Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([CH:30]5[CH2:31][CH2:32][O:27][CH2:28][CH2:29]5)=[O:34])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CCOCC1

Procedure:
The title compound, off-white solid (28 mg, 34%), MS (ISP) m/z=441.5 [(M+H)+], mp 227° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (75 mg, 0.19 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:10]=1.O>CO.C(#N)C>[N:1]1([C:13]2[CH:12]=[C:11]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:10]=[C:9]([Cl:8])[N:14]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: C1CNC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: FC(F)(F)COCc1cc(N2CCC2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of azetidine (0.224 g, 2.39 mmol) and sodium methoxide (0.326 mL, 1.75 mmol) in MeOH (2 mL) was added to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)-methyl)pyrimidine (0.208 g, 0.80 mmol) in acetonitrile (2 mL). The mixture was stirred at 0° C. for 15 minutes. Water was added. The mixture was purified by preparative HPLC to give the title compound, 0.091 g (41%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[C:19]([C:24]([F:27])([F:26])[F:25])=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1[N:39]=[C:40]=[O:41]>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=1[NH:39][C:40]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:22]3[NH:21][C:20](=[O:23])[C:19]([C:24]([F:27])([F:26])[F:25])=[N:18][C:17]=3[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1)=[O:41]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(Oc2ccnc3nc(C(F)(F)F)c(=O)[nH]c23)c2ccccc12
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)Nc1ccc(Oc2ccnc3nc(C(F)(F)F)c(=O)[nH]c23)c2ccccc12

Procedure:
Method F2 was used with 8-(4-aminonaphthalen-1-yloxy)-3-(trifluoromethyl)pyrido[2,3-b]pyrazin-2(1H)-one and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound was obtained as a slightly yellow solid (5 mg, 5%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:16][C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH2:6]1.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:16][C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CNC3)cc2)c2ccccc2C)ccn1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)C1
Yield: 24.4 %

Procedure:
Acetyl chloride (30 mg) was added at room temperature to a solution of (R)-3-(4-(azetidin-3-yl)phenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one (example 482, step 1; 70 mg) and N,N-diisopropylethylamine (98 mg) in dichloromethane (4 mL), then after 2 h the reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Flash chromatography (silica gel, 10 g, 2% to 5% methanol in dichlormethane) produced the title compound (19 mg). Colourless oil, MS (ESI+): m/z=413.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: O=c1[nH]c2ncccc2c2cc(NC3CCN(Cc4ccccc4)CC3)ccc12
Yield: 50.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 456 using 6 (400 mg, 1.73 mmol) and 1-benzyl-piperidin-4-amine (1.31 mL, 6.94 mmol) to provide 457 (337 mg, 50% yield) as a white powder. LC-MS (M+H=385, obsd.=385).
Reaction SMILES: [F:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:9]1=[O:25].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[C:9]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(F)C(=O)OC1)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OCC(N2CCC3(CCNCC3)C2=O)=C1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-fluoro-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (109 mg, 0.308 mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (1.896 mL, 24.61 mmol) and the resulting solution was stirred at rt for 1 h. After removing the volatiles, the residue was dissolved in methanol and loaded onto an ion exchange column. After washing with methanol, the product was eluted with 2N ammonia in methanol solution which was concentrated to give the title compound. LC/MS: (M+1)+: 255.09.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[N:16]=3)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CS(C)=O>[CH3:14][C:13]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:7]=2)[N:10]=[C:11]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)[N:12]=1
Reactant: C1COCCN1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(Cl)c1
Solvent: CS(C)=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(N2CCOCC2)c1
Temperature: 130 °C
Yield: 62.4 %

Procedure:
5-(1-((2-Chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (50 mg, 0.115 mmol) and morpholine (100 mg, 1.15 mmol) were dissolved in DMSO (0.5 mL) in a sealed tube reaction vessel. The reaction was heated at 130° C. overnight and then cooled to RT. The reaction was then filtered and purified by prep-HPLC (MeCN/H2O 30%—MeCN 70% containing 0.1% TFA). The product was taken up in EtOAc (10 mL), washed with sat. NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated to afford 4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)morpholine as a yellow solid (35 mg, 63%). MS (ES+) C22H20F3N7O3 requires: 487. found 488 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.28 (d, J=8.8 Hz, 2H), 8.18 (d, J=5.3 Hz, 1H), 7.34 (d, J=8.8 Hz, 2H), 6.44 (d, J=5.3 Hz, 1H), 6.37 (s, 1H), 5.37 (s, 2H), 3.82-3.77 (m, 4H), 3.51-3.45 (m, 4H), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:19].[CH3:20][O:21][CH2:22][CH2:23][C:24](Cl)=O>N1C=CC=CC=1>[CH3:20][O:21][CH2:22][CH2:23][C:24]1[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1
Reactant: CSCCCCCNc1c(N)cnc2ccccc12
Reactant: COCCC(=O)Cl
Solvent: c1ccncc1
Product: COCCc1nc2cnc3ccccc3c2n1CCCCCSC
Temperature: 0 °C
Yield: 67.5 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, N4-[5-(methylthio)pentyl]quinoline-3,4-diamine (3.56 g, 12.93 mmol) and anhydrous pyridine (52 mL) under a nitrogen atmosphere. The resulting homogeneous solution was cooled to 0° C. in an ice-water bath. To the cooled solution was added neat 3-methoxypropionyl chloride (2.74 g, 22.36 mmol). After addition of the acid chloride, the reaction was heated to reflux for 14 hours at which time the acylated intermediate was completely consumed. The solution was cooled and then partitioned between chloroform and saturated aqueous ammonium chloride. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-(2-methoxyethyl)-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline (3.0 g, 8.73 mmol) which was isolated as a brown oil and used without further purification.
Reaction SMILES: Cl.[C:2]1([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[O:18]=[C:19]1[NH:28][C:27]2[N:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH:33]=O)[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[C:22]=2[CH2:21][CH2:20]1>>[C:2]1([N:12]2[CH2:17][CH2:16][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:25]3[N:26]=[C:27]4[C:22]([CH2:21][CH2:20][C:19](=[O:18])[NH:28]4)=[C:23]([C:35]([F:37])([F:36])[F:38])[CH:24]=3)[CH2:14][CH2:13]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=CCCCOc1cc(C(F)(F)F)c2c(n1)NC(=O)CC2
Agent: Cl
Product: O=C1CCc2c(C(F)(F)F)cc(OCCCCN3CCN(c4cccc5ccccc45)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 1-naphthalen-1-yl-piperazine hydrochloride was coupled by reductive amination to 4-(7-oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 499.1 (Exact Mass: 489.22).
Reaction SMILES: C(OC(=O)[N:7]([C:15]1[CH:20]=[N:19][C:18](I)=[C:17]([Cl:22])[N:16]=1)[CH2:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)(C)(C)C.Cl[C:25]([F:31])([F:30])C(OC)=O.[F-:32].[K+]>CN(C=O)C.[Cu]I>[Cl:22][C:17]1[N:16]=[C:15]([NH:7][CH2:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:20]=[N:19][C:18]=1[C:25]([F:31])([F:32])[F:30]
Reactant: CC(C)(C)OC(=O)N(CC1CCOCC1)c1cnc(I)c(Cl)n1
Reactant: COC(=O)C(F)(F)Cl
Reactant: [F-]
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ncc(NCC2CCOCC2)nc1Cl
Temperature: 115 °C
Yield: 153.9 %

Procedure:
t-butyl-6-chloro-5-iodopyrazin-2-yl((tetrahydro-2H-pyran-4-yl)methyl)carbamate (0.0569 g, 0.125 mmol), methyl 2-chloro-2,2-difluoroacetate (0.047 ml, 0.063 g, 0.439 mmol), potassium fluoride (0.015 g, 0.251 mmol), and copper (I) iodide (0.100 g, 0.527 mmol) were dissovled in anhydrous DMF (0.80 ml) and placed under argon. The reaction mixture was then heated at 115° C. for 17 hr. It was allowed to cool to ambient temperature. The reaction mixture was filtered through a pad of Celite. The filtrate was poured into brine (25 ml). This was extracted with EtOAc (3×25 ml). The combined extracts were washed with H2O (1×25 ml) followed by brine (1×25 ml). The organic layer was dried (Na2SO4), filtered, and the solvent removed in vacuo to give 0.0401 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 25 EtOAc/75 heptane to 100 EtOAc gave 0.0569 g (55%) of 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine. LCMS (m/z): 296.0 (MH+), retention time=0.93 min. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.39 (qd, J=12.33, 4.50 Hz, 2H) 1.68 (d, J=11.35 Hz, 3H)1.80-2.00 (m, J=14.87, 7.63, 7.63, 3.52 Hz, 1H) 3.32-3.47 (m, 4H) 4.01 (dd, J=11.35, 3.52 Hz, 2H) 5.26 (br. s., 1H) 7.76 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)=[O:2].[CH2:18]([Mg]Br)[CH2:19][CH2:20][CH2:21][CH3:22].O>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=Cc1cccc(NC(=O)c2ccccn2)c1
Reactant: CCCCC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(O)c1cccc(NC(=O)c2ccccn2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The aldehyde (1.1 g) was dissolved in dry tetrahydrofuran, and cooled in an ice bath. To this cold solution was added dropwise, a solution of pentylmagnesium bromide (prepared from 1-bromopentane (1.9 g) and magnesium turnings (0.31 g) in dry ether). The reaction mixture was stirred at 0° C. for two hours, allowed to warm to room temperature and was carefully poured into cold water. The aqueous solution was extracted with ethyl acetate, and the organic extract was washed with aqueous ammonium chloride solution, brine and then dried over anhydrous magnesium sulfate. All volatilss were removed to leave a viscous liquid which quickly solidified on standing. This solid was crystallized from ethyl acetate/hexane to give pure product.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)=O.CC(C)=O.C([N-]C(C)C)(C)C.[Li+].CN1CCCN(C)C1=O.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[CH2:38]([CH:3]([C:2]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:1])[C:4]([OH:6])=[O:5])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(c1ccccc1)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
In accordance with a modified literature procedure (Pfeffer, P. E.; Silbert, L. S.; Chirinko, J. M. J. Org. Chem. 37(3), 1972, 451-458), a solution of 3,3-dimethyl-3-phenyl propionic acid (0.22 g, 1.2 mmol, from Reference Example 22) in tetrahydrofuran (2 mL) is cooled to −40° C. (dry ice/acetone) while stirring under a nitrogen atmosphere. Lithium diisopropylamide (Aldrich, 2.0 M solution in tetrahydrofuran/ethylbenzene/heptane, 1.4 mL, 2.8 mmol) is added dropwise via syringe, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPU, 0.16 mL, 1.3 mmol). The reaction mixture is then allowed to warm to room temperature and to stir for 30 minutes before being re-cooled to 0° C. (ice water bath). Benzyl bromide (0.15 mL, 1.3 mmol) is then added neat via syringe and the reaction mixture is allowed to stir overnight while warming to room temperature. The reaction is quenched by the addition of 10% aqueous hydrochloric acid solution and extracted thrice with ethyl acetate. The combined extracts are washed twice with 10% aqueous hydrochloric acid solution and once with saturated sodium chloride solution, dried over anhydrous sodium sulfite, and concentrated under reduced pressure. Flash chromatography (silica gel, ether/hexanes) is performed to give a straw colored gum (0.91 g, 70% for two combined reactions). MS (ES−): (M−H)=266.9
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[O:19]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]([N:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52](OC3C=CC([N+]([O-])=O)=CC=3)=[O:53])[CH2:47][CH2:46]2)=[O:44])=[O:34])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C>[O:19]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]([N:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52]([N:9]3[CH2:10][CH2:11][C:6]4([CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH2:8]3)=[O:53])[CH2:47][CH2:46]2)=[O:44])=[O:34])=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C1CCC2(C1)CCNCC2
Reactant: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1)Oc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)N2CCC3(CCCC3)CC2)CC1)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A solution of 8-aza-spiro[4.5]decane hydrochloride (791 mg, 4.50 mmol) and triethylamine (2.24 mL, 16.1 mmol) in 20 mL of anhydrous dimethylformamide was added under nitrogen dropwise to a solution of the carbonate prepared in Example 5 (2.00 g, 3.22 mmol) in 25 mL of anhydrous dimethylformamide. After the addition the reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate, extracted one time with 1N HCl, multiple times with saturated Na2CO3 and then water, dried (MgSO4) and the solvent removed under reduced pressure to give 1.65 g of an oil. Purification of the oil on silica gel (230-400 mesh) using 20% ethyl acetate-methylene chloride as the eluent gave 1.01 g (52%) of the title compound as a light yellow oil, MS [M+H]+ 622.
Reaction SMILES: [ClH:1].[C:2](N)(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC[O-].[Na+].[CH3:15][N:16]([CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([NH:24][NH2:25])=O)[CH3:17].Cl.CCOCC>C(O)C>[ClH:1].[CH3:15][N:16]([CH3:17])[CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:21]([C:22]2[N:9]=[C:2]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:25][N:24]=2)[CH:20]=1
Reactant: CN(C)Cc1cccc(C(=O)NN)c1
Reactant: N=C(N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CN(C)Cc1cccc(-c2n[nH]c(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred ethanolic suspension of benzamidine hydrochloride salt (235 mg, 1.5 mmol, 1.5 eq.), was added 1.2N NaOEt in ethanol (1.7 ml, 2 eq.) over 3 minutes, the mixture was further stirred for 30 min. at r.t. To this was added 3-dimethylaminomethyl-benzoic acid hydrazide (193 mg, 1 mmol) in ethanol at 20° C. and the mixture heated to reflux for 24 hrs. Upon cooling the product mixture was filtered, solvent evaporated and residue subjected to preparative reversed-phase HPLC purification using a YMC ODS-AQ column (20×50 mm) and a (0.1% trifluoroacetic acid) water-acetonitrile gradient (25 ml/min. flow rate). The pure fractions were concentrated and the product obtained was converted to the hydrochloride salt by addition of excess 2N HCl/ether solution (1.0 ml) followed by solvent evaporation and high vacuum drying to afford the title compound (84 mg, 0.27 mmol, 27% yield) as a yellow foam. MS: m/e=279.4 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][N:9]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:7]1=O)=[O:5])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)=O>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][N:9]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:7]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1=O
Reactant: Nc1ccccc1
Solvent: O=CO
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccc2)CN(C(=O)c2ccccc2)C1

Procedure:
A mixture of 100 g of 1-benzoyl-3-oxopyrrolidin-4-carboxylic acid ethyl ester, 42 ml of aniline and 23 ml of formic acid in 1.2 liters of ethanol is heated to reflux for 15 hours, concentrated by evaporation and the residue is crystallised from the ether/methylene chloride. 3-Anilino-1-benzoyl-2,5-dihydro-1H-pyrrol-4-carboxylic acid ethyl ester is obtained. M.P. 149°-151°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]1=2)#[N:2].[O:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH2:43].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(O)(=O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([NH:43][C:39]3[O:38][CH:42]=[CH:41][N:40]=3)(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]1=2)#[N:2]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ncco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3ncco3)ccc21
Reaction time: 0.08 h

Procedure:
A round bottom flask was charged with perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (INTERMEDIATE AB, 40.69 mg, 0.074 mmol), oxazole-2-amine (9.32 mg, 0.11 mmol, Ryan Scientific, Mt. Pleasant, S.C.) and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (155 μl, 0.155 mmol) was added dropwise over 30 s to give a light-yellow solution. After 5 min, the flask was lowered into an ice bath for 1 h. Additional portions of oxazole-2-amine (ca. 5 mg) and LHMDS solution (0.05 mL) were added in sequence. After an additional 45 min, glacial acetic acid (1 drop) was added. The mixture was concentrated under a vacuum. The product was purified by chromatography on silica gel (12 g column with 0 to 10% MeOH/DCM) to give 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(oxazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.86 (br. s., 1 H), 8.38 (d, J=2.1 Hz, 1 H), 8.05 (dd, J=1.8, 8.8 Hz, 1 H), 7.71 (d, J=8.6 Hz, 1 H), 7.59 (d, J=1.7 Hz, 1 H), 7.31 (d, J=2.1 Hz, 1 H), 7.26-7.17 (m, 2 H), 6.80 (d, J=8.5 Hz, 1 H), 4.36-4.27 (m, 2 H), 3.87-3.82 (m, 2 H). m/z (ESI) 451.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[O:31][C:30]([CH3:32])=[N:29][C:28]=1[C:33](O)=[O:34]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[O:34])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COc1ccccc1-c1oc(C)nc1C(=O)O
Product: COc1ccccc1-c1oc(C)nc1C(=O)Nc1ccn(Cc2ccc(C(C)=O)o2)n1

Procedure:
Following general procedure B followed by either C or D, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(2-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.90 min; [M+H]+=421.09.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O.C(OCC)(=O)C>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:3][CH:4]=2)=[N:12][N:11]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2)o1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCOCC3)nc2)o1
Temperature: 160 °C
Yield: 70511.3 %

Procedure:
To a solution of 2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (200 mg, 0.59 mmol) in DMSO (2 mL) was added morpholine (257 mg, 2.95 mmol) and the reaction mixture was heated for 1 h at 160° C. After cooling to ambient temperature it was diluted with ethyl acetate (20 mL) and washed with aqueous sodium carbonate (saturated) and water. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=80:20 to 70:30) afforded the title compound (162 g, 70%) as a white solid. MS: m/e=390.3 [M+H]+.