Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][C:12]=1[O:21][CH3:22].[CH3:24][O:25][C@@H:26]1[CH2:30][NH:29][C@H:28]([CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:27]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:29]2[CH2:30][C@@H:26]([O:25][CH3:24])[CH2:27][C@H:28]2[CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[O:20])=[CH:13][C:12]=1[O:21][CH3:22]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86.6 %

Procedure:
A mixture of 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (398 mg, 1.19 mmol), methyl 4-[(2S,4S)-4-methoxy-2-pyrrolidinyl]methoxybenzoate (317 mg, 1.19 mmol), EDC.HCl (342 mg, 1.79 mmol), HOBT (242 mg, 1.79 mmol) and Et3N (0.83 ml, 5.95 mmol) in DMF (5 ml) was stirred at room temperature for 13 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/Aectone (10/1)CHCl3/MeOH (20/1)], to give methyl 4-[(2S,4S)-1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-methoxy-2-pyrrolidinyl]methoxybenzoate (600 mg, 87%) as a colorless amorphous solid 1H-NMR (CDCl3) δ1.99-2.06 (m, 1H), 2.34 (d, J=13.9 Hz, 1H), 3.30 (s, 3H), 3.59 (d, J=7.4 Hz, 1H), 3.62 (d, J=3.2 Hz, 2H), 3.83 (s, 3H), 3.88 (s, 3H), 4.00-4.18 (m, 3H), 4.42-4.51 (m, 2H), 6.82-7.07 (m, 7H), 7.28 (d, J=8.3 Hz, 1H), 7.35 (dd, J=7.9, 1.5 Hz, 1H), 7.94-8.00 (m, 3H), 8.18 (d, J=8.3 Hz, 1H); MS (ESI) m/z 582 (M++1), 5.84 (M++3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30](C=O)C>>[C:29]([C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2)#[N:30]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(Br)cc2c1NCCC2
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1cc2c(c(C(=O)OCc3ccccc3)c1)NCCC2
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline-8-carboxylic acid (4.91 g) in DMF (80 ml) was added benzyl bromide (2.5 ml) and potassium carbonate (7.88 g). The reaction mixture was stirred at room temperature for an hour, and then insoluble material was filtered off. To this filtrate was added ethyl acetate-n-hexane (1:1, 400 ml), washed with water, aqueous saturated sodium chloride solution successively and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (6.71 g, quant.).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:48][CH2:49][CH3:50])[N:18]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)[C:19](=[O:32])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:23][C:22]=1[F:31])[CH3:14]>O>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:48][CH2:49][CH3:50])[N:18]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:46]3[NH:3][C:4](=[O:7])[O:5][N:47]=3)=[CH:38][CH:39]=2)[C:19](=[O:32])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:29])[CH3:30])=[CH:23][C:22]=1[F:31])[CH3:14]
Reactant: CCCc1nc(CC)c(-c2ccc(OC(C)C)cc2F)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)c(-c2ccc(OC(C)C)cc2F)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of hydroxylammonium chloride (0.80 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-5-(2-fluoro-4-isopropoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.35 g) was added, and the mixture was stirred at 90° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 66%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][N:10]2[C:20](=[O:21])[CH2:19][NH:18][C:17](=O)[CH:16]=[C:11]23)=[CH:4][CH:3]=[N:2]1.O=P(Cl)(Cl)Cl.[CH:28]1([C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)[CH2:30][CH2:29]1.N1C=CC=CC=1>ClCCCl>[CH:28]1([C:31]2[N:32]=[CH:33][N:34]([C:17]3[CH:16]=[C:11]4[C:12]5[C:7]([CH2:8][CH2:9][N:10]4[C:20](=[O:21])[CH2:19][N:18]=3)=[C:6]([C:5]3[O:1][N:2]=[CH:3][CH:4]=3)[CH:15]=[CH:14][CH:13]=5)[CH:35]=2)[CH2:30][CH2:29]1
Reactant: O=C1C=C2c3cccc(-c4ccno4)c3CCN2C(=O)CN1
Reactant: c1nc(C2CC2)c[nH]1
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1CN=C(n2cnc(C3CC3)c2)C=C2c3cccc(-c4ccno4)c3CCN12
Temperature: 100 °C
Yield: 35.2 %

Procedure:
Example 100. A solution of 9-(isoxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (90 mg, 0.31 mmol) in DCE (4 mL) was treated with POCl3 (57 μL, 0.61 mmol) and the mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. phases were then dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (4 mL) and 4-cyclopropyl-1H-imidazole (50 mg, 0.46 mmol) and pyridine (74 μL, 0.91 mmol) were then added. The mixture was heated to 110° C. for 1 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, cHex/AcOEt 100:0 to 0:100 and DCm/MeOH 99:1 to 90:10) afforded the title compound (42 mg) as a pale red solid. UPLC-MS: MS 386.2 (M+H+); UPLC rt 0.85 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.67-0.79 (m, 2 H); 0.80-0.91 (m, 2 H); 1.80-1.91 (m, 1 H); 3.17 (t, J=6.06 Hz, 2 H); 3.90 (t, J=6.19 Hz, 2 H); 4.37 (s, 2 H); 6.47 (s, 1 H); 6.63 (s, 1 H); 7.18 (s, 1 H); 7.50 (t, J=7.83 Hz, 1 H); 7.70-7.83 (m, 2 H); 7.88 (s, 1 H); 8.38 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:10]=1)[CH2:5][C:6]#N.[OH2:16].[OH-:17].[K+]>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:6]([OH:17])=[O:16])[CH:8]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:10]=1
Reactant: O
Reactant: [OH-]
Reactant: N#CCc1cc(Cl)cc(OC(F)(F)F)c1
Agent: [K+]
Solvent: CC(C)O
Product: O=C(O)Cc1cc(Cl)cc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 76 %

Procedure:
To a solution of 3-chloro-5-trifluoromethoxybenzyl cyanide (6.3 g, 26.7 mmol; see step (ii) above) in 2-propanol (100 mL) was added water (200 mL) and potassium hydroxide (7.5 g, 133.5 mmol). The solution was refluxed for 18 h, cooled to room temperature, and the 2-propanol was removed in vacuo. The aqueous phase was washed with CH2Cl2 (2×) and the washings discarded. The basic aqueous phase was acidified with 2N HCl and extracted with CH2Cl2 (3×). The CH2Cl2 extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (5.2 g, 76%) as an oil which was used in the next step without further purification.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:50])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[CH2:48][CH3:49])[CH:21]=[CH:22][C:16]=2[O:15]1>C(OCC)(=O)C>[CH3:50][C:14]1([CH3:13])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]3[CH2:48][CH3:49])[CH:21]=[CH:22][C:16]=2[O:15]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(CC)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.75 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C. for 30 min, 4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 mL), N,N′-carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.40 g, 66%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][CH2:22][CH3:23].[OH:24]O>CO.C(O)(C)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH2:22][CH3:23])=[O:24]
Reactant: OO
Reactant: CCSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: CC(C)O
Solvent: CO
Product: CCS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethylthiopyrazole (22.25 g) in methanol was added a solution of sulfuiric acid (1.5 g) in isopropanol. Hydrogen peroxide (6.95 g of 30% aqueous solution) was added and the temperature raised to 60° C. After two hours, the reaction was filtered and the solid washed with methanol. The filtrate was washed (water), dried and recrystallized (methanol) to give 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethylsulfinylpyrazole (18.4 g), m.p. 173-174° C.
Reaction SMILES: O1C2C(=CC=CC=2)C=CC1=O.C(N(CC)CC)C.[OH:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH3:31])=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:32]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([CH3:31])=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Agent: O=c1ccc2ccccc2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(=O)oc2cc(OC(=O)c3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The route shown in Scheme 1 exemplifies synthesis of the coumarin compounds of the present invention. Triethylamine is added to a solution of 7-hydroxy-4-methyl-chromen-2-one (i) and a benzoyl chloride (ii) in THF at room temperature. The reaction mixture is stirred at room temperature overnight and filtered. The filtrate is concentrated to afford a 7-benzoyloxy-4-methyl-coumarin (iii). A mixture of compound (iii) and finely powdered aluminum chloride is heated at 170° C. for 2 hours to afford an 8-benzoyl-7-hydroxy-4-methyl-chromen-2-one (iv). A mixture of compound (iv), 2-bromoacetophenone (v), and K2CO3 in CH3CN is refluxed overnight. The reaction mixture is filtered and the filtrate is concentrated. The residue is purified by column chromatography to afford a pure 8-benzoyl-4-methyl-9-phenyl-furo[2,3-h]chromen-2-one (vi).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[H-].[Na+].Cl[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[N:17][CH:18]=1>CN(C=O)C.C1(C)C=CC=CC=1>[C:22]1([CH3:25])[CH:23]=[CH:24][C:19]([C:16]2[N:17]=[CH:18][C:13]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(-c2ccc(Cl)cn2)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (18.0 ml, 353.7 mmol) is slowly added to a soln. of 2-amino-5-chloropyridine (15.0 g, 116.7 mmol) in 47% aq. HBr (75.0 ml) at −10° C. An aq. soln. of NaNO2 (28.1 g, 407.3 mmol) is slowly added. The mixture is stirred for 1 h at −10 to −5° C., then for 1 h at 5° C. The mixture is neutralised with 5M aq. NaOH soln. maintaining the temperature below 25° C. The precipitate is filtered and recrystallized from pentane to give 2-bromo-5-chloropyridine. 2-Bromo-5-chloropyridine (5.0 g, 26.0 mmol), p-tolylboronic acid (4.0 g, 29.4 mmol) and tetrakis(triphenylphosphine)palladium (1.44 g, 1.2 mmol) are dissolved in toluene:EtOH 9:1 (1375 ml). A 2M aq. Na2CO3 soln. (62.5 ml) is added to the reaction mixture. The mixture is stirred at 90° C. for 24 h, cooled to rt and filtered over celite. The toluene layer is separated and washed with brine. The aq. layers are extracted with AcOEt. The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown solid which is purified by FC (silica gel, eluent toluene) to give 5-chloro-2-p-tolyl-pyridine. (R)-3-Quinuclidinol (2.97 g, 23.4 mmol) is added to a suspension of NaH (0.96 g of a 60% dispersion in mineral oil, 22.8 mmol) in DMF (90 ml). The mixture is stirred for 1 h at rt. 5-Chloro-2-p-tolyl-pyridine (4.00 g, 19.6 mmol) is added and the mixture is heated for 135 h at 135° C. The reaction mixture is diluted with toluene and washed with 1 M aq. NaOH soln. and brine. The aq. layers are re-extracted with toluene (3×). The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown oil which is purified by FC (silica gel, eluents: AcOEt, then AcOEt/MeOH/NEt3 87:10:3) and recrystallized from CH3CN to give (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane; mp ° C.: 110-112; [α]Drt=+21.2° (0.50, MeOH), M+H+ 295.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11].[H-].[Na+].[CH2:41]([O:44][P:45]([O:51][CH2:52][CH2:53][C:54]([CH3:58])([CH3:57])[CH2:55]Cl)([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:42]=[CH2:43].[O:59]1CCCC1>>[CH2:41]([O:44][P:45]([O:51][CH2:52][CH2:53][C:54]([CH3:58])([CH3:57])[C:55]([O:38][C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11])=[O:59])([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:42]=[CH2:43]
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: C=CCOP(=O)(OCC=C)OCCC(C)(C)CCl
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: C=CCOP(=O)(OCC=C)OCCC(C)(C)C(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Yield: 15 %

Procedure:
According to a similar procedure to that described in Example 1-(12), 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (1.09 g, 2.0 mmol) described in Reference example 1, sodium hydride (55% dispersion in mineral oil; 104.7 mg, 2.4 mmol), and 4-[[bis(allyloxy)phosphoryl]oxy]-2,2-dimethylbutyl chloride were reacted in tetrahydrofuran (10 ml) and the reaction mixture was worked up to afford, after extraction, the title compound as a crude oil. The crude oily product was subjected to chromatography on a silica gel (75 g) column (eluent; ethyl acetate:hexane=2:1˜3:1) to afford the title compound (238.8 mg, 15% yield) as a pale yellow amorphous solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O.[Br:23][C:24]1[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]2[O:31][C:30]([CH2:33]I)([CH3:32])[CH2:29][C:28]=2[C:35]=1[CH3:36]>C(OCC)(=O)C.O>[Br:23][C:24]1[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]2[O:31][C:30]([CH2:32][N:8]3[CH2:9][CH2:10][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)([CH3:33])[CH2:29][C:28]=2[C:35]=1[CH3:36]
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CI)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(C)c2c(c(C)c1Br)CC(C)(CN1CCC3(CC1)OCCO3)O2
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
1,4-dioxa-8-azaspiro[4.5]decane (725 mg, 5.06 mmol) and potassium carbonate (699 mg, 5.06 mmol) were added to a solution of DMA (3 mL) containing 5-bromo-2-(iodomethyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (400 mg, 1.01 mmol) synthesized in Reference Example 133, and the mixture was stirred under microwave irradiation at 200° C. for 10 minutes. The reaction solution was cooled to room temperature, and water and ethyl acetate were added thereto to separate an organic layer. The organic layer was washed with water and saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-80:20) to give 310 mg of the title compound (yield: 75%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:14][N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:16]=3[CH2:17][O:18][CH3:19])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[N:36]=[N:37][N:38](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:39]=1>CO.ClCCl>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:14][N:15]([CH2:20][C:21]([F:23])([F:22])[F:24])[C:16]=3[CH2:17][O:18][CH3:19])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[NH:39][N:38]=[N:37][N:36]=1
Reactant: CCCCc1nn(CC(F)(F)F)c(COC)c1Cc1ccc2oc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(Br)c2c1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(CC(F)(F)F)c(COC)c1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.8 %

Procedure:
dl-1-Camphor sulphonic acid (67 mg) was added to a solution of Intermediate 14a (268 mg) in methanol (5 ml) and dichloromethane (2 ml). The mixture was stirred at room temperature for 48 h. The solvent was evaporated and the residue purified by flash column chromatography eluting with System G (100:100:1) to give the title compound as a colourless foam (55 mg) after azeotroping with heptane to remove acetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.C[C:9]1[CH:10]=[C:11]([CH:15](C=O)[C:16](OC)=[O:17])C=CC=1.N1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:23][C:24]1[CH:9]=[C:10]([C:11]2[N:4]3[N:3]=[C:2]([CH3:1])[CH:6]=[C:5]3[NH:7][C:16](=[O:17])[CH:15]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: COC(=O)C(C=O)c1cccc(C)c1
Reactant: c1ccncc1
Product: Cc1cccc(-c2cc(=O)[nH]c3cc(C)nn23)c1
Temperature: 25 °C

Procedure:
3-Methylpyrazol-5-amine (431 mg) and methyl 3-methylphenyl-3-oxopropanoate (812 mg) are stirred overnight at 93° C. in a pyridine (10 mL) solvent. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (673 mg).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[N:12]/[OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:24][C:25]1[C:30]([F:31])=[CH:29][C:28]([C:32]([C:34]([F:37])([F:36])[F:35])=[CH2:33])=[CH:27][C:26]=1[F:38].Cl>CN(C=O)C.O>[Cl:24][C:25]1[C:26]([F:38])=[CH:27][C:28]([C:32]2([C:34]([F:37])([F:35])[F:36])[O:13][N:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[B:2]([OH:1])[O:3][C:4]([CH3:15])([CH3:14])[C:5]=4[CH:10]=3)[CH2:33]2)=[CH:29][C:30]=1[F:31]
Reactant: CC1(C)OB(O)c2ccc(/C=N/O)cc21
Reactant: C=C(c1cc(F)c(Cl)c(F)c1)C(F)(F)F
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(F)c(Cl)c(F)c4)(C(F)(F)F)C3)cc21
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 34.4 %

Procedure:
To a solution of (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (200 mg, 0.98 mmol) in DMF (7 mL) at rt was added NCS (157 mg, 1.17 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 h and cooled to rt. This mixture was added dropwise to a solution of 2-chloro-1,3-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (237 mg, 0.98 mmol) and TEA (218 mg, 2.16 mmol) in DMF (7 mL) at 0° C. The mixture was stirred at this temperature for 1 h, and then at rt overnight. The mixture was acidified with 3 N HCl to pH of 2, then poured into water and extracted with EA (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=2:1) to give the final title compound (150 mg, yield 35%) as white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.24 (s, 1H), 7.82-7.73 (m, 3H), 7.71-7.60 (m, 2H), 4.50 (d, J=18.3 Hz, 1H), 4.44 (d, J=18.3 Hz, 1H), 1.51 (s, 3H), 1.50 (s, 3H) ppm; HPLC purity: 95.5% at 214 nm and 97.8% at 254 nm; MS: m/z=446 (M+1, ESI+).