Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][OH:27])[CH2:24][O:23][C:22]3=[O:28])=[C:17]([F:29])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:33]I>CN(C)C=O.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][O:27][CH3:33])[CH2:24][O:23][C:22]3=[O:28])=[C:17]([F:29])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)c(F)c2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Yield: 56.8 %

Procedure:
(R)-4-[3-fluoro-4-(4-hydroxymethyl-2-oxooxazolidin-3-yl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester (494 mg) described in Preparation Example 92 was dissolved in N,N-dimethylformamide (3.7 mL), sodium hydride (51 mg, 60% in oil) was added under ice-cooling and the mixture was stirred. Then, under ice-cooling, methyl iodide (182 mg) was added and the mixture was stirred at room temperature. The reaction mixture was added to saturated brine under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (290 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH3:34]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30]([NH2:34])=[O:32])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: N
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: NC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 90 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (250 mg, 0.55 mmol) was reacted with ammonia to give the title compound as a white solid (210 mg, 90%); NMR Spectrum 4.87 (s, 2H), 5.77 (s, 2H), 6.97 (m, 2H), 7.29 (m, 1H), 7.37 (d, 1H), 7.59 (br s, 1H), 7.76-7.66 (m, 3H), 7.84 (br s, 1H), 7.91 (m, 1H), 8.14 (s, 1H), 8.57-8.52 (m, 3H), 10.98 (br s, 1H); Mass spectrum MH+ 426.
Reaction SMILES: [O:1]=[S:2]1(=O)[CH2:7][CH2:6][N:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[O:34][CH3:35])=[CH:26][N:25](S(C5C=CC(C)=CC=5)(=O)=O)[C:22]4=[N:23][CH:24]=3)[CH:14]=2)[CH2:9][C:10](O)=[O:11])[CH2:4][CH2:3]1.[CH3:47][NH:48][CH3:49].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[OH-:83].[K+]>CN(C=O)C.CO>[O:83]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[O:34][CH3:35])=[CH:26][NH:25][C:22]4=[N:23][CH:24]=3)[CH:14]=2)[CH2:9][C:10]([N:48]([CH3:49])[CH3:47])=[O:11])[CH2:6][CH2:7]1
Reactant: CNC
Reactant: [OH-]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(CC(=O)O)N4CCS(=O)(=O)CC4)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(CC(=O)N(C)C)N4CCS(=O)(=O)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a solution of 3-(1,1-dioxothiomorpholin-4-yl)-3-{3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-propionic acid (100 mg, 0.15 mmol), dimethylamine (2 N solution in THF, 0.15 mL, 0.30 mmol), diisopropylethylamine (23 mg, 0.18 mmol) in DMF (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (68 mg, 0.18 mmol). The resulting solution was stirred at room temperature for 1 hour. Methanol (1 mL) and potassium hydroxide (50% w/v in water, 0.2 mL) were added and the resulting mixture was stirred for 30 minutes. The mixture was directly purified by mass-triggered reverse-phase HPLC to afford 3-(1,1-dioxothiomorpholin-4-yl)-3-{3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-N,N-dimethyl-propionamide as a white solid (31 mg, 39%). MS: m/z 533 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 2.75 (s, 3H), 2.82 (br, 2H), 2.88 (dd, 1H), 2.96 (br, 2H), 3.02 (s, 3H), 3.07 (br, 4H), 3.105 (dd, 1H), 3.83 (s, 3H), 4.41 (br, 1H), 7.05 (t, 1H), 7.15 (d, 1H), 7.30 (t, 1H), 7.30 (dt, 1H), 7.31 (d, 1H), 7.44 (t, 1H), 7.61 (d, 1H), 7.65 (s, 1H), 7.74 (d, 1H), 8.18 (d, 1H), 8.57 (d, 1H), 11.93 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C([Li])CCC.[CH:18](OCC)=[O:19].C(O)(=O)C>O1CCCC1.CCCCCC>[CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH:18]=[O:19])[CH:2]=[CH2:3]
Reactant: CCOC=O
Reactant: C=CCn1cnc2ccccc21
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCn1c(C=O)nc2ccccc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of 10 g (0.053 mole) of 1-allylbenzimidazole in 75 ml of tetrahydrofuran cooled to -78° C. was added 20.68 ml (0.053 mole) of 2.6M n-butyllithium in hexane over a period of 15 minutes. After 30 minutes of stirring 4.28 ml (0.053 mole) of ethyl formate was added and the reaction allowed to stir for one hour. Acetic acid (3.03 ml, 0.053 mole) was added, the cooling bath removed and the mixture allowed to warm to -20° C. The mixture was poured into water and the product extracted (3×100 ml) with ethyl acetate. The extracts were combined, dried over magnesium sulfate and concentrated to a brown oil which was chromatographed on 350 g of silica gel using ethyl acetate-chloroform as the eluent, 2.3 g.
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]=1[F:14].[F-].[K+].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[F:10][C:6]1[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]([F:14])=[C:2]([S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Reactant: Sc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1c(F)c(F)c(Sc2ccccc2)c(C#N)c1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A 2.0 g amount of tetrafluoroisophthalonitrile and 0.87 g of potassium fluoride were dissolved in 10 ml of acetonitrile. After cooling the mixture to a temperature of 0° C. by an ice-water bath, 1.1 g of phenyl mercaptan was dropwise added by a syringe. While mixture was maintained at a temperature of about 0° C., the mixture was stirred for 8 hours and the solvent was then distilled off. A 50 ml amount of water was added to the mixture and potassium fluoride was dissolved. The mixture was extracted with chloroform, and the extract was dried with magnesium sulfate. The chloroform was distilled off in vacuo and the resultant liquid was then distilled in vacuo to obtain 1.8 g (63% yield) of the desired compound No. 41 at a boiling point of 65° C. to 67° C./0.7 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.Cl[CH2:15][C:16]#[N:17]>O1CCCC1>[Cl:1][C:2]1[CH:13]=[C:12]2[C:5](=[CH:4][CH:3]=1)[NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH:11][CH2:15][C:16]#[N:17]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: N#CCCl
Solvent: C1CCOC1
Product: N#CCNCCc1c[nH]c2ccc(Cl)cc12

Procedure:
Using the procedure of Step A of Example 22, 21.4 g of 5-chlorotryptamine, 7.7 ml of chloroacetonitrile and 18.1 ml of 1,5-diaza[5,4,0]undec-5-ene in 210 ml of tetrahydrofuran were reacted to obtain 19.3 g of the expected product melting at 80° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[CH2:10]([O:14][C:15]1[CH:16]=[C:17]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:18]=[CH:19][C:20]=1[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][CH3:32])[CH:25]=1)[CH2:11][CH2:12][CH3:13]>C(C(C)=O)C.C(OCC)(=O)C>[CH2:8]([O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:1])=[O:36])=[CH:16][C:15]=2[O:14][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:25][C:26]=1[O:31][CH3:32])[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CCI
Reactant: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(O)c(OC)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCCCOc1cc(CCC(=O)OCC)ccc1CCCc1ccc(OCC)c(OC)c1
Temperature: 70 °C
Yield: 87.5 %

Procedure:
0.21 g (0.75 mmol) of potassium carbonate and then 0.12 ml (0.75 mmol) of iodoethane are added to a solution of 0.25 g (0.62 mmol) of methyl 3-{3-butoxy-4-[3-(4-hydroxy-3-methoxyphenyl)propyl]phenyl}propanoate (prepared according to Example 1d) in 25 ml of methyl ethyl ketone. The reaction mixture is heated at 70° C. for 24 hours. The reaction medium is cooled, diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated and the residue is then purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 240 mg (93%) of ethyl 3-{4-[3-(4-ethoxy-3-methoxyphenyl)propyl]-3-butoxyphenyl}propanoate are obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].CO>C(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(cc3-4)CCc3nc([C@@H]4CC[C@H](C)N4C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c3-5)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reaction time: 13 h
Yield: 583.8 %

Procedure:
tert-Butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (8.33 g, 1.049 mmol) was suspended in DCM and activated MnO2 (55.0 g, 630 mmol) was added in a single portion. After 13 h, MeOH (200 mL) was added and the slurry was filtered over celite. The filter cake was washed with MeOH (600 mL) and the filtrate was concentrated under reduced pressure. The crude material was purified by silica column chromatography (0% to 45% MeOH/EtOAc) to afford tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (4.85 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[N:3](C(=O)N)[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[OH-].[Na+].CO>O>[NH2:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)=[CH:5][NH:4][N:3]=1
Reactant: NC(=O)n1ncc(-c2ccc(Cc3ccccc3)cc2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1n[nH]cc1-c1ccc(Cc2ccccc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 3-amino-4-(4-benzylphenyl)-2-carbamoylpyrazole (1.00 g), sodium hydroxide (1.00 g), methanol (40 ml) and water (40 ml) was stirred under heating reflux for 3.5 hours, and ice-water was added.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CNc1cccc(C2CCC(=O)CC2)n1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CNc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(6-methylamino-pyridin-2-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7](Cl)=[CH:6][C:5]=1[NH:12][C:13](=[O:15])[CH3:14])([O-:3])=[O:2].C[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[OH-].[K+].[K+].[Br-].[CH3:27]S(C)=O>>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[CH3:27])=[CH:6][C:5]=1[NH:12][C:13](=[O:15])[CH3:14])([O-:3])=[O:2]
Reactant: CS(C)=O
Reactant: CN1CCNCC1
Reactant: CC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Product: CC(=O)Nc1cc(N2CCNCC2C)c(F)cc1[N+](=O)[O-]
Yield: 80 %

Procedure:
N-[2-Nitro-4-fluoro-5-(methylpiperazin-1-yl)phenyl]acetamide (25.0 g, 80%) was prepared by an analogous procedure as described in preparation 1 (step 3) using N-(2-nitro-4-fluoro-5-chlorophenyl)acetamide (25.0 g, 0.107 mol) (obtained in preparation 1, step 2), 4-methylpiperazine (53.5 g, 0.535 mol), potassium hydroxide (9.05 g, 0.16 mol) and dimethyl sulfoxide (100 mL). mp 90-91° C.; IR (KBr) 3339, 1707, 1582 cm-1 ; 1H NMR (CDCl3) δ 2.24 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.56 (t, J=5.0 Hz, 4H, N(CH2)2), 3.42 (t, J=5.0 Hz, 4H, N(CH2)2), 7.90 (d, J=14.1 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 10.70 (brs, 1H, NH); Mass (m/z) 296 (M+.).
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:29]=[C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[N:31]1[CH2:40][CH2:41][CH2:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][CH:50]=1)[CH:46]=O>>[OH:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1/[CH:5]=[CH:46]/[C:45]1[CH:44]=[C:43]([CH2:42][CH2:41][CH2:40][N:31]2[C:32](=[O:39])[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:30]2=[O:29])[CH:50]=[CH:49][CH:48]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C/c2ccccc2O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Hydroxybenzyltriphenylphosphonium bromide was coupled with phthalimide 29 according to the method used in Example 45 except that the reaction was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure and partitioned between EtOAc and water. The combined organics were washed with saturated aqueous NH4Cl and water, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (5 to 60% EtOAc-hexanes gradient) gave (E)-2-(3-(3-(2-hydroxystyryl)phenyl)propyl)isoindoline-1,3-dione as a light yellow foam. Yield (0.165 g, 43%): 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.78-7.84 (m, 4H), 7.53 (dd, J=8.0, 1.6 Hz, 1H), 7.28-7.38 (m, 3H), 7.22 (t, J=8.4 Hz, 1H), 7.05-7.14 (m, 3H), 6.76-6.86 (m, 2H), 3.61 (t, J=6.8 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 1.89-1.97 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:42])[CH:5]([OH:41])[CH2:6][NH:7][C:8](=[O:40])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C.C1COCC1>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([CH:15]([NH:28][C:29]([NH:31][C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)=[O:30])[C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH:5]([OH:41])[C:4]([OH:42])=[O:3])=[O:40])=[CH:10][CH:11]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1
Reactant: CCOC(=O)C(O)CNC(=O)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)NC(c1ccc(C(=O)NCC(O)C(=O)O)cc1)c1ccc(C2=CCCCC2)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
A solution of (RS)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester (0.99 g, 1.61 mmol) in ethanol (15 mL) and THF (15 mL) was stirred and 1 M sodium hydroxide (6 mL) was added. The mixture was stirred at 40° C. for 4 hours and acidified with 1 N hydrochloric acid. After evaporation in vacuo the residue was purified on semipreperative HPLC (Gilson system). The pure fractions were combined and evaporated in vacuo to afford 0.74 g (79%) of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:20][CH2:21][CH2:22][OH:23])([CH2:16][CH2:17][CH2:18][OH:19])[C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35].Cl.[O:39]1C[CH2:42][CH2:41][CH2:40]1>C(OCC)(=O)C>[C:33]([O:23][CH2:22][CH2:21][CH2:20][C:5]1([CH2:16][CH2:17][CH2:18][O:19][C:40](=[O:39])[CH:41]=[CH2:42])[C:4]2[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=2)(=[O:36])[CH:34]=[CH2:35]
Reactant: OCCCC1(CCCO)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: C=CC(=O)Cl
Reactant: C1CCOC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)OCCCC1(CCCOC(=O)C=C)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A solution containing 15 grams of 3-[2,7-Dibromo-9-(3-hydroxypropyl)-9H-fluorene-9-yl]-propane-1-ol and 18.7 grams of diisopropylethylamine in 150 ml of tetrahydrofuran was cooled to 10° C., and to it was slowly added a solution of 7.7 grams of acryloyl chloride in 18 ml of tetrahydrofuran. The temperature was maintained at 10° C. during the addition. After stirring at 10° C. for one hour the mixture was poured into a mixture containing 100 ml of 2% aqueous HCl and 100 ml of ethyl acetate. The organic phase was separated and dried over anhydrous sodium sulfate. The solvent was removed and the residue purified by column chromatography on silica gel eluted with 15% ethyl acetate in hexane to give 8.5 grams of acrylic acid 3-[9-(acryloyloxy-propyl)-2,7-dibromo-9H-fluoren-9-yl]-propyl ester. This product was verified by NMR analysis to be present and pure.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:58]2[C:53](=[CH:54][C:55]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:56][CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C>[NH:50]1[C:58]2[C:53](=[CH:54][C:55]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)=[CH:56][CH:57]=2)[CH:52]=[CH:51]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc3[nH]ccc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5[nH]ccc5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 62.8 %

Procedure:
DIEA (0.014 mL, 0.073 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.066 mmol) and HATU (0.030 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-Indol-5-yl)-phenylamine (0.015 g, 0.066 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 56% yield: LCMS (ESI) m/z 411 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH3:32])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][C:12]([C:18]([O:20]C)=[O:19])=[CH:11][C:10]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl>O1CCCC1.CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH3:32])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:15](=[O:16])(=[O:17])[CH2:14][CH2:13][C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[CH:22]=1
Reactant: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1C
Temperature: 65 °C
Yield: 82.3 %

Procedure:
Into a mixed solution of methyl 7-[3-methyl-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (470 mg) in tetrahydrofuran (10 ml) and methanol (5 ml) was added a 1 N aqueous solution of potassium carbonate (2.9 ml), and the resulting mixture was heated at 65° C. for one day. After cooling, the reaction mixture was mixed with water, was acidified (pH=4) with 1N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 7-[3-methyl-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (375 mg) as a brown oily substance.