Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]1[CH:9](O)[C:8]2[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:7]=2[S:6]1(=[O:17])=[O:16])(C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Cl:15][C:14]1[C:7]2[S:6](=[O:17])(=[O:16])[N:5]=[CH:9][C:8]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)N1C(O)c2cccc(Cl)c2S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=S1(=O)N=Cc2cccc(Cl)c21
Reaction time: 16 h
Yield: 69.9 %

Procedure:
A solution of 37 g of 2-t-butyl-3-hydroxy-7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide and 0.2 g of tosic acid in 370 mls of benzene was refluxed through a Dean-Stark water separator for 16 hours, cooled in ice and filtered to give 18.9 g of the title compound as colorless crystals, m.p. 162°-164° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:11]([CH2:33][C@H:34]([CH:38]=[O:39])[CH:35]([CH3:37])[CH3:36])[O:10][C:9]1([CH3:41])[CH3:40])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:43].[K+].S([O-])([O-])=O.[Na+].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:11]([CH2:33][C@H:34]([C:38]([OH:43])=[O:39])[CH:35]([CH3:36])[CH3:37])[O:10][C:9]1([CH3:40])[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C=O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Reaction time: 48 h

Procedure:
53 g of 3-tert-butoxycarbonyl-5(S)-(2(S)-formyl-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine are dissolved in 470 ml of toluene, and, at 0° C., 470 ml of water, 79.1 g of potassium permanganate and 9.7 g of tetrabutylammonium bromide are added in succession thereto. The reaction mixture is stirred for a further 48 hours at 0°-5° C., and then, at 10° C., 1.2 liters of 10% sodium sulfite solution are added. After a further 30 minutes, 1.95 liters of 10% citric acid solution and 1.2 liters of water are added. The product is extracted by repeated extraction with ethyl acetate. The extracts are concentrated by evaporation and purified by FC (2.3 kg of silica gel, ethyl acetate/hexane=3:7). The title compound is obtained: Rf (ethyl acetate/hexane=1:2)=0.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=1>>[C:17]1([C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(O)c1
Reactant: Brc1cccc(-c2ccccc2)c1
Product: COc1cccc(Oc2cccc(-c3ccccc3)c2)c1

Procedure:
Under the Ullmann conditions used in Example 8, steps A and B, above, 13.3 g of 3-methoxyphenol (107 mmole) was condensed with 1-bromo-3-phenylbenzene, giving, after purifying over silica gel, (0-30% EtOAc in hexane gradient) 17.8 g (60%) of 3-(3-phenylphenoxy)anisole as a crystalline solid, melting at 41-42° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH2:12])[CH:6]=1.[CH:14](OCC)(OCC)OCC>O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH:14]=[N:12][C:7]=2[CH:6]=1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Solvent: O
Product: COC(=O)Cc1ccc2ocnc2c1
Temperature: 25 °C

Procedure:
Methyl-2-(3-amino-4-hydroxyphenyl)acetate (1.39 g, 7.67 mmol) was combined at RT with triethyl orthoformate (10 ml). The reaction mixture was heated to reflux for 12 h and then cooled to RT. Water (70 mL) was added thereto and the reaction mixture was extracted with EA. The combined organic phases were dried over MgSO4 and filtered. The solvent was removed under a vacuum and the residue purified by means of column chromatography (n-hexane/EA=2:1).
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([NH:9][CH2:10][CH2:11][S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:8])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>O>[F:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][CH2:11][SH:12])=[O:8])=[CH:32][CH:33]=1
Reactant: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(CF)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCS)c1ccc(CF)cc1
Reaction time: 0.08 h

Procedure:
To 1.4 mg (3.0 μmol) of 4-fluoromethyl-N-[2-(tritylsulphanyl)ethyl]benzamide was added 50 μl of TFA/TIS/H2O(95:2.5:2.5) mixture. The flask was swirled gently for 5 minutes and then concentrated in vacuo. LC-MS analysis (column Phenomenex Luna 3 μm C18(2) 50×2.00 mm; solvents: A=water/0.1% HCOOH and B=acetonitrile/0.1% HCOOH; gradient 5-60% B over 10 min; flow 0.3 ml/min, UV detection at 214 and 254 nm, ESI-MS) gave a peak (tR 6.8 min) with m/z at 214 corresponding to MH+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH3:26]>>[C:2]1([O:1][CH2:8][CH2:9][N:10]2[C:11]3[C:20]4[N:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:21]=[C:22]2[CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnc2cccnc2c1NCCOc1ccccc1
Reactant: CCCCC(=O)Cl
Product: CCCCc1nc2cnc3cccnc3c2n1CCOc1ccccc1
Yield: 73.5 %

Procedure:
Using the general method of Example 73 Part A and Part B, N4-(2-phenoxyethyl)[1,5]naphthyridine-3,4-diamine (4.4 g, 15.7 mmol) was reacted with valeryl chloride (1.95 mL, 16.4 mmol) and the resulting amide intermediate was cyclized to provide 4.0 g of 2-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl phenyl ether as a white solid, m.p. 150-150.5° C. Analysis: Calculated for C21H22N4O: %C, 72.81; %H, 6.40; %N, 16.17; Found: %C, 72.78; %H, 6.40; %N, 16.31. 1H NMR (300 MHz, DMSO): δ 9.25 (s, 1H), 9.00 (dd, J=4.3, 1.7 Hz, 1H), 8.52 (dd, J=8.4, 1.7 Hz, 1H), 7.74 (dd, J=8.4, 4.3 Hz, 1H), 7.25-7.20 (m, 2H), 6.91-6.84 (m, 3H), 5.22 (t, J=5.2 Hz, 2H), 4.53 (t, J=5.2 Hz, 2H), 3.09 (t, J=7.7 Hz, 2H), 1.91 (pentet, J=7.6 Hz, 2H), 1.55-1.43 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); MS (EI): m/e 346.1794 (346.1793 calc'd for C21H22N4O).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:14][C:15]1[C:16]([F:24])=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[C:16]=2[F:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1cccc(Cl)c1F
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
1.2 ml of 4-tert-butylbenzaldehyde (7.14 mmol), 1 g of 2-(3-chloro-2-fluoro-phenyl)-ethylamine hydrochloride (4.76 mmol) and 658 mg of potassium carbonate (4.76 mmol) were suspended in 14 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 270 mg (7.14 mmol) of sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 1.2 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4) to give 860 mg light yellow oil (56%). MS (ISP) 320.3 (M+H)+.
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)[CH2:13][C:12]3([CH3:27])[CH3:26])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:20]=[C:21]([NH:28][C:29]4([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]4)[CH:22]=[CH:23][CH:24]=2)[CH2:13][C:12]3([CH3:27])[CH3:26])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Reactant: NC1(C(=O)O)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Temperature: 25 °C
Yield: 77 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (150 mg, 0.34 mmol), copper(I) iodide (20 mg, 0.1 mmol), 1-amino-cyclopropanecarboxylic acid (138 mg, 1.3 mmol) and potassium carbonate (140 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(6-cyclobutylsulfamoyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (123 mg, 80.0%) as a white solid: MS (ESI) M+1=470.2.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[C:28](O)(=[O:31])[CH2:29][CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1
Reactant: CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Temperature: 25 °C

Procedure:
To a solution in DMF (1.5 ml) of trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate A) (150 mg, 0.34 mmol) were added propionic acid (27 mg, 0.36 mmol), DIPEA (177 mg, 1.37 mmol) and TBTU (115 mg, 0.36 mmol). The reaction mixture was stirred over night at room temperature then sat. aq. NaHCO3 sol. was added and the product was extracted with EtOAc. After drying (Na2SO4) the solvent was evaporated and the product was purified by flash chromatography on silica gel (CH2Cl2/MeOH/25% NH3 aq 140:10:1) to yield the title compound as a white solid (123 mg, 93%), MS (ISP) m/z=385.3 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=O)[CH2:15][CH3:16])[CH2:9]2)=[CH:5][CH:4]=1.[OH-].[K+].O.NN.[NH4+].[Cl-]>C(O)COCCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][CH3:16])[CH2:9]2)=[CH:18][CH:19]=1
Reactant: CCC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Agent: NN
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: CCCC1CCCN(Cc2ccc(OC)cc2)C1
Temperature: 120 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
Combine 1-[1-(4-Methoxy-benzyl)-piperidin-3-yl]-propan-1-one (277.3 mg, 1.07 mmol), Diethylene glycol (10 mL), KOH (178.0 mg, 3.18 mmol), and Hydrazine-monohydrate (1.0 mL) at room temperature under a Nitrogen atmosphere. Heat the reaction mixture to 120° C. for 2 hours and then 220° C. for 4 hours. Cool reaction to room temperature and then pour the reaction mixture over sat NH4Cl (aq). Extract with Ethyl acetate, wash with brine, and dry over Na2SO4. Concentrate under reduced pressure and flash chromatograph using 3% 1N NH3 MeOH in CH2Cl2 to give 105.2 mg (40% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 0.9 (3H, t), 1.1-1.4 (4H, m), 1.5-1.7 (3H, m), 1.7 (1H, d), 1.9 (1H, td), 2.7-2.9 (2H, m), 3.5 (2H, dd), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); MS m/z 248 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:9])[CH:5]=[C:4]([CH:17]=[CH2:18])[N:3]=1.[F:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:2]3[N:7]=[C:6]([C:8]([NH:10][C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:9])[CH:5]=[C:4]([CH:17]=[CH2:18])[N:3]=3)=[CH:27][CH:26]=2)=[CH:22][CH:21]=1
Reactant: C=Cc1cc(C(=O)N[C@@H](C)C(=O)OC)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=Cc1cc(C(=O)N[C@@H](C)C(=O)OC)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 100 °C
Yield: 43.6 %

Procedure:
To a solution of (S)-methyl 2-(2-chloro-6-vinylpyrimidine-4-carboxamido)propanoate (0.444 g, 1.65 mmol) in dioxane (10 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.521 g, 1.66 mmol), 2M aqueous Na2CO3 (1.65 mL, 3.30 mmol), and PdCl2(dppf) (0.071 g, 0.087 mmol). The reaction vessel was flushed with argon, sealed and heated at 100° C. overnight. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 10-40% EtOAc in hexanes. The product fractions were evaporated in vacuo to give (S)-methyl 2-(2(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxamido)propanoate as a tan-yellow oil (0.304 g, 0.72 mmol, 44% yield). LC/MS: m/z=422.2 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:3]1[CH:17]=CC1C=CC=CC=1.I([O-])(=O)(=O)=[O:26].[Na+].O>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH:17]([C:3]1[CH:2]([OH:1])[CH2:6][C:5](=[O:7])[C:4]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:26]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CC1=C(CCCCCCC(=O)O)C(=O)CC1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture consisting of 13 parts of dl- 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoic acid, 17.8 parts of sodium periodate, 55 parts of water, 160 parts of dioxane and 2 parts of a 2% osmium tetroxide in dioxane solution is stirred under nitrogen at room temperature for about 4 hours. That reaction mixture is then extracted with ether and the ether layer is separated and extracted several times with 0.5% aqueous sodium chloride. The salt extracts are saturated with sodium chloride, then extracted with ether. The ether layer is separated, dried over anhydrous sodium sulfate, concentrated and dried under reduced pressure to afford dl- 2-formyl-3-hydroxy-5-oxocyclopent-1-eneheptanoic acid, characterized by an ultraviolet absorption maximum at about 228 millimicrons with a molecular extinction coefficient of about 10,100.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.N#N>O=[Mn]=O.O1CCOCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(F)cc1
Agent: O=[Mn]=O
Agent: N#N
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
(4-Chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol (224.2 mg, 0.526 mmol, Intermediate 46: step a), 1,4-dioxane (2.6 mL) and activated MnO2 (232 mg, 2.67 mmol) were combined in a round-bottom flask and the mixture was refluxed under a positive pressure of N2 overnight. The reaction was allowed to cool to ambient temperature, then filtered through Celite® and rinsed with dichloromethane. The filtrate was washed with water, and the aqueous layer was extracted with additional dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated to provide the title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1([C:16]([NH2:18])=[O:17])[CH2:15]CC[CH2:12]1)(=[O:10])=[O:9].BrC1C=CC=CC=1S(C(C)(C)C#N)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]([CH3:15])([CH3:12])[C:16]([NH2:18])=[O:17])(=[O:10])=[O:9]
Reactant: NC(=O)C1(S(=O)(=O)c2ccccc2Br)CCCC1
Agent: CC(C)(C#N)S(=O)(=O)c1ccccc1Br
Product: CC(C)(C(N)=O)S(=O)(=O)c1ccccc1Br

Procedure:
The title compound was prepared using conditions analogous to those used to make 1-(2-bromophenylsulfonyl)cyclopentanecarboxamide starting with 2-((2-bromophenyl)sulfonyl)-2-methylpropanenitrile.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:7]2[C:8](=[N:12][C:13]3[C:14]=2[NH:15][C:16]2[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=1>>[Cl:5][C:6]1[C:7]2[C:8](=[N:12][C:13]3[C:14]=2[NH:15][C:16]2[C:21]([CH:22]=3)=[CH:20][C:19]([N+:1]([O-:4])=[O:2])=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1cccc2nc3cc4ccccc4[nH]c-3c12
Product: O=[N+]([O-])c1ccc2[nH]c3c4c(Cl)cccc4nc-3cc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Fuming nitric acid (d=1.42) was added dropwise to 6-chloroindolo[3,2-b]quinoline 2.52 g (0.01 mol) at 0° C. The resulting mixture was left overnight at room temperature and then poured into ice water. Deposited crystals were collected by filteration, washed with an aqueous solution saturated with KHCO3 and recrystallized from tetrahydrofuran and CH2Cl2 to obtain 6-chloro-2nitroindolo[3,2-b]quinoline (melting point: 280° to 290° C. (decomp.)) 2.50 g (yield: 84%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]#[N:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li+].CC([N-]C(C)C)C.[CH:20]([C:22]1[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:21]>C1COCC1.CO.[NH4+].[Cl-].[Cl-].[Na+].O.CCOC(C)=O>[C:10]([C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[C:2]([CH:20]([OH:21])[C:22]3[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]4[C:23]=3[CH:24]=[CH:25][N:26]4[C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[O:1][C:5]=2[CH:6]=1)#[N:11]
Reactant: N#Cc1ccc2ccoc2c1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1cc2ccc(C#N)cc2o1
Reaction time: 0.5 h

Procedure:
To a solution of benzofuran-6-carbonitrile (CAS #: 17450-68-9) (29.7 mg, 0.207 mmol) in THF (1.7 mL), 1.8M LDA (heptane/THF/ethylbenzene, 0.125 mL, 0.225 mmol) was added at −78° C. After stirring for 30 min., a solution of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 19-D) (50 mg, 0.173 mmol) in THF (1.0 mL) was added to the reaction mixture at the same temperature. After stirring for 5 minutes the reaction mixture was diluted with MeOH (1 mL), sat. aq. NH4Cl (5 mL), brine (5 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (s, 1H) 7.68-7.80 (m, 1H) 7.60 (dd, J=8.08, 1.52 Hz, 1H) 7.52 (d, J=3.79 Hz, 1H) 6.91 (s, 1H) 6.72-6.86 (m, 2H) 6.49 (dd, J=4.80, 1.01 Hz, 1H) 6.32 (d, J=5.05 Hz, 1H) 3.85 (s, 3H) 2.53 (s, 3H) 1.51-1.61 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=1
Reactant: Cc1ccc(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)nc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)nc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
0.20 g of 5-(4-chlorophenyl)-6-methyl-4-(5-methyl-2-pyridyl)-2H-pyridazin-3-one and 3.2 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours on an oil bath of 120° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.20 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.18 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(5-methyl-2-pyridyl)pyridazine (hereinafter, described as compound (3) of the present invention.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([N+:23]([O-])=O)[C:21]=2[NH2:22])[CH:5]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:7]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:16]2[C:21]([NH2:22])=[C:20]([NH2:23])[CH:19]=[N:18][CH:17]=2)[CH:5]=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH:7]=1
Reactant: CN1CCN(Cc2cc(F)cc(-c3cncc([N+](=O)[O-])c3N)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(Cc2cc(F)cc(-c3cncc(N)c3N)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
To a solution of 3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)-5-nitropyridin-4-amine (CIV) (265 mg, 0.77 mmol) in MeOH (5 mL) was added 10% Pd/C (40 mg, 15% by wt). The solution was purged with hydrogen and stirred for 4 h at room temperature under hydrogen. The suspension was filtered through Celite and concentrated under vacuum to produce 5-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)pyridine-3,4-diamine (CV) as a tan solid (210 mg, 0.66 mmol, 86% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.32-2.40 (m, 8H), 3.51 (s, 2H), 4.71 (brs, 2H), 5.05 (brs, 2H), 7.06-7.10 (m, 2H), 7.14 (s, 1H), 7.43 (s, 1H), 7.67 (s, 1H); ESIMS found C17H22FN5 m/z 316 (M+H).