Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:15])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.O.[CH3:24][NH:25][C:26](=[S:29])[NH:27][NH2:28]>CO>[CH3:24][NH:25][C:26]([NH:27][N:28]=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][O:6][C:7]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])=[S:29]
Reactant: CNC(=S)NN
Reactant: O=C(Nc1ccccc1)OCCCC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC(=S)NN=C(CCCOC(=O)Nc1ccccc1)c1ccccc1
Reaction time: 21 h
Yield: 83.9 %

Procedure:
Phenyl-carbamic acid 4-oxo-4-phenyl-butyl ester (2.80 g, 9.88 mmol), prepared in the previous step, was suspended in 60 ml of methanol and the mixture warmed to dissolve the solid. While still warm 2.7 ml of 1 N HCl, 2.7 ml of water and 4-methyl-3-thiosemicarbazide (1.04 g, 9.92 mmol) were added and the reaction stirred under nitrogen for 21 hours. The solid formed was removed by filtration and dried under high vacuum to give the title compound (3.07 g, 84%) as a white solid, mp 155-157° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[S:19](Cl)(=[O:21])=[O:20]>C1(C)C=CC=CC=1>[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[S:19]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:20])=[O:21]
Reactant: Oc1ccccc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)Oc2ccccc2)c(C)c1
Reaction time: 1 h

Procedure:
9.4 g of phenol is added to a mixture containing 9.17 g of 48% NaOH, 50 ml of water and 50 ml of toluene. To the resulting mixture is added 22.9 g of mesitylenesulfonyl chloride, and reaction is carried out at 60° to 65° C. for 1 hour. After separating the aqueous layer, toluene is removed from the toluene layer by distillation. The resulting desired compound is purified with methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(O)C>C(COC)OC>[CH:13]([O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]2[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:1]=[C:2]2[CH:11]=1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)Oc1cc(N)nc2ccccc12
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(cc(OC(C)C)c3ccccc32)n1
Reaction time: 1 h

Procedure:
2.8 g of 2-amino-4-isopropoxyquinoline were dissolved in 50 ml of dimethoxyethane and 4 g of ethyl bromopyruvate were added thereto. The mixture obtained was allowed to stand at room temperature for 1 hour and then was reduced in volume under vacuum. 50 ml of ethanol were added thereto and the resultant mixture was refluxed for 90 minutes. The ethanol was evaporated off under vacuum and the residue was dissolved in 100 ml of 2 N HCl. The acid solution thus obtained was washed with 50 ml of ethyl acetate and then was made alkaline with sodium carbonate. The mixture was extracted three times with 50 ml of chloroform and the combined chloroform extracts were washed with 100 ml of water, dried over MgSO4 and then was evaporated to dryness under reduced pressure to obtain an orange oil. The oil was purified by column chromatography (silica gel-chloroform as eluant) and then was crystallized from diethyl ether to obtain colorless needles of ethyl 5-isopropoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 127°-129° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[C:8]1([CH3:14])[CH:13]=[CH:12]C=[CH:10][CH:9]=1.[OH-].[Na+]>O>[CH3:14][C:8]1[CH:9]=[CH:10][C:2]([C:3]([OH:5])=[O:4])=[CH:12][CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
A mixture of K2S2O8 (1.35 g), trifluoroacetic acid (4 mL), and the catalyst solution as prepared in Example 4(a) (1 mL) was stirred in air for 10 minutes. After toluene (5 mL) was added, the mixture was stirred under CO (1 atm) at room temperature for 66 hours. The mixture was diluted with water (5 mL), basified with NaOH, washed with ether, acidified with HCl, and thoroughly extracted with ether. The combined etherial extracts were evaporated to dryness. The residue was sublimed under vacuum to give 225 mg (TON=10) of p-toluic acid of >95% purity (1H NMR).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][N:4]=1)[NH2:2].[CH2:11]([O:13][C:14](=[O:26])[C:15](=O)[CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:12]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:1]([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][N:4]=2)[N:2]=1)=[O:26])[CH3:12]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Reactant: COc1ccc(NN)nc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(OC)cn2)n1

Procedure:
The above-obtained 2-hydrazino-5-methoxypyridine (705 mg) and the 2,4-dioxo-4-phenylbutyric acid ethyl ester (1.12 g) prepared in Referential Example 123-1) in ethanol (25 mL) was refluxed under heat for 19 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel chromatography (hexane-ethyl acetate), to thereby give 1-(5-methoxy-2-pyridyl)-5-phenylpyrazole-3-carboxylic acid ethyl ester as an amorphous product (705 mg, 43%).
Reaction SMILES: [OH:1][CH:2]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH2:3]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:29]([O:28][C:26]([N:24]1[C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH2:3][CH:2]([O:1][C:33](=[O:35])[CH3:34])[CH2:25]1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CC(O)C3)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 7-hydroxy-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 4) (500 mg, 1.159 mmol) in pyridine (3 ml) was treated slowly with acetic anhydride (0.219 ml, 2.317 mmol) and the resulting yellow solution was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and purification of the crude material by chromatography on silica eluting with 0-60% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:29][C:10]=1[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:15]=1)=[O:12])=[O:7].[SH:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46]([OH:48])=[O:47].C(N(CC)C(C)C)(C)C>O1CCCC1.[I-].[K+]>[N:33]1([C:30]2[CH:31]=[CH:32][C:9]([NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:41]=[CH:40][CH:39]=3)[CH2:2][S:42][C:43]3[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=3)[C:46]([OH:48])=[O:47])=[O:7])=[C:10]([C:11](=[O:12])[NH:13][C:14]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:15]=3)[CH:29]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CCl)c1
Reactant: O=C(O)c1cccc(S)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3ccn(-c4cccc(C(F)(F)F)c4)n3)c2)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 63.3 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 21a (1.6 g, 2.56 mmol, 1.00 equiv) in tetrahydrofuran (100 mL), 3-mercaptobenzoic acid (390 mg, 2.53 mmol, 0.99 equiv), potassium iodide (21.2 mg, 0.13 mmol, 0.05 equiv), and N,N-diisopropylethylamine (660 mg, 5.12 mmol, 2.00 equiv). The resulting solution was stirred for 24 h at 40° C. in an oil bath. The reaction progress was monitored by TLC/LCMS. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O, extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of hydrochloric acid (1 mol/L) and 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:1). This resulted in 1.12 g (63%) of product as a yellow to green solid. 1H-NMR (400 MHz, CDCl3, ppm): δ 11.68(s, 1H), 9.75(s, 1H), 8.60-8.56(d, J=9.2 Hz, 1H), 8.00(s, 1H), 7.91(s, 3H), 7.88-7.81(m, 2H), 7.80-7.79(d, J=2.1 Hz, 1H), 7.66-7.65(d, J=2.4 Hz, 4H), 7.53-7.38(m, 2H), 7.33-7.25(m, 1H), 7.10-7.08(m, 1H), 4.20(s, 2H), 3.17(s, 4H), 1.69-1.54(m, 6H). MS (ES, m/z): 700 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:8]([OH:10])=[O:9])[S:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>ClCCl.CO>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=[O:9])[S:6][CH:7]=1)=[O:16]
Reactant: CSc1csc(C(=O)O)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1csc(C(=O)O)c1
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A stirred solution of 2.46 g (14.1 mmoles) of 4-methylthio-2-thiophenecarboxylic acid (prepared as described in Example 28 below) in 150 ml dichloromethane and 10 ml methanol was cooled to icebath temperature. A 120 ml dichloromethane solution of 2.82 g (13.9 mmoles) of m-chloroperoxybenzoic acid (technical grade, 80-85%) was slowly added to the cooled reaction solution. After 1 hour the reaction was essentially complete with a colorless precipitate forming. The precipitate was filtered and dried to give 1.18 g (6.20 mmoles) of desired compound as a colorless solid, m.p. 188°-190° C. The concentrated mother liquor was chromatographed (silica gel) to give an additional 0.83 g (4.36 mmoles) of desired 4-methylsulfinyl-2-thiophenecarboxylic acid, total yield 75% (10.56 mmoles).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[Mg].[C:16]1([CH3:24])[C:17]([CH:22]=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>O1CCCC1>[CH3:24][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1)[OH:23]
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Reactant: Cc1ccccc1C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)c1ccc(C2=NC(C)(C)CO2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-bromophenyl)-4,4-dimethyl-2-oxazoline (1 g) in dry tetrahydrofuran (10 ml) are added dropwise magnesium (526 mg) and dry tetrahydrofuran (50 ml) under refluxing. The heating of the mixture is stopped, and thereto is added 2-(4-bromphenyl)-4,4-dimethyl-2-oxazoline (4 g) at a slowly refluxing rate, during which the mixture is stirred for 30 minutes, and then thereto is added o-tolualdehyde (2.16 ml) under ice-cooling. The mixture is stirred under ice-cooling for one hour, and stirred at room temperature for two hours, and the reaction is quenched with adding thereto a saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate, and the organic layer is washed successively with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=4~2:1) to give 2-{4-[1-(2-methylphenyl)-1-hydroxymethyl]phenyl}-4,4-dimethyl-2-oxazoline (3.07 g) as white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[C-:20]#[N:21].[K+].O>CS(C)=O>[C:14]1([C:5]2[O:6][C:7]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[C:3]([CH2:2][C:20]#[N:21])[N:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [C-]#N
Reactant: ClCc1nc(-c2ccccc2)oc1-c1cccnc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1nc(-c2ccccc2)oc1-c1cccnc1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 4-(chloromethyl)-2-phenyl-5-(pyridin-3-yl)oxazole (197 mg, 728 μmol) in DMSO (4 mL) was added at RT potassium cyanide (56.9 mg, 873 μmol). Stirring was continued for 1 h and the reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The organic phases were washed with water (2×20 mL) and brine (1×20 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 168 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow solid (80 mg, 306 μmol, 42.1%).
Reaction SMILES: C([Mg]Cl)(C)C.C1COCC1.[CH3:11][C:12]1([CH3:24])[O:16][C@@H:15]([CH2:17][N:18]2[CH:22]=[C:21](I)[CH:20]=[N:19]2)[CH2:14][O:13]1.CO[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1>>[CH3:11][C:12]1([CH3:24])[O:16][C@@H:15]([CH2:17][N:18]2[CH:22]=[C:21]([B:27]3[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]3)[CH:20]=[N:19]2)[CH2:14][O:13]1
Reactant: CC1(C)OC[C@H](Cn2cc(I)cn2)O1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.6 %

Procedure:
Isopropylmagnesium chloride in THF (2.0 M, 6.91 mL, 13.82 mmol) was added to a solution of 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-4-iodo-1H-pyrazole (Compound 5F, 2.13 g, 6.91 mmol) in THF (60 mL, 800 mmol) at rt. After 10 minutes, the mixture was treated with 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.40 mL, 20.74 mmol) and stirred for an additional 20 minutes at rt. The reaction was then quenched with sat. NH4Cl and the mixture was concentrated in vacuo to a solid. The crude product was dissolved in DCM, washed with water (2×), dried with sodium sulfate, filtered and concentrated in vacuo to a clear oil. The crude material was purified using a Teledyne ISCO Combiflash® Rf system [20% EtOAc/hexanes] to afford 1.12 g of the title compound (53%). 1H NMR (400 MHz, CD3OD) δ 7.74 (s, 1H), 7.50 (s, 1H), 4.36-4.44 (m, 1H), 4.21-4.34 (m, 2H), 4.05 (dd, J=6.3, 8.6 Hz, 1H), 3.73 (dd, J=5.9, 8.7 Hz, 1H), 1.31 (d, J=8.6 Hz, 6H), 1.25 (s, 12H). MS (ESI): m/z 309.00 [M+H]+. UPLC: tR=1.42 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCN(C(C)C)C(C)C.[NH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:20]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: NCC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of Boc-(D)-Arg(Tos)-OH (1 g, 2.34 mmol) in CH2Cl2 (10 mL) was added DIEA (1 mL) at 0° C. To the clear solution was added Gly-OBn.eHCl (0.52 g, 2.58 mmol) and BOP (1.2 g, 2.8 mmol). The solution was stirred for 4 h at 0° C. Solvents were evaporated and residue was dissolved in a mixture of EtOAc (100 mL) and water (20 mL). The organic layer was washed with sat. NaHCO3 (10 mL), water (10 mL), 1N HCl (10 mL) and sat. NaCl (3×10 mL), dried with MgSO4, filtered and evaporated. The solid residue was purified by column chromatography on silica gel (EtOAc) to give 1.12 g of the title compound as a powder. ES-MS (M+H)+=576.3
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:12]([NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCOCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CNCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
2-(Benzyloxy)ethanamine (12.3146 g; manufactured by Bionet Co., Ltd.) was dissolved in CH2Cl2 (150 mL), and benzaldehyde (8.7219 g; manufactured by Kanto Chemical Co., Inc.) and anhydrous sodium sulfate (67.7879 g; manufactured by Wako Pure Chemical Industries, Ltd.) were added to the solution. The mixture was stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (150 mL), and sodium borohydride (3.4129 g; manufactured by Kanto Chemical Co., Inc.) was added thereto. The mixture as stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, water added thereto, and then the mixture was extracted two times with ethyl acetate. The organic layer was washed twice with water and once with brine, and was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and thus the title compound (20.188 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:23][C:24]1[S:28][C:27]([NH2:29])=[N:26][CH:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:29][C:27]2[S:28][C:24]([CH3:23])=[CH:25][N:26]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)s1
Reaction time: 2 h
Yield: 69.8 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 84 mg, 0.24 mmol), 5-methyl-thiazol-2-ylamine (28 mg, 0.24 mmol) and N,N-diisopropylethylamine (127 μL, 0.73 mmol) were combined in methylene chloride (2 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(5-methyl-thiazol-2-yl)-acetamide (74 mg, 69%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C18H20ClN3O4S2 [M+] 441.06, found 442 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.66 (m, 4 H, 2×CH2), 1.89 (m, 4 H, 2×CH2), 2.45 (d, J=1.2 Hz, 3 H, ArCH3), 3.31 (s, 3 H, SO2CH3), 4.93 (m, 1 H, OCH), 7.15 (brq, 1 H, Ar), 7.59 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.70 (d, Jm=1.5 Hz, 1 H, Ar), 8.21 (d, Jo=8.2 Hz, 1 H, Ar), 10.03 (s, 1 H, NH).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=O)[CH3:8])[CH3:3].[CH3:12][C:13]([CH3:15])=[O:14]>>[CH3:3][C:2]([CH3:1])=[CH:4][CH2:5][CH2:6]/[C:7](/[CH3:8])=[CH:9]/[CH:10]=[CH:12]/[C:13]([CH3:15])=[O:14]
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: CC(C)=O
Product: CC(=O)/C=C/C=C(\C)CCC=C(C)C

Procedure:
WO 2003/047747 and WO 2003/047748 (publ. Jun. 12, 2003) describe metal oxide catalysts based on γ-aluminum oxide, their use during the aldol condensation of citral and acetone to give pseudoionone, and also special columns for carrying out the reaction by reactive distillation. The metal oxides are oxides of the elements with the atomic numbers 39 (Y) and 57 (La)-71 (Lu), with yttrium oxide and praseodymium oxide being emphasized as being preferred. When using a catalyst of 5% Pr on γ-Al2O3, in the 24 hour operation, pseudoionone was obtained with a yield of 66.7% and a selectivity of 97.3% based on citral. The concentration of the active components based on the total weight of the supported catalyst is in the range of 5 to 12% by weight, preferably 7.5 to 10% by weight. Whereas, as a result of extensive screening investigations, γ-Al2O3 has proven to be a particularly suitable support material, which relates to the activity of the catalyst, it is emphasized that both the geometry of the catalyst support and also the maintenance of the aforementioned concentrations are of decisive importance for obtaining good space-time yields.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][CH:8]=2)[C:4](=[O:18])[CH2:3]1.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:11]([C:10]4[CH:9]=[CH:8][C:7]([N:5]5[CH2:6][CH:2]([CH3:1])[CH2:3][C:4]5=[O:18])=[CH:17][CH:16]=4)=[O:13])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1ccc(N2CC(C)CC2=O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)CC3=O)cc2)CC1
Yield: 22.9 %

Procedure:
Using ethyl 4-(4-methyl-2-oxopyrrolidin-1-yl)benzoate (124 mg) described in Preparation Example 48 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (109 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (48 mg) was obtained.