Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.[C:13]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+]>O1CCCC1.CN(C)C=O>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][CH2:5]/[CH:4]=[CH:3]\[CH2:2][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: ClC/C=C\COC1CCCCO1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C/C=C\COC1CCCCO1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
2-[4-Chloro-(Z)-2-butenyloxy]tetrahydro-2H-pyran (100 g) was dissolved in 2000 ml of dry tetrahydrofuran/600 ml of dry N,N-dimethylformamide. To the solution was added 100 g of diethyl malonate, and then 25 g of 60% sodium hydride with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=9:1) to provide 65.5 g of the objective compound as oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:34]([N:9]1[CH2:8][CH2:7][C:6]([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1)(=[O:36])[CH3:35]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (0.24 g, 0.576 mmol), triethylamine (0.32 ml) and catalytic amount of 4-Dimethylaminopyridine in 6.0 mL of CH2Cl2 was added a solution of acetyl chloride (0.068 ml, 0.864 mmol) in 1.0 mL of CH2Cl2. The reaction stirred at room temperature for 4 h and washed with H2O, brine, dried over MgSO4, filtered through a pad of silica gel and concentrated to provide 0.242 g (100%) of the desired product as a colorless gum. Electrospray Mass Spec: 422.2 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: O=C(Cl)OCc1cccc(Cl)c1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCc3cccc(Cl)c3)C2)cc1

Procedure:
3-Chlorobenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.20 mmol) and 3-chlorobenzyl carbonochloridate (68 mg, 0.22 mmol) according to General Procedure H to give 20 mg (21.3%) of white solid. Anal. Calcd. for C26H31ClN4O2 m/z 466.2, found: 467.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.46 (d, J=8.8 Hz, 2H), 7.35 (m, 1H), 7.30 (m, 4H), 7.28 (m, 2H), 7.23 (m, 1H), 6.96 (d, J=3 Hz, 2H), 5.0 (m, 2H), 3.71 (m, 1H), 3.58 (m, 1H), 3.29 (m, 1H), 2.98 (m, 1H), 2.72 (m, 2H), 2.52 (m, 1H), 2.04 (m, 1H), 1.92 (m, 2H), 1.78 (m, 3H), 1.62 (m, 1H), 1.34 (m, 4H), 1.20 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=2[CH:9]=O)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=3[CH2:9][NH:19][C:4]=2[CH:3]=1
Reactant: COc1ccc(C=O)c(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)Oc1ccc(Cl)cc1NC2
Yield: 60.1 %

Procedure:
3.50 g of 2-(4-chloro-2-nitrophenoxy)-4-methoxybenzaldehyde, prepared as described above in Example 5, in tetrahydrofuran (THF) (35 mL) was shaken in a Parr hydrogenator at 5 psi hydrogen with Raney nickel at 25° C. for 6 hours. The catalyst was filtered from the reaction and the solution evaporated in vacuo. The crude product was chromatographed, as described above in Example 2, through silica gel 60 using hexane:ethyl acetate (2:1), and recrystallized from ethanol (3A) to yield 1.79 g (60.1%) of product as white crystals. Melting Point: 113°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH3:19])[CH2:15][C:16](O)=O)=[O:13])[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:23]=[C:24]([NH2:30])[C:25]([NH2:29])=[CH:26][C:27]=1[F:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CCOC(C)=O.CN(C=O)C>[ClH:1].[Cl:21][C:22]1[C:27]([F:28])=[CH:26][C:25]2[N:29]=[C:16]([CH2:15][N:14]([CH3:19])[C:12](=[O:13])[CH2:11][N:7]3[C:6]4[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[S:9][C:8]3=[O:10])[NH:30][C:24]=2[CH:23]=1
Reactant: CN(CC(=O)O)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Reactant: Nc1cc(F)c(Cl)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1nc2cc(F)c(Cl)cc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.8 %

Procedure:
To a mixture of N-[(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetyl]-N-methylglycine (150 mg), 4-chloro-5-fluorobenzene-1,2-diamine (81 mg), and DMF (5 mL) were added HOBt (77 mg) and WSC.HCl (107 mg), followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc, and washed with water, a saturated aqueous NaHCO3 solution, and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. To the residue was added acetic acid (5 mL), followed by heating and stirring at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The obtained solid was washed with EtOAc and then with MeOH, and suspended in MeOH (3 mL). 4 M hydrogen chloride/EtOAc (120 μL) was added thereto, followed by stirring at room temperature for 1 hour. The resulting solid was collected by filtration and then washed with MeOH to obtain N-[(6-chloro-5-fluoro-1H-benzimidazol-2-yl)methyl]-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide hydrochloride (146 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH2:11])[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[C:23]([CH3:25])[C:22]([C:26](O)=[O:27])=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH:11][C:26]([C:22]2[C:23]([CH3:25])=[N:24][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=3)=[N:20][CH:21]=2)=[O:27])[CH:3]=1
Reactant: Cc1cn(N)c2cccnc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2ncccc21
Reaction time: 1 h
Yield: 44 %

Procedure:
A mixture of 3-methyl-pyrrolo[3,2-b]pyridin-1-yl amine (75% pure) (240 mg, <1.63 mmol), 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (379 mg, 1.63 mmol), HATU (744 mg, 1.96 mmol) and DIPEA (388 mg, 4.89 mmol) in DMF (5 mL) is heated at 1500 C. for 1 h. The reaction is quenched with water, extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 10% MeOH in DCM. The resulting product is recrystallized with ether to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (197 mg, 44%). MS: 362 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.14 (s, 1H), 8.40 (d, 1H), 8.36 (d, 1H), 8.22 (d, 1H), 7.85(d, 1H), 7.55 (q 1H), 7.47 (s, 1H), 7.25-7.34 (m, 2H), 2.83 (s, 3H), 2.42(s, 3H). IC50=2 nM.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:27](=[O:28])[C:26]2[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:25]=2[F:24])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(C[C@H]2CCCO2)n1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)n(C[C@H]2CCCO2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a solution of the product of Example 1C (7.8 g) and triethylamine (14.6 mL, 105 mmol) in THF (60 mL) at ambient temperature was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (5.3 mL, 35.0 mmol) dropwise over 10 min. The mixture was stirred at ambient temperature for 3 h. The mixture was quenched with saturated, aqueous NaHCO3 (20 mL) and diluted with EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 40% hexanes/EtOAc) gave the title compound (11.0 g, 26.6 mmol). MS (DCI/NH3) m/z 414 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([F:17])[C:9]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:9]2[C:10]([F:17])=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[F:7])[CH:6]=1
Reactant: Clc1c[nH]cn1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(-n2cnc(Cl)c2)c(F)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
Step J (1): A mixture of 4-chloro-1H-imidazole (1.18 g, 11.5 mmol), 1,2,3-trifluoro-5-nitrobenzene (1.7 g, 9.60 mmol) and potassium carbonate (1.86 g, 13.4 mmol) in DMF (10 mL) was heated at 50° C. for 2 h. The reaction mixture was allowed to cool to rt and was stirred for 16 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (50% EtOAc/hexane) to afford 4-chloro-1-(2,6-difluoro-4-nitrophenyl)-1H-imidazole (2.0 g, 80% yield). LC-MS (M+H)+=260.1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.03-8.10 (m, 2 H) 7.71 (q, J=1.83 Hz, 1 H) 7.19 (q, J=1.93 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]4[O:23][C:22](=[O:24])[N:21]([C:25]5[CH:26]=[CH:27][C:28]6[S:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=6[CH:35]=5)[CH2:20]4)[C:3]=1[C:4]=23.[BH4-].[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]4[O:23][C:22](=[O:24])[N:21]([C:25]5[CH:26]=[CH:27][C:28]6[S:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=6[CH:35]=5)[CH2:20]4)[C:3]=1[C:4]=23
Reactant: O=C1CSc2ccc(N3C[C@H](CCCN[C@@H]4Cn5c(=O)cnc6ccc(F)c4c65)OC3=O)cc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1CSc2ccc(N3C[C@H](CCCN[C@@H]4CN5C(=O)CNc6ccc(F)c4c65)OC3=O)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A solution of the compound of Example 79 (42 mg) in DCM/MeOH (2:1; 6 mL) was treated with NaBH4 (3.2 mg). After 30 min stirring at rt, the reaction mixture was quenched with 1M. HCl (1 mL) and partitioned between DCM and aq. NH4OH. The org. layer was washed with water, dried over MgSO4, concentrated under reduced pressure and purified by CC (EA/MeOH 19:1 to 9:1), affording a beige solid (29 mg; 69% yield).
Reaction SMILES: CO[C:3](=[O:26])[CH:4]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[CH3:27][NH:28][C:29]([NH2:31])=[O:30].C[O-].[Mg+2].C[O-].CO>>[Cl:25][C:20]1[CH:19]=[C:18]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:3]([NH:31][C:29]([NH:28][CH3:27])=[O:30])=[O:26])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 11.8 %

Procedure:
2-(3,4-Dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (400 mg, 0.99 mmol) and methylurea (110.7 mg, 1.49 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. % , 2.85 mL, 1.99 mmol) was heated under reflux at 110° C. for 6 h. The reaction mixture was then concentrated in vacuo and filtered through a plug of celite (ethyl acetate as eluent). Flash chromatography (Merck Silica gel 60, 230-400 mesh, 100% ethyl acetate) afforded 1-{2-(3,4-dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionyl}-3-methyl-urea (52 mg, 11.8%) as a white solid: mp 68-70° C.; FAB-HRMS m/e calcd for C21H28Cl2N2O4 (M+H)+ 443.1504. found 443.1499.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:4]([CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])=[C:4]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27]
Reactant: CCOC(=O)C(O)c1c(C)c(F)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)c(F)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 4 h
Yield: 70.3 %

Procedure:
A solution of ethyl 2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (˜1.54 g, 3.76 mmol) in DCM (60 mL) was treated with Dess-Martin periodinane (1.91 g, 4.51 mmol) at 23° C. After 4 h, the orange reaction was slowly added to 10% Na2S2O3 (28 mL) at 23° C. After 5 min of stirring, the reaction was diluted with H2O (40 mL) and extracted with DCM (3×20 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was dissolved in benzene. The solution was wet-loaded onto a 40 g “gold” ISCO silica gel column and purified by flash chromatography (hexane→ethyl acetate/hexanes 1:4) giving the desired product (1.08 g, 70% yield over 2 steps from ethyl 2-tert-butoxy-2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate). 1H NMR (400 MHz, CDCl3) δ 8.16-8.08 (m, 2H), 7.76-7.68 (m, 2H), 4.41 (q, J=7.1 Hz, 2H), 2.39 (d, JHF=3.2 Hz, 3H), 1.40 (t, J=7.1 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−122.3 (app. s, 1F), −73.3 (s, 3F).
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]1=[O:14])(=O)C.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:17]=1[CH:18]=O.C(N(CC)CC)C>CN(C=O)C>[C:11]([N:7]1[CH2:6][C:5](=[O:14])[NH:4]/[C:9](=[CH:18]\[C:17]2[C:16]([Cl:15])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:24])/[C:8]1=[O:10])(=[O:13])[CH3:12]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(=O)N/C(=C\c2c(Cl)cccc2Cl)C1=O
Yield: 40 %

Procedure:
1,4-Diacetyl-2,5-piperazinedione prepared by the published procedure mentioned in Reference Example 3, was stirred in DMF with 2,6-dichlorobenzaldehyde and triethylamine and heated to 120°-130° C. for 1-3 h. The title compound was obtained with a yield of 40%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.Cl[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC#N>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4](=[O:9])[N:3]=1
Reactant: ClCOCc1ccccc1
Reactant: Nc1nc(O)ncc1F
Solvent: CC#N
Product: Nc1nc(=O)n(COCc2ccccc2)cc1F
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 44.9 %

Procedure:
A 25 mL Schlenk-type flask was charged with 4-amino-5-fluoropyrimidin-2-ol (500 mg, 3.87 mmol), CH3CN (10 mL), and BSA (1.42 mL, 5.81 mmol). The resulting white suspension was then heated at 65° C. After 90 min, the clear, colorless solution was cooled to room temperature and benzyl chloromethyl ether (1.07 mL, 7.72 mmol) was added, giving a cloudy white suspension. After stirring for 2 h at room temperature, the reaction mixture was concentrated in vacuo to give a white residue which was purified by reverse phase column chromatography yielding 4-amino-1-(benzyloxymethyl)-5-fluoropyrimidin-2(1H)-one (14; 433 mg, 45%) as a white solid: mp 213-217° C.; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=6.5 Hz, 1H), 7.81 (br s, 1H), 7.56 (br s, 1H), 7.24-7.36 (m, 5H), 5.11 (s, 2H), 4.54 (s, 2H); IR 3302 (s), 3082 (s), 2939 (w), 2869 (w), 1688 (s), 1619 (s), 1522 (s), 1468 (m), 1333 (m), 1131 (w), 1054 (m) cm−1; ESIMS m/z 250 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH2:23])[CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37].N1C=CC=CC=1>ClCCl.CN(C1C=CN=CC=1)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]2[CH:11]=[C:10]([NH:23][S:36]([C:27]3[CH:28]=[CH:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:26]=3)(=[O:38])=[O:37])[CH:9]=[C:8]([O:7][C:6]3[CH:24]=[CH:25][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:13]=2)=[CH:16][CH:17]=1)#[N:22]
Reactant: N#Cc1ccc(Oc2cc(N)cc(Oc3ccc(C#N)cc3)c2)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(Oc2cc(NS(=O)(=O)c3ccc4ccccc4c3)cc(Oc3ccc(C#N)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
[3,5-Bis-(4-cyano-phenoxy)-phenyl]-amine (0.35 g, 1.07 mmol) and 2-naphthyl-sulphonyl chloride (0.29 g, 1.28 mmol) were dissolved in 10 ml of dichloromethane and cooled to 0° C. Further 0.18 ml (2.14 mmol) of pyridine and 15 mg (0.107 mmol) of DMAP was added to the reaction mixture and allowed to stirred overnight at RT. After completion, reaction mixture was diluted with 50 ml of dichloromethane and washed with 50 ml 1N HCl solution and then with brine. Organic layer was dried over anhydrous sodium sulphate and concentrated under vacuo. Thus obtained crude product was subjected to column chromatography and eluted with ethylacetate and hexane mixture to afford 0.4 g of the required product. Percentage purity (LCMS): 90.4% M+1=517.1+1.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>C1COCC1>[CH2:3]([O:4][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:13]#[N:14])[CH:2]([CH3:5])[CH3:1]
Reactant: CC(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)COc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 149.8 %

Procedure:
To a solution of 2-methylpropan-1-ol (9.6 mL, 0.104 mol) in anhydrous THF (200 mL) was added NaH (60% in mineral oil, 4.565 g, 0.114 mol) in small portions at 0° C. under N2. After it was stirred at room temperature for 30 min, the reaction mixture was cooled down to −70 C. and 2,6-dinitrobenzonitrile (20.0 g, 0.104 mol) was added portionwise. After the addition was complete, the reaction mixture was stirred at −70° C.—RT overnight, then poured into ice water (600 mL). The resultant precipitate was collected by filtration and rinsed with water, hexane, and air dried to provide 2-isobutoxy-6-nitrobenzonitrile as a light yellow solid (34.3 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 1.0 (d, J=6.8 Hz, 6H), 2.04-2.11 (m, 1H), 4.02 (d, J=6.8 Hz, 2H), 7.69-7.71 (m, 1H), 7.84-7.90 (m, 2H). MS 221 (MH+).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.CN1CCOCC1>[Cu].[Cu]Cl.CN(C)C(=O)C>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: Nc1ccc(F)cc1
Agent: Cl[Cu]
Agent: [Cu]
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Nc1ccc(F)cc1
Temperature: 115 °C
Reaction time: 10 h

Procedure:
To N,N-dimethylacetamide 150 mL solution of 2-chloro-4-nitrobenzoic acid 30 g, were added 4-fluoroaniline 29 mL, copper powder 2.8 g, copper (I) chloride 5.3 g and N-methylmorpholine 33 mL at room temperature, and it was stirred at 110 to 120° C. for 10 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and 1.0 mol/L hydrochloric acid 700 mL and ethyl acetate 700 mL were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue, solid matter was filtrated to give 2-(4-fluoroanilino)-4-nitrobenzoic acid 9.7 g of red solid.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:26])[CH:17]([NH:18][C:19](=[O:25])[CH2:20][C:21](=[O:24])[CH2:22][Br:23])[C@H:4]2[S:3]1.O.[N:28]([O-])=[O:29].[Na+]>C(O)(=O)C.O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:13])([Cl:15])[Cl:14])=[O:9])[N:5]2[C:16](=[O:26])[CH:17]([NH:18][C:19](=[O:25])[C:20](=[N:28][OH:29])[C:21](=[O:24])[CH2:22][Br:23])[C@H:4]2[S:3]1
Reactant: O=N[O-]
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2S1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]2S1

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-7-(3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (2.54 g.) in glacial acetic acid (25 ml.) was added dropwise a solution of sodium nitrite hydrate (0.33 g.) in water (1 ml.) over 3 minutes with stirring at 10° to 15° C., and then the mixture was stirred for 1 hour at the same temperature. After the reaction mixture was poured into cold water (70 ml.), the precipitates were collected by filtration and then dried to give brown powder of 2,2,2-trichloroethyl 2-methyl-7-(2-hydroxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (a mixture of syn and anti isomers) (2.0 g.), mp 76° to 80° C. (dec.).