Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([C:5]1[C:25](=[O:26])[C:24](C(C)(C)C)=[CH:23][C:7](=[C:8]2[CH:14]=[C:13](C(C)(C)C)[C:11](=[O:12])[C:10](C(C)(C)C)=[CH:9]2)[CH:6]=1)(C)C>[Pd]>[C:11]1([OH:12])[CH:10]=[CH:9][C:8]([C:7]2[CH:23]=[CH:24][C:25]([OH:26])=[CH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)C1=CC(=C2C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Product: Oc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 3 h
Yield: 85.4 %

Procedure:
10 g (24.5 mmol) of 3,3',5,5',-tetra-tert-butyl-diphenoquinone in 40 ml of ethylbenzene was hydrogenated as in Example 9. The filtered reaction mixture containing 4,4'-bis(2,6-di-tert-butylphenol) was transferred to a heavy walled bottle containing a magnetic stirring bar and as strong solid acid 9 g of Nafion® 117, which was obtained from the Du Pont Company as a film, which was cut into small pieces, treated with conc. HCl at 70° C. for one hour, washed with water and acetone and dried in an oven at 70° C. over night. The reactor was placed in an oil bath at 170° C. with stirring. The dealkylation was completed within 30 minutes. 3.8 g (20.4 mmol) of 4,4'-biphenol was obtained in the same way as described in Example 9 (83.3% yield). The filtrate containing 14.3 g p- and m-tert-butyl-ethylbenzene was placed in a popbottle containing 0.2 g 5% Pd/C, 10 g 3,3',5,5',-tetra-tert-butyl-diphenoquinone, and magnetic stirring bar. The hydrogenation was completed after 3 hours at 130° C. under 25 psi H2 pressure. The removal and washing of the catalyst was done as described above. The filtrate was transferred to a popbottle containing a magnetic stirring bar and the catalyst from the previous dealkylation, which had been treated with conc. HNO3, washed with acetone and water and dried at 70° C. overnight. The reaction mixture was kept at 170° C. for 45 minutes, cooled and worked up in the same way as above. 3.9 g (20.9 mmole) of 4,4'-biphenol was obtained (85.5% yield). The filtrate contained 22.2 g of p- and m-tert-butyl-ethylbenzene (69.9% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2([C:13]([F:16])([F:15])[F:14])CC[O:10]2)[CH:3]=1.F[C:18]1[CH:23]=CC(O)=C(C(O)C(F)(F)F)[CH:19]=1.C1(O)C=CC=CC=1.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>>[F:16][C:13]([F:14])([F:15])[C:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:23][CH:18]=[CH2:19])=[O:10]
Reactant: Oc1ccc(F)cc1C1(C(F)(F)F)CCO1
Reactant: Oc1ccc(F)cc1C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: Oc1ccccc1
Product: C=CCOc1ccc(F)cc1C(=O)C(F)(F)F

Procedure:
Synthesis of the requisite 4-fluoro-2-[2-(trifluoromethyl)oxetan-2-yl]phenol may be carried out from 4-fluoro-2-(2,2,2-trifluoro-1-hydroxyethyl)phenol (see J. Zhang et al., Synth. Commun. 2011, 41, 3045-3052). Selective alkylation of the phenol, using allyl bromide and a base such as potassium carbonate, followed by a Swern oxidation of the benzylic alcohol, provides 2,2,2-trifluoro-1-[5-fluoro-2-(prop-2-en-1-yloxy)phenyl]ethanone. This material was reacted with trimethylsulfoxonium iodide and potassium tert-butoxide to afford 2-[5-fluoro-2-(prop-2-en-1-yloxy)phenyl]-2-(trifluoromethyl)oxetane; the allyl group was removed using tetrakis(triphenylphosphine)palladium(0) and morpholine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]\[C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[C:5]([O:22][Si](C(C)(C)C)(C)C)=[C:4]([O:30][Si](C(C)(C)C)(C)C)[CH:3]=1.[F-].[K+]>CO.CN(C)C=O.C(O)(=O)C.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]\[C:10]2[CH:11]=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)[C:5]([OH:22])=[C:4]([OH:30])[CH:3]=1
Reactant: COc1cc(/C=C\c2cc(Br)cc(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Agent: [F-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(/C=C\c2cc(Br)cc(O)c2O)cc(OC)c1OC
Reaction time: 30 h

Procedure:
To a solution of 20 (0.19 g, 0.32 mmol) in methanol:dimethylformamide 1:1 (4 mL), acetic acid was added (0.114 mL, 1.9 mmol) followed by potassium fluoride (0.110 mg, 1.9 mmol). The mixture was stirred for 30 hours then diluted with tertbutylmethyl ether (50 mL) and washed with water (20 mL) then brine (20 mL), then dried over sodium sulphate. The solvent was removed under reduced pressure to give a crude which was purified by column (cyclohexane:AcOEt 7:3+1% AcOH) to give 0.097 g of ZSB-74:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[C:9]#[N:10].O.[OH-].[Na+]>O1CCCC1>[CH3:11][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:7])[CH2:9][NH2:10]
Reactant: CC(C)(C#N)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CN)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Powdered lithium aluminum hydride (137 mg, 3.61 mmol) was added portionwise to a solution of 2-methyl-2-phenylpropanenitrile (436 mg, 3.00 mmol) in tetrahydrofuran (20 mL). The resulting mixture was stirred at 80° C. overnight. The reaction was then cooled to 0° C. and water (66 μL, 3.7 mmol), 10% sodium hydroxide (1.44 g, 3.6 mmol) and water (195 μL, 10.8 mmol), respectively, were added dropwise into the reaction mixture. The suspension was filtered through anhydrous magnesium sulfate and the solution was concentrated under vacuum to give 2-methyl-2-phenylpropan-1-amine (400 mg) as a yellow oil, which was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Mg].II.BrC1SC2C=CC=CC=2C=1.CON(C)[C:27](=[O:29])[CH3:28]>O1CCCC1>[S:6]1[CH:7]=[CH:8][C:4]2[CH:3]=[C:2]([C:27](=[O:29])[CH3:28])[CH:10]=[CH:9][C:5]1=2
Reactant: Brc1ccc2sccc2c1
Reactant: CON(C)C(C)=O
Agent: Brc1cc2ccccc2s1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Approximately 1 ml of a solution of 5-bromobenzo[b]thiophene (6.6 g; prepared in a manner similar to that described in Example 21) in tetrahydrofuran (35 ml) was added under nitrogen to a mixture of magnesium turnings (0.8 g), tetrahydrofuran (7 ml) and a few small crystals of iodine, heat was applied to initiate the reaction, then the remainder of the bromobenzo[b]thiophene solution was added at reflux temperature over 20 minutes. When the addition was complete, the mixture was heated under reflux for 45 minutes, then a solution of N-methoxy-N-methylacetamide (3.8 g) in tetrahydrofuran (35 ml) was added. The mixture was heated under reflux for 30 minutes, cooled to ambient temperature, then quenched by the addition of 2M hydrochloric acid (90 ml) and stirred at ambient temperature for 30 minutes. The majority of the tetrahydrofuran was removed in vacuo, then water (150 ml) was added to the residue and the product was extracted into ethyl acetate (150 ml). The extract was washed with saturated aqueous sodium chloride solution (100 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography over silica using a 95:5 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-5-yl]ethan-1-one (2.35 g) as a white solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:3]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.Cl.[CH3:44][NH:45][O:46][CH3:47].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:45]([O:46][CH3:47])[CH3:44])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)cc1Nc1ccccc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)cc1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500 mL round bottom flask, 4-chloro-2-(2-chloro-phenylamino)-benzoic acid (1.15 g, 4.08 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 2.28 g, 4.89 mmol), N,O-dimethylhydroxylamine hydrochloride (0.80 g, 8.2 mmol) and N,N-diisopropylethylamine (7.5 mL, 42.9 mmol) were added to dichloromethane (60.0 mL). The mixture was stirred at room temperature overnight. LCMS the next day indicated a mixture of starting material and product. The reaction was further charged with N,O-dimethylhydroxylamine hydrochloride (1.61 g, 16.5 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 1.86 g, 4.89 mmol) and the mixture was stirred overnight at room temperature. LCMS the next day showed complete consumption of starting material. The reaction mixture was poured into ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water and brine. The organic layer was dried, filtered and concentrated. The crude was purified by flash chromatography using 0-15% ethyl acetate-hexanes to give 4-chloro-2-(2-chloro-phenylamino)-N-methoxy-N-methyl-benzamide as an orange oil. 1H NMR (DMSO-d6) δ ppm 8.03 (s, 1H) 7.39-7.58 (m, 2H) 7.20-7.37 (m, 2H) 6.92-7.17 (m, 3H) 3.52 (s, 3H) 3.24 (s, 3H). MS calcd. for C15H14Cl2N2O2 [(M+H)+] 326.0, obsd. 324.9, [(M-C2H6NO2)+] 265.0, obsd. 264.0.
Reaction SMILES: C([Li])CCC.[B:6](OC(C)C)([O:11]C(C)C)[O:7]C(C)C.C(=O)=O.CC(C)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH2:34])=[CH:29][N:28]=1.Cl>C1COCC1.FC1C=CC(C=C)=CN=1>[F:26][C:27]1[C:32]([B:6]([OH:11])[OH:7])=[CH:31][C:30]([CH:33]=[CH2:34])=[CH:29][N:28]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C=Cc1ccc(F)nc1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C=Cc1cnc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 639.6 %

Procedure:
2-Fluoro-5-vinylpyridine (64.8 mg, 0.526 mmol) was dissolved in THF (2.0 mL) and the reaction flask was cooled in a dry ice/acetone bath. Then, n-butyllithium (1.6 M solution in hexanes, 0.40 mL, 0.64 mmol) was added via syringe dropwise, turning the solution red. The reaction was stirred at −78° C. for 45 minutes, and then triisopropyl borate (Aldrich, St. Louis, Mo. 98+%, 0.190 mL, 0.826 mmol) was added, and the reaction was allowed to slowly warm up to room temperature (the dry ice/acetone bath was removed after 80 minutes). The reaction was stirred at room temperature for 45 minutes, and then quenched with water. The layers were separated, and the organic phase was discarded. The aqueous phase was treated with 5N HCl to lower the pH from 9 to 4. Then, the aqueous phase was extracted with 10:1 DCM/MeOH, and the organic extracts were combined and set aside. In a separate flask, 2-fluoro-5-vinylpyridine (4.15 g, 33.7 mmol) was decanted from a solid precipitate, which was washed with THF. The 2-fluoro-5-vinylpyridine was dissolved in THF (120 mL), and the reaction flask was cooled in a dry ice/acetone bath under nitrogen. Then, n-butyllithium solution (1.6 M in hexanes, 25.5 mL, 40.8 mmol) was added via syringe, turning the yellow solution into a deep red color. The reaction was stirred at −78° C. for 50 minutes, and then triisopropyl borate (Aldrich, St. Louis, Mo. 98+%, 11.5 mL, 50.0 mmol) was added via syringe, and the reaction was allowed to warm to room temperature (after 90 minutes, the dry ice/acetone bath was removed). Almost 5 hours after the addition of triisopropyl borate, the reaction was quenched with water (125 ml), slowly at first. The biphasic solution was stirred for 15 minutes, and then the layers were separated. The organic phase extracted one time with saturated sodium bicarbonate. This sodium bicarbonate washing was discarded. The organic phase was extracted two times with 1 N NaOH (60 mL and then 50 mL). These aqueous extractions were combined, treated with concentrated HCl to lower the pH to 4, and extracted with 10:1 DCM/MeOH. These organic extracts did not contain product, so they were discarded, along with these second aqueous extractions. The original aqueous phase (from the initial phase separation after quenching the reaction with water) was treated with 5N HCl to lower the pH to around 3-4. This aqueous phase was extracted with 10:1 DCM/MeOH. These organic extracts were combined with the organic extracts from the first reaction, concentrated, and dried under high vacuum at room temperature to afford 2-fluoro-5-vinylpyridin-3-ylboronic acid (882 mg, 61% purity, 11% yield over 2 steps). MS (ESI pos. ion) m/z 168 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](Br)[CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:12].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([C:8]2[CH:9]=[CH:10][C:5]3[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:6]=3[CH:7]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cn1c(=O)[nH]c2ccc(Br)cc21
Product: Cn1c(=O)[nH]c2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared from 1-methyl-6-bromo-1,3-dihydro-benzoimidazol-2-one and 3-chloro-phenyl boronic acid in the same fashion as that of Example 5. mp 219-220° C.; 1H-NMR (DMSO-d6) δ 11.0 (s, 1H), 7.75 (bs, 1H), 7.65 (dd, 1H, J=7.5, 1.76 Hz), 7.49-7.44 (m, 2H), 7.39-7.32 (m, 2H), 7.06 (d, 1H, J=7.94 Hz), 3.35 (s, 3H), MS (ES) m/z 259([M+H]+, 100%); Anal. Calc. For C14H11ClN2O: C, 65, H, 4.29, N, 10.83. Found: C, 64.44, H, 4.36 N, 10.6.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>N1C=CC=CC=1>[F:27][C:13]([F:12])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[N:24]([C:30]([N:29]([CH3:33])[CH3:28])=[O:31])[C:23](=[O:25])[O:22][N:21]=2)[CH:15]=1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 20 h
Yield: 63.7 %

Procedure:
To 1 ml of pyridine were added 0.26 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.18 g of N,N-dimethylcarbamoyl chloride was added at room temperature. After stirring for 20 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.25 g of 3-(4-trifluoromethylpyridin-2-yl)-N,N-dimethyl-1,2,4-oxadiazol-5-one-4-carboxamide (present compound (14)).
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([NH:9][C:10]([NH:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6].O.[OH-].[Li+]>C1COCC1.CO.O>[C:13]12([NH:12][C:10](=[O:11])[NH:9][C@@H:4]([C:5]([CH3:7])([CH3:6])[CH3:8])[C:3]([OH:23])=[O:2])[CH2:14][CH:15]3[CH2:16][CH:17]([CH2:18][CH:19]([CH2:21]3)[CH2:20]1)[CH2:22]2
Reactant: COC(=O)[C@@H](NC(=O)NC12CC3CC(CC(C3)C1)C2)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[C@H](NC(=O)NC12CC3CC(CC(C3)C1)C2)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
To a solution of (S)-2-(3-Adamantan-1-yl-ureido)-3,3-dimethyl-butyric acid methyl ester (265 mg, 0.822 mmol) in THF (4 mL) and MeOH (4 mL) was added a pre-made solution of lithium hydroxide monohydrate (69 mg, 1.644 mmol) in water (4.00 mL). The cloudy white solution was stirred at rt for 5 hrs. The volatiles were removed, and the reaction mixture was diluted with dilute citric acid solution and extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, evaporated to obtain white solid (232 mg, 92%) as product. The crude material was used without further purification.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]([N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:23]
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C=Nc1ccccc1Cl
Product: O=C(Nc1ccccc1Cl)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 4-benzylpiperidine and 2-chlorophenyl isocyanate. 1H NMR (400 MHz, CDCl3): 8.19 (dd, J=8.3, 1.5 Hz, 1H), 7.33-7.12 (m, 7H), 7.03 (br s, 1H), 6.96-6.90 (m, 1H), 4.12-4.05 (m, 2H), 2.85 (td, J=13, 2.3 Hz, 2H), 2.57 (d, J=6.8 Hz, 2H), 1.82-1.69 (m, 3H), 1.34-1.20 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].Cl[CH2:23][CH:24]1[O:28][C:27](=[O:29])[NH:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:29]=[C:27]1[NH:26][CH2:25][CH:24]([CH2:23][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[O:28]1
Reactant: O=C1NCC(CCl)O1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NCC(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)O1
Temperature: 25 °C
Reaction time: 11 h
Yield: 30.1 %

Procedure:
A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.37 g, 4.89 mmol), 5-(chloromethyl)-1,3-oxazolidin-2-one (1.34 g, 5.38 mmol) and cesium carbonate (2.39 g, 7.34 mmol) in N,N-dimethylformamide (8.0 mL) was stirred at ambient temperature for 11 h and filtered. The solid was washed with ethyl acetate and the filtrate was washed with water (3×15 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography to afford 1′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.56 g, 25%): mp 195-202° C.; 1H NMR (300 MHz, CDCl3) δ 7.35-7.30 (m, 1H), 7.17-7.04 (m, 3H), 6.50 (s, 1H), 6.12 (s, 1H), 5.84 (s, 2H), 5.27 (br, 1H), 5.02-4.96 (m, 1H), 4.91-4.87 (m, 1H), 4.68-4.64 (m, 1H), 4.14-3.96 (m, 2H), 3.75-3.68 (m, 1H), 3.55-3.44 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 178.9, 158.5, 155.9, 149.0, 142.4, 142.2, 131.7, 129.4, 124.0, 123.9, 119.2, 109.6, 102.8, 101.6, 93.7, 80.3, 74.9, 58.1, 43.5, 43.1; MS (ES+) m/z 403.2 (M+23), 381.2 (M+1).
Reaction SMILES: [C:1](=[O:6])(OC)OC.C[O-].[Na+].[NH2:10][C:11]1[C:16]([CH2:17][NH:18][CH3:19])=[CH:15][C:14]([Br:20])=[CH:13][N:12]=1>CO.O>[Br:20][C:14]1[CH:13]=[N:12][C:11]2[NH:10][C:1](=[O:6])[N:18]([CH3:19])[CH2:17][C:16]=2[CH:15]=1
Reactant: CNCc1cc(Br)cnc1N
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1Cc2cc(Br)cnc2NC1=O
Temperature: 50 °C
Yield: 67.1 %

Procedure:
To a solution of dimethyl carbonate (2.14 g, 23.7 mmole) and sodium methoxide (1.0 mL, 4.5 mmole. 25% wt in CH3OH) in CH3OH (25 mL) was added 2-amino-5-bromo-3-(methylaminomethyl)pyridine (1.0 g, 4.62 mmole). The reaction was heated at 50° C. overnight, diluted with H2O (1 mL) and concentrated. Toluene was added to the reaction residue and the contents were heated to reflux for 12 hr under a Dean-Stark apparatus. The reaction was cooled to RT, diluted with EtOAc, and washed with H2O. Purification on Silica gel (9:1 CHCl3/CH3OH containing 5% NH4OH) gave the title compound (0.75 g, 67%) as an off-white solid: MS (ES) m/e 243 (M+H)+.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Cl[CH2:11][C:12]1[CH:24]=[CH:23][C:15]([O:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:14][CH:13]=1.CC(N(C(C)C)CC)C.C(OCC)(=O)C>CS(C)=O.O>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[O:16][C:15]1[CH:23]=[CH:24][C:12]([CH2:11][N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)=[CH:13][CH:14]=1
Reactant: ClCc1ccc(Oc2ncccn2)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCN(Cc2ccc(Oc3ncccn3)cc2)CC1
Yield: 99.6 %

Procedure:
A solution of 1.47 grams (0.0096 mole) of 4-piperidone monohydrate hydrochloride, 2.1 grams (0.0096 mole) of 2-[4-(chloromethyl)phenoxy]pyrimidine, and 4.34 grams (0.0336 mole) of bis(methylethyl)ethylamine in 35 mL of dimethylsulfoxide (DMSO) was stirred at ambient temperature for about 24 hours. The reaction mixture was then diluted with 200 mL of water and was extracted two times with 200 mL of ethyl acetate. The extracts were then combined and washed two times with 75 mL of an aqueous mixture of 10% lithium chloride. The resultant organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica get using 1:2 ethyl acetate:petroleum ether as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.71 grams of the subject compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([NH:15]C(=O)C(O)CC(C)C)([C:13]#[N:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.CN1CCOCC1.C(N)C1C=CC=CC=1>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[NH2:15][C:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1
Reactant: CC(C)CC(O)C(=O)NC1(C#N)CCN(Cc2ccccc2)C1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: NCc1ccccc1
Product: N#CC1(N)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.4 %

Procedure:
To a solution of 2-hydroxy-4-methyl-pentanoic acid (1-benzyl-3-cyano-pyrrolidin-3-yl)-amide (0.315 g, 1.0 mmol) in dry THF (27 mL) was added DMAP (0.171 g, 1.4 mmol), p-nitrophenyl chloroformate (0.221 g, 1.1 mmol), and N-methylmorpholine (0. 121 mL, 1.1 mmol). The resulting mixture was allowed to stir overnight (20 h) under argon at room temperature, then treated with benzylamine (0.150 g, 1.4 mmol) and allowed to stir overnight (24 h). When the reaction was complete, the mixture was diluted with EtOAc (50 mL), then washed sequentially with saturated aq. NaHCO3 (50 mL), water and brine, dried over Na2SO4, filtered and concentrated to give 0.180 g (40% yield ) of the desired product after purification by prep-HPLC; 1H NMR (CDCl3) 7.25 (10H, m), 6.25 (1H, s), 5.4-5.1 (2H, m), 4.45 (2H, m), 3.65 (2H, m), 3.1-3.0 (1H, m), 2.98-2.57 (5H, m), 2.16 (1H, m), 1.73 (2H, m), 0.9 (6H, m). MS, m/z 449=M+1.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([C:7]([N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][N:21]3[CH2:20][CH2:19][N:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][CH3:10])[CH2:23][CH2:22]3)[CH2:26][CH2:27]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1N1CCN(CC2CCNCC2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CC2CCN(C(=O)C3CCCCC3)CC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
Cyclohexanecarbonyl chloride (0.506 g, 3.5 mmol) was added to a solution of 1-(2-methoxyphenyl)-4-piperidin-4-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 1 and triethylamine (2 equivalents, 1 mL) in CH2Cl2 (30 mL) and the solution stirred under N2 at 0° C. for 16 hours. The mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3×25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (0.765 g, 55% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid.