Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:27][CH:23]3[CH2:26][CH2:25][CH2:24]3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NC1CCC1
Reactant: CCCCc1noc(CO)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1noc(CO)c1COc1ccc(C(=O)NC2CCC2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.6 %

Procedure:
To a solution of 6-[3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (49 mg, 0.16 mmol) in DMF (2 mL) was added cyclobutylamine (25 mg, 0.35 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (82 mg, 0.26 mmol) and N-ethyldiisopropylamine (136 μL, 0.80 mmol) with DMF (1 mL). The reaction mixture was stirred for 17 h at room temperature. The reaction was partitioned between water and ethyl acetate. The aqueous phase was extracted two times with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated to a yellow oil. The crude material was purified by chromatography (silica, dichloromethane:methanol 100:0 to 97:3) to afford the title compound (36 mg, 63%) as a colorless gum. MS: m/e=360.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[F:23])[CH2:35][CH2:34]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccccc1N1CCN(CCCc2cc(-c3ccc(Cl)cc3)n(-c3ccccc3)n2)CC1

Procedure:
108 mg (83%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257 mmol), 1-(2-fluorophenyl)piperazine (46 mg, 0.257 mmol), DIPEA (0.070 mL, 0.386 mmol) and NaBH(OAc)3 (163 mg, 0.771 mmol).
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)C.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)Cc1ccncc1
Solvent: CO
Product: CNCCc1ccncc1

Procedure:
Ethyl-4-pyridylacetate (2 g) was allowed to stand in methanol (50 ml), saturated with methylamine gas, for 3 days. The solution was evaporated under reduced pressure and the residue heated under reflux for 16 hours in toluene (20 ml) with boranedimethylsulphide complex (1.26 ml). The solution was cooled then treated with methanol (1.5 ml) for 1 hour. Hydrogen chloride gas was bubbled through the solution until the pH was less than 2. The solution was heated under reflux for 1 hour then cooled and concentrated. Aqueous sodium hydroxide was added and the mixture extracted with ethyl acetate. The ethyl acetate solution was dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[OH:27])=[O:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:27][C:20]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)c(C(C)=O)c1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (59 mg), 2-hydroxy-5-methoxyacetophenone (213 mg), and 4-dimethylaminopyridine (173 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 10 min. The reaction solution was cooled to room temperature, the solvent was then removed therefrom by distillation under the reduced pressure, and chloroform was added to the residue. The mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (46.5 mg, yield 50%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(NC(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C)C=O>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19]([CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=Cc1ccccc1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(I)ccc1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C=Cc2ccccc2)ccc1O
Yield: 38.3 %

Procedure:
A mixture of N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodo-benzamide (475 mg, 1 mmol), styrene (130 mg, 1.25 mmol), palladium acetate (4.5 mg, 0.02 mmol), tris(ortho-tolyl)phosphine (12.2 mg, 0.04 mmol), diisopropylamine (388 mg, 3 mmol) and N,N-dimethylformamide (2 mL) was refluxed for 8 hours. After cooling, water was added to the reaction mixture, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was purified by column chromatography on silica gel (hexane-isopropyl ether: 2/1→1/1) to give the title compound (173 mg, 38.3%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C[CH:17]([CH:21]1[C:25]2=[C:26](Br)[C:27]3[C:28]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][C:30]([F:33])=[CH:31][C:32]=3[N:24]2[CH2:23][CH2:22]1)[C:18]([O-:20])=[O:19]>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:26]2[C:27]3[C:28]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][C:30]([F:33])=[CH:31][C:32]=3[N:24]3[CH2:23][CH2:22][CH:21]([CH2:17][C:18]([OH:20])=[O:19])[C:25]=23)[CH:2]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Br)c1c(S(C)(=O)=O)cc(F)cc12
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Product: CS(=O)(=O)c1cc(F)cc2c1c(-c1cccc(-c3ccccc3)c1)c1n2CCC1CC(=O)O

Procedure:
Starting from 1,1′-biphenyl-3-ylboronic acid and (+/−)-methyl[9-bromo-6-fluoro-8-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 126, Step 1), the title compound was synthesized following the procedures described in Step 2 of Example 126 and Step 10 of Example 7.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[OH-].[Na+].[Na].NC1C=CSC=1C(O)=[O:22].[Cl-].[Na+].Cl.C(Cl)(Cl)=O>O1CCCC1.O.C(O)CCC>[NH:2]1[C:3]2[CH:7]=[CH:6][S:5][C:4]=2[C:8](=[O:9])[O:10][C:11]1=[O:22]
Reactant: Nc1ccsc1C(=O)O
Reactant: COC(=O)c1sccc1N
Agent: Cl
Agent: O=C(Cl)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCO
Solvent: O
Product: O=c1[nH]c2ccsc2c(=O)o1
Reaction time: 0.25 h

Procedure:
A mixture of 175 g (0.93 mol) of methyl 3-amino-2-thiophenecarboxylate hydrochloride, 1.8 l of n-butanol and 77 g of sodium hydroxide is heated to boiling under reflux for 30 minutes. After concentration of the suspension obtained, the resulting mixture of sodium salt of 3-amino-2-thiophenecarboxylic acid and sodium chloride is used directly for the next step. For this purpose, the mixture is treated with 800 ml of water, 280 ml of concentrated hydrochloric acid and 230 ml of tetrahydrofuran. At 15° to 25° phosgene is conducted through this mixture and subsequently air is conducted through the mixture for 15 minutes. The precipitated solid material is filtered off under suction, washed with water and dried. There is obtained 2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione of melting point 220°-221°.
Reaction SMILES: [N+:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[N:12]=[C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26]CC4C=CC=CC=4)=[O:25])=[CH:20][CH:19]=3)[C:10]=2[F:34])=[CH:6][C:5]=1[O:37]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[N:12]=[C:11]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([OH:26])=[O:25])=[CH:22][CH:23]=3)[C:10]=2[F:34])=[CH:6][C:5]=1[OH:37]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2nc(F)c(F)c(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)c2F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2c(F)c(F)nc(Oc3ccc(C(=O)O)cc3)c2F)cc1O
Reaction time: 8 h
Yield: 91 %

Procedure:
40 g of the 4-(4-nitro-3-benzyloxyphenoxy)-2-(4-benzyloxycarbonylphenoxy)-3,5,6-trifluoropyridine prepared as described in Example 7 (0.066 mol) are dissolved in 600 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 4 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated using hydrogen at a pressure of 1 bar at room temperature in an autoclave with vigorous stirring; the reaction is terminated after 3 days. The orange solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 91%).
Reaction SMILES: [CH2:1]1[O:21][C:20]2[C:3](=[CH:4][CH2:5][C:6]([O:22][CH3:23])([CH:19]=2)[CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:2]1.[BH4-].[Na+]>C(O)C>[CH2:1]1[O:21][C:20]2[C:3](=[CH:4][CH2:5][C:6]([O:22][CH3:23])([CH:19]=2)[CH2:7][CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:2]1
Reactant: CCOC(=O)C(=CC1(OC)C=C2OCOC2=CC1)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC1(OC)C=C2OCOC2=CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.2 %

Procedure:
To a solution of the diethyl 2-(4,5-methylenedioxy-1-methoxybenylidene)-malonate (23.4 g, 0.073 mol) in ethanol (100 ml) was added sodium borohydride (2.8 g, 0.073 mol) and the mixture was stirred at rt for 5 h. The reaction was quenched with water and extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried (Na2SO4) and evaporated to afford the title compound as an oil (20.3 g, 86%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1.[OH:18][CH2:19][C:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>CCOCC>[C:29]([O:28][C:27](=[O:33])[NH:26][C:20]([CH3:25])([CH2:21][CH:22]([CH3:23])[CH3:24])[CH2:19][O:18][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: Cn1c(=O)c2cnccc2c2ccc(Cl)cc21
Solvent: CCOCC
Product: CC(C)CC(C)(COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Yield: 28 %

Procedure:
Synthesis of 8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one was described in example 2, Part C. 8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (0.15 g, 0.613 mmol) and tert-butyl (1-hydroxy-2,4-dimethylpentan-2-yl)carbamate (0.284 g, 1.226 mmol) were subjected to ether synthesis as described in Example 16, Part H, to afford product, tert-butyl(2,4-dimethyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.3 g, 28% yield) as pale yellow solid. LC/MS (ESI) m/e 440.2 [(M+H)+, calcd for C25H34N3O4, 440.2]; LC/MS retention time (method C): tR=2.67 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15]CC3C=CC=CC=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5].C([O-])=O.[NH4+]>C(O)C.C(O)C.O.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5]
Reactant: COC(=O)[C@@H](C)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)[C@@H](C)n1ccc2cc(O)ccc21
Temperature: 40 °C
Yield: 98.2 %

Procedure:
A mixture of (R)-2-(5-benzyloxy-indol-1-yl)-propionic acid methyl ester (20.0 g, 0.065 mol) and palladium hydroxide (2.0 g, wet 20% Pd on carbon) in ethanol (340 mL) under argon was heated to 40° C. To this suspension was slowly added a solution of ammonium formate (5.04 g, 0.078 mol) in ethanol/water (110.5/9.6 mL). Fifteen percent (15%) of the solution was added initially over a period of 40 minutes to ensure that the reaction had initiated (indicated by reverse phase HPLC). The remaining solution was then slowly added over a period of 1.5 h. The reaction was monitored by reverse phase HPLC. Upon completion, the reaction mixture was cooled to rt and filtered through a silica gel pad. The pad was washed with ethanol. The combined fractions were concentrated to dryness under vacuum at 30° C. The crude product was purified by silica gel chromatography using a gradient of 5-35% ethyl acetate/hexanes to give 14.00 g (98%) of (R)-2-(5-hydroxy-indol-1-yl)-propionic acid methyl ester as an oil. Chiral HPLC indicated an ee value of the desired enantiomer as 95%. 1H NMR (400 MHz, DMSO-d6) δ 8.7 (s, 1H), 7.3 (s, 1H), 7.1 (d, 1H), 6.8 (s, 1H), 6.61 (d, 1H), 6.28 (d, 1H), 5.32 (q, 1H), 3.60 (s, 3H), 1.70 (d, 3H); LC/MS (+esi) m/z 220.1 (M+H)+, RT 2.07 min.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]3[C:17]([CH2:18][C@@H:19]([C:21]([OH:23])=[O:22])[NH2:20])=[CH:16][N:15]=[CH:14]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:24]=O.[ClH:26]>>[ClH:26].[ClH:26].[C:1]12([CH2:11][CH2:12][N:13]3[C:17]4[CH2:18][CH:19]([C:21]([OH:23])=[O:22])[NH:20][CH2:24][C:16]=4[N:15]=[CH:14]3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: N[C@@H](Cc1cncn1CCC12CC3CC(CC(C3)C1)C2)C(=O)O
Reactant: C=O
Agent: Cl
Product: O=C(O)C1Cc2c(ncn2CCC23CC4CC(CC(C4)C2)C3)CN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.8 g 3-(2-(1-adamantyl)ethyl)histidine.2HCl in 100 mL 1N HCl is treated with 5 mL 36% formaldehyde, stirring 30 min at 25° C. followed by 90 min at reflux. Evaporation gives 1-(2-(1-adamantyl)ethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-pyridine-6-carboxylic acid dihydrochloride as a white solid. NMR (D2O) 8.90 (s,1H,2-Im).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:15])=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:16]([NH:20][OH:21])([CH3:19])([CH3:18])[CH3:17]>>[N+:1]([C:4]1[C:5]([OH:15])=[C:6]([CH:7]=[N+:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[O-:21])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Reactant: CC(C)(C)NO
Product: CC(C)(C)[N+]([O-])=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O

Procedure:
The title compound was prepared according to the procedure described in Example 13 using 3,5-dinitro-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 4.4% yield as a yellow crystalline solid, m.p. 200.3° C. (Rf=0.15 on a silica gel plate using 10:1 EtOAc/MeOH as an eluant).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]=3)=[C:11]([NH:19][C:20](=[O:32])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28]COC)[O:10][N:9]=2)=[CH:4][CH:3]=1.S([O-])(O)(=O)=O.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]=3)=[C:11]([NH:19][C:20](=[O:32])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COCOc1ccccc1CC(=O)Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Cc1ccccc1O)Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
Fifty (50) mg of 3-(4-fluorophenyl)-5-[(2-methoxymethoxy-phenyl)acetylamino]-4-(4-pyrimidinyl)isoxazole was dissolved in 30 mL of dichloromethane and into which 460 mg of sodium hydrogensulfate reagent as fixed on silica gel was added, followed by 4 hours' stirring at room temperature. After addition of saturated aqueous sodium hydrogencarbonate solution, the reaction solution was extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and from which the solvent was distilled off under reduced pressure. Thus obtained residue was washed with ether-hexane to provide 16 mg (yield: 34%) of the title compound.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]#[N:14])=[CH:9][CH:10]=2)[NH:5]1.Cl[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N+:17]=1[O-].P(Cl)(Cl)Cl>C(=O)([O-])O.[Na+].CN(C)C=O>[C:13]([C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=3)=[C:4]([OH:3])[NH:5]2)=[CH:10][CH:9]=1)#[N:14]
Reactant: CCOC(=O)c1ccc(Cl)[n+]([O-])c1
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: CCOC(=O)c1ccc(-c2c(O)[nH]c3cc(C#N)ccc23)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
To a N,N-dimethylformamide (6 mL) suspension of sodium hydride (97%, 0.144 g, 6.0 mmol) was added 2-oxoindoline-6-carbonitrile (0.712 g, 4.5 mmol). The formed mixture was stirred for 10 min at room temperature followed by the addition of ethyl 6-chloronicotinate 1-oxide (0.605 g, 3.0 mmol). The resulting reaction mixture was set under N2 atmosphere and stirred for 2 h at room temperature. The N,N-dimethylformamide reaction solution was diluted with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform and ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The remaining N,N-dimethylformamide was removed by co-evaporation with toluene. The residue was dissolved in chloroform (10 mL) and phosphorus trichloride (1.65 g, 12.0 mmol) was added. The reaction mixture was stirred for 30 min at 60° C. and then cooled to room temperature. The mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. The resulting brown precipitate was filtered off and the mother liquor was extracted with chloroform (4×). The organic layers were concentrated in vacuo and the residue was combined with the filtrate and was washed with ethyl acetate and diethyl ether to afford 0.55 g (60% yield) of the title compound as a yellow-brown solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.85 (s, 1H), 8.06 (s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.29 (d, J=8.8 Hz, 1H), 4.33 (m, 2H), 1.35 (t, J=7.2 Hz, 3H); MS (EI) m/z 308 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:12][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[CH3:11]
Reactant: Cc1cn2nc(Cl)ccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccc(Cl)nn2c1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
To a solution of 6-chloro-2-methylimidazo[1,2-b]pyridazine (2.00 g, 11.9 mmol, 1.0 equiv) in chloroform (50 mL) was added N-bromosuccinimide (2.55 g, 14.3 mmol, 1.2 equiv). The reaction was stirred at room temperature for 15 h. Purification by column chromatography using 50% ethyl acetate in hexanes elution gave 2.64 g of the yellow solid, 90%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[CH:3]=1.[CH2:22]([O:24][C:25](=[O:39])[C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:28][CH:27]=1)[CH3:23].CC([O-])(C)C.[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:22]([O:24][C:25](=[O:39])[C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([N:33]2[CH2:38][CH2:37][N:36]([C:2]3[CH:3]=[C:4]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=4)[CH:5]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:7]=3)[CH2:35][CH2:34]2)=[N:28][CH:27]=1)[CH3:23]
Reactant: Fc1ccc(-c2cc(Cl)nc(N3CCOCC3)c2)cc1Cl
Reactant: CCOC(=O)c1cnc(N2CCNCC2)c(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)c(Cl)c4)cc(N4CCOCC4)n3)CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a de-gassed mixture of 4-[6-chloro-4-(3-chloro-4-fluoro-phenyl)-pyridin-2-yl]-morpholine (50 mg, 0.153 mmol)), 5-chloro-6-piperazin-1-yl-nicotinic acid ethyl ester (0.183 mmol), and 1M (THF) t-BuOK (0.183 mmol), in toluene (3 mL) under nitrogen add Pd2(dba)3 (0.006 mmol) and BINAP (0.008 mmol). Stir the mixture at 80° C. for 16 h, concentrate, and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, and purify by preparative TLC (3:1 hexanes/EtOAc) to give the title ester.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:8][C@H:9]([O:10][CH3:11])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:11][O:10][C@H:9]1[CH2:8][NH:7][C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12
Reactant: CO[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CO[C@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 1.5 h

Procedure:
(3R,3aR,6S,6aS)-(9H-Fluoren-9-yl)methyl 3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (6b). Ethanol (15 mL) was added dropwise to a mixture of 10% palladium on charcoal (30 mg) and anti-(31) (315 mg, 1.07 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1.5 hours then 10% palladium on charcoal (30 mg) was added. The mixture was stirred for 2 hours then 10% palladium on charcoal (50 mg) was added. The mixture was stirred for 4.5 hours then filtered through celite in vacuo. The filter cake was washed with ethanol then the solvents removed in vacuo from the filtrate to obtain the crude (3R,3aR,6S,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol which was used without further purification.