Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(C(C)(C)C)C(C)(C)C.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CCO.C(OCC)C.O>[C:18]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1ccccn1
Reactant: OB(O)c1ccccc1
Agent: CC(C)(C)P(Cl)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: c1ccc(-c2ccccn2)cc1
Temperature: 25 °C

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 23.7 mg (0.044 mmol) of (t-Bu)2PCl)2PdCl2, 0.50 g (4.4 mmol) of 2-chloropyridine, 0.65 g (5.33 mmol) of PhB(OH)2 and 0.92 g (6.67 mmol) of K2CO3 in 3 mL of EtOH (95%). The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 100 mL of diethyl ether and 20 mL of H2O. The layers were separated, and organic layer was washed with H2O (50 mL), brine (30 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 2-phenylpyridine. LC-MS Found: 156.2 (M++1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:8][C:5]1[N:4]=[N:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: OB(O)c1ccccc1
Product: Cc1ccc(-c2ccccc2)nn1

Procedure:
Synthesized using 3-chloro-6-methylpyridazine (1.00 g, 7.78 mmol) and phenylboronic acid (1.42 g, 11.67 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (2:1) as eluent. White solid. Yield: 1.00 g, 76%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.76 (s, 3H), 7.39 (d, J=8.5 Hz, 1H), 7.46-7.55 (m, 3H), 7.76 (d, J=8.5 Hz, 1H), 8.03-8.09 (m, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=22.0, 123.9, 126.9, 127.2, 128.9, 129.7, 134.4, 136.4, 157.2, 158.5; (ESI): m/z=170.96 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Br)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:23][N:24]2[CH3:27])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:31]3[CH2:30][CH2:29][CH:28]([C:22]4[C:21]5[C:25](=[CH:26][C:18]([F:17])=[CH:19][CH:20]=5)[N:24]([CH3:27])[N:23]=4)[CH2:33][CH2:32]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cn1nc(C2CCNCC2)c2ccc(F)cc21
Reactant: CC(=O)N1CCc2c(sc(C)c2CCBr)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCC(c3nn(C)c4cc(F)ccc34)CC2)C1
Temperature: 90 °C
Reaction time: 22 h
Yield: 60.8 %

Procedure:
A mixture of 590 mg of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, 580 mg of 4-(6-fluoro-1-methyl- 1H-indazol-3-yl) piperidine, 780 mg of potassium carbonate and 415 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90° C. for 22 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 540 mg of 6-acetyl-3-(2-(4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 213°-216° C. as oxalate thereof.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:27][NH2:28]>C(Cl)Cl.C(O)C>[N:27](=[C:12](/[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)\[C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:8][CH:9]=1)\[NH2:28]
Reactant: NN
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1cc(/C(=N/N)c2csc(-c3ccccc3)n2)cc(OC)c1OC

Procedure:
To a mixture of 1h (230 mg, 0.65 mmol) in 3 mL CH2Cl2 and 3 mL ethanol was added hydrazine hydrate (2 mL). Then the mixture was refluxed for overnight. After completion of the reaction, the residue was absorbed on silica gel and purified by column chromatography to give compounds 2d-cis (80 mg) and 2d-trans (56 mg). NMR (300 MHz, CDCl3) δ 8.01-7.98 (m, 2H), 7.49-7.46 (m, 5H), 7.33 (s, 1H), 6.82 (s, 2H), 3.87 (s, 3H), 3.85 (s, 6H). MS (ESI) m/z 370.1 (M+H)+.
Reaction SMILES: CI.CN([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=2)[NH:9][CH:8]=1)C.[C-:22]#[N:23].[K+].O>CS(C)=O>[C:22]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH:14]=2)[NH:9][CH:8]=1)#[N:23]
Reactant: [C-]#N
Reactant: CN(C)Cc1c[nH]c2ccc(CNS(C)(=O)=O)cc12
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CC#N)c2c1
Reaction time: 2 h
Yield: 17.1 %

Procedure:
Methyl iodide (0.15 ml) was added to a stirred solution of N-[[3-[(dimethylamino)methyl]-1H-indol-5-yl]methyl]methanesulphonamide (0.5 g) in dimethyl sulphoxide (20 ml) followed by potassium cyanide (0.3 g) and the resulting solution stirred for 2 h, before pouring it into water (80 ml) and extracting with ethyl acetate (2×30 ml). The combined organic extracts were washed with water (30 ml), hydrochloric acid (2N, 30 ml) dried (Na2SO4) and evaporated to dryness to give a fawn foam which was purified on a silica column (kieselgel 60, 10 g) eluted with ethyl acetate to give the title compound as a white solid (0.08 g) m.p. 106°-9° after crystallisation from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1.[OH-].[Na+].[C:14](Cl)(=[O:16])[CH3:15]>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH:9][C:14](=[O:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(CCNC(C)=O)cc1
Reaction time: 8 h
Yield: 106.6 %

Procedure:
4-Methoxyphenethylamine (50 g, 330 mmol) was added to dichloromethane (50 ml) and then 2N sodium hydroxide solution (25 ml) was added thereto. Acetyl chloride (26 ml, 364 mmol) was slowly added at 0° C. to the reaction mixture, which was then stirred overnight. The reaction mixture was diluted with dichloromethane, washed with water and a saturated sodium chloride solution, and then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 68 g of the titled compound as a white solid. The product was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]1[C:2]2[CH:19]=[CH:18][C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:10]=[CH:9][C:8]=3[C:3]=2[O:4][C:5]=1[CH2:6][OH:7].[Mn]([O-])([O-])(=O)=O.[Ba+2]>C(Cl)Cl>[CH:1]1[C:2]2[CH:19]=[CH:18][C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:10]=[CH:9][C:8]=3[C:3]=2[O:4][C:5]=1[CH:6]=[O:7]
Reactant: OCc1cc2ccc3c4ccccc4ccc3c2o1
Agent: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Product: O=Cc1cc2ccc3c4ccccc4ccc3c2o1
Yield: 89.3 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet line with bubbler was added phenanthro[1,2-b]furan-2-methanol (14A, 5.84 g, 23.5 mmol), barium manganate (Aldrich, 12.06 g, 47 mmol) and dry CH2Cl2 (400 mL). The mixture was refluxed for 6 h, filtered and the resulting dark yellow solution filtered through a small plug of SiO2 to remove inorganic salts and polar baseline material. The solvent was then removed by rotary evaporation and the crude material recrystallized using CH2Cl2 /hexane to give after drying 5.17 g (91% yield) of phenanthro[1,2-b]furan-2-carbaldehyde, mp 169° , (C,H).
Reaction SMILES: [C:1]([N:18]([CH2:24][CH3:25])[C@H:19]([C:21]([OH:23])=[O:22])[CH3:20])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:32](O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.CN(C)C=O.[Ag]C#N>[CH2:32]([O:22][C:21](=[O:23])[C@H:19]([CH3:20])[N:18]([C:1]([O:3][CH2:4][CH:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2])[CH2:24][CH3:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCc1ccccc1
Reactant: CCN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)C(=O)O
Agent: N#C[Ag]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 377.2 %

Procedure:
A suspension of 848 mg (2.5 mmol) of (S)-N-Fmoc-N-ethylalanine in 10 mL of dichloromethane was treated with 436 μL (5.0 mmol) of oxalyl chloride followed by a catalytic amount (1 drop) of dimethylformamide. The mixture was stirred for one hour, then concentrated in vacuo. The yellow, oily residue was treated with 10 mL of toluene followed by 517 mg (0.5 mmol) of benzyl alcohol and 669 mg (5.0 mmol) of silver cyanide. The mixture was heated in an 80° C. oil bath with vigorous stirring for 20 minutes, then cooled and filtered through a pad of diatomaceous earth. The filtrate was concentrated, and the residue was purified by silica gel column chromatography, using 10% acetone in hexane as eluant. Ester (23) (810 mg) was obtained as a colorless oil; TLC: Rf =0.28, 15% acetone/hexane; 1H NMR (300 MHz) consistent with structure.
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[NH:14][C:13]1=[O:20])=O)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C@H:12]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[NH:14][C:13]1=[O:20]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1N

Procedure:
(3S,4S)-3-benzyloxycarbonylamino-4-acetoxy-azetidin-2-one (912 mg, 3.28 mmol) is hydrogenated with 1 g of 10% palladium on activated carbon in 35 ml of ethyl acetate at 50 psi hydrogen pressure at room temperature for 1.5 hours. After removal of catalyst by filtration, desubstitution (3S,4S)-3-amino-4-acetoxy-azetidin-2-one in ethyl acetate is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[O:18][C:14]=4[CH:13]=3)[C:7]=2[CH:24]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[O:18][C:14]=4[CH:13]=3)[C:7]=2[CH:24]=1
Reactant: COc1ccc2ncn(Cc3ccc4nc(S(C)=O)oc4c3)c2c1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)oc4c3)c2c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
A mixture of 6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methyl sulfinyl)benzo[d]oxazole (595 mg, 1.74 mmol), (1R,2R)-2-aminocyclohexanol (301 mg, 2.6 mmol) and DIEA (449 mg, 3.48 mmol) in DMA (12 mL) was stirred at 120° C. for 1.5 h. The reaction mixture was cooled to rt, poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give (1R,2R)-2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol as a white solid (198 mg, 29.0%). 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.80 (d, J=6.9 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.36 (s, 1H), 7.14 (s, 3H), 6.80 (dd, J=2.4, 9.0 Hz, 1H), 5.42 (s, 2H), 4.68 (d, J=3.3 Hz, 1H), 3.76 (s, 3H), 3.33 (br s, 2H), 1.89 (br s, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/z 393 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28]([OH:30])=O)[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C(O[N:41]1[N:49]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.O.NN>CN(C=O)C.O>[NH:41]([C:28]([C:25]1[CH:24]=[C:23]([C:19]2[CH:18]=[C:17]([O:16][C:15]3[CH:31]=[CH:32][C:12]([NH:11][C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[O:10])=[CH:13][CH:14]=3)[CH:22]=[CH:21][N:20]=2)[NH:27][CH:26]=1)=[O:30])[NH2:49]
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NN)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100 mg, 0.23 mmol) in 10 ml of anhydrous DMF were added HATU (105 mg, 0.28 mmol) and N,N-diisopropylethylamine (89 mg, 0.69 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of hydrazine monohydrate (0.25 ml, 5.2 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 1-[4-({2-[4-(hydrazinocarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3-(3-methylphenyl)urea as white solid. Yield: 98 mg, 95%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:37])[F:38])=[CH:33][CH:32]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone (example 22) was reacted with 4-trifluoromethoxy-phenyl boronic acid to give the title compound as light yellow solid. MS: 477.2 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:7]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1nc2c(N)nc3cnccc3c2n1CC(C)C
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3c(c2n1CC(C)C)CCNC3

Procedure:
A catalytic amount of platinum oxide was added to a solution of 2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.5 g, 1.68 mol)) in trifluoroacetic acid (20 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic. The dichloromethane layer was separated. The aqueous layer was extracted three times with dichloromethane (100 mL). The dichloromethane extracts were combined, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene then purified by flash chromatography (silica gel eluting with 20% methanol in dichloromethane with a trace of ammonium hydroxide) to provide 6,7,8,9-tetrahydro-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p. 164–166° C. Analysis: Calculated for C17H27N5+0.5H2O: % C, 65.77; % H, 9.09; % N, 22.56; Found: % C, 65.99; % H, 8.71; % N, 22.23.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[C:15](=O)[CH3:16].[CH:21]([O:24][C:25]1[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([NH2:32])[CH:26]=1)([CH3:23])[CH3:22]>C(O)(C)C>[C:18]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:26]2[C:25]([O:24][CH:21]([CH3:22])[CH3:23])=[N:30][C:29]([NH2:31])=[N:28][C:27]=2[NH:32][C:15]=1[CH3:16])(=[O:20])[CH3:19]
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Reactant: CC(C)Oc1cc(N)nc(N)n1
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2nc(N)nc(OC(C)C)c2C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.37 mmol) of 3-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione and 62 mg (0.37 mmol) of 6-isopropoxypyrimidine-2,4-diamine are dissolved in 5 ml of isopropanol and heated under reflux under argon for 2 days. The mixture is filtered and the remaining solid is washed with isopropanol. 80 mg (51% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: IC1C=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])C=1.[C:12]([N:19]1CCC(N)C[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH3:26][CH2:27][N:28]([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])C>CN1C(=O)CCC1>[F:11][C:8]([F:9])([F:10])[C:4]1[CH:33]=[C:32]([N:28]2[CH2:27][CH2:26][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:31][CH2:29]2)[CH:34]=[CH:6][N:5]=1
Reactant: FC(F)(F)c1cc(I)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccnc(C(F)(F)F)c2)CC1
Yield: 76.4 %

Procedure:
To a mixture of 4-iodo-2-(trifluoromethyl)pyridine (356 mg, 1.3 mmol) and Boc-4-aminopiperidine (340 mg, 1.7 mmol) in NMP (2.6 mL) was added DIPEA (319 L, 1.83 mmol). Argon was bubbled through the cloudy solution for 5 minutes before the reaction mixture was heated in the microwave for 3×30 minutes to 150° C. The mixture was then poured into water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 50 g, 0 to 100% ethyl acetate in heptane) afforded the title compound (343 mg, 76%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:28]([OH:30])=[O:29].CO>O>[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O-:27])=[O:26])[CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:28]([O-:30])=[O:29].[NH3+:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH3+:14]
Reactant: NCCCCCCCCCCCCN
Reactant: O=C(O)c1ccc2ccc(C(=O)O)cc2c1
Solvent: CO
Solvent: O
Product: O=C([O-])c1ccc2ccc(C(=O)[O-])cc2c1
Product: [NH3+]CCCCCCCCCCCC[NH3+]

Procedure:
Equimolar proportions of dodecamethylene diamine and naphthalene-2,7-dicarboxylic acid were dissolved in water, and then methanol was poured into the solution to form dodecamethylene diammonium naphthalene-2,7-dicarboxylate (12-N salt). The procedure of Examples 1 to 3 was repeated except that the 12-N salt was used instead of the 6-N salt, and hexamethylene diammonium monomethylterephthalate isophthalate (6-MTIA salt) was used instead of the 6-I salt. The properties of the resulting polyamides are shown in Table 8.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.C1C[O:19][CH2:18][CH2:17]1>>[Br:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:17]/[C:18]([O:4][CH2:2][CH3:5])=[O:19])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)/C=C/c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of triethyl phosphonoacetate (13.1 g, 0.0589 mol) was added slowly (dropwise) to a solution of Potassium-tert-butoxide (6.59 g, 0.0589 mol), in dry THF (150 mL) at −5° C., stirred for 30-45 mins at the same temperature, then a solution of 4-Bromo benzaldehyde (10 g, 0.054 mol), in dry THF (50 mL) was slowly added dropwise at −5° C. over a period of 15 mins, stirred the reaction mixture for 30 mins at the same temperature. After completion of reaction by TLC, the reaction mixture was poured into ice water (300 mL), extracted with EtOAc (2×200 mL). The combined organic extracts were washed with sat NaHCO3 solution (200 mL), water (200 mL), brine (200 mL) and dried over anhydrous Na2SO4, filtered and evaporated to get crude (E)-ethyl 3-(4-bromophenyl)acrylate (10 g, 72%) as pale green liquid. This is carried to next step without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:17]2[N:16]([CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:14]=3[C:13]=2[C:12]([Cl:39])=[CH:11][CH:10]=1.[OH-].[Na+]>C(Cl)Cl>[ClH:8].[Cl:8][C:9]1[C:17]2[N:16]([CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:14]=3[C:13]=2[C:12]([Cl:39])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3c(Cl)ccc(Cl)c23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: Clc1ccc(Cl)c2c1c1c(n2CCOc2ccccc2)CCNCC1
Reaction time: 5 h
Yield: 59 %

Procedure:
TFA (0.65 mL, 8.4 mmol) was added to a solution of tert-butyl 7,10-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.20 g, 0.42 mmol) in CH2Cl2 (6 mL). After 5 h, the reaction was made basic with 10% aqueous NaOH and extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to give a crude solid. After the hydrochloride salt was prepared, it was further purified by recrystallization from MeOH/EtOAc to give 51 mg (30%) of a white solid: mp 261.0-263.0° C.; 1H NMR (300 MHz, DMSO) δ 9.24 (br s, 2H), 7.26 (m, 2H), 7.16 (d, J=8.3 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 6.90 (m, 3H), 4.97 (t, J=4.9 Hz, 2H), 4.26 (m, 2H), 3.53 (m, 2H); 13C NMR (300 MHz, DMSO) δ 157.8, 141.3, 131.1, 129.4, 125.5, 123.4, 123.2, 121.3, 120.8, 114.4, 114.1, 111.4, 67.7, 44.8, 43.2, 43.1, 22.2, 20.9; IR (diffuse reflectance) 2965, 2952, 2826, 2794, 2741, 2676, 2650, 2443, 1496, 1467, 1241, 1234, 1170, 804, 755 cm−1; MS (EI) m/z 374 (M+), 339, 334, 332, 84, 78, 77, 65, 63, 61; Anal. Calcd for C20H20Cl2N2O.HCl: C, 58.34; H, 5.14; N, 6.80; found: C, 58.25; H, 5.23; N, 6.80.
Reaction SMILES: O.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[CH2:11]1[C:16](=[O:17])[O:15][CH2:14][C:12]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:12]2[CH2:14][O:15][C:16](=[O:17])[CH:11]=2)=[CH:5][CH:4]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: O=C1COC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(NCc2ccc(Cl)nc2)CO1

Procedure:
On a water separator, 5.00 g (35.1 mmol) of 1-(6-chloropyridin-3-yl)methylamine, 3.51 g (35.1 mmol) of tetronic acid and 20 mg (0.12 mmol) of 4-toluenesulphonic acid in 200 ml of toluene are heated under reflux for 24 hours. The reaction mixture is concentrated, and the residue that remains is then purified by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate. This gives 4.96 g (63% of theory) of 4-[[(6-chloropyridin-3-yl)methyl]amino]furan-2(5H)-one, which can be used for subsequent reactions.