Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[CH:25][N:26]=4)=[C:18]([CH2:27][CH3:28])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=C(CC)C(O)=CC=3OCCC)OC(=O)CC(=O)C2)CCCC1.[CH3:57][C:58]1[CH:59]=[N:60][C:61]2[N:62]([N:64]=[C:65]([CH:67]=O)[N:66]=2)[CH:63]=1.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[CH:25][N:26]=4)=[C:18]([CH2:27][CH3:28])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:67][C:65]3[N:66]=[C:61]4[N:60]=[CH:59][C:58]([CH3:57])=[CH:63][N:62]4[N:64]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc2nc(C=O)nn2c1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1-c1ncco1
Agent: CCCOc1cc(O)c(CC)cc1CCC1(C2CCCC2)CC(=O)CC(=O)O1
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(C)cn4n3)C(=O)O2)ccc1-c1ncco1

Procedure:
The title compound was prepared analogously to example A(1) where 6-cyclopentyl-6-{2-[3-ethyl-4-(1,3-oxazol-2-yl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione (Example A(135)) was substituted in place of 6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-propoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione in that example and 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. Yield (58 mg, 11%). 1H NMR (300 MHz, CDCl3): δ ppm 1.19 (t, J=7.44 Hz, 3H) 1.40 (d, J=4.33 Hz, 1H) 1.53-1.67 (m, 8H) 2.01-2.10 (m, 2H) 2.39 (s, 1H) 2.45-2.49 (m, 3H) 2.54-2.64 (m, 1H) 2.71 (dd, J=11.87, 5.46 Hz, 2H) 2.76-2.85 (m, 1H) 3.01 (q, J=7.47 Hz, 2H) 4.10 (s, 2H) 7.05-7.11 (m, 2H) 7.29 (s, 1H) 7.73 (s, 1H) 7.78 (d, J=7.91 Hz, 1H) 8.61 (s, 1H) 8.68 (d, J=2.07 Hz, 1H). MS (ESI): 528 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]O.[H-].[Na+].F[C:10]1[CH:11]=[C:12]([CH:20]([NH:22][CH:23]2[CH2:25][CH2:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.O>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:10]1[CH:11]=[C:12]([CH:20]([NH:22][CH:23]2[CH2:25][CH2:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: COCCCO
Reactant: CC(NC1CC1)c1cc(F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCc1cc(C(C)NC2CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-methoxy-1-propanol (0.14 mL) in N,N-dimethylformamide (3.0 mL) was added 60% oil-based sodium hydride (97 mg), and the mixture was stirred at room temperature for 10 minutes. Then, thereto was added dropwise a solution of N-{1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}cyclopropylamine (300 mg) in N,N-dimethylformamide (1.0 mL), and the mixture was heated to stir at 40° C. for 4 hours. After cooling to room temperature, thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1→2/3) to give N-{1-[3-(3-methoxypropyl)-5-(trifluoromethyl)phenyl]ethyl}cyclopropanamine [REx(31-1)] (227 mg) as a colorless oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.[C:13]([C:15]1[CH:16]=[C:17]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[CH:18]=[CH:19][C:20]=1[S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])#[N:14]>C1COCC1>[C:13]([C:15]1[CH:16]=[C:17]([NH:26][C:27](=[O:28])[O:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=2)[CH:18]=[CH:19][C:20]=1[S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])#[N:14]
Reactant: OCCc1ccc(Br)cc1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(Br)cc2)cc1C#N
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
NaH (138 mg, 3.45 mmol, 60% dispersion in oil) was added to a solution of 2-(4-bromophenyl)ethanol (833 mg, 4.1 mmol) in THF (7 mL) at 0° C. and stirred for 10 min. The mixture was cooled to −40° C. and 25A (500 mg, 1.38 mmol) in THF (7 mL) was added. After stirring warming to 0° C. over 1 h and stirring at 0° C. for 3 h the mixture was partitioned between EtOAc and brine (100 mL each). The layers were separated and the organic layer washed with 5% NaOH, brine and concentrated in vacuo. The crude solid was purified by flash chromatrography (0% to 50% EtOAc in Hexanes) to yield 26A (600 mg, 99%) as a white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.12 (t, J=7.47 Hz, 2 H) 2.95 (t, J=6.59 Hz, 2 H) 3.38 (q, J=7.18 Hz, 2 H) 4.36 (t, J=6.59 Hz, 2 H) 7.27 (d, J=8.35 Hz, 2 H) 7.92 (dd, 1 H) 8.00 (d, 1 H) 8.08 (d, J=2.20 Hz, 1 H) 10.51 (s, 1 H).
Reaction SMILES: C(F)(F)F.C([O:9][K])(C)(C)C.CN(C=O)C.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:16]([OH:9])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)O[K]
Reactant: O=Cc1ccccc1
Agent: FC(F)F
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1
Product: OCc1ccccc1

Procedure:
Shono and co-workers found that when they used CF3H/tBuOK/DMF to react with benzaldehyde at −50° C., benzyl alcohol and benzoic acid were formed by the competing Cannizzaro reaction (Shono, T.; Ishifume, M.; Okada, T.; Kashimura, S. J. Org. Chem. 1991, 56, 2). As mentioned above, the product of the present method is substantially free of benzyl alcohol and benzoic acid. Although Russell and Roques repeated the Shono reaction using excess CF3H (9.5 eq.) and tBuOK (2.2 eq.) at −50° C., and 67% yield of trifluoromethylated product 5 was formed and no benzyl alcohol was detected (Russell, J.; Roques, N. Tetrahedron 1998, 54, 13771), they reported that the high reaction temperature with excess base could lead to Cannizzaro reaction and jeopardize the nucleophilic trifluoromethylation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1
Reactant: Fc1ccccc1S
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2F)CC1
Temperature: 80 °C
Yield: 97.8 %

Procedure:
A mixture of 2-fluorobenzenethiol (0.764 mL, 7.15 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), and K2CO3 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80° C. overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure gave tert-butyl 4-((2-fluorophenyl)thio)piperidine-1-carboxylate as a yellow oil (1.98 g, 98%), which was carried forward without purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:9]([Mg]Br)[CH2:10][CH2:11][CH2:12][CH3:13].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]([C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[CH:5]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:4]=1
Reactant: Clc1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)N1C=CC(Cl)=CC1C1CCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
To a stirred mixture of 4-chloropyridine hydrochloride (3 g, 20 mmol) in 200 mL of THF at −78° C. was added 24 mL (48 mmol) of pentylmagnesium bromide (2M soln in ether) slowly dropwise. After being stirred at −78° C. for 20 minutes, phenyl chloroformate (2.51 mL, 20 mmol) was added and the mixture was stirred for 30 minutes at −78° C. The cooling bath was removed and the reaction mixture was allowed to stir while slowly warming to room temperature. Aqueous 20% NH4Cl (50 mL) and ether (80 mL) were added, the layers were separated, and the queous phase was extracted twice with ether. The combined organic extracts were washed successively with 50 mL portions of saturated aqueous CuSO4, water, saturated NaHCO3, and brine. The organic phase was dried over MgSO4, filtered through Celite, and evaporated to give the crude product. Purification by column chromatography (silica gel, 5% EtOAc in hexanes) afforded 5.25 g (86.4%) of the product as a yellow oil that was homogeneous by TLC analysis. 1H NMR (250 MHz) δ7.61-5.67 (m, 5 H), 5.66 (d, 1 H), 5.28 (m, 1 H), 5.01 (m, 1 H), 2.21 (m, 1 H), 1.98-1.28 (m, 8 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9](=[C:12]1[NH:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][S:13]1)[C:10]#[N:11].[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([O-:23])=[C:9]([C:10]#[N:11])[C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1.[CH2:24]([NH3+:28])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN
Reactant: N#CC(C(=O)c1ccccc1Cl)=C1NC(c2ccccc2)=CS1
Solvent: C1COCCO1
Product: CCCC[NH3+]
Product: N#CC(=C([O-])c1ccccc1Cl)c1nc(-c2ccccc2)cs1

Procedure:
10.17 g (0.03 mol) of 3-(2-chlorophenyl)-3-oxo-2-(4-phenyl-2,3-dihydrothiazole-2-ylidene)-propionitrile were suspended in 15 ml dioxane and were reacted at 25° C. with 2.19 g (0.03 mol) n-butylamine. After short stirring a solution was formed. The solution was then concentrated in a vacuum and the residue was treated with a small amount of a cyclohexane-chloroform mixture. The crystals were removed by suction and digested with hot diisopropylether.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].IC>C(#N)C.CN(C)C=O>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CC#N
Product: c1ccc([C@@H]2C[C@H]2NCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
To a solution of tert-butyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (Example 1, 100 mg, 0.303 mmol) in acetonitrile (2 ml) and N,N-dimethylformamide (DMF) (0.5 ml) was added potassium carbonate (125 mg, 0.908 mmol) followed by iodomethane (0.038 ml, 0.605 mmol). The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. The oil was dissolved in 2 mL of dioxane and 1 mL of HCl. The reaction mixture was heated under reflux for 15 min, and then evaporated to dryness. 4-(((trans-2-Phenylcyclopropyl)amino)methyl)piperidine (12 mg, 0.041 mmol, 13.41% yield) was isolated as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.35 (d, J=4.29 Hz, 2H), 7.14-7.30 (m, 3H), 3.47 (d, J=13.14 Hz, 2H), 3.35-3.42 (m, 2H), 3.12-3.27 (m, 2H), 3.09 (d, J=8.34 Hz, 3H), 2.89-3.05 (m, 1H), 2.77-2.89 (m, 1H), 2.04-2.52 (m, 3H), 1.83 (d, J=5.56 Hz, 1H), 1.37-1.73 (m, 3H); LC-MS Rt=0.38 min; MS (ESI): 245.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1)[CH2:22][CH3:23].[Cl-].[NH4+]>CS(C)=O>[CH2:21]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[CH:29][CH:30]=1)[CH2:22][CH3:23]
Reactant: CCCOc1ccc(CCl)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(CN2CCC(C(=O)OCC)CC2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A solution of 47.5 grams (0.30 mole) of ethyl piperidin-4-ylcarboxylate in 70 mL (0.40 mole) of N,N-diisopropylethylamine was stirred, and a solution of 52.5 grams (0.29 mole) of 4-propoxyphenylmethyl chloride in 50 mL of dimethyl sulfoxide was added dropwise. The reaction caused the reaction mixture temperature to rise to about 35° C. Upon completion of the addition the reaction mixture was stirred for 30 minutes, warmed to 40° C., and then allowed to cool to ambient temperature. After this time the reaction mixture was poured into 500 mL of aqueous 10% ammonium chloride. The mixture was extracted with three 250 mL portions of diethyl ether, and the combined extracts were washed with two 250 mL portions of an aqueous solution saturated with ammonium chloride, one 250 mL portion of water, and one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 80.0 grams of ethyl N-(4-propoxyphenylmethyl)-piperidin-4-ylcarboxylate. The NMR spectrum was consistent with the proposed structure:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.Cl[C:22]1[CH:34]=[C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:35])[N:23]=1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:19][O:20][C:22]1[CH:34]=[C:26]2[N:27]([CH:31]([CH3:32])[CH3:33])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:35])[N:23]=1
Reactant: CC(C)N1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)nc3)c(F)c1)nc2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol (126 mg, 0.439 mmol) and 8-chloro-1-isopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (20 mg, 0.088 mmol) in N,N-dimethylformamide (DMF) (8 mL), was added NaH (35.1 mg, 0.878 mmol) 25 and stirred for 1 h at rt. The reaction mixture was quenched by addition of sat. aq. NH4Cl solution and was filtered. The solution was purified by MDAP to afford the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].Cl.[CH3:15][NH:16][O:17][CH3:18].Cl.CN(C)CCCN=C=NCC.C(N(C1C=CC=CN=1)CC)C>ClCCl>[CH3:15][N:16]([O:17][CH3:18])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: CCN(CC)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
Dissolve 3-Fluoro-4-nitro-benzoic acid (10.7 g, 57.71 mmol) in 1000 mL anhydrous dichloromethane. Add N,O-Dimethylhydroxylamine hydrochloride (4.5 g, 46.17 mmol), followed by 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.60 g, 86.57 mmol) and 4 diethylaminopyridine (6.77 g, 55.4 mmol). Stir at room temperature under nitrogen atmosphere overnight. Concentrate under reduced pressure and partition the residue between ethyl acetate (300 mL) and water (100 mL). Wash the organic layer with saturated aqueous sodium chloride (4×30 mL) and dry over magnesium sulfate. Concentrate under reduced pressure to provide the desired compound (7.4 g, 56%).
Reaction SMILES: C(#N)CC.[N:5]([CH:8]1C[CH2:11][CH2:10][CH2:9]1)=C=S.BrCC(C1ON=C(C2C=CC=CC=2)C=1)=O.C(#N)CCC.[O:33]([C:40]1[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[S:48])=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Br[CH2:50][C:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:52]>>[NH2:5][C:8]1[C:9]([CH2:10][CH3:11])=[C:47]([NH:46][C:43]2[CH:44]=[CH:45][C:40]([O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:41][CH:42]=2)[S:48][C:50]=1[C:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:52]
Reactant: S=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: S=C=NC1CCCC1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C(CBr)c1cc(-c2ccccc2)no1
Solvent: CCC#N
Solvent: CCCC#N
Product: CCc1c(Nc2ccc(Oc3ccccc3)cc2)sc(C(=O)c2ccccc2)c1N

Procedure:
[3-Amino-4-ethyl-5-(4-phenoxy-phenylamino)-thiophen-2-yl]-phenyl-methanone was prepared as described in Example 43 substituting Propanenitrile, Isothiocyanato-cyclopentane and 2-Bromo-1-(3-phenyl-isoxazol-5-yl)-ethanone with butanenitrile, 4-phenoxyphenylisothiocyanate and 2-Bromo-1-phenyl-ethanone respectively to provide compound 1-243. MS (ESI) [M+H+]+=415.0
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=O)[CH2:3]1)[CH2:9]2.[NH3:13].CO.[H][H]>[Pd]>[NH2:13][CH:5]1[CH:6]2[CH2:11][C:2]3([OH:1])[CH2:9][CH:8]([CH2:10][CH:4]1[CH2:3]3)[CH2:7]2
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: [H][H]
Reactant: N
Agent: [Pd]
Solvent: CO
Product: NC1C2CC3CC1CC(O)(C3)C2

Procedure:
5-Hydroxy-adamantan-2-one (15 g, 90.24 mmol, International Specialty) and Pd/C (1.498 g, Degussa 19985880, 5%, 50% water) were added to a Parr reactor, followed by ammonia in methanol solution (7N, 300.4 ml, 2.1 mol). The reactor was pressurized with hydrogen at 200-250 psi for 18 h. The mixture was then filtered over a pad of celite and concentrated in vacuo to give 4-amino-adamantan-1-ol (15.15 g, 4/1=trans/cis by NMR-D2O) as a white solid. This material is used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:7][N:6]=[CH:5][N:4]=1.C(O)C.O.[OH-].[Li+]>O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: COC(=O)Cc1cncnc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ncncc1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 0.21 g (1.14 mmol) of methyl (4-methoxy-5-pyrimidinyl)acetate from Step A above in 0.5 mL of water and 1.5 mL of ethanol was added 81 mg (1.9 mmol) of lithium hydroxide hydrate. The reaction mixture was stirred at ambient temperature for 2 h then concentrated in vacuo to remove all volatiles. The residue was diluted with 3 mL of 2.0 M aqueous hydrogen chloride and then concentrated in vacuo to remove all volatiles to yield the title compound as an off white solid (191 mg, 90%). 1H-NMR (500 MHz, CD3OD) δ: 8.72 (s, 1H), 8.35 (s, 1H), 4.01 (s, 3H), 3.57 (s, 2H). LC-MS: m/z (E/S) 169 (MH)+.
Reaction SMILES: [NH2:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH2:34]([S:41](Cl)(=[O:43])=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([S:41]([NH:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10])(=[O:43])=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](N)C(=O)NCC(=O)OCc2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
The oily residue of the compound of Example 9 was dissolved in 5 mL of DMF, cooled to 0° C. and neutralized with 1 mL of TEA. To the solution was added BnSO2Cl (397 mg, 2.0 mmol) and the solution was stirred at 0° C. for 3 h and 25° C. for 3 h. DMF was removed and residue was dissolved in 100 mL of EtOAc and 20 mL of water. The organic layer was separated, washed with sat. NaHCO3 (10 mL), water (10 mL), 1 N HCl (10 mL) and sat. NaCl (3×10 mL), dried with MgSO4, filtered and evaporated. The solid residue was purified by column chromatography on silica gel (EtOAc) to give the title compound (328 mg, 30% yield) as a powder. ES—MS (M+H)+630.5
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[CH:8]=1)([O-:3])=[O:2].CCN(CC)CC.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([C@H:9]2[CH2:10][C@H:11]([O:13][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:12]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cn(C2CC(O)C2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](n3cnc([N+](=O)[O-])c3)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(4-nitro-imidazol-1-yl)-cyclobutanol (Preparation 4, Step 1; 4 g, 22 mmol) was treated with Et3N (7.7 mL, 55 mmol) in methylene chloride (150 mL) followed by p-toluenesulfonyl chloride (TsCl) (5 g, 26.4 mmol) and 4-N,N-dimethylaminopyridine (DMAP) (268 mg, 2.2 mmol). The resulting mixture was stirred at room temperature for 24 h. Analysis by thin layer chromatography showed two new spots. The reaction mixture was diluted with methylene chloride and was washed with water (1×) and brine (1×). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (1:1 to 2:1 hexanes-ethyl acetate) allowed for separation of the trans and cis diastereomers. The first spot to elute (high Rf) was the trans-isomer, trans-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (2.7 g, 37% yield); 1H NMR (400 MHz, CDCl3) δ7.79 (s, 1H), 7.77 (m, 2H), 7.44 (d, J=1.7 Hz, 1H), 7.36 (dd, J=0.5, 8.0 Hz, 2H), 5.034 (m, 1H), 4.94 (m, 1H), 2.9 (m, 2H), 2.7 (m, 2H); MS (AP/Cl): 338.1 (M+H)+. The second spot to elute was the cis-isomer, cis-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (2.9 g, 39% yield); 1H NMR (400 MHz, CDCl3) δ7.8 (m, 3H), 7.43 (d, J=1.4 Hz, 1H), 7.36 (dd, J=0.6, 8.5 Hz, 2H), 4.74 (m, 1H), 4.30 (m, 1H), 3.05 (m, 2H), 2.6-2.5 (m, 2H), 2.45 (s, 3H); MS (AP/Cl): 338.1 (M+H)+. Relative configurations were determined by the measurement of nuclear Overhauser effects.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[C:16](=[O:17])[CH:15]3[CH2:18][CH2:19][N:12]2[CH2:13][CH2:14]3)=[CH:4][CH:3]=1.[CH3:20][S:21]([Cl:24])(=[O:23])=[O:22]>>[ClH:24].[O:17]=[C:16]1[CH:15]2[CH2:18][CH2:19][N:12]([CH2:13][CH2:14]2)[CH:11]1[CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CCCC2C(=O)C3CCN2CC3)cc1
Product: CS(=O)(=O)Nc1ccc(CCCC2C(=O)C3CCN2CC3)cc1
Product: Cl

Procedure:
In a manner similar to Example X, react 2-[3-(4-aminophenyl)propyl]-1-azabicyclo[2.2.2]octan-3-one with methanesulfonyl chloride to afford the title compound.