Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[O-:13]C1C=CC=CC=1.[K+]>C(O)COCCO>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:13]
Reactant: [O-]c1ccccc1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: [K+]
Solvent: OCCOCCO
Product: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Temperature: 160 °C

Procedure:
3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution of potassium phenoxide (8.66 g) in diethylene glycol (66 mL) and the mixture is heated to 160° C. for approximately 15 hours. The resulting dark brown solution is cooled to room temperature, poured. onto 100 mL cold water, and extracted twice with diethyl ether. The pooled organic extracts are washed with water, 10% aqueous sodium hydroxide, and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the resulting oil is distilled in a Kugelrohr apparatus to provide a yellow oil that solidifies on standing. Recrystallization from ethanol-water provides the desired product as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:27][CH3:26])[C:11]([C@@H:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])=[CH:10]2
Reactant: C[C@@H](c1cc2cccc(F)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: CSc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccccc1-c1nc2c(F)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 83.5 %

Procedure:
(S)-2-(1-(2-Chloro-8-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione (14.0 g, 39.5 mmol), 2-(methylthio)phenylboronic acid (9.95 g, 59.2 mmol), and potassium carbonate (16.4 g, 118 mmol) were combined in 300 mL of anhydrous DMF under an atmosphere of N2. The solution was sparged with N2 for ˜5 min before adding PdCl2(dppf)CH2Cl2 (3.22 g, 3.95 mmol). The solution was heated at 100° C. for 3 h, and then cooled to 50° C. The solution was concentrated under vacuum to give a brownish residue, which was diluted with EtOAc (600 mL). The organic layers were then washed with H2O (3×80 mL), followed by brine (1×100 mL). The combined aq. layers were extracted with DCM (3×200 mL). The combined organic layers were dried over MgSO4 and then concentrated under vacuum. The residue obtained was purified by silica gel flash chromatography eluting with a gradient of 20% hexane to 40% EtOAc/hexane. The fractions containing the pure product were combined and concentrated under vacuum to give 2-((1S)-1-(8-fluoro-2-(2-(methylthio)phenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (14.6 g, 33.0 mmol, 84% yield) as a light yellow foam. The proton NMR reflects a 53/47 ratio of atropisomers at 25° C. 1H NMR (500 MHz, CDCl3) δ ppm 8.71 (br s, 0.53H), 8.65 (br s, 0.47H), 7.79 (m, 1H), 7.66 (s, 4H), 7.55 (m, 1H), 7.45-7.27 (series of m, 3.6; H), 6.87 (m, 1.4H), 5.70 (q J=6.4 Hz, 0.47H), 5.63 (q, J=6.8 Hz, 0.53H), 2.47 (br s, 1.4H), 1.91 (m, 3H), 1.52 (br s, 1.6H). Mass Spectrum (ESI) m/e=443.2 (M+1).
Reaction SMILES: Br[CH:2]1[CH2:16][C@@H:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@@H:4]2[C:3]1=[O:17].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>CC(C)=O>[N:18]1([CH:2]2[CH2:16][C@@H:5]3[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@@H:4]3[C:3]2=[O:17])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(Br)C(=O)[C@H]2C1
Reactant: c1c[nH]cn1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H]2CC(n3ccnc3)C(=O)[C@H]2C1

Procedure:
A solution of (3aR,6aS)-tert-butyl 5-bromo-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (300 mg, 0.986 mmol) from Step 1, 1H-imidazole (201 mg, 2.96 mmol), and acetone (0.5 mL) in a 4 mL vial was stirred for 1.5 h at 80° C. The reaction mixture was then concentrated. The crude product was purified chromatographically using a 12 g silica gel cartridge with a gradient of 0-10% CH3OH/CH2Cl2 over 20 min to give (3aR,6aS)-tert-butyl 5-(1H-imidazol-1-yl)-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate: MS (ESI+) m/z 292 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.[CH3:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](Br)[CH:32]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([CH2:30][C:31]1[CH:32]=[C:33]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)[CH:34]=[CH:35][CH:36]=1)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)Cc1cccc(Br)c1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CS(C)(=O)=O)c3)cc2C1

Procedure:
The title compound was prepared from N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide and (3-bromophenyl)methyl methyl sulfone in a similar manner to Example 16.
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[C:4]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:3]=1.[F:27][C:28]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]2[C:29]=1[CH:30](O)[CH2:31][CH2:32][O:33]2.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[F:27][C:28]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]2[C:29]=1[C@@H:30]([O:1][C:2]1[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([S:12]([C:15]4[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=4)(=[O:14])=[O:13])[C:6]=3[CH:5]=[C:4]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:3]=1)[CH2:31][CH2:32][O:33]2
Reactant: Cc1ccc(S(=O)(=O)n2c(C)nc3c(O)cc(C(=O)N(C)C)cc32)cc1
Reactant: OC1CCOc2cc(F)cc(F)c21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(C)nc3c(O[C@H]4CCOc5cc(F)cc(F)c54)cc(C(=O)N(C)C)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a stirred mixture of 4-hydroxy-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzimidazole-6-carboxamide (21.2 g, 56.8 mmol, STEP 4), (+)-5,7-difluoro-3,4-dihydro-2H-chromen-4-ol (15.86 g, 85.1 mmol, STEP 8) and tributylphosphine (22.9 g, 113 mmol) in toluene (840 mL) was added 1,1′-(azodicarbonyl)dipiperidine (ADDP) (19.3 g, 76.5 mmol) at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (300 mL). The filtrate was concentrated in vacuum. The residue was purified by column chromatography on silica get (ethyl acetate:hexane gradient elution from 1:20 to 20:1) to afford crude solids (27.0 g). The solids were recrystallized from 2-propanol (130 mL) to give the title compound as a colorless crystal (23.2 g, 75%, >99% ee)
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[CH:11][C:12]3[C:13]([Br:19])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](Cl)=[O:31]>>[Br:19][C:13]1[C:12]2[C:11]([C:30]([C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]=3)=[O:31])=[C:10]3[CH:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:7][CH2:8][N:9]3[C:17]=2[CH:16]=[C:15]([F:18])[CH:14]=1
Reactant: O=C(Cl)c1ccc2ccccc2n1
Reactant: CC(C(=O)[O-])C1CCn2c1cc1c(Br)cc(F)cc12
Product: O=C(O)CC1CCn2c1c(C(=O)c1ccc3ccccc3n1)c1c(Br)cc(F)cc12

Procedure:
Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (Example 7, Step 8) and quinoline-2-carbonyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:30]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=4[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:28][CH3:29])[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: c1c[nH]cn1
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCn1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
1-{2-[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone (compound 318) (77 mg), imidazole (38 mg), and potassium carbonate (131 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (52 mg, 61%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=O.C=O.CO.[C:14](#[N:16])C>C(O)C.C(Cl)Cl>[CH:8]1[N:16]=[CH:14][N:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=12
Reactant: O=Cc1ccccn1
Reactant: CC#N
Agent: C=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: c1ccn2cncc2c1
Temperature: 25 °C

Procedure:
Imidazo[1,5-a]pyridine fluorophores were prepared by adding 1 equivalent (equiv) of 3 M hydrochloric acid in ethanol (an additional equivalent of acid was used in reactions with basic substrates) and picolinaldehyde or other 2-acylpyridine to 1 equiv of a 0.5 M solution of 1 equiv of primary amine in dry ethanol or acetonitrile and 1.5 equiv of formalin. The reaction was stirred at room temperature for the specified period of time (i.e., from about 15 min to about 12 hours) and monitored by analytical thin layer chromatography (TLC) (10% methanol in DCM) for the appearance of a blue fluorescent product spot by UV light. Crude reaction mixtures were concentrated in vacuo (˜15 Torr) and dried under high vacuum at 0.2 Torr (for from 2 to 12 hours).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCCNC2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
4-[2-(Piperidin-3-yloxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (Preparation 49A) (311 mg, 0.86 mmol) was dissolved in CH2Cl2 (15 mL) under nitrogen and cooled to 0° C. Benzoyl chloride (0.3 mL, 2.58 mmol) was added followed by dropwise addition of triethylamine (0.48 mL, 3.44 mmol). The mixture was warmed to r.t. and stirred for about 16 hours. Methylene chloride (20 mL) was added, and the solution was washed with saturated NaHCO3 (20 mL)and brine (20 mL), and then dried over magnesium sulfate. The solvents were removed under reduced pressure, and the residue was purified by flash column chromatography on silica to afford the final compound as a white solid (330 mg, 83%).
Reaction SMILES: C1(N=C=O)C=CC=CC=1.[Cl:10][C:11]1[C:19]([O:20][CH3:21])=[C:18]([Cl:22])[C:17]([O:23][CH3:24])=[C:13]([CH:14]=[N:15]O)[C:12]=1[OH:25].O>O1CCCC1>[Cl:22][C:18]1[C:19]([O:20][CH3:21])=[C:11]([Cl:10])[C:12]2[O:25][N:15]=[CH:14][C:13]=2[C:17]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(O)c(C=NO)c(OC)c1Cl
Solvent: O
Solvent: C1CCOC1
Solvent: O=C=Nc1ccccc1
Product: COc1c(Cl)c(OC)c2cnoc2c1Cl
Reaction time: 16 h
Yield: 56.5 %

Procedure:
Phenylisocyanate (1.19 g) is added slowly to a solution of 2.66 g of 3,5-dichloro-4,6,-dimethoxysalicylaldoxime in 20 ml of tetrahydrofuran. The clear solution is allowed to stand at room temperature for 16 hours. It is poured into 250 ml of water and the resulting precipitate is filtered, washed with water, and recrystallized from ethanol to give 1.4 g (56.5%) of 5,7-dichloro-4,6-dimethoxy-1,2-benzisoxazole, m.p. 138°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10].[Br:11]Br.C(OCC)(=O)C>CO.C(O)(=O)C>[Br:11][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([NH2:10])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cccc(C)c1N
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(Br)cc(C)c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
In a 100 mL round bottom flask, 2-methoxy-6-methyl-phenylamine (4.54 g, 33.16 mmol) was dissolved in 15 mL MeOH and 5 mL acetic acid. The flask was cooled to 0° C. Bromine (1.7 mL, 33.16 mmol) in 5 mL acetic acid was added to the reaction dropwise (over 30 minutes). The reaction mixture was stirred at 0° C. for 2 hours, then was warmed up to room temperature for 1 hour. The reaction mixture was concentrated down. 1N NaOH was added to neutralize the reaction at 0° C. Ethyl acetate was added to extract the reaction mixture. The organic layer was concentrated after drying over anhydrous sodium sulfate to give a dark brown solid (5.8 g, 81%). LC-MS shows 218.0 (M+1). 1H NMR (300 MHz, CDCl3): δ 6.88 (s, 1H), 6.81 (s, 1H), 3.84 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([O:10][CH2:11][CH:12]=[CH2:13])[CH:6]([OH:9])[CH:7]=[CH2:8])[CH3:2].[CH3:15][C:16](OC(C)=O)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCN(CC)CC.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([O:10][CH2:11][CH:12]=[CH2:13])[CH:6]([O:9][C:16](=[O:17])[CH3:15])[CH:7]=[CH2:8])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCOC(C(=O)OCC)C(O)C=C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(C(=O)OCC)C(C=C)OC(C)=O
Temperature: 25 °C

Procedure:
To a solution of 2-allyloxy-3-hydroxy-pent-4-enoic acid ethyl ester (100 mg, 0.5 mmol) and DMAP (30 mg, 0.25 mmol) in CH2Cl2-Et3N (9:1, 10 mL) was added Ac2O (76 mg, 0.75 mmol). The resulting solution was stirred at ambient temperature for 1H. The solution was diluted with CH2Cl2 (40 mL), washed with H2O (20 mL×2), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([O:11]C)=O)=[CH:4][CH:3]=1.[NH3:30]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([NH2:30])=[O:11])=[CH:6][CH:7]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(=O)(=O)CC)cccc21
Reactant: N
Solvent: CO
Product: CCC(C(N)=O)(c1ccc(Cl)cc1)n1ccc2c(NS(=O)(=O)CC)cccc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The product from Step A above (0.43 g, 1.0 mmol) was dissolved in a 7 N solution of ammonia in methanol (25 mL). After stirring at RT for 10 h, the resulting mixture was concentrated under reduced pressure. The residue was dissolved in dioxane/water, acidified with TFA, and purified directly on RP-HPLC to give the title compound. LC/MS m/z=420.1 [M+H]+. The two enantiomers were separated by SFC chiral separation.
Reaction SMILES: O[C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[OH:8].[C:9]1([CH3:15])[CH:14]=[CH:13]C=CC=1.[NH2:16][CH2:17][CH2:18][CH2:19][OH:20].C>C(O)CCC.O>[CH2:15]([O:8][C:3]1[C:4](=[O:7])[C:5](=[O:6])[C:2]=1[NH:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:9][CH2:14][CH3:13]
Reactant: Cc1ccccc1
Reactant: NCCCO
Reactant: O=c1c(O)c(O)c1=O
Solvent: O
Solvent: CCCCO
Product: CCCCOc1c(NCCCO)c(=O)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry of 1,2-dihydroxy-1-cyclobutene-3,4-dione (15.0 g, 131.5 mmol), 45 mL of 1-butanol and 30 mL of toluene was heated at reflux under a nitrogen atmosphere with stirring under a Dean-Stark Water separator until water stopped passing over. The reaction mixture was then cooled to 0° C. and a solution of 3-amino-1-propanol (9.88 g, 131.5 mmol) in 10 mL of 1-butanol was added dropwise. After 1 hour at ambient temperature, charcoal was added and the mixture filtered through a pad of diatomaceous earth. The filtrate was evaporated under reduced pressure to give 28.9 g of the title compound as an oil. A portion of the product (24.7 g) was dissolved in dichloromethane and filtered through a pad of about 200 g of silica gel. The pad was washed with 1.6 L of dichloromethane:methanol (9:1), and the filtrate was evaporated in vacuo to produce 22.7 g of the title compound.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[C:13]([N:16]([OH:37])[CH:17]([C:19]1[C:20]([Cl:36])=[C:21]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][NH2:31])=[O:29])[CH:22]=[CH:23][CH:24]=1)[CH3:18])(=[O:15])[CH3:14].C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[O:7]=[C:6]1[O:29][C:28]([C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[NH:25][C:21]2[C:20]([Cl:36])=[C:19]([CH:17]([N:16]([OH:37])[C:13](=[O:15])[CH3:14])[CH3:18])[CH:24]=[CH:23][CH:22]=2)=[N:30][NH:31]1
Reactant: CC(=O)N(O)C(C)c1cccc(Nc2ccccc2C(=O)NN)c1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(O)C(C)c1cccc(Nc2ccccc2-c2n[nH]c(=O)o2)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
CDI (0.63 g, 3.9 mmoles) is added to a solution of 2-[[3-[1-(acetylhydroxyamino)ethyl]-2-chlorophenyl]amino]benzoic acid hydrazide (1.4 g, 3.9 mmoles) and triethylamine (0.81 g, 8.1 mmoles,) in 25 mL of THF at 0° C. under an argon atmosphere. The reaction mixture is stirred at 0° C. for 30 minutes under Ar, and then at room temperature overnight. The reaction mixture is partitioned between 50 mL of 1.0 N HCl and 50 mL of EtOAc. The organic layer is washed with 100 mL of 1.0 N HCl, 100 mL of water, and 100 mL of brine. Drying over MgSO4 and evaporation of the solvent gives an off white solid. Flash chromatography over silica gel in EtOAc gives 0.27 g (18%) of N-[1-[3-[[2-(4,5-dihydro-5-oxo-1,3,4-oxadiazol-2-yl) phenyl]amino]-2-chlorophenyl]ethyl] -N-hydroxyacetamide; m.p. 186°-189° C. dec.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][CH2:15][CH:16]([OH:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][CH:16]([OH:29])[CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: OC(CCCl)COc1cccc(C(F)(F)F)c1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: OC(CCN1CCN(c2ccccc2)CC1)COc1cccc(C(F)(F)F)c1
Yield: 42.3 %

Procedure:
This compound was prepared according to the procedure of Example 6. A mixture of 2.4 g (0.015 mole) of 1-phenylpiperazine, 4.0 g (0.015 mole) of 4-chloro-1-(3-trifluoromethylphenoxy)-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 2.5 g (42%) of a tan powder, m.p. 73°-74° C. Recrystallizing solvent used was ligroin.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH:15]1([C:18]#[CH:19])[CH2:17][CH2:16]1>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:15]1([C:18]#[C:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: C#CC1CC1
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C(#CC1CC1)c1ccccc1
Temperature: 75 °C
Yield: 99.2 %

Procedure:
To a degassed solution of iodobenzene (0.549 mL, 4.90 mmol), dichlorobis(triphenylphosphine)-palladium(II) (0.206 g, 0.294 mmol), copper(I) iodide (0.047 g, 0.245 mmol) and diisopropylamine (3.49 mL, 24.5 mmol) in N,N-dimethylformamide (20 mL) was added cyclopropylacetylene (0.622 mL, 7.35 mmol). The reaction mixture was heated to 75° C. for 45 minutes. The reaction mixture was then diluted with ethyl acetate (150 mL), washed with a 10% aqueous solution of lithium chloride (2×100 mL), washed with a 2M aqueous solution of ammonium hydroxide (100 mL), washed with brine (100 mL), and dried over anhydrous sodium sulfate. Concentration afforded a crude product which was purified by silica gel chromatography with hexanes/dichloromethane (10/1) to give (cyclopropylethynyl)benzene (691 mg). The compound had an HPLC ret. time=3.40 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100.
Reaction SMILES: [CH2:1]([N:8](C)[C:9](=[O:25])[CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:15]=1)=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2([OH:13])[N:8]([CH3:1])[C:9](=[O:25])[CH2:10][CH2:11]2)=[CH:15][C:16]=1[S:21](=[O:24])(=[O:23])[NH2:22]
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)CCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
2 g of 4-(4-chloro-3-sulfamoylphenyl)-4-oxobutanoic acid N-benzyl-N-methylamide are hydrogenated in the presence of 0.5 g of palladium black in 40 ml of methanol in a duck-shaped shaking vessel until the theoretical amount of hydrogen has been taken up, the catalyst is filtered off, the filtrate is concentrated and the residue is worked up analogously to the instructions 1, to give 5-(4-chloro-3-sulfamoylphenyl)-5-hydroxy-1-methyl-2-oxopyrrolidine. Melting point 147°-149° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=2)[N:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Oc2cccc(C(F)(F)F)c2)n1
Yield: 96.8 %

Procedure:
0.32 g of the compound from example 2 are stirred with 0.18 g 3-trifluoromethylphenol and 0.25 g potassium carbonate in 25 ml dry acetonitrile at reflux for 4 hrs. The mixture is diluted with water and extracted with ethyl acetate. 0.39 g of the title compound were isolated (m.p. 124-127° C.).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.IC.[CH2:11](Cl)[Cl:12]>>[Cl-:12].[CH3:8][N+:5]1([CH3:11])[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: ClCCl
Reactant: CN1CCC(O)CC1
Solvent: CI
Product: C[N+]1(C)CCC(O)CC1
Product: [Cl-]

Procedure:
This compound was prepared by the procedure described for 2-[4-(N,N,N-trimethylammonium)phenyl]ethanol chloride. Typical reagent levels were as follows: 4-hydroxy-1-methylpiperidine (21.7 g, 0.188 mol), iodomethane (40.0 g, 0.280 mol), and methylene chloride (50 ml).