Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].CO.[OH-].[K+].C[O:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=2)[N:24]=1)=[O:18].[OH-].[K+].Cl>O>[NH2:31][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:2][OH:3])=[O:9])[S:21][CH:22]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: NO
Reactant: COC(=O)CCCCCCC(=O)Nc1nc(-c2cccc(N)c2)cs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cccc(-c2csc(NC(=O)CCCCCCC(=O)NO)n2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of hydroxylamine hydrochloride (0.958 g, 13.8 mmol) in MeOH-KOH (0.772 g, 13.8 mmol) was added at 40° C. for 10 minutes. The reaction mixture was cooled to 0° C. and filtered. Compound 20 (0.250 g, 0.69 mmol) was added to the filtrate followed by KOH (50 mg, 0.89 mmol) at room temperature. After 2 hours, water (20 ml) was added, followed by 1 N HCl until pH reached 6.5. The reaction mixture was extracted with EtOAc, and organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was removed by rotary evaporation. The crude solid was purified by preparative HPLC to give compound 23 (0.110 g, 43.9%). 1H NMR (300 MHz, CD3OD) δ 7.98 (1H, d, J=7.8 Hz), 7.90 (1H, s), 7.55 (1H, t, J=7.8 Hz), 7.51 (1H, s), 7.29 (1H, dd, J=7.8, 1.2 Hz), 2.51 (2H, t, J=7.2 Hz), 2.11 (2H, t, J=7.2 Hz), 1.74 (2H, t, J=7.0 Hz), 1.65 (2H, t, J=7.0 Hz), 1.50-1.35 (4H, m). 13C NMR (100 MHz, CD3OD) δ 172.1, 158.0, 147.4, 136.3, 129.7, 125.1, 120.8, 119.2, 108.5, 34.6, 28.0, 27.9, 24.7, 24.3.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[C:12]([CH3:24])[S:11][C:10]=2[CH:25]=1.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[N:28]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:1][N:2]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[N:28]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=3)=[C:12]([CH3:24])[S:11][C:10]=2[CH:25]=1
Reactant: CNCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)c(C)sc2c1
Reactant: Cc1nccc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nccc(N(C)CCOc2ccc3c(-c4ccc(C(F)(F)F)cc4)c(C)sc3c2)n1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
A solution of 40 mg (0.109 mmol) Methyl-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amine (example 51.1), 0.0211 g (0.164 mmol) of 4-chloro-2-methyl-pyrimidine [Ger. Offen. (1990), DE3905364 A1] and 0.038 ml (0.22 mmol) N-ethyl-diisopropylamine in 1 ml of N,N-dimethylformamide was stirred for 2 hours at 80° C. The reaction mixture was then cooled to room temperature, poured into 30 ml of ice-water and extracted 3 times with 10 ml of ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 95:5:1 v/v/v mixture of dichloromethane, methanol and saturated aqueous ammonia as the eluent giving 37.3 mg (74.5%) Methyl-(2-methyl-pyrimidin-4-yl)-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amine as light brown solid, MS: 458 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8](Br)=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:4])=[O:3].C(N)[CH2:19][NH2:20]>CN1CCCC1=O.O>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]([C:19]#[N:20])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:4])=[O:3]
Reactant: CC(C)c1cc(S(C)(=O)=O)c(C(C)C)cc1Br
Reactant: NCCN
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(S(C)(=O)=O)c(C(C)C)cc1C#N

Procedure:
A mixture of 4-bromo-2,5-diisopropylphenyl methyl sulfone (19.9 g) prepared in Example 10A and 7.2 g of cuprous cyanide was heated in 100 ml of N-methyl pyrrolidone at 195°C under nitrogen for 2 hours. The reaction mixture was poured into a stirred solution of 25 g of ethylenediamine in 500 ml of water. The mixture was filtered and the residual product extracted into tetrahydrofuran. The extract was washed with 5% HCl and finally with saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was removed to give 4-cyano-2,5-diisopropylphenyl methyl sulfone. Further purification by recrystallization from n-hexane gave 4-cyano-2,5-diisopropylphenyl methyl sulfone having a mp of 134°-137°C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:27][CH:26]=1)=[O:33]
Reactant: CC(C)(C)C(=O)c1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)C(C)(C)C)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 1-(4-Hydroxyphenyl)-2,2-dimethyl-propan-1-one from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C24H30O6 [M+NH4]+: 437 [M+H]+: 415.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]1>C1COCC1.CO.O>[OH:3][CH:4]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]1
Reactant: O=C1CC(C(=O)OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)C1CC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
NaBH4 (215 mg; 5.68 mmol) was added to the solution of benzyl 3-oxocyclobutanecarboxylate (2.3 g; 11.3 mmol) in THF (30 mL) and MeOH (1.5 mL). The reaction mixture was stirred for 0.5 hour at 0° C., diluted with water (20 mL), and extracted with DCM (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reverse phase flash chromatography to afford 1.24 g (53%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[C:13]=2[O:25][CH3:26])[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35].O.O.[OH-].[Li+]>CO.C1COCC1>[CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:13]=2[O:25][CH3:26])[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35]
Reactant: CCOC(=O)CCc1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3ncnc(CCC(=O)O)c3OC)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To a solution of ethyl 3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methoxypyrimidin-4-yl)propanoate (1.13 g) in methanol (5.0 mL) and THF (10 mL) were added water (5.0 mL) and lithium hydroxide monohydrate (450 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (330 mg) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[SH:8].[H-].[Na+].I[CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[S:8][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CC(=O)c1ccc(S)c(Cl)c1
Reactant: IC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(SC2CCOCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
The product from step 1 (3.0 g, 16.07 mmol) was added to a suspension of sodium hydride (964.3 mg, 32.14 mmol) in DMF at 0° C. After 5 min 4-iodo-tetrahydro-pyran (3.41 g, 16.07 mmol) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with water at 0° C. and neutralized with trifluoroacetic acid. Evaporation and purification of the crude product by silica gel chromatography using ethyl acetate/n-heptane gave the desired product (1.385 g, 32%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][CH:7]([OH:21])[CH2:8][NH:9][CH:10]([CH3:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)[CH:27]=[O:28]>>[Si:13]([O:12][CH2:11][CH:10]([N:9]1[CH2:8][CH:7]([CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=2)[O:21][C:27]1=[O:28])[CH3:20])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)NCC(O)COc1cccc(F)c1
Reactant: CN(C)C=O
Product: CC(CO[Si](C)(C)C(C)(C)C)N1CC(COc2cccc(F)c2)OC1=O

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 2.00 g of 1-(3-fluorophenoxymethyl)-2-(2-t-butyldimethylsilyloxy-1-methylethylamino)ethanol (prepared as described in Preparation 71), 20 ml of anhydrous dimethylformamide and 1.09 g of N,N'-carbonyldiimidazole were used, to give 0.74 g of the title compound having an Rf value of 0.29 (on silica gel thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent) from a polar diastereomer and 1.03 g of the title compound, melting at 54° C. to 58° C. from a less polar diastereomer.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].CN1C=CN=C1.[N+:20]([CH:23]=[C:24]1[NH:29][CH2:28][CH2:27][CH2:26][S:25]1)([O-:22])=[O:21].[O-][Si]([O-])=O.[Mg+2]>O1CCCC1.C(Cl)Cl.O>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](=[O:7])[C:23]([N+:20]([O-:22])=[O:21])=[C:24]1[NH:29][CH2:28][CH2:27][CH2:26][S:25]1
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])C=C1NCCCS1
Agent: Cn1ccnc1
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(COc1ccc(Cl)cc1Cl)C(=C1NCCCS1)[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A solution of 7.2 g of 2,4-dichlorophenoxyacetyl chloride in 20 ml of tetrahydrofuran was added dropwise to a solution of 2.5 g of 1-methylimidazole in 80 ml of tetrahydrofuran at 0.5°. The resulting slurry was stirred for 30 minutes at 5°, then 4.8 g of 5B was added all at once. The mixture was stirred overnight. Then 0.5 equivalent mole of the imidazole complex in 50 ml of tetrahydrofuran was prepared and added at 5°. The stirred mixture was allowed to rise slowly to room temperature, and stirred overnight. The solvent was stripped; the residue was treated with 1:1 volume mixture of water and methylene chloride. The phases were separated, the water phase was extracted with methylene chloride, the methylene chloride solutions were combined, washed with water and saturated salt solution, dried (MgSO4) and the solvent was stripped to give an oil. The oil was passed through Florisil to give a mush, which was triturated with pentane to give 3-(2,4-dichlorophenoxy)- 1-nitro-1-(tetrahydro-2H-1,3-thiazin-2-ylidene)-2-propanone (5C), as a pale yellow solid, m.p.: 164°-164.5°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1CCCc2[nH]c3ccc(F)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cc(F)ccc1n2Cc1ccc(F)cc1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
6-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.3940 g, 0.0019 mol) is added to a slurry of pentane-washed NaH (0.0966 g, 0.0024 mol) in DMF (3 mL) and after stirring for 10 min, p-fluorobenzyl bromide (0.29 mL, 0.0023 mol) is added. After stirring for 4 h at room temperature, the mixture is partitioned between water and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (100 mL) using methanol/dichloromethane (0.5/99.5) to give 0.5678 g (94%) of the title compound. An aliquot is recrystallized from ethyl acetate/heptane; mp 182.5-183° C.; MS (ESI+) for C19H15F2NO m/z 312.2 (M+H)+; IR (drift) 1631, 1511, 1483, 1466, 1449, 1256, 1228, 1218, 1137, 1094, 867, 836, 813, 808, 802 cm−1; 1H NMR (CDCl3) δ2.24, 2.58, 2.86, 5.28, 6.94, 7.13, 7.96. Anal. Calcd for C19H15F2NO: C, 73.30; H, 4.86; N, 4.50. Found: C, 73.27; H, 4.92; N, 4.54.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:21]=[CH:20][C:13]([O:14][CH2:15][C@H:16]([OH:19])[CH2:17][OH:18])=[C:12](Br)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]1([S:7]([C:10]2[CH:21]=[CH:20][C:13]3[O:14][CH2:15][C@@H:16]([CH2:17][OH:18])[O:19][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(OC[C@H](O)CO)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)O[C@H](CO)CO2
Temperature: 80 °C

Procedure:
A suspension of 3-(4-benzenesulfonyl-2-bromo-phenoxy)-propane 1-2-(R)-diol (0.390 g, 0.001 mol), Pd(OAc)2 (0.007 g, 0.00003 mol, 3 mol %), racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.012 g, 0.00003, 3 mol %) and K3PO4 (0.320 g, 0.0015, 1.5 equiv) in toluene (1 mL) was heated under argon atmosphere at 80° C. for 5 hours. After cooling to ambient temperature the mixture was diluted with ethyl acetate (1 mL), washed with water and saturated sodium chloride, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (eluting with hexane-ethyl acetate; 1:1, v/v) to give (7-benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2(R)-yl)-methanol as an oil which solidified upon standing. (0.160 g; 52%). m. p. 112.0-113.5° C., [α]=+36.7° (CHCl3, c=1).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[H-].[Na+].[CH2:31](I)[CH2:32][CH2:33][CH3:34]>>[CH2:31]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][O:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:2])=[O:28])[CH2:18][CH2:17]2)=[CH:20]1)[CH2:32][CH2:33][CH3:34]
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Product: CCCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 0.119 g (0.31 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester, 0.022 g (0.53 mmol) of NaH in 60% of mineral oil and 0.044 mL (0.41 mmol) of butyl iodide. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.054 g (42% of yield) of the desired product.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(chloromethyl)-4-methoxybenzene (0.46 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.83 g, 62%).
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[S:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:2][CH3:3].S(Cl)(Cl)=O.[NH2:24][C:25]1[S:26][C:27]2[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:32][CH:31]=[C:30]([O:40][CH3:41])[C:28]=2[N:29]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:24][C:25]2[S:26][C:27]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:31]=[C:30]([O:40][CH3:41])[C:28]=3[N:29]=2)=[O:14])=[CH:15][CH:16]=1)(=[O:6])=[O:7])[CH2:18][CH3:19]
Reactant: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)Nc2nc3c(OC)ccc(-c4ccccc4)c3s2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a suspension of 4-dipropylsulfamoyl-benzoic acid (185 mg, 0.65 mmol) in toluene (10 ml) was added thionylchloride (600 mg, 5 mmol) and the mixture heated to 80° C. for 17 h. After cooling the solvent was evaporated and the resudue was taken up in THF (20 ml), 2-amino-4-methoxy-7-phenyl-benzothiazole (128 mg, 0.5 mmol), triethylamine (105 μl, 0.75 mmol), and DMAP (6 mg, 0.05 mmol) were then added and the mixture was stirred for 1 hour at r.t. followed by 1 hour at 60° C. After cooling to r.t. the reaction mixture was quenched by addition of 10% aq. Na2CO3 solution (30 ml) and EtOAc (30 ml) and vigorous stirring. After separation of the phases the aqueous phase was extracted with EtOAc (30 ml) and the combined orgainc phases were washed with 10% aq. Na2CO3, dried with Na2SO4, filtered and evaporated. The residue was then chromatographed over SiO2 (Merck 230-400 mesh) eluting with a gradient of cyclohexane/EtOAc from (1:4) to 100% EtOAc. After pooling and evaporation of the product fractions the title compound was obtained as a white solid (240 mg, 92% yield), MS: m/e=524.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]([OH:11])=O)=[CH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.COC(=O)[CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[Cl:36].[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:36][C:29]1[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=1[CH2:27][C:9]([C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)=[O:11]
Reactant: COC(=O)Cc1cc(OC)ccc1Cl
Reactant: Cn1cc(C(=O)O)ccc1=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)c(CC(=O)c2ccc(=O)n(C)c2)c1
Temperature: 50 °C
Reaction time: 1.17 h

Procedure:
To a solution of 1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (7.95 g) in N,N-dimethylformamide (385 ml) was added 1,1′-carbonyldiimidazole (8.42 g). The mixture was stirred at 50° C. for 70 min. The mixture was cooled to −10° C. and (2-chloro-5-methoxy-phenyl)-acetic acid methyl ester (10.61 g) was added. Sodium hydride (60% dispersion in mineral oil, 6.59 g) was added portionwise over 30 min. The mixture was slowly warmed to room temperature and stirred for 6 h. The mixture was poured into ice water (800 ml) and saturated aqueous ammonium chloride solution (250 ml) and was extracted with ethyl acetate (5×). The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness. The residue was dissolved in dimethylsulfoxide (100 ml). NaCl (3.15 g) and water (1.32 ml) were added and the mixture was heated to 140° C. for 5 h. After cooling to room temperature, ice water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness to give a light brown solid. The solid was washed with cyclohexane and a small amount of dichloromethane to give the title compound as a colorless solid. More product could be obtained by chromatographic purification of the mother liquor ((SiO2, cyclohexane/EtOAc 7:3=>EtOAc). Colorless solid (9.37 g). MS (m/e)=292.1 [M+H+].
Reaction SMILES: S1C=CC=C1.C(O)C.[F:9][C:10]1[CH:38]=[CH:37][C:13]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:36])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-])=O)[CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1.[H][H]>[Pt].CO>[NH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]([NH:25][CH2:24][CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][CH:16]([C:14](=[O:15])[C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:38][CH:37]=2)[CH2:17][CH2:18]1)=[O:36]
Reactant: O=C(NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 45 %

Procedure:
To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol are added 18 parts of N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2-nitrobenzamide and 200 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 7.5 parts (45%) of 2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide; mp. 113.2° C.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]([NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[CH:17]=[C:16]([C:18]([CH2:36][CH3:37])([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([CH2:33][CH3:34])([OH:32])[CH2:30][CH3:31])=[C:23]([CH3:35])[CH:22]=3)[CH2:19][CH3:20])[S:15][C:14]=2[CH:38]=1)=[O:9])([CH3:6])[CH3:5].[OH-].[Na+]>>[CH2:36]([C:18]([C:16]1[S:15][C:14]2[CH:38]=[C:10]([C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:39])=[O:2])=[O:9])[CH:11]=[CH:12][C:13]=2[CH:17]=1)([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([CH2:30][CH3:31])([OH:32])[CH2:33][CH3:34])=[C:23]([CH3:35])[CH:22]=1)[CH2:19][CH3:20])[CH3:37]
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc3ccc(C(=O)NC(C)(C)C(=O)OC)cc3s2)cc1C
Agent: [Na+]
Agent: [OH-]
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc3ccc(C(=O)NC(C)(C)C(=O)O)cc3s2)cc1C
Yield: 91 %

Procedure:
Using the procedure analogous to Example 5, from 2-[(2-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-benzo[b]thiophene-6-carbonyl)-amino]-2-methyl-propionic acid methyl ester, example 30 (0.10 g, 0.18 mmol) and NaOH (0.036 g, 0.90 mmol) to furnish the titled compound (0.088 g, 0.016 mmol, 91%). LC/MS (m/z): calcd. for C31H41NO5S (M+H)+: 540.3; found: 540.3.