Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([Cl:18])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Nitrophenyl)propanoic acid prepared in Example DD (12.5 g, 64 mmol) was suspended in CH2Cl2 (300 mL) and treated with oxalyl chloride (7.4 mL, 85 mmol) and DMF (5 drops). The solution was stirred overnight at room temperature. The solution was concentrated, and the residue was dissolved in CH2Cl2 and re-concentrated. The crude product was used as is in the next step.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C=O)C.[C:14]1([CH2:20][CH2:21][CH:22]=[N:23][OH:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C>O>[C:14]1([CH2:20][CH2:21][C:22]([Cl:1])=[N:23][OH:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ON=CCCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: ON=C(Cl)CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N-chlorosuccinimide (2.24 g, 16.6 mmol) in abs. DMF (11 ml) was added to a solution of compound Z (2.06 g, 13.8 mmol) in abs. DMF (10 ml) at a temperature of 30-40° C. within 20 min. Cooling in an ice bath was carried out if necessary. The reaction mixture was stirred for 3 h at RT and then mixed with diethyl ether (120 ml) and water (80 ml). The phases were separated. The aqueous phase was extracted with diethyl ether (2×50 ml). The combined organic extracts were washed successively with water (80 ml) and sat. NaCl solution (100 ml). The organic phase was dried and concentrated. 3-phenyl propanehydroximoyl chloride was obtained as a light green oil (2.47 g) and immediately reacted further.
Reaction SMILES: [F:1][C:2]([F:27])([C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:15][CH:14]=1)=O)[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:28][C:29]([S:32]([NH2:34])=[O:33])([CH3:31])[CH3:30]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[F:1][C:2]([F:27])([C:3](=[O:4])[N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:11](=[N:34][S:32]([C:29]([CH3:31])([CH3:30])[CH3:28])=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:15][CH:14]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=C(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)C(=O)N1CCCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N=C(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a solution of Intermediate 103B (1.97 g, 5.01 mmol) and 2-methylpropane-2-sulfinamide (1.821 g, 15.02 mmol) in anhydrous THF (25.04 mL) was added Ti(OEt)4 (5.19 mL, 25.04 mmol). The reaction was heated at refluxed temperature overnight. The reaction was cooled to rt, poured into brine, diluted with EtOAc, and stirred for 30 min. The titanium oxide was removed by filtering through a plug of Celite®. The filtrate layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (80 g silica gel, eluted with EtOAc in hexanes to yield the desired product (1.62 g, 59%) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J=8.80 Hz, 2H), 6.95 (d, J=9.08 Hz, 2H), 4.07 (t, J=6.05 Hz, 2H), 3.62-3.69 (m, 1H), 3.52-3.58 (m, 1H), 3.39 (t, J=5.09 Hz, 2H), 2.26-2.37 (m, 2H), 2.05-2.11 (m, 2H), 1.53-1.70 (m, 7H), 1.25 (s, 9H).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH3:18])[C:6]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)=[O:7])[CH2:2][CH3:3].[CH3:19][C@@H:20]([CH2:32][CH3:33])[CH2:21][O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)=[O:24].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:4][C@@H:5]([CH3:18])[C:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:28]2[CH:29]=[CH:30][C:25]([C:23]([O:22][CH2:21][C@@H:20]([CH3:19])[CH2:32][CH3:33])=[O:24])=[CH:26][CH:27]=2)=[O:14])=[CH:16][CH:17]=1)=[O:7])[CH2:2][CH3:3]
Reactant: CCCO[C@@H](C)C(=O)Oc1ccc(C(=O)O)cc1
Reactant: CC[C@H](C)COC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCO[C@@H](C)C(=O)Oc1ccc(C(=O)Oc2ccc(C(=O)OC[C@@H](C)CC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
In 12 ml of methylene chloride were dissolved 107 mg of 4-[2-(S)-propoxypropanoyloxy]benzoic acid, 95 mg of 4-[(S)-2-methyl butoxycarbonyl]phenol, and 140 mg of dicyclohexylcarbodiimide, and a catalytic amount of 4-dimethylaminopyridine was added to the solution, followed by stirring at room temperature. After 5 hours, diethyl ether was added to the reaction mixture, and any insoluble matter was removed by filtration. The filtrate was washed successively with a 10% hydrochloric acid aqueous solution, a saturated sodium bicarbonate aqueous solution, water, and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. The solvent was removed from the residue by distillation, and the resulting oily substance was purified by silica gel column chromatography to obtain 139 mg of the entitled compound as a transparent oily substance. This compound did not crystalize even when allowed to stand at room temperature or less for a long time. The structure of the compound was confirmed by NMR and IR spectra.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[NH:3]1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C.C([O:57][C:58](=[O:79])[C@H:59]([OH:78])[CH2:60][N:61]([CH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[CH:75]=[C:74]([Cl:76])[CH:73]=[CH:72][C:71]=2[F:77])=[CH:66][CH:65]=1)[NH2:62])C.CCO.[Li+].[OH-].O>>[Cl:76][C:74]1[CH:73]=[CH:72][C:71]([F:77])=[C:70]([C:67]2[CH:68]=[CH:69][C:64]([CH2:63][N:61]([CH2:60][C@@H:59]([OH:78])[C:58]([OH:79])=[O:57])[NH:62][C:13]([C:4]3[NH:3][C:2](=[O:1])[N:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:5]=3)=[O:15])=[CH:65][CH:66]=2)[CH:75]=1
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: O=C(O)c1nn(-c2ccccc2)c(=O)[nH]1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
5-Oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic acid (56.4 mg, 275 μmol) was combined with HCTU (154 mg, 371 μmol) in DMF (852 μL, 11 mmol) and stirred for 15 minutes at room temperature. DIPEA (72 μL, 413 μmol) and (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (50 mg, 0.1 mmol) were added, and the resulting mixture was stirred overnight at room temperature. EtOH (402 μL, 6.9 mmol) and 1 M LiOH in water (1.1 mL, 1.1 mmol) were added and the resulting mixture was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure and the residue was purified by preparative HPLC to yield the title compound (39.8 mg, purity 100%). MS m/z [M+H]+ calc'd for C25H21ClFN5O5, 526.12. found 526.0.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:15][C:11]1[CH:10]=[C:9]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: BrBr
Reactant: Cc1cccc(C(=O)c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To a 1000 mL RB flask fitted with magnetic stirrer, was charged with 375 mL of CCl4. The solvent was cooled to 0° C. and to the stirred solvent was added phenyl-m-tolyl-methanone (15.0 g, 76.45 mmol) followed by the addition of bromine (24.43 g, 152.9 mmol) at 0° C. and the mixture was allowed to stir at the same temperature for 30 minutes. The resulting solution was refluxed at 80° C. for 24 h. After completion of the reaction (reaction monitored by TLC), RM was cooled to 10° C. and quenched with the addition of solid sodium bicarbonate (15 g, 178.57 mmol). The organic layer was washed with saturated sodium bicarbonate solution (300 mL×2) and saturated brine solution (300 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to get the product as a white solid (6.8 g, Yield: 32.3%): 1H NMR (300 MHz, CDCl3): δ 7.74-7.76 (m, 2H), 7.71-7.72 (t, 2H), 7.51-7.67 (m, 2H), 7.40-7.45 (m, 3H), 4.46 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][N:6]=[C:5]([C:11]#[N:12])[CH:4]=1.[CH3:13][Si:14]([CH3:30])([CH3:29])[CH2:15][CH2:16][O:17][CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C:20]1=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)C>CN(C=O)C>[O:28]=[C:20]1[N:19]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:30])([CH3:29])[CH3:13])[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]21[CH2:9][C:8]1[CH:7]=[N:6][C:5]([C:11]#[N:12])=[CH:4][C:3]=1[CH2:2]2
Reactant: N#Cc1cc(CBr)c(CBr)cn1
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cnc(C#N)cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 4,5-bis(bromomethyl)pyridine-2-carbonitrile from Step B (729 mg, 2.52 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (665 mg, 2.52 mmol, described in Intermediate 1) in DMF (75 mL) was added cesium carbonate (2.46 g, 7.55 mmol), portionwise, over 5 min. After 2 h, acetic acid (0.15 mL) was added and the mixture was concentrated to a volume of about 25 mL, then partitioned between CHCl3 (100 mL), saturated aqueous NaHCO3 (30 mL) and brine (50 mL). The organic layer was removed and the aqueous layer was extracted further with CHCl3 (100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=393 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:31]2[CH2:30][CH2:29][N:28]([CH2:27][C:26]3[CH:34]=[CH:35][C:23]([F:22])=[CH:24][CH:25]=3)[CH2:33][CH2:32]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: Fc1ccc(CN2CCNCC2)cc1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(Cc5ccc(F)cc5)CC4)cc3nc21
Yield: 57.8 %

Procedure:
7-Fluoro-8-[4-(4-fluorobenzyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 2, but from 1.6 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 5 g of 4-(4-fluorobenzyl)piperazine in 16 cm3 of pyridine. After recrystallizing twice from 25 cm3 of dimethylformamide on each occasion, 1.4 g of 7-fluoro-8-[4-(4-fluorobenzyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 311° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]([C:14]([F:17])([F:16])[F:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.O[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:8]1([C:6]2[CH:7]=[C:3]([CH2:2][O:1][C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)[S:4][C:5]=2[C:14]([F:17])([F:15])[F:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCc1cc(-c2ccccc2)c(C(F)(F)F)s1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2cc(-c3ccccc3)c(C(F)(F)F)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of 1.95 g (7.5 mmol) of 2-hydroxymethyl-4-phenyl-5-trifluoromethyl-thiophene (from Step A), 925 mg (7.6 mmol) of 4-hydroxybenzaldehyde and 3.0 g (11.4 mmol) of triphenylphosphene in 40 mL of THF at 0° C. was treated with 2.0 g (11.4 mmol) of diethylazodicarboxylate. The resulting mixture was warmed to rt, stirred for 2 h, then concentrated. Chromatography on a Biotage 75S cartridge using 9:1 v/v heptane/EtOAc as the eluant afforded 2.5 g of impure title compound. Chromatography on a Biotage 40M cartridge using 19:1 v/v hexanes/EtOAc (1L), then 4:1 v/v hexanes/EtOAc (1L) as the eluant afforded 1.65 g (60%) of the title compound: 1H NMR (500 Mhz) δ 5.32 (s, 2H), 7.10 (d, J=8.5, 2H), 7.12 (s, 1H), 7.41-7.43 (5H), 7.85-7.90 (2H), 9.92 (s, 1H).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24]O)[CH:19]=[CH:20][CH:21]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][N:26]4[CH:30]=[N:29][CH:28]=[N:27]4)[CH:19]=[CH:20][CH:21]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCc1cccc(OCc2coc(/C=C/c3ccccc3)n2)c1
Reactant: c1nc[nH]n1
Product: C(=C/c1nc(COc2cccc(CCCn3cncn3)c2)co1)\c1ccccc1
Yield: 61 %

Procedure:
In substantially the same manner as in Working Example 1, 3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol was allowed to react with 1,2,4-triazole to give 1-[3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazole. The yield was 61%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 59-60° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[C:10]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:6]=1[F:16])[CH3:2].[OH:18]OS([O-])=O.[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CO.O>[CH3:14][C:12]([S:11]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:16])[C:5]=1[C:4]([NH:3][CH2:1][CH3:2])=[O:17])=[O:18])([CH3:13])[CH3:15]
Reactant: O=S([O-])OO
Reactant: CCNC(=O)c1c(F)cccc1SC(C)(C)C
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCNC(=O)c1c(F)cccc1S(=O)C(C)(C)C
Reaction time: 0.03 h
Yield: 60 %

Procedure:
A 0° C. solution of N-ethyl-2-fluoro-6-(1,1-dimethylethylthio)benzamide (3.45 g, 13.51 mmol) in methanol (100mL) was combined with a 0° C. solution of OXONE® (8.31 g, 13.51 mmol) in water (100 mL). This mixture was stirred for 2 min, then was poured into 25% aq sodium metabisulfite (100 mL) and extracted with ether (3×100 mL). The combined organics were washed with brine followed with water, then was dried (MgSO4), concentrated, and recrystallized from ethyl acetate—hexanes to afford 2.2 g of the title compound as a white solid, a 60% yield. m.p. 114-116° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[S:19].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O1CCOCC1.O>[CH3:16][N:17]([CH3:21])[C:18]([O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)=[S:19]
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: CN(C)C(=S)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C(=S)Oc1cc(CC(=O)O)cc(C(F)(F)F)c1

Procedure:
The product from example 25 step (iv) (0.5 g), dimethylthiocarbamoyl chloride (0.32 ml), DMAP (0.026 g) and triethylamine (0.60 ml) in dry dioxane (10 ml) were stirred at 100° C. for 15 h. The mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was purified by flash column chromatography (eluent ether) to give the subtitle compound (0.52 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[O:12][C:13]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N:14][N:15]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:21]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[O:12][C:13]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)=[N:14][N:15]=3)=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cccc(Br)n1
Product: O=C(Nc1nnc(-c2ccco2)o1)c1cccc(-c2ccc(-c3ccccc3)cc2)n1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 6-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-2-pyridinecarboxamide prepared in Reference Example 11 instead of compound Ia-50 and using commercially available 4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]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.[CH3:64][N:65]([CH3:71])[CH:66]1[CH2:70][CH2:69][NH:68][CH2:67]1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28]([N:68]5[CH2:69][CH2:70][C@H:66]([N:65]([CH3:71])[CH3:64])[CH2:67]5)=[O:29])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CN(C)C1CCNC1
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)c2ccc3c(c2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a stirred solution of 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid (70 mg; 0.16 mmol) in DMF (5 ml) was added HATU (103 mg; 0.27 mmol), DIPEA (50 μl; 0.27 mmol) and (S)-(+3-(dimethylamino)pyrrolidine (50 μl; 0.38 mmol). The reaction mixture was stirred at r.t. for 4 h upon which time it was diluted with EtOAc (20 ml) and washed successively with satd. NaHCO3 (20 ml) and brine (2×20 ml). The organic layer was dried (Na2SO4), concentrated and purified by prep. LCMS to give 420 as an off-white solid (50 mg; 58%). δH (400 MHz, CDCl3) 1.77-1.92 (br m, 1H), 2.06-2.17 (m, 1H), 2.24 (br s, 3H), 2.35 (br s, 3H), 2.60-2.83 (m, 1H), 3.16 (br s, 2H), 3.29-3.98 (m, 4H), 4.33 (br s, 2H), 6.94-7.20 (m, 4H), 7.32-7.39 (m, 1H), 7.50-7.60 (m, 1H), 7.77 (s, 1H), 8.11 (s, [M+H]+: 522
Reaction SMILES: CO.II.CC(C)([O-])C.[Na+].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].C[O-].[Na+].[C:22]([NH:25][CH:26]1[CH:31]([CH:32]([OH:37])[CH:33]([OH:36])[CH2:34][OH:35])[O:30][C:29]([C:38]([O:40]C)=[O:39])=[CH:28][CH:27]1[NH:42][C:43]#[N:44])(=[O:24])[CH3:23]>CO.O>[C:22]([NH:25][CH:26]1[CH:31]([CH:32]([OH:37])[CH:33]([OH:36])[CH2:34][OH:35])[O:30][C:29]([C:38]([OH:40])=[O:39])=[CH:28][CH:27]1[NH:42][C:43]#[N:44])(=[O:24])[CH3:23]
Reactant: COC(=O)C1=CC(NC#N)C(NC(C)=O)C(C(O)C(O)CO)O1
Agent: CC(C)(C)[O-]
Agent: C[O-]
Agent: II
Solvent: CO
Solvent: O
Product: CC(=O)NC1C(NC#N)C=C(C(=O)O)OC1C(O)C(O)CO

Procedure:
A] treating a compound of formula (V) with a cyanogen halide which may be selected from cyanogen fluoride, cyanogen chloride, cyanogen bromide or cyanogen iodide to obtain methyl 5-acetamido-4-cyanamido-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate (VIII); B] deacetylating the intermediate (VIII) to obtain methyl 5-acetamido-4-cyanamido-6-(1,2,3-trihydroxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate (IX). The reaction may be carried out in the presence of a deacetylating agent which may be selected from the group consisting of methanol/iodine, methanol/water, sodium t-butoxide, potassium carbonate, sodium hydroxide, or sodium methoxide; C] hydrolyzing the compound (IX) in a basic medium to obtain 5-acetamido-4-cyanamido-6-(1,2,3-trihydroxypropyl)-5,6-dihydro-4H-pyran-2-carboxylic acid of formula (VII). The base used in the reaction may be organic or inorganic. The organic base may be selected from the group consisting of pyridine, dimethylamine, trimethylamine and sodium ethoxide. The inorganic base may be selected from the group consisting of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate; and D] reacting the compound (VII) with ammonium formate in the presence of ammonia which may be in the form of gaseous ammonia, liquid ammonia or aqueous ammonia and at a high temperature, for example ranging from 80° C. to 100° C., to obtain zanamivir (I).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]2[C:3]=1[C:4]([CH:13]=O)=[CH:5][NH:6]2.[NH2:15][CH:16]([CH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]2[C:3]=1[C:4]([CH2:13][NH:15][CH:16]([CH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][NH:6]2
Reactant: N#Cc1ccc(Br)c2c(C=O)c[nH]c12
Reactant: CCOC(=O)C(N)C(OCC)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(NCc1c[nH]c2c(C#N)ccc(Br)c12)C(OCC)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of 4-bromo-3-formyl-1H-indole-7-carbonitrile (1.08 g, 4.34 mmol), ethyl 2-amino-3,3-diethoxypropanoate (prepared according to the procedure of U.S. Pat. No. 7,470,680; 1.780 g, 6.94 mmol), and molecular sieves (2.17 g, 2 g) in 1,2-dichloroethane (79 mL) and THF (29.6 mL) at 0° C. was treated with sodium triacetoxyborohydride (2.57 g, 12.14 mmol) and the resulting mixture was stirred at room temperature overnight. After 24 h, LCMS residual starting material, so additional sodium triacetoxyborohydride (1.38 g, 1.5 eq.) and molecular sieves (2 g) were added and stirring was continued for 4 h more. The mixture was diluted with EtOAc and filtered through a CELITE® pad and the solids were washed with EtOAc. The filtrates were diluted with EtOAc and washed with NaHCO3 (aq) and brine, dried and concentrated to afford a dark-colored oil. The residue was subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexane (gradient from 15:85 to 100:0) to provide the desired product as a brown syrup (0.67 g, 35% yield). LCMS (M+H)+ m/z 438.2, 440.2.