Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH:15]1([NH:18][C:19]([C@@H:21]2[C@H:26]([NH:27][C:28]3[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[C:29]=3[NH2:36])[C@@H:25]3[CH2:37][C@H:22]2[CH:23]=[CH:24]3)=[O:20])[CH2:17][CH2:16]1.C([O-])(=O)C.[NH4+]>>[CH:15]1([NH:18][C:19]([C@@H:21]2[C@H:26]([NH:27][C:28]3[C:33]([Cl:34])=[CH:32][N:31]=[C:30]4[NH:35][C:7]([C:6]5[S:5][C:4]([N:9]6[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10]6)=[N:3][C:2]=5[Cl:1])=[N:36][C:29]=34)[C@@H:25]3[CH2:37][C@H:22]2[CH:23]=[CH:24]3)=[O:20])[CH2:17][CH2:16]1
Reactant: Nc1ncc(Cl)c(N[C@H]2[C@@H](C(=O)NC3CC3)[C@@H]3C=C[C@H]2C3)c1N
Reactant: O=Cc1sc(N2CCC(O)C2)nc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=C(NC1CC1)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CC[C@@H](O)C5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 11.1 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-(3-hydroxy-pyrrolidin-1-yl)-thiazole-5-carbaldehyde (174.40 mg, 0.74951 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid cyclopropylamide (200 mg, 0.6 mmol), and Ammonium acetate (92.439 mg, 1.1992 mmol) were reacted to produce 36.26 mg (10%) of the title compound. (300 MHz, DMSO-d6) 12.68 (s, 1H), 8.30 (s, 1H), 7.94 (s, 1H), 6.93 (s, 1H), 6.38-6.30 (m, 2H), 4.99 (t, J=17 Hz, 8.5 Hz, 1H), 3.44 (m, 4H), 2.84 (s, 1H), 2.76 (s, 1H), 2.66 (m, 1H), 2.23 (d, J=8 Hz, 1H), 2.01 (m, 4H), 1.38 (d, J=8 Hz, 1H), 0.63 (m, 2H), 0.37 (m, 2H). MS=546 (M+H), HPLC: 2.35 min. (G Method)
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=S)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20][NH2:21]>>[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20][NH:21][C:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[N:11]=1
Reactant: S=C1Nc2cccnc2Nc2ccccc21
Reactant: COC(CN)OC
Product: COC(CNC1=Nc2cccnc2Nc2ccccc21)OC
Temperature: 95 °C

Procedure:
A mixture of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-thione (3.21 g, 14 mmol) and 2,2-dimethoxyethylamine (7.6 mL, 70 mmol) was heated to 95° C. for 1 hour. After cooling to room temperature the solvent was evaporated in vacuo. The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=O)[O-:18])=[CH:12][C:11]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:28][O:29][CH:30]([O:34][CH3:35])[CH2:31][NH:32][CH3:33]>C1(C)C=CC=CC=1>[CH2:1]([C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:32]([CH2:31][CH:30]([O:34][CH3:35])[O:29][CH3:28])[CH3:33])=[O:18])=[CH:12][C:11]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CNCC(OC)OC
Reactant: CCCCCc1cccc(Oc2ccc(NC(=O)[O-])cc2CCCCC)c1
Solvent: Cc1ccccc1
Product: CCCCCc1cccc(Oc2ccc(NC(=O)N(C)CC(OC)OC)cc2CCCCC)c1

Procedure:
[4-(3-Pentylphenoxy)-3-pentylphenyl]carbamate (0.1 mole) and toluene (100 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. N-(2,2-dimethoxyethyl)methanamine (0.15 mole) is added to the vessel and the mixture is refluxed for 16 hours. Solvent is then removed by mild warming under reduced pressure to yield the desired product N-[4-(3-pentylphenoxy)-3-pentylphenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea.
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14](=[O:26])[N:15]([CH2:23][CH:24]=[CH2:25])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1>N1C=CC=CC=1>[CH2:1]([S:8]([NH:12][C:13]1[C:14](=[O:26])[N:15]([CH2:23][CH:24]=[CH2:25])[C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: C=CCn1c(C(F)(F)F)ccc(N)c1=O
Solvent: c1ccncc1
Product: C=CCn1c(C(F)(F)F)ccc(NS(=O)(=O)Cc2ccccc2)c1=O
Yield: 96.7 %

Procedure:
Benzylsulfonyl chloride (103 mg, 0.542 mmol) was added to a stirred solution of 3-amino-6-trifluoromethyl-1-allyl-2-pyridinone (106.5 mg, 0.488 mmol) in pyridine (1 ml) at 0° C. After 1 h the reaction was evaporated in vacuo and the residue was partitioned between methylene chloride and 10% potassium hydrogen sulfate solution, dried (Na2 SO4), and evaporated in vacuo to give the title compound (175.8 mg): 1H NMR (CDCl3) selected signals at δ4.42 (s, 2H), 4.74 (d, J=5.5 Hz, 2H), 5.16-5.31 (m, 2H), 5.86-5.96 (m, 1H), 6.55 (d, J=7.7 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.27-7.33 (m, 5H), 7.70 (br s, 1H, NH).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][N:31]([CH:35]2[CH2:40][CH2:39][N:38]([C:41](=[O:59])[C@H:42]([OH:58])[CH2:43][S:44]([C:47]3[CH:56]=[CH:55][C:54]4[C:49](=[CH:50][CH:51]=[C:52]([Cl:57])[CH:53]=4)[CH:48]=3)(=[O:46])=[O:45])[CH2:37][CH2:36]2)[C:30]1=[O:60])(C(C)(C)C)(C)C>C1COCC1>[Cl:57][C:52]1[CH:53]=[C:54]2[C:49](=[CH:50][CH:51]=1)[CH:48]=[C:47]([S:44]([CH2:43][C@@H:42]([OH:58])[C:41]([N:38]1[CH2:37][CH2:36][CH:35]([N:31]3[CH2:32][CH2:33][CH2:34][N:29]([CH2:28][CH2:27][OH:26])[C:30]3=[O:60])[CH2:40][CH2:39]1)=[O:59])(=[O:45])=[O:46])[CH:56]=[CH:55]2
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCCN(C2CCN(C(=O)[C@H](O)CS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCCN(CCO)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
Tetrabutylammonium fluoride (0.12 g) was added to a solution of 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(1-{(2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}piperidin-4-yl)tetrahydropyrimidin-2(1H)-one (0.25 g) obtained in Example 40c) in THF (10 mL), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with an aqueous 5% citric acid solution and saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=95/5 to ethyl acetate/methanol=90/10) to obtain the title compound (0.11 g, 54%) as a white powder.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)cc2)CCN3CCC)cc1
Reaction time: 0.25 h
Yield: 42 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(3-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.29 g) in methylene chloride (8.7 ml) was added dropwise a solution of m-chloroperbenzoic acid (120 g) in methylene chloride (5.8 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(3-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 247) (125 mg).
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:41]([C:35]1([CH3:34])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:42])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: CN[C@H](Cc1ccccc1)CN1CC=C(c2cc(F)ccc2OC)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)C2(C)CCCCC2)CC1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
Under a N2 atmosphere, a solution of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridine-1-yl]-ethyl}-methyl-amine (0.18 g, 0.49 mmole) and triethylamine (0.14 mL, 1.0 mmole) in dichloromethane (10 mL) was cooled to 0° C. To the solution, 1-methyl-1-cyclohexanecarboxylic acid chloride (0.10 g, 0.59 mmole) in 1 mL dichloromethane was added and the resulting mixture was stirred at 0° C. to room temperature (ice melt) overnight. The solvent was evaporated and the residue dissolved in EtOAc (50 mL) and water (50 mL). The layers were separated and the organics washed with water (50 mL), brine (25 mL) and dried over Na2SO4, filtered and concentrated. Flash chromatography (elution with 1:4 EtOAc-hexane) gave 0.13 g (55% yield) of the titled compound. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid. m.p. 146-151° C.
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][N:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:6]=1)C.ClC(OCC)=O.[OH:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:7]2[C:8]3=[CH:9][N:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[C:13]3[C:5]([CH2:4][O:32][CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][C:36]3=[O:40])=[CH:6]2)=[CH:24][CH:23]=1
Reactant: O=C1CCCN1CCO
Reactant: COC(=O)c1cc2c(CN(C)C)cn(Cc3ccc(F)cc3)c2cn1
Agent: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(COCCN3CCCC3=O)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a stirring solution of methyl 3-[(dimethylamino)methyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (1.04 g, 3.05 mmol) in DCM (16 mL) under nitrogen was added ethyl chloroformate (0.330 g, 3.05 mmol). The solution was stirred for 2 hours at room temperature. At this time, 1-(2-hydroxyethyl)pyrrolidin-2-one (1.57 g, 12.18 mmol), ethyl(diisopropyl)amine (1.97 g, 15.23 mmol), and DMF (16 mL) were added to the reaction and the reaction heated to 55° C. After stirring for 24 hours (55° C.) the reaction was judged to be complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give red oil. The crude material was diluted with EtOAc (40 mL) and washed with water (4×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the target compound, which was purified by chromatography on a column of silica gel. Fractions were combined to afford 0.961 g (76% yield) of methyl 1-(4-fluorobenzyl)-3-{[2-(2-oxopyrrolidin-1-yl)ethoxy]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate as an off white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.90-2.01 (m, 2H) 2.32 (t, J=8.10 Hz, 2H) 3.42-3.51 (m, 4H) 3.64 (t, J=5.27 Hz, 2H) 4.00 (s, 3H) 4.69 (s, 2H) 5.36 (s, 2H) 7.01 (t, J=8.57 Hz, 2H) 7.11-7.18 (m, 2H) 7.28 (s, 1H) 8.51 (s, 1H) 8.73 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:14]=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2ccc(Br)cc2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(Br)cc1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a mixture of 4-{[1-(4-bromo-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (9.8 g, 29.5 mmol) and ytterbium(III) triflate hydrate (1.83 g, 2.95 mmol) in dry tetrahydrofuran (20 mL) at 25° C. was added isobutyraldehyde (2.1 g, 29.5 mmol) and water (0.53 mL, 29.5 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(4-bromo-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (11.9 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H22BrNO3 M+: 404.3, observed: 404.1, 406.1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[OH:20][C:21]1[CH:22]=[C:23](OB(O)O)[CH:24]=[CH:25][CH:26]=1>>[OH:20][C:21]1[CH:26]=[C:25]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)Oc1cccc(O)c1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Product: O=C1CCCc2cc(-c3cccc(O)c3)ccc21
Reaction time: 4 h
Yield: 29 %

Procedure:
The compound is prepared by the reaction of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-yl trifluoromethanesulfonate (1.78 g, 6.04 mmol, 1 eq) with 3-hydroxyphenylboric acid (1 g, 7.25 mmol, 1.2 eq) according to method A within 4 h. Purification by column chromatography with dichloromethane as the eluent yields the desired product in a yield of 29%, 900 mg.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])[N:23]([CH2:24][CH2:25][NH2:26])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1.Cl.CON(OC)CCCN=C=NCC>ClCCl>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])[N:23]([CH2:24][CH2:25][NH:26][C:7]([CH:5]3[CH2:4][CH2:3][C:2](=[O:1])[O:6]3)=[O:9])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: O=C1CC[C@@H](C(=O)O)O1
Agent: CCN=C=NCCCN(OC)OC
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)C1CCC(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-(+)-5-oxo-2-tetrahydrofurancarboxylic acid (0.23 g, 1.7 mmole in anhydrous dichloromethane (30 mL) was slowly added to a solution of 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) in anhydrous dichloromethane (100 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then a solution of 1-[3-(dimethoxyamino)propyl]-3-ethylcarbodiimide hydrochloride (0.37 g, 1.9 mmol) in anhydrous dichloromethane (50 mL) was added dropwise. The reaction mixture was stirred at ambient temperature overnight and then filtered to remove solids. The filtrate was washed twice with 10% sodium hydroxide and then with brine, dried, and then concentrated under vacuum to provide 0.3 g of crude product. This material was purified by column chromatography (silica gel eluting with dichloromethane) followed by recrystallization from acetonitrile to provide 0.1 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-5-oxotetrahydro-2-furancarboxamide as a white powder, m.p. 153-154° C. Analysis: Calculated for C20H24N6O3: %C, 60.59; %H, 6.10; %N, 21.19; Found: %C, 60.34; %H, 6.14; %N, 21.13. HRMS (EI) calcd for C20H24N6O3 (M+) 396.1909 found 396.1905
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].[N:9]1([NH:15][C:16]([C:18]2[N:19]=[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])[N:21]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:22]=2[CH3:23])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N:9]1([NH:15][C:16]([C:18]2[N:19]=[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])[N:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6])=[CH:28][CH:29]=3)[C:22]=2[CH3:23])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: FC(F)(F)CCCI
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OCCCC(F)(F)F)cc1
Yield: 46 %

Procedure:
1-Iodo-4,4,4-trifluorobutane (376 mg, 1.58 mmol) was added dropwise to a suspension of 2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide, from Ex 2, Step 1 (351 mg, 0.79 mmol) and K2CO3 (218 mg, 1.58 mmol) in 50 ml acetone. The reaction mixture was refluxed overnight, cooled, filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:2) afforded 200 mg (46%) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6]2>Br.C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6]2
Reactant: COC(=O)CC1CCc2cc(OC)ccc2C1=O
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)CC1CCc2cc(O)ccc2C1=O
Temperature: 0 °C

Procedure:
A solution of the 6-methoxy-1-tetralone derivative (860 mg) (from Example 13) in 47% HBr (15 ml) and glacial acetic acid (5 ml) was refluxed for 30 hours and poured into ice-water. The product was extracted into ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was esterified with 10% HCl in methanol to give, after work-up, the title compound, m.p. 121°-123°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>>[O:21]=[C:19]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:1][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][C:10]1=2
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C

Procedure:
A sample of 4-benzyloxy-3-carboxyphenylacetic acid is treated with an excess of thionyl chloride at reflux for 2 hours. The excess thionyl chloride is removed in vacuo and the remaining 4-benzyloxy-3-(chlorocarbonyl)phenylacetyl chloride is dissolved in methylene chloride-nitromethane and treated with an equivalent amount of aluminum chloride. The reaction mixture is stirred several hours at room temperature, refluxed for two hours and quenched with dilute hydrochloric acid. The layers are separated, the organic phase dried and evaporated in vacuo to a residue which, on crystallization from isopropyl alcohol yields 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, mp 137°-"° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[O:17])=[O:32])=[CH:26][CH:25]=1
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(NCCCOc1cccc(CN2CCCCC2)c1)NNC(=O)Nc1ccc(Cl)cc1

Procedure:
The compound is prepared by a method analogous to that of Example 20 from N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-hydrazine carboxamide and 4-chlorophenyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]2[C:23]([NH:24][CH2:25][C:26]([O:28]CC)=O)=[CH:22][CH:21]=[C:20]([O:31][CH3:32])[N:19]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC.[O-2].[O-2].[Mn+4]>[CH3:32][O:31][C:20]1[CH:21]=[CH:22][C:23]2[N:24]=[CH:25][C:26](=[O:28])[N:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:14][CH2:13]3)[C:18]=2[N:19]=1
Reactant: CCOC(=O)CNc1ccc(OC)nc1NCCN1CCC(NC(=O)OC(C)(C)C)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Yield: 43.1 %

Procedure:
A solution of ethyl N-[2-({2-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]ethyl}amino)-6-(methyloxy)-3-pyridinyl]glycinate (1.2 g, 2.7 mmol) in toluene (400 ml) was heated to reflux under argon for 24 hours. This solution was treated at rt with manganese dioxide (2.0 g, 23 mmol). After 7 h the mixture was filtered, washing with warm toluene then evaporated affording a dark oil. Chromatography on silica eluting with 0-100% ethyl acetate in hexane afforded a yellow solid (470 mg, 43%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12](=[O:19])[N:11]([C:20]2[CH:21]=[CH:22][C:23]3[S:27][N:26]=[C:25]([C:28]4[CH:33]=[C:32]([O:34][CH:35]([CH3:43])[C:36]([O:38]C(C)(C)C)=[O:37])[CH:31]=[CH:30][C:29]=4[CH3:44])[C:24]=3[CH:45]=2)[C:10]1=[O:46]>C(Cl)Cl>[CH3:8][N:9]1[C:14]([C:15]([F:17])([F:18])[F:16])=[CH:13][C:12](=[O:19])[N:11]([C:20]2[CH:21]=[CH:22][C:23]3[S:27][N:26]=[C:25]([C:28]4[CH:33]=[C:32]([O:34][CH:35]([CH3:43])[C:36]([OH:38])=[O:37])[CH:31]=[CH:30][C:29]=4[CH3:44])[C:24]=3[CH:45]=2)[C:10]1=[O:46]
Reactant: Cc1ccc(OC(C)C(=O)OC(C)(C)C)cc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(OC(C)C(=O)O)cc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trifluoroacetic acid (75 mL) is added to a solution of tert-butyl 2-{{2-{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1 (2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}-p-tolyl}oxy}propionate (12.0 g, 21.4 mmol) in methylene chloride. The reaction mixture is stirred at room temperature for 24 hours and concentrated in vacuo to give the title product as a yellow foam which is identified by NMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[O:20]1[CH2:24][CH:23]=[CH:22][CH2:21]1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[O:20]1[CH:21]=[CH:22][CH:23]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:24]1
Reactant: C1=CCOC1
Reactant: Fc1ncccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ncccc1C1C=COC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 500 mL round bottomed flask charged with 2-fluoro-3-iodopyridine (15.05 g, 67.5 mmol, Asymchem), tetrabutylammonium chloride (18.80 g, 67.6 mmol, Alfa Aesar), potassium carbonate (28.60 g, 207 mmol, Aldrich) and palladium(ii) acetate (1.48 g, 6.59 mmol, Strem) was added DMF (75 mL) followed by 2,5-dihydrofuran (50.00 mL, 678 mmol, Aldrich) and the reaction mixture was stirred vigorously at 25° C. for 2 h. The mixture was poured into 500 mL of water and the mixture was extracted with EtOAc (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco (330 gram)) eluting with EtOAc:hexanes (0:1→1:2) to give a clear colorless oil. MS (ESI, pos. ion) m/z: 166.1 (M+1).