Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[NH:20][S:19]2(=[O:25])=[O:24])=[C:14]([OH:26])[CH:13]=1.[OH-].[K+].Cl>O.CO.CC#N>[OH:26][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[N:18]1[CH2:22][C:21](=[O:23])[NH:20][S:19]1(=[O:25])=[O:24])[CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:27])=[O:2]
Reactant: COC(=O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: O=C(O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Temperature: 60 °C

Procedure:
To a solution of {2-[3-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-phenyl}-acetic acid methyl ester in water/MeOH/MeCN (1:1:1) is added KOH and the mixture is heated at 60° C. for 1 h. The mixture is cooled to RT and is acidified with 1N HCl. The mixture is purified by preparative HPLC to give the title compound. (M−1)−=375. HPLC retention time=0.63 min (Method A).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]2)[CH:12]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CCOC(=O)c1cnn(-c2cccc(Br)c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3Cl)c2)c1
Yield: 78.8 %

Procedure:
To a solution of the product from Step 2 (0.477 g, 1.6 mmol) in n-propanol (2.76 mL) and water (0.56 mL) were added 2-chlorophenylboronic acid (0.328 g, 2.1 mmol), palladium acetate (0.001 g, 0.3 mol %), triphenylphosphine (0.004 g, 0.9 mol %) and 2M sodium carbonate (0.96 mL, 1.9 mmol), and the reaction was refluxed for 16 hours. The reaction mixture was cooled and partitioned between EtOAc and water. The organic phase was washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. It was then filtered, concentrated and purified by chromatography using 20% EtOAc in hexanes to yield 0.412 g of the product (79%).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[CH2:33](I)[CH3:34].C(OC(C)C)(=O)C>O.CN(C)C=O>[CH2:33]([O:12][C:11](=[O:13])[C:10](=[CH2:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)[CH3:34].[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: CCI
Agent: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Product: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30 g (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H), prepared according to Example 33 is added to 38.4 g caseium carbonate. Dimethylformamide (50 ml) is then added. Ethyl iodide (8.26 ml) is then added and the mixture is stirred for 16 h at room temperature. Water (1200 ml) and isopropyl acetate (120 ml) are added. The phases are separated. The aqueous phase is washed with isopropyl acetate (2×120 ml). The combined organic phases are washed with 20% aqueous sodium chloride solution (180 ml) and then dried (MgSO4). The mixture is concentrated under reduced pressure to afford (R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid ethyl ester (2-a, R1=Boc, R2=H, R3=CO2Et). 1H NMR (CDCl3): 1.31 (3H), 1.40 (9H), 2.37 (1H), 2.59 (1H), 2.84 (1H), 2.93 (1H), 4.06 (1H), 4.24 (2H), 4.56 (1H), 5.62 (1H), 6.25 (1H), 7.29 (2H), 7.35 (1H), 7.45 (2H), 7.54 (2H), 7.59 (2H).
Reaction SMILES: C(N(CC)CC)C.Cl.[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[CH3:28][CH:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>CN(C=O)C.CCOC(C)=O.O>[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:22]1[CH2:27][CH2:26][N:25]([S:31]([CH:29]([CH3:30])[CH3:28])(=[O:33])=[O:32])[CH2:24][CH2:23]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
Triethylamine (2.6 mL, 18.7 mmol) was added to a solution of 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide hydrochloride in DMF (15 mL) at 0° C. The mixture was stirred at room temperature for 10 min, and 2-propanesulfonyl chloride (1.04 mL, 9.32 mmol) was added. Stirring continued for another 30 min, and the reaction mixture was diluted with 1:1 EtOAc/H2O (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with saturated NaCl (1×100 mL), dried (MgSO4), and concentrated under reduced pressure. The crude product was washed with MeOH (2×10 mL) to give the title compound (1.5 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.[CH2:11]([O:13][P:14]([CH2:23][CH2:24][CH2:25][NH2:26])([CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[O:15])[CH3:12].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:11]([O:13][P:14]([CH2:23][CH2:24][CH2:25][NH:26][CH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1)([CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[O:15])[CH3:12]
Reactant: CCOC(OCC)P(=O)(CCCN)OCC
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(OCC)P(=O)(CCCNCc1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.41 g of 3,5-dichlorobenzaldehyde are added to a solution of 2.53 g of 3-aminopropyl(diethoxymethyl)-phosphinic acid ethyl ester in 10 ml of anhydrous methanol and the resulting clear solution is stirred at room temperature for 30 minutes. There are then added first 0.6 g of glacial acetic acid and then, dropwise, 0.21 g of sodium cyanoborohydride dissolved in 5 ml of methanol. An exothermic reaction begins. The reaction mixture is stirred for 3 hours at 20°, adjusted to pH 8, and the solvent is removed. The residue is dissolved in dichloromethane and washed with water. The organic phase is separated off, dried over sodium sulfate and concentrated to dryness by evaporation. The oil that remains behind is purified by chromatography on silica gel, yielding 3-(3,5-dichlorobenzylamino)propyl(diethoxymethyl)-phosphinic acid ethyl ester in the form of a yellowish oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])[C:6]([OH:8])=[O:7])=[O:2].[C:19]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O.O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:18])[C:14]([F:16])([F:15])[F:17])[C:6]([O:8][CH3:19])=[O:7])=[O:2]
Reactant: CC(Oc1ccc(C(=O)O)cc1C=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC(C)C(F)(F)F)c(C=O)c1
Reaction time: 2 h
Yield: 23.6 %

Procedure:
To a solution of 3-formyl-4-(2,2,2-trifluoro-1-methylethoxy)benzoic acid (490 mg) and K2CO3 (387 mg) in acetone (10 ml) was added iodomethane (350 μl) at room temperature, followed by stirring for 2 hours. The reaction mixture was diluted with water (15 ml), and extracted with EtOAc (30 ml). The organic layer was dried over anhydrous MgSO4, and filtered to remove the desiccant, and the solvent was concentrated. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=95:5 to 80:20) to obtain methyl 3-formyl-4-(2,2,2-trifluoro-1-methylethoxy)benzoate (122 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:13]=1)=[O:11])([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3].Cl.[F:26][C:27]1([F:31])[CH2:30][NH:29][CH2:28]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:29]2[CH2:30][C:27]([F:31])([F:26])[CH2:28]2)=[C:14]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:13]=1)=[O:11])([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3]
Reactant: FC1(F)CNC1
Reactant: CC(C)(NC(=O)c1ccc(Br)c(OCC(F)(F)F)n1)c1nccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC(F)(F)F)n1)c1nccs1
Temperature: 120 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide (Example 288a) (63.6 mg, 150 μmol) in dry toluene (1 ml) was added 3,3-difluoroazetidine hydrochloride (21.4 mg, 165 μmol), BINAP (9.34 mg, 15.0 μmol), Pd(OAc)2 (3.37 mg, 15.0 μmol) and Cs2CO3 (122 mg, 375 μmol). The reaction was stirred at 120° C. overnight and controlled by LC-MS. Evaporation of the volatiles, residue was redissolved in DMF and directly purified by preparative HPLC to give the title compound (21 mg, 48 umol, 32%), MS (EI): m/e=437.4 [M+H]+.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([CH2:25][N:26]([CH:42]([CH3:44])[CH3:43])[C:27](=[O:41])[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[C@H:22]([CH2:45]O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([CH2:25][N:26]([CH:42]([CH3:44])[CH3:43])[C:27](=[O:41])[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[C@H:22]([CH2:45][N:51]2[C:47](=[O:57])[C:48]3[C:49](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:50]2=[O:52])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN2C(=O)c3ccccc3C2=O)C(C)C)ccc1C

Procedure:
DEAD is slowly added to a solution of (3S,4R)-3-hydroxymethyl-4-({isopropyl-[3-(3-methoxy-propoxy)-4-methyl-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (210 mg, 0.44 mmol), phthalimide (07 mg, 0.66 mmol) and PPh3 (173 mg, 0.66 mmol) in THF (5 mL) at RT. The resulting yellow solution is stirred for another 2 h before H2O is added and the mixture is extracted with ethyl acetate. Drying (Na2SO4) of the extracts, filtration and evaporation of the solvent affords the crude product which is purified by preparative HPLC (Waters C18 ODB, eluent: CH3CN/H2O 5%/2 min, CH3CN/H2O 5-100%/10 min, 100% CH3CN/2.5 min, flow 20 mL/min) to give the desired product. MS (LC-MS): 630.2 [M+Na]+; tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.40 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[Sn].Cl.[H][H]>>[ClH:2].[NH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([Cl:2])[CH:10]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: [H][H]
Agent: Cl
Agent: [Sn]
Product: N#Cc1ccc(N)cc1Cl

Procedure:
A suspension of 25 g. 2-chloro-4-nitrobenzonitrile hydrochloride and 3 g. granular tin in 147 ml. concentrated hydrochloric acid was warmed to 50°C. and when vigorous hydrogen evolution started 56 g. tin was added in 3 to 5 g. portions with cooling to maintain reaction at 90 to 100°C. The mixture was heated at reflux for 45 minutes, the unreacted tin was separated by decantation, and the resulting solution was concentrated under reduced pressure till about 80 ml. of water was collected, the residual solution was made strongly alkaline with 130 ml. 35% sodium hydroxide solution, and the solids were collected by filtration, dissolved in ether and treated with ethereal hydrogen chloride to give, on filtration, 4-amino-2-chlorobenzonitrile hydrochloride; m.p. 170°-180°C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])[O:3]1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[NH:35][N:36]=[CH:37][C:30]=12.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[NH:35]1[C:31]2=[N:32][CH:33]=[N:34][C:29]([NH:20][CH:18]([C:4]3[O:3][C:2](=[O:1])[C:11]4[C:6]([C:5]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH3:19])=[C:30]2[CH:37]=[N:36]1
Reactant: Clc1ncnc2[nH]ncc12
Reactant: CC(NC(=O)OC(C)(C)C)c1oc(=O)c2ccccc2c1-c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]ncc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 55.6 %

Procedure:
3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (Intermediate E1, 141 mg, 0.136 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (42.0 mg, 0.272 mmol) and DIEA (95 μL, 0.543 mmol) were stirred at 80° C. for 3 hrs in tert-butanol (800 μL). The reaction was quenched by the addition of 1 mL of 1M HClaqueous and the resulting crude was straightforward purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (29 mg, 56%).
Reaction SMILES: [S:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C([Sn](=O)CCCC)CCC.[CH:29]1[CH:34]=[CH:33][C:32]([CH2:35]Br)=[CH:31][CH:30]=1>CO.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[CH2:35]([O:6][C@H:5]1[C@@H:7]([OH:8])[C@@H:9]([CH2:11][OH:12])[O:10][C@@H:2]([S:1][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:3]1[OH:4])[C:32]1[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1
Reactant: OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](O)[C@@H](O)[C@H]1O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCCC[Sn](=O)CCCC
Agent: [Br-]
Solvent: CO
Product: OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](O)[C@@H](OCc2ccccc2)[C@H]1O
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of phenyl 1-thio-β-D-galactopyranoside (2.1) (3.00 g, 11.0 mmol) and dibutyltin oxide (3.00 g, 12.1 mmol) in dry methanol (80 ml) was refluxed for 2 hours to produce a clear mixture. The solvent was then evaporated under reduced pressure. The resultant residue was dissolved in dry benzene (80 mL) followed by the addition of Bu4NBr (3.90 g, 12.11 mmol) and BnBr (1.3 ml, 12.1 mmol). The mixture was refluxed overnight. After cooling to room temperature, the mixture was concentrated and the residue was purified by silica gel chromatography (50% EtOAc/petroleum ether) to afford the title compound (2.71 g, 7.48 mmol, 67%). 1H NMR (400 MHz, CDCl3): δ 7.60-7.20 (m, 10H, PhH), 4.77, 4.68 (ABq, J=11.7 Hz, 1H each, OCH2Ph), 4.59 (d, J=9.5 Hz, 1H, H-1), 4.08 (d, J=2.6 Hz, 1H, H-4), 3.76 (dd, J=9.5, 9.5 Hz, 1H, H-2), 3.75 (dd, J=11.4, 5.8 Hz, 1H, H-6), 3.70 (dd, J=11.4, 5.8 Hz, 1H, H-6), 3.50 (dd, J=5.8, 5.8 Hz, 1H, H-5), 3.41 (dd, J=9.5, 2.6 Hz, 1H, H-3); 13C NMR (100 MHz, CDCl3): δ 131.0, 128.6, 128.1, 127.8, 127.4, 126.8, 89.1, 82.5, 79.2, 71.5, 69.0, 66.2, 61.4; HRMS calcd for C19H26O5SN [M+NH4]+: 380.1532. found 380.1527.
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][C:53]1[C:61]([O:62][CH3:63])=[CH:60][CH:59]=[CH:58][C:54]=1[C:55](Cl)=[O:56])([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:42]=[CH2:43]>O1CCCC1>[CH2:48]([O:47][P:45]([O:51][CH2:52][C:53]1[C:61]([O:62][CH3:63])=[CH:60][CH:59]=[CH:58][C:54]=1[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:56])([O:44][CH2:41][CH:42]=[CH2:43])=[O:46])[CH:49]=[CH2:50]
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)OCc1c(OC)cccc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOP(=O)(OCC=C)OCc1c(OC)cccc1C(=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: 49 %

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 (542.6 mg, 1.00 mmol) described in Reference example 1, sodium hydride (55% dispersion in mineral oil; 52.4 mg, 1.20 mmol), and the crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methoxybenzoyl chloride were reacted in tetrahydrofuran (7 ml), and the reaction mixture was worked up to afford, after extraction, the title compound as a crude oil. The crude oil was subjected to chromatography on a silica gel (30 g) column (eluent; ethyl acetate:hexane=2:1˜4:1) to afford the title compound (425.5 mg, 49% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:40]=[CH:39][C:28]([O:29][C:30]2[N:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](Cl)=[O:33])=[CH:27][CH:26]=1>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:29][C:30]2[N:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:33])=[CH:39][CH:40]=1
Reactant: O=C(Cl)c1cccnc1Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3cccnc3Oc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-(4-chlorophenoxy)nicotinoyl chloride: ESMS m/e: 549.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH:13]=[CH:14][C:15]([O:17]CC)=[O:16].[OH-].[K+]>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH:13]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C=Cc1ccc(OC)c(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C=CC(=O)O)c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 3-(2,3,4-trimethoxyphenyl)propenoate (1.15 g) was dissolved in ethanol (20 mL), and to the solution 10% potassium hydroxide (1.21 g) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was adjusted to pH 2 with 2 M hydrochloric acid and extracted with ethyl acetate. The resultant organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:7]=1[CH:8]=O>>[CH:1]1([NH:4][CH2:8][C:7]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:6]=2[Cl:5])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=Cc1cc(Cl)ccc1Cl
Product: Clc1ccc(Cl)c(CNC2CC2)c1

Procedure:
prepared by reaction of cyclopropylamine with 2,5-dichloro-benzaldehyde.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:5]([CH2:15][CH3:16])[C:6]([NH:8][C:9]1[O:10][CH:11]=[C:12]([CH3:14])[N:13]=1)=[O:7])[CH3:4].[CH2:17](I)[CH3:18]>CN(C)C=O>[CH2:17]([N:8]([C:9]1[O:10][CH:11]=[C:12]([CH3:14])[N:13]=1)[C:6](=[O:7])[CH:5]([CH2:3][CH3:4])[CH2:15][CH3:16])[CH3:18]
Reactant: CCC(CC)C(=O)Nc1nc(C)co1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)C(=O)N(CC)c1nc(C)co1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
Sodium hydride (2.8 g. of a 50% dispersion in oil, 0.058 mol) was added in small portions to a stirred solution of 2-(2-ethylbutyramido)-4-methyloxazole (8.0 g., 0.041 mol) in dimethylformamide (100 ml.) at -5° to 0° C. The mixture was stirred for 2 hours at room temperature and then ethyl iodide (4.7 ml. 0.058 mol) was added. The mixture was stirred for a further 2 hours at room temperature and then poured onto ice-water (250 ml.) and extracted with ether (3 × 100 ml.). The extract was washed with dilute hydrochloric acid, then with sodium chloride solution, dried over sodium sulphate and evaporated. The residue was distilled under vacuum to give the product 4.7 g. (51%) b.p. 71-72° C/0.3 mm.
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][C:53]1[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][C:54]=1[C:55](Cl)=[O:56])([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:42]=[CH2:43]>>[CH2:48]([O:47][P:45]([O:51][CH2:52][C:53]1[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][C:54]=1[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:56])([O:44][CH2:41][CH:42]=[CH2:43])=[O:46])[CH:49]=[CH2:50]
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)OCc1ccc(C)cc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: C=CCOP(=O)(OCC=C)OCc1ccc(C)cc1C(=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: 43 %

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoate (690 mg, 1.54 mmol) was treated with trifluoroacetic acid to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoic acid as a crude product. According to a similar procedure to that described in Example 4-(6), the above product was treated with oxalyl chloride and N,N-dimethylformamide to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoyl chloride as a crude product. 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 (670 mg, 1.23 mmol) described in Reference example 1 was treated with sodium hydride and then reacted with the crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoyl chloride (the whole amount) obtained above to afford, after purification by column chromatography, the title compound (448 mg, 43% yield) as a pale yellow, candy-like material.