Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([SH:11])[C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[S:22](Br)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(C)(C)c1cc2nc(N)sc2cc1S
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Sc2cc3sc(N)nc3cc2C(C)(C)C)cc1

Procedure:
The title compound was prepared according to General Method 15 using 2-amino-5-tert-butyl-benzothiazole-6-thiol (7.0 g, 29 mmol), pyridine (2.3 g, 29 mmol), tosyl bromide (6.9 g, 29 mmol), carbon tetrachloride (100 mL), and EtOAc (100 mL). The crude reaction mixture was purified by flash chromatography (5% EtOAc in hexanes to 50% EtOAc in hexanes as eluents). MS(APCI): 393 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[CH3:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[N:32]=[N:33][C:29]([CH3:28])=[N:30]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: Cc1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3nnc(C)n3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, pale yellow oil, MS: m/e=458.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 5-methyl-1H-tetrazole.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:34][CH3:35])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)[CH3:21]>C(#N)C>[CH2:34]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH3:35]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CCOCCC1CCCCN1
Solvent: CC#N
Product: CCN(CC)CCOCCC1CCCCN1C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 79 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[2-(diethylamino)ethoxy]ethyl]piperidine (b.p.0.4 mmHg 95°-99° C.) in a yield of 79% of theory. Colourless crystals, m.p. 134°-136° C. (acetonitrile).
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1([S:15]/[CH:16]=[C:17]2/[C:18](=[O:23])[O:19][CH2:20][CH2:21][CH2:22]/2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(Cl)Cl>[OH:19][CH2:20][CH2:21][CH2:22]/[C:17](=[CH:16]\[S:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[C:18]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:23]
Reactant: Nc1ccccc1
Reactant: O=C1OCCC/C1=C\Sc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Nc1ccccc1)/C(=C/Sc1ccccc1)CCCO
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
6.4 ml of diethylalumiun chloride (1 mol/1 of hexane solution) was added to 10 ml of methylene chloride solution including 0.6 g of aniline at room temperature. After stirring for 5 minutes, methylene chloride solution including 1.28 g of (E)-3-(phenylthiomethylene)tetrahydro-2H-pyran-2-one was dropped into the resulting solution. After stirring at room temperature for 2 hours, the solution was added with 10% hydrochloric acid, then stirred at room temperature for 30 minutes. The solution was extracted with ethyl acetate, and the organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.64 g of the title compound.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12](=[O:15])([O-])[O-:13].[K+].[K+].C[NH:19][CH2:20][CH2:21]NC>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu](I)I>[O:15]=[C:12]1[N:19]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:21][O:13]1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CNCCNC
Reactant: O=C([O-])[O-]
Agent: I[Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCOC2=O)cc1
Temperature: 150 °C

Procedure:
A mixture of 1 g of methyl 4-iodobenzoate, 399 mg of 2-oxozolidone, 1.1 g of potassium carbonate, 34 mg of N,N′-dimethylethylenediamine and 73 mg of copper iodide in 10 mL of toluene was heated to 150° C. in a sealed microwave reactor for 2 h. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (20-70% ethyl acetate/hexane) to afford methyl 4-(2-oxooxazolidin-3-yl)benzoate. 530 mg of methyl 4-(2-oxooxazolidin-3-yl)benzoate was hydrolyzed via Procedure M to give 4-(2-oxooxazolidin-3-yl)benzoic acid. 70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-oxooxazolidin-3-yl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxooxazolidin-3-yl)benzamide. MS (Q1) 394.2 (M)+.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([OH:16])[CH:8]=1)[CH3:6])C.[OH-].[Na+].C(O)(=O)C>CCO.O>[OH:16][C:9]1[CH:8]=[C:7]([CH:5]([CH3:6])[C:4]([OH:17])=[O:3])[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 45 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(3-Hydroxy-4-nitro-phenyl)-propionic acid ethyl ester (1.48 g) in 90% aq. EtOH was added NaOH (1.24 g) at room temperature. After stirred for 14 h at 45° C., the reaction mixture was cooled to room temperature, diluted with water. The resulting aqueous layer was acidified with acetic acid and then extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. (1.30 mg, 99.5%, yellow solid)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[CH3:10])[C:5]([C:36](O)=[O:37])=[CH:4][N:3]=1.[CH2:39]([N:41]=[C:42]=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.CNC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[CH3:10])[C:5]([C:36]([N:41]([CH3:42])[CH3:39])=[O:37])=[CH:4][N:3]=1
Reactant: COc1cc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C(=O)O)n(-c4ccccc4)c(=O)c23)ccn1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C(=O)N(C)C)n(-c4ccccc4)c(=O)c23)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-amino-4-((1-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)-pyrimidine-5-carboxylic acid (44 mg, 0.087 mmol) in anhydrous N,N-dimethylmethanamide (3 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (25 mg, 0.13 mmol) and hydroxybenzotriazole (18 mg, 0.13 mmol) were added and the resulting mixture was stirred at RT for 30 min. To this mixture, dimethylamine (2M in THF, 0.065 mL, 0.13 mmol) and N,N-diisopropylethylamine (0.040 mL, 0.19 mmol) were added and the reaction mixture was stirred at RT for 3 h. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product 112, (S)-2-amino-4-((1-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)-N,N-dimethylpyrimidine-5-carboxamide. ESI-MS m/z: 533.8 [M−H]
Reaction SMILES: [C:1]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11](SC)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.CCN(C(C)C)C(C)C.[CH3:42][N:43]1[CH2:48][CH2:47][N:46]([C:49]2[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=2)[CH2:45][CH2:44]1>ClCCl>[C:1]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]([NH:53][C:52]2[CH:51]=[CH:50][C:49]([N:46]3[CH2:45][CH2:44][N:43]([CH3:42])[CH2:48][CH2:47]3)=[CH:55][CH:54]=2)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cnc(SC)nc1C(=O)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1ccccc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of Example 3A (200 mg, 0.661 mmol) in dichloromethane (2.2 mL) was added meta-chloroperoxybenzoic acid (179 mg, 0.728 mmol) in a single portion. After 1 hour, the reaction mixture was partitioned between 10% sodium thiosulfate solution and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL). Hunig's base (231 μl, 1.323 mmol) and 4-(4-methylpiperazin-1-yl)aniline (127 mg, 0.661 mmol) were added to the solution, and the reaction was heated to 45° C. for 3 hours. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was concentrated under reduced pressure. The crude residue was purified by MPLC (10 g SiO2), eluting with dichloromethane to 10% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 446.3 [M+H]+.
Reaction SMILES: ClS(O)(=O)=O.C1([C:12]2[C:13](=[O:23])[O:14][CH2:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C=CC=CC=1>ClCCl>[C:17]1([C:16]2[CH2:15][O:14][C:13](=[O:23])[CH:12]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OCC(c2ccccc2)=C1c1ccccc1
Agent: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=C1C=C(c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To 20 mL of stirring chlorosulfonic acid cooled to -5° C. was added 3,4-diphenyl-2-(5H)-furanone (Step 1) (3.160 g, 13.4 mmol) portionwise over 30 minutes. The solution was warmed to room temperature and maintained at that temperature for 16 hours. The reaction mixture was diluted with dichloromethane and quenched into ice water. The phases were separated and the aqueous phase extracted with dichloromethane, the combined dichloromethane extract was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was diluted with dichloromethane and added to excess concentrated NH4OH. The mixture was stirred for 1 hour. The phases were separated and the aqueous phase was extracted with dichloromethane. The organic extract was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a white solid that was crystallized from aqueous ethanol to afford pure 3-[(4-aminosulfonyl)phenyl)]-4-phenyl-2-(5H)-furanone (2.110 g, 50%): mp 225.5-226.5° C. 1H NMR (CDCl3 /300 MHz) 7.79 (d, 2H, J=8.4 Hz), 7.41 (d, 2H, J=8.4 Hz), 6.38 (brs, 2H), 5.09 (s, 2H). FABLRMS m/z 316 (m+H). Anal. Calc'd for C16H13NO4S: C, 60.94; H, 4.16; N, 4.44. Found: C, 60.86; H, 4.18; N, 4.40.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[N:30][CH:31]=1>>[CH:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[N:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:23])[CH3:24]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(C)C)cc3)ccc2[nH]1
Reactant: CC(C)Oc1ccc(Br)cn1
Product: CC(C)Oc1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(OC(C)C)nc2)cc1

Procedure:
The title compound was prepared in accordance with Example 10 using 5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester and 5-bromo-2-isopropoxypyridine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][CH:14]1[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]1.[OH-].[Na+]>C(O)(C)C.O>[OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2CCO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: OCCn1c(NC2CCNCC2)nc2ccccc21
Reaction time: 36 h

Procedure:
Combine (1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine (5.0 mmol) and sodium hydroxide (2.0 g) in isopropanol (20 mL) and water (0.1 mL). Heat to reflux. After 36 hours, cool and evaporate the reaction mixture in vacuo to give a residue. Combine the residue and water. Extract the diluted residue three times with ethyl acetate. Combine the organic layers and extract with brine, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[F:51][C:52]([F:63])([F:62])[C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[CH2:56]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][CH2:56][C:55]2[CH:59]=[CH:60][CH:61]=[C:53]([C:52]([F:51])([F:62])[F:63])[CH:54]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCc4cccc(C(F)(F)F)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 77.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (68 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (125 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-trifluoromethylphenethyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (88 mg, yield 73%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[C:9]([O:19][CH3:20])[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>C(O)C>[CH3:20][O:19][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]
Reactant: COC(=O)c1cccc(OC)c1-c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1-c1c(OC)cccc1C(=O)O
Yield: 96.3 %

Procedure:
A stirred mixture of 188.4 mg (0.69 mmol) of ester prepared in Step A and 0.28 mL (1.39 mmol) of 5N NaOH in 2 mL of ethanol was refluxed under nitrogen for 1.5 hours. The mixture was partitioned between EtOAc, ice, 2N HCl, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 171.6 mg of the title acid which was used without further purification.
Reaction SMILES: Cl.[C@H:2]12[CH2:18][C@H:5]([N:6]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][CH:9]=3)[CH2:7]1)[CH2:4][NH:3]2.C(N(C(C)C)CC)(C)C.[C:28](Cl)(=[O:34])/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH3:33]>ClCCl>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:6]2[CH2:7][C@@H:2]3[CH2:18][C@H:5]2[CH2:4][N:3]3[C:28](=[O:34])/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH3:33])=[CH:9][CH:10]=1
Reactant: c1ccc2c(N3C[C@@H]4C[C@H]3CN4)ccnc2c1
Reactant: CCC/C=C/C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC/C=C/C(=O)N1C[C@@H]2C[C@H]1CN2c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28 %

Procedure:
To 4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-5-yl]quinoline hydrochloride (26.2 mg, 0.1 mmol), dissolved in 0.5 ml anhydrous dichloromethane, polymer-supported diisopropylethylamine (80 mg, 3-4 mmol/g) was added followed by (E)-hex-2-enoyl chloride (19.9 mg, 0.15 mmol) dissolved in anhydrous dichloromethane (1 ml). The mixture was shaken at room temperature for 20 minutes, filtered and the filtrate evaporated to dryness under reduced pressure. The raw product was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 9 mg of a solid (0.028 mmol, 28%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2B(O)O)[CH:35]=[CH:34][CH:33]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:41]=2[N:32]=[CH:33][CH:34]=[CH:35]3)[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=1
Reactant: OB(O)c1cccc2cccnc12
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1cccc2cccnc12
Yield: 54.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and quinolin-8-ylboronic acid (0.086 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.057 g (52%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[C:16]2[CH2:24][C:23]3[C:18](=[CH:19][C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=3)[C:17]2=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O-])([O-])=O.[Cs+].[Cs+].CI>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[C:16]2[CH2:24][C:23]3[C:18](=[CH:19][C:20]([C:25]([O:27][CH3:29])=[O:26])=[CH:21][CH:22]=3)[C:17]2=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=C2Cc3ccc(C(=O)O)cc3C2=O)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)C(=O)C(=CCC1CCN(C(=O)OC(C)(C)C)CC1)C2

Procedure:
A slurry of 2-1 (4.5 g, 11.7 mmol) in CH3OH (120 mL) was treated with Cs2CO3 (1.9 g, 5.85 mmol) to give a homogenous solution. The solvent was removed in vacuo and the resulting solid was dissolved in DMF (120 mL) and treated with methyliodide (0.72 mL, 11.7 mmol) at room temperature for 18 h. The solution was diluted with EtOAc and washed with H2O, sat. NaHCO3 and brine. The organic layer was dried (MgSO4), filtered, concentrated, and chromatographed (30% EtOAc/Hexanes) to give 2-2 as a white solid. Rf (30% EtOAc/Hexanes) 0.15 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.28 (d, 1H), 7.58 (d, 1H), 6.94 (m, 1H), 4.1 (bd, 2H), 3.93 (s, 3H), 3.7 (s, 2H), 2.7 (bt, 2H), 2.28 (t, 2H), 1.7 (m, 3H), 1.45 (m, 9H), 1.2 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11](OCC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=C/CCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C/C=C/CCc1ccccc1
Reaction time: 3 h

Procedure:
A solution of (E)-ethyl 5-phenylpent-2-enoate (732 mg) in dry toluene (5 ml) was cooled to −78° C. DIBAL-H (1 M in hexanes, 7.17 ml) was added dropwise and the mixture was stirred for 3 h. A second portion of DIBAL-H (1 M in hexanes, 0.717 ml) was added and stirring was continued for another 3 h. The mixture was allowed to warm-up to RT and hydrolyzed with 1 M aqueous HCl (5 ml). Additional 3M aqueous HCl was added until pH=1 and the aqueous layer was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was dissolved in dichloromethane (5 ml) and TEMPO (28.0 mg), potassium bromide (42.6 mg) and water (5 ml) were added. Aqueous sodium hypochlorite solution (13%, 1.642 ml) was added dropwise. The mixture was stirred at room temperature for 15 h. After phase separation the aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with 1 M HCl, water and brine, dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography to yield a slightly orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH:27]([CH2:31][C:32]([OH:34])=[O:33])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:28]2[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24])[CH2:26][CH:27]2[CH2:31][C:32]([OH:34])=[O:33])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNC(CC(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Br)ccc2[N+](=O)[O-])C(CC(=O)O)C1
Temperature: 70 °C

Procedure:
4-Bromo-2-fluoro-1-nitrobenzene (5.3 g, 24.1 mmol) was dissolved in acetonitrile (70 mL) and water (10 mL). To this mixture, potassium carbonate (10 g, 72.3 mmol) and 2-(4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (7.1 g, 28.9 mmol) were added. The resulting mixture was heated at 70° C. for 2 days. The mixture thus obtained was concentrated and ethyl acetate was added. 1 N HCl was then added slowly to the reaction solution until pH=6. The water layer was separated and washed multiple times with ethyl acetate. The organic layers thus obtained were combined and concentrated. The crude material thus obtained was purified by silica gel chromatography eluting with a gradient of 0% to 10% of methanol in dichloromethane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.28 (br s), 7.71-7.83 (m, 1H), 7.56-7.66 (m, 1H), 7.30-7.40 (m, 1H), 3.56-3.82 (m, 3H), 3.33-3.44 (m, 1H), 2.99-3.24 (m, 2H), 2.87 (m, 1H), 2.32-2.47 (m, 1H), 2.17-2.29 (m, 1H), 1.32-1.51 (s, 9H); MS (DCI+) m/z 444.1 (M+H)+.