Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]([F:34])([F:33])[C:28]1[CH:32]=[CH:31][NH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:30]1[CH:31]=[CH:32][C:28]([C:27]([F:34])([F:33])[F:26])=[N:29]1)[C:11]([C@@H:12]([N:14]1[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]1=[O:23])[CH3:13])=[CH:10]2
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](c1cc2cccc(Cl)c2nc1-n1ccc(C(F)(F)F)n1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (0.2000 g, 0.539 mmol), 3-(trifluoromethyl)pyrazole (0.0733 g, 0.539 mmol), cesium carbonate (0.351 g, 1.08 mmol) and in DMF (1.80 mL, 0.539 mmol) was stirred at 100° C. After 2 h, The mixture was cooled to room temperature. To the cooled mixture was added water (30 mL). The mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL×1), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 10 min, then 10 to 50% gradient of EtOAc in hexane over 20 min, then 50% isocratic of EtOAc for 10 min as eluent to give 2-((S)-1-(8-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dione as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (1 H, s), 8.51 (1 H, d, J=2.2 Hz), 8.25 (1 H, dd, J=8.4, 1.0 Hz), 8.08 (1 H, dd, J=7.7, 0.9 Hz), 7.63-7.85 (5 H, m), 6.92 (1 H, d, J=2.7 Hz), 5.94-6.05 (1 H, m), 1.83 (3 H, d, J=7.0 Hz); LC-MS (ESI) m/z 471.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:39]2[CH:38]=[N:37][N:36]([CH3:35])[CH:40]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)cn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A 50 mL, 2-neck round bottom flask was charged with tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (520 mg, 1.042 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (282 mg, 1.355 mmol), potassium carbonate (504 mg, 3.65 mmol), and DMA (3 mL). The reaction flask was degassed followed by addition of 1,1-bis(di-tert-butylphosphino)ferrocene palladium chloride (21 mg, 0.032 mmol). Under N2 atmosphere, the reaction mixture was heated in an oil bath at 80° C. for 2.5 h and then allowed to cool to RT. In a separate 50 mL recovery flask was added de-ionized H2O (12 mL) and the vessel was cooled in an ice/water bath. When the internal temperature of the water reached 2° C., the reaction mixture was transferred to the recovery flask at a rate which kept the internal temperature below 10° C. Following the addition, the reaction vessel was rinsed with DMA (1 mL). The rinse was added to the recovery flask and the resulting aqueous slurry was stirred in an ice bath for 10 min and was then allowed to warm to RT with stirring. When the internal temperature reached 22° C., the mixture was filtered. The filter cake was rinsed with de-ionized H2O (2×5 mL) and air-dried under suction. The solids were re-suspended in glacial acetic acid (3 mL) and stirred at RT for 1 h. Isopropanol (1 mL) was added and the mixture was stirred at RT. De-ionized water (3.4 mL) was added to induce crystallization. Precipitation occurred, but some solids were sticky, so the mixture was heated in a 40° C. oil bath, with stirring, for 20 min. The mixture was allowed to cool to RT with stirring and then filtered. The filter cake was rinsed with a 3:3:1 mixture of HOAc/H2O/IPA (2.1 mL), briefly air-dried under suction, and then dried in a vacuum oven at 60° C. to give the title compound as a tan solid (352 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9H), 1.53 (s, 9H), 1.65 (m, 3H), 1.76 (m, 3H), 3.94 (s, 3H), 4.03 (br s, 1H), 4.38 (br s, 1H), 4.67 (s, 2H), 5.12 (br s, 1H), 5.77 (br s, 1H), 8.25 (br s, 1H), 8.96 (br s, 1H). [M+H] calc'd for C27H37FN6O5, 545. found, 545.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Cl[C:13]1[NH:22][C:21](=[O:23])[C:20]2[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=2)[N:14]=1>COC(O)C>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][N:2]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:1]2
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Reactant: Nc1cccc2c1CCNC2
Agent: COC(C)O
Product: COc1cc2nc(N3CCc4c(N)cccc4C3)[nH]c(=O)c2cc1OC
Temperature: 60 °C
Reaction time: 48 h
Yield: 49.7 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-isoquinolin-5-ylamine 24a (3.83 g, 25.84 mmol) and 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b (5.9 g, 24.54 mmol) in methoxyethanol (60 mL) was heated to 60° C. with stirring for 48 h. The volatiles were evaporated and the residue was purified by flash column chromatography eluting with 3% methanol in dichloromethane containing 0.3% of ammonium hydroxide to yield 4.3 g of 2-(5-amino-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-3H-quinazolin-4-one 110.
Reaction SMILES: [H-].[Na+].C(O)C.[Cl-].[CH2:7]([O:9][C:10](=[O:40])[CH2:11][O:12][C:13]1[CH:38]=[CH:37][C:16]([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:15][C:14]=1[CH3:39])[CH3:8].[CH3:41][C:42]1[N:43]=[C:44]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[S:45][C:46]=1[CH:47]=O>O>[CH2:7]([O:9][C:10](=[O:40])[CH2:11][O:12][C:13]1[CH:38]=[CH:37][C:16]([CH:17]=[CH:47][C:46]2[S:45][C:44]([C:49]3[CH:50]=[CH:51][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:53][CH:54]=3)=[N:43][C:42]=2[CH3:41])=[CH:15][C:14]=1[CH3:39])[CH3:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: CCOC(=O)COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)COc1ccc(C=Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydride (0.040 g, 60% dispersion in mineral oil) was added to anhydrous ethanol (20 ml) followed by [4-(2-ethoxy-2-oxoethoxy)-3-methylbenzyl](triphenyl)phosphonium chloride (intermediate 18, 0.45 g) after 10 minutes. After a further 10 minutes 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (intermediate 2, 0.24 g) was added and the reaction mixture stirred at ambient temperature for 3 hours. The reaction mixture was treated with water and then the mixture extracted with chloroform. The chloroform solution was separated with a hydrophobic frit and excess aldehyde removed using 3-[4-(hydrazinosulfonyl)phenyl]propionyl AM resin (0.50 g). The crude product remaining after this treatment was purified by Biotage™ chromatography using a mixture of petroleum ether:ethyl acetate (5:1) as eluent to give the title compound as a mixture of E and Z isomers.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.Cl.[CH3:42][N:43]([CH3:50])[CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:47]1[CH2:48][CH2:49][CH:44]([N:43]([CH3:50])[CH3:42])[CH2:45][CH2:46]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N(C)C)CC3)ccc2[nH]1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-dimethylamino-piperidine dihydrochloride (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow foam (67%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[CH:2]=1.C(Cl)(=O)C([Cl:14])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:10][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7]([Cl:14])=[O:8]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Cl)c1

Procedure:
Meanwhile, the 3-methylbenzoyl chloride acylating agent was prepared by suspending 3.016 g (22.0 mmol) of m-toluic acid in 100 ml benzene. To this solution was added 2.0 equiv. (3.84 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at O° C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][C:15]([CH3:17])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)(C(F)(F)F)=O>[CH3:14][C:15]1([CH3:17])[O:1][C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4](=[O:6])[O:5]1
Reactant: CC(C)=O
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2cc([N+](=O)[O-])ccc2O1
Reaction time: 1 h
Yield: 89.3 %

Procedure:
A mixture of 2-hydroxy-5-nitrobenzoic acid (50.0 g. 0.27 mol), acetone (40 mL, 0.54 mol) and trifluoroacetic anhydride (100 mL, 0.71 mol) in TFA (300 mL) was heated at reflux. After 1 hour, a supplementary amount of acetone (60 mL, 0.82 mol) was added and the reaction mixture was refluxed for 48 hours. The solvents were evaporated under reduced pressure. The residual brown solid was dissolved in DCM (800 mL) and washed with a mixture of saturated aqueous NaHCO3 (400 mL) and water (400 mL). The aqueous layer was extracted with DCM (2×400 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residual brown oil was taken up in cold pentane (300 mL, 0° C.) and a yellow solid precipitated off. Filtration and washing with pentane gave 53.8 g (88%) of the title compound as a yellow solid. HPLC, Rt: 2.9 min (purity: 99.8%). 1H NMR (CDCl3) δ: 8.88 (d, J=2.8 Hz, 1H), 8.44 (dd, J=9.0, 2.8 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 1.80 (s, 6H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9](Br)[C:10]([O:13][CH:14](F)F)=[N:11][CH:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:18][O:19][C:20]1[N:25]=[C:24](B(O)O)[CH:23]=[CH:22][CH:21]=1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][O:13][C:10]1[C:9]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[N:25]=2)=[CH:8][C:7]([CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:12][N:11]=1
Reactant: FC(F)Oc1ncc(Cn2cncn2)cc1Br
Reactant: COc1cccc(B(O)O)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: COc1cccc(-c2cc(Cn3cncn3)cnc2OC)n1
Temperature: 120 °C
Yield: 25 %

Procedure:
A solution of 5-((1H-1,2,4-triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine (Intermediate 13, 50 mg, 0.16 mmol), (6-methoxypyridin-2-yl)boronic acid (46 mg, 0.30 mmol), in EtOH (2.45 mL), benzene (7.00 mL), was combined with tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.02 mmol), and 4 M aqueous sodium carbonate (3 mL) in a microwave vial. The vial was sealed, purged with nitrogen and heated under microwave conditions to 120° C. for 12 minutes. Water was removed from the reaction with a pipette, and the crude reaction mix was filtered thru CELITE®, and washed with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 30-70% EtOAc/hexanes) afforded the title compound (11.9 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.58 (d, J=2.7 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 7.24 (s, 1H), 6.91-6.84 (m, 2H), 5.93 (d, J=4.3 Hz, 1H), 4.69 (s, 2H), 3.97 (s, 3H), 3.14 (s, 3H). [M+H]=298.02.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(#N)C.CO>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Yield: 100 %

Procedure:
A mixture of tert-butyl N′-(3-nitroquinolin-4-yl)hydrazinecarboxylate (5.00 g, 16.4 mmol) and 5% platinum on carbon (0.50 g) in acetonitrile (90 mL) and methanol (30 mL) was shaken under hydrogen pressure on a Parr apparatus. When the reaction was complete, the mixture was filtered through a layer of CELITE filter agent. The filter cake was rinsed with 3:1 acetonitrile:methanol. The filtrate was concentrated under reduced pressure to yield 4.50 g of crude tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22](=[O:28])[C@H:23]([C@@H:25]([CH3:27])[OH:26])[NH2:24]>C(Cl)(Cl)Cl.CO>[CH3:20][O:21][C:22](=[O:28])[C@H:23]([C@@H:25]([CH3:27])[OH:26])[NH:24][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)[C@@H](C)O

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and L-threonine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.1 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@@H:5]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:17](=O)(OC1C=CC([N+]([O-])=O)=CC=1)[O:18]C1C=CC([N+]([O-])=O)=CC=1>ClCCCl>[CH3:16][C@@H:13]([CH2:14][CH3:15])[C@H:5]([N:4]1[CH2:3][CH2:2][NH:1][C:17]1=[O:18])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](NCCN)C(=O)OC(C)(C)C
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCNC1=O
Temperature: 70 °C
Yield: 91.9 %

Procedure:
To a solution containing the product from Example 3G (0.50 g, 2.08 mmol) in 1,2-dichloroethane (90.0 mL) was added bis(4nitrophenyl) carbonate (0.80 g, 2.63 mmol), and the mixture was heated to 70° C. for 12 hours. The reaction mixture was cooled and concentrated. The residue was dissolved in ethyl acetate, and washed with 10% Na2CO3 (3×), brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending ethyl acetate to give the product (0.49 g, 88% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[C:3]=1[C:17]([NH2:19])=[O:18].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.N1CCCCC1>C(O)C>[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=3)[C:3]=2[C:17]([NH2:19])=[O:18])=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N=Cc1ccc(O)cc1
Yield: 47 %

Procedure:
5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 100 mL of ethanol and 4-hydroxybenzaldehyde (12.945 g, 2.00 eq.) and piperidine (0.25 eq.) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-hydroxybenzylidene)amino)-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (9.00 g, 47% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+].Cl>C(O)C.O>[CH:13](=[C:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)C(=Cc1ccccc1)C2
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a 0° C. mixture of 9.66 g (59.6 mmol) of 6-methoxy-l-indanone and 6.32 g (59.6 mmol) of benzaldehyde in 10 ml ethanol was added 9.66 ml of a 4% KOH in ethanol solution. The reaction was stirred 1 hour and then added to 300 ml water and the pH of the quench adjusted to 2 with 1N hydrochloric acid. The resultant mixture was extracted with 3×300 ml ether, and the extracts combined, dried over MgSO4, evaporated and the residue triturated with ether to yield 10.8 g (72%) of present title compound as a solid.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][O:12][CH3:13])([CH3:7])[CH2:3][C:4](=O)[CH3:5].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.Cl([O-])(=O)(=O)=O.C[NH2+]C>[Pt]=O>[CH3:1][C:2]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][O:12][CH3:13])([CH3:7])[CH2:3][CH:4]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:5]
Reactant: C1CCNCC1
Reactant: COCCC(=O)NC(C)(C)CC(C)=O
Agent: O=[Pt]
Agent: C[NH2+]C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: COCCC(=O)NC(C)(C)CC(C)N1CCCCC1

Procedure:
Following the procedure of Example 4, a mixture of 201 parts (1 mole) of N-(1,1-dimethyl-3-oxobutyl)-3-methoxypropionamide, 170 parts (2 moles) of piperidine, 0.5 part of platinum oxide and 1 part of dimethylammonium perchlorate is hydrogenated in the Parr apparatus, starting at a pressure of 70 psi. and recharging when the pressure has reached 39 psi. After workup as described in Example 4, the desired product, N-(1,1-dimethyl-3-piperidinobutyl)-3-methoxypropionamide, is obtained boiling at 112°-115° C./0.25 mm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[C:14]#[N:15].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]([C:14]#[N:15])=[C:2]2[N:26]1[CH2:27][CH2:28][N:23]([C:21]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)=[O:22])[CH2:24][CH2:25]1
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: N#Cc1c(Cl)c2cc(F)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Yield: 71 %

Procedure:
This compound was prepared from 4-chloro-6-fluoro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (96) and 2-furoyl piperazine according to general procedure E to yield 2.87 g (71%) of 6-fluoro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (99) as white solids. MP 312° C.; 1H-NMR (DMSO-d6): δ 3.69 (m, 4H), 3.93 (m, 4H), 6.66 (dd, J=1.6, 3.6 Hz, 1H), 7.08 (d, J=3.6 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 8.07 (dd, J=2.8, 9.2 Hz, 1H), 8.69 (d, J=2.8 Hz, 1H), 12.30 (s, 1H); EIMS: 368 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[F:27][C:28]([F:32])([F:31])[CH2:29][SH:30].[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][S:30][CH2:29][C:28]([F:32])([F:31])[F:27])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Reactant: FC(F)(F)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (2.0 g, 4.72 mmol) and 2,2,2-trifluoroethanethiol (0.46 mL, 5.18 mmol) in 1,4-dioxane (40 mL) at 0° C. was added sodium hydride (60% in mineral oil; 0.207 g, 5.18 mmol), and the reaction was stirred at 0° C. for 30 minutes. The mixture was partitioned between EtOAc and H2O. The aqueous layer was separated and acidified, and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[I:17]I>C(Cl)Cl.O.O.O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Fe+2].[N+]([O-])([O-])=O>[I:17][C:15]1[CH:14]=[CH:13][C:4]([O:5][CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[C:3]([CH2:1][CH3:2])[CH:16]=1
Reactant: II
Reactant: CCc1ccccc1OCCN1CCCC1
Agent: [Fe+2]
Agent: O=[N+]([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CCc1cc(I)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A finely triturated mixture of 0.8 g of silica gel (0.2-0.5 mm) and 0.41 g (1.00 mmol) of iron (II) nitrate nonahydrate was added to a solution of 0.44 g (2.01 mmol) of 1-[2-(2-ethylphenoxy)ethyl]pyrrolidine and 0.28 g (1.10 mmol) of iodine in 5 mL of DCM and the mixture was stirred for 12 hours at RT. The reaction mixture was filtered and the filtrate was evaporated down in vacuo. The residue was purified by column chromatography (silica gel, DCM/MeOH/sat. aqueous ammonia 9:1:0.1). Yield: 0.286 g (41% of theoretical); C14H20INO (M=345.219); calc.: molpeak (M+H)+: 346; found: molpeak (M+H)+: 346; HPLC-MS: 6.74 minutes (method A).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Cl[CH2:10][CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: OCCCl
Reactant: Oc1ccccc1O
Product: OCCOc1ccccc1O

Procedure:
reaction of catechol with 2-chloroethanol to obtain 2-(2-hydroxyethoxy)phenol of formula: ##STR30## b) reaction of the 2-(2-hydroxyethoxy)phenol obtained in a) with 1,2-dibromethane to obtain 1,2-bis [2-(2-hydroxyethoxy)pbenoxy]etbane and