:16][NH:15]1
Reactant: Nc1ncccc1O
Agent: CC1CCCNC1=N
Solvent: CC(=O)O
Product: N=C1NCCCC1O

Procedure:
The method of preparation of 2-imino-3-methylpiperidine acetate, EXAMPLE 6, was used to convert 2-amino-3-hydroxypyridine to the title compound which was obtained as a white solid. The analysis of the product was found to be consistent with the proposed structure. m.p. 128°-130° C. MH+=115; 1H NMR (D2O): δ4.34-4.28 (m, 1H); 3.20-3.10 (m, 2H); 2.05-1.50 (m, 4H); 1.71 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:3][C@@H:4]([C@@H:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH3:9])[C:5](=[O:7])[N:6]=1.[CH3:19]N>>[CH3:9][C@H:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[C@@H:4]1[O:3][C:2]([NH:1][CH3:19])=[N:6][C:5]1=[O:7]
Reactant: CN
Reactant: C[C@H](c1c[nH]c2ccccc12)[C@@H]1OC(N)=NC1=O
Product: CNC1=NC(=O)[C@H]([C@H](C)c2c[nH]c3ccccc23)O1
Reaction time: 3 h
Yield: 60 %

Procedure:
(5S)-2-Amino-5-[(1R)-1-(indol-3-yl)ethyl]-4-oxazolone (1.22 g) was dissolved in 40% aqueous solution of methylamine (9 ml). The vessel was stoppered and kept standing for 3 hours at 5° C. The reaction mixture was concentrated under reduced pressure to make the volume to about half. The precipitated solid substance was collected by filtration and washed with water (20 ml). The solid substance was recrystallized from methanol-water to give indolmycin (0.777 g) as white crystals (yield: 60%).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Cl:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C@@H:21]3[CH2:23][C@H:22]3[CH2:24][CH2:25][OH:26])[CH2:17][CH2:16]2)=[N:13][CH:14]=1.[Cl-].F[C:29]1[CH:34]=[CH:33][NH+:32]=[CH:31][CH:30]=1>C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C@@H:21]3[CH2:23][C@H:22]3[CH2:24][CH2:25][O:26][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1
Reactant: Fc1cc[nH+]cc1
Reactant: OCC[C@@H]1C[C@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cnc(N2CCC([C@@H]3C[C@H]3CCOc3ccncc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (100%, 20 mg, 0.85 mmol) was weighed into a vial, DMF (anhydrous, 2.1 mL) was added, followed by addition of rac-trans 2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (60 mg, 0.21 mmol) and the mixture stirred at room temperature for 5 min. The 4-fluoropyridinium chloride was then added and stirred at room temperature for 10 min. The mixture was heated to 50° C. for 1.5 hours, cooled to room temperature, and diluted with ethyl acetate (5 mL), quenched with saturated aq.NH4Cl (5 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (30% ethyl acetate/hexane) to yield the titled compound as a white solid. LC-MS (M+1): 359.54. Compounds Reported in Table 3 are Prepared by a General Procedure Analogous to that Described in Example 6, Steps 1 and 2, Described Above
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH:8]2[C:20](=[O:21])[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:4]=[CH:5][N:6]=1.[H-].[Na+].[CH3:24]OS(OC)(=O)=O>CN(C)C=O>[CH3:24][N:12]1[C:11]2[CH2:10][CH2:9][CH:8]([CH2:7][N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])[C:20](=[O:21])[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: Cc1nccn1CC1CCc2[nH]c3ccccc3c2C1=O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (1.0 g) in dry dimethylformamide (10 ml) was added dropwise under nitrogen to a stirred, ice-cooled suspension of sodium hydride (80% in oil; 0.11 g) in dry dimethylformamide (5 ml). After 0.5 h dimethylsulphate (0.34 ml) was added, and the solution stirred at room temperature for 4 h. The resultant solid was filtered off, washed with ice-cold dry dimethylformamide (2×5 ml) and dry ether (3×15 ml) and dried to give the title compound as a solid (0.25 g) m.p. 223°-224° (dec).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[Br:25]Br>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:9][CH2:10][C:11]2[CH:19]=[C:18]([Br:25])[CH:17]=[CH:16][C:12]=2[NH:13][C:14]1=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2NC1=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2cc(Br)ccc2NC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A round-bottom flask containing ((R)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-carbamic acid tert-butyl ester (0.338 g, 1.20 mmol) was fitted with a stirbar and septa. Acetic acid (glacial, 5 mL) and bromine (0.37 g, 2.3 mmol) were added, in that order, giving a solution that was stirred at room temperature for 1.5 hours. The reaction was then poured into ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 solution (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (10% to 50% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:33])[CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=4[C:25](OC)=[O:26])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:35][NH:36][O:37][CH3:38].CC[Mg+].[Br-].CCOCC>C1COCC1>[CH3:35][N:36]([O:37][CH3:38])[C:25](=[O:26])[C:24]1[CH:29]=[CH:30][CH:31]=[CH:32][C:23]=1[CH2:22][CH2:21][C@@H:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:13]=[CH:12][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[OH:33]
Reactant: CNOC
Reactant: COC(=O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: CC[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CON(C)C(=O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of the hydroxy ester of Step 3 (4.519 g, 9.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.777 g, 28.5 mmol) in 95 mL of anhydrous THF at 0° C. was added dropwise 3M EtMgBr in Et2O (22 mL 66 mmol) over ≃40 min. The mixture was then stirred at 0° C. for 30 min. and poured into ice-cold saturated NH4Cl. The product was extracted in EtOAc, dried over Na2SO4, and concentrated to yield the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:9])([F:8])[O:4][CH2:5][CH2:6][NH2:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1.C(N(CC)C(C)C)(C)C>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:7][CH2:6][CH2:5][O:4][C:3]([F:9])([F:8])[F:2])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1
Reactant: NCCOC(F)(F)F
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)ccc1NCCOC(F)(F)F

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 2-(trifluoromethoxy)ethanamine hydrochloride (J. Org. Chem. 2001, 66, 1061-1063), 4-bromo-1-fluoro-2-nitrobenzene (Wako Pure Chemical Industries, Ltd.) and N,N-diisopropylethylamine.
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]([F:35])([F:34])[F:33])[CH:25]=2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.IC.[C:38](=O)([O-])[O-].[K+].[K+]>O>[OH:1][C:2]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:38])=[C:26]([O:31][C:32]([F:34])([F:35])[F:33])[CH:25]=2)[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2ccc(O)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
A solution of tert-butyl 4-{(1-hydroxycyclohexyl)[4-hydroxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate (0.35 g 0.72 mmol) (See Example 400, step 1) and iodomethane (0.16 g, 1.08 mmol) in N-N′-dimethylformamide (5 mL) was treated with potassium carbonate (0.12 g, 0.86 mmol), and the solution was stirred at room temperature for 16 hours. The reaction was then poured into water and extracted 3 times with ethyl acetate. The combined extracts were washed twice with water, then dried over magnesium sulfate and concentrated to afford 0.31 g of tert-butyl 4-[(1-hydroxycyclohexyl)[4-methoxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[C@@H:12]([C:13]([O-:15])=O)[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:6](=[O:29])[C@@H:5]1[CH2:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)(=[O:3])[CH3:2].C([N:44]1[C@H:52]([C:53]([O-:55])=[O:54])CC(=O)C2C=CC=CC=2N(CC2C=CC=CC=2)C(=O)[C@H]1CC12CC3CC(CC(C3)C1)C2)(=O)C>>[C:1]([N:4]1[C@@H:12]([C:13]([NH:44][CH2:52][C:53]([OH:55])=[O:54])=[O:15])[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:6](=[O:29])[C@@H:5]1[CH2:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Reactant: CC(=O)N1[C@@H](C(=O)[O-])CC(=O)c2ccccc2N(Cc2ccccc2F)C(=O)[C@@H]1CC12CC3CC(CC(C3)C1)C2
Product: CC(=O)N1[C@@H](C(=O)NCC(=O)O)CC(=O)c2ccccc2N(Cc2ccccc2F)C(=O)[C@@H]1CC12CC3CC(CC(C3)C1)C2

Procedure:
The compound was prepared by an identical route to that used to prepare example 22 except that (3S,5R)-4-acetyl-3-(1-adamantyl)methyl-1-(2-fluorobenzyl)-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate was used in step a in place of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:13]2[C@H:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][O:15][C:14]2=[O:25])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.CO[CH2:37][NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([C:11](=[O:12])[N:13]2[C@H:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:16][O:15][C:14]2=[O:25])[CH2:37][NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(CCc1ccc(F)c(F)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCNC(=O)OCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H](Cc1ccc(F)c(F)c1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
To a solution of (4R)-3-[3-(3,4-difluorophenyl)propanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (1 g, 2.90 mmol) in dichloromethane (29.0 ml) at −60° C. was added TiCl4 (0.335 ml, 3.04 mmol) dropwise. After 30 min, DIPEA (0.556 ml, 3.19 mmol) was added and the solution stirred at 1 h at 0° C. phenylmethyl [(methyloxy)methyl]carbamate (1.131 g, 5.79 mmol)[prepared according to Barnett, C. J. et al, Tetrahedron Lett. 1997, 38, 5, 735.] was added and the reaction mixture stirred at 0° C. for 4 h. The solution was quenched with aqueous saturated ammonium chloride solution and extracted several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (0-50% EtOAc in hexanes) affording phenylmethyl {(2S)-2-[(3,4-difluorophenyl)methyl]-3-oxo-3-[(4R)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]propyl}carbamate (548 mg, 0.506 mmol, 17.49% yield) as a clear oil:
Reaction SMILES: [H-].[Na+].C[CH:4](C)[C@H:5]([C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)[C:6](=[O:12])[CH2:7]P(=O)(O)O.P(=O)(O)O.[CH:25]([C@H:27]1[C@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][C@H:32]2[C@@H:28]1[CH2:29][C:30](=[O:44])[O:31]2)=O>COCCOC>[O:12]=[C:6]([C@@H:5]([C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)[CH3:4])/[CH:7]=[CH:25]/[C@H:27]1[C@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][C@H:32]2[C@@H:28]1[CH2:29][C:30](=[O:44])[O:31]2
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: Cc1cccc([C@H](C(=O)CP(=O)(O)O)C(C)C)c1
Agent: O=[PH](O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc([C@@H](C)C(=O)/C=C/[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2OC(=O)c2ccccc2)c1
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Sodium hydride (55%) (8.75 g) was dispersed in 1,2-dimethoxyethane (DME) (300 mL) and the mixture was ice-cooled. A solution of phosphonate {dimethyl (3R)-2-oxo-3-(m-tolyl)butylphosphonate} (54.7 g) synthesized in Example 2 in DME (50 mL) was added, and the mixture was stirred for 1 hr. To the above-mentioned solution was added a solution of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one (50.0 g) in DME (400 mL), and the mixture was stirred for 1 hr. The reaction was quenched with 350 mL of 10% brine, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the residue was concentrated under reduced pressure. The concentrated crude product was recrystallized from t-butyl methyl ether to give the title compound (64.7 g). The structural property was as described below.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[CH2:11]([N:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>O1CCCC1>[CH2:11]([N:14]([CH2:18][CH3:19])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: CCS(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC)C(=O)n1cnc(S(=O)(=O)CC)n1

Procedure:
A mixture of 6.45 g. 3-ethylsulphonyl-1,2,4-triazole, 5.9 g. N-allyl-N-ethylcarbamoyl chloride, 6.5 ml. dry triethylamine and 80 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 6 hours. The reaction mixture was worked up as described in Example 1 to produce a solid residue which was recrystallized from benzene/petroleum ether, b.p. 40° - 60°C. to give 1-(N-allyl-N-ethylcarbamoyl)-3-ethylsulphonyl-1,2,4-triazole, m.p. 41° - 43°C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@H:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:26](Cl)(Cl)=[O:27]>ClCCl>[CH2:1]([N:8]1[CH2:9][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[O:11][S:26]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H](CNCc1ccccc1)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S1O[C@@H](c2ccc(Cl)cc2)CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.4 %

Procedure:
To a suspension of (S)-2-benzylamino-1-(4-chlorophenyl)ethanol (15.76 g, 60.21 mmol) and triethylamine (33.6 ml, 241 mmol) in dichloromethane (300 ml) was added a solution of thionyl chloride (4.83 ml, 66.2 mmol) in dichloromethane (20 ml) at −78° C. over 20 min. The resulting suspension was stirred at −78° C. for 20 min and at 0° C. for additional 20 min. The reaction mixture was partitioned between ether and water, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10-20% ethyl acetate-hexane) to afford (2RS,5S)-3-benzyl-5-(4-chlorophenyl)-1,2,3-oxathiazolidine 2-oxide (16.2 g 87.4%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:18]I>CN(C=O)C.O>[CH3:18][O:1][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: N#Cc1ccc(C2(O)CCOCC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2ccc(C#N)cc2)CCOCC1

Procedure:
To a solution of 4-(4-hydroxytetrahydro-2H-pyran-4-yl)benzonitrile (Step 1 of Intermediate I, 300 mg, 1.48 mmol) in DMF (6.5 mL) was added sodium hydride (60% suspension in mineral oil, 65 mg, 1.62 mmol) at a temperature of ˜5° C. The reaction mixture was allowed to stirr for 1 h at this temperature, before methyl iodide (110 μL, 1.77 mmol) was added. Stirring was continued over night at rt. The mixture was diluted with water and extracted with diethyl ether. The organic extract was dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 20:1→4:1) to afford the title compound in pure form (238 mg, 74%): 1H NMR (500 MHz, CDCl3) δ 7.68 (d, 2H), 7.51 (d, 2H), 3.89-3.82 (m, 4H), 2.99 (s, 3H), 2.03-1.98 (m, 2H), 1.94-1.91 (m, 2H); DCI(NH3)-MS m/z 235 (M+NH4)+; HPLC RT (Method I) 3.99 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C(O[C:15](OCC)(OCC)[CH2:16][CH3:17])C>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:15]([CH2:16][CH3:17])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(CC)(OCC)OCC
Reactant: NNC(=O)c1ccc(Br)cc1
Product: CCc1nnc(-c2ccc(Br)cc2)o1

Procedure:
A mixture of 4-bromobenzoic acid hydrazide (3.23 g) and triethylorthopropionate (25 ml) was heated at reflux for 7 hours. The mixture was evaporated to give a solid which was recrystallised from ethyl acetate to give 2-(4-bromphenyl)-5-ethyl-1,3,4-oxadiazole (3.65 g), as a solid, m.p. 101°-102° C.; microanalysis found: C, 47.3; H, 3.6; N, 10.9%; C10H9BrN2O requires: C, 47.5; H, 3.58; N, 11.1%; NMR(CDCl3): 1.44(3H,t), 2.96(2H,q), 7.65(2H,d) and 7.90(2h,D); m/z 253(M+H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1/[CH:20]=[CH:21]/[C:22]#[N:23]>CS(C)=O.C(OCC)(=O)C>[Br:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1[CH:20]1[CH2:4][CH:21]1[C:22]#[N:23]
Reactant: Cn1cc2c(/C=C/C#N)c(Br)ccc2n1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1cc2c(C3CC3C#N)c(Br)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a suspension of sodium hydride (19.6 mg, 0.490 mmol) in dimethyl sulfoxide (2 mL) was added trimethylsulfoxonium iodide (117 mg, 0.531 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. Thereto was added a solution of (2E)-3-(5-bromo-2-methyl-2H-indazol-4-yl)acrylonitrile (107 mg, 0.408 mmol) in dimethyl sulfoxide (2 mL), and the mixture was stirred for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→100/0) to give the title compound (50.0 mg, yield 44%).