Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][CH:4]=1)#N.[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+].O.[CH3:27][N:28](C)C=O>>[OH:16][B:15]1[C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([N:20]4[CH:27]=[N:28][N:22]=[N:21]4)=[CH:19][CH:18]=3)=[CH:17][C:12]=2[CH2:13][O:14]1
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: OB1OCc2cc(Oc3ccc(-n4cnnn4)cc3)ccc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 23 %

Procedure:
A mixture of 5-(4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole (200 mg, 0.797 mmol), sodium azide (103 mg, 1.59 mmol), and ammonium chloride (85 mg, 1.6 mmol) in N,N-dimethylformamide (5 mL) was stirred at 80° C. for two days. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) followed by trituration with ethyl acetate to give the target compound (55 mg, 23%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:52][CH:53]1[C:79](=[O:80])[N:55]2[C:56]([C:63]([O:65][CH:66]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[O:64])=[C:57]([CH:60]=[CH:61][CH3:62])[CH2:58][S:59][C@H:54]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>ClCCl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)/[C:27]([NH:52][CH:53]2[C:79](=[O:80])[N:55]3[C:56]([C:63]([O:65][CH:66]([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[C:73]4[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=4)=[O:64])=[C:57](/[CH:60]=[CH:61]\[CH3:62])[CH2:58][S:59][C@H:54]23)=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Product: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetic acid (873 mg, 1.30 m moles) and dichloromethane (5 ml) was added phsophorous pentachloride (297 ng, 1.43 m moles) at -5° C. The mixture was allowed to stand for 20 min at the same temperature and added dropwise to a solution of diphenylmethyl 7-amino-3-(1-propenyl)-3-cephem-4-carboxylate hydrochloride (443 mg, 1 m mole) and N,O-bis(trimethylsilyl)acetamide (0.74 ml, 4.4 m moles) in dichloromethane (5 ml) at -5° C. The reaction mixture was allowed to stand for 20 min. at the same temperature and poured into ice-water. Extraction of the mixture with ethyl acetate and evaporation of the extracts under reduced pressure gave the crude product as an oil, which was chromatographed on a column of silica gel (eluted with chloroform) to give the title compound as an amorphous powder. Yield 510 mg (48%).
Reaction SMILES: [CH2:1]([O:3][C:4](C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[CH2:26]([N:28]([CH2:39][CH3:40])[C:29]1[CH:34]=[CH:33][C:32]([C:35](=O)[CH3:36])=[C:31]([OH:38])[CH:30]=1)[CH3:27].[C:41]1(C)C=CC=CC=1>>[CH2:1]([O:3][C:4](=[O:5])[CH:36]=[C:35]([C:32]1[CH:33]=[CH:34][C:29]([N:28]([CH2:39][CH3:40])[CH2:26][CH3:27])=[CH:30][C:31]=1[OH:38])[CH3:41])[CH3:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Reactant: CCN(CC)c1ccc(C(C)=O)c(O)c1
Product: CCOC(=O)C=C(C)c1ccc(N(CC)CC)cc1O

Procedure:
To a suspension of 5.27 g ethoxycarbonylmethylenetriphenylphosphorane in 10 ml of toluene, a solution of 2.02 g 1-(4-diethylamino-2-hydroxy-phenyl)ethanone (DE 28 44 606) was dropped in at room temperature. Then the reaction mixture was heated to reflux. After refluxing for 31 hours the mixture was cooled down and evaporated to dryness. The resulting dark oil was purified by chromatography to yield a colourless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][O:35]1.O>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][O:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCO3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirring mixture of 2-butoxy-8-methoxy-1H-purin-6-amine trifluoroacetate salt (200 mg) and potassium carbonate (236 mg) in dry N,N-dimethylformamide (2 ml) was heated with stirring at 60° C. for 1 h. 2-(2-Bromoethyl)tetrahydrofuran (122 mg) was added and the stirring mixture heated at 50° C. for 4 h. After allowing to cool, water was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and stripped to give a brown oil. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to afford the title compound as a clear oil, yield 122 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:35])=[C:4]([N:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)[CH:5]=[C:6]([N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)CCl>[NH2:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:9](=[O:10])[O:11][CH3:12])[CH:5]=[C:4]([N:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)[C:3]=1[F:35].[C:38]([OH:40])([C:37]([F:42])([F:41])[F:36])=[O:39]
Reactant: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl 4-(3-amino-2-fluoro-5-((4-methoxybenzyl)(methoxycarbonyl)amino)phenyl)piperazine-1-carboxylate (317 mg, 0.474 mmol) was dissolved in ClCH2CH2Cl (4 ml): Trifluoroacetic acid (1 ml; 12.98 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours, then evaporated to dryness. 470.1 mg crude methyl (3-amino-4-fluoro-5-(piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate, TFA (470.1 mg) were isolated.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH:5]([CH3:8])[CH2:4][NH:3]1.C(N(CC)CC)C.[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26]([N:3]3[CH2:4][CH:5]([CH3:8])[NH:6][CH2:7][CH:2]3[CH3:1])(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC1CNC(C)CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1CN(S(=O)(=O)c2cccc3cnccc23)C(C)CN1
Reaction time: 3 h
Yield: 59.5 %

Procedure:
In 30 ml of methylene chloride were dissolved 1.75 g of 2,5-dimethylpiperazine and 1.53 g of triethylamine, and to the solution was added dropwise 20 ml of a methylene chloride solution containing 1.73 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the methylene chloride solution, the mixed solution obtained was stirred at a temperature of 5° C. to 10° C. for three hours, and then the reaction mixture solution was washed with water and dried with anhydrous magnesium sulfate. After the methylene chloride was distilled therefrom, the residue obtained was subjected to an alumina column chromatography (alumina: 50 g; solvent: chloroform) to give 1.38 g of 1-(5-isoquinolinesulfonyl)-2,5-dimethylpiperazine, Compound (40) in a yield of 59%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl.[OH-].[Na+]>[Cl:9][C:5]1[CH:6]=[C:7]2[C:2]([NH:1][C:16](=[O:20])[C:17](=[O:18])[NH:8]2)=[C:3]([C:10]([F:13])([F:11])[F:12])[CH:4]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(Cl)cc(C(F)(F)F)c2[nH]c1=O
Temperature: 25 °C
Yield: 50.5 %

Procedure:
A mixture of 2,3-diamino-5-chlorobenzotrifluoride (180 mg, 0.86 mmol) and oxalic acid dihydrate (108 mg, 0.86 mmol, used as received) in 2N HCl (4 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed by cold water (2×2 mL), collected by filtration, and dried at 60° C. for 2 h, affording 136 mg of crude title compound (53%) as a yellow powder. The crude title compound was dissolved in 1N NaOH (6 mL) and filtered. The filtrate was acidified to pH =6, affording 115 mg of title compound. Recrystallization from DMSO/H2O gave 95 mg of pure title compound (37%) as yellow microcrystals. Mp: 302°-4° C. (dec. from 295° C.). IR (KBr, cm-1) 3401, 3255, 1754, 1694, 1528. 1H NMR (DMSO-d6): a 7.374 (d, 1H, J=1.8 Hz); 7.474 (d, 1H, J=1.8 Hz); 11.347 (s, 1H); 12.215 (s, 1H). HRMS: calcd for C9H4ClF3N2O2 (M+) m/z: 263.9912; found: 263.9909.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH2:20]=O>CO>[CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH:6][CH2:20][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[S:5]
Reactant: C1CCNCC1
Reactant: CC(C)C(C(N)=S)c1ccccn1
Reactant: C=O
Solvent: CO
Product: CC(C)C(C(=S)NCN1CCCCC1)c1ccccn1
Temperature: -60 °C
Reaction time: 72 h

Procedure:
A solution of 1.0 g. (0.005 mole) of 3-methyl-2-(2-pyridyl)thiobutanamide in 20 ml. of methanol is treated with 0.65 g. (0.0075 mole) of piperidine and then with 0.23 g. of formaldehyde. The mixture is kept for 72 hours at 25°C., then concentrated in vacuo at 25°C. The residue is suspended in water and then extracted into chloroform. The chloroform is evaporated from the extracts and the residue is dissolved in hexane and cooled to -60°C. on a dry ice bath. Upon warming to 25°C., the hexane solution was decanted from insoluble oil and then evaporated in vacuo. The residue is vacuum dried at 0.005 mm. and 25°C. to give 3-methyl-N-piperidinomethyl-2-(2-pyridyl)thiobutanamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.Cl.[F:62][C@@H:63]1[CH2:67][CH2:66][NH:65][CH2:64]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22]([N:65]3[CH2:66][CH2:67][C@@H:63]([F:62])[CH2:64]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 96.5 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.140 g, 0.54 mmol), triethylamine (0.4 mL, 2.6 mmol) and (R)-3-fluoropyrrolidine hydrochloride (68 mg, 0.54 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-((R)-3-fluoro-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 25a (0.162 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[C:11]=2[Cl:18])[C:4]([C:19]([OH:21])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.[NH3:28].O1CCOCC1>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[C:11]=2[Cl:18])[C:4]([C:19]([NH2:28])=[O:21])=[CH:3]1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Cl)c(Cl)c2Cl)cc1=O
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(C(N)=O)c(Nc2ccc(Cl)c(Cl)c2Cl)cc1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product of Example 65, 1-methyl-6-oxo-4-(2,3,4-trichloro-phenylamino)-1,6-dihydro-pyridine-3-carboxylic acid (0.4 g, 1.15 mmol) was dissolved in DCM (20 mL). Added one drop of DMF and then oxalyl chloride (0.11 mL, 1.27 mmol) was added. Reaction was stirred at rt for 1.5 hours. Then 0.5 N NH3/dioxane (10 mL) was added and stirred for 72 hours. The solvent was removed in vacuum. Ethyl acetate was added and washed with sat. NaHCO3 soln. Filtered solid and dried in vacuum oven 1 hour. Tried to recrystalize using hexanes (5 mL) and EtOAc (30 mL) but never dissolved. Solvent removed in vacuum and took the residue up in ethyl acetate (10 mL)/MeOH (2 mL). Still did not dissolve. Cooled, filtered and dried in vacuum oven overnight at 60° C. Obtained white solid (210.0 mg, 52.7% y.). MS (APCI+) 347,349 [M+H]; HPLC 2.954 m. 94.68%; C13H10Cl3N3O2; CHN Calc. C)45.05% H)2.91% N)12.12% found C)27.56% H)1.29% N)3.96%; NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 8.11 (s, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H), 5.67 (s, 1H), 3.31 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[C:4]=1[CH2:11][OH:12].N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].O>O1CCCC1>[Si:22]([O:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:11][OH:12])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: COc1cccc(CO)c1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CO[Si](C)(C)C(C)(C)C)c1CO
Temperature: 0 °C
Yield: 52.9 %

Procedure:
3-Methoxy-1,2-benzenedimethanol (1.30 g, 7.73 mmol) obtained from Example 21-(1) was dissolved in tetrahydrofuran (15 ml), and imidazole (526.2 mg, 7.73 mmol) and tert-butylchlorodimethylsilane (1.165 g, 7.73 mmol) were added thereto at 0° C. with stirring. The mixture was stirred at room temperature for 2 hours, then water was added thereto, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel (60 g) column (eluent; ethyl acetate:hexane=1:4) to afford the title compound (1.156 g, 53% yield) as an oil.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13]CCCCC.[CH2:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[O-2].[Ba+2:35].[C:36](=[O:38])=[O:37]>O>[C:36](=[O:19])([O-:38])[O-:37].[Ba+2:35].[CH2:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O-:33])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[Ba+2:35].[CH2:7]([C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[O-:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: CCCCCCCc1ccccc1O
Reactant: O=C=O
Agent: [Ba+2]
Agent: [O-2]
Solvent: O
Product: CCCCCCCc1ccccc1[O-]
Product: O=C([O-])[O-]

Procedure:
To a mixture of 268 grams (1.0 equivalent) oleyl alcohol, 124 grams (0.6 equivalent) of heptylphenol, 1000 grams of mineral oil, and 190 grams of water was added at 70° C. 306 grams (4.0 equivalents) of barium oxide. This mixture was heated at reflux temperature for an hour and then treated with carbon dioxide at 150° C. until the mixture was neutral. The mixture was filtered through Hyflo to yield a liquid product having the following analyses:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:27](OCC=C)[CH:28]=[CH2:29].C([OH:37])C=C>>[CH2:29]([C:3]1[CH:4]=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:2]=1[OH:37])[CH:28]=[CH2:27]
Reactant: C=CCO
Reactant: C=CCOCC=C
Reactant: Clc1ccc(-c2c(-c3ccccc3Cl)nn3c(Cl)ccnc23)cc1
Agent: [H-]
Agent: [Na+]
Product: C=CCc1cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c1O
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a suspension of 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (I-13A-1a; 1.72 g, 4.6 mmol) in allyl alcohol (50 ml) at 0° C. was added NaH (60% dispersion in oil, 0.28 g, 6.9 mmol), portionwise over 3 minutes. After warming to room temperature, the reaction was stirred overnight. The resultant allyl ether was then heated at 125° C. for 1.5 hours to facilitate the rearrangement. The reaction was concentrated, in vacuo, to give a residue which was partitioned between ethyl acetate and water adjusted to pH=4 with 1M aqueous HCl. The organic layer which contained dispersed solids was separated, washed with brine, and the solids then collected by vacuum filtration to give product I-15A-1a (1.24 g, 68%) as a solid: +ESI MS (M+1) 396.4; 1H NMR (400 MHz, CD3OD) δ 7.64 (s 1H), 7.52–7.48 (m, 1H), 7.43–7.48 (m, 3H), 7.30 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 6.06–5.92 (m, 1H), 5.21–5.14 (m, 1H), 5.12–5.07 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([C:14]2[NH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[NH2:23]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O>[NH2:23][N:15]1[C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=[C:14]1[C:12]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Br:1])[CH:11]=1)=[O:13]
Reactant: CCc1ccc(C(=O)c2ccc(C(=O)OC)c(Br)c2)[nH]1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)c2ccc(C(=O)OC)c(Br)c2)n1N
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of methyl 2-bromo-4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate (330 mg) in N,N-dimethylformamide (5 mL) was added 60% sodium hydride in oil (58.4 mg) in an ice-bath over 5 miutes. After stirring for 1 hour, (aminooxy)(diphenyl)phosphine oxide (340 mg) was added portionwise over 40 minutes. The resulting mixture was stirred for 1 hour in the bath. The reaction was quenched by adding water (10 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (two times) and brine, dried over magnesium sulfate, and evaporated. The residue was dissolved in ethyl acetatec-hexane (1-5), and to the solution was added silicagel. The mixture was filtered, and the filtrate was evaporated to give methyl 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-2-bromobenzoate as an orange solid (310 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1.ClC1C=CC=C(C(OO)=[O:28])C=1.C(=O)([O-])O.[Na+].N([O-])=O.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:28])=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[O:19])[CH2:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc[n+]([O-])c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In benzene (4 ml) was dissolved 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (272 mg), and to the solution was added m-chloroperbenzoic acid (267 mg). The mixture was stirred at room temperature for 1 hour, and to the mixture were added ethyl acetate (70 ml), saturated sodium hydrogen carbonate solution (30 ml) and sodium nitrite (100 mg). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was washed with ethyl acetate and dried to give 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-1-oxide (205 mg) as pale yellow crystals.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.C(O)(=O)C.[F:10][C:11]([F:39])([F:38])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[NH:22][C:23]1[N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:27](=[O:33])[CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=1.C(=O)(O)[O-].[Na+]>CCOCC>[F:39][C:11]([F:38])([F:10])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=1[NH:22][C:23]1[N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:27](=[O:33])[C:26]([Cl:4])=[C:25]([C:34]([F:35])([F:36])[F:37])[N:24]=1
Reactant: CC(C)Cn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)Cn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
Sulfuryl chloride (0.16 ml) was added to acetic acid (14 ml) solution of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-isobutyl-6-trifluoromethyl-4(3H)-pyrimidinone (630 mg, 1.41 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, ether (50 ml) and saturated sodium bicarbonate aqueous solution (50 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ether (30 ml×2). The thus obtained ether layers were combined, washed with sodium bicarbonate aqueous solution (50 ml) and saturated brine (50 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. By purifying the thus obtained crude product by a column chromatography (dichloromethane:hexane=7:3), white solid of 2-{2,5-bis(trifluoromethyl)phenyl}amino-5-chloro-3-isobutyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 57] was obtained.