Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:18])=O)=[CH:11][CH:10]=2)[CH2:5]CC[CH2:2]1.N(C1C=CC(OCCN(C)C)=CC=1)=C=[S:21]>>[CH3:2][N:1]([CH3:5])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:18])=[S:21])=[CH:11][CH:10]=1
Reactant: NC(=O)Nc1ccc(OCCN2CCCC2)cc1
Reactant: CN(C)CCOc1ccc(N=C=S)cc1
Product: CN(C)CCOc1ccc(NC(N)=S)cc1

Procedure:
The title compound is prepared as described in Example 1 for [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea but using [2-(4-isothiocyanato-phenoxy)-ethyl]-dimethyl-amine. The title compound: ES-MS: 240.0 [M+H]+; single peak at tR=3.52 min (System 1).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:15]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)=[CH:15][C:16]=1[O:21][C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1
Reactant: COC(OC)c1ccc(Cl)c(Oc2ccncc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Cl)c(Oc2ccncc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 4-chloro-3-(4-pyridyloxy)-benzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 gave 9-[4-chloro-3-(4-pyridyloxy)-phenyl]-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide water gave a yellow crystalline solid of melting point 242-244° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][O:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36].S([O-])(O)(=O)=O.[Na+]>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][O:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([C:35](=[O:37])[CH3:36])[CH2:24][CH2:23]3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc(COCC2CCNCC2)cc(-c2cccc(C#N)c2)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(COCC2CCN(C(C)=O)CC2)cc(-c2cccc(C#N)c2)c1
Yield: 78 %

Procedure:
In 20 ml of dichloromethane, was dissolved 298 mg of the compound obtained in Example 16. To the resulting solution, was added 3.0 ml of triethylamine. To the obtained mixture, 0.46 ml of acetyl chloride was added under cooling with ice and stirring. The mixture was stirred at 0° C. to room temperature for 18 hours. The obtained mixture was poured into a saturated aqueous solution of sodium hydrogensulfate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine and subsequently dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to afford 260 mg (78%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[S:8].[H-].[Na+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][CH2:2][CH2:3][CH2:4][C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[S:8])=[CH:21][CH:20]=1
Reactant: COC(=S)c1ccccc1CCCO
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=S)c1ccccc1CCCOCc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To an ice bath cooled solution of methyl 2-(3-hydroxyprop-1-yl)thiobenzoate (3.7 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% in oil, 719 mg) and the solution was stirred at the same temperature for 30 minutes. 4-Methoxybenzyl chloride (2.56 g) was added to the solution and the mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with ethyl acetate (100 ml) and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give a crude oil. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate=10:1) to give methyl 2-[3-(4-methoxyphenyl)methoxyprop-1-yl]thiobenzoate (2.13 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:20]#[N:21])=[C:18]([SH:22])[N:17]=[C:16]([NH2:23])[C:15]=2[C:24]#[N:25])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].Cl[CH2:27][C:28]1[N:29]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[S:31][CH:32]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:20]#[N:21])=[C:18]([S:22][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[S:31][CH:32]=3)[N:17]=[C:16]([NH2:23])[C:15]=2[C:24]#[N:25])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)N1CCC(c2c(C#N)c(N)nc(S)c2C#N)CC1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)N1CCC(c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
34 mg (0.06 mmol) of the compound from Example 24A are dissolved in 1.2 ml of dry DMF, and 17 mg (0.07 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 19 mg (0.23 mmol) of sodium bicarbonate are added. The reaction mixture is stirred at RT for 8 h. The mixture is then filtered, and about 0.5 ml of water is added to the filtrate. The precipitate formed is filtered off with suction and dried under reduced pressure at +50° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[S:14](=[O:18])(=[O:17])([OH:16])[OH:15].[CH3:19]O>>[S:14]([OH:18])([OH:17])(=[O:16])=[O:15].[CH3:19][O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: CO
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
The same esterification procedure as in Example 1 was followed with the exception that 165.2 g of L-phenylalanine and 165.2 g of methanol were used and that the hydrochloric acid was replaced with 120.1 g of 98% sulfuric acid. The reaction was conducted at 60° C. for 8 hours, followed by cooling in order to deposit the crystals, which were collected by filtration and then dried to obtain 184.9 g (63.8% yield) of L-phenylalanine methyl ester sulfate having a purity of 95.7% and containing 0.3% of water and 2.4% of L-phenylalanine.
Reaction SMILES: C([O:4][CH2:5][C:6]1([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=2[C:21]#[N:22])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=O)C.O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([C:25]1[C:24]([CH3:31])=[N:20][C:16]2[C:15]([C:21]=1[NH2:22])=[C:14]([O:13][CH2:12][C:6]1([CH2:5][OH:4])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)[CH:19]=[CH:18][CH:17]=2)=[O:27])[CH3:30]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)OCC1(COc2cccc(N)c2C#N)CCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3(CO)CCCCC3)c2c1N

Procedure:
Prepared as in Example 2a from (1-((3-amino-2-cyanophenoxy)methyl)cyclohexyl)-methyl acetate (Tachdjian, C. et al. PCT Inn. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as an off-white solid (60%). MS 373 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C@H:11]([NH2:13])[CH3:12])=[CH:3][CH:2]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:13][C@@H:11]([C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=1)[CH3:12])=[CH:40][CH:41]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](N)c1ccnc2ccccc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3ccnc4ccccc34)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(quinolin-4-yl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 554 [M+H]+.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:27][CH2:28][NH2:29]>C(Cl)Cl>[C:1]1([O:7][C:8](=[O:9])[NH:29][CH2:28][CH2:27][C:21]2[C:20]3[C:24](=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=3)[NH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(F)cc12)Oc1ccccc1
Reaction time: 24 h

Procedure:
Chloroformic acid phenyl ester (310 μl, 2.45 mmole) and pyridine (415 μl, 5.13 mmole) were added to a solution of 2-(5-fluoro-1H-indol-3-yl)-ethylamine (0.5 g, 2.33 mmole) in abs. DCM (10 ml). Stirring was then performed for 24 h at RT. Working up was performed by extracting the batch with water (2×20 ml), with 1M HCl (2×20 ml) and with 1M NaOH (2×20 ml). The organic phase was dried with Na2SO4 and evaporated. [2-(5-Fluoro-1H-indol-3-yl)-ethyl]-carbamic acid phenyl ester was obtained as a colorless solid in a yield of 0.69 g (100%).
Reaction SMILES: C([O-])(=[O:3])C.[K+].Br[CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([O:31][CH3:32])=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[CH:17]=[C:16]2[NH:22][C:23]1[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=1[Cl:30]>>[Cl:30][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:29])[C:23]=1[NH:22][C:16]1[C:15]2[C:20](=[C:11]([O:10][CH2:9][CH2:8][CH2:7][OH:3])[C:12]([O:31][CH3:32])=[CH:13][CH:14]=2)[O:19][C:18](=[O:21])[CH:17]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCBr
Agent: [K+]
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCO

Procedure:
The title compound can be prepared from potassium acetate and 8-(3-bromopropoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 30) following the procedures outlined in Examples 52 & 42. 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 4.44 (t, 1H), 4.07 (t, 2H), 3.92 (s, 3H), 3.57 (q, 2H), 1.82 (m, 2H); MS (ESI): 410.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]2[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]3[S:19][CH2:18][C:12]4([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[O:11][C:10]=32)=[CH:5][CH:4]=1.[CH2:24]([C@H:31]1[CH2:33][O:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:32][C@@H:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:33][N:15]1[CH2:16][CH2:17][C:12]2([O:11][C:10]3[C:20]4[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]=3[S:19][CH2:18]2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:21]=4)[CH2:13][CH2:14]1
Reactant: COc1ccc2c(c1)C1=C(SCC3(CCNCC3)O1)C(=O)C2=O
Reactant: c1ccc(C[C@H]2CO2)cc1
Product: COc1ccc2c(c1)C1=C(SCC3(CCN(C[C@@H](O)Cc4ccccc4)CC3)O1)C(=O)C2=O

Procedure:
Compound 209 was synthesized using 9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-benzyloxirane following conditions outlined in procedure Y. M.p.=110° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.92 (d, J=8.8 Hz, 1H), 7.21-7.31 (m, 6H), 7.11 (m, 1H), 4.10 (m, 1H), 3.92 (s, 3H), 3.15 (s, 2H), 3.10 (s, 2H), 2.76 (m, 4H), 2.60 (m, 2H), 2.22 (m, 2H), 1.95 (m, 2H); LCMS: 466 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:11]1[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1
Reactant: COc1ccc(C)c(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C)c(Oc2ccc(N)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 2-{[2-methyl-5-(methyloxy)phenyl]oxy}-5-nitropyridine (Intermediate 53, 1.5 g) in ethanol (100 mL) was added Pd/C (5%, 200 mg) and the mixture was stirred at room temperature under H2 atmosphere overnight. The mixture was filtered through a pad of celite and the filtrate was evaporated to afford a yellow oil, which was purified by column chromatography on silica gel (mobile phase: EtOAc/PE=1/5-1/2). This afforded the title compound (850 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].Cl.[N:20]1([C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OCC)(=O)C>C(#N)C>[S:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:4]=3[N:3]([CH2:1][CH3:2])[CH2:17][CH3:18])=[O:8])[CH2:24][CH2:25]2)=[N:27]1
Reactant: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nsc3ccccc23)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-diethylamino-5-methanesulfonyl-benzoic acid (Example 2.5) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid. MS (m/e): 473.4 (M+H+; 100%)
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[CH:23]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+]>C(O)C.C(OC(C)C)(=O)C>[O:37]1[C:36]2[CH:40]=[CH:41][C:33]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccsc3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: CCO
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3ccsc3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)O
Temperature: 52.5 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
To a solution of the 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (649 mg, 0.944 mmol) in ethanol (40 mL) was added aqueous 1.0 N sodium hydroxide (35 mL) at room temperature. The resulting suspension was heated to 50-55° C. and the mixture was stirred for 5 h. Then, the reaction mixture was concentrated and the residue was diluted with water (20 mL) and extracted with diethyl ether (50 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N hydrochloric acid and the precipitated white organic compound was extracted into ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with brine solution (100 mL) and the organic layers were dried over anhydrous magnesium sulfate. Filtration and removal of the solvent afforded the crude product which was dissolved in hot iso-propyl acetate (10 mL) and then diluted with hexanes (5 mL). The resulting light yellow solution was stored in the refrigerator for 2 days. The white solids were collected by filtration and washed with hexanes. After air-drying, 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy}-butyric acid (404 mg, 68%) was isolated as a white solids, mp=110-112° C.: ES(+)-HRMS m/e calculated for C36H38O8S (M+Na)+ 653.2179, found 653.2183. Elemental analysis: (C36H38O8S): C=68.49 (calcd, 68.55), H=5.93 (6.07), S=5.15 (5.08).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:43]([OH:47])[CH2:44][CH2:45][OH:46]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:46][CH2:45][CH2:44][CH2:43][OH:47])[N:18]=[C:17]([N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCN(c3ccccc3)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(c3ccccc3)CC2)nc1OCCCO

Procedure:
The procedure described in Synthesis Example 3 was repeated by use of 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-phenylpiperazinyl)-4-pyrimidinyl]benzenesulfonamide and 1,3-propanediol, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([CH3:14])[N:4]=1.[H-].[Na+].F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>CN(C=O)C>[CH3:14][N:5]1[N:4]=[C:3]([CH2:2][O:1][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:13]
Reactant: O=Cc1ccc(F)cc1
Reactant: Cn1nc(CO)c2ccccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(COc2ccc(C=O)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.4 %

Procedure:
##STR29## To a stirred solution of 4-hydroxymethyl-2-methyl-1(2H)-pthalazinone (350 mg, 1.84 mmol) (prepared according to the procedure described in Chem. Pharm. Bull., 28 (1980) 2763) in dry DMF (30 mL) was added NaH (88 mg, 3.68 mmol) in portions over 30 min at 25-30° C., followed by 4-fluorobenzaldehyde (228 mg, 1.84 mmol) added dropwise, keeping the temperature between 0-15° C. The reaction mixture was stirred at room temperature further for 6 h. Ice (200 g) was added to the reaction mixture and extracted with EtOAc. The EtOAc layer was washed with water, dried over anhydrous Na2SO4 and concentrated to obtain the title compound (300 mg, 50%). mp: 168-170° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][O:40][CH3:41])=[N:35][CH:36]=1.O>CN(C=O)C>[CH3:41][O:40][CH2:39][CH2:38][O:37][C:34]1[N:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[C:4]([CH3:23])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:6]([CH3:8])[CH:7]=2)=[CH:32][CH:33]=1
Reactant: COCCOc1ccc(Br)cn1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of N-(4-(4-Hydroxy-2,6-dimethylphenyl)-thiazol-2-yl)isonicotinamide (5-3, 0.98 g, 3.0 mmol) in DMF (10 mL) were added cesium carbonate (1.95 g, 6.0 mmol, 2.0 equiv) and Cu (58.5 mg, 0.90 mmol, 0.3 equiv). The mixture was stirred at 100-110° C. for 1.0 h and added with 5-bromo-2-(2-methoxyethoxy)pyridine (17-2, 1.04 g, 4.5 mmol). The solution heated at 130° C. for 24 h. The reaction mixture was added with water (40 mL) and extracted with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=3/1-1/3) to give 17 (0.94 g) in 66% yield: 1H NMR (500 MHz, CDCl3) δ 8.81 (d, 2 H), 7.93 (d, 1 H), 7.88 (d, 2 H), 7.32 (m, 1 H), 6.82 (d, 2 H), 6.57 (s, 2 H), 4.45 (t, 2 H), 3.75 (t, 2 H), 3.44 (s, 3 H), 1.99 (s, 6 H), ESI-MS=m/z 477.2 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:10]2[C:5](=[CH:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][O:2]1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[O:19]1[CH:6]2[C:5]31[CH:10]([CH2:9][CH2:8][CH2:7]2)[CH2:1][O:2][CH2:3][CH2:4]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=C2CCOCC2CCC1
Solvent: ClCCl
Product: C1CC2COCCC23OC3C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3,4,6,7,8,8a-hexahydro-1H-isochromene (0.120 g, 0.868 mmol) in CH2Cl2 (6 mL) at 0° C. was added MCPBA (˜77%, 0.300 g, 1.30 mmol). The mixture was stirred at rt for 1 hr. It was quenched with sat'd. aq. sodium sulfite. The mixture was diluted with CH2Cl2 and said. aq. NaHCO3 then extracted with CH2Cl2. The combined organics were dried (anhd. Na2—SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][NH2:13].[BH4-].[Na+]>CO>[CH3:12][NH:13][CH2:10][C:2]1[S:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: O=Cc1cc2cnccc2s1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc2cnccc2s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A solution of thieno[3,2-c]pyridine-2-carbaldehyde (720 mg, 4.41 mmol) in a 2.0 M solution of methylamine in methanol (25 mL) was stirred at room temperature for S hours. After this time, the mixture was concentrated to dryness, dissolved in anhydrous methanol (10 mL) then cooled to 0° C. To this solution was added NaBH4 (167 mg, 4.41 mmol) in one portion. The mixture was allowed to warm to room temperature and stirred at this temperature overnight. The mixture was concentrated, dissolved in CH2Cl2 (100 mL) and treated with 1.0 N NaOH (20 mL). The aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic fractions were washed with brine, dried over Na2SO4 then concentrated to give a yellow residue which was subjected to flash chromatography on silica gel (10% 2M NH3 in MeOH:CH2Cl2). The title compound was obtained as a white solid in 63.6% yield: 1H-NMR (300 MHz, CDCl3) δ 9.01 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 7.76 (d, J=5.5 Hz, 1H), 7.29 (s, 1H), 4.10 (s, 2H), 2.54 (s, 3H); MS (ES) m/e 179 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:9](OC)([O:10]C)[CH2:8][CH2:7][N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5]1)[CH3:2].O.C(O)(C(F)(F)F)=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[CH2:1]([O:3][CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][N:6]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5]1)[CH3:2]
Reactant: CCOC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC1CN(C(=O)OC(C)(C)C)CCC1=O
Yield: 95.5 %

Procedure:
The same operation as in Example (90b) was performed using tert-butyl 3-ethoxy-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (112a) (4.99 g, 14.2 mmol), a water/TFA mixed solution (1/1, 35 mL) and di-tert-butyl dicarbonate (4.37 g, 20 mol). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 3.3 g of the title compound as a light brown oily substance (77%).