Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:19][CH:18]([OH:20])[CH2:17]2)[S:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl>[C:1]([NH:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:17][CH:18]([O:20][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:19]2)[S:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1csc(N2CC(O)C2)n1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3ccccc3)cs2)C1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]-3-hydroxyazetidine (582 mg, 2.01 mmol) (obtained as described in Reference Example 64(2)) in methylene chloride (30 ml) were added methanesulfonyl chloride (0.19 ml, 2.41 mmol), triethylamine (0.34 ml, 2.41 mmol) and pyridine (5.8 ml) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (739 mg, yield 100%) as a pale yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([C:16]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)[C:3]#[C:4][CH3:5].[CH2:25](I)[CH3:26].C(=O)([O-])[O-].[K+].[K+].[CH3:34][C:35](C)=O>>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([C:16]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19][N:18]([CH2:34][CH3:35])[CH2:17]2)(=[O:14])=[O:15])=[CH:9][CH:8]=1)[C:3]#[C:4][CH3:5]
Reactant: CC(C)=O
Reactant: CCI
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCCNC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCCN(CC)C2)cc1

Procedure:
3-{[4-(2-Butynyloxy)phenyl]sulfonyl}-3-piperidinecarboxylate hydrogen chloride (2.97 g, 8.0 mmol), ethyl iodide (1.28 g, 8 mmol) and dry powdered potassium carbonate (3.8 g) in dry acetone (60 ml) was heated to reflux for 18 hours. The mixture was allowed to cool and the potassium salts were filtered and concentrated. The residue was extracted with chloroform and washed with H2O, dried over sodium sulfate and concentrated to afford ethyl 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-ethyl-3-piperidinecarboxylate. This product was used without further purification. Amber gum, yield 3.47 g (99%/0); MS (ES): m/z 394 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C=CC=CC=1[S:20]([NH2:23])(=[O:22])=[O:21])=C.C(C1C=CC=CC=1S(N)(=O)=[O:34])C=C.[Si](C)(C)(C)C>[C].[H][H].[Cu]>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:7][CH:9]1[O:21][S:20](=[O:34])(=[O:22])[NH2:23]
Reactant: C=CCc1ccccc1S(N)(=O)=O
Reactant: C=Cc1ccccc1S(N)(=O)=O
Reactant: [H][H]
Agent: [Cu]
Agent: C=C[C@@H]1C[C@H]1c1ccccc1
Solvent: C[Si](C)(C)C
Product: NS(=O)(=O)OC1Cc2ccccc2C1

Procedure:
NBS was recrystallized from water according to the guidelines of Armarego and Chai (Armarego, W. L. F. and Chai, C. L. L. (2003) In: Purification of Laboratory Chemicals; 5th ed., Elsevier Science: New York. p-TsNH2 and K2CO3 (anhydrous, granular) were used as received. Olefins (except Entries 10 and 11, Table 1) were filtered over a plug of alumina and distilled prior to use. Trans-2-phenyl-1-vinylcyclopropane 9 was prepared according the procedure of Fu, et al. (1991) (“MECHANISTIC STUDY OF A SYNTHETICALLY USEFUL MONOOXYGENASE MODEL USING THE HYPERSENSITIVE PROBE TRANS-2-PHENYL-1-VINYLCYCLOPROPANE,” J. Org. Chem. 56(23):6497-6500). Sulfamate indan-2-yl ester 7 was prepared according to the procedure of Espino, et al. (2001) (“Synthesis of 1,3-Difunctionalized Amine Derivatives through Selective C—H Bond Oxidation,” J. Am. Chem. Soc. 123(28):6935-6936) 2-Vinylbenzenesulfonamide (Entry 10, Table 1) and 2-allylbenzenesulfonamide (Entry 11, Table 1) were prepared according the procedure of Dauban and Dodd (Dauban, P. et al. (2000) “SYNTHESIS OF CYCLIC SULFONAMIDES VIA INTRAMOLECULAR COPPER-CATALYZED REACTION OF UNSATURATED IMINOIODINANES,” Org. Lett. 2(15):2327-2329). Dirhodium(II,II) caprolactamate [Rh2(cap)4.2CH3CN] was prepared as previously described (Doyle, M. P. et al. (1993) “ELECTRONIC AND STERIC CONTROL IN CARBON-HYDROGEN INSERTION REACTIONS OF DIAZZOACETOACETATES CATALYZED BY DIRHODIUM(II) CARBPXYLATES AND CARBOXAMIDES,” J. Am. Chem. Soc. 115(3):958-964). 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were obtained on a Bruker DRX-400 NMR as solutions in CDCl3. Chemical shifts are reported in parts per million (ppm, δ) downfield from Me4Si (TMS); coupling constants are reported in Hertz (Hz). UV-Visible spectra were obtained on a Varian Cary 50 spectrophotometer using a xenon flash lamp. Preparative chromatographic purification was performed using SiliCycle (60 Å, 40-63 mesh) silica gel according to the method of Still, W. C. et al. (1978) (“RAPID CHROMATOGRAPHIC TECHNIQUE FOR PREPARATIVE SEPARATIONS WITH MODERATE RESOLUTION,” J. Org. Chem. 43(14):2923-2925). Thin layer chromatography (TLC) was performed on Merck 0.25 mm silica gel 60 F254 plates with visualization by fluorescence quenching or aqueous KMnO4 stain. Anhydrous CH2Cl2 was purified prior to use by nitrogen forced-flow over activated alumina as described by Pangbom, A. B. et al. (1996) (“SAFE AND CONVENIENT PROCEDURE FOR SOLVENT PURIFICATION,” Organometallics 15(5): 1518-1520).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].C1C=CC=CC=1.[CH3:18][NH:19][CH3:20].[CH2:21]=O>O>[CH3:18][N:19]([CH2:10][C:4]1[C:5]([CH3:9])=[C:6]([OH:7])[C:8]([CH3:21])=[C:2]([CH3:1])[C:3]=1[OH:11])[CH3:20]
Reactant: C=O
Reactant: CNC
Reactant: Cc1cc(O)c(C)c(C)c1O
Solvent: c1ccccc1
Solvent: O
Product: Cc1c(C)c(O)c(CN(C)C)c(C)c1O
Reaction time: 8 h

Procedure:
Trimethylhydroquinone (7.61 g.) was suspended under N2 in 60 ml. of benzene and 15 ml. of 25% dimethylamine in H2O. Aqueous formaldehyde solution (37%, 7.5 ml.) was added over 15 minutes and stirring was continued at 25° overnight. The benzene layer was washed with H2O, dried over Na2SO4, and stripped of solvent to give 2-dimethylaminomethyl-3,5,6-trimethylhydroquinone as a light tan solid. A similarly prepared sample of this material, which is quite susceptible to air oxidation, had a m.p. of 103°-108.5° with decomposition, after isolation from methanol-H2O.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:20])=[C:4]([CH3:19])[C:5]([Si:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([CH3:10])[CH3:9])([CH3:7])[CH:6]=1.CCCCC.C([Li:30])CCC>C(OCC)C.CCCCCC>[CH3:1][C:2]1[C:3]([CH3:20])=[C:4]([CH3:19])[C:5]([Si:8]([N-:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)([CH3:10])[CH3:9])([CH3:7])[CH:6]=1.[Li+:30].[Li+:30].[CH3:1][C:2]1[C:3]([CH3:20])=[C:4]([CH3:19])[C:5]([Si:8]([N-:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)([CH3:10])[CH3:9])([CH3:7])[CH:6]=1
Reactant: CC1=CC(C)([Si](C)(C)Nc2ccc(F)cc2)C(C)=C1C
Reactant: [Li]CCCC
Solvent: CCCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=CC(C)([Si](C)(C)[N-]c2ccc(F)cc2)C(C)=C1C
Product: [Li+]

Procedure:
((Tetramethylcyclopentadienyl)dimethylsilyl)-(4-fluorophenyl) amine in diethyl ether solvent and butyl lithium 2.5M in hexane solvent were combined in equivalent amounts. A white precipitate formed. Pentane was added to the slurry. The precipitate was filtered, washed with pentane and dried. 1H NMR (THF-d8) δ 7.28 (m, 2.0), 6.77 (m, 2), 3.27 (s, 2.7), 2.05 (s, 5.2), 2.01 (s, 5.2), 0.44 (s, 4.6).
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][N:7]([CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][CH3:29])[CH:22]=1)[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].S(Cl)([C:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[C:38]([N:39]([CH3:41])[CH3:40])[C:37]=2[CH:36]=[CH:35][CH:34]=1)(=O)=O>O.C(#N)C>[CH3:40][N:39]([CH3:41])[C:38]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:37]=1[CH:36]=[CH:35][CH:34]=[C:33]2[N:28]([CH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][CH2:19][CH2:18][CH2:17][N:7]([CH3:6])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH3:29]
Reactant: CNCc1cccc(OCCCN(C)CCC(=O)OC(C)(C)C)c1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN(CCCOc1cccc(CN(C)c2cccc3c(N(C)C)cccc23)c1)CCC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
The NaHCO3 solution (133 mg, 1.58 mmol) in water (2 mL) is added at RT to the solution of crude tert-butyl 3-(methyl(3-(3-((methylamino)methyl)phenoxy)propyl)amino)propanoate (455 mg, 1.35 mmol) and of dansyl chloride (364 mg, 1.35 mmol) in acetonitrile (35 mL). This mixture is stirred for 1 h 30 at the same temperature under argon. And the solvent is then evaporated under reduced pressure and the obtained oil is purified by chromatography on silica gel (eluent—DCM followed by the mixture DCM:MeOH=100:1). The final product is obtained as a fluorescent pale green amorphous gum (522 mg, 68%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]=[CH2:15])[C:10]([O:12][CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCC(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
A mixture of 2-[(tert-butoxycarbonyl)amino]pent-4-enoic acid (20.0 g), potassium carbonate (13.2 g) and N,N-dimethylformamide (100 mL) was stirred for 15 min. The mixture was cooled to 0° C., iodomethane (9.2 g) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the residue was washed with ethyl acetate. The filtrate was successively washed with 5% hydrochloric acid and brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (21.0 g).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C([C:7](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])=O.N1C=CC=C[CH:19]=1>>[CH3:3][O:2][N:4]=[CH:19][C:15]1[CH:14]=[CH:13][C:12]([CH:11]=[CH:7][C:8]([OH:10])=[O:9])=[CH:17][CH:16]=1
Reactant: O=CC(=Cc1ccccc1)C(=O)O
Reactant: CON
Reactant: c1ccncc1
Agent: Cl
Product: CON=Cc1ccc(C=CC(=O)O)cc1
Reaction time: 2 h

Procedure:
Methoxylamine hydrochloride (0.996 g, 0.0119 mol) is added to a solution of formylcinnamic acid (2 g, 0.0114 mol) in pyridine (20 ml) and is stirred for 2 hours. The reaction mixture is evaporated under vacuum and the residue is diluted with 2N aqueous HCl. The resulting precipitate is filtered and dried under vacuum (2.00 g, 85%).
Reaction SMILES: CB(C)Br.[N:5]([C@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:18]=2)[CH2:9]1)=[N+]=[N-].[CH2:36](O)C>ClCCCl>[CH3:36][NH:5][C@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:18]=2)[CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)n2cc([C@@H]3C[C@@H](N=[N+]=[N-])c4ccccc43)c3ccccc32)cc1
Reactant: CCO
Agent: CB(C)Br
Solvent: ClCCCl
Product: CN[C@@H]1C[C@@H](c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Dimethylbromoborane (1.77 mL, 1.05 equiv) (Synthesized according to Nöth, H., Vahrenkamp, H. Journal of Organometallic Chemistry 11(1968), 399-405) was added to 3-((1R,3R)-3-azido-indan-1-yl)-1-(toluene-4-sulfonyl)-1H-indole (17.3 mmol ) in 100 mL 1,2-dichloro-ethane under argon at 0° C. The reaction mixture was warmed to room temperature and stirred 2.5 hours. 1 mL Ethanol was added. The reaction mixture was extracted with ethyl acetate and 0.5N aqueous NaOH. The organic phase was washed with brine, dried over MgSO4, concentrated in vacuo to give methyl-{(1R,3R)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-indan-1-yl}-amine after flash chromatography (ethyl acetate, methanol, triethylamine, silica gel). Methyl-{(1R,3R)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-indan-1-yl}-amine was dissolved in 8 mL acetone and 20 mL methanol. 8 mL 28% Aqueous NaOH was added and the reaction mixture was stirred in two portions at 120° C. for 10 minutes under microwave irradiation using the Emry Optimizer™ instrument. The reaction mixture was poured into 250 mL water and a precipitate was formed. Recrystallization gave 2.15 g [(1R,3R)-3-(1H-indol-3-yl)-indan-1-yl]-methyl-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=1[O:20][CH3:21].[Li]CCCC.[B:27](OC)([O:30]C)[O:28]C.O>C1COCC1>[CH3:21][O:20][C:11]1[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH2:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:27]([OH:30])[OH:28]
Reactant: COB(OC)OC
Reactant: COc1cc(OC)c(CSc2ccccc2Br)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c(CSc2ccccc2B(O)O)c(OC)c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 46 %

Procedure:
To a solution of 4.22 g (2-bromophenyl)(2,4,6-trimethoxybenzyl)sulfane (11.56 mmol) in 150 ml dry THF at −78° C. was added slowly 5.6 ml 2.5M n-BuLi. The solution was stirred at −78° C. for 25 minutes. 1.6 ml B(OMe)3 was added at −78° C. The reaction was stirred 2 hours at RT. 100 ml water was added, stirred overnight. The mixture was extracted with ethyl acetate (2×100 ml). The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by gradient chromatography (hexane:ethyl acetate 60:40) yielded 1.762 g product (5.3 mmol, 46% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:12][S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:9][CH:10]=[CH2:11])[C:3]=1[F:19].ClC1C=CN=C(/C=N/[S@](C(C)(C)C)=O)C=1F.C([Mg]Br)C=C>C1COCC1.C(O)(C)C.CCCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@H:8]([NH:12][S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:9][CH:10]=[CH2:11])[C:3]=1[F:19]
Reactant: C=CC[C@H](N[S@@](=O)C(C)(C)C)c1nccc(Cl)c1F
Agent: C=CC[Mg]Br
Agent: CC(C)(C)[S@](=O)/N=C/c1nccc(Cl)c1F
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: C=CC[C@@H](N[S@@](=O)C(C)(C)C)c1nccc(Cl)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
(S)-N-((S)-1-(4-Chloro-3-fluoropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide: To a solution of (S,E)-N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.03 g, 3.92 mmol) in THF (100 mL) was added allyl magnesium bromide (1 M in ether) (4.70 mL, 4.70 mmol) dropwise and the resulting solution was stirred for 1 h at −78° C. The reaction mixture was then warmed to rt and then quenched with saturated NH4Cl solution. The reaction mixture was extracted with EtOAc (3×). The combined organic layers were concentrated in vacuo, and the residue was then subjected to silica gel purification to provide a mixture of the S and R isomers. MS (ESI) m/z: 305.1 (M+H)+. Chiral separation: AD column eluting with 30% isopropanol in heptane provided peak 1 as the desired (S)-N-((S)-1-(4-Chloro-3-fluoropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (0.710 g, 59%) and peak2 as (S)-N-((R)-1-(4-chloro-3-fluoropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (0.081 g, 7% yield).
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:27][CH3:28])=[C:11]([CH:26]=1)[C:12]([NH:14][C@H:15]1[C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]1([CH3:25])[CH3:24])=[O:13].[CH:29](Cl)(Cl)Cl>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:27][CH3:28])=[C:11]([CH:26]=1)[C:12]([NH:14][C@H:15]1[C@H:17]([C:18]2[CH:19]=[CH:20][C:21]([S:2]([CH3:29])(=[O:5])=[O:3])=[CH:22][CH:23]=2)[C:16]1([CH3:24])[CH3:25])=[O:13]
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)N[C@H]1[C@H](c2ccccc2)C1(C)C
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(Cl)cc1C(=O)N[C@H]1[C@H](c2ccc(S(C)(=O)=O)cc2)C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Chlorosulfonic acid (0.17 mL) was added at 0° C. to a solution of 5-chloro-N-(Trans-2,2-dimethyl-3-phenyl-cyclopropyl)-2-methoxy-benzamide (165 mg, 0.5 mmol) in chloroform (8 mL), and the resulting mixture was stirred at room temperature for 1.5 hour. The reaction was then quenched by addition of ice and the resulting mixture was extracted with diethyl ether. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and cooled to 0° C. Hydrazine (0.05 mL) was added and the resulting mixture was stirred for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in ethanol (15 mL). Sodium acetate (205 mg) and methyl iodide (355 mg) were added and the resulting mixture was heated to reflux for 18 hours. The reaction mixture was then evaporated under reduced pressure and the residue was partitioned between brine and diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was absorbed onto silica gel and purified by flash chromatography (EtOAc/hexane, 0-25%) to give 37 mg of 5-chloro-N-[trans-3-(4-methanesulfonyl-phenyl)-2,2-dimethyl-cyclopropyl]-2-methoxy-benzamide colorless viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(hydroxymethyl)oxazolidin-2-one (6.07 g, 18 mM) in dry dichloromethane (200 ml) under nitrogen was treated with triethylamine (2.54 g, 25 mM), and methanesulfonyl chloride (2.47 g, 22 mM) run in dropwise over 30 minutes at 0°. After stirring 2 hours at 0°, the mixture was diluted with water (200 ml), the organic layer separated, washed with hydrochloric acid (2N, 100 ml), sodium bicarbonate solution (5%, 100 ml), brine (100 ml) and dried (magnesium sulfate). The residue after evaporation was dissolved in the minimum of dichloromethane, and excess isohexane added to precipitate the desired product (7.05 g).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1F
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1F

Procedure:
1-(5-(4-Fluoro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was prepared from 2-(4-fluoro-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc/hexanes) gave the product as a pale yellow solid (0.072 g, 16% yield). MS: m/z 456.4 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([C:8]#[N:9])=[CH:5][CH2:4][CH2:3]1.[C:10](OC=C)(=[O:13])[CH2:11][CH3:12]>CC(OC)(C)C>[C:10]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]=[C:6]([C:8]#[N:9])[CH2:7]1)(=[O:13])[CH2:11][CH3:12]
Reactant: N#CC1=CCCC(O)C1
Reactant: C=COC(=O)CC
Solvent: COC(C)(C)C
Product: CCC(=O)OC1CCC=C(C#N)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 2 L flask containing racemic 5-hydroxycyclohex-1-ene-1-carbonitrile (151 g, 1.22 mol), vinyl propionate (147 g, 1.47 mol), and MTBE (1.5 L) was added the enzyme AMANO Lipase PS from Burlholderiacepacia (20 g, Sigma-Aldrich). The mixture was stirred at ambient temperature for 48 hours. The mixture was filtered through celite and rinsed with MTBE. The filtrate was concentrated in vacuo to remove both solvent and unreacted vinyl propionate. The residue was diluted with brine (1.5 L) and extracted with hexanes (1000 mL+600 mL×3 respectively). The combined organics was washed with H2O (400 mL×5), then dried over anhydrous Na2SO4, and concentrated in vacuo to afford the title compound, which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N#Cc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OS(N)(=O)=O)cc1
Yield: 51 %

Procedure:
This compound was prepared by the procedure of Example 84 from a solution of 11.9 g (0.10 mole) of 4-cyanophenol (Aldrich Chemical Co.) and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 75 ml of toluene. The solid product was recrystallized from benzene-acetonitrile to give 10.1 g (51%) of white solid, mp 154°-156° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([C:20]5[O:24][C:23]([CH:25]=O)=[CH:22][CH:21]=5)[CH:18]=[CH:19][C:14]4=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([C:20]5[O:24][C:23]([CH2:25][N:27]6[CH2:32][CH2:31][O:30][CH2:29][CH2:28]6)=[CH:22][CH:21]=5)[CH:18]=[CH:19][C:14]4=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2ccc3nnc(Cc4ccc5c(c4)CCO5)n3n2)o1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1cc2c(cc1Cc1nnc3ccc(-c4ccc(CN5CCOCC5)o4)nn13)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
5-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-furan-2-carbaldehyde (21.6 mg, 0.06 mmol), morpholine (6.5 μL, 0.07 mmol) and AcOH (2 drops) were combined in DCM (1 mL). To this was added sodium triacetoxyborohydride (19 mg, 0.09 mmol) and the reaction was stirred at rt for 2 hours. The reaction was concentrated in vacuo followed by purification by HPLC (5-65% CH3CN over 35 min) resulting in the title compound (5.9 mg, 27%) as a solid. 1H-NMR (CD3OD/CDCl3): δ 8.23-8.21 (1H, d, J=9.6 Hz), 7.81-7.78 (1H, d, J=9.8 Hz), 7.42-7.41 (1H, d, J=3.5 Hz), 7.22 (1H, s), 7.17-7.15 (1H, d, J=9.6 Hz), 6.99-6.98 (1H, d, J=3.5 Hz), 6.67-6.65 (1H, d, J=8.3 Hz), 4.57 (2H, s), 4.45-4.38 (4H, m), 3.94 (4H, br s), 3.40-3.33 (4H, m), 3.17-3.13 (2H, t, J=8.8 Hz). ESI-MS (m/z): Calcd. For C23H23N5O3: 417.18; found: 418.3 (M+H).