Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH2:4]1.[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[S-:34].[Na+]>>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[S:34][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:24])([CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH2:4]1
Reactant: [S-]c1nc2ccccc2s1
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Agent: [Na+]
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CSc2nc3ccccc3s2)OC(C)(C)O1

Procedure:
The procedure was carried out in the same manner as in Example 11, except that 3.5 g of 2-methyl-1-phenylpropan-2-yl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate was used in place of 30 g thereof, and sodium benzo[d]thiazole-2-thiolate (3.8 g) prepared in Example 10 was used in place of sodium 1-phenyl-1H-tetrazole-5-thiolate. The title compound was obtained (4.6 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].N1C=CC=CC=1>C(Cl)Cl>[CH3:18][S:19]([NH:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cn1cc(N)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cn1cc(NS(C)(=O)=O)c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
To a suspension of ethyl 2-(3-amino-1H-indol-1-yl)acetate hydrochloride (220 mg, 0.864 mmol) in dry DCM (4 ml), cooled at 0° C. under nitrogen, methanesulfonyl chloride (67.3 μl, 0.864 mmol) and dry pyridine (559 μl, 6.91 mmol) were added. After stirring at 0° C. for 4 hours, the mixture was partitioned between 5% aqueous citric acid and DCM; the organic phase was washed with water, dried over Na2SO4 and evaporated to give ethyl 2-(3-(methylsulfonamido)-1H-indol-1-yl)acetate (221 mg, 0.746 mmol, 86% yield). MS/ESI+ 319.0 [MNa]+. This product was used in the next step without any additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.Cl[C:17]([O:19][CH3:20])=[O:18]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a stirred solution of 2 (7.0 g, 41.3 mmol) in anhydrous THF (100 mL) at −78° C. under a nitrogen atmosphere was added n-BuLi (24.7 mL, 2.5 M in hexanes, 61.8 mmol). After 1 hour, methyl chloroformate (9.6 ml, 124 mmol) was added and the reaction mixture was stirred for an extra hour at the same temperature, quenched with excess methanol and allowed to warm to room temperature. The solvent was then evaporated and the residue was purified by flash chromatography using hexane—AcOEt (70:30) as an eluent. The product from the column was re-crystallized from ethyl acetate to afford title compound 37 (4.3 g, 46% yield) as a white solid 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.75 (dd, J=0.8 and 4.8 Hz, 1H), 8.26 (d, J=0.8 Hz, 1H), 7.74 (dd, J=0.8 and 5.2 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O.N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:21][C:13]1[NH:12][C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-chloro-2-oxindole (167 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 5-chloro-3-(1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].O>CN(C=O)C>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
Piperazine (12.9 g) was dissolved in DMF (100 mL), and a solution of 2-fluoronitrobenzene (7.06 g) in DMF (30 mL) was added dropwise. The mixture was stirred at room temperature for 3 hr. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated to give 1-(2-nitrophenyl)piperazine (7.7 g) as a red oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[CH2:19][CH2:20]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (5 g, 20.57 mmol) and tert-butyl (4-oxocyclohexyl)carbamate (5.67 g, 26.74 mmol) in methanol (50 mL), acetic acid (1.2 g, 20.57 mmol) was added and reaction stirred at room temperature for 4 h. Then sodium cyanoborohydride (1.68 g, 26.74 mmol) was added and reaction stirred 18 h. On completion, solvent was removed under reduced pressure; water was added and extracted with DCM. Combined organic were dried, concentrated and purified by column chromatography using silica (100-200 mesh size) to afford the desired compound (3 g, 33%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11].[OH-].[K+].O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(C)(C)c1cc(F)ccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C(=O)O)c1cc(F)ccc1Br

Procedure:
A mixture of methyl 2-(2-bromo-5-fluorophenyl)-2-methylpropanoate (0.529 g, 3.12 mmol, J. Am. Chem. Soc., 2008, 130, 15157-15166), potassium hydroxide (3.2 g, 57 mmol), water (10 mL) and ethanol (30 mL) was refluxed for 20 h.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8](C)=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH:4]([CH3:15])[CH2:3]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl[CH2:22]Cl>>[CH3:13][C:5]1([CH3:14])[C:6]2[C:11](=[CH:10][C:9]([CH3:22])=[CH:8][CH:7]=2)[C:2]([CH3:16])([CH3:1])[CH2:3][CH:4]1[CH3:15]
Reactant: ClCCl
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)CC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc2c(c1)C(C)(C)CC(C)C2(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
The starting material 1,1,2,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene is prepared as follows. A 100 ml four-necked round bottom flask is charged with 1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (HMT) (20 g) and dichloromethane (32.6 g) and cooled to 0° C. with a dry ice/isopropanol bath. To the flask is then added, with stirring, anhydrous AlCl3 (2.507 g). The temperature of the flask is maintained between about 0° C. and 10° C. while the reaction is allowed to proceed for about 2.5 hrs. The reaction is then quenched with ice water (25 ml), and the resultant product washed with deionized water. The aqueous layer is extracted twice with ether, the organics are combined, dried over K2CO3 and rotoevaporated to yield a crude product (18.26 g) containing 37.22 weight percent of a mixture of 1,1,2,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene, HMT, 1,1,3,5-tetramethyl-3-isopropylindane and 1,3,3,5-tetramethyl-1-isopropylindane. The indanes are removed from the mixture by preparative gas chromatography. The desired compound, 1,1,2,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene, is then separated from HMT using a vacuum spinning band fractional distillation apparatus.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:26])[C:10]([C:23]([OH:25])=O)=[CH:11][N:12]([CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:13]=2)=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=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.[NH2:70][C:71]1[CH:76]=[CH:75][C:74]([C:77]2[C:78]([NH2:93])=[N:79][CH:80]=[C:81]([C:83]3[CH:88]=[CH:87][C:86]([O:89][CH3:90])=[C:85]([O:91][CH3:92])[CH:84]=3)[CH:82]=2)=[CH:73][CH:72]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[NH2:93][C:78]1[C:77]([C:74]2[CH:73]=[CH:72][C:71]([NH:70][C:23]([C:10]3[C:9](=[O:26])[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:13][N:12]([CH2:14][CH2:15][O:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[CH:11]=3)=[O:25])=[CH:76][CH:75]=2)=[CH:82][C:81]([C:83]2[CH:88]=[CH:87][C:86]([O:89][CH3:90])=[C:85]([O:91][CH3:92])[CH:84]=2)=[CH:80][N:79]=1
Reactant: COc1ccc(-c2cnc(N)c(-c3ccc(N)cc3)c2)cc1OC
Reactant: O=C(O)c1cn(CCOC2CCCCO2)cc(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cnc(N)c(-c3ccc(NC(=O)c4cn(CCOC5CCCCO5)cc(-c5ccc(F)cc5)c4=O)cc3)c2)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(4-Fluorophenyl)-4-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,4-dihydropyridine-3-carboxylic acid was dissolved in DMF (2 ml), and HOAt (41 mg), HATU (170 mg), DMAP (18 mg) and DIPEA (88 μl) were added at room temperature. The reaction mixture was stirred at room temperature for three hours. The compound obtained in Step 2 of Example 1 (96 mg) was added to the reaction mixture at room temperature, followed by stirring overnight. Water was added to the reaction mixture, and the precipitated solid was collected by filtration to give 281 mg of the crude purified title compound as a solid. One hundred forty one mg of the solid was purified by PLC [dichloromethane:methanol=20:1 (v/v)], and the eluate was concentrated under reduced pressure. The residue was purified by PLC [ethyl acetate:methanol=15:1 (v/v)] to give 72 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])[CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]1.[H-].[Na+]>CC1CCCO1.CS(C)=O.ClCCl.O>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[S:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:32][CH2:31][CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)=[CH:8][CH:7]=1)(=[O:10])=[O:11]
Reactant: OCC1CCOCC1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(CBr)cc2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(COCC3CCOCC3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of crude 4-(bromomethyl)-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide (100 mg, 0.122 mmol) and (tetrahydro-2H-pyran-4-yl)methanol (14.15 mg, 0.122 mmol) in 2-methyltetrahydrofuran (2-MeTHF) (1 mL) and dimethyl sulfoxide (DMSO) (0.5 mL) was added sodium hydride (approximately 4.87 mg, 0.122 mmol, 60% dispersed in oil) in one charge. The reaction mixture was stirred at 20° C. for 16 hours. The reaction was then quenched with methanol (0.5 mL) and water (0.5 mL) and concentrated in vacuo to give a residue in DMSO. This was diluted with dichloromethane (10 mL) and water (10 mL) and stirred vigorously for 10 minutes. The layers were separated by hydrophobic frit and the organic fraction evaporated to give the crude product. The sample was then purified by mass directed autoprep (formic acid modifier). The appropriate fractions were concentrated under a stream of nitrogen to give the required product, 4.2 mg. LCMS [LCMS1] Rt 1.44 min, m/z (ES+) 446 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH:17]4[CH2:18][CH2:19][CH2:20][CH2:21][O:16]4)[CH:24]=3)=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: O=Cc1cccc(OC2CCCCO2)c1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: c1cc(CNc2ccc(OCCN3CCCC3)cc2)cc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a solution of 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (1.92 g, 9.30 mmol) and 3-(tetrahydro-pyran-2-yloxy)-benzaldehyde (2.01 g, 9.76 mmol) in 35 mL methylene chloride was added magnesium sulfate (3.91 g, 32.5 mmol). The reaction mixture was stirred overnight under nitrogen at room temperature. The reaction mixture was filtered and concentrated. The residue was resuspended in 40 mL of 2:1 ethanol:methanol and was treated with sodium borohydride (1.76 g, 46.5 mmol) which was added in portions at room temperature over a period of 1 hr. The reaction was stirred at room temperature overnight. To this mixture was added water and saturated aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and the organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (methylene chloride to 10% methanol/methylene chloride) afforded 2.34 g (64%) of the title compound. MS 397.2 (M+1)+
Reaction SMILES: C(OC([N:7]1[C@@H:11]([CH3:12])[CH:10]=[C:9]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:30])[C@@H:23]4[C@H:27]([OH:29])[CH3:28])[C:20]=3[C:31]([O:33]CC=C)=[O:32])[S:16][CH:17]=2)[CH2:8]1)=O)C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.P([O-])([O-])([O-])=O>ClCCl>[OH:29][C@@H:27]([C@H:23]1[C:22](=[O:30])[N:21]2[C@@H:24]1[C@@H:25]([CH3:26])[C:19]([S:18][C:15]1[S:16][CH:17]=[C:13]([C:9]3[CH2:8][NH:7][C@@H:11]([CH3:12])[CH:10]=3)[N:14]=1)=[C:20]2[C:31]([OH:33])=[O:32])[CH3:28]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H]1C=C(c2csc(SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)n2)CN1
Temperature: 0 °C
Yield: 50.8 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(4-{(5S)-1-[(allyloxy)carbonyl]-5-methyl-2,5-dihydro-1H-pyrrol-3-yl}-1,3-thiazol-2-yl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (70 mg, 0.13 mmol) in dichloromethane (2 ml) were added acetic acid (19 μl) and tributyltin hydride (0.32 ml, 1.2 mmol) and added at room temperature bis(triphenylphosphine)palladium chloride(II) (91 mg, 0.013 mmol). Ten minutes later the reaction mixture was poured into a mixture of ice (10 g) and phosphate buffer (pH7.0, 10 ml). After separation of the mixture with a separating funnel, the organic layer was extracted twice with water and the aqueous layer was washed twice with dichloromethane (3 ml). The organic solvent in the aqueous layer was evaporated under reduced pressure, and the residue was purified by polymer chromatography (CHP-20P). The fractions eluted with 1–3% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-({4-[(5S)-5-methyl-2,5-dihydro-1H-pyrrol-3-yl}-1,3-thiazol-2-yl)sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (26.9 mg) as a white amorphous.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][C:5](=[O:14])[NH:4]1.CCN(CC)CC.[CH3:22][C:23]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])[CH3:24]>CN(C1C=CN=CC=1)C.CN(C=O)C>[Si:26]([O:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][C:5](=[O:14])[NH:4]1)([C:23]([CH3:25])([CH3:24])[CH3:22])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1N[C@@H](CO)[C@H](c2ccccc2)O1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC[C@@H]1NC(=O)O[C@H]1c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To a solution of (4S,5S)-4-hydroxymethyl-5-phenyl-oxazolidin-2-one (3.50 g, 17.2 mmol), NEt3 (4.80 mL, 34.4 mmol), and DMAP (105 mg, 861 μmol) in DMF (20 mL) was added dropwise TBDPSCl (4.86 mL, 18.9 mmol) at room temperature. The reaction was stirred for 3 hours at room temperature. The reaction mixture was then concentrated and diluted with TBME, the organic layers were separated, washed with aqueous NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (120 g SiO2) using EtOAc in heptane from 0% to 60% in order to give the title compound as a white solid (4.28 g, 57%). LC-MS: [M+H] 432.2; Rt 1.36 min; (LCMS method 2).
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[Si:32]([O:39][C:40]1[CH:41]=[C:42]([Mg]Br)[CH:43]=[CH:44][CH:45]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].II.[Mg]>C1COCC1.C(Cl)Cl.CO>[Si:32]([O:39][C:40]1[CH:41]=[C:42]([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[O:9])[CH:43]=[CH:44][CH:45]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc([Mg]Br)c1
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)sc2c1
Yield: 73.1 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (1.6 g, 3.75 mmol) in THF (15 mL) was treated with a 0.6 M THF solution of 3-(t-butyldimethylsilyloxy)phenylmagnesium bromide (16 mL, 9.60 mmol) (prepared from the product of preparation 3, catalytic iodine, and magnesium turnings in THF) to provide, after chromatography (silica gel, 5-10% MeOH in CH2Cl2) 1.65 g (73%) of the title compound as a yellow oil: 1H NMR d 0.11 (s, 6H), 0.95 (s, 9H), 1.45 (m, 2H), 1.61 (m, 4H), 2.50 (m, 4H), 2.76 (t, J=5.9 Hz, 2H), 3.89 (s, 3H), 4.09 (t, J=5.9 Hz, 2H), 6.69 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 2H), 6.90 (s, 1H), 6.96-7.10 (m, 3H), 7.34 (m, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.2 Hz, 2H); MS (FD) m/e 601 (M+); Anal. calc'd. for C35H43NO4SSi: C, 69.85; H, 7.20; N, 2.33. Found: C, 69.83; H, 7.34; N, 2.34.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[F:13][C:14]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:15]=1[C:16]([NH:18][C:19]([NH:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:10])[F:11])=[CH:4][N:3]=1)=[O:20])=[O:17]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ncc(C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ncc(C(F)(F)F)cc1Cl

Procedure:
For example, 2-amino-3-chloro-5-trifluoromethylpyridine is reacted with 2,6-difluorobenzoylisocyanate in toluene at 40° C. for 30 minutes, whereby N-(2,6-difluorobenzoyl)-N'-(3-chloro-5-trifluoromethyl-2-pyridyl)urea having a melting point of 214° to 217° C. can be obtained. This compound is effective in inhibiting and controlling various pests, particularly noxious insects. For example, in the insecticidal testing of the compound in a concentration of 800 ppm against larvae of diamondback moth in 3rd or 4th instar, a 100% insecticidal effect can be obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(O[CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(N)cc2)CC1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a 100 mL round-bottomed flask was added 4-aminobenzenethiol (4.9 g, 39.1 mmol) and potassium carbonate (9.72 g, 70.3 mmol) in dimethylformamide (20 ml). tert-Butyl 4-(tosyloxy)piperidine-1-carboxylate (5 g, 14.07 mmol) was added and the reaction was stirred in a sealed flask at 70° C. for 20 hours. The mixture was cooled and filtered through a plug of silica gel with dichloromethane. The filtrate was concentrated under vacuum and chromatographed to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3.Cl.[F:28][C:29]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30]1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:28][C:29]1([F:34])[CH2:33][CH2:32][N:31]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:11][CH:10]=4)[CH2:30]1
Reactant: FC1(F)CCNC1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1cnc(Cl)cc12
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1cnc(N3CCC(F)(F)C3)cc12
Temperature: 90 °C

Procedure:
To a resealable tube charged with a mixture of (S)-3-chloro-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.085 g, 0.233 mmol), 3,3-difluoropyrrolidine HCl (0.100 g, 0.699 mmol), pd2(dba)3 (10.67 mg, 0.012 mmol), and 2-(dicyclohexylphosphino)-2′-(n,n-dimethylamino)biphenyl (0.014 g, 0.035 mmol) was added 1.0 M lithium bis(trimethylsilyl)amide (1.398 mL, 1.398 mmol) in THF and the resulting mixture was heated at 90° C. for 17 h. The mixture was concentrated and purified by reverse phase HPLC to afford (S)-3-(3,3-difluoropyrrolidin-1-yl)-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine.