Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)C.[Pt]=O>[C:1]1([C:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]2)([CH2:11][CH2:12][N:13]([CH:14]([CH3:16])[CH3:15])[CH:17]([CH3:18])[CH3:19])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N(CCC(C(N)=O)(c1ccccc1)c1ccccn1)C(C)C
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CC(C)N(CCC(C(N)=O)(c1ccccc1)C1CCCCN1)C(C)C
Yield: 24.3 %

Procedure:
A mixture of 105.3 g (0.31 mole) of racemic 2-phenyl-2-(2-pyridyl)-4-[N,N-bis(1-methylethyl)amino]butanamide and 27 ml (ca. 0.32 mole) of concentrated aqueous hydrochloric acid in 2.5 liters of ethanol was hydrogenated (50 psi) over platinum oxide catalyst. After filtration to remove the catalyst, the reaction mixture was reduced to a syrupy residue, dissolved in an ice/water mixture, and neutralized with a slight excess of 25% sodium hydroxide. The product mixture was extracted into diethyl ether, which was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was crystallized twice from Skellysolve B containing a small amount of diethyl ether, to yield 26.0 g of the title compound as a white solid, m.p. 107°-108°. Structure assignment was confirmed by proton and carbon-13 NMR spectra and by elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][C:37]4([OH:44])[CH2:42][CH2:41][S:40](=[O:43])[CH2:39][CH2:38]4)=[CH:30][C:29]=3[CH3:45])[CH:25]=[CH:26][CH:27]=2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH:5]=[CH:4][C:3]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].SCC(O)=O.O.[OH-].[Li+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:29]([CH3:45])=[CH:30][C:31]([O:35][CH2:36][C:37]4([OH:44])[CH2:42][CH2:41][S:40](=[O:43])[CH2:39][CH2:38]4)=[CH:32][C:33]=3[CH3:34])[CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:4][C:3]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49]
Reactant: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(OCC4(O)CCS(=O)CC4)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(OCC4(O)CCS(=O)CC4)cc3C)c2)cc1F
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl) [(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (2.24 g, 3.04 mmol) in ethyl acetate (15 mL) was added m-chloroperbenzoic acid (70%, 0.46 g, 1.88 mmol) under stirring at 0° C., and the mixture was stirred at room temperature for 3 days. The reaction mixture was washed with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-ethyl acetate-ethyl acetate/methanol=17/3) to give ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxy-1-oxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.36 g, yield 60%) as a colorless amorphous powder. To a solution of the obtained ethyl 3-(2-fluoro-4-{({4′-[(4-hydroxy-1-oxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.36 g, 1.81 mmol) and mercaptoacetic acid (0.38 mL, 5.43 mmol) in N,N-dimethylformamide (10 mL) was added lithium hydroxide monohydrate (0.46 g, 10.86 mmol) under stirring at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-ethyl acetate) to give the title compound (0.52 g, yield 50%) as a colorless oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:30]([N:32]1[CH2:73][CH2:72][CH2:71][C@H:33]1[C:34]([NH:36][C@H:37]([C:49]([NH:51][C@H:52]([C:56]([NH:58][C@H:59]([C:68]([NH2:70])=[O:69])[CH2:60][C:61]1[CH:66]=[CH:65][C:64]([OH:67])=[CH:63][CH:62]=1)=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50])[CH2:38][C:39](=[O:48])[O:40]CC1C=CC=CC=1)=[O:35])=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:29])[N:8](C(OCC1C=CC=CC=1)=O)C(OCC1C=CC=CC=1)=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C@H:2]([C:30]([N:32]1[CH2:73][CH2:72][CH2:71][C@H:33]1[C:34]([NH:36][C@H:37]([C:49]([NH:51][C@H:52]([C:56]([NH:58][C@H:59]([C:68]([NH2:70])=[O:69])[CH2:60][C:61]1[CH:62]=[CH:63][C:64]([OH:67])=[CH:65][CH:66]=1)=[O:57])[CH:53]([CH3:54])[CH3:55])=[O:50])[CH2:38][C:39](=[O:40])[OH:48])=[O:35])=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:29]
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Yield: 102.1 %

Procedure:
Z-Arg(Z,Z)-Pro-Asp(OBzl)-Val-Tyr-NH2 (0.5 g) was hydrogenated with Pd-black (0.5 g) and ammonium formate (0.5 g) in CH3OH (40 ml) overnight. The catalyst was filtered and the filtrate was removed on rotary evaporator. The residue was dissolved in H2O and lyophilized. The crude peptide was then placed on a Sephadex DEAE column (60 cm×2.5 cm) and eluted with 0.01M NH4HCO3 ; pH 7.9. The flow rate was 90 ml/hr and fractions of 10 ml were collected. The peptide was eluted between tubes 17-29, which were pooled and lyophilized to give 290 mg of the title product.
Reaction SMILES: CC(C)([O-:4])C.[K+].[C:7]([O:11][C:12](=[O:36])[NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]2[CH2:33][C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=4)[N:25]=[CH:24][C:23]=3[O:22][CH2:21]2)[CH2:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8]>CS(C)=O.C(O)(C)(C)C>[C:7]([O:11][C:12](=[O:36])[NH:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([CH:20]2[CH:33]([OH:4])[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=4)[N:25]=[CH:24][C:23]=3[O:22][CH2:21]2)[CH2:18][CH2:19]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: COc1ccc2ncc3c(c2c1)C(O)C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (354 mg, 3.15 mmol, 2.5 eq) is added at room temperature to a stirred solution of [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester (2.6 g, 1.26 mmol, 1.0 eq) in dimethyl sulfoxide (45 mL) and tert-butanol (13 mL) under oxygen atmosphere. After 1 hour stirring under oxygen atmosphere, the reaction mixture is purged with nitrogen, and extracted with dichloromethane (3×200 mL) and water (200 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 250:1 to 100:1, v/v) to afford [trans-4-(4-hydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester as a white solid that is further purified by preparative HPLC to obtain a white solid (70 mg, 42% yield).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[I-:16].[K+]>O.CS(C)=O.OS(O)(=O)=O>[F:15][C:14]1[C:6]([I:16])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: [I-]
Reactant: Nc1c(F)cccc1C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cccc(F)c1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Sodium nitrite (6.7 g, 97 mmol) in water (25 mL) was added to a solution of 2-amino-3-fluorobenzoic acid (10.0 g, 64 mmol) in DMSO (25 mL) and 30% H2SO4 (75 mL) at 0° C. The mixture was stirred for 1 hour at 0° C. and then potassium iodide (27 g, 161 mmol) was added dropwise as a solution in water (25 mL). The ice bath was removed and the mixture was stirred at room temperature for 4 hours, and then partitioned between EtOAc and 2M sodium sulfite. The layers were mixed, separated, and the organic layer was washed with 2M sodium sulfite once and brine once, dried over anhydrous MgSO4, and concentrated in vacuo to give 14.90 g of a yellow solid. MS m/e=265 (M−H)+.
Reaction SMILES: [N+:1]([CH:4]1[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[N:6]([CH:12]([CH3:14])[CH3:13])[CH2:5]1)([O-])=O.[N+](C1CN(CC)N(CC)C1)([O-])=O>>[NH2:1][CH:4]1[CH2:5][N:6]([CH:12]([CH3:13])[CH3:14])[N:7]([CH:9]([CH3:11])[CH3:10])[CH2:8]1
Reactant: CC(C)N1CC([N+](=O)[O-])CN1C(C)C
Agent: CCN1CC([N+](=O)[O-])CN1CC
Product: CC(C)N1CC(N)CN1C(C)C

Procedure:
Following the procedure of Example 6, but substituting an equal molar amount of 4-nitro-1,2-diisopropyl-pyrazolidine for 4-nitro-1,2-diethyl-pyrazolidine, the title compound is obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:19](=[O:21])[CH3:20])[CH2:14]2)=[O:10])=[C:7]([O:24][CH2:25][CH3:26])[CH:6]=1)(=[O:3])[CH3:2].[Cl:27]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([NH:4][C:5]1[C:23]([Cl:27])=[CH:22][C:8]([C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:19](=[O:21])[CH3:20])[CH2:14]2)=[O:10])=[C:7]([O:24][CH2:25][CH3:26])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOc1cc(NC(C)=O)ccc1C(=O)NCC1CN(C(C)=O)CCO1
Solvent: CN(C)C=O
Product: CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)NCC1CN(C(C)=O)CCO1
Yield: 67.4 %

Procedure:
A solution of 19 (1.78 g, 4.9 mmol) and N-chlorosuccinimide (0.687 g, 5.1 mmol, 1.05 equiv) in DMF (30 mL) was stirred for 1 h at 70° C. The reaction mixture was then concentrated under reduced pressure to dryness. The residue was triturated with H2O and the resulting solids were removed by filtration and recrystallized from CH3OH to yield 20 (1.314 g).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C)C=O>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Cc1ccc(Oc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(OC[C@@H]3CCCN3C(=O)OC(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79 %

Procedure:
4-p-Tolyloxy-phenol (2 g, 9.98 mmol) was taken into anhydrous dimethylformamide (40 mL) and cooled to 0° C. A 60% dispersion of Sodium hydride (0.52 g, 13 mmol) was added portionwise over 10 min. The reaction was kept at 0° C. for 45 min. and then heated to 35° C. for 15 min. (S)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.26 g, 11.9 mmol) was taken into anhydrous dimethylformamide (20 mL) and added to the reaction dropwise over 5 min. The reaction was heated at 75° C. for 12 h. The reaction was quenched with water under nitrogen atmosphere. The mixture was extracted with ethyl acetate (3×). The ethyl acetate was washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude product was purified by flash chromatography (20:1 silica ratio, eluted with 10% ethyl acetate in hexane) to obtain the title product (3.02 g, 7.88 mmol, 79% yield); MS; m/z 383, found 384 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 1.40 (s, 9H), 1.80 (s, 1H), 1.89-1.92 (m, 3H), 2.26 (s, 3H), 3.27 (s, 2H), 3.86 (s, 1H), 4.00-4.06 (m, 2H), 6.81-6.83 (m, 2H), 6.91-6.98 (m, 4H), 7.13-7.15 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13])[O:8][CH:7]([C:15]([F:18])([F:17])[F:16])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:14][C:10]1[C:11]([O:12][CH3:13])=[C:2]([Cl:1])[CH:3]=[C:4]2[C:9]=1[O:8][CH:7]([C:15]([F:18])([F:16])[F:17])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(OC)c(C)c2OC1C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1=Cc2cc(Cl)c(OC)c(CBr)c2OC1C(F)(F)F
Temperature: 60 °C

Procedure:
The ethyl 6-chloro-7-methoxy-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 3a, Step 3 (3.3 g, 9.4 mmole) was dissolved in CCl4 (30 mL) and the solution was heated to 60° C. NBS (1.84 g, 10.3 mmole) and Bzo2O (100 mg) were added to the above warm solution and the reaction was heated to reflux overnight. Additional NBS (1.84 g, 10.3 mmole) and Bzo2O (100 mg) were added to the above warm solution and the reaction was heated for 2 hrs. LCMS indicated that >95% product was formed. The reaction was cooled down and solid was filtered off. The filtrate was washed with NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and evaporated to dry. The crude compound was used as crude (1H NMR indicated that the ratio of starting material/product is 40/60).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].S(OS([O-])(=O)=O)([O-])(=O)=O.[Ce+3].S(OS([O-])(=O)=O)([O-])(=O)=O.S(OS([O-])(=O)=O)([O-])(=O)=O.[Ce+3].[CH3:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[C:1]([O:4][CH2:5]/[CH:6]=[CH:2]/[CH2:1][O:4][CH2:5][C:38]1[CH:37]=[CH:36][CH:41]=[CH:40][CH:39]=1)(=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCCCCC
Agent: O=S(=O)([O-])OS(=O)(=O)[O-]
Agent: [Ce+3]
Product: CC(=O)OC/C=C/COCc1ccccc1

Procedure:
TLC: Rf =0.52, silica gel, 20% ethyl acetate in hexane, UV & cerium disulfate.
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].[H-].[Na+].[C:14]([C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=2)[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]1)#[N:15].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])[CH:24]=2)[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]1)#[N:15]
Reactant: CC1CC(C#N)(c2cccc(I)c2)CCO1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CC(C#N)(c2cccc(S[Si](C(C)C)(C(C)C)C(C)C)c2)CCO1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
To a stirred solution of triisopropylsilanethiol (Tetrahedron Lett. 1994, 35, 3221.; 684 mg, 3.6 mmol) in toluene (5 ml) was added sodium hydride (60% oil dispersion, 144 mg, 3.6 mmol) under a nitrogen atmosphere. After stirring for 15 min, the resulting solution was added to a mixture of (2SR, 4RS)-4-cyano-4-(3-iodophenyl)-2-methyl-3,4,5,6-tetrahydro-2H-pyran (1.07 g, 3.27 mmol) and tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.1 mmol) in toluene (20 ml), and the mixture was heated at 80° C. for 1 h. The resulting mixture was cooled, poured into water (50 ml) and extracted with Et2O (100 ml). The organic extract was washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated. Purification by silica gel column chromatography, eluting with ethyl acetate-hexane (1:9), gave 1.23 g (96%) of the titled compound as a red oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[N:9]=[CH:8][CH:7]=[C:6]2[O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:29])=[C:23]([F:38])[CH:22]=1)#[N:2].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH:60]1([NH2:63])[CH2:62][CH2:61]1.O.[OH-].[Na+]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([NH:63][CH:60]1[CH2:62][CH2:61]1)=[O:18])[N:9]=[CH:8][CH:7]=[C:6]2[O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[O:29])=[C:23]([F:38])[CH:22]=1)#[N:2]
Reactant: NC1CC1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCCCC(=O)NC1CC1

Procedure:
N-(4-(6-Cyano-7-(3-carboxypropoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea (100 mg) was dissolved in dimethylformamide (3 ml), and then 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (44 mg) and 1-hydroxy-1H-benzotriazole (35 mg) were added while stirring on ice and the mixture was stirred at room temperature for 30 minutes. Cyclopropylamine (16 μl) was then added and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was poured into 1N sodium hydroxide water and extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine and dried over magnesium sulfate. The organic layer was concentrated, and the obtained solid was washed with ether and a small amount of ethyl acetate to obtain 38 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](S(C1C=CC=CC=1)(=O)=O)[C:7]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:6]2>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:6]2
Reactant: COc1ccc2c(c1)cc(S(N)(=O)=O)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2[nH]c(S(N)(=O)=O)cc2c1
Temperature: 90 °C
Yield: 4647.7 %

Procedure:
5-methoxy-1-benzenesulfonyl-2-sulfamoylindole (22.0 gm, 0.97 mmol) was dissolved in 10% sodium hydroxide (250 ml) and warmed to 90° C. for 1 hour. The cooled reaction mixture was extracted with ethyl acetate (2×150 ml) and neutralized with concentrated hydrochloric acid. The precipitate was collected via filtration and the filtrate was extracted with ethyl acetate (4×200 ml). The precipitate collected earlier was combined with the extracts and the extracts were washed with water (2×100 ml), brine (2×100 ml) and dried (MgSO4). The organic solvent was removed under vacuum to yield a brown solid 10.2 gm. The solid was recrystallized from water using decolorizing carbon to yield white crystals; 4.5 gm., m.p. 208°-209° C.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[CH2:13][CH2:14][C@:15]4([CH3:25])[C@@:19]5([O:24][C:22](=[O:23])[CH2:21][CH2:20]5)[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH:10]=[CH:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.CC([O:29]C([C@H]1[C@H]2[C@H]3[C@](C)(CC[C@@H]2[C@]2(C)C(=CC(CC2)=O)C1)[C@@]1(OC(=O)CC1)CC3)=O)C.C[C@@]12[C@H]3CC[C@]4(C)[C@](O)(CCC(O)=O)CC[C@H]4[C@@H]3[C@H](C(OC)=O)CC1=CC(=O)CC2.C[C@@]12[C@H]3CC[C@]4(C)[C@](O)(CCC(O)=O)CC[C@H]4[C@@H]3[C@@H]3[C@@H](C3)C1=CC(=O)CC2.CC(S[C@H]1[C@H]2[C@H]3[C@](C)(CC[C@@H]2[C@]2(C)C(=CC(CC2)=O)C1)[C@@]1(OC(=O)CC1)CC3)=O.C[C@@]12[C@](O)(C)CC[C@H]1[C@@H]1CC[C@@]34O[C@]3(C)C(O)=C(C#N)C[C@]4(C)[C@H]1CC2.CC(S[C@H]1[C@H]2[C@H]3[C@](C)(CC[C@@H]2[C@]2(C)C(=CC(C=C2)=O)C1)[C@@]1(OC(=O)CC1)[C@@H]1[C@H]3C1)=O.CCC[C@H]1[C@H]2[C@H]3[C@](C)(CC[C@@H]2[C@]2(C)C(=CC(CC2)=O)C1)[C@](O)(CCC(O)=O)CC3.C[C@@]12[C@@]3(OC(=O)CC3)[C@@H]3[C@@H](C3)[C@H]1[C@@H]1[C@@H]3[C@H](C4[C@@](C)([C@H]1CC2)C=CC(=O)C=4)C3.CC(S[C@H]1[C@H]2[C@H]3[C@](C)(CC[C@@H]2[C@]2(C)C(=CC(CC2)=O)C1)[C@@]1(OCCC1)CC3)=O.C[C@@]12[C@H]3CC[C@]4(C)[C@@]5(OC(=O)CC5)CC[C@H]4[C@@H]3[C@H]3[C@H](C3)C1=CC(=O)CC2.C[C@@]12[C@@]34O[C@@H]3C[C@]3(C)[C@@]5(OC(=O)CC5)CC[C@H]3[C@@H]4[C@H](C(OC)=O)CC1=CC(=O)CC2>>[CH3:1][C@@:2]12[C@H:12]3[CH2:13][CH2:14][C@:15]4([CH3:25])[C@:19]([OH:29])([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH:10]=[CH:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2
Reactant: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]21CCC(=O)O1
Reactant: CC(C)OC(=O)[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC[C@@]34CCC(=O)O4)[C@H]12
Agent: CC(=O)S[C@@H]1CC2=CC(=O)C=C[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H]([C@@H]4C[C@@H]4[C@@]34CCC(=O)O4)[C@H]12
Agent: CC(=O)S[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC[C@@]34CCC(=O)O4)[C@H]12
Agent: CC(=O)S[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC[C@@]34CCCO4)[C@H]12
Product: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(O)CCC(=O)O

Procedure:
canrenone; dicirenone; mexrenoate; prorenoate; spironolactone, epostane, mespirenone; oxprenoate, spirorenone, spiroxasone, prorenone, eplerenone.
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[O:16][CH3:17])=[O:7])C.OS(O)(=O)=O.N>>[F:15][C:11]1[C:10]([O:16][CH3:17])=[C:9]2[C:14]([CH:4]=[CH:5][C:6]([OH:7])=[N:8]2)=[CH:13][CH:12]=1
Reactant: CCO/C=C/C(=O)Nc1cccc(F)c1OC
Agent: N
Agent: O=S(=O)(O)O
Product: COc1c(F)ccc2ccc(O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of (E)-N-(3-fluoro-2-methoxyphenyl)-3-ethoxypropenamide (3a) (3.16 g, 13.2 mmol) and 25 mL of concentrated H2SO4 was allowed to stir overnight at room temperature. The solution was poured over ice and concentrated NH3 was added until pH 5 to precipitate out the product. The mixture was filtered, washed and dried to give the product (2.55 g, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 11.35 (bs, 1H), 7.86 (d, J=9.6Hz, 1H), 7.41 (dd, J=8.8, 5.6 Hz, 1H), 7.08 (dd, J=11.2, 8.8 Hz, 1H), 6.45 (d, J=10 Hz, 1H), 3.87 (s, 3H). 19F NMR (376 MHz, DMSO-d6) −128.88 (dd, J=11.5, 5.5 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][NH:21][C:22](=[O:29])[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:26]1[CH2:27][CH2:28][CH:23]([C:22]([NH:21][CH3:20])=[O:29])[CH2:24][CH2:25]1
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)cc(Cl)c2c1
Reactant: CNC(=O)C1CCNCC1
Product: CNC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccc(F)cc23)CC1

Procedure:
The named compound was made in a manner analogous to that of Example 4(c) using 4-chloro-2-(4-chlorophenyl)-6-fluoroquinoline, prepared as described in Example 4(b), and N-methylisonipecotamide as starting materials. It was obtained as colorless needles, mp 279°-282°dec on recrystallization from pyridine.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[CH2:14]([C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH:23]=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH:23]=[CH:5][C:6]#[N:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=Cc1ccc(Cl)cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 10.5 g (0.437 mole) of mineral oil free sodium hydride in 1.2 liters of tetrahydrofuran was added dropwise 58.4 g (0.328 mole) of diethylcyanomethyl phosphonate. After the hyrogen evolution had ceased ca 60 min, 69.4 g (0.3 mole) of 2-benzyl-4-chlorobenzaldehyde, in 75 ml of tetrahydrofuran was added dropwise. The mixture was stirred overnight at room temperature. The tetrahydrofuran solution was decanted, and concentrated at room temperature. The residue was partitioned between 2 liters of water and 1.5 liters of ether. The ether solution was separated, washed with water, and dried with sodium sulfate. The ether was removed at reduced pressure to give a yellow oil which was used without further purification.