Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2.C1(C)C=C(C)C=C(C)C=1S(O[NH2:25])(=O)=O.O>O1CCCC1>[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[NH2:25]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Clc1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nn1ncc2c(Cl)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.8 %

Procedure:
Sodium hydride (60 % wt suspension in mineral oil; 0.33 g, 8.3 mmol) is suspended in dry tetrahydrofuran (THF, 10 mL) and is cooled to 0° C. A mixture of 4-chloroindazole (1.05 g, 6.9 mmol) and THF (10 mL) is added to the slurry at 4° C. After the addition is completed, the mixture is stirred for 30 min. Then a mixture of O-mesitylenesulfonylhydroxylamine (1.25 g, 7 mmol) and THF (10 mL) is added slowly, at a temperature below 5° C. After the addition is completed, the reaction mixture is allowed to reach room temperature and is subsequently stirred for 3 h. Then the mixture is cooled again to 0° C., and a second aliquot of O-mesitylenesulfonylhydroxylamine (1.25 g, 7 mmol) in THF (10 mL) is added slowly. The mixture is allowed to reach ambient temperature and is subsequently stirred overnight. The reaction mixture is worked up by adding it to water, extracting into ethyl acetate, and drying over sodium sulfate. The crude product (1.2 g) is obtained after filtration of the drying agent and evaporation of the solvent. This material is used for the next reaction step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:24][C:25]([F:38])([F:37])[S:26]([O:29]S(C(F)(F)F)(=O)=O)(=[O:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:38])([F:37])[S:26]([OH:29])(=[O:28])=[O:27].[F:24][C:25]([F:38])([F:37])[S:26]([OH:29])(=[O:28])=[O:27].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 22.46 grams (79.5 mmol.) of bisphenol A and 75 ml. of pyridine in 200 ml. of methylene chloride was cooled to 0° C., and 50 grams (177 mmol.) of trifluoromethanesulfonic anhydride was added over 40 minutes at a rate to maintain the temperature of the reaction mixture below 10° C. The resulting clear yellow solution was allowed to warm to room temperature, stirred for 14 hours, diluted with methylene chloride and washed twice with 5% aqueous hydrochloric acid solution and three times with water. After drying over magnesium sulfate, the solvent was removed to yield bisphenol A bis(trifluoromethanesulfonate) as a white powder.
Reaction SMILES: [Na].[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5]([OH:7])=[O:6].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OC(N[C@H](C(N[C@H](C(O)=O)CC(O)=O)=O)CC(=O)O)=O)C1C=CC=CC=1.[OH-].[Na+]>O>[CH2:11]([O:18][C:19]([NH:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5]([OH:7])=[O:6])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: O=C(O)C[C@H](NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
731 grams of 96.4% N-benzyloxycarbonyl aspartic acid, which was prepared byreaction of the sodium salt of L-aspartic acid with benzylchloroformate at a pH of about 11.3, and which contained about 0.44 weight percent of N-benzyloxycarbonyl aspartyl aspartic acid was added to 2000 grams of tap water at room temperature. To this solution were slowly added 300 milliliters of 50% sodium hydroxide. The temperature and pH of the slurry rose from about 22° C. and 2.19 to 55° C. and 11.3 respectively. The resulting alkaline solution was then heated to 85° C. During the first 20 minutes of heating, the pH of the alkaline solution dropped to about 9.9. The pH was raised by the addition of 20 milliliters of additional 50% sodium hydroxide to the alkaline solution and the solution stirred for 30 minutes until the pH appeared to stabilize at 10.42, measured at 85° C.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH3:14][C:15]1[CH:19]=[C:18]([NH2:20])[N:17]([CH:21]([CH3:23])[CH3:22])[N:16]=1>C1C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:19]3[C:15]([CH3:14])=[N:16][N:17]([CH:21]([CH3:23])[CH3:22])[C:18]=3[N:20]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: Cc1cc(N)n(C(C)C)n1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)C
Temperature: 25 °C

Procedure:
A solution of ethyl 4-cyclopropyl-2,4-dioxobutanoate (700 mg, 3.76 mmol), 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (523 mg, 3.76 mmol) and benzene (20 mL) were heated at 65° C. for 6 hr, and then allowed to cool to room temperature for 2 d. The solvent was removed under reduced pressure and the residue purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex). The final product was collected as 0.77 g (71%). LCMS E-S (M+H)=288.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04-1.11 (m, 2H), 1.13-1.20 (m, 4H), 1.47 (t, J=7.20 Hz, 6H), 1.55 (d, J=6.82 Hz, 12H), 2.16-2.25 (m, 2H), 2.68 (s, 6H), 4.49 (q, J=7.07 Hz, 4H), 5.20 (spt, J=6.78 Hz, 2H), 7.41 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=1.N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:35][C:36]1[CH:37]=[CH:38][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:45][CH:46]=1)=[O:27])#[N:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)/C=C/c2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of ethyl 4-aminobenzoate (160 mg, 0.968 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the objective product as a solid material. Yield (amount) 361 mg, yield (rate) 86.2%
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:39]=[CH:40][C:41]=1[CH3:42])[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:10]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:41]1[CH:40]=[CH:39][C:6]([CH2:7][CH2:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:10]=2)=[CH:5][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: Cc1ccc(CCc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cc1C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(CCc2nc(Nc3ccc(N4CCNCC4)cc3)ncc2C(F)(F)F)cc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.5 %

Procedure:
To tert-butyl 4-(4-((4-(3-carbamoyl-4-methylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I73) (0.029 g, 0.054 mmol) in DCM (2 mL) was added TFA (0.100 mL, 1.36 mmol) and the mixture stirred overnight (16 hours) at room temperature. The resulting mixture was then concentrated under reduced pressure and the residue taken up in EtOAc (10 mL). The resulting organic suspension was washed with 10% aqueous NaOH (10 mL) and the aqueous layer extracted with EtOAc (2×10 mL). The combined organics were washed with water (15 mL) then concentrated under reduced pressure. The residue was taken up in DCM (4 mL) and TFA (0.200 mL) and stirred overnight (16 hours). The resulting mixture was concentrated under reduced pressure then diluted with EtOAc (15 mL). The resulting solution was washed with 10% aqueous NaOH (15 mL) then the aqueous layer was extracted with EtOAc (15 mL). The combined organic extracts were washed with water (20 mL) then dried using a phase separation cartridge before concentrating under reduced pressure to give the title compound (19) (5.1 mg, 21%); 1H NMR (400 MHz, d5-DMSO) δ 9.96 (s, 1H), 8.60 (s, 1H), 7.67 (s, 1H), 7.53 (d, J=9.0 Hz, 2H), 7.33 (s, 1H), 7.25 (s, 1H), 7.16 (m, 2H), 6.90 (d, J=9.1 Hz, 2H), 3.01 (m, 8H), 2.83 (m, 4H), 2.32 (s, 3H). LCMS Method C: rt 4.76 min; m/z 485.1 [M+H]+.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[CH3:9][C:10]1([CH3:22])[N:14]([C:15](=[O:18])[CH2:16][NH2:17])[C@@H:13]([CH2:19][CH:20]=[CH2:21])[CH2:12][O:11]1.[N:23]([O-])=O.[Na+]>C(Cl)Cl.O>[N+:17](=[CH:16][C:15]([N:14]1[C@@H:13]([CH2:19][CH:20]=[CH2:21])[CH2:12][O:11][C:10]1([CH3:22])[CH3:9])=[O:18])=[N-:23]
Reactant: O=N[O-]
Reactant: C=CC[C@H]1COC(C)(C)N1C(=O)CN
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CC[C@H]1COC(C)(C)N1C(=O)C=[N+]=[N-]
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
{2-[(4S)-2,2-dimethyl-4-(2-propen-1-yl)-1,3-oxazolidin-3-yl]-2-oxoethyl}amine trifluoromethansulfonate D23 (67.0 g) was dissolved in DCM (670 ml) and pH=5 Buffer solution (670 ml) and cooled to 2° C. (internal). Sodium nitrite (26.5 g, 385 mmol) dissolved in water (134 ml) was added dropwise to the reaction mixture stirred at 2° C. over 30 min. The reaction mixture was stirred at 3° C. for 2.5 hours. Phases were separated. Water phase was back-extracted with DCM (1×670 ml, 1×335 ml). The combined organic layers, dried (Na2SO4), were evaporated (bath temperature 30° C.) to give 43 g of crude product. This crude was purified over silica pad [(230-400 Mesh) eluting with Cy/EtOAc 8/2, 7/3, 6/4] to give the title compound D24 (36.58 g) as pale yellow oil. UPLC (Acid GEN_QC): rt=0.59 minutes, peak observed: 210 (M+1) C10H15N3O2 requires 209. 1H NMR (400 MHz, CDCl3) δ ppm 1.58 (s, 3 H) 1.69 (s, 3 H) 2.25-2.50 (m, 2 H) 3.43-3.70 (m, 1 H) 3.82-4.01 (m, 2 H) 4.84 (s, 1 H) 5.09-5.24 (m, 2 H) 5.63-5.84 (m, 1 H)
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:3])[CH3:2].[CH2:20](Br)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+]>O1CCCC1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]=1[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(-c2ccc(Cl)cc2)[nH]c2ccccc12
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccc(Cl)cc2)n(CCc2ccccc2)c2ccccc12
Reaction time: 6 h
Yield: 46 %

Procedure:
A solution of 3-acetyl-2-(4-chlorophenyl)indole (53.9 mg, 0.2 mmol) and phenethylbromide (30 μL, 0.22 mmol) in tetrahydrofuran is treated with NaH (60% dispersion in mineral oil, 24 mg, 0.6 mmol) at room temperature, shaken for 6 h, quenched with saturated NaHCO3 and extracted with ethyl acetate. The extracts are combined and concentrated in vacuo to afford the title product, 34 mg (46% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [CH:1]([NH:3][CH:4](P(OCCCC)(OCCCC)=O)[C:5]([O:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:10])=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38](=O)[CH2:39][O:40][C:41](=[O:45])[CH:42]([CH3:44])[CH3:43]>CC(C)=O>[C:41]([O:40][CH2:39][C:38]1[CH2:37][S:2][CH:1]=[N:3][C:4]=1[C:5]([O:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=1)=[O:10])=[O:6])(=[O:45])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)C(=O)OCC(=O)CCl
Reactant: CCCCOP(=O)(OCCCC)C(NC=S)C(=O)OCC(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)C(=O)OCC1=C(C(=O)OCC(=O)c2ccc(Br)cc2)N=CSC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of p-bromophenacyl α-thioformamido-dibutylphosphonoacetate (6.10 g) in acetone (50 ml) is treated with powdered potassium carbonate (4.98 g). The mixture is stirred under a nitrogen atmosphere while 1-chloro-3-isobutyryloxy-2-propanone (2.32 g) in acetone (10 ml) is added dropwise over 10 minutes. The reaction mixture is stirred an additional 3 hours at room temperature, then filtered. Evaporaton of the filtrate under reduced pressure leaves a dark oil which is extracted with carbon tetrachloride (2 × 50 ml). The combined extracts are washed with 0.5 M dipotassium hydrogen phosphate, water, and saturated brine, dried over magnesium sulfate, and evaporaged in vacuo to give crude p-bromophenacyl 5-isobutyryloxymethyl-6H-1,3-thiazine-4-carboxylate.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([CH2:12][CH:13]=[CH2:14])/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][CH3:11])=[O:8].CCN(S(F)(F)[F:21])CC.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:21][CH2:2][CH2:3][CH:4]([CH2:12][CH:13]=[CH2:14])/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCN(CC)S(F)(F)F
Reactant: C=CCC(/C=C/C(=O)OCC)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(/C=C/C(=O)OCC)CCF
Reaction time: 1 h

Procedure:
Ethyl(E)-4-(2-hydroxyethyl)-hepta-2,6-dienoate (5 g, 27.1 mmol) was dissolved in tetrahydrofuran (40 mL). To the solution, DAST (4.8 g, 29.8 mmol) was added under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was poured to a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, then dried, and then concentrated. The residue was purified by silica gel column chromatography (200 g) to obtain the compound of interest as an oil substance (2.2 g, 44%).
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[Cl:5][C:6]1[C:7]([O:22][CH3:23])=[CH:8][C:9]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[CH2:12][C:11](=[O:20])[C:10]=2[CH:21]=1>O.C1C=CC=CC=1.C(O)C>[Cl:5][C:6]1[C:7]([O:22][CH3:23])=[CH:8][C:9]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[CH2:12][CH:11]([OH:20])[C:10]=2[CH:21]=1
Reactant: COc1cc2c(cc1Cl)C(=O)Cc1ccccc1S2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: c1ccccc1
Product: COc1cc2c(cc1Cl)C(O)Cc1ccccc1S2
Yield: 83 %

Procedure:
A solution of sodium borohydride (0.5 g) in water (3.5 ml), containing 0.1 ml of 15% sodium hydroxide solution was slowly added dropwise to a solution of the ketone from the preceding preparation (6.2 g) in a mixture of benzene (40 ml) and ethanol (100 ml). The stirred mixture was refluxed for 3 hours, the volatile components evaporated under diminished pressure, the residue diluted with water and extracted with benzene. A conventional isolation procedure, followed by crystallization of the crude product from ethanol (25 ml), yielding 5.2 g (83%) of 8-chloro-10-hydroxy-7-methoxy-10,11-dihydrodibenzo(b,f)thiepine, m.p. 130°-132° C.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([C:33]([F:36])([F:35])[F:34])[CH:25]=1)([O-:23])=[O:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[C:1]([NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][C:26]=3[C:33]([F:34])([F:35])[F:36])[CH2:18][CH2:19]2)[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3C(F)(F)F)CC2)c1
Reaction time: 1 h

Procedure:
To a stirred solution of N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (3.99 mmol, 1.1 g), 4-nitro-2-(trifluoromethyl)benzoic acid (3.83 mmol. 0.9 g) and triethylamine (28.7 mmol, 4 mL. 2.90 g) in dichloromethane (20 mL) was added 1-propanephosphonic acid cyclic anhydride (8.94 mmol, 5.3 mL, 5.69 g, 50% solution in ethyl acetate) dropwise. After 1 hour stirring, ethyl acetate was added and the organic mixture was washed with saturated sodium hydrogen carbonate (×2), water (×2) and finally brine. The organic mixture was dried with sodium sulfate and concentrated under vacuum to give the intermediate N-tert-butyl-3-((4-(4-nitro-2(trifluoromethyl)benzoyl)piperazin-1-yl)methyl)benzamide.
Reaction SMILES: CS(O[C:6]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:33][C:32]([C:38]4[CH:43]=[C:42]([Cl:44])[C:41]([Cl:45])=[C:40]([Cl:46])[CH:39]=4)([C:34]([F:37])([F:36])[F:35])[O:31][N:30]=3)=[CH:25][CH:24]=2)[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[N-:47]=[N+:48]=[N-:49].[Na+].CS(C)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N:47]([C:6]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:33][C:32]([C:38]4[CH:43]=[C:42]([Cl:44])[C:41]([Cl:45])=[C:40]([Cl:46])[CH:39]=4)([C:34]([F:37])([F:36])[F:35])[O:31][N:30]=3)=[CH:25][CH:24]=2)[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)=[N+:48]=[N-:49]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: [N-]=[N+]=NC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a solution of 1.19 grams (1.88 mmole, 1.0 eq) of 1-benzhydryl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol in 17 mL of CH2Cl2 was added 500 μL (2.8 mmole, 1.5 eq) of diisopropyl-ethylamine, neat via syringe, followed by 438 mg (2.5 mmole, 1.3 eq) of methylsulfonic anhydride solid. After stirring 3.5 hours at room temperature an aliquot of the reaction mixture was placed in 1.0 mL of methanol and analyzed via LC/MS. The chromatograph indicated the starting material was consumed. The reaction with diluted with 20 mL of CH2Cl2 and 20 mL of saturated NaHCO3 solution. After stirring for 2 hours the layers were separated via a Biotage Phase Separator cartridge. The organic layer was concentrated under reduced pressure to give 1.29 grams (96% yield) of intermediate 1-benzhydryl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-yl methanesulfonate as light yellow solid. A 227 mg sample of 1-benzhydryl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-yl methanesulfonate (0.35 mmole, 1.0 eq) and 72.1 mg of sodium azide (1.1 mmole, 3.1 eq) were weighed into a 100 mL flask, to this was added 3 mL of anhydrous DMSO. After stirring for 1.5 hours at room temperature the reaction was diluted with 30 mL of CH2Cl2 and 15 mL of saturated NaHCO3 solution. After stirring this mixture for 1 hour the layers were separated via a Biotage Phase Separator cartridge. The water layer was rinsed with additional CH2Cl2 and the combined organic layers were concentrated by evaporation utilizing a stream of N2 gas. The resulting crude oil was purified via silica gel column chromatography eluting with 100% CH2Cl2. Evaporation of the appropriate fractions gave 144.5 mg of product, 3-(4-(3-azido-1-benzhydrylazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole, (63% yield) as a glassy yellow solid. ms 656 [M+H], HPLC retention time: 3.600 minutes.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O=CCCCNC(=O)C1C=CC=CC=1>>[C:1]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH:20]=[O:21])[CH2:15][CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cccc2ccccc12)N1CCN(CCO)CC1
Agent: O=CCCCNC(=O)c1ccccc1
Product: O=CCN1CCN(C(=O)c2cccc3ccccc23)CC1

Procedure:
(4-Naphthoyl-piperazin-1-yl)-acetaldehyde (39C) is prepared from 39B as described for 1E.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C.Cl>[C:1]1([S:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:20][CH:21]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCCCS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=S(=O)(CCCOc1ccc(CO)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
1.8 g of 4-(3-benzenesulfonylpropyloxy)benzaldehyde were dissolved in 30 ml of ethanol, and the resultant solution was further added with 0.11 g of sodium borohydride and then stirred for 1 hour at room temperature. After completed the reaction, the solvent used was removed by distillation under reduced pressure, and the residue obtained was dissolved in a mixture of ethyl acetate and dilute hydrochloric acid. The ethyl acetate layer resulted was then washed with dilute hydrochloric acid, aqueous solution of sodium hydroxide and water in series. The organic layer resulted was then dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure, thereby affording 1.5 g of 4-(3-benzenesulfonylpropyloxy)benzyl alcohol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH:26]([C:27]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccccc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[K+]>>[S:17]([CH2:9][C:8]#[C:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC#CC1=CCCCC1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)CC#CC2=CCCCC2)cc1
Yield: 92 %

Procedure:
3-cyclohexenyl-2-propyn-1-ol (95)(3.04 g, 22.3 mmol), p-toluene sulfonyl chloride (4.04 g, 21.2 mmol) and potassium hydroxide (6.26 g, 112 mmol) were reacted using the above procedure to yield the product (5.66 g, 19.5 mmol, 91.8%) as a light yellow oil. 1H NMR (CDCl3): 7.79 (d, J=8.1 Hz, 2 H), 7.31 (d, J=8.1 Hz, 2 H), 5.97 (m, 1 H), 4.81 (s, 2 H), 2.42 (s, 3 H), 2.02 (m, 2 H), 1.92 (m, 2 H), 1.53 (m, 4 H). FAB LRMS (m/e): calcd. for (MH+)(C16H19O3S): 29 1, found 29 1.