Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[C:39]([C:44]([O:46]C)=[O:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+].O.Cl>C(O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[C:39]([C:44]([OH:46])=[O:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COC(=O)c1ccccc1-c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccccc2C(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′ methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-2-carboxylate (50 mg, 0.07 mmol), aqueous potassium hydroxide (1.1 mL, 3M, 3.3 mmol), water (1.5 mL) and ethanol (3.6 mL) were stirred at 20° C. for 23 hours. The reaction mixture was acidified by HCl (aq., 1N). Volatiles were removed under reduced pressure. The resulting mixture was worked up with ethyl acetate, washed with brine. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to an oil. This oil was purified by a reverse-phase preparative HPLC (column: Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% v/v TFA buffered)/H2O (0.1% v/v TFA buffered) gradient mixture to afford 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-2-carboxylic acid. LCMS calc.=697.15; found=698.16 (M+1)+. 1H NMR signals are doubled because of atropisomerism 1H NMR (CDCl3, 500 MHz) δ 7.94 (t, J=7.0 Hz, 1H), 7.85 (d, J=7.0 Hz, 1H), 7.68-7.63 (m, 2.5H), 7.63-7.59 (m, 1.5H), 7.59-7.54 (m, 1H), 7.47-7.35 (m, 4H), 7.14 (dd, J=8.0, 2.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 5.53 (d, J=8.0 Hz, 0.4H), 5.42 (d, J=8.0 Hz, 0.6H), 5.02 (d, J=15.5 Hz, 0.6H), 4.85 (d, J=15.5 Hz, 0.4H), 4.11-4.02 (m, 0.4H), 3.87-3.77 (m, 3.6H), 0.99 (d, J=6.5 Hz, 0.6H), 0.93 (d, J=7.0 Hz, 0.4H), 0.58 (d, J=7.0 Hz, 1.2H), 0.54 (d, J=6.5 Hz, 1.8H).
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[CH:6]1.[OH-].[K+]>C(O)C.O>[CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:6]1
Reactant: CCOC(=O)CCc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(CCc1ccccc1)C(=O)Cn1cc(CCC(=O)O)c2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 0.7 g (1.4 mmol) of N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyethyl)indol-1-yl]acetamide in 20 ml of ethanol is added a solution of 0.2 g of potassium hydroxide in 3 ml of water. The mixture is stirred at room temperature for 18 hours and concentrated in vacuo. The residue is dissolved in water and the resulting solution adjusted to pH 4 with 1N aqueous HCl solution. The precipitate which forms is extracted into ethyl acetate. The organic solution is washed with brine, dried over magnesium sulfate and concentrated in vacuo to give N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxyethyl)indol-1-yl]acetamide as a beige powder (m.p. 122°-125° C.).
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH2:10][C:11](=O)[C:12]3[CH:18]=[CH:17][CH:16]=[C:15](F)[C:13]=3[S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH2:21].NN>C(O)C.O1CCOCC1>[C:1]([C:4]1[C:9]2[CH2:10][CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:21])[C:13]=3[S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cccc2c1CC(=O)c1cccc(F)c1S2
Reactant: O
Agent: NN
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1cccc2c1CCc1cccc(O)c1S2
Reaction time: 2 h
Yield: 12.7 %

Procedure:
5.0 g of 9-carboxy-4-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one and 5.0 g of 100% hydrazine hydrate were dissolved in the mixed solvent of 50 ml of ethanol and 50 ml of dioxane. The resulting mixture was heated under reflux for 5 hours. The solvent was evaporated under reduced pressure to obtain the residue, which was washed with ethanol. To this was added 5.0 g of sodium hydroxide in 100 ml of diethylene glycol and the resulting mixture was heated with stirring at 180°-200° C. for 2 hours. After cooling, water was added to the mixture, which was extracted with benzene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain a glutinous residue which was chromatographed over silica gel, and eluted with benzene-ethyl acetate (1:1). Recrystallization of the thus obtained crude product from methanol-water afforded 600 mg of 9-carboxy-4-hydroxy-10,11-dihydrodibenzo-[b,f] thiepin having a melting point of 171°-173° C.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[C:8]2[CH2:16][OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[C:23]([F:26])[C:24]=1O.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[C:23]([F:26])[C:24]=1[O:17][CH2:16][C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[CH:10][C:9]=1[C:12]([F:13])([F:14])[F:15]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: OCc1c(C(F)(F)F)ccn1-c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccccc2)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [1-phenyl-3-(trifluoromethyl)-1H-pyrrol-2-yl]methanol (260 mg, 1.05 mmol, 1.00 equiv, 97%), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (281 mg, 1.22 mmol, 1.20 equiv), ADDP (642 mg, 2.56 mmol, 2.50 equiv), Bu3P (309 mg, 1.53 mmol, 1.50 equiv) and toluene (5 mL). The resulting solution was stirred overnight at 60° C. in an oil bath. The resulting mixture was then concentrated under vacuum. The resulting mixture was washed with diethyl ether (50 mL). The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to yield ethyl 3-(3,5-difluoro-4-[[1-phenyl-3-(trifluoromethyl)-1H-pyrrol-2-yl]methoxy]phenyl)propanoate as yellow oil (220 mg, 45%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([OH:12])=O)[CH2:2]2.[CH:13]([C:16]1[CH:17]=[C:18]([C:22]([NH2:25])([CH3:24])[CH3:23])[CH:19]=[CH:20][CH:21]=1)([CH3:15])[CH3:14]>>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([CH2:9][C:10]([NH:25][C:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]([CH3:15])[CH3:14])[CH:17]=1)([CH3:24])[CH3:23])=[O:12])[CH2:2]2
Reactant: O=C(O)CC1CN2CCC1CC2
Reactant: CC(C)c1cccc(C(C)(C)N)c1
Product: CC(C)c1cccc(C(C)(C)NC(=O)CC2CN3CCC2CC3)c1
Yield: 10 %

Procedure:
Using general procedure I, (1-aza-bicyclo[2.2.2]oct-3-yl)-acetic acid (200 mg, 1.20 mmol) and 1-(3-isopropyl-phenyl)-1-methyl-ethylamine gave the title compound as a white solid (42 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ 7.15-1.20 (m, 3H), 7.05 (d, J=8.4 Hz, 1H), 3.41-3.45 (m, 1H), 3.26 (s, 2H), 3.15-3.22 (m, 2H), 2.71-2.82 (m, 2H), 2.41-2.47 (m, 3H), 2.05-2.12 (m, 1H), 1.79-1.90 (m, 4H), 1.61 (d, J=8.0 Hz, 6H), 1.21 (d, J=6.4 Hz, 6H) ppm. 13C NMR (400 MHz, DMSO-d6) δ 171.1, 148.7, 147.3, 128.1, 123.9, 122.8, 122.2, 55.6, 52.1, 46.5, 45.9, 38.8, 34.5, 30.7, 28.9, 28.5, 23.8, 23.4, 18.0 ppm. Purity: 96.8% HPLCMS (210 nm); retention time 1.93 min; (M+1) 329.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:4]=1.[Cl:14][C:15]1[C:16]([O:38][CH3:39])=[CH:17][C:18]([O:36][CH3:37])=[C:19]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[CH2:24]2)[CH:20]=1>>[Cl:14][C:15]1[C:16]([O:38][CH3:39])=[CH:17][C:18]([O:36][CH3:37])=[C:19]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[C:26]([CH2:2][C:3]3[O:7][N:6]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[N:4]=3)=[C:25]([OH:30])[CH2:24]2)[CH:20]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: ClCc1nc(-c2ccccn2)no1
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc(-c4ccccn4)no3)C(=O)O2)cc1Cl
Yield: 9 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]pyridine (from Step 1, below) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 9%.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:11])=[CH:7][CH:8]=2)[C:3]1=O.Cl.[NH:14]1[CH:18]=[C:17]([CH2:19][C:20]([NH2:22])=[S:21])[N:16]=[CH:15]1>>[F:11][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C:2]3[S:21][C:20]([CH2:19][C:17]4[N:16]=[CH:15][NH:14][CH:18]=4)=[N:22][C:3]=3[C:4]=2[CH:5]=1
Reactant: O=C1c2cc(F)ccc2CC1Br
Reactant: NC(=S)Cc1c[nH]cn1
Agent: Cl
Product: Fc1ccc2c(c1)-c1nc(Cc3c[nH]cn3)sc1C2

Procedure:
Starting compounds: 2-bromo-6-fluoro-1-indanone, 4-imidazolylthioacetamide hydrochloride
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([C:8]([OH:10])=[O:9])[CH:5]=[N:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:16]O>>[NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([C:8]([O:10][CH3:16])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: CO
Reactant: Cc1c(N)cncc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cncc(N)c1C
Temperature: 50 °C
Reaction time: 64 h
Yield: 80 %

Procedure:
To a stirred solution of 5-amino-4-methylpyridine-3-carboxylic acid (0.94 g, 6.18 mmol) in MeOH (20 ml at 0° C. was added thionyl chloride drop-wise. The solution was then heated to 50° C. for 3.5 h, a further 10 ml of MeOH was added and the reaction heated at 50° C. for 5 h followed by stirring at room temperature for 64 h. The solvent was then evaporated under reduced pressure and saturated NaHCO3 solution was added until pH7-8. The product was extracted into EtOAc (2×50 ml) and the combined organics were washed with brine (50 ml) dried using Na2SO4, filtered and evaporated to afford the title compound as an off-white powder (824 mg, 80%) which was suitable for use in the next stage without any purification. LC-MS m/z=167.0, 1H NMR (500 MHz, Chloroform-d) δ 8.52 (d, J=34.2 Hz, 1H), 8.16 (s, 1H), 3.95 (d, J=4.8 Hz, 3H), 3.78 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:9]([CH3:15])([C:11](OC)=[O:12])[CH3:10])[C:5]([N+:21]([O-])=O)=[CH:4][N:3]=1.Cl>C(O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:21][C:11](=[O:12])[C:9]([CH3:15])([CH3:10])[N:8]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:6]=2[N:7]=1
Reactant: COC(=O)C(C)(C)N(CCC(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC(C)CCN1c2nc(Cl)ncc2NC(=O)C1(C)C
Temperature: 25 °C
Yield: 65 %

Procedure:
To a stirred solution of methyl N-(2-chloro-5-nitropyrimidin-4-yl)-2-methyl-N-(3-methylbutyl)alaninate (2.0 g, 5.8 mmol) in ethanol (125 mL) was added iron powder (3.2 g, 58 mmol), the resulting mixture was heated to reflux. 1N aqueous hydrochloric acid was added to the reaction mixture (added in small portions, 5.0 ml total), The reaction mixture was heated at reflux until the completion of the reaction as monitored by TLC. The reaction was cooled to room temperature and filtered. The filtrate was evaporated to give a residue which was triturated using isopropyl ether to give titled compound (yield: 65%). 1HNMR (300 MHz, CDCl3): δ 0.97 (s, 3H), 1.0 (s, 3H), 1.37-1.56 (m, 7H), 1.65-1.80 (m, 2H), 3.52-3.58 (m, 2H), 7.62 (s, 1H), 9.13 (br s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[CH:26]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=1)[CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>O1CCOCC1>[CH3:49][O:48][C:46]([C:43]1[CH:42]=[CH:41][C:40]([CH2:39][CH:26](/[CH:25]=[CH:24]/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][C:6]2=[O:10])[CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)=[CH:45][CH:44]=1)=[O:47]
Reactant: O=C1CCCN1CCCCl
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCCC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
2.33 g (14.4 mmol) of 1-(3-chloropropyl)pyrrolidin-2-one [CAS Reg. No. 91152-30-6] and 4.69 g (14.4 mmol) of anhydrous cesium carbonate are added to a solution of 3.2 g (7.2 mmol) of methyl 4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (enantiomer 1, Example 19A) in 50 ml of dry dioxane, and the mixture is then stirred at 60° C. for 12 h. The mixture is then filtered, and the filtrate is evaporated to dryness. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→2:1→1:1). This gives 2.98 g (5.23 mmol, 72% of theory) of a colorless oil.
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH2:11][CH:12]([CH2:17][CH2:18][C:19]([O-])=[O:20])[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=[C:7]([O:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:24])[CH:6]=1)(=O)C.[NH3:34]>CO>[OH:4][C:5]1[C:10]2[CH2:11][CH:12]([CH2:17][CH2:18][C:19]([NH2:34])=[O:20])[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=[C:7]([O:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:24])[CH:6]=1
Reactant: N
Reactant: CC(=O)Oc1cc(OC(C)CCCc2ccccc2)cc2c1CC(CCC(=O)[O-])C(C)(C)O2
Solvent: CO
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)OC(C)(C)C(CCC(N)=O)C2
Reaction time: 8 h

Procedure:
Methyl dl-3-[5-acetoxy-2,2-dimethyl-7-(5-phenyl-2-pentyloxy)-3,4-dihydro-2H-benzopyran-3-yl]propionate, 4.68 g (0.01 mole), is dissolved in methanol and anhydrous ammonia is passed through the mixture at room temperature. The resulting mixture is heated at reflux for two hours while passing ammonia through it. After standing overnight the volatiles are removed by evaporation and the residue purified by column chromatography on silica gel to provide dl-3-[5-hydroxy-2,2-dimethyl-7-(5-phenyl-2-pentyloxy)-3,4-dihydro-2H-benzopyran-3-yl]propionamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34].Cl.[C:39]1([S:45]([CH2:48][CH2:49][NH2:50])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([NH:50][CH2:49][CH2:48][S:45]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)(=[O:47])=[O:46])=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34]
Reactant: O=C(O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: NCCS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1)NCCS(=O)(=O)c1ccccc1

Procedure:
Prepared according to Procedure (I) utilizing 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furyl)-2-propenoic acid (0.25 g, 0.45 mmol), 2-(phenylsulfonyl)-ethylamine hydrochloride (0.30 g, 1.36 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.26 g, 1.36 mmol) and diisopropylethylamine (0.55 mL, 3.18 mmol) in acetonitrile. Electrospray MS m/z 683 (MH+).
Reaction SMILES: C[C:2]1[C:14]2[CH2:13][C:12]3[C:7](=CC=CC=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:13]1[C:14]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:7][CH2:12]1
Reactant: Cc1cccc2c1Cc1ccccc1-2
Agent: [Pd]
Product: c1ccc2c(c1)CCC2
Temperature: 250 °C
Yield: 96 %

Procedure:
The fraction was charged in an autoclave, and Pd/C (5% Pd supported on charcoal) was added in a proportion of 1% based on the fraction. The resulting mixture was heated to 250° C., followed by a reaction under spontaneous pressure for 2 hours. After completion of the reaction, the reaction mixture was analyzed by gas chromatography. A mixture of position isomers of methylfluorene was found to have been formed with a yield of 96% (based on methyltetrahydrofluorene), and indane with a yield of 99% (based on indene).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[C:14]([OH:16])[CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:28]([O:30][C:31](=[O:56])[CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]Br)[C:37]=1[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:29]>CC(C)=O.CN(C=O)C>[CH2:28]([O:30][C:31](=[O:56])[CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:16][C:14]2[CH:13]=[C:12]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH:15]=2)[C:37]=1[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:29]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CC(C)C(=O)c1cc(O)cc(-c2ccc3c(c2)OCO3)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)C(C)C)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 1-(3-benzo[1,3]dioxol-5-yl-5-hydroxy-phenyl)-2-methyl-propan-1-one (109 mg) in a mixture of acetone and DMF (2:1, 3 mL) were added cesium carbonate (624 mg) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (190 mg). The resulting mixture was stirred at 75° C. overnight. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 194 mg of the title compound (75% yield). HRMS calcd for C40H50O9 [M+Na]+ 697.3347, observed 697.3344.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[NH2:20][S:17]([C:11]1[C:10]([Cl:21])=[CH:9][C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)=[C:13]([CH:12]=1)[C:14]([O:16][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:15])(=[O:19])=[O:18]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: ClCc1ccccc1
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(C(=O)OCc2ccccc2)c(NCc2ccco2)cc1Cl

Procedure:
In a similar manner to Example 3, furosemide can be reacted with benzyl chloride in DMF to yield benzyl 5-aminosulfonyl-4-chloro-2-[(2-furanylmethyl)amino]benzoate.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)c(C)sc3n2)cc1
Reactant: NCCc1ccccc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccccc3)c3c(C)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein phenethylamine is reacted with 4-(4-chloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-phenethylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2ncccc2O)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ncccc3O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(3-hydroxy-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: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O)([OH:33])=[O:32]>C(O)C>[C:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1)([OH:33])=[O:32]
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: O=Cc1cccc(C(=O)O)c1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (20.3 mg, 0.0377 mM), then 3-carboxy-benzaldehyde (5.7 mg, 0.038 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was washed with methanol to thus give the title compound (14.0 mg, yield: 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:18](=O)[O:17][C:15](=[O:16])[C:5]2=[C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]=12.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>C1(C)C=CC=CC=1>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][N:24]1[C:15](=[O:16])[C:5]2[C:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][C:7]=3[C:2]([CH3:1])=[CH:3][C:4]=2[C:18]1=[O:17]
Reactant: CN(C)CCN
Reactant: Cc1cc2c(c3c1oc1ccccc13)C(=O)OC2=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(c3c1oc1ccccc13)C(=O)N(CCN(C)C)C2=O
Yield: 89.4 %

Procedure:
To 50 ml of toluene were added 140 mg of 4-methyldibenzofuran-1,2-dicarboxylic anhydride and 270 mg of N,N-dimethylethylenediamine. The mixture was azeotropicallyl refluxed for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethanol to obtain 160 mg (yield: 89%) of 2-(2-dimethylaminoethyl)-5-methyl-1H-benzofuro[3,2-e]isoindole-1,3(2H)-dione as light yellow needles.