Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[NH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1)[NH2:7].Cl>O>[N:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]([CH3:21])[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:12][CH:13]=1)=[N+:7]=[N-:1]
Reactant: O=N[O-]
Reactant: CC1NC(=O)NN=C1c1ccc(NN)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(N=[N+]=[N-])cc1
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of sodium nitrite (0.3 g) in water (2 ml) was added dropwise to a solution of 6-(4-hydrazinophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one hydrochloride (0.92 g) in a mixture of 1N-hydrochloric acid (3 ml) and water (20 ml) under ice cooling. After stirring for 30 minutes, the resultant precipitates were collected by filtration and washed successively with water, methanol and diisopropyl ether to give 0.56 g of 6-(4-azidophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[N:15]1([CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2ccnc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cn(CC2CCNCC2)cn1

Procedure:
The title compound(0.187 g, 0.705 mmoles) from Step C was stirred in 4N HCl in dioxane (20 mL) for 2 h and then evaporated to dryness to give the title compound which was used to couple with the tricyclic acid.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@@H:13]2[C@@H:17]3[CH2:18][CH2:19][CH2:20][C@@H:21]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([CH2:40][CH2:41][C:42]([NH:44][NH2:45])=[O:43])[CH:33]=4)[N:16]3[C:15](=[O:46])[O:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[C:58](Cl)(Cl)=[O:59]>C(Cl)Cl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@@H:13]2[C@@H:17]3[CH2:18][CH2:19][CH2:20][C@@H:21]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[CH:33]=[C:34]([CH2:40][CH2:41][C:42]5[O:43][C:58](=[O:59])[NH:45][N:44]=5)[CH:35]=[CH:36][C:37]=4[O:38][CH3:39])[N:16]3[C:15](=[O:46])[O:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:47])[F:48])[CH:8]=1
Reactant: COc1ccc(CCC(=O)NN)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CCC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCc2n[nH]c(=O)o2)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CCC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46600 %

Procedure:
To 3-[2′-{(1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-5-yl}-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]propanehydrazide (10 mg, 0.015 mmol) in DCM (2 mL) was added DIPEA (5.6 mg, 0.044 mmol) and phosgene (4.30 mg, 0.44 mmol). The reaction was stirred at room temperature for 30 minutes before the reaction was directly purified by column chromatography to yield (1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2′-methoxy-5′-[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl]-4-(trifluoromethyl)biphenyl-2-yl}hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one (5 mg, 6.99 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 3:1 ratio: 1H NMR (500 MHz, CDCl3) δ9.23 (s, 1H), 7.88 (s, 1H), 7.80 (s, 2H), 7.79 (s, 1H, minor rotamer), 7.65 (s, 2H, major rotamer) 7.62 (m, 1H) 7.4 (d, J=7.8 Hz, 1H, major rotamer), 7.25 (d, J=7.8 Hz, 1H, minor rotamer), 7.09 (s, 1H), 7.02 (m, 2H), 5.58 (m, 1H, minor rotamer) 5.42 (m, 1H, major rotamer), 4.19 (m, 1H), 3.85 (s, 3H, minor rotamer), 3.80 (s, 3H, major rotamer), 3.0-2.85 (m, 4H), 1.98 (m, 2H), 1.5-1.6 (m, 4H). MS ESI calc'd. for C33H27F9N3O5 [M+H]+ 716.2. found 716.3. RTA (95% HS): 942 nM
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])C(O)=O.CN(C)C=O>ClCCl>[Cl:7][C:8]1[CH:9]=[C:1]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]([F:20])([F:21])[F:22])[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1ccc(OCC(F)(F)F)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.9 %

Procedure:
Oxalyl chloride (0.053 ml, 0.6 mmol) was added to a stirred solution of the 3-chloro-4-[(2,2,2-trifluoroethyl)oxy]benzoic acid (D20; 76 mg, 0.30 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at 0° under nitrogen and the mixture was allowed to warm to room temperature with stirring overnight. The solvent was evaporated to give the title compound as a yellow solid (ca 90 mg) which was used crude in the next reaction (D48).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12](O)=O)[C:2]([CH3:4])=[O:3].[NH2:15][C:16]1[C:17](=[O:35])[N:18]([CH2:32][CH2:33][CH3:34])[C:19](=[O:31])[N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]=1[NH2:22]>>[NH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[NH:15][C:16]2[C:17](=[O:35])[N:18]([CH2:32][CH2:33][CH3:34])[C:19](=[O:31])[N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:21]=2[N:22]=1)[C:2]([CH3:4])=[O:3]
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccccc2)c1=O
Reactant: CC(=O)Nc1ccccc1CC(=O)O
Product: CCCn1c(=O)c2[nH]c(Cc3ccccc3NC(C)=O)nc2n(CCc2ccccc2)c1=O

Procedure:
By the method of Example 2, 2-(acetamino)phenylacetic acid is reacted with 5,6-diamino-1-(2-phenylethyl)-3-propyluracil to yield 8-(2-acetaminobenzyl)-3-(2-phenylethyl)-1-propylxanthine. By methods well known in the art, 8-(2-acetaminobenzyl)-3-(2-phenylethyl)-1-propylxanthine is hydrolyzed with base to yield 8-(2-aminobenzyl)-3-(2-phenylethyl)-1-propylxanthine. In turn, 5,6-diamino-1-(2-(phenylethyl)-3-propyluracil is made by the synthetic methods of Example 1, starting with phenethylamine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([O:24][C:25]1[CH:34]=[CH:33][C:32](Cl)=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])([CH3:23])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Ni].ClC1C=C[C-](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.C1(P([C-]2C=CC=C2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Fe+2]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:32]2[CH:31]=[C:26]([C:25]([O:24][CH:21]([CH3:23])[CH3:22])=[CH:34][CH:33]=2)[C:27]([O:29][CH3:30])=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)ccc1OC(C)C
Reactant: COc1ccc(B(O)O)cc1CNC(=O)OC(C)(C)C
Agent: [Fe+2]
Agent: [Ni]
Agent: Clc1cc[c-]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(OC)c(CNC(=O)OC(C)(C)C)c2)ccc1OC(C)C
Temperature: 95 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
230 mg of 3-{[(t-Butoxycarbonyl)amino]methyl}-4-methoxyphenylboronic acid, 197 mg of methyl 2-isopropoxy-5-chlorobenzoate, 30 mg of dichlorobistriphenylphosphinoferrocene nickel and 570 mg of potassium phosphate were dissolved in dioxane, and the mixture was stirred overnight at 95° C. in a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified by a silica gel column, to give 194 mg of the title compound in the 5:1 hexane-ethyl acetate fraction.
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[N+](=[CH2:21])=[N-]>>[CH3:21][O:13][C:12](=[O:14])[CH2:11][CH2:10][C:9](=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([OH:1])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(O)CCCCCCC(=O)CCC(=O)O
Reactant: C=[N+]=[N-]
Product: CCCC(O)CCCCCCC(=O)CCC(=O)OC

Procedure:
In order to determine the stereochemistry at the 11-position, 1 was hydrolyzed first with base and then with acid to yield 11-hydroxy-4-oxo-tetradecanoic acid (8). The long chain fatty acid (8) was reacted with excess diazomethane to furnish 11-hydroxy-4-oxo-tetradecanoic acid methyl ester (9). Compound 9 was converted to the two Mosher esters 10 and 11 with (R)- and (S)-methoxyphenylacetic acid (MPA), using the EDCI/DMAP coupling conditions. (Seco, J. M.; Quinoa, E.; Riguera, R., Tetrahedron: Asymmetry 2001, 12, 2915-2925.) The resulting 11-MPA esters 10 and 11 were subjected to NMR analysis. The chemical shift differences ΔδRS were significant (Scheme 1), which made it possible to conclude that 1 had the (S)-configuration at C-11. The sugars were determined as D-glucose and D-fucose by hydrolysis and determination of the sign of rotation of the isolated carbohydrates. This conclusion was supported by MM2 calculations, which indicated that only the diastereomer with both D-sugars would give the relatively strong ROESY correlations between H-11 and H—F-1 and between H—F-2 and H-G-1 that were exhibited in the spectrum of 1.
Reaction SMILES: COC1C=C2C(=CC=1OC)C(=O)CC2.Cl.[N+](C1C=CC(CNO)=CC=1)([O-])=O.N1C=CC=CC=1.[N+:34]([C:37]1[CH:59]=[CH:58][C:40]([CH2:41][O:42]/[N:43]=[C:44]2\[CH2:45]C[CH2:47][C:48]3[C:53]\2=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH3:57])[CH:49]=3)=[CH:39][CH:38]=1)([O-:36])=[O:35]>C(O)C.C(OCC)(=O)C.CCCCCC>[N+:34]([C:37]1[CH:59]=[CH:58][C:40]([CH2:41][O:42]/[N:43]=[C:44]2\[CH2:45][CH2:47][C:48]3[C:53]\2=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH3:57])[CH:49]=3)=[CH:39][CH:38]=1)([O-:36])=[O:35]
Reactant: COc1cc2c(cc1OC)/C(=N/OCc1ccc([N+](=O)[O-])cc1)CCC2
Agent: COc1cc2c(cc1OC)C(=O)CC2
Agent: Cl
Agent: O=[N+]([O-])c1ccc(CNO)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cc2c(cc1OC)/C(=N/OCc1ccc([N+](=O)[O-])cc1)CC2
Yield: 53 %

Procedure:
5,6-Dimethoxy-1-indanone (104 mg, 0.54 mmol) was subjected to reaction with (4-nitrobenzyl)hydroxylamine hydrochloride (125 mg, 0.61 mmol) in ethanol (5 mL) and pyridine (0.7 mL, 9.03 mmol) under the same conditions as described for (E)-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one O-4-nitrobenzyl oxime. Subjection of the material obtained on work up to flash chromatography (3:7 v/v ethyl acetate/hexane elution) afforded a ca. 3:1 mixture of the E- and Z-isomeric forms of the title compound (98 mg, 53%) as a pale-yellow crystalline solid, m.p. 139-144° C., Rf 0.3.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH:11]1[CH2:13][CH2:12]1)=[N+:2]=[N-:3].O=[C:15]([CH3:21])[CH2:16][C:17]([O:19]C)=[O:18].C[O-].[Na+]>CO.O>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([N:1]2[C:15]([CH3:21])=[C:16]([C:17]([OH:19])=[O:18])[N:3]=[N:2]2)=[C:5]([CH:11]2[CH2:13][CH2:12]2)[CH:6]=1
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1C1CC1
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)nnn1-c1ccc(Cl)cc1C1CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1-azido-4-chloro-2-cyclopropylbenzene (204 mg, 1.054 mmol) and methyl 3-oxobutanoate (0.341 ml, 3.16 mmol) in MeOH (2 ml) was added sodium methoxide (5M in MeOH) (1.264 ml, 6.32 mmol) dropwise and the mixture was stirred at RT for 2.5 h. The mixture was heated at 50° C. for 5 hrs and then left to stir at RT for 16 hrs. The resulting mixture was diluted with water, extracted with diethylether (×2) and the organic extracts were discarded. To the aqueous layer was added 6M HCl (aq) until acidic and this was extracted with diethyl ether. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as an orange oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[C:11]([Cl:24])=[CH:10][C:9]=1[F:25])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Ca+2].[Cl-].C(O)C.O>CN1CCCC1=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=2)[C:11]([Cl:24])=[CH:10][C:9]=1[F:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cn2)c(Cl)cc1F
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cn2)c(Cl)cc1F
Yield: 57.2 %

Procedure:
A mixture of tert-butyl{4-chloro-2-fluoro-5-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (4.66 g, 12.1 mmol), reduced iron (61.2 mmol), calcium chloride (680 mg, 6.13 mmol) and ethanol (90 mL)/water (10 mL)/1-methyl-2-pyrrolidone (40 mL) was stirred with heating under reflux for 5 hr. Reduced iron (5.00 g, 89.5 mmol) and calcium chloride (700 mg, 6.31 mmol) were further added, and the mixture was stirred with heating under reflux for 16 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 mL), and washed with water (100 mL×2) and saturated brine (50 mL). The obtained organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=90/10→10/90) to give the title compound (2.45 g, 57%) as a yellow powder.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:20](=[O:32])[N:19]2[CH3:33])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[CH3:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[CH3:30])[CH2:23][N:21]1[CH2:22][CH:18]([CH2:17][CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:34])=[O:3])=[CH:14][CH:13]=2)[N:19]([CH3:33])[C:20]1=[O:32]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(C)c(C)c3)C(=O)N2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(CN2CC(CCOc3ccc(OC(C)(C)C(=O)O)cc3)N(C)C2=O)cc1C
Yield: 54.3 %

Procedure:
A solution of 2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.098 g, 0.209 mmol) in ethanol (8 mL) was treated with aqueous 5 N NaOH (0.5 mL) and heated to reflux 1 h. The reaction mixture was cooled, the solvent removed in vacuo. The resultant residue was acidified with aqueous 1 N HCl (5 mL) and extracted with Et2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford 0.050 g (54%) 2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. HRMS (ES+) m/z exact mass calcd for C25H33N2O5 [M+1] 4.41.2389, found 441.2390. 1H NMR.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:7][CH2:6][C:5]([CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[N+:27]([O-:29])=[O:28])([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][O:3]1.C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[F-:57].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:1][C:2]1([CH3:30])[O:7][CH2:6][C:5]([CH2:8][F:57])([CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[N+:27]([O-:29])=[O:28])[CH2:4][O:3]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(CCn3ccnc3[N+](=O)[O-])COC(C)(C)OC2)cc1
Reactant: [F-]
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)OCC(CF)(CCn2ccnc2[N+](=O)[O-])CO1

Procedure:
5 mg (11.4 μmol equivalents) of 2,2-dimethyl-5-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane was dissolved in 1 mL of acetonitrile, 14 mg (34.5 μmol equivalents) of Kryptofix 222 (trade name, Merck), 0.82 g (14.1 μmol equivalents) of potassium fluoride, and 0.4 mg (2.9 μmol equivalents) of potassium carbonate were added thereto, and the mixture was refluxed while heating for 5 hours. After completion of the reaction, water was added and the mixture was extracted three times with chloroform. The combined chloroform layers were dried with anhydrous magnesium sulfate and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography to give a trace amount of 2,2-dimethyl-5-fluoromethyl-5-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-1,3-dioxane.
Reaction SMILES: [F:1][C:2]([F:18])([C:6]([F:17])([F:16])[C:7]([F:15])([F:14])[O:8][C:9]([F:13])=[C:10]([F:12])[F:11])[C:3](O)=[O:4].O=S(Cl)[Cl:21].Cl>N1C=CC=CC=1>[F:1][C:2]([F:18])([C:6]([F:17])([F:16])[C:7]([F:15])([F:14])[O:8][C:9]([F:13])=[C:10]([F:12])[F:11])[C:3]([Cl:21])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)OC(F)=C(F)F
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)OC(F)=C(F)F
Yield: 80 %

Procedure:
(2') A mixture of 23 g of perfluoro(4-vinyloxybutyric acid), excess amount of SOCl2 and 0.5 ml of pyridine was refluxed until generation of gaseous HCl was discontinued and distilled in a distillation apparatus with a Vigreaux column, whereby 24 g of perfluoro(4-vinyloxybutyric acid) chloride was obtained as a fraction having a boiling point of 97.5°-100° C. (yield: 80%).
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[CH3:31][C:32]1[O:36][C:35]([C:37]([NH:39][NH2:40])=O)=[CH:34][CH:33]=1>ClCCl>[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:37]([C:35]3[O:36][C:32]([CH3:31])=[CH:33][CH:34]=3)=[N:39][N:40]=[C:26]2[CH2:25]1)=[O:23]
Reactant: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Reactant: Cc1ccc(C(=O)NN)o1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2nnc3n2CCN(C(=O)c2ccc(F)c(Cl)c2Cl)C3)o1
Reaction time: 1 h

Procedure:
Triethyloxonium tetrafluoroborate (197 mg, 1.039 mmol) was added to a solution of the 4-[(2,3-dichloro-4-fluorophenyl)carbonyl]-2-piperazinone (I34) (275 mg, 0.945 mmol) in Dichloromethane (DCM) (6 mL) and the reaction was stirred for 1 h. To this was added the 5-methyl-2-furancarbohydrazide (I85) (159 mg, 1.134 mmol) and the reaction was stirred for 2 h. The solvent was evaporated and 1-butanol (6.00 mL) was added. The mixture was heated at reflux for 3 h. LCMS: Product peak observed. After cooling the solvent was evaporated and the residue was partitioned between water/EtOAc. The organic layer was dried (Na2SO4) and the solvent evaporated to afford a brown oil. This was purified by MDAP to afford a colourless solid of desired material in 38 mg.
Reaction SMILES: BrC(C(OCC)=O)C(OCC)=O.COC1C=C([O-])C=CC=1.[Na+].COC1C=C(C=CC=1)OC(C(OCC)=O)C(OCC)=O.COC1C=C(C=CC=1)OC1C(=O)NC=NC=1O.Cl[C:61]1[C:66]([O:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([O:74][CH3:75])[CH:69]=2)=[C:65]([Cl:76])[N:64]=[CH:63][N:62]=1.[K].[C:78]([C:82]1[CH:87]=[CH:86][C:85]([S:88]([NH2:91])(=[O:90])=[O:89])=[CH:84][CH:83]=1)([CH3:81])([CH3:80])[CH3:79]>CO>[C:78]([C:82]1[CH:87]=[CH:86][C:85]([S:88]([NH:91][C:61]2[C:66]([O:67][C:68]3[CH:73]=[CH:72][CH:71]=[C:70]([O:74][CH3:75])[CH:69]=3)=[C:65]([Cl:76])[N:64]=[CH:63][N:62]=2)(=[O:89])=[O:90])=[CH:84][CH:83]=1)([CH3:81])([CH3:79])[CH3:80]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cccc(Oc2c(Cl)ncnc2Cl)c1
Agent: CCOC(=O)C(Br)C(=O)OCC
Agent: CCOC(=O)C(Oc1cccc(OC)c1)C(=O)OCC
Agent: COc1cccc(Oc2c(O)nc[nH]c2=O)c1
Solvent: CO
Product: COc1cccc(Oc2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
Diethyl bromomalonate was converted with sodium m-methoxyphenolate in analogy to Example 1, paragraph c), into diethyl (m-methoxyphenoxy)malonate, colorless liquid. B.p. 143° C./0.05 Torr. The thus-obtained malonic ester was converted in analogy to Example 1, paragraph d), into 5-(m-methoxyphenoxy)-6-hydroxy-4(3H)-pyrimidinone from which in analogy to Example 1, paragraph e), there was prepared 4,6-dichloro-5-(m-methoxyphenoxy)pyrimidine, m.p. 109°-110° C. Reaction of the last-named compound with p-t-butylbenzenesulfonamide potassium yielded p-t-butyl-N-[6-chloro-5-(m-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide, m.p. 152° C. (from methanol).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][S:9][C@@H:8]([CH2:11][S:12][CH3:13])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>CO>[C:4]([C@@H:6]1[CH2:10][S:9][C@@H:8]([CH2:11][S:12][CH3:13])[CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@@H]1CS[C@@H](CSC)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSC[C@H]1C[C@H](C(=O)O)CS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of trans-4-ethoxycarbonyl-2-methylthiomethyltetrahydrothiophene (compound No. 18-1, 307 mg) in methanol (10 ml), 1N sodium hydroxide solution (2.8 ml) was added under nitrogen atmosphere and the mixture was stirred for 1 hour at room temperature. The mixture was acidified with 1N hydrochloric acid and concentrated in vacuo. Saturated aqueous sodium chloride solution was added to the aqueous residue and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 260 mg (85%) of the titled compound (compound No. 19-1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Sn](CCCC)(CCCC)CCCC)=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)(O)[O-].[Na+].[F:39]C(F)(F)S([O-])(=O)=O.[Na+].F[P-](F)(F)(F)(F)F.F[P-](F)(F)(F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CC(C)=O.[Ag]=O>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:39])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: O=[Ag]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)=O
Product: COC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
To N-Boc-4-(Tributylstannyl)-L-phenylalanine Methyl Ester (56.9 mg, 0.100 mmol, 1.00 equiv) in acetone (2.0 mL) at 23° C. was added silver oxide (1.16 mg, 0.00500 mmol, 0.05 equiv), sodium bicarbonate (16.8 mg, 0.200 mmol, 2.00 equiv), sodium trifluoromethanesulfonate (17.2 mg, 0.100 mmol, 1.00 equiv) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (2) (70.5 mg, 0.150 mmol, 1.50 equiv). The reaction mixture was stirred for 5 h at 65° C. in a sealed vial, then cooled to 23° C. and concentrated in vacuo. The residue was purified by preparative TLC with hexane/EtOAc 5:1 (v/v) to afford 25.2 mg of the title compound as a white solid (85% yield).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:12](OCC)(=O)[CH2:13][CH2:14]C.[O-]CC.[Na+]>O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([CH2:12][CH2:13][CH3:14])=[O:9])[CH:3]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: CCCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCCC(=O)c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of ethyl nicotinate (15.1 g, 0.1 mole), ethyl butyrate (17.4 g, 0.15 mole) and sodium ethoxide (10.2 g, 0.15 mole) was stirred and heated under nitrogen at 100° C. for five hours. After cooling, the mixture was diluted with water (150 ml), extracted with diethyl ether (50 ml) and the aqueous layer made acidic to pH1 with concentrated hydrochloric acid (50 ml). The aqueous layer was heated at 90° C. for 2 hours, cooled, and made alkaline with solid potassium carbonate and extracted with diethyl ether (3×75 ml). The dried (magnesium sulphate) organic layer was concentrated and distilled to give propyl 3-pyridyl ketone (b.pt. 118°-120° C./14 mm Hg).