Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:24]=1[NH2:25].C(Cl)Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][C:24]1[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:23]=1[CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1c(C)cccc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (0.8 g, 2.5 mmol) and 2,6-dimethylaniline (0.45 g, 3.7 mmol) in toluene (12 ml) was heated to 90° C. and stirred 3.0 h. After cooling to room temperature, methylene chloride and water were added. The mixture was neutralized with a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated. Chromatography (SiO2 ; EtOAc) gave 0.7 g (68%) of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:36])=[O:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(OS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(OS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[(2-n-butyl-6-benzenesulphonyloxy-benzimidazol-1-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)#[N:2].[N:20]([Sn](CCCC)(CCCC)CCCC)=[N+:21]=[N-:22]>C1(C)C=CC=CC=1>[N:2]1[NH:20][N:21]=[N:22][C:1]=1[C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(CC(=O)Nc2sccc2C#N)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)Nc2sccc2-c2nn[nH]n2)cc1
Reaction time: 6 h

Procedure:
N-(3-cyanothiophen-2-yl)-2-(4-methoxyphenyl)acetamide (285 mg, 1.05 mmol), and azidotributylstannane (614 mg, 1.85 mmol) in toluene (10 ml) was placed into a preheated oil bath at 100° C. After stirring for 6 h, The solution was concentrated and directly purified by HPLC to yield N-(3-(2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide. Method [7] Retention time 4.92 min by HPLC (MH+ 316). 1H NMR (300 MHz, DMSO) δ 11.05 (s, 1H), 7.37 (d, J=6.0 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.23 (d, J=6.0 Hz, 1H), 6.94 (d, J=8.4 Hz, 2H), 3.88 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15])=[N:12][CH:13]=2)[CH:7]=1.[F:35][C:36]([F:48])([F:47])[O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C(Cl)Cl.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]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:40]3[CH:41]=[CH:42][CH:43]=[C:38]([O:37][C:36]([F:35])([F:47])[F:48])[CH:39]=3)=[CH:30][CH:29]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15])=[N:12][CH:13]=2)[CH:7]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(Br)cc2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3cccc(OC(F)(F)F)c3)cc2)cn1

Procedure:
tert-Butyl 3-(5-(5-chloro-2-(((4-bromophenyl)amino)methyl)phenyl)picolinamido)propanoate (82 mg, 0.15 mmol), (3-(trifluoromethoxy)phenyl)boronic acid (41 mg, 0.20 mmol), Pd(dppf)Cl2 (18 mg, 0.02 mmol), and K2CO3 (55 mg, 0.40 mmol) were dissolved in 1,4-dioxane (1.5 mL) and water (0.5 mL) and heated to 120° C. in the microwave. After 1 h the resulting mixture was diluted with DCM, dried (Na2SO4), filtered through CELITE, and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[CH:14]=[CH:13][C:5]=1[C:6](Cl)=[N:7]2.[NH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[CH:14]=[CH:13][C:5]=1[C:6]([NH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[N:7]2
Reactant: Cn1cc(-c2ccc3c(Cl)nc4ccnc(Cl)c4c3c2)cn1
Reactant: Nc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3c(Nc4cccnc4)nc4ccnc(Cl)c4c3c2)cn1
Temperature: 85 °C

Procedure:
To a solution of 1,6-dichloro-9-(1-methyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphthyridine (50 mg, 0.152 mmol) and 3-aminopyridine (14.30 mg, 0.152 mmol) in THF (1.5 mL), sodium tert-butoxide (43.8 mg, 0.456 mmol) was added. The reaction mixture was heated to 85° C. for 1 h. After cooling to room temperature, aqueous ammonium chloride (saturated) and ethyl acetate were added. The mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford 1-chloro-9-(1-methyl-1H-pyrazol-4-yl)-N-pyridin-3-ylbenzo[c]-1,6-naphthyridin-6-amine as a yellow solid. LRMS (APCI) calc'd for (C21H15ClN6) [M+H]+, 387.1; found 387.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[OH-].[Na+]>CCO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(OCCCCl)cc1
Yield: 97.9 %

Procedure:
A mixture of 1-chloro-3-(4-nitrophenoxy)propane (830 mg, 3.85 mmol), stannous chloride dihydrate (4.3 g, 19.25 mmol), and EtOH (20 mL) was heated under reflux for 3 hours. The mixture was cooled, 2.5N NaOH (19 mL) was added, and the precipitate was removed by filtration. The filtrate was concentrated to 10 mL and extracted with EtOAc. The extracts were dried (MgSO4) and concentrated to give 700 mg (98%) of product as a brown oil.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([CH:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13]C)=[S:12])=[N:6][N:5]=[N:4]1>O>[CH3:2][N:3]1[C:7]([CH:8]([CH3:15])[CH2:9][CH2:10][C:11]([OH:13])=[S:12])=[N:6][N:5]=[N:4]1
Reactant: COC(=S)CCC(C)c1nnnn1C
Agent: Cl
Solvent: O
Product: CC(CCC(O)=S)c1nnnn1C

Procedure:
20% aqueous Hydrochloric acid (150 ml) is added to methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiovalerate (17 g) and the mixture is refluxed for 2 hours. After cooling, the reaction mixture is diluted with water and extracted with chloroform. The chlorofom solution is washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform is distilled off to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-valeric acid, colorless liquid, nD26 =1.5133.
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]=1[C:3]1[O:4][C:5]2[C:10]([C:11](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=c1c(I)coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2nc3ccccc3[nH]2)oc2ccccc12
Temperature: 0 °C
Yield: 87.3 %

Procedure:
To an eggplant type flask (25 ml), 3-iodochromone (136 mg) prepared in Example 1, benzimidazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added and the mixture was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and the purified compound was recrystallized from benzene/hexane to give the titled compound (114.5 mg; yield=87.0 %) as white needle crystals. Melting point: 232° C. 1H-NMR(CDCl3, δ ppm): 6.59 (s, H3), 8.28 (dd, H5), 7.48-7.64 (m, H6), 7.78 (t, H7), 7.48-7.64 (m, H8), 8.48 (s, H2'), 7.86-7.94 (m, H4'), 7.45-7.50 (m, H5'), 7.45-7.50 (m, H6'), 7.86-7.94 (m, H7').
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][S:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.CCCCCC.C(OCC)(=O)C.O>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:24][C:23]3[CH:25]=[CH:26][C:20]([S:19][CH3:18])=[CH:21][CH:22]=3)[CH:7]=2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: CSc1ccc(N)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2cc(Oc3ccc([N+](=O)[O-])cc3)ncn2)cc1
Yield: 18.9 %

Procedure:
4-Chloro-6-(4-nitrophenoxy)pyrimidine (2.33 g, 9.25 mmol), 4-(methylthio)aniline (1.29 g, 9.25 mmol) and diisopropylethylamine (1.79 g, 13.9 mmol) were heated and stirred in 1-methylpyrrolidone (10 ml) at 80° C. for 18 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated saline and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:hexane=1:3), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (620 mg, 1.75 mmol, 19%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]2.B(O[O-])=[O:30].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([OH:30])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c2C1=O
Reactant: O=BO[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(O)cc(F)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of 144g (16.0 g, 40.9 mmol) in THF (200 mL) and H2O (200 mL) was added sodium perborate (26.4 g, 171.8 mmol) in one portion at RT under N2. See FIG. 3. The mixture was stirred at room temperature for 8 h. The mixture was filtered and the filtration was extracted with EtOAc (400 mL×5). The combined organic phase was washed with saturated brine (200 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=30/1, 5/1) to afford 9.50 g (82.6%) of tert-butyl 8-fluoro-6-hydroxy-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate 144h. 1H NMR (400 MHz, CDCl3) δ 6.56-6.60 (d, J=13.6 Hz, 1H), 6.49 (s, 1H), 3.83-3.86 (m, 2H), 2.82-2.84 (m, 2H), 1.49 (s, 9H), 1.20 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:27]=[CH:26][C:25]4[O:24][CH2:23][O:22][C:21]=4[CH:20]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([N+:38]([O-:40])=[O:39])=[CH:33][N:32]=1.[Cl-].[NH4+]>CN(C=O)C>[CH3:37][C:35]1[C:34]([N+:38]([O-:40])=[O:39])=[CH:33][N:32]=[C:31]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][C:19]4[CH:27]=[CH:26][C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=4)[CH2:16][CH2:17]3)=[O:11])=[CH:6][CH:7]=2)[CH:36]=1
Reactant: O=C(CCc1ccc(O)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-hydroxyphenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one (0.38 g, 1.0 mmol) was dissolved in DMF (6 mL). To the resulting solution was added 60% sodium hydride (0.05 g, 1.2 mmol) and 2-chloro-4-methyl-5-nitropyridine (0.196 g, 1.1 mmol), and the resulting reaction solution was stirred overnight at room temperature. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield the intermediate product 3-(4-(4-methyl-5-nitropyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one. The 3-(4-(4-methyl-5-nitropyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one was dissolved in a mixed solvent consisting of ethanol (4 mL) and dioxane (1 mL). To this solution was added 10% palladium-carbon (0.034 g), and the resulting solution was subjected to catalytic reduction for 8 hours at atmospheric pressure and room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:methanol=20:1), to thereby yield 0.22 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)N5CCCCC5)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
In a dried reaction flask, the crude 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (Compound 1) (0.4 g, about 0.9 mmol), piperidine (0.18 mL, 1.818 mmol), DIEA (0.18 mL, 1.04 mmol) and HATU (0.342 g, 0.9 mmol) were added to a mixed solvent of DMF (4.5 mL) and dichloromethane (4.5 mL). The mixture was stirred at room temperature for 3 hr. Water was added. The mixture was filtered to obtain a crude yellow solid, which was washed with methanol to produce a purified product (0.375 g) in 85.4% yield.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1>[Fe](Cl)(Cl)Cl>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(C)cc1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Product: Cc1ccc(C)c(Cc2ccccc2)c1
Reaction time: 3 h

Procedure:
63.3 Parts of benzyl chloride at 20° are slowly added during 2 hours to a mixture of 1 part of iron (III) chloride and 531 parts of p-xylene held at a temperature of 115°-120° C. The rate of hydrogen chloride evolution is found to be directly proportional to the rate of benzyl chloride addition. After addition, the mixture is held at 120° C. for 3 hours then filtered to remove insoluble matter, and the unreacted p-xylene (406 parts) removed by atmospheric distillation at 135°-145° C. The residue is distilled under reduced pressure at 2-3 mm Hg and a further fraction of p-xylene (64 parts) is obtained at 30°-40° C. The total recovery of p-xylene is 470 parts (98% recovery). The product, 2,5-dimethyldiphenylmethane is obtained at 126°-134° C.: yield 80 parts (82% of theory). A residue of 10.1 parts of polymer remains after distillation.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CO.CCOC(C)=O>[CH3:23][S:24]([O:13][CH2:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1cc(-c2ccccc2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 5-phenylisoxazole-3-carbaldehyde (500 mg, 2.89 mmol) in MeOH (10 mL) at 0° C., was added NaBH4 (327 mg, 8.67 mmol). The reaction was slowly warmed to room temperature, stirred for 15 h and concentrated in vacuo. The solid obtained was dissolved in EtOAc, washed with H2O (1×) and saturated NH4Cl (3×). The organic layers were combined, dried over MgSO4, filtered, concentrated and dissolved in anhydrous CH2Cl2 (8 mL). The mixture was cooled to 0° C., followed by addition of Et3N (1.02 mL, 7.25 mmol) and methanesulfonyl chloride (337 μL, 4.35 mmol). The reaction was slowly warmed to room temperature and stirred for 15 h. Upon completion, the reaction was quenched with aqueous NaHCO3 (5 mL) and extracted with EtOAc. The combined organic layers were washed with NaHCO3 (2×), dried over MgSO4, filtered, concentrated and carried onto the next step without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1F)[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN1CCCN(C)C1=O.C(#N)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH:15]=[O:16]
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Solvent: CC#N
Product: O=Cc1ccc(N2CCC3(CC2)OCCO3)c(Br)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4.5]decane (6.87 g, 48 mmol), 3-bromo-4-fluorobenzaldehyde (8.12 g, 40 mmol), and potassium carbonate (6.63 g, 48 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12 mL) and acetonitrile (8 mL) was heated at 80° C. under N2 atmosphere for one day. Reaction mixture was cooled down to room temperature and poured onto water (150 mL). The mixture was extracted with methylene chloride. The organic layer was dried (MgSO4) and concentrated to give the title compound as an off-white solid (12.4 g, 96%); mp 63–64° C.; 1H NMR (300 MHz, CDCl3) δ 1.93 (t, J=5.7 Hz, 4H), 3.25 (t, J=5.4 Hz, 4H); 4.02 (s, 4H), 7.12 (d, J=4.2 Hz, 1H), 7.75 (dd, J=8.4, 2.1 Hz, 2H), 8.06 (d, J=1.8 Hz, 1H), 9.84 (s, 1H); MS (ES) m/z: 325.7 (MH+); HRMS Calcd. for C14H16BrNO3 (MH+): 325.0314. Found: 325.0288.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[N:13]=2)[C:8](=[O:16])[C:7]([C:17]([OH:19])=O)=[CH:6]1.[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[N:13]=2)[C:8](=[O:16])[C:7]([C:17]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:19])=[CH:6]1
Reactant: Nc1nnn[nH]1
Reactant: COCCn1cc(C(=O)O)c(=O)c2ccc(C)nc21
Solvent: CN(C)C=O
Product: COCCn1cc(C(=O)Nc2nnn[nH]2)c(=O)c2ccc(C)nc21
Reaction time: 2 h

Procedure:
1,4-Dihydro-1-(2-methoxyethyl)-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.5 g) and N,N'-carbonyldiimidazole (0.31 g) in dimethylformamide (50 ml) were warmed at 60° for 1 hour. 5-Amino-1H-tetrazol (0.16 g) was added and the solution was stirred at 60° for 2 hours and cooled. The solid was collected and crystallised from dimethylformamide and had m.p. 245°-246° (d).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][C:7]1[N+:8]([O-])=[C:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]>C(Cl)Cl>[Cl:3][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: COC(=O)c1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
POCl3 (2.23 mL, 24.3 mmol) was added dropwise to a stirred solution of N-oxide 1 (5.0 g, 20.2 mmol) in dry DCM (100 mL) and the mixture stirred at 40° C. for 16 h. The solution was poured into a slurry of ice/1 M NaOH solution (100 mL) and the mixture stirred for 10 min. The mixture was extracted with DCM (3×50 mL), the combined organic extract dried and the solvent evaporated. The residue was purified by column chromatography, eluting with 20% EtOAc/pet. ether, to give benzoate 2 (4.12 g, 77%) as a white powder: mp (EtOAc) 127-128° C.; 1H NMR (CDCl3) δ 8.06-8.12 (m, 4H, H-2, H-3, H-5, H-6), 4.56 (s, 2H, CH2Cl), 3.94 (s, 3H, OCH3), 2.45 (s, 3H, CH3); MS m/z 266.6 (MH+, 100%). Anal. calcd for C13H12ClNO3: C, 58.77; H, 4.55; N, 5.27. Found: C, 58.82; H, 4.43; N, 5.18%.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][CH:6]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[CH:21])=[C:14]([O:22][CH3:23])[CH:13]=1)=[O:8].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH2:1]([O:5][CH:6]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[CH:21])=[C:14]([O:22][CH3:23])[CH:13]=1)=[O:8])[CH:2]=[CH2:3]
Reactant: C#CCOc1ccc(CCNC(=O)C(O)Cc2ccc(C)cc2)cc1OC
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOc1ccc(CCNC(=O)C(Cc2ccc(C)cc2)OCC=C)cc1OC
Reaction time: 16 h

Procedure:
Allyl bromide (1.2 g, 10 mmol) is added slowly at room temperature to a mixture of 2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-3-p-tolyl-propionamide (3.0 g, 8.2 mmol), 30% sodium hydroxide solution (6.5 ml, 41 mmol) and catalytic amounts of tetrabutylammonium bromide (50 mg) in 30 ml of dichloromethane. The reaction is stirred for 16 hours at +40° C. Subsequently the mixture is evaporated and the residue is diluted with water and dichloromethane. The phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated. The remaining oil is purified by chromatography on silica gel (ethyl acetate/hexane 1:1) to give 2-allyloxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-3-p-tolyl-propionamide (E1.17).