Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22]([O:24]CC)=O.[C:29]1([N:35]=[C:36](Cl)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:20][C:13]1[NH:12][C:11]2[CH:21]=[C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:22](=[O:24])[C:10]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:27])([F:28])[F:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reactant: ClC(=Nc1ccccc1)c1ccccc1
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3ccccc3)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-phenylbenzimidoyl chloride (1.8 g, 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]([CH2:13][CH:14]=[CH2:15])[CH3:12].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:9][N:10]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1)[CH3:12]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: Fc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C/C=C/c1cccc(F)c1)N(C)C(=O)OC(C)(C)C
Temperature: 112 °C
Yield: 108.4 %

Procedure:
A 180 mL thick-walled glass pressure tube was charged with 3-bromofluorobenzene (0.95 g, 5.41 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.08 g, 5.41 mmol), prepared as previously described, palladium(II) acetate (12.2 mg, 0.05 mmol), tri-o-tolylphosphine (65.92 mg, 0.22 mmol), triethylamine (3 mL, 21.52 mmol) and anhydrous acetonitrile (6 mL). The tube was flushed with nitrogen, sealed and the mixture was stirred and heated at 112° C. (oil bath temperature) for 66 h. The resulting mixture containing oily, brown solids, was cooled to ambient temperature and concentrated on a rotary evaporator. The resulting orange-yellow solids were diluted with water (20 mL) and extracted with CH2Cl2 (4×20 mL). The combined CH2Cl2 extracts were washed with saturated NaCl solution (30 mL), dried (Na2SO4), filtered, concentrated by rotary evaporation, and the residue was dried under high vacuum to produce a light-brown oil (1.72 g). The crude product was purified by column chromatography on silica gel (90 g), eluting with ethyl acetate-hexane (15:85, v/v). Selected fractions containing the product (Rf 0.29) were combined, concentrated by rotary evaporation and the residue was vacuum dried to give 1.36 g (85.8%) of a light-yellow oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(NS(C1C=C[C:37]([N:40]=[CH:41]C2C=CC(OC)=C(F)C=2)=CC=1)(=O)=O)(C)(C)C>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:16]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH3:25])=[CH:21][CH:22]=3)=[CH:41][N:40]=[CH:37]2)=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1ccc(C=Nc2ccc(S(=O)(=O)NC(C)(C)C)cc2)cc1
Reactant: COc1ccc(C=Nc2ccc(S(=O)(=O)NC(C)(C)C)cc2)cc1F
Product: CCOc1ccc(-c2cncn2-c2ccc(S(=O)(=O)NC(C)(C)C)cc2)cc1
Yield: 77 %

Procedure:
Following a similar process to that described in example 3, but starting from N-tert-butyl-4-[(4-ethoxybenzylidene)amino]benzenesulfonamide (obtained in example 6) instead of from N-tert-butyl-4-[(3-fluoro-4-methoxybenzylidene)amino]benzenesulfonamide, the title compound is obtained in 77% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[C:5](=[N:14][OH:15])[C:6](=[O:13])[NH:7]2.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CS(C)=O>[C:17]([O:15][N:14]=[C:5]1[C:4](=[O:16])[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[NH:7][C:6]1=[O:13])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C(=O)C1=NO
Solvent: CS(C)=O
Product: CC(=O)ON=C1C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 201 mg (0.776 mmole) of 17b in 2 mL of DMSO was added 0.4 mL of acetic anhydride and the solution was stirred overnight. Solid precipitate was observed after about 1 hr. To the mixture was added 10 mL of ice-water and the mixture was stirred until all of the ice melted. The mixture was filtered and washed with water, and dried to leave 228 mg (97%) of 18b as a yellow solid, mp 194°-195° C. 1H NMR (DMSO-d6), 2.292 (s, 3), 7.095 (m, 1), 7.34 (m, 1), 11.39 (s, 0.4), 11.51 (s, 0.6).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.FC(F)(F)S(O[C:17]1[CH:30]=[C:29]2[C:20]([O:21][C:22]3[C:23]([F:51])=[CH:24][C:25]([C:44]#[C:45][C:46]4([CH3:50])[CH2:49][O:48][CH2:47]4)=[CH:26][C:27]=3[C@:28]32[N:35]=[C:34]([NH:36]C(OC(C)(C)C)=O)[CH2:33][O:32][CH2:31]3)=[CH:19][CH:18]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:51][C:23]1[C:22]2[O:21][C:20]3[C:29](=[CH:30][C:17]([C:7]4[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:18][CH:19]=3)[C@:28]3([N:35]=[C:34]([NH2:36])[CH2:33][O:32][CH2:31]3)[C:27]=2[CH:26]=[C:25]([C:44]#[C:45][C:46]2([CH3:50])[CH2:49][O:48][CH2:47]2)[CH:24]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC1(C#Cc2cc(F)c3c(c2)[C@]2(COCC(NC(=O)OC(C)(C)C)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)COC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C#Cc2cc(F)c3c(c2)[C@]2(COCC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)COC1
Temperature: 85 °C
Yield: 15.5 %

Procedure:
In a microwave vial, 2-fluoropyridin-3-ylboronic acid (0.065 g, 0.459 mmol), Pd(PPh3)4 (0.042 g, 0.037 mmol) and (S)-5-(tert-butoxycarbonylamino)-4′-fluoro-2′-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (0.230 g, 0.367 mmol) were taken up in DMF (3 mL). Aqueous sodium carbonate (1.0 M, 1.10 mL, 1.10 mmol) was added. Argon was blown through the vessel which was then sealed and heated in an 85° C. oil bath for 4 h. The reaction was cooled and concentrated, and the residue was diluted with water (15 mL) and the aqueous phase was extracted with 3% MeOH-DCM (3×25 mL). The organics were combined, washed with dilute brine (7 mL), dried over sodium sulfate and concentrated. The residue was purified through silica gel (33 mL) which had been deactivated with Et3N (3.3 mL), using 33% EtOAc in hexane. The resulting residue was transferred to a microwave vessel in DCM (3 mL), and TFA (0.283 mL, 3.67 mmol) was added. The vessel was sealed and heated in a 60° C. oil bath for 1.5 h. The reaction was cooled and concentrated, and the residue was neutralized with 0.5 M aqueous Na2CO3 (15 mL). The aqueous phase was extracted with 5% MeOH-DCM (3×25 mL). The organics were combined, washed with dilute brine (7 mL) and dried over sodium sulfate. The residue was purified through silica gel (33 mL) using 7.5% MeOH-DCM to afford 27 mg of (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine. m/z=474.0[M+H]+.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[CH2:19][CH2:18][N:17]=[C:16]1[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C[O-].[Na+].[CH3:30][O:31][CH:32]([O:36][CH3:37])N(C)C>CO>[CH3:30][O:31][CH:32]([O:36][CH3:37])[N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][C:16]2[NH:17][CH2:18][CH2:19][N:15]=2)[CH2:22][CH2:23]1
Reactant: COC(OC)N(C)C
Reactant: C1CNC(CC2CCNCC2)=N1
Agent: C[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: COC(OC)N1CCC(CC2=NCCN2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture containing the dihydrochloride salt of 4-[(4,5-dihydro-1H-imidazol-2-yl)methyl]piperidine (8.5 g, 0.035 M) and methanol (160 ml) which contained sodium methoxide (0.071 M) was stirred at room temperature for 10 minutes and dimethylformamide dimethyl acetal (170 ml) was added and heated at 90° C. for 6 hrs. The excess of dimethylformamide dimethyl acetal was removed to give 4-[(4,5-dihydro-1H-imidazol-2-yl)methyl]piperidine carboxaldehyde dimethyl acetal. To the mixture of 6-aminopenicillanic acid (6.3 g, 0.029 M) and diisopropylethylamine (5.1 ml) in dried chloroform was added the solution (20 ml CHCl3 and 5 ml MeOH) of the above piperidine carboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C. for 1 hr and at room temperature for 3 hrs. After this period, the solvent was removed in vacuo and dissolved in 150 ml of water. The aqueous solution, washed with ethyl acetate was acidified to pH 3 with dilute hydrochloric acid and purified on Sephadex LH20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (8.1 g, 62% yield).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:17][C:18]#[N:19])[C:5]=2[CH:4]=[N:3]1.[OH-:20].[K+].O>CC(O)(C)C>[CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:17][C:18]([NH2:19])=[O:20])[C:5]=2[CH:4]=[N:3]1
Reactant: [OH-]
Reactant: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CC#N
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CC(N)=O
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a solution warmed at 85° C. of (1,7-dimethyl-9-oxo-1,9-dihydro-4H-pyrazolo[4,3-b]quinolin-4-yl)acetonitrile (EXAMPLE 51, 69 mg, 0.27 mmol) in 2-methyl-2-propanol (5 ml) was added powdered potassium hydroxide (76 mg, 1.4 mmol). The mixture was stirred at 85° C. for 10 min. After cooling to ca. 40° C., the mixture was poured into water (30 ml) and extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with brine (50 ml), dried over magnesium sulfate, and concentrated in vacuo. The residue was washed with diisopropyl ether and ethyl acetate to give 43 mg (59%) of the title compound as a yellow solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1
Reactant: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(CN2CCC(CN)CC2)CCCC1
Yield: 99.9 %

Procedure:
A solution of methyl 1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidine-1-yl)methyl]cyclopentanecarboxylate (1.16 g, 3.27 mmol, Step2) in CH2Cl2 (25 mL) and trifluoroacetic acid (5 mL) was stirred at room temperature for 1.5 h. The reaction mixture was then concentrated and basified with sat. NaHCO3 aq. (100 mL), extracted with CHCl3 (100 mL) for five times. The combined extract was dried and concentrated to give 0.831 g (100%) of title compound as yellow syrup.
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1>CO>[N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:30][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[C:8]2=[O:16])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C1Cc2ccccc2N1N1CCOCC1
Reactant: O=Cc1ccncc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
A mixture of 1,3-dihydro-1-(4-morpholinyl)-2H-indol-2-one (301 mg, 1.38 mmole), triethylamine (0.22 ml, 1.52 mmole), 4-pyridinecarboxaldehyde (0.15 ml, 1.52 mmole) in methanol (3 ml) was refluxed for 30 minutes. The volatiles were evaporated and the crude product was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude red oil was characterized by mass spec., m/e 308 (M+H, 100%) for the aldol/dehydration product. The crude material was immediately dissolved in methanol (10 ml), cooled to 0° C., to which was added sodium borohydride (168 mg). After stirring 30 minutes, normal extractive workup afforded a yellow foam, which was purified by column chromatography using 5% methanol-chloroform. The product was recrystallized from hexane-ethyl acetate to give 259 mg of a powder, m.p. 108°-110° C. Anal (C18H19N3O2): C,H,N.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:4].O[CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15]>S(=O)(=O)(O)O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:1][NH:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[S:7][CH:6]=1)=[O:4]
Reactant: O=C(NCO)C(F)(F)F
Reactant: CNC(=O)c1ccsc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CNC(=O)c1csc(CNC(=O)C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To suspension of N-methyl-3-thiophenecarboxamide (1.12 g) (prepared according to J. Org. Chem. (1976), 41(23), 3668-74) in concentrated aqueous sulphuric acid (25 ml) at 0-5° C. was added N-(hydroxymethyl)trifluoroacetamide (1.134 g). The suspension was allowed to warm to 20° C. and stirred for 2 h. The mixture was poured onto ice (150 g) and diluted with ethyl acetate (200 ml). The biphase mixture was diluted with saturated sodium hydrogen carbonate (200 ml) and treated with sodium hydrogen carbonate (21 g). The phases were separated and the organic phase washed with saturated sodium hydrogen carbonate (150 ml×2). The combined aqueous phases were extracted with ethyl acetate (100 ml). The combined organic extracts were concentrated in vacuo. The residue was pre-absorbed onto silica and purified by biotage (90 g) eluting with 1:1 to 0:1 cyclohexane:ethyl acetate to give the title compound as a white solid (0.7129).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@H:3]1[CH3:7].[Cl:8][C:9]1[C:16]([CH3:17])=[C:15](F)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].C(=O)([O-])[O-].[Li+].[Li+]>CS(C)=O>[Cl:8][C:9]1[C:16]([CH3:17])=[C:15]([N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[C@@H:3]2[CH3:7])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: C[C@@H]1NCC[C@@H]1O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: Cc1c(N2CC[C@H](O)[C@@H]2C)ccc(C#N)c1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of (2S,3S)-3-hydroxy-2-methylpyrrolidine, 2-chloro-4-fluoro-3-methylbenzonitrile (424 mg), lithium carbonate (370 mg) and DMSO (12.5 ml) was stirred at 100° C. for 2 hr. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic layer was washed with water, dried (sodium sulfate), and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), and crystallized from ethyl acetate-hexane to give the title compound (114 mg) as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[N:7]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=3)[C:14]=2[CH3:24])[N:7]=1)[CH3:2]
Reactant: CCCn1cc(Br)cn1
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)OCC)n3)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: [6-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-pyridin-2-yl]-acetic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].CN(C=O)C.Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>>[CH:19]1([CH2:18][N:8]2[C:9]3[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)[CH2:21][CH2:20]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: BrCC1CC1
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(ccn2CC2CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 5-cyano-indole (0.15 mg, 1.05 mmol) in dry DMF (3.5 mL) sodium hydride (55% in oil) (69 mg, 1.58 mmol) was added in one portion at 0° C. The mixture was stirred at 0° C. for 30 min and (bromomethyl)-cyclopropane (0.133 mL, 1.37 mmol) was added. The resulting mixture was allowed to warm to room temperature, and stirred for 30 min. After completion monitored by TLC, reaction mixture was quenched with ice and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (EtOAc:hexane, 1:9) to give the product as a colorless solid (180 mg, 87%). 1H NMR (CDCl3, 400 MHz,): 0.40 (m, 1H), 0.68 (m, 1H), 0.89 (m, 1H), 4.02 (d, J=6.7 Hz, 2H), 6.60 (d, J=3.2 Hz, 7.98 (s, 1H), 7.36 (d, J=3.2 Hz, 2H), 1H), 7.42 (d, J=3.4 Hz, 2H). 13C NMR (CDCl3, 100 MHz,): 4.14, 11.1, 50.9, 102.2, 110.2, 120.9, 124.3, 126.5, 128.2, 129.8, 137.6.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH:10]=[CH:9][C:8]=2[OH:23])=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[C:32](F)=[CH:33][C:34]([F:57])=[C:35]([S:37]([N:40]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=2[O:55][CH3:56])[C:41]2[S:42][CH:43]=[N:44][N:45]=2)(=[O:39])=[O:38])[CH:36]=1>CS(C)=O>[Cl:30][C:31]1[C:32]([O:23][C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)=[CH:12][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[CH:33][C:34]([F:57])=[C:35]([S:37]([N:40]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=2[O:55][CH3:56])[C:41]2[S:42][CH:43]=[N:44][N:45]=2)(=[O:38])=[O:39])[CH:36]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(-c2ccnc(C(F)(F)F)c2)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccnc(C(F)(F)F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
2-(Pyridazin-4-yl)-4-(2-(trifluoromethyl)pyridine-4-yl)phenol (Preparation 79, 0.105 mg, 0.33 mmol) was dissolved in DMSO (3 mL) and potassium carbonate (91 mg, 0.66 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzensulfonamide (Preparation 16, 153 mg, 0.33 mmol). The mixture was stirred at room temperature for 3 hours and then partitioned between ethyl acetate (40 mL) and 1M aqueous sodium hydroxide solution (10 mL). The organic layer was separated and dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (207 mg, 81%) as a beige solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13]B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([CH3:13])[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1
Reactant: CB(O)O
Reactant: COc1cc(Br)c2occc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C)c2occc2c1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of the product from Step C (3.6 g, 16 mmol), methylboronic acid (1.4 g, 24 mmol), Pd(dppf)2Cl2 (0.65 g, 0.8 mmol) and Cs2CO3 (13.0 g, 40 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) was refluxed for 3 hrs under N2 atmosphere. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was diluted with EtOAc (200 mL) and washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluted with PE) to afford the title compound (1.0 g, 38%) as an oil. 1H-NMR (600 MHz, CDCl3) δ 7.63 (d, J=1.6 Hz, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.76 (s, 1H), 6.73 (d, J=1.8 Hz, 1H), 3.86 (s, 3H), 2.53 (s, 3H) ppm.
Reaction SMILES: C(OC(C1(C(OCC)=O)CC1)=O)C.[CH2:14]([O:16][C:17]([C:19]1([C:22]2(O)[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH:23]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:21][CH2:20]1)=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1([C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[C:23]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:20][CH2:21]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(C2(O)ON=C(c3ccc(OC)cc3)C2c2ccccc2)CC1
Agent: CCOC(=O)C1(C(=O)OCC)CC1
Product: CCOC(=O)C1(c2onc(-c3ccc(OC)cc3)c2-c2ccccc2)CC1

Procedure:
The title compound is prepared using the experimental procedure described in Example 147B except cyclopropane-1,1-dicarboxylic acid diethyl ester is used instead of cyclopropane-1,1-dicarboxylic acid dimethyl ester in Example 147A. The intermediate serving as the starting material for Example 147B is therefore 1-[5-hydroxy-3-(4-methoxy-phenyl)-4-phenyl-4,5-dihydro-isoxazol-5-yl]-cyclopropanecarboxylic acid ethyl ester instead of 1-[5-hydroxy-3-(4-methoxy-phenyl)-4-phenyl-4,5-dihydro-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][NH:5][C:4]1=[O:7])[CH3:2].[C:8]([O-:11])(=[O:10])[CH3:9].[Na+].C(O)(=O)C.C(OO)(=O)C>C(OCC)(=O)C.O.O.O.[Os](Cl)(Cl)Cl.O>[C:8]([O:11][CH:6]1[NH:5][C:4](=[O:7])[CH:3]1[CH2:1][CH3:2])(=[O:10])[CH3:9]
Reactant: CCC1CNC1=O
Reactant: CC(=O)[O-]
Agent: Cl[Os](Cl)Cl
Agent: CC(=O)OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC1C(=O)NC1OC(C)=O
Yield: 99.3 %

Procedure:
To a solution prepared by mixing 500 mg (5 mmole) of 3-ethylazetidin-2-one, 415 mg (5 mmole) of anhydrous sodium acetate, 5 ml of acetic acid, and 30 mg (abut 2 mole % based on the amount of 3-ethylazetidin-2-one) of osmium trichloride trihydrate was added dropwise, with stirring , 2.8 g (11 mmole) of a 30% peracetic acid solution in ethyl acetate at room temperature over a period of 2 hours or more. The reaction mixture was further stirred at room temperature for 4 hours, subsequently poured into 80 ml of water, and then extracted thrice with 100 ml of hexane. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was separated and purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1 by volume). Thus, 780 mg of 4-acetoxy-3-ethylazetidin-2-one was obtained. The percent yield was 78%.