Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:13]O.C([O-])=O.[Na+].[OH-].[Na+]>C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:13]
Reactant: NO
Reactant: COc1ccc(Br)cc1C=O
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: COc1ccc(Br)cc1C#N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 6.45 g 5-bromo-o-anisaldehyde, 2.2 g of hydroxylamine hydrochloride, 4.1 g of sodium formate and 20 mL formic acid were heated at 100° C. with stirring for 1 h. The reaction mixture was poured onto ice water and the mixture was made basic by the careful addition of 50% sodium hydroxide. The product was extracted with ether, the ether extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was crystallized from ether/hexane to afford 5-bromo-2-methoxybenzonitrile.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].C(=O)([O-])O.[Na+]>C1COCC1>[C:40]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:18](=[O:19])[N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:22][CH2:23]1)(=[O:42])[CH3:41]
Reactant: O=C(NC1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(NC(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Reaction time: 1 h
Yield: 69 %

Procedure:
The compound obtained in Example 13 (435 mg, 1.00 mmol). triethylamine (0.335 ml) were dissolved in THF (10 ml), and under ice cooling, to the solution was added acetyl chloride (0.142 ml). The mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 ml) under ice cooling, and the mixture was extracted with ethyl acetate (15 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel log, ethyl acetate/methanol=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added ethyl acetate and resulting precipitates were collected by filtration. The filtrate was concentrated under reduced pressure. To the concentrate was added diethyl ether, and the resulting precipitates were collected by filtration. The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (331 mg, 0.69 mmol, Yield 69%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30]([O:32][CH:33](OCC)OCC)[CH3:31]>>[C:16]([C:3]1[CH:4]=[N:5][N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[C:2]=1[N:1]=[CH:33][O:32][CH2:30][CH3:31])#[N:17]
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC=Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl

Procedure:
A mixture of 5-amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (10 g) and p-toluenesulphonic acid hydrate (0.1 g) in triethylorthoformate (40 ml) was heated at reflux for 1 hour. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution was added. The organic phase was removed, dried over anhydrous magnesium sulphate and evaporated to give a colourless solid which was recrystallised from a mixture of ethyl acetate and hexane to give 4-cyano-5-ethoxymethyleneamino-1-(2,3,4-trichlorophenyl)pyrazole (11.0 g), m.p. 131°-132° C., in the form of colourless crystals.
Reaction SMILES: C(O)C.[OH-].[K+].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[C:7]1=[O:16].[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>CS(C)=O>[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[C:7]2=[O:16])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1ccc(CBr)cc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(=O)Oc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
An ethanol solution of potassium hydroxide (16.6 g. in 400 ml.) was added to a stirred solution of indoline-2,3-dione (isatin) (43.6 g.) in dimethylsulphoxide (400 ml.). After 10 minutes a solution of 4-acetoxybenzyl bromide (76.3 g.) in dimethylsulphoxide (40 ml.) was added. The mixture was stirred for 72 hours and then poured into ice/water (~1000 ml.). The gum which first formed slowly crystallised. The solid which formed was recrystallised from methanol (500 ml.) to give 1-(4-acetoxybenzyl)indoline-2,3-dione as a solid, m.p. 159°-161° C.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:15].[C:24]1([P:30](Cl)(Cl)=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCCCCC.C(OCC)C.C1CCCCC1>[C:24]1([P:30]2(=[O:31])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][N:16]2[CH2:14][CH3:15])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNCc1ccccc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CCN1Cc2ccccc2P1(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (8 g, 0.125 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature at 0° C., a solution of N-ethylbenzylamine (8.1 g, 0.06 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 3 hours at 26° C. and then cooled to -71° C. using a solid carbon dioxide-acetone bath. A solution of phenylphosphonic dichloride (12.5 g, 0.064 mol) in 30 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to -20° C. When the reaction temperature began to decrease, the solid carbon dioxide-acetone bath was removed and the reaction mixture was stirred for 2 hours. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 12 ml. of acetic acid. After stirring for 10 minutes, the cyclohexane was removed on a rotary evaporator, and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield an orange oil. This oil was distilled at 170° C. and 0.2 torr, yielding a yellow oil which was then slurried in diethyl ether to yield a white solid. The white solid was purified on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was slurried in ether to yield 1-phenyl-2-ethyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as a crystalline precipitate. A second crop was obtained from the ether filtrate and the combined product yield was recrystallized from methylcyclohexane to yield 1-phenyl-2-ethyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.3 g, 8% yield) as white crystals having a melting point of 94°-95° C. and the following analysis:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([O:49][CH2:50][CH3:51])(=[O:48])[CH:46]=[CH2:47]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:13]([O:12][C:10]([CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH:47]=[CH:46][C:45]([O:49][CH2:50][CH3:51])=[O:48])=[CH:3][CH:4]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CSc1ccc(Br)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1ccc(SCC(=O)OC(C)(C)C)cc1
Yield: 73.7 %

Procedure:
3.46 g of t-butyl [(4-bromophenyl)thio]acetate was mixed with 8 ml diisopropylethylamine, 0.6 g of triphenylphosphine, 5.2 ml ethyl acrylate and 35 ml acetonitrile to form a solution. 0.26 g of palladium acetate was further added to the solution and refluxed under a stream of argon for 44 hours. The reaction mixture was extracted with ethyl acetate, washed with water. The aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, and then dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated and purified via column chromatography on silica gel (ethyl acetate:hexane=1:20) to give ethyl 4-[[(t-butoxycarbonyl)methyl]thio]cinnamate (2.7 g, 73.7%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C=O.C(OCC)C>[Si:15]([O:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccnc1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.3 %

Procedure:
To a solution of 2-chloro-3-(hydroxymethyl)pyridine (Read, M. W; and Ray, P. S.; J. Heterocyclic. Chem., 1995, 32, 1595-1597., 2.81 g, 19.1 mmol) and imidazole (3.25 g, 47.7 mmol) in N,N-dimethylformamide (30 ml) was added tert-butyldimethylsilyl chloride (3.74 g, 24.8 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 17 h. The solution was diluted with diethyl ether (200 ml), and the resulting solution was washed with water (100 ml×3), and dried (MgSO4). Removal of solvent gave an oily residue. Purification by flash column chromatography eluting with ethyl acetate/hexane (1:15) afforded 3.61 g (73%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][N:22]([CH3:35])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][NH:33][CH3:34])=[CH:25][CH:24]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH2:32][CH2:31][CH2:30][O:29][C:26]3[CH:25]=[CH:24][C:23]([N:22]([CH3:21])[CH3:35])=[CH:28][CH:27]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCCOc1ccc(N(C)C)cc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCOc1ccc(N(C)C)cc1)CC2

Procedure:
The title compound is prepared from [3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane, N-[3-(4-dimethylaminophenyloxy)-propyl]-methylamine and triethylamine analogously to Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([N+:15]#[C-:16])[CH:3]=1.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:14][CH:13]=2)[NH:15][C:16]=1[C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH3:12]
Reactant: [C-]#[N+]c1cc(Cl)ccc1/C=C/C(=O)OCC
Reactant: O=C(Cl)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC#N
Product: CCOC(=O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
A mixture of ethyl trans-4-chloro-2-isocyanocinnamate (step 4, 1.2 g, 5.1 mmol), tributyltin hydride (1.6 g, 5.6 mmol) and AIBN (43 mg, 0.26 mmol) in acetonitrile (30 ml) was heated at 100° C. After 1 h, tetrakis(triphenylphosphine)palladium (580 mg, 0.50 mmol) and benzoyl chloride (0.65 ml, 5.6 mmol) were added and the mixture was heated for a further 17 h. The mixture was cooled and poured into 2N aqueous HCl (50 ml) and extracted with diethyl ether (80 ml×2). The combined organic extracts were washed with saturated aqueous potassium fluoride (50 ml) and dried (MgSO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1:5) to afford 0.43 g (25%) of the title compound as white solids.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH:27]1[CH2:36][C:35](=[O:37])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH:27]1[CH2:36][CH:35]([OH:37])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1
Reactant: O=C1CC(c2cc(F)ccc2F)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1cc(F)ccc1F)O2

Procedure:
2-(2,5-Difluorophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 1.0 g of 2-(2,5-difluorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 7.39-7.22 (m, 3H), 6.89 (d, 1H, J 2.8 Hz), 6.63 (d, 1H, J 8.7 Hz), 6.56 (dd, 1H, J 8.7, 2.8 Hz), 5.50 (d, 1H, J 6.8 Hz), 5.35 (d, 1H, J 11.2 Hz), 4.89 (m, 1H), 2.28 (m, 1H), 1.95 (m, 1H).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1>O1CCCC1.C(Cl)Cl>[CH3:1][NH:2][S:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To 20 ml of a 2 molar solution of methylamine in tetrahydrofuran chilled in an ice bath was added a solution of 5.16 g of 4-(4-chlorophenyloxy)benzene-sulfonyl chloride in 50 ml of tetrahydrofuran and 20 ml of CH2Cl2. The mixture was refluxed for 2 hours and the solvent removed under vacuum and the residue partitioned between CH2Cl2.H2O (1:1). The CH2Cl2 layer was separated and washed with 2 N citric acid, brine and dried (Na2SO4). The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with CH2Cl2. The filtrate was concentrated to give 4.5 g of N-methyl-4-(4-chlorophenoxy)benzene-sulfonamide as a yellow solid, m.p. 80-83° C.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[CH2:6][N:5]([CH2:9][C:10]#[CH:11])[C:4]1=[O:12].[CH3:13][C:14]1([CH3:29])[C@H:16](/[CH:17]=[C:18](\[CH3:25])/[CH:19]=[N:20][O:21][CH2:22][CH2:23][CH3:24])[C@H:15]1[C:26](O)=[O:27].C(Cl)(Cl)Cl.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.[Cl-].[Na+].O>[CH3:29][C:14]1([CH3:13])[C@H:16](/[CH:17]=[C:18](\[CH3:25])/[CH:19]=[N:20][O:21][CH2:22][CH2:23][CH3:24])[C@H:15]1[C:26]([O:1][CH2:2][N:3]1[C:7](=[O:8])[CH2:6][N:5]([CH2:9][C:10]#[CH:11])[C:4]1=[O:12])=[O:27]
Reactant: CCCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: C#CCN1CC(=O)N(CO)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@@H](/C=C(\C)C=NOCCC)C2(C)C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
Under nitrogen atmosphere, to a mixture of 0.17 g of 3-hydroxymethyl-1-(2-propynyl)imidazolidine-2,4-dione, 0.25 g of (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-propoxyimino-1-propenyl]cyclopropanecarboxylic acid, catalytic amount of 4-dimethylaminopyridine and 3 ml of anhydrous chloroform was added 0.23 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the mixture was stirred at room temperature overnight. Thereafter, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.20 g of 2,5-dioxo-3-(2-propynyl)imidazolidin-1-ylmethyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-propoxyimino-1-propenyl]cyclopropanecarboxylate (hereinafter, referred to as the present compound (4)) represented by the formula (4):
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:15](=[N:17][O:18][CH3:19])[CH3:16])[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[CH2:1]([O:8][N:9]=[C:10]([C:15](=[N:17][O:18][CH3:19])[CH3:16])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON=C(C)C(=NOCc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CON=C(C)C(=NOCc1ccccc1)C(=O)O
Yield: 99.7 %

Procedure:
To a solution of 3.2 g (12.1 mmol) of methyl 2-benzyloxyimino-3-methoxyiminobutyrate in 50 ml of methanol, 1.01 g (24.2 mmol) of sodium hydroxide and 10 ml of water were added and the mixture was heated under reflux for 24 hours. After distilling the solvent off under reduced pressure and adding 50 ml of water, the mixture was washed with 50 ml of diethylether. The aqueous layer was made acidic by adding a concentrated hydrochloric acid, and then the mixture was extracted three times with 50 ml of diethylether. After washing with water and with a saturated aqueous sodium chloride, the organic layer was dried over with anhydrous magnesium sulfate and the solvent was distilled off to obtain 3.02 g (yield: 100% ) of 2-benzyloxyimino-3-methoxyiminobutyric acid as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[Si:10]([O:9][CH2:8][C:6]1[N:7]=[C:2]([C:17]2([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=[CH:4][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Reactant: O=C1CCCCC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(C2(O)CCCCC2)n1
Yield: 15 %

Procedure:
Prepared from 6-bromo-O-(tert-butyldimethylsilyl)-2-pyridinemethanol and cyclohexanone by the method described in Example 10 to give the title compound (0.49 g, 15%) as a yellow oil; NMR δH (400 MHz, CDCl3) 0.13 (6H, s), 0.96 (9H, s), 1.61-1.91 (10H, m), 4.82 (2H, s), 5.17 (1H, s), 7.21 (1H, dd, J 8.0 Hz, 1.0 Hz), 7.38 (1H, dd, J 7.5 Hz), 1.0 Hz), 7.71 (1H, t, J 7.5 Hz). TLC (Hex:EtOAc (9:1)) Rf=0.30**
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[S:12]1[CH:16]=[CH:15][N:14]2[CH:17]=[N:18][CH:19]=[C:13]12>C(=S)=S.ClCCl>[C:5]([C:19]1[N:18]=[CH:17][N:14]2[CH:15]=[CH:16][S:12][C:13]=12)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)Cl
Reactant: c1cn2cncc2s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1ncn2ccsc12

Procedure:
Aluminum chloride (6.0 g) was added to a solution of 6.1 ml of pivaloyl chloride in 50 ml of carbon disulfide. The mixture was stirred. A solution of 1.2 g of imidazo[5,1-b]thiazole in 20 ml of dichloromethane was added thereto, and the mixture was stirred at room temperature for 48 hr. Dichloromethane (200 ml) was added to the reaction mixture. The mixture was washed with water and a saturated aqueous sodium hydrogencarbonate solution in that order, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 0.92 g of 7-pivaloylimidazo[5,1-b]thiazole.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([NH:14]CC2C=CC=CC=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:14][CH:10]1[CH2:11][C:12](=[O:13])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:22]
Reactant: [H][H]
Reactant: O=C1CC(NCc2ccccc2)C(=O)N1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC1CC(=O)N(Cc2ccccc2)C1=O
Yield: 91 %

Procedure:
56.5 g (0.184 mol) of 95% strength 1-benzyl-3-benzylaminopyrrolidine-2,5-dione are dissolved in 700 ml of ethanol and hydrogenated with 2 g of palladium on charcoal (5%) for 4 hours at 70° C. and 60 bar of hydrogen pressure. The catalyst is then filtered off, the filtrate is concentrated, and the residue is dried at 50° C./0.1 mbar. This gives 36.2 g of product with a content of 94%, determined by gas chromatography and corresponding to a yield of 91% of theory. Melting point 74° to 77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:9]([O:11]CC)=[O:10])=[C:4]([CH3:20])[CH:3]=1.Cl>CO.C1COCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:14]([CH3:19])[C:15]([F:16])([F:17])[F:18])[C:9]([OH:11])=[O:10])=[C:4]([CH3:20])[CH:3]=1
Reactant: CCOC(=O)C(c1ccc(Cl)cc1C)[C@@H](C)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(Cl)ccc1C(C(=O)O)[C@@H](C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.10 g (crude, about 10.04 mmol) of ethyl (3R)-2-(4-chloro-2-methylphenyl)-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) were dissolved in a mixture of 10 ml of methanol, 10 ml of THF and 5 ml of water, and 8.03 g of 50% strength aqueous sodium hydroxide solution were added at 0° C. The reaction mixture was stirred at RT overnight. The mixture was then acidified with 1 N hydrochloric acid (pH about 2) and extracted three times with ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1 to 4:1). This gave 1.46 g (51.8% of theory) of the target product as a mixture of diastereomers (about 5:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[Br-].C([O-])(O)=O.[Na+].[O-]Cl.[Na+]>C1(C)C=CC=CC=1.O.CC1(C)N([O])C(C)(C)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1
Yield: 95.4 %

Procedure:
3-hydroxy-piperidine-1-carboxylic acid t-butyl ester (4.0 g, 20 mmol) synthesized in Section (1) was dissolved in a mixed solution (2:1:2, 100 mL) of toluene, water and ethyl ester, and 1.0 mol% TEMPO (31 mg), and NaBr (2.3 g) were sequentially added thereto. A mixture of NaHCO3 (4.7 g) and NaOCl (5%, 36 mL) was slowly added to the mixture under cooling conditions (0 to 4° C.). After the reaction was complete, the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtered organic layer was concentrated under reduced pressure to afford 3.8 g (yield: 95%) of the title compound.
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:9][CH2:8][NH:7][C@H:6]1[CH3:10])([CH3:4])[CH3:3].[Cl:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>>[Cl:11][C:12]1[CH:19]=[C:18]([N:7]2[CH2:8][CH2:9][C@H:5]([C:2]([OH:1])([CH3:4])[CH3:3])[C@@H:6]2[CH3:10])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1ccc(F)cc1Cl
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Cl)c1

Procedure:
Using compound 1 and 2-chloro-4-fluorobenzonitrile as starting materials, the title compound was obtained by the same manner as shown in Example 1.