Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[C:15]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:16]=[CH:17][C:18]=3[Cl:22])[N:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[C:15]([O:23][CH:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)[CH:16]=[CH:17][C:18]=3[Cl:22])[N:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:6]
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Nc2ncc3c(Cl)ccc(OC4CCNCC4)c3n2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Nc2ncc3c(Cl)ccc(OC4CCNCC4)c3n2)cc1Cl)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A mixture of 2-chloro-4-(5-chloro-8-(piperidin-4-yloxy) quinazolin-2-ylamino) benzoic acid (1 eq), morpholine (3 eq), HATU (1.5 eq) and DIEA (4 eq) in NMP was stirred at room temperature for 4 h. The reaction mixture was concentrated and purified by semi-prep HPLC to provide pure product in 50% yield. ES/MS m/z 502.3 (MH+).
Reaction SMILES: Cl[C:2]1[CH2:19][C:18]2[C:17]([OH:20])=[C:16]3[C:7]([C:8](=[O:22])[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]3=[O:21])=[C:6]([OH:23])[C:5]=2[CH2:4][CH:3]=1.C(O)(=[O:26])C>>[OH:23][C:6]1[C:5]2[CH2:4][CH2:3][C:2](=[O:26])[CH2:19][C:18]=2[C:17]([OH:20])=[C:16]2[C:7]=1[C:8](=[O:22])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]2=[O:21]
Reactant: CC(=O)O
Reactant: O=C1c2ccccc2C(=O)c2c(O)c3c(c(O)c21)CC=C(Cl)C3
Product: O=C1CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Temperature: 25 °C
Yield: 76 %

Procedure:
There was prepared a mixture of glacial acetic acid (0.3 ml and concentrated sulfuric acid) 1.5 ml (which was cooled to 0° C. in an ice water bath). To this acid mixture was added 9-chloro-7,10-dihydro-6,11-dihydroxy-5,12-naphthacenedione (III) in a single batch and the mixture stirred. The mixture was permitted to warm slowly to ambient temperature over 3 hours at which temperature it was stirred for a further 24 hours. At the conclusion of this time the mixture was poured onto ice (ca. 25 g) and the organic layer extracted with chloroform (25 ml,×4) the chloroform extracts were combined, washed with saturated aqueous sodium bicarbonate, and with water, dried over anhydrous sodium sulfate, filtered, and the solvent removed from the filtrate under reduced pressure. The residue was washed with ether and further dried in vacuo to yield the "red ketone" 7,10-dihydro-6,11dihydroxy-5,9,12(8H)naphthacenetrione (IV) (18 mg, 76%). This product was shown to be homogeneous by thin layer chromatographic analysis and had the same Rf as an authentic sample (silica gel, 0.7% methanolic chloroform, Rf =0.59.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]=O)[CH:14]=1)[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][NH:26][CH:23]2[CH2:25][CH2:24]2)[CH:14]=1)[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(C=O)c1)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(CNC2CC2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A mixture of [2-(4-chloro-3-formyl-phenyl)-ethyl]-cyclopropyl-carbamic acid tert-butyl ester (1.32 g, 4.08 mmol) and cyclopropylamine (0.438 mL, 6.1 mmol) in MeOH (41 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (232 mg) was added in portions. The mixture was stirred for 1 h, and the solvents were removed under reduced pressure. EtOAc (100 mL) was added, and the mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 95:5) yielded the title compound (883 mg, 59%). LC-MS: tR=0.82 min; ES+: 365.38.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH3:24][Li].Cl>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19]([OH:23])([CH3:24])[CH:20]([CH3:21])[CH3:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: [Li]C
Reactant: CC(C)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C(C)(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: -50 °C

Procedure:
40 ml of tetrahydrofuran was added to a flask that had been dried overnight at 100° C. in vacuo and 4.5 g (0.0134 mole) of the ketone of Example 12 was added. All processes were done under an argon atmosphere. The solution was cooled to about -50° C. in a dry ice/acetone bath and 19.16 ml (0.026 mole) of 1.4 M methyl lithium in tetrahydrofuran was added dropwise maintaining the temperature to about -60° C. to -50° C. When addition was complete, the reaction mixture was warmed to about 0° C. and 1 N hydrochloric acid was added. The reaction mixture was extracted three times with ethyl acetate, the extracts combined, washed with water twice, dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed on silica to give the title compound identical with that of Example 15.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O[CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH:16]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc([N+](=O)[O-])c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
To a mixture of 3-nitrophenol (4.0 g, 28.8 mmol), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (5.94 g, 31.7 mmol), PPh3 (8.3 g, 31.7 mmol) in THF (40 mL) at 0° C. over argon was added DEAD (5.52 g, 31.7 mmol). The reaction was warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated and purified by column chromatography to obtain tert-butyl 3-(3-nitrophenoxy)pyrrolidine-1-carboxylate (8.73 g, 98% yield)
Reaction SMILES: [OH:1][C:2]1[C:16]([CH3:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH3:19])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=O.C1(C)C=CC=CC=1.Cl>O.[Zn]>[OH:1][C:2]1[C:16]([CH3:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH3:19])[C:3]=1[CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: Cc1cc(C)c(C(=O)CCCCC(=O)O)c(O)c1C
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(CCCCCC(=O)O)c(O)c1C

Procedure:
To 5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (formula II-1 wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.262 part) were added water (16 volume parts), toluene (20 volume parts), concentrated hydrochloric acid (4 volume parts) and zinc amalgam prepared from 2 parts of zinc. The mixture was refluxed for 16 hours, during which time concentrated hydrochloric acid (6 volume parts) was added in three portions. After cooling, the reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with water and dried. The solvents were distilled off under reduced pressure to obtain 6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanoic acid (formula II-2 wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.251 part) as colorless needles melting at 96°-108° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[CH3:15][Sn:16](Cl)([CH3:18])[CH3:17]>C(OCC)C>[CH3:15][Sn:16]([CH3:18])([CH3:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14]
Reactant: C[Sn](C)(C)Cl
Reactant: COc1ccccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccccc1[Sn](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a stirring solution of n-BuLi (2.6 mL, 2.5M in hexane, 6.42 mmol) in diethyl ether (2.5 mL) at −78C was added 2-bromoanisole (1.0 g, 5.35 mmol) in diethyl ether (2 mL) dropwise. After stirring for 1 h at −78C, trimethyltin chloride (6.4 mL, 1.0M in THF, 6.42 mmol) was added dropwise. The mixture was allowed to stir an additional 2 h while slowly warming to room temperature. The mixture was then washed with saturated aqueous NaHCO3. The aqueous layer was extracted with diethyl ether (1×50 mL) and the organic layers were combined, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, hexane) to yield the title compound as a colorless oil (1.11 g, 76%). 1HNMR (400 MHz, CDCl3) δ 7.47 (d, 1H), 7.40 (t, 1H), 7.05 (t, 1H), 6.90 (d, 1H), 3.36 (s, 3H), 0.34 (s, 9H).
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[I:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>C(O)C>[I:12][C:13]1[CH:14]=[C:15]([NH:16][C:3](=[O:5])[CH2:2][C:1]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:13]([I:12])[CH:14]=2)=[O:9])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccc(N)cc1I
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: Cc1ccc(NC(=O)CC(=O)Nc2ccc(C)c(I)c2)cc1I
Temperature: 210 °C
Yield: 81.3 %

Procedure:
A mixture of diethyl malonate (16.0 g, 100 mmol) and 3-iodo-4-methylaniline (46.6 g, 200 mmol) was heated at 210° C. for 20 min, allowing the liberated ethanol to evaporate. After cooling the solid formed was triturated in hot ethanol (200 mL) to afford the title compound (43.4 g, 81%). Light brown solid, ISP-MS: m/e=535.0 ([M+H]+).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][OH:15]>O1CCOCC1>[CH3:18][O:17][C:13]([CH2:14][O:15][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:16]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)COc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
0.4 g of sodium hydride was added to a mixture of 1.59 g of 2-chloro-3-nitropyridine, 0.95 g of methyl glycolate and 10 ml of 1,4-dioxane at 10° C. The mixture was stirred at room temperature for 2 hours, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.5 g of 2-(methoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[S:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])(=[O:33])=[O:32]>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([S:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])(=[O:33])=[O:32])[CH2:28][CH:29]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: Cc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)cn1
Product: COC(=O)CCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(c5cnc(C)cn5)CC4)sc3c2)CC1

Procedure:
Compound 50D was prepared from Compound 50C and methyl 3-(chlorosulfonyl)propanoate in a similar manner to the procedure described for Compound Example 16.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[N:16]=2)[N:11]=[CH:10][C:9]=1[OH:20].[CH2:21]([O:28][C:29](=[O:41])[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37](=[O:40])[CH2:38]Br)[CH2:33][CH2:32]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([O:28][C:29](=[O:41])[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]2([OH:40])[NH:7][C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[N:16]=4)[N:11]=[CH:10][C:9]=3[O:20][CH2:38]2)[CH2:33][CH2:32]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc2ncc(O)c(N)c2n1
Reactant: O=C(N[C@H]1CC[C@H](C(=O)CBr)CC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc3c(c2n1)NC(O)([C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1)CO3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (246 mg, 1.78 mmol, 2.0 eq) is added at room temperature to a stirred solution of 4-amino-6-methoxy-[1,5]naphthyridin-3-ol (170 mg, 0.89 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL), followed by [trans-4-(2-bromo-acetyl)-cyclohexyl]-carbamic acid benzyl ester (315 mg, 0.89 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×20 mL) and a saturated ammonium chloride aqueous solution (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford [trans-4-(3-hydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid benzyl ester (2.33 g, 88% Yield).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH2:8]=[O:9]>>[OH:9][CH2:8][N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7]
Reactant: C=O
Reactant: O=C1C=CC(=O)N1
Product: O=C1C=CC(=O)N1CO
Reaction time: 8 h

Procedure:
Maleimide (2.0 g) and 10% formaline (6.8 g) were stirred at 100° C. for 60 minutes. The reaction was let to cool and then kept overnight at 4° C. The product was filtered, washed with water and ethanol. Yield: 1.3 g, melting point 96,5-97° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O.[CH2:6]([NH:12][C:13](=[S:16])SC)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)C>[CH2:6]([N:12]1[C:13]([SH:16])=[N:3][N:2]=[N:1]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCNC(=S)SC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCn1nnnc1S
Temperature: 90 °C
Yield: 103 %

Procedure:
Sodium azide (155.9 g.) and water (0.8 l.) were added under stirring to a solution of methyl N-hexyldithiocarbamate (430 g.) in ethanol (1.7 l.) and the resulting mixture was refluxed for 3.5 hours at 90° C. Ethanol was distilled off from the reaction mixture and the residue was washed with diethyl ether (1 l.), adjusted to pH 2.0 with conc. hydrochloric acid and extracted with diethyl ether (1 l.). The extract was washed with water, dried over magnesium sulfate and concentrated to give an oil of 1-hexyl-1H-tetrazole-5-thiol (431.3 g.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[NH:22][CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4.Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[N:22]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:21][CH2:20][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16]4
Reactant: ClCCCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(Cc1ccccc1)CC3
Temperature: 50 °C
Yield: 87 %

Procedure:
To a stirred solution of 3-(3-chloropropyloxy)morphinan.HCl 54 (3 mg, 0.008 mmol) in dry DMF (0.15 mL) was added potassium carbonate (7 mg, 0.024 mmol), benzylbromide (2 μL, 0.032 mmol) sequentially and the mixture was stirred at 50° C. After starting material disappeared on TLC, solvent was concentrated and column chromatography gave 3 mg (87%) of the title compound: 1H NMR (300 MHz, CDCl3) δ7.15˜7.35 (5H, m); 7.05 (1H, d); 6.80 (1H, s); 6.73 (1H, d); 4.10 (2H, t); 3.55˜3.85 (4H, m); 3.05 (1H, m); 2.80 (1H, m); 2.56 (1H, m); 2.40 (1H, m); 2.00˜2.30 (4H, m); 1.00˜1.90 (10H, m).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[N:18]1([C:24]2[C:32]3[N:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[NH:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[F:36][C:33]([F:34])([F:35])[C:30]1[NH:31][C:32]2[C:24]([N:18]3[CH2:19][CH2:20][N:21]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:22][CH2:23]3)=[CH:25][CH:26]=[CH:27][C:28]=2[N:29]=1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: FC(F)(F)c1nc2c(N3CCNCC3)cccc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5nc(C(F)(F)F)[nH]c45)CC3)nc2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.7 %

Procedure:
To a suspension of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yloxy)-butyraldehyde (0.297 g, 1.266 mmol, 1.32 eq) and 4-piperazin-1-yl-2-trifluoromethyl-1H-benzoimidazole (0.258 g, 0.953 mmol, 1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.723 g, 3.413 mmol, 3.58 eq). The slurry was allowed to stir overnight at room temperature (18 h). Analysis by HPLC showed reaction mostly complete. The mixture was diluted with Ethyl Acetate and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.166 g, 35%). MS: APCI: M+1: 489.2 (Exact Mass: 488.21).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](Cl)[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][NH:13][CH3:14].O1CCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:13]([CH3:14])[CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CNC
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Solvent: C1CCOC1
Product: CN(C)c1cc(C(=O)O)cc(Cl)n1
Temperature: 80 °C
Yield: 44 %

Procedure:
2,6-Dichloroisonicotinic acid (2.00 g, 10.42 mmol) was placed in a pressure tube and a solution of dimethylamine in tetrahydrofuran (26 mL, 2 M, 52 mmol) added. The vessel was sealed and heated for 22 h at 80° C. The mixture was cooled to room temperature, transferred to a round-bottom flask and concentrated to dryness. The resulting white semi-solid was taken up in 30 mL of 0.1 N sodium hydroxide solution. 1 N HCl was added dropwise with stirring to adjust the pH of the solution to ca. 3.5, at which point a pale yellow solid formed. This was collected by filtration and dried under vacuum at 45° C. overnight to provide 2-chloro-6-(dimethylamino)isonicotinic acid inner salt (916 mg, 44%). Further acidification of the aqueous solution to pH 1 resulted in the formation of a bright yellow solid, which was also collected and dried under vacuum to give 2-chloro-6-(dimethylamino) isonicotinic acid hydrochloride (1.15 g, 46%). m/z: 201+ [M+H]; 199− [M−H]. For the HCl salt: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.64 (br. s., 1H), 6.96 (d, J=1.0 Hz, 1H), 6.89 (d, J=0.8 Hz, 1H), 3.06 (s, 6H), 2.53 (t, J=5.1 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([C:18]#[N:19])=[CH:15]2)=[CH:10][CH:9]=1.[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[C@@H:31]1[CH2:33][O:32]1>CCO>[OH:32][C@H:31]([C:22]1[CH:23]=[CH:24][C:25]2[C:26](=[O:30])[O:27][CH2:28][C:29]=2[C:21]=1[CH3:20])[CH2:33][N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][C:14]([C:18]#[N:19])=[CH:15]3)=[CH:10][CH:9]=2)[C:2](=[O:1])[CH2:7]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: N#Cc1ccc2ccc(N3CCNCC3=O)cc2c1
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(c3ccc4ccc(C#N)cc4c3)C(=O)C2)ccc2c1COC2=O
Temperature: 145 °C

Procedure:
A mixture of 7-(2-oxopiperazin-1-yl)naphthalene-2-carbonitrile [I-7] (35 mg, 0.14 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (40 mg, 0.21 mmol) in EtOH (2 mL) in a 5 mL microwave tube was heated to 145° C. for 2 hours. LC showed formation of the title product, which was purified by silica gel flash chromatography. LC-MS (IE, m/z): 442 [M+1]+.
Reaction SMILES: C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44])[C:14]([NH:16][C@H:17]([CH2:36][CH2:37][OH:38])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([C:31](=[N:33][O:34]C)[CH3:32])[N:28]([CH3:30])[CH:29]=2)=[CH:21][CH:20]=1)=[O:15].C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44])[C:14]([NH:16][C@H:17]([CH2:36][CH2:37][OH:38])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:26]=[C:27]([C:31](=[N:33][OH:34])[CH3:32])[N:28]([CH3:30])[CH:29]=2)=[CH:23][CH:24]=1)=[O:15]
Reactant: CON=C(C)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(=NO)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Temperature: 65 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
A mixture of 2-amino-4′-bromoacetophene hydrochloride (10.0 g, 40 mmol), sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) and compound 2 (19.2 g, 80 mmol) in dioxane (70 mL) was stirred at 65° C. until TLC showed no compound 2 left (about 2 h). The reaction mixture was carefully neutralized with saturated NaHCO3 solution and extracted with ethyl acetate. The organic solution was dried over Na2SO4 and concentrated. Purification with flash column chromatography (EtOAc:Hexs 1:1) gave product 3 (9.11 g, 79%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([SH:13])[CH:10]=[CH:11][CH:12]=1.[F:14][C:15]1[C:20](F)=[CH:19][C:18]([CH2:22][OH:23])=[C:17]([N+:24]([O-:26])=[O:25])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:20]2[C:15]([F:14])=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([CH2:22][OH:23])[CH:19]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1CO
Reactant: Sc1cccc(C2OCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Sc2cccc(C3OCCCO3)c2)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[1,3]Dioxan-2-yl-benzenethiol (2.57 g, 14.02 mmol), prepared as described in Example 1, Step C, (4,5-difluoro-2-nitro-phenyl)-methanol (2.65 g, 14.02 mmol), and cesium carbonate (9.1 g, 28 mmol) were combined in DMF (100 mL). The resulting mixture was stirred overnight at room temperature. Water was added, and the resulting mixture was then extracted with ethyl acetate. The organic layer was dried with Na2SO4 and filtered, and the solvent was removed to yield an oil, which was purified via silica column chromatography (50% EtOAc/heptane) to yield a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.P([O-])(O)(O)=[O:10].[Na+].OO.Cl([O-])=O.[Na+]>O.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[O:8])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cc(Br)cs1
Reaction time: 1 h
Yield: 334.9 %

Procedure:
To a flask equipped with a mechanical stirrer was added 25 g (130 mmol) 4-bromothiophene-2-carbaldehyde (Aldrich Chemical Company), acetonitrile (200 mL), and 4.5 g (37.5 mmol) of sodium dihydrogen phosphate dissolved in 35 mL of water. After cooling this mixture on an ice-salt bath, 15 mL (169 mmol) of 35% hydrogen peroxide and 15.3 g (169 mmol) of sodium chlorite were added, and the mixture was stirred for 1 h. The reaction mixture was then stirred at room temperature for 3 h. The solvent was removed in vacuo, and the solid was suspended in a mixture of water (175 mL) and 1 N hydrochloric acid (4 mL) and stirred for 10 min at rt. The solid was collected on a Büchner funnel and washed with water (2×150 mL) to afford 26 g (97%) of 4-bromothiophene-2-carboxylic acid, which was used in the next step without further purification.