Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:24]([O:35][CH:36]([CH3:38])[CH3:37])[CH:23]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:24]([O:35][CH:36]([CH3:38])[CH3:37])[CH:23]=2)=[CH:9][CH:8]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: CCOC(=O)CCc1ccc(O)cc1OC(C)C
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(OC(C)C)c2)cc1)c1ccccc1
Yield: 13.73 %

Procedure:
Compound 60 was synthesized from (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone O-methyloxime (0.268 g, 0.99 mmol) and ethyl 3-(4-hydroxy-2-isopropoxyphenyl)propanoate (0.25 g, 0.99 mmol) by following the procedure described in scheme 15 (0.04 g, yield: 13.73%); Purity: 97.21%.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[N:3]=1.P(Cl)(Cl)([Cl:22])=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:22][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(-c2ccccc2C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cnc(-c2ccccc2C)nc1Cl
Temperature: -5 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A solution of 4.00 g of ethyl 4-hydroxy-2-o-tolylpyrimidine-5-carboxylate (15.5 mmol) in 11.6 mL of phosphorous oxychloride (124 mmol) was heated to reflux (calcium chloride filled tube as protection from the outside atmosphere). After 3 h, the excess POCl3 was removed by distillation (˜20 Torr, 90-100° C. oil bath). The residual red oil on cooling solidified. The solids were pulverized and covered with 100 mL of EtOAc. The slurry was cooled to −5° C. and agitated vigorously for 10 min with 25 mL of a potassium carbonate solution (2 M, 50 mmol). The resulting organic phase was separated, dried (MgSO4), filtered and evaporated to give, after triturating in hexanes, the title compound as a light orange solid, 3.58 g, 84% yield.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:16][C@@H:5]2[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][C@@H:4]2[CH2:3]1.C(O)(C(F)(F)F)=O.[OH-]>CO>[CH3:1][C:2]1[CH2:3][C@H:4]2[CH2:8][NH:7][CH2:6][C@H:5]2[CH:16]=1
Reactant: C=C1C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2C1
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC1=C[C@@H]2CNC[C@@H]2C1
Reaction time: 0.5 h
Yield: 148 %

Procedure:
(3aR,6aS)-tert-Butyl 5-methylenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Tetrahedron 1993, 49(23), 5047-54) (114 mg, 0.51 mmol) was taken into a minimum of neat TFA and the solution was allowed to stand for 30 minutes at room temperature. The mixture was then concentrated and the residue taken into methanol and concentrated again then dried. The residue thus obtained was taken into methanol (5 mL) and basified using Bio-Rad AG-1X hydroxide form resin. The mixture was then filtered and concentrated and dried to give impure (±)-(3aR,6aS)-5-methyl-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (93 mg) as an amorphous residue that was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][C:12](=[O:14])[CH3:13])=[C:4]([O:15][CH3:16])[CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[K+]>O1CCOCC1>[CH3:16][O:15][C:4]1[CH:3]=[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: C1COCCN1
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1NC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: COc1cc(N2CCOCC2)cc([N+](=O)[O-])c1NC(C)=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A mixture of N-(4-bromo-2-methoxy-6-nitrophenyl)acetamide (2.89 g), morpholine (2.61 g), BINAP (1.21 g) and t-BuOK (1.53 g) in dioxane (50 mL) was degassed with N2 and the mixture was stirred at 110° C. in a sealed tube overnight. It was cooled to room temperature and filtered. The filtrate was concentrated in-vacuo. The residue was purified by silica gel chromatography eluted with MeOH/DCM=1/50 to afford the desired product (1.03 g, 35%) 1H NMR (300 MHz, CDCl3) δ ppm 2.15 (s, 1H), 3.18 (t, 4H, J=4.8 Hz), 3.85 (t, 4H, J=4.8 Hz), 3.88 (s, 3H), 6.63 (d, 1H, J=2.7 Hz), 6.96 (d, 1H, J=2.7 Hz).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]([Cl:17])=[C:15]([Cl:18])[C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=1)C>[OH-].[Na+].C(O)C>[Cl:17][C:16]1[C:7]([O:6][CH2:5][C:4]([OH:19])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([CH3:14])[S:11][C:10]=2[C:15]=1[Cl:18]
Reactant: CCOC(=O)COc1cc2cc(C)sc2c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A mixture of 2.6 g of ethyl[(6,7-dichloro-2-methylbenzo[b]thien-5-yl)oxy]acetate in 20 ml of 20% sodium hydroxide solution and 20 ml of ethanol is warmed on a steam bath for 1 hour. The cooled mixture is concentrated in vacuo to remove the ethanol and the aqueous mixture is acidified with conc. hydrochloric acid to pH 2. After stirring at room temperature for 2 hours, the solid collected on a filter, dried and recrystallized from acetone-hexane to give 2.0 g of [(6,7-dichloro-2-methylbenzo[b]thien-5-yl)oxy]acetic acid as white needles, mp 215°-216°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[S:16]([O:8][C:7]1[C:2]([NH:1][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[CH:3][C:4]([CH3:9])=[CH:5][CH:6]=1)([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(O)c(N)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(C)ccc2OS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-amino-p-cresol (12.3 g, 0.10 mol) in 125 ml of pyridine was added p-toluenesulfonyl chloride (38.1 g, 0.20 mol) in one portion. Stirring was continued overnight at ambient temperature. TLC now indicated no starting material, but there were two products. Another 7.6 g (20 percent excess) of p-toluenesulfonyl chloride was added and stirring continued for 6 hours. The reaction was poured into excess hydrochloric acid and stirred until completely solidified. The tan solid precipitate was filtered, washed with water and nearly dried. The damp filter cake was dissolved in one liter of boiling ethanol and let stand overnight at ambient temperature. Yield 33.0 g (76 percent) of crystals. NMR was consistent for the product.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:49][CH2:50][F:51])(=O)=O.O>CN(C=O)C>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH2:49][CH2:50][F:51])[CH2:35][CH2:36]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Reactant: CS(=O)(=O)OCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCN(CCF)CC5)cn4)sc23)c(F)c1)NC1CC1
Temperature: 80 °C

Procedure:
To a solution of 49 (70 mg, 0.111 mmol, scheme 26) in DMF (2 mL) were added K2CO3 (77 mg, 0.555 mmol) and 419 (79 mg, 0.555 mmol). The mixture was heated to 80° C. for 16 hours. Water was added to form a precipitate that was collected by filtration, rinsed with water and purified via Biotage [linear gradient 0-20%, (methanol/dichloromethane; SiliaFlash 10 g cartridge]. Title compound 420 was obtained as a white solid (38.9 mg, 62% yield). 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.68 (s, 1H), 8.53 (d, J=1.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 7.85 (dd, J=8.1, 2.0 Hz, 1H), 7.72 (dd, J=13.5, 2.4 Hz, 1H), 7.37 (t, J=9.0 Hz, 1H), 7.22-7.17 (m, 1H), 6.64 (d, J=5.4 Hz, 1H), 6.54 (bd, J=2.3 Hz, 1H), 4.55 (t, J=4.9 Hz, 1H), 4.45 (t, J=4.9 Hz, 1H), 3.54 (s, 2H), 2.89-2.83 (m, 2H), 2.62 (t, J=5.0 Hz, 1H), 2.59-2.51 (m, 1H), 2.56 (t, J=5.1 Hz, 1H), 2.50-2.32 (m, 8H), 0.68-0.62 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 565.23 (M+H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1cccs1
Product: Cc1ccc(-c2cccs2)cc1

Procedure:
2-Bromothiophene and 4-methylphenylboronic acid were treated in a manner similar to Reference Example 20-(1) to give the target compound.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Br:11]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:11][C:7]1[CH:6]=[CH:5][C:4]([O:8][CH3:9])=[CH:3][C:2]=1[CH:1]=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C=O)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.7 %

Procedure:
To a solution of m-anisaldehyde (55.4 g, 0.41 mol) in DMF (400 mL) was added a solution of N-bromosuccinimide (124.0 g, 0.69 mol) dropwise at room temperature. After the addition, the reaction solution was stirred at room temperature for 12 h, then poured into a mixture of ice and water and stirred for 10 min. The precipitate was collected by filtration and dissolved in ethyl acetate. The resulting solution was washed with water (2×) and brine, dried over sodium sulfate and concentrated in vacuo to give Compound 19 (76.4 g, 87%) as an off-white solid: 1H NMR (CDCl3, 500 MHz) δ 10.32 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.42 (d, J=3.5 Hz, 1H), 7.04 (dd, J=9.0, 3.0 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH:16]([OH:18])[C:15](=[O:19])[C:14]([CH3:20])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:21]COC)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl>CO.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH:16]([OH:18])[C:15](=[O:19])[C:14]([CH3:20])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(O)C2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC12Cc3cc(O)ccc3C1=C(C)C(=O)C(O)C2
Temperature: 80 °C

Procedure:
A solution of (2SR,9aRS)-9a-butyl-2-hydroxy-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (73 mg, 0.22 mmol) in methanol (5 mL) was placed under a nitrogen atmosphere, treated with 2N aqueous HCl (0.33 mL, 0.66 mmol), and stirred with heating in an oil bath at 80° C. for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with 5% aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under vacuum to an oil. The crude product was purified by PLC on a 0.1×20×20 cm silica gel GF plate, developing twice with 4:1 hexanes-EtOAc. The band at Rf 0.12-0.20 was eluted with EtOAc and the eluant evaporated under vacuum to a gum (50 mg). This material crystallized from benzene to afford (2SR,9aRS)-9a-butyl-2,7-dihydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.O>[CH2:33]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)OC(CCN1CCN(c2ccc(OCc3ccccc3)cc2)CC1)c1ccccc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
The compound ‘carbamic acid 3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-1-phenyl-propyl ester (2 mmol) prepared in Example 84 was dissolved in tetrahydrofuran (25 mL), and potassium carbonate (K2CO3, 2.4 mmol) and benzylbromide (2.4 mmol) were added thereto, and the resulting mixture was stirred at 70° C. for 10 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].C([Li])CCC.[CH:15](N1CCCCC1)=[O:16]>O1CCCC1.CCCCCC>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH:15]=[O:16])=[CH2:5]
Reactant: C=Cc1ccccc1Br
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccccc1C=O
Temperature: -65 °C

Procedure:
To a solution of 2-bromostyrene (115 mmol) in dry tetrahydrofuran (200 ml) at -65° C. under nitrogen was added dropwise n-butyllithium (115 mmol) in hexane. The reaction mixture was stirred at -65° C. for an additional hour and a solution of N-formylpiperidine (125 mmol) in tetrahydrofuran (50 ml) was added dropwise. The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was cooled to 0° C. and then quenched with saturated ammonium chloride (50 ml). The reaction mixture was extracted with diethyl ether (2×50 ml) and the combined organic phases were washed with 3N hydrochloric acid (2×50 ml), saturated aqueous sodium bicarbonate (50 ml), and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield the Compound 2a which was directly used in the next reaction.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([B:25]([OH:27])[OH:26])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[Cl:38][C:39]1[C:40]2[C:50]([F:51])=[CH:49][CH:48]=[C:47]([F:52])[C:41]=2[S:42][C:43]=1[C:44](Cl)=[O:45]>C(Cl)Cl>[C:1]([N:8]([CH3:28])[CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH2:16][C:17]2[CH:18]=[C:19]([B:25]([OH:26])[OH:27])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:44]([C:43]2[S:42][C:41]3[C:47]([F:52])=[CH:48][CH:49]=[C:50]([F:51])[C:40]=3[C:39]=2[Cl:38])=[O:45])[CH2:13][CH2:14]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of boronic acid 4 (7.60 g, 19.4 mmol) in DCM (300 mL) at 0° C. is treated with DIPEA (7.40 mL, 42.7 mmol), followed by acid chloride 8 (6.21 g, 23.3 mmol) in one portion. After warming to RT, the solution is stirred 3 h. Analysis by LC/MS at this juncture confirmed the reaction is complete. Thus the solvent is removed in vacuo and the residue purified by chromatography (gradient elution—60% EtOAc in heptane with 0.5% triethylamine increasing to neat EtOAc with 0.5% triethylamine, then 10-20% MeOH in EtOAc with 0.5% triethylamine) to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:22])[CH2:20][CH2:19][C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1ccco1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccco1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
A solution of 1-benzylpiperazine (352 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-(furan-2-yl)propionyl chloride (396.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:2). The fractions containing the 1-(4-benzylpiperazin-1-yl)-3-(furan-2-yl)propan-1-one are collected and the solvent is removed in vacuo to give 497 mg of colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[F:13][C:14]([F:25])([F:24])[CH2:15][S:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([S:16][CH2:15][C:14]([F:25])([F:24])[F:13])[N:22]=1)=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccnc(SCC(F)(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccnc(SCC(F)(F)F)n1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-nitrobenzoyl chloride (1.85 g, 10 mmol) in CH2Cl2 (10 mL) was slowly added to a solution of 2-(2,2,2-trifluoro-ethylsulfanyl)-pyrimidin-4-ylamine (2.1 g, 10 mmol) and triethylamine (2 g, 20 mmol) in CH2Cl2 (80 mL) between 0 and max 7° C. The mixture was stirred overnight at room temperature and then poured into ice-water. The phases were separated and the organic part was dried with Na2SO4, filtered and concentrated in vacuo to provide a viscous oil. The crude product was purified by prep-HPLC (1.5 g, 41.8%).
Reaction SMILES: Br.CO[C:4]1[O:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1.[OH-:15].[K+].Cl>O.C(O)(=O)C>[OH:15][C:12]1[CH:13]=[CH:14][C:6]2[O:5][CH2:4][CH2:9][C:8](=[O:10])[C:7]=2[CH:11]=1
Reactant: [OH-]
Reactant: COc1cc(=O)c2ccccc2o1
Agent: Br
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCOc2ccc(O)cc21
Yield: 81.2 %

Procedure:
Glacial acetic acid and HBr (>40%) each 20 ml are successively added to methoxy benzopyran-4-one 2.9 g (0.0163 mol), stirred and refluxed for 1 h, and then the reactant liquor is modulated pH for 10-11 by KOH, the water layer is modulated pH for 2-3 by concentrated hydrochloric acid, and then extracted by ethyl acetate; the organic layers are combined and dried over anhydrous Na2SO4, cooled to precipitate black solid, and recrystallized by ethyl acetate, to obtain bright yellow crystal 2.17 g, m.p.: 142-144° C., yield: 81.2%.
Reaction SMILES: [BrH:1].C(O)(=O)C.[CH2:6]([S:8][C:9]1[C:18]([O:19]C)=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][N:12]([CH3:14])[CH3:13])[CH3:7]>C(OCC)C>[BrH:1].[CH3:14][N:12]([CH2:11][C:10]1[C:9]([S:8][CH2:6][CH3:7])=[C:18]([OH:19])[CH:17]=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCSc1c(CN(C)C)cccc1OC
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCSc1c(O)cccc1CN(C)C
Temperature: 100 °C
Reaction time: 17 h

Procedure:
30% Hydrogen bromide in acetic acid (3.6 mL, 18.05 mmol) was added to (2-ethylsulfanyl-3-methoxybenzyl)-dimethylamine (800 mg, 3.55 mmol) and the reaction mixture was heated with stirring at 100° C. After 17 h, the reaction was complete by LC/MS analysis and was then allowed to cool to room temperature. Diethyl ether (100 mL) was added with stirring and after 20 min the orange diethyl ether solution was decanted off. This procedure was repeated until a tan solid precipitated. 3-Dimethylaminomethyl-2-ethylsulfanyl-phenol hydrobromide (770 mg, 100%) was filtered off as a tan solid.
Reaction SMILES: [CH2:1]([C:3]1[C:24]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:23][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2].[C:34]([O-:37])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[C:24]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:23][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[N:9]([CH2:26][CH2:27][N:28]4[CH2:33][CH2:34][O:37][CH2:30][CH2:29]4)[C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2c(cc1NCCN1CCOCC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(cc1NCCN1CCOCC1)C(C)(C)c1c(c3ccc(C#N)cc3n1CCN1CCOCC1)C2=O
Temperature: 90 °C
Reaction time: 17 h
Yield: 101.9 %

Procedure:
9-Ethyl-6,6-dimethyl-8-(2-morpholin-4-yl-ethylamino)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (10 mg) was dissolved in DMF (1 ml), added with K2CO3 (10 mg) and 1-(2-chloroethyl)morpholine (8 mg), and then stirred at 90° C. for 17 hrs. The reaction mixture was diluted with ethyl acetate (10 ml). The organic layer was washed with 10% brine and concentrated under reduced pressure. The resulting residues were purified by silica gel column (dichloromethane/methanol=99/1 to 90/10) to obtain the title compound (6.4 mg, yield 58%).
Reaction SMILES: [C:1]1(B(O)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Br[C:11]1[CH:16]=[C:15]([CH2:17][S:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[CH:13][C:12]=1[NH2:27]>>[C:1]1([C:13]2[CH:14]=[C:15]([CH2:17][S:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])[CH:16]=[CH:11][C:12]=2[NH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1Br
Reactant: OB(O)C1=CCCCC1
Product: Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1

Procedure:
The title compound was prepared according to the Suzuki coupling procedure of the Example 1, step (e) using cyclohex-1-enyl boronic acid (157 mg, 1.25 mmol) and 2-bromo-4-(morpholine-4-sulfonylmethyl)-phenylamine (as prepared in the previous step, 335 mg, 1.00 mmol) and purified on silica (20% EtOAc/hexanes) (276 mg, 82%). 1H-NMR (CDCl3; 400 MHz): δ 7.05 (dd, 1H, J=8.2, 1.9 Hz), 6.95 (d, 1H, J=1.9 Hz) 6.67 (d, 1H, J=8.2 Hz), 5.76 (br s, 1H), 4.12 (s, 2H), 3.90 (br s, 2H), 3.60-3.62 (m, 4H), 3.09-3.12 (m, 4H), 2.19-2.23 (m, 4H), 1.24-1.62 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C@H:11]2[CH2:13][O:12]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:14].[OH:15][CH2:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1>C(O)C>[OH:12][C@@H:11]([C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:14])[O:5][CH2:4]2)[CH2:13][N:22]1[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:18][C@H:17]1[CH2:16][OH:15]
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: Cc1c([C@H](O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc2c1COC2=O

Procedure:
(S)-4-Methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one (0.75 g, 3.95 mmol) and (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.02 g, 4.73 mmol) in ethanol (12 mL) were heated in microwave at 150° C. for 1.5 h. The reaction solution was concentrated and the residue was purified by MPLC on a Biotage system using 40-100% ethyl acetate/hexane to give the title compound. LC/MS: (M+1)+: 407.15.