Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([C:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:5][C:3]#[N:4])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% wt in mineral oil) (0.780 g, 32.5 mmol) in THF (100 mL) at room temperature was added diethyl cyanomethylphosphonate (4.50 g, 25.4 mmol) (4 mL). The mixture was stirred for 30 min and benzophenone (4.22 g, 23.2 mmol) was added. The reaction mixture was stirred at room temperature for 1d, and partially concentrated, diluted with Et2O, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 5% to 20% EtOAc in hexanes) gave 3,3-diphenylacrylonitrile.
Reaction SMILES: [C:1]1([CH:7]2[CH2:19][C:18](=O)[C:17]3[C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[NH:10][C:9]=3[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[NH:24]([N:25]=[C:18]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[NH:10][C:9]=2[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19]1)[C:21]([NH2:23])=[NH:22]
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2)Cc2[nH]c3c(c21)CCCC3
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2[nH]c3c(c21)CCCC3
Yield: 49.1 %

Procedure:
A mixture of 2-phenyl-1,2,3,4,5,6,7,8-octahydrocarbazol-4-one (0.8 g), aminoguanidine hydrochloride (0.35 g), concentrated hydrochloric acid (0.15 ml), water (0.15 ml) and ethanol (50 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution. The solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (EtOAc/MeOH) and dissolved in ethanol. To the solution was added 1N hydrochloric acid (4 ml), and the solvent was evaporated. The residue was recrystallized from ethanol to give 4-guanidinoimino-2-phenyl-1,2,3,4,5,6,7,8-octahydrocarbazole hydrochloride (Compound 5) (0.53 g) as amorphous.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C@H:10]1[CH2:17][CH2:16][CH2:15][C@:12]2([O:14][CH2:13]2)[CH2:11]1>CO>[CH2:1]([NH:8][CH2:13][C@:12]1([OH:14])[CH2:15][CH2:16][CH2:17][C@H:10]([CH3:9])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CCC[C@@]2(CO2)C1
Reactant: NCc1ccccc1
Solvent: CO
Product: C[C@H]1CCC[C@@](O)(CNCc2ccccc2)C1
Yield: 69.5 %

Procedure:
A methanol (1 ml) solution of benzylamine (5.9 g) and (3S,5S)-5-methyl-1-oxaspiro[2.5]octane (3.5 g) were heated in a microwave (100 W) for 30 minutes at 100° C., then concentrated in vacuo and purified by flash column chromatography (SiO2, 20% ethyl acetate/iso-hexane as eluent) to afford the subtitle compound as a colourless oil (4.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:33])[C:19]=1[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[O:22]>>[Cl:33][C:18]1[CH:17]=[N:16][CH:15]=[C:14]([Cl:13])[C:19]=1/[CH:20]=[C:21](\[O:22][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)/[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)c2ccc([N+](=O)[O-])cc2)cc1OC

Procedure:
The compound was obtained starting from 4-nitro-benzoyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanone, following the procedure of Example 7.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[CH2:32][CH3:33].Cl>C(O)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[CH2:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CCc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Product: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 22.1 %

Procedure:
A mixture of 1.1 g (3.481 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.746 g (4.525 mmole) of 4-amino-3-ethylbenzoic acid, 10 mL of ethanol and 40 mL of 1M hydrochloric acid was heated at reflux for 18 hours. The mixture was cooled and the white precipitate was collected by filtratration, washed with cold water and dried in vacuum to give 0.3421 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) as off-white solid.
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:5](OC)=[O:6])#[N:2]>[Ni].N.CO>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH:4]2[CH2:3][CH2:1][NH:2][C:5]2=[O:6])=[CH:10][CH:11]=1
Reactant: COC(=O)C(CC#N)c1ccc(F)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: O=C1NCCC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Methyl 3-cyano-2-(4-fluorophenyl)propanoate (2.09 g, 10.09 mmol; Example 189A) and 7 M NH3-methanol (100 mL) were added to Raney® nickel, solvent washed (20.90 g, 356 mmol) in a 250 mL stainless steel pressure bottle and stirred for 17 hours under hydrogen at 30 psi and room temperature. The mixture was filtered through a nylon membrane and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.36-7.16 (m, 2H), 7.12-6.94 (m, 2H), 6.04 (s, 1H), 3.61 (t, J=9.2, 1H), 3.54-3.39 (m, 2H), 2.71-2.53 (m, 1H), 2.23 (ddd, J=8.4, 12.9, 17.7, 1H); MS (ESI+) m/z 179.9 (M+H)+.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](OC)=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](OC)=[CH:10][CH:9]=1.Cl>C(OCC)C>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(Cc1ccccc1)NCC(O)COc1ccccc1

Procedure:
Using the method of Example 5, supra, 1,2-epoxy-3-phenoxypropane (600 mg, 4 mmol) and 1,1-dimethyl-2-phenylethylamine (596 mg, 4 mmol) yielded the title compound: GC/EI-MS, m/z (rel. int.) 284 (M+1, 1), 208 (100), 162 (1), 133 (7), 91 (27), 77 (15), 70 (22). The free base in diethyl ether was treated with excess 1M HCl (diethyl ether). The resulting solid was recrystallized from hot acetonitrile to afford 596 mg of the hydrochloride product as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:12]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:14])=[CH:20][CH:19]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccccc2c1O
Temperature: 200 °C
Reaction time: 18 h

Procedure:
A mixture of 0.50 g of ethyl 4-hydroxy-3-quinolinecarboxylate (J. Amer. Chem. Soc., 68, 1264 (1946)) and 5.0 mL of 4-chlorobenzylamine is stirred 18 h at 200° C. The mixture is cooled to 25° C. and it is diluted with 25 mL of hexanes. After stirring for an additional 1 h the solid precipitate is collected by filtration and washed with 10 mL of hexanes. It is dried at 20 torr and 45° C. for 18 h. The yield is 0.28 g.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH3:29])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH3:29])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:32])[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Product: CCOC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A176) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: C([N:8]([C:23]([C:25]1([CH3:36])[C:30](=[O:31])[NH:29][C:28]2[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=2[S:26]1)=[O:24])[C@H:9]([C:11]([NH:13][C@@H:14]([C:20](=[O:22])[NH2:21])[CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[O:12])[CH3:10])C1C=CC=CC=1>CO.[Pd]>[CH3:36][C:25]1([C:23]([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:20](=[O:22])[NH2:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:12])[CH3:10])=[O:24])[C:30](=[O:31])[NH:29][C:28]2[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=2[S:26]1
Reactant: C[C@@H](C(=O)N[C@H](CCC(=O)[O-])C(N)=O)N(Cc1ccccc1)C(=O)C1(C)Sc2ccccc2NC1=O
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)C1(C)Sc2ccccc2NC1=O)C(=O)N[C@H](CCC(=O)O)C(N)=O
Reaction time: 12 h
Yield: 59.2 %

Procedure:
Benzyl-N-(3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzothiazine-2-carbonyl)-L-alanyl-D-isoglutaminate (485 mg, 1.06 mmoles) was dissolved in methanol (17 ml), Pd/C (10%, 75 mg) was added thereto and it was hydrogenated at normal pressure for 12 hours. After the removal of the catalyst and evaporation of the solvent, there were obtained 265 mg (59.3%) of the title product in the form of a white powder, m.p. 124°-125° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]3[CH:29]=[C:30]([C:34]4[N:35]=[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]5[CH:42]=4)[CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:7]3[CH:29]=[C:30]([C:34]4[N:35]=[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]5[CH:42]=4)[CH:31]=[C:32]([CH3:33])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2cn3ccccc3n2)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cn3ccccc3n2)cc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 208 from tert.butyl 4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[C:32]#[CH:33])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>ClCCl.CO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[C:32]#[C:33][C:2]3[CH:16]=[CH:15][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][C:10]([OH:13])([CH3:14])[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC1(O)CCN(Cc2ccc(I)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CC1(O)CCN(Cc2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)-4-methylpiperidin-4-ol and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 25 mg (13% of theory); melting point: 192° C.-193° C.; C28H27ClN2O2 (M=458.99); calc.: molecular ion peak (M+H)+: 459/461; found: molecular ion peak (M+H)+: 459/461; Rf value: 0.2 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: C([O:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([O:24]C(=O)C)=[CH:15][C:16]=3[O:20]C(=O)C)[O:11][C:10]=2[CH2:28][Br:29])=[CH:7][CH:6]=1)(=O)C.Br>>[OH:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([OH:24])=[CH:15][C:16]=3[OH:20])[O:11][C:10]=2[CH2:28][Br:29])=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(-c2c(CBr)oc3cc(OC(C)=O)cc(OC(C)=O)c3c2=O)cc1
Agent: Br
Product: O=c1c(-c2ccc(O)cc2)c(CBr)oc2cc(O)cc(O)c12
Temperature: 100 °C
Yield: 94.3 %

Procedure:
A mixture of 4',5,7-triacetoxy-2-bromomethylisoflavone (1 g) and 48% hydrobromic acid (7 ml) was heated at 100° C. for one hour, the reaction mixture was cooled with stirring, and the solid which separated out was collected by filtration and washed with water, giving 0.7 g of 4',5,7-trihydroxy-2-bromomethylisoflavone.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1.[CH3:11][S:12]([O-])(=[O:14])=[O:13].[Na+]>CS(C)=O.CCOC(C)=O.[Cu]I>[CH3:11][S:12]([C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1)(=[O:14])=[O:13]
Reactant: CCC(=O)c1cnc(Br)s1
Reactant: CS(=O)(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(=O)c1cnc(S(C)(=O)=O)s1
Temperature: 120 °C

Procedure:
To a solution of 1-(2-bromo-thiazol-5-yl)-propan-1-one (75 mg, 0.34 mmol) in dimethyl sulfoxide (3 mL) was added the sodium methanesulfonate (41 mg, 0.34 mmol) followed by copper (I) iodide (65 mg, 0.34 mmol). The mixture was heated in a microwave at 120° C. for 1 hour. The reaction was diluted with EtOAc (20 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to afford 1-(2-methanesulfonyl-thiazol-5-yl)-propan-1-one which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>CN(C)C=O.[Cu]>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)[CH:26]=1
Reactant: Brc1cccnc1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl 4-hydroxybenzoate (25.0 g, 110 mmol) in N,N-dimethylformamide (60 ml) was added potassium tert-butoxide (12.3 g, 110 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was evaporated under reduced pressure, and 3-bromopyridine (25.0 g, 110 mmol), a copper powder (1.76 g, 27.2 mmol) and N,N-dimethylformamide (80 ml) were added. The mixture was stirred at 120° C. for 8 hrs. The reaction solution was filtered with celite and the filtrate was evaporated under reduced pressure. To the residue was added water (500 ml) and the mixture was extracted with ethyl acetate (500 ml). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-2:1) to give the objective substance (18.0 g, 54%, crude).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:33](I)[CH3:34]>C(OCC)(=O)C>[CH2:33]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)[CH3:34]
Reactant: CCI
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 1 g and potassium carbonate 1.95 g were added to dimethylformamide 10 ml, ethyl iodide 0.48 ml was added, and the mixture was reacted at a temperature of 100° C. for two hours. After the solution was cooled to room temperature, ethyl acetate 200 ml was added. The ethyl acetate solution was washed with water 100 ml twice and a saturated sodium chloride solution 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, and concentrated to 40 ml under reduced pressure. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.65 g. FAB MASS; 311 (M+1) 1H-NMR (ppm, in CDCl3); 1.45 (3H, t), 4.10 (2H, q), 6.00 (2H, s), 6.68-6.70 (3H, m), 6.82 (1H, d, J=7.9 Hz), 7.24 (1H, dd, J=8.2 Hz), 7.49 (1H, d, J=1.5 Hz), 7.63 (1H, d, J=8.2 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O-:14])=[O:13])=O)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[BH4-].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[O:13]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)[O-])cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(C2OC(=O)c3ccccc32)cc1[N+](=O)[O-]
Reaction time: 0.67 h

Procedure:
To a solution of 2-[(4-amino-3-nitrophenyl)carbonyl]benzoate (8.36 g, 27.8 mmol) in THF (100 mL) and methanol (30 mL) at 0° C. was added sodium borohydride (3.0 g, 79 mmol). The mixture was stirred for 40 min, and then unreacted hydride was quenched with 10% aqueous citric acid. The organic solvents were removed in vacuo. An orange solid precipitated from the resulting aqueous mixture. This solid was collected by filtration, rinsed with water, triturated with ether, and dried in vacuo. Desired 3-(4-amino-3-nitrophenyl)-2-benzofuran-1(3H)-one was obtained as a bright orange solid (5.23 g, 19.4 mmol, 69% yield). 1H NMR (400 MHz, d6-DMSO): 8.03 (d, 1H), 7.90 (d, 1H), 7.76 (t, 1H), 7.65-7.60 (m, 3H), 7.45 (d, 1H), 7.11 (dd, 1H), 6.99 (d, 1H), 6.66 (s, 1H); MS (EI) for Cl4H10N2O4: 303 (MNa+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[N:6]1[CH:5]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)[CH:7]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: c1cc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)ccn1

Procedure:
The title compound was prepared from the product of Example 65A and 4-pyridinylboronic acid according to General Method B: LC-MS Method B (ESI+) m/z 307.0 (M+H)+, retention time 1.54 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22](O)=[O:23])[CH:19]=[C:18]([Cl:25])[CH:17]=4)[CH2:14][C:13](=[O:26])[NH:12][CH:11]3[C:27](=[CH2:30])[CH2:28][CH3:29])[C:5]2=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:34].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22]([F:34])=[O:23])[CH:19]=[C:18]([Cl:25])[CH:17]=4)[CH2:14][C:13](=[O:26])[NH:12][CH:11]3[C:27](=[CH2:30])[CH2:28][CH3:29])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(CC)C1NC(=O)CC(c2cc(Cl)cc(C(=O)O)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(CC)C1NC(=O)CC(c2cc(Cl)cc(C(=O)F)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-hydroxycarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.43 mmol) prepared in example 93 in dichloromethane (20 mL) at 0° C. was added cyanuric fluoride (48 mg, 0.35 mmol) (Alfa) and pyridine (37 mg, 0.48 mmol). After the mixture was stirred at 0° C. for 2 h, the mixture was partitioned between H2O and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO4, concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-fluorocarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow gum and used for the next step without further purification (Yield: 0.2 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=[O:23])[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:36][CH2:37]O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([O:24][CH2:36][CH3:37])=[O:23])[CH2:15]2)[C:10]([F:13])([CH3:11])[CH3:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCO
Reactant: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C(=O)O)c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc([C@H](c2ccc(Cl)cc2)N2CC([C@@H](c3cc(F)cc(Br)c3)C(C)(C)F)C2)c1

Procedure:
To a mixture of 5.72 g (10.4 mmol) of 3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]benzoic acid in 230 mL of EtOH, was added a solution of 25 mL of 4N HCl in dioxane. After 7.5 h at reflux, the solution was cooled and concentrated to remove solvents. To the residue were added 150 mL of CH2Cl2 and 30 mL of H2O and the pH was adjusted to 7-8 with aq NaHCO3. The aqueous layer was extracted with three 100 mL portions of CH2Cl2 and the combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 1.25 (d, 3H, J1=22 Hz), 1.27 (d, 3H, J1=22 Hz), 1.40(t, 3H, J=7.1 Hz), 2.34(t, 1H, J=7.5 Hz), 2.83-2.89(m, 2H), 3.10-3.15(m, 2H), 3.62 (m, 1H), 4.30(s, 1H), 4.38 (q, 2H, J1=14.2 Hz, J2=7.1 Hz), 6.85 (d, 1H, J=9.4 Hz), 7.10-7.11(m, 2H), 7.26-7.38 (m, 5H), 7.55 (d, 1H, J=7.8 Hz), 7.86 (d, 1H, J=7.7 Hz), 8.05 (s, 1H); Mass Spectrum: m/e=576, (M+1, 35Cl 79Br), 578 (M+1, 37Cl79Br/35Cl 81Br), 580 (M+1, 37Cl 81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.O[N:12]=[C:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[NH2:14]>N1CCCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:7][N:12]=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[NH:14]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C=O
Reactant: NC(=NO)c1ccco1
Solvent: C1CCNCC1
Product: Cc1cc(Cl)ccc1C1NC(c2ccco2)=NO1
Temperature: 100 °C
Yield: 24.2 %

Procedure:
A mixture of 4-chloro-2-methylbenzaldehyde (229 mg, 1.49 mmol), N′-hydroxyfuran-2-carboximidamide (263 mg, 2.1 mmol) and one drop of piperidine was heated to 100° C. for 4 h. It was cooled to RT and purified by automated column chromatography on the ISCO-companion (SiO2, gradient heptane/ethyl acetate) to give the 5-(4-chloro-2-methylphenyl)-3-(furan-2-yl)-4,5-dihydro-1,2,4-oxadiazole product (94 mg, 0.36 mmol) as an off-white solid with an HPLC purity 99%. The overall yield was approximately 24%. LC-MS [M+H] 263 (C13H11ClN2O2+H, expected 263.05).