Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[CH:11]1([CH2:14][C:15](O)=[O:16])[CH2:13][CH2:12]1.C1(N=C=NC2CCCCC2)CCCCC1.C1(=O)CCCCC1=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:11]1([CH2:14][C:15]([CH:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]2=[O:9])=[O:16])[CH2:13][CH2:12]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C(O)CC1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C1CCCCC1=O
Solvent: ClCCl
Product: CC1(C)CC(=O)C(C(=O)CC2CC2)C(=O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
5,5-Dimethyl-1,3-cyclohexanedione (1.051 g, 7.5 mmol, 1.5 eq), cyclopropylacetic acid (500.6 mg, 5.0 mmol), and 4-dimethylaminopyridine (916.3 mg, 7.5 mmol, 1.5 eq) were dissolved in 10 mL of CH2Cl2, cooled to 0° C. in an ice bath. A solution of N,N′-dicyclohexylcarbodiimide (1.238 g, 16.0 mmol, 1.2 eq) in 5 mL of CH2Cl2 was added dropwise over two minutes to the cyclohexanedione solution. The reaction mixture was then stirred at 0° C. for 10 minutes and at room temperature for 16 hours. The reaction mixture was then filtered and the filtrate purified by column chromatography (hexane to 30% EtOAc/hexane) to yield 1.022 g (92% yield) 2-(2-Cyclopropyl-acetyl)-5,5-dimethyl-cyclohexane-1,3-dione as a pale yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9](=O)[C:8]2[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[S:6]1(=[O:18])=[O:17].Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9](=[N:20][OH:21])[C:8]2[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[S:6]1(=[O:18])=[O:17]
Reactant: NO
Reactant: Cn1ccc2c1C(=O)CCN(CCCCl)S2(=O)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1ccc2c1C(=NO)CCN(CCCCl)S2(=O)=O
Yield: 79.5 %

Procedure:
A suspension of 404 mg (1.39 mmol) of Compound 18, 290 mg (4.17 mmol) of hydroxylamine hydrochloride and 342 mg (4.17 mmol) of sodium acetate in 40 ml of methanol was refluxed for 22 hours. To the reaction mixture, 97 mg (1.39 mmol) of hydroxylamine hydrochloride and 114 mg (1.39 mmol) of sodium acetate were added, followed by further refluxing for 19 hours. The reaction mixture was concentrated under reduced pressure and a half-saturated aqueous solution of potassium carbonate was added to the residue. The thus-obtained mixture was extracted with chloroform (3 times). The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform), whereby 338 mg of the title compound were obtained (yield: 80%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[S:12][C:13](Br)=[N:14][N:15]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O1CCOCC1>[Br:10][C:11]1[S:12][C:13]([N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[N:14][N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1nnc(Br)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2nnc(Br)s2)CC1
Temperature: 120 °C
Yield: 77.1 %

Procedure:
DIPEA (430 μL, 2.460 mmol) was added to a stirred solution of 2,5-dibromo-1,3,4-thiadiazole (300 mg, 1.230 mmol) and tert-butyl piperazine-1-carboxylate (275 mg, 1.476 mmol) in dioxane (4 mL). The reaction mixture was heated at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered under vacuum, rinsed with dioxane, and the filtrate was concentrated in vacuo to afford the crude product as an orange oily residue. The crude material was purified by preparative HPLC under neutral conditions (ammonium formate modified) to afford the title compound as a yellow solid (331 mg, 77% yield). LC-MS: Rt 1.18 min; MS m/z 351.1 [M+2]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.38-3.55 (m, 8H), 1.41 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1([NH2:9])[CH2:8][O:7][CH2:6][O:5][CH2:4]1)[CH3:2].[OH-].[Na+].O.[Cl:13][CH2:14][C:15](Cl)=[O:16]>C(Cl)Cl>[Cl:13][CH2:14][C:15]([NH:9][C:3]1([CH2:1][CH3:2])[CH2:8][O:7][CH2:6][O:5][CH2:4]1)=[O:16]
Reactant: CCC1(N)COCOC1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCC1(NC(=O)CCl)COCOC1

Procedure:
Five and two-tenths g (0.04 mole) of 5-ethyl-5-amino-1,3-dioxane, 3.2 g (0.04 mole) of 50% sodium hydroxide, 10 ml of water, and 90 ml of methylene chloride were combined in a reaction flask. The mixture was cooled to below 35° C. Four and one-half g of chloroacetylchloride were added dropwise. The reaction mixture was stirred for one-half hour, washed with water and dried over magnesium sulfate. The solvent was vacuum stripped. Yield was 5.8 g of 5-chloroacetylamino-5-ethyl-1,3-dioxane. m.p.=89°-95° C. Structure was confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Br:24]N1C(=O)CCC1=O.C(OC(=O)C)C>CN(C)C=O>[Br:24][C:13]1[CH:14]=[CH:15][C:10]([N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(N(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(c2ccc(Br)cc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
N,N-bis(4-methoxyphenyl)aniline 1 (9.0 g, 29.5 mmol) was dissolved in 100 mL dimethylformamide in a 250 mL round bottom flask. N-bromosuccinimide (5.25 g, 29.5 mmol) was dissolved in 30 mL dimethylformamide and added dropwise to the reaction mixture. The reaction was allowed to stir at room temperature while being monitored by thin layer chromatography (TLC) (Reaction Time=23 h). The reaction mixture was quenched using 600 mL water and extracted with 4×150 mL dichloromethane. The organic layers were combined and washed with 4×150 mL saturated sodium thiosulfate solution and dried over sodium sulfate. The solvent was removed under reduced pressure. The product was purified along with materials prepared previously using flash chromatography on silica gel eluting with 5:1 hexanes:ethylacetate (12.1 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 4H), 6.90 (d, J=9.0 Hz, 4H), 6.73 (d, J=9.0 Hz, 2H), 3.77 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[O:7])[N:4]([CH:17]2[CH:24]3[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)[C:3]1=[O:27]>C(O)C.O1CCCC1.[C].[Pd]>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]([N:5]1[C:2]([CH3:1])([CH3:28])[C:3](=[O:27])[N:4]1[CH:17]1[CH:24]2[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:26][CH:18]1[CH2:19]3)[CH2:23]2)=[O:7]
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 4,4-dimethyl-1-[(2-nitrophenyl)carbonyl]-2-(adamantan-2-yl)-1,2-diazetidin-3-one (16.7 mg, 0.0436 mmol) prepared in Example 124 in ethanol-tetrahydrofuran was added with 10% palladium carbon (catalyst amount), and under a hydrogen atmosphere, the resultant was stirred at room temperature for 1 hour. The reaction solution was filtered using celite and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (14.8 mg, 96.1%) was obtained as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=[NH:16].[CH:17]([N:20]=[C:21]=[N:22][CH:23]([CH3:25])[CH3:24])([CH3:19])[CH3:18]>C(O)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=[N:16][C:21]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:20][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)N=C=NC(C)C
Reactant: N=c1ccccn1CCc1ccccc1Br
Solvent: CC(C)(C)O
Product: CC(C)N=C(N=c1ccccn1CCc1ccccc1Br)NC(C)C
Temperature: 25 °C
Yield: 45.4 %

Procedure:
A solution of 1-[2-(2-bromophenyl)ethyl]-2-iminopyridine (2.77 g, 0.01 mole) and diisopropylcarbodiimide (1.05 g, 0.012 mole) in 30 ml of t-butanol is heated at reflux in a nitrogen atmosphere for 24 hours. The solution is cooled to room temperature and concentrated in vacuo to give a solid. This is recrystallized from 50 ml of hexane to yield a semi-solid, after cooling to -30°C. Recrystallization of this material from 70 ml of hexane yields 1.83 g of the title compound which sinters at 119°C and melts at 125°-128°C.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C.O>[CH2:14]([O:6][C:5](=[O:7])[C@@H:2]([N:1]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][OH:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](CO)N(Cc1ccccc1)Cc1ccccc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 51.9 %

Procedure:
A solution of L-serine (2.1 g, 20 mmol) in acetonitrile/water (52 mL, 25:1) was added to solid potassium carbonate (13.8 g, 100 mmol) and the mixture was treated with benzyl bromide (8.92 mL, 75 mmol). After stirring for 20 h at 55° C. the mixture was cooled to room temperature, filtered, diluted with ethyl acetate and the organics were washed with water, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography eluting with a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (3.9 g, 52%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.52 (dd, J=7.3, 4.5 Hz, 1H), 3.61 (d, J=7.6 Hz, 1H), 3.67 (d, J=13.6 Hz, 2H), 3.75-3.85 (m, 2H), 3.92 (d, J=13.6 Hz, 2H), 5.23, 5.32 (ABq, JAB=12.0 Hz, 2H), 7.22-7.37 (m, 10H), 7.38-7.48 (m, 5H). LCMS (m/z) 376.2 [M+H], Tr=3.25 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=O)[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([Cl:17])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(=O)[nH]nc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nnc1-c1ccccc1

Procedure:
A 24.4 g. portion of 5-methyl-6-phenyl-3(2H)-pyridazinone (prepared as described above) and 250 ml. of phosphorus oxychloride are heated on a steam bath for 6 hours. The reaction mixture is concentrated free of phosphorus oxychloride in vacuo and the concentrate is triturated with cold water. The resulting solid is filtered, washed with water, recrystallized twice from methanol and dried giving a white solid, m.p. 125°-126° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:3]=1.Cl.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[N:28]([C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[F:20])[N:29]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[CH:3]=1
Reactant: O=C(C=Cc1cc(Br)ccn1)C(F)(F)C(F)(F)F
Reactant: NNc1ccc(F)cc1F
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccn2)c(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
1-(4-Bromo-pyridin-2-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (2.2 g, 6.6 mmol) prepared in Step 3, 2,4-difluorophenylhydrazine hydrochloride (1.8 g, 6.6 mmol), and piperidine (1.3 mL, 13.2 mmol) were added to ethanol (66.1 mL). The reaction mixture was stirred at 90° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 2.1 g of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Br.[CH3:12][N:13]([CH2:15][C:16]1[C:17]([S:23][CH3:24])=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:13]([CH3:12])[CH3:14])[C:17]=2[S:23][CH3:24])[CH:3]=1
Reactant: CSc1c(O)cccc1CN(C)C
Reactant: N#Cc1ccc(Cl)cc1F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Yield: 57.6 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.974 g, 6.26 mmol), 3-dimethylaminomethyl-2-methylsulfanyl-phenol hydrobromide (1.74 g, 6.26 mmol) and cesium carbonate (4.08 g, 12.5 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 17 h. The reaction was complete by LC/MS analysis. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10% sodium carbonate solution (2×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-dimethylaminomethyl-2-methylsulfanyl-phenoxy)-benzonitrile (1.2 g, 58%) as a yellow oil. Fumaric acid (92 mg, 0.3 mmol) in methanol (5 mL) was added to 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (91 mg, 0.26 mmol). The solvent was removed in vacuo and diethyl ether (20 mL) was added with stirring. After 17 h, 4-chloro-2-(3-dimethylaminomethyl-2-methysulfanyl-phenoxy)-benzonitrile fumarate (63.2 mg, 47%) was filtered off as a white solid.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=2[CH:4]=1)[NH2:2].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:15]1(=[N:2][NH:1][C:3]2[N:8]=[N:7][C:6]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=3[CH:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NNc1cc2c(nn1)CCCCCC2
Reactant: O=C1CCCCC1
Product: c1c(NN=C2CCCCC2)nnc2c1CCCCCC2

Procedure:
A solution of 10.0 g of 3-hydrazino-5,6,7,8,9,10-hexahydrocyclooct[c]pyridazine in 100 cc of cyclohexanone is boiled at reflux at a bath temperature of 180° for 1 hour and 45 minutes. The mixture is concentrated in a vacuum, whereby the crystalline title compound is obtained and is recrystallized from isopropanol. M.P. 160°-162° (decomp.).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:29][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate (0.454 g, 1.24 mmol) (from example 97, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.050 g, 1.24 mmol) dissolved in water (1 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.076 mL, 1.24 mmol) was added during 5 min. The resulting solution was stirred at −40° C. for 2 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (6 mL, 36.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a slightly yellow oil. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.268 g, 64.5%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.47-1.75 (m, 2H), 1.85-2.14 (m, 2H), 2.71-3.00 (m, 2H), 3.02-3.16 (m, 2H), 3.40-3.76 (m, 3H), 4.22 (d, br., 1H), 4.59 (d, br., 1H), 5.64 (s, 1H), 6.95-7.03 (m, 2H), 7.15 (s, br., 2H). MS m/z 335 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH2:21]([CH:23]([CH2:26][CH3:27])[CH:24]=[O:25])[CH3:22]>C1COCC1>[CH2:21]([CH:23]([CH2:26][CH3:27])[CH:24]([C:15]1[N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[N:12]=[CH:13][CH:14]=1)[OH:25])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)n2cccn2)cc1
Reactant: CCC(C=O)CC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ccnn1S(=O)(=O)c1ccc(C)cc1
Yield: 74.9 %

Procedure:
To 1-[(4-methylphenyl)sulfonyl]-1H-pyrazole (0.50 g, 2.26 mmol) [J. Chem. Res., Synopses, 10, 327 (1979)] in THF (23 mL) at −78° C. was added a solution of t-butyllithium (1.7 M in pentane, 1.5 mL, 2.49 mmol) dropwise. After 10 min 2-ethylbutyraldehyde (0.31 mL, 2.49 mmol) was added. After 10 min the reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and then diluted with H2O (30 mL) and extracted with EtOAc (3×30 mL). The organic extract was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (EtOAc/hexane, 3:7) to give 0.546 g (75%) of 2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl}butan-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:20](O)[CH2:21][CH2:22][OH:23].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)C.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[O:19][CH2:20][CH2:21][CH2:22][OH:23])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(F)c2)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(F)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
A solution of 3-(3-fluorophenylsulfonyloxy)-5-methylphenol (930 mg, 3.3 mmol, as prepared in the preceding step), 1,3-propanediol (0.75 mL, 10 mmol), 1,1'-(azodicarbonyl)dipiperidine (1.76 g, 7.0 mmol), and anhydrous tetrahydrofuran (20 mL) was cooled to 0° C. under nitrogen. Tri-n-butylphosphine (1.7 mL, 7.0 mmol) was added dropwise over 8.5 minutes. The mixture was stirred at 0° C. for 5 minutes then at ambient temperature for 5.5 hours. Diethyl ether (100 mL) was added, and the mixture was stirred for 15 minutes. The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography through silica gel (25% to 35% ethyl acetate in hexane) to give the title compound as a yellow oil (877 mg, 78%). 1H-NMR (300 MHz, CDCl3) δ 7.65-7.68 (m, 1H), 7.50-7.60 (m, 2H), 7.35-7.41 (m, 1H), 6.63 (br s, 1H), 6.41 (br s, 1H), 6.38 (br t, 1H, J=2.1 Hz), 4.01 (t, 2H, J=6.0 Hz), 3.82 (br t, 2H, J=6.0 Hz), 2.25 (s, 3H), 1.99 (pentet, 2H, J=6.0 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H17FO5S: 363.1 (M+Na), 379.0 (M+K). Found: 362.8, 378.9.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:3].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]([CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:2]([N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[O:3])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: CCN(CC)CCNc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)CCN(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 18.2 %

Procedure:
tert-Butyl 4-chlorocarbonyl-piperazine-1-carboxylate (0.97 g, 3.9 mmol) was added to a solution of 4-chloro-N-(2-(diethylamino)ethyl)benzenamine (884 mg, 3.9 mmol) and N,N-diisopropylethylamine (1.9 mL, 11.7 mmol) in DCM (8 mL). The reaction mixture was heated at reflux for 20 hours. The mixture was cooled to room temperature, quenched with saturated NH4Cl (10 mL), and extracted with DCM (2×20 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl 4-(N-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate (311 mg, 18%). MS (APCI+) [M+H]+439.4. 1H NMR (CDCl3, 400 MHz) 7.29 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 3.70-3.66 (m, 2H), 3.45-3.42 (m, 2H), 3.24-3.21 (m, 4H), 3.15-3.12 (m, 2H), 2.61-2.57 (m, 2H), 2.52 (q, J=7.2 Hz, 4H), 1.42 (s, 9H), 0.99 (t, J=7.2 Hz, 6H).
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)[CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 20 h
Yield: 61.9 %

Procedure:
To a solution of 4-piperidone hydrochloride monohydrate (10.0 g, 0.065 mol) in DMF (80 mL) are added 4-Fluoro-2-methoxy-1-nitro-benzene (10.0 g, 0.058 mol) and potassium carbonate (20.2 g), and the mixture is stirred at 70° C. for 20 h. After a filtration, the filtrate is poured into H2O (ca. 300 mL), and the resulting precipitates are collected by a filtration followed by washing with H2O for several times to give title compound (8.98 g) in 61% yield. Orange solid. 1H-NMR (400 MHz, CDCl3, δ): 2.65-2.62 (4H, m), 3.81-3.78 (4H, m), 3.98 (3H, s), 6.34 (1H, d), 6.45 (1H, dd), 8.05 (1H, d).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([OH:11])=O)(=[O:3])[CH3:2].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[NH2:26]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([NH:26][C:25]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:23]([C:22]([F:21])([F:34])[F:35])[CH:24]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Product: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 63.1 %

Procedure:
Using 5-acetyl-2-benzyloxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound (5.47 g, 63.1%) as a slight yellowish green solid.