Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[NH:3]1>CN(C=O)C.[O-2].[Mn+4].[O-2]>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[NH:3]1
Reactant: O=c1[nH]c2ccc(CO)cc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]c(=O)[nH]c2c1

Procedure:
25.7 g (0.157 mol) of 20b in DMF are stirred with 81.7 g (0.939 mol) of manganese(IV) oxide for 2 days in analogy to Example 8b.
Reaction SMILES: [SH:1][CH2:2][C:3]([NH2:5])=[O:4].[Cl:6][C:7](=[CH2:12])[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:12][S:1][CH2:2][C:3]([NH2:5])=[O:4]
Reactant: NC(=O)CS
Reactant: C=C(Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Cl)CSCC(N)=O
Yield: 85.8 %

Procedure:
2-Mercaptoacetamide (10.0 g) and methyl 2-chloroacrylate (13.24 g) were dissolved in warm acetone (100 ml), and potassium carbonate (7.58 g) was added in one portion. Heat was evolved. The mixture was heated to reflux for 2 hours. The red solution was filtered hot using a filter aid, and the residue washed with hot acetone (×2). The filtrate and washings were combined and evaporated to obtain the title compound as a red oil (19.92 g) 1H n.m.r. δ (CDCl3 /DMSO-d6) 3.05-3.18 (4H, overlapping s and d, CH2COR and CH2CH) 3.76 (3H,s,CO2Me), 4.67 (1H,t, J=7Hz, CHCH2), 6.92 (1H, br s, CONH), 7.43 (1H, br s, CONH).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.Cl.O1CCCCC1[N:25]1[C:29]2[CH:30]=[CH:31][C:32]([C@@H:34]([NH2:36])[CH3:35])=[CH:33][C:28]=2[N:27]=[CH:26]1.CCN(C(C)C)C(C)C>CCCCO>[NH:25]1[C:29]2[CH:30]=[CH:31][C:32]([C@@H:34]([NH:36][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:13]=[C:12]([CH:14]5[CH2:16][CH2:15]5)[NH:11][N:10]=4)[C:5]([Cl:17])=[CH:4][N:3]=3)[CH3:35])=[CH:33][C:28]=2[N:27]=[CH:26]1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Reactant: C[C@H](N)c1ccc2c(c1)ncn2C1CCCCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc2[nH]cnc2c1
Temperature: 160 °C

Procedure:
To a solution of 57 (135 mg, 0.5 mmol) in n-BuOH (3 mL) in a microwave vial was added 126 (184 mg, 0.75 mmol), then DIPEA (0.26 mL, 1.5 mmol) was added dropwise. The vial was sealed with a rubber septa and heated in the microwave for 90 min at 160° C. The solvent was evaporated under reduced pressure and the crude residue was taken up in DCM (5 mL) and MeOH (5 mL) and the solvent was again concentrated in vacuo. The residue was diluted in DMF (2 mL) and filtered to remove any undissolved solids. The filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC to afford 13 mg (6%) of I-46.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[CH:5]([OH:7])[CH3:6].Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]#[N:18])[CH:12]=1.[Cl-].[NH4+]>CN(C)C=O>[F:3][C:4]([F:9])([F:8])[CH:5]([CH3:6])[O:7][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]#[N:18])[CH:12]=1
Reactant: N#Cc1cc(Cl)ccn1
Reactant: CC(O)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(Oc1ccnc(C#N)c1)C(F)(F)F
Reaction time: 0.67 h
Yield: 78.5 %

Procedure:
Into 6 ml of N,N-dimethylformamide was suspended 0.16 g of sodium hydride (60% oily), and 0.4 g of 1,1,1-trifluoro-2-propanol was added at 10° C. After stirring for 40 minutes, 0.4 g of 4-chloropyridine-2-carbonitrile was added, the mixture was stirred for 2 hours, and the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert-butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.49 g of 4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carbonitrile.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl[CH2:19][C:20](Cl)=[O:21]>C(#N)C>[CH2:1]([N:8]1[C:20](=[O:21])[CH2:19][O:11][CH2:10][C@H:9]1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: O=C(O)[C@H](CO)NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(O)[C@@H]1COCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
A 5 L 3-neck round bottom flask was charged with (S)-(+)-N-benzylserine (229 g, 1.17 mol), sodium hydroxide (58.7 g, 1.47 mol), and water (1 L). The resulting solution was cooled to 0° C. and chloroacetyl chloride (170.4 g, 1.5 mol) added dropwise at a rate to maintain the temperature below 4° C. After addition was complete the reaction was stirred at 0° C. for 30 minutes. The cold bath was then removed and a solution of 30% sodium hydroxide (350 mL) added. An exotherm was observed and the reaction temperature reached 29° C. The reaction mixture was further heated to 33° C. and maintained at this temperature for 2 hours. Cooling to room temperature followed by acidification to pH 1 with 37% hydrochloric acid resulted in the formation of a thick white precipitate, which was isolated by filtration. The filter cake was slurried in acetonitrile (1 L), filtered, and the filtrate concentrated. Drying of the resulting solid afforded 68.1 g (25%) of (S)-(+)-4-benzylmorpholin-5-one-3-carboxylic acid as a crystalline white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]([CH3:30])=[C:7]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[CH3:41][C:42]1[CH:43]=[CH:44][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:46][CH:47]=1.O>CN(C=O)C.CCOC(C)=O.O>[C:42]1([CH3:41])[CH:43]=[CH:44][C:45]([S:48]([OH:51])(=[O:49])=[O:50])=[CH:46][CH:47]=1.[CH3:3][C:4]1[N:5]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:6]([CH3:30])=[C:7]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:22])([F:24])[F:23])[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reactant: ClCCN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1=C(C)N(CCN2CCOCC2)C(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Temperature: 3 °C
Reaction time: 4.5 h
Yield: 66.5 %

Procedure:
A suspension of 30.3 g (0.758 mol) of 60% NaH in mineral oil in 164 ml of DMF was cooled to 3° C. and a solution of 100.0 g (0.252 mol) of diethyl 1,4-dihydro-2,6-dimethyl-4-[2-(trifluoromethyl)phenyl]3,5-pyridinedicarboxylate in 100 ml of warm DMF was added dropwise over 30 min, keeping the temperature at 15° C. or less. After the addition was complete, 75.5 g (0.406 mol) of N-(2-chloroethyl)morpholine hydrochloride was added in portions over 25 min, keeping the temperature at approximately 15° C. The cooling bath was then replaced with a heating mantle and the reaction mixture was heated at 84°-100° C.for 4.5 hrs. After cooling to 31° C. over 50 min, the reaction mixture was poured into a stirred mixture of 500 ml of H2O and 300 ml of EtOAc. When all the solids dissolved, the phases were separated and the EtOAc phase was dried over anhydrous Na2SO4 and filtered. To this stirred EtOAc solution was added a solution of 47.9 g (0.252 mol) of p-TSA H2O in 300 ml of EtOAc, giving immediate precipitation of diethyl 1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)-ethyl]-4-[2-(trifluoromethyl)-phenyl]-3,5-pyridinecarboxylate p-toluenesulfonate salt. After stirring for 20 min, the product was collected, washed with EtOAc, and dried in vacuo to yield 114.5 g (67%) of diethyl 1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)ethyl]-4-[2-(trifluoromethyl)-phenyl]-3,5-pyridinedicarboxylate p-toluenesulfonate salt as a white solid: mp 204°-206° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:11][CH2:12][N:13]([C:30]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:31])[CH2:14][CH2:15]2)=[N:4][CH:3]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCN(C(=O)N3CCCCC3)CC2)CC1

Procedure:
Prepared in a similar manner to Example 554 using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and 1-piperidinecarbonyl chloride
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:16][C:17]1[CH:18]=[N:19][NH:20][CH:21]=1.C([O-])([O-])=O.[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[F:12][C:11]([F:14])([F:13])[CH:10]([C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[N:19]1[CH:18]=[C:17]([CH3:16])[CH:21]=[N:20]1)[OH:15]
Reactant: COc1ccc(Br)c(C(O)C(F)(F)F)c1
Reactant: Cc1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-n2cc(C)cn2)c(C(O)C(F)(F)F)c1
Temperature: 130 °C
Yield: 15.7 %

Procedure:
1-(2-Bromo-5-methoxy-phenyl)-2,2,2-trifluoro-ethanol (0.570 g, 2.0 mmol), 4-methyl pyrazole (0.164 g, 2.0 mmol), CuI (0.057 g, 0.3 mmol), K2CO3 (0.580g, 4.2 mmol), (1R,2R)-N,N′-dimethyl-cyclohexane-1,2-diamine (0.071 g, 0.5 mmol) and toluene (10 ml) were combined in a 20 ml pressure tube, and the mixture was heated at 130° C. (oil bath temperature) for 12 h. The mixture was diluted with ethyl acetate and washed with H2O (2×20 ml), brine, and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography using 5-10% ethyl acetate in hexane as solvent to afford 2,2,2-trifluoro-1-[5-methoxy-2-(4-methyl-pyrazol-1-yl)-phenyl]-ethanol (90 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]1([N:19]2[CH:24]=[C:23]([CH:25]=[CH2:26])[CH:22]=[CH:21][C:20]2=[O:27])[CH2:18][CH2:17]1.[OH-].[K+]>CN1C(=O)CCC1>[CH:16]1([N:19]2[CH:24]=[C:23]([CH2:25][CH2:26][N:6]3[C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=4[C:4]4[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]3=4)[CH:22]=[CH:21][C:20]2=[O:27])[CH2:18][CH2:17]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(=O)n(C2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(=O)n(C3CC3)c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 1-cyclopropyl-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP, at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:18].[C:19](O)(=[O:23])[C:20](O)=[O:21].S(=O)(=O)(O)O>CN(C)C=O>[NH:1]1[C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8]([C:7](=[O:17])[C:6]=3[CH:5]=[CH:4][C:3]=2[NH:18][C:20](=[O:21])[C:19]1=[O:23])=[CH:9][CH:10]=[CH:11][CH:12]=4
Reactant: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Reactant: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)c2c1ccc1[nH]c(=O)c(=O)[nH]c21
Reaction time: 16 h

Procedure:
1,2-Diaminoanthraquinone (1.19 g, 5 mmol) is dissolved in N,N-dimethylformamide (30 mL), and oxalic acid (0.46 g, 5 mmol) and concentrated sulfuric acid (0.1 mL) is added thereinto. After reverse flow for 16 hours, the reacted mixture is transferred into icy water (200 mL) for precipitation. The precipitate is collected and washed by hot alcohol and, so as to obtain the black compound 26, and the production rate is 30%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[Cl:10])(=O)[CH3:2].[CH:11]([NH:13][NH2:14])=[O:12]>C(O)C>[Cl:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[C:1](=[N:14][NH:13][CH:11]=[O:12])[CH3:2]
Reactant: NNC=O
Reactant: CC(=O)c1ccncc1Cl
Solvent: CCO
Product: CC(=NNC=O)c1ccncc1Cl

Procedure:
A mixture of 6.30 gm (0.0405 mole) of 4-acetyl-3-chloropyridine, 2.46 gm (0.041 mole) of formic acid hydrazide and 100 ml of ethanol was refluxed 18 hr. The mixture was chilled in the freezer to give a solid which was collected in two crops. The product was purified by chromatography [keiselgel 60 (230-400 mesh)] and eluting with 5% methanol/methylene chloride to give 2.56 gm (32%) of white flakes which have a melting point of 175.2° C.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>C(=S)=S.C(OCC)(=O)C>[C:18]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCCCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: CCOC(C)=O
Product: CCCCCCCC(=O)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 10.00 g (60.2 mM) of fluorene in 100 ml of dry carbon disulfide, 9.40 g (70.5 mM) of anhydrous aluminum chloride was added while being cooled on an ice-common salt bath. Under cooling on the bath, 10.3 ml (60.3 mM) of octanoylchloride was gradually added dropwise to the mixture at -2.5° to 1° C., followed by stirring for 2 hours and 50 minutes without cooling on the bath. After the reaction, the reaction mixture was poured into a mixture of 150 g of ice and 50 ml of hydrochloric acid. To the resultant mixture, 100 ml of ethyl acetate was added, followed by stirring at room temperature to precipitate a crystal. The crystal was recovered by filtration and recrystallized from acetone to obtain 3.70 g of 2-octanoylfluorene. The organic layer separated from the filtrate was washed with water, dried with anhydrous sodium sulfate, and condensed into about 100 ml of the resultant solution, followed by cooling on an ice bath to precipitate a crystal. The crystal was recovered by filtration and recrystallized from acetone to obtain 4.09 g of 2-octanoylfluorene. The total amount of 2-octanoylfluorene obtained was 7.79 g (Yield: 44.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1cc(Cl)ccc1Cl
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3cc(Cl)ccc3Cl)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) and 2,5-dichlorophenylboronic acid (191 mg, 1.0 mmol) to afford after chromatographic purification the title compound (105 mg, 47%). 1H NMR (CDCl3, 300 MHz) δ 7.30–7.36 (m, 2H), 7.15–7.19 (m, 1H), 7.01 (s, 1H), 3.82–4.22 (m, 2H), 3.82–3.96 (m, 1H), 2.82–3.52 (m, 7H), 1.82–1.90 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 445 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=O)[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.[CH3:33][O:34][NH2:35]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=[N:35][O:34][CH3:33])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CON
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C=O
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C=NOC
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate obtained by the method described in Example (28a) (100 mg, 0.21 mmol) was dissolved in pyridine (3 mL). Methoxyamine hydrochloride (28 mg, 0.34 mmol) was added, and the mixture was stirred at 60° C. for two hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with 1 N hydrochloric acid and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, ethyl acetate) to obtain 107 mg of the title compound (100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:37]([CH3:36])(=[O:39])=[O:38])=[C:5]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C#N
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C(C#N)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (71.2 mg, 150 μmol) was initially charged in dry THF (3 ml), and sodium hydride (60% in mineral oil; 8.4 mg, 210 μmol; 1.4 eq.) was added at 0° C. The mixture was warmed to RT and stirred for 20 min. A solution of methanesulfonyl chloride (24.1 mg, 210 μmol; 1.4 eq.) in THF (1 ml) was then slowly added dropwise. After a reaction time of 20 h, the reaction mixture was concentrated and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). This gave the title compound as a colorless solid (70 mg, 84% of theory).
Reaction SMILES: [CH:1]1([C:7]2[NH:8][C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:10]([C:12]([O:14]C)=[O:13])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].O>C(O)C>[CH:1]1([C:7]2[NH:8][C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:10]([C:12]([OH:14])=[O:13])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1nc(C2CCCCC2)[nH]c1-c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2[nH]c(C3CCCCC3)nc2C(=O)O)cc1
Yield: 45.5 %

Procedure:
Methyl 2-cyclohexyl-5-(4-methylphenyl)imidazole-4-carboxylate (900 mg) was dissolved in ethyl alcohol (20 ml). Lithium hydroxide hydrate (1.1 g) and water (10 ml) were added, and the mixture was refluxed under heating for 2.5 hr and concentrated under reduced pressure. To the obtained residue were added water and ethyl acetate, and the mixture was partitioned. The aqueous layer was filtered, and aqueous citric acid was added to the filtrate. The precipitated crystals were collected by filtration to give 2-cyclohexyl-5-(4-methylphenyl)imidazole-4-carboxylic acid (390 mg), melting point 205-206° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]([Mg]Br)#[C:16][CH3:17].C(=O)([O-])O.[Na+]>O1CCCC1>[OH:1][C:2]1([C:15]#[C:16][CH3:17])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC#C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (2.99 g) was dissolved in 30 ml of tetrahydrofuran, cooled down to −78° C., 40 ml of a 0.5N solution of 1-propynyl magnesium bromide in 40 ml of tetrahydrofuran was dropped thereinto and temperature of the mixture was raised to room temperature followed by stirring for one night. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution to stop the reaction and the product was extracted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride and dried over sodium sulfate. The solvent was evaporated in vacuo and the resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1.41 g of the title compound as a crude product.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(#N)C.[Cl:31][C:32]1[CH:40]=[C:39]2[C:35]([C:36]3([C@@H:45]([C:46]4[CH:51]=[CH:50][N:49]=[C:48]([Cl:52])[CH:47]=4)[C@H:44]([C:53]([NH:55][C@@H:56]4[CH2:61][CH2:60][C@@H:59]([C:62]([OH:65])([CH3:64])[CH3:63])[O:58][CH2:57]4)=[O:54])[N:43]([C@H](C4C=CC=CC=4)[C@@H](O)C4C=CC=CC=4)[C:42]43[CH2:85][CH2:84][C:83]([CH3:87])([CH3:86])[CH2:82][CH2:81]4)[C:37](=[O:41])[NH:38]2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:31][C:32]1[CH:40]=[C:39]2[C:35]([C@@:36]3([C@@H:45]([C:46]4[CH:51]=[CH:50][N:49]=[C:48]([Cl:52])[CH:47]=4)[C@H:44]([C:53]([NH:55][C@@H:56]4[CH2:61][CH2:60][C@@H:59]([C:62]([OH:65])([CH3:64])[CH3:63])[O:58][CH2:57]4)=[O:54])[NH:43][C:42]43[CH2:85][CH2:84][C:83]([CH3:87])([CH3:86])[CH2:82][CH2:81]4)[C:37](=[O:41])[NH:38]2)=[CH:34][CH:33]=1
Reactant: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)N[C@@H]1CC[C@@H](C(C)(C)O)OC1)[C@H](c1ccnc(Cl)c1)C21C(=O)Nc2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: CC#N
Product: CC1(C)CCC2(CC1)N[C@@H](C(=O)N[C@@H]1CC[C@@H](C(C)(C)O)OC1)[C@H](c1ccnc(Cl)c1)[C@]21C(=O)Nc2cc(Cl)ccc21
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
Cerium (IV) diammonium nitrate (132 mg, 0.24 mmol) was added to an acetonitrile (10 ml)/water (3 ml) solution of the compound (98 mg, 0.12 mmol) obtained in Step 1 above under ice cooling and the resulting mixture was stirred for 10 minutes. Potassium carbonate (65 mg, 0.48 mmol) was added to the reaction mixture and insoluble matter was removed by filtration through celite. The filtrate was diluted with ethyl acetate, washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in chloroform (9 ml) and methanol (1 ml), silica gel (980 mg) was added and the resulting mixture was stirred overnight at room temperature. Insoluble matter was removed by filtration and the residue was purified by NH-silica gel column chromatography (chloroform) to give 39 mg (53%) of the title compound as a colorless solid.