Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH2:8][NH:9][CH2:10][CH2:11][C:12]1([C:25]([O:27][CH3:28])=[O:26])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][C:13]1=[O:24])C1C=CC=CC=1.Br.C(O)(=O)C.BrBr.[CH3:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[CH2:8]([N:9]1[CH2:10][CH2:11][C:12]2([C:25]([O:27][CH3:28])=[O:26])[C:13](=[O:24])[CH:14]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][C:21]=12)[C:38]1[CH:37]=[CH:36][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)C1(CCNCCc2ccccc2)C(=O)CCc2ccc(OC)cc21
Reactant: CCCCCC
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: COC(=O)C12CCN(Cc3ccccc3)C(Cc3ccc(OC)cc31)C2=O
Reaction time: 0.5 h

Procedure:
A solution of IV hydrobromide (0.13 m.) in 350 ml. acetic acid was treated dropwise with a solution of bromine (0.13 m) in 50 ml. acetic acid. After stirring for 1/2 hour, the reaction was diluted with 1.5 1. "Skellysolve B" (essentially n-hexane) and cooled. The precipitated residue was separated by decantation and washed with cold "Skellysolve B". The residue was taken up in methylene chloride and treated with dilute ammonium hydroxide until basic. The layers were separated and the aqueous layer extracted two times more with methylene chloride. The combined extracts were dried (MgSO4) and concentrated. The residue was taken up in acetone and allowed to crystallize with stirring. The crystals were collected to give V (69%). The analytical sample was recrystallized from methanol; mp 158°-160° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.[Cl:11][CH2:12][C:13]#[C:14][CH2:15]Cl>C(O)C>[Cl:11][CH2:12][C:13]#[C:14][CH2:15][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCC#CCCl
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ClCC#CCOc1ccccc1
Temperature: 30 °C
Yield: 53.8 %

Procedure:
A mixture of phenol (50.8 g), potassium hydroxide (30 g), ethanol (200 ml) and water (50 ml) was stirred and heated under reflux for 1 hour, then cooled to 30° C. A solution of 1,4-dichlorobut-2-yne (100 g) in ethanol (60 ml) was added dropwise over 3.5 hours, then the mixture was stirred at ambient temperature for 18 hours and filtered. The filter cake was washed with ethanol (60 ml), and the filtrate and washings were combined. The solvents were removed in vacuo, and the residue was distilled to give 1-chloro-4-phenoxybut-2-yne as a colourless oil (52.5 g), b.p. 92°-98° C. at 0.53 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:12])=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:8]=1
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(C(=O)N3CCOCC3)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.2 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (7 mg, 0.0165 mmol), 4-dimethylaminopyridine (1.0 mg, 0.0081 mmol) and morpholine (2.9 mg, 0.0333 mmol) were dissolved in methylene chloride (2 ml), WSC-HCl (9.5 mg, 0.0495 mmol) was added thereto and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (8.0 mg, 0.0162 mmol, 98%).
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][S:8](=[O:25])(=[O:24])[NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[N:14]=1)(C)(C)C.Cl>O1CCOCC1>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:14]=[C:10]([NH:9][S:8]([CH2:7][C:6]([OH:26])=[O:5])(=[O:25])=[O:24])[S:11][CH:12]=2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ccc(-c2csc(NS(=O)(=O)CC(=O)OC(C)(C)C)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1ccc(-c2csc(NS(=O)(=O)CC(=O)O)n2)cc1

Procedure:
[4-(4-Isopropyl-phenyl)-thiazol-2-ylsulfamoyl]-acetic acid tert-butyl ester was combined with 4M HCl in dioxane as in general procedure G1 to furnish [4-(4-Isopropyl-phenyl)-thiazol-2-ylsulfamoyl]-acetic acid. LCMS m/z: 342 (M+1)+; 1H NMR (DMSO-d6, 400 MHz): δ 1.22 (d, 6H); 2.92 (m, 1H); 4.04 (s, 2H); 7.17 (s, 1H); 7.33 (d, 2H); 7.66 (d, 2H); 12.98 (s); 13.2 (s).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:16]([NH:17][C:18](=[O:32])[CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=3)=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])C.C(O)C.C(=O)(O)[O-].[Na+].Cl>O>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH:20]=[CH:19][C:18]([NH:17][C:16]2[C:8]3[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][C:10](=[O:12])[C:9]=3[CH:13]=[CH:14][CH:15]=2)=[O:32])=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc3c(=O)cc(C(=O)OCC)oc23)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCc1ccc(C=CC(=O)Nc2cccc3c(=O)cc(C(=O)O)oc23)cc1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
8-(p-pentylcinnamoyl)amino-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester (132 mg; synthesized in example 3) was dissolved into ethanol (10 ml). To the solution, an aqueous solution (1 ml) of sodium bicarbonate (126 mg) was added. The mixture was refluxed for 15 min. To the reaction solution mixture cooled to room temperature, water (20 ml) and 1N hydrochloric acid (2 ml) were added. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried, and concentrated under reduced pressure. The residue was washed with a mixture of ethyl acetate and hexane (1:1), and dried to give the title compound (62 mg) having the following physical data:
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1.[F:29][C:30]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:31]=1[CH2:32][Cl:33].Cl>O1CCOCC1>[ClH:33].[F:29][C:30]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:31]=1[CH2:32][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: Fc1ccc(CCl)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: NCc1ccccc1
Product: Nc1nc(N)c2c(OCC3CCN(Cc4ccc(F)cc4F)CC3)cccc2n1
Temperature: 25 °C
Yield: 78 %

Procedure:
The benzylamine was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (75 mg; 0.27 mmol) and 2,4-difluorobenzyl chloride (69 mg; 0.35 mmol) via Method BB. Solids were suspended in 2 mL dioxane and 0.5 mL 4M HCl in dioxane was added and after 2 hours stirring at room temperature solids were collected by filtration to yield 92 mg. (78% yield). 1HNMR (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 11.2 (s, 1H), 8.84 (s, 1H), 8.23 (s, 1H), 7.88 (q, J=8.8, 6.4 Hz, 1H), 7.7 (m, 2H), 7.4 (m, 1H), 7.23 (m, 1H), 7.02 (m, 2H), 4.28 (d, J=4.4 Hz, 2H), 4.17 (d, J=6.4 Hz, 2H), 3.4 (br d, J=11.6 Hz, 2H), 2.95 (m, 2H), 2.23 (m, 1H), 1.81 (d, J=13.2 Hz, 2H), 1.73 (m, 2H). MS m/z (ESI) 400 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7]([CH:13]=[O:14])[CH:6]([CH3:15])[CH2:5]2.Cl[CH2:17][C:18]([CH3:20])=[CH2:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:15][CH:6]1[CH2:5][C:4]2[C:8](=[C:9]([CH3:12])[C:10]([CH3:11])=[C:2]([O:1][CH2:19][C:18]([CH3:20])=[CH2:17])[CH:3]=2)[N:7]1[CH:13]=[O:14]
Reactant: C=C(C)CCl
Reactant: Cc1c(O)cc2c(c1C)N(C=O)C(C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1cc2c(c(C)c1C)N(C=O)C(C)C2
Temperature: 60 °C
Reaction time: 14 h
Yield: 96.4 %

Procedure:
A suspension of 2,3-dihydro-5-hydroxy-2,6,7-trimethyl-1H-indole-1-carbaldehyde (0.5 g, 2.4 mmol), 3-chloro-2-methyl-1-propene (0.29 mL, 2.9 mmol) and potassium carbonate (0.50 g, 3.6 mmol) in DMF (6 mL) was stirred at 60° C. for 14 hours under the nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate two times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel columns chromatography (hexane-ethyl acetate 3:1) to obtain 0.60 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)[N:4]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:14][CH:13]=2)[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
A mixture of ({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine (1.563 g, 5.29 mmol), triethylamine (1.48 ml, 10.58 mmol) in dichloromethane (40 ml) was stirred under argon in an ice bath. Methanesulfonyl chloride (1.213 g, 0.82 ml, 10.58 mmol) was added dropwise with stirring. The resulting mixture was allowed to stir at room temperature for 5 h. Then the reaction mixture was partitioned between dichloromethane and water. The organic layer was separated and dried over sodium sulphate. The desired product was isolated by column chromatography on silica using 10 to 70% ethyl acetate in n-pentane to give an oil which was then triturated with n-pentane to give the title compound as a white solid (1.602 g, 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([O:27][CH3:28])[CH2:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:49][CH:50]1[CH2:53][NH:52][CH2:51]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:28][O:27][C:23]1([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[N:13]=[C:12]([C:8]4[CH:9]=[C:10]([CH3:11])[N:6]([CH2:5][C:4]5[CH:3]=[C:2]([N:52]6[CH2:53][CH:50]([OH:49])[CH2:51]6)[CH:31]=[CH:30][CH:29]=5)[N:7]=4)[O:16][N:15]=3)=[CH:18][CH:19]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: COC1(c2ccc(-c3noc(-c4cc(C)n(Cc5cccc(Br)c5)n4)n3)cc2)CCC1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Product: COC1(c2ccc(-c3noc(-c4cc(C)n(Cc5cccc(N6CC(O)C6)c5)n4)n3)cc2)CCC1

Procedure:
Analogously to the process described in Example 3, 150 mg (0.313 mmol) of the compound from Example 7A and 146 mg (0.469 mmol) of the compound from Example 8A were used to obtain 53 mg (36% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[NH2:21][OH:22].Cl.O>C(O)C>[F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[N:21][OH:22])=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=O)cc2)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=NO)cc2)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-fluoro-3-(4-formylphenyl)azetidine-1-carboxylate (Preparation 6, 460 mg, 1.65 mmol) in ethanol (30 mL) was added NH2OH.HCl (127 mg, 1.8 mmol) and water (2.5 mL). The solution was heated to 50° C. for 1 hour and then allowed to stir at room temperature for 2 hours. The reactants were concentrated under vacuum to remove the ethanol. Water (5 mL) was added to the remaining residue and extracted with EtOAc (2×10 mL). Combined organic phases were dried (Na2SO4) and concentrated under vacuum to afford the intermediate as a solid. Yield 485 mg. 1H NMR (CDCl3) δ 8.17 (s, 1H), 7.65 (d, 2H), 7.50 (d, 2H), 5.32 (s, 1H), 4.37-4.50 (m, 2H), 4.28 (m, 2H), 1.45-1.55 (m, 9H). LC/MS retention time=2.926 minutes; MS calculated for (C15H19FN2O3), 294.13; found 195.0 M-Boc.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:14](=[O:26])[N:13]([CH2:27][C:28]4[O:32][N:31]=[C:30]([CH2:33][CH3:34])[N:29]=4)[C:12]=3[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[CH2:35]([O:37][C:38]1[C:47]([O:48][CH3:49])=[CH:46][C:45]2[C:44]([C:50]3[CH:58]=[CH:57][C:53]([C:54](O)=[O:55])=[CH:52][CH:51]=3)=[N:43][C@@H:42]3[CH2:59][CH2:60][S:61][CH2:62][C@@H:41]3[C:40]=2[CH:39]=1)[CH3:36].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH:20]4[CH2:21][CH2:22][N:23]([C:54]([C:53]5[CH:57]=[CH:58][C:50]([C:44]6[C:45]7[CH:46]=[C:47]([O:48][CH3:49])[C:38]([O:37][CH2:35][CH3:36])=[CH:39][C:40]=7[C@H:41]7[CH2:62][S:61][CH2:60][CH2:59][C@H:42]7[N:43]=6)=[CH:51][CH:52]=5)=[O:55])[CH2:24][CH2:25]4)[C:14](=[O:26])[N:13]([CH2:27][C:28]4[O:32][N:31]=[C:30]([CH2:33][CH3:34])[N:29]=4)[C:12]=3[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)c(F)c4)cc32)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)c(F)c6)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(3,4-difluorophenyl)-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (228 mg; compound B89) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (191 mg; compound C10) and HOBt (74 mg) and EDCI (92 mg) in DMF (10 ml) according to the procedure described in example 46 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: DCM/ethanol, 100/0/to 95/5 (v/v)] and by preparative HPLC as a solid.
Reaction SMILES: [C:1]([N:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C(O)C>[C:1]([N:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:20][CH2:19]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCCCCCN(C(C)=O)c1ccccc1OC1CCNCC1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCN(C(C)=O)c1ccccc1OC1CCN(Cc2ccccc2)CC1
Yield: 68.8 %

Procedure:
To a solution of 4-(N-acetyl-N-hexylaminophenyloxy)piperidine (1.4 g) in ethanol (10 ml) were added potassium carbonate (1.2 g) and benzyl chloride (0.54 g) and the mixture was heated under reflux overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate (50 ml×3). The combined extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: methylene chloride/methanol =10/1 (v/v)) to obtain 4-(N-acetyl-N-hexylaminophenyloxy)-1-phenylmethylpiperidine (1.2 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:8]1([O:18][CH3:19])[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([C:8]1([O:18][CH3:19])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1(Cc2ccccc2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COC1(Cc2ccccc2)CCC(=O)CC1
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of Example 11B (8.5 g, 32.5 mmol) in acetone (200 mL) was treated with water (100 mL) and p-toluenesulfonic acid monohydrate (1 g), heated to reflux, stirred overnight, and concentrated to remove the acetone. The remaining aqueous solution was extracted with ethyl acetate (3×1 00 mL) and the combined extracts were washed sequentially with 1N NaOH, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (6.95 g, 95%). MS (CI) m/e 236.2 (M+18)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:32])=[CH:17][CH:16]=1)=[O:22]
Reactant: Cc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccccc1-c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 68.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), o-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.047 g (68%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH:15]=O)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]>>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH:15]=[C:23]3[S:19][C:20](=[O:25])[NH:21][C:22]3=[O:24])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17]
Reactant: COC(=O)CN1C(=O)COc2ccc(C=O)cc21
Reactant: O=C1CSC(=O)N1
Product: COC(=O)CN1C(=O)COc2ccc(C=C3SC(=O)NC3=O)cc21

Procedure:
Following the general method as outlined in Example 1, starting from (6-Formyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-acetic acid methyl ester (intermediate 64) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1
Reactant: COCn1c(-c2nccs2)cc2cccc(NS(=O)(=O)c3cccs3)c21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1cccc2cc(-c3nccs3)n(COC)c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-[1-(methoxymethyl)-2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (0.68 g), ethyl bromoacetate (0.23 mL), potassium carbonate (0.35 g) and N,N-dimethylformamide (6 mL) was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.82 g, quantitative) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 124-125° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and p-anisoyl chloride (0.4 g, 2.5 mmol) in THF (30 mL) was cooled to 5° C. Triethylamine (0.5 g, 4.8 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL). The mixture was filtered, and the solid was slurried with ethanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-methoxy-benzamide (0.8 g, 90%) as a white solid: mp 289-291° C.; 1H NMR (DMSO-d6) δ 2.01-2.05 (m, 1H), 2.32-2.65 (m, 2H), 2.86-3.00 (m, 1H), 3.81 (s, 3H, OCH3), 4.40-4.60 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 7.02 (d, J=8.6 Hz, 2H, Ar), 7.46-7.64 (m, 3H, Ar), 7.85 (d, J=8.7 Hz, 2H, Ar), 8.93 (t, J=5.3 Hz, 1H, NH), 11.00 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.58, 31.17, 46.28, 51.59, 55.32, 113.51, 121.57, 126.25, 128.27, 129.06, 130.64, 131.58, 134.93, 140.07, 161.63, 165.81, 168.07, 170.98, 172.81; Anal. calcd. for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.51; H, 5.04; N, 10.09.
Reaction SMILES: [CH2:1]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:20][CH:21]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(CCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of tert-butyl 4-phenethylbenzoate (50 mg, 0.18 mmol) in dichloromethane (8 mL), trifluoroacetic acid (2 mL) was added. The mixture was stirred 0.5 hour. Once the start material has been consumed, the resultant mixture was concentrated to give 4-phenethylbenzoic acid (36 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[F:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([F:28])[CH:27]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[CH2:34][CH2:33]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Product: COc1nc(C)c(C)cc1NC(=S)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 47 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.