Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15](=[O:17])[CH3:16].[C:18]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[C:18]([N:26]1[CH2:31][CH2:30][C:29]2([CH2:16][C:15](=[O:17])[C:8]3[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=3[O:6]2)[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: COc1ccc(O)c(C(C)=O)c1
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3ccccc3)CC1)O2
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
Pyrrolidine (8.35 ml, 7.11 g, 0.1 mol) was added to a suspension of 2'-hydroxy-5'-methoxyacetophenone (16.62 g, 0.1 mol) in methanol (100 ml). The mixture was stirred for 10 minutes, then 1-benzoyl-4-piperidone (20.32 g, 0.1 mol) was added and the mixture was heated under reflux for 7 hr. The mixture was cooled and the solvent was evaporated under reduced pressure. Water (400 ml) was added and the mixture was extracted with ethyl acetate (3×400 ml). The combined organic fractions were evaporated under reduced pressure and the residue was recrystallized from methanol to give the ketone as a pale yellow solid (29.54 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[CH3:11].[S:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)(=[O:15])(=[O:14])[NH2:13]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:20][C:19]2[CH:21]=[CH:22][C:16]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:17][CH:18]=2)=[CH:5][C:4]=1[CH3:11]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(C=O)cc1C
Product: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-methoxy-3-methylbenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a yellow powder (yield 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][N:17]=[C:16]([O:19][CH3:20])[C:15]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:24][CH3:25])[N:17]=[C:16]([O:19][CH3:20])[C:15]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1n[nH]c(C2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc(OC)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.83 h

Procedure:
A solution of 30 mg (0.10 mmol) of 1-tert-butoxycarbonyl-4-(3-methoxy-4-methyl-(1H)-pyrazol-5-yl)piperidine (from Step D) in 1 mL of DMF at 0° C. was treated with 3.5 mg (0.15 mmol) of 95% NaH and 0.012 mL (0.15 mmol) of ethyliodide. After 50 minutes, the reaction was partitioned between 25 mL of EtOAc and 25 mL of brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 99:1 v/v CH2Cl2/acetone, 98:2 v/v CH2Cl2/acetone and 97:3 v/v CH2Cl2/acetone as the gradient to afford the title compound: RF: 0.39 (19:1 v/v CH2Cl2/acetone); 1H-NMR (500 MHz) δ 1.33 (t, J=7.1, 3H), 1.49 (s, 9H), 1.69–1.72 (m, 2H), 1.82–1.90 (m, 2H), 1.91 (s, 3H), 2.68–2.74 (m, 3H), 3.88 (s, 3H), 3.98 (q, J=7.1, 2H), 4.25 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.[CH3:11][Li]>CCOCC>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[N:3][CH:4]=1)(=[O:10])[CH3:11]
Reactant: O=C(O)c1ccc(F)nc1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 20 gm. (142 mmoles) of 2-fluoro-5-pyridinecarboxylic acid (J. Am. Chem. Soc., 71, 1125 (1949)) in 750 ml of ether, stirred and cooled in ice, was added 225 ml of 1.6M methyl lithium (360 mmoles) in ether over 1 hour. The reaction was stirred for an additional 2 hours, then 300 ml of ice water was added. The aqueous layer was washed with 2×100 ml fresh ether, acidified and extracted with ether to give 5.0 gm. (25%) of unreacted starting acid.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][C:4]#[C:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=2[F:25])[N:8](C(OC(C)(C)C)=O)[CH:7]=1.[NH4+].[Cl-]>C1COCC1.CO.CCOC(C)=O.[Zn]>[CH3:33][N:2]([CH3:1])[CH2:3][C:4]#[C:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=2[F:25])[NH:8][CH:7]=1
Reactant: CN(C)CC#Cc1cn(C(=O)OC(C)(C)C)c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CC#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a mixture of tert-butyl 3-(3-(dimethylamino)prop-1-ynyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (170 mg, 0.374 mmol) in THF (10 mL) and MeOH (10 mL), was added Zn powder (<10 micron, 500 mg) and NH4Cl (500 mg). The reaction mixture was stirred at rt for 2 h, diluted with EtOAc, and filtered through a pad of Celite®. The filtrate was washed with sat. aq. KH2PO4 solution, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (110 mg, 90%) as a yellow solid. LC/MS(ESI+) m/z 325 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)=[O:4].Br[C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.[Al+3].[Cl-].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[CH:8][CH:9]=1)=[O:4]
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)o1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Furan-2-carboxylic acid methyl ester (500 mg, 3.97 mmol) and 1-bromo-adamantane (853 mg, 3.97 mmol) were dissolved in ortho-dichlorobenzene (6 ml) and cooled to 0° C. before adding AlCl3 (1.06 g, 7.94 mmol) as a solid. The reaction mixture was allowed to warm up to room temperature, stirred for 4 h, then heated to 40° C. for 2 h and left standing at room temperature overnight. The reaction mixture was cooled to 0° C. and quenched with H2O (10 ml). The organic layer was separated and the aqueous layer was extracted with DCM (3×20 ml). The combined organic layers were dried (MgSO4), filtered and the DCM removed in vacuo. The ortho-dichlorobenzene solution was loaded to a silica-gel column and flushed with heptane (100 ml). The title compound was then eluted using a stepped gradient of 0-10% EtOAc in heptane.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)([CH3:3])[CH3:2].[C:9]1([OH:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>>[C:9]1([O:19][CH2:5][CH:6]([OH:8])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccc2ccccc12
Reactant: CC(C)N1CC(O)C1
Product: CC(C)NCC(O)COc1cccc2ccccc12

Procedure:
1-(isopropyl)-3-azetidinol and α-naphthol were reacted in the same manner as in Example 6 to form 1(-α-naphthoxy)-3-(iso-propylamino)-2-propanol. Then the propanol was dissolved in anhydrous ether and was converted to a hydrochloride by blowing a hydrochloric acid gas into the resulting solution. As a result, 1-(α-naphthoxy)-3-(iso-propylamino)-2-propanol hydrochloride melting at 162°-164° C. was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:32]=[CH:31][C:15]([C:16]([NH:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:28](O)=[O:29])=[O:17])=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:28]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:29])=[O:17])=[CH:31][CH:32]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(C(=O)Nc2c(C(=O)O)[nH]c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2[nH]c3ccccc3c2NC(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 14.2 %

Procedure:
To a solution p-anisidine (79 mg, 0.645 mmol) in methylene chloride (5 mL) was added 3-(4-methoxybenzoyl)amino-2-indolecarboxylic acid (200 mg, 0.645 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (247 mg, 1.29 mmol), and 4-dimethylaminopyridine (8.0 mg, 0.065 mmol). The resulting solution was stirred at room temperature for 6 h. The resulting precipitate was collected via vacuum filtration to provide 38 mg (14%) of the title compound as a white solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:19]1([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: c1cnc2c(c1)NCC2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2ncccc21
Yield: 55.1 %

Procedure:
The product is prepared according to the procedure described in example 5, using 350 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 177 mg of 4-azaindoline and 340 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 216 μl of pyridine and 6.5 ml of N,N-dimethylformamide. 252 mg of 2-[2-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:14][CH2:15][CH2:16]Br)[CH2:12]Br.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:16][CH2:15][O:14][CH2:11][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: BrCCOCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Yield: 65 %

Procedure:
(R)-(+)-1-(4-Bromophenyl)ethylamine (0.98 g), 2,2′-dibromodiethyl ether (1.36 g) and diisopropylethylamine (2.5 ml) were stirred in dimethylformamide (20 ml) under argon at 100° C. for 18 h. The reaction mixture was allowed to cool to room temperature, then partitioned between diethyl ether (50 ml) and water (50 ml). The aqueous phase was extracted further with diethyl ether (50 ml) and the combined organic phases were washed with water (100 ml), dried (MgSO4), concentrated in vacuo, redissolved in toluene and purified by Bondelute® chromatography, eluting with 0–50% ethyl acetate/iso-hexane to give the product as a yellow oil (0.86 g).
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S([O-])(=O)=O)=C[CH:2]=1.[NH+]1C=CC=CC=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[C:21]([OH:28])[CH:20]=1.C(OCC)(=O)C>COC(OC)(C)C>[F:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[NH:25][C:1]([CH3:6])([CH3:2])[O:28][C:21]=2[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: NC(=O)c1ccc(F)cc1O
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)c2ccc(F)cc2O1
Temperature: 83 °C
Yield: 701.1 %

Procedure:
Pyridinium toluene-4-sulfonate (49 mg, 0.19 mmol) was added to a mixture of 4-fluoro-2-hydroxybenzamide (0.3 g, 1.93 mmol) in 2,2-dimethoxypropane (5 mL) and heated at 83° C. for 20 hours. The reaction mixture was reduced in vacuo and ethyl acetate (30 mL) added. The mixture was washed with 10% potassium carbonate solution (2×20 mL), brine (20 mL), dried (MgSO4), and reduced in vacuo to give a white solid. The material was chromatographed on silica, eluting with 40-70% ethyl acetate in isohexane, to give the desired compound as a white solid (0.26 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([C@@H:10]([OH:13])CO)[CH2:9][C@H:4]2[O:3]1.I([O-])(=O)(=O)=O.[Na+]>CO>[CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]=[O:13])[CH2:9][C@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2O[C@H]([C@@H](O)CO)C[C@H]2O1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Product: CC1(C)O[C@H]2O[C@H](C=O)C[C@H]2O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.3 %

Procedure:
To a solution of (1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]ethane-1,2-diol (compound 1c, 18 g, 90 mmol) in the MeOH (250 mL) cooled in ice bath was added sodium metaperiodate (23.1 g, 108 mmol). After being stirred at room temperature for 12 hours, the resulting suspension was filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:2 EtOAc in petroleum ether) to afford 14 g of (3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde (compound 1d). MS obsd. (ESI+) [(M+NH4)+]: 190.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][CH2:11][C:12]([OH:14])=[O:13]>CO.[C].[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: Cc1ccc(C=CCC(=O)O)c(C)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(CCCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 171.8 %

Procedure:
(2-Carboxyethyl)triphenylphosphonium bromide (150 g, 361 mmol) was suspended in tetrahydrofuran (500 mL) and 2,4-dimethylbenzaldehyde (55.4 mL, 397 mmol) was added thereto. A solution of potassium t-butoxide (81.1 g, 722 mmol) in tetrahydrofuran (300 mL) was added thereto under nitrogen atmosphere over 10 minutes and the mixture was stirred under ice-cooling for 3 hours. Water was added to the reaction mixture to stop the reaction and the temperature of the liquid was returned to room temperature. The mixture was concentrated under reduced pressure, a 8N aqueous sodium hydroxide solution was added thereto to bring pH to 11 and ether was added thereto to separate it. A 12N aqueous hydrochloric acid solution was added to an aqueous phase to bring pH to 2 and ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1-6:1) to obtain 4-(2,4-dimethylphenyl)-3-butenoic acid (37.0 g, yield: 54%). 10% Palladium-carbon (7.96 g, 50% hydrous) was added to a solution of the obtained 4-(2,4-dimethylphenyl)-3-butenoic acid (37.0 g, 195 mmol) in methanol (400 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After the palladium-carbon in the reaction mixture was Celite-filtered, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1) to obtain the title compound (64.4 g, yield: 84%).
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1.[SH2:24]>CN(C)C=O.N1CCOCC1>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[SH:24])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: S
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: C[C@]12C[C@H](O)[C@@]3(F)[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2S
Reaction time: 8 h

Procedure:
Into a chilled solution (ice bath) of 3 g of (11β)-9-fluoro-11-hydroxyandrosta-1,4-dien-3,17-dione in 12 ml of dimethylformamide and 15 ml of morpholine, there was introduced a stream of hydrogen sulfide. Once the exothermic reaction had ceased, the ice bath was removed, the hydrogen sulfide stream was reduced to about one bubble every two seconds and continued overnight. The next day the reaction mixture was poured into ice water, the resulting solid filtered off, washed with water, and dried to yield 3 g of crude product. HPLC analysis indicated the presence of 11% starting material and 88% product. The above 3 g were combined with 2 g of crude product that had been obtained from two earlier batches and chromatographed on silica gel. Elution with chloroform-20% ethyl acetate yielded 2 g of the title compound as a white solid. Crystallization from acetonitrile furnished the analytically pure sample (1.5 g), melting point 295°-297° C. Further elution gave 1 g of the starting steroid. Recrystallization of the thiol from acetic acid yielded needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.[S:35]1[CH:39]=[N:38][N:37]=[C:36]1[NH2:40].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:36]4[S:35][CH:39]=[N:38][N:37]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: Nc1nncs1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Yield: 75.8 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE NNN; 102.15 mg, 0.198 mmol), 1,3,4-thiadiazol-2-amine (40.1 mg, 0.396 mmol), cesium carbonate (194 mg, 0.594 mmol), and DMF (1 mL) (1:30 pm). The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7% MeOH/DCM) to give 1-(4-chloro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (64.78 mg, 0.150 mmol, 76% yield) as a white solid. m/z (ESI) 433.0 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.OS(O)(=O)=O.CCCCCC.[Pd]>[CH2:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(Cc2ccccc2)c1
Reaction time: 8 h

Procedure:
To a Parr bottle containing 3-benzoylbenzoic acid (0.044 moles) (Aldrich) in 150 mL of ethyl acetate and 4.5 mL of concentrated H2SO4 was added 10 grams of 5% Pd/C. The mixture was hydrogenated on a Parr apparatus under hydrogen (45 psi) overnight. The reaction mixture was then filtered through Hyflo, washing with ethyl acetate. The filterate was dried over Na2SO4, filtered and concentrated to give an oil. The oil was slurried in hexane and the resulting white solid was collected by filtration to afford 3-benzylbenzoic acid, which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([SH:7])[CH2:5][CH3:6].Cl[C:9]1[C:14]([CH2:15][CH3:16])=[N:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])=[C:11]([CH2:27][CH3:28])[N:10]=1>C1COCC1>[CH:4]([S:7][C:9]1[C:14]([CH2:15][CH3:16])=[N:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])=[C:11]([CH2:27][CH3:28])[N:10]=1)([CH2:5][CH3:6])[CH3:3]
Reactant: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1Cl
Reactant: CCC(C)S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1SC(C)CC
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
NaH (60 mg, 1.5 mmol. 60% in mineral oil) is added to a solution of butane-2-thiol (170 μL, 1.5 mmol) in THF (5 mL). After 10 minutes, 2-chloro-5-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine (100 mg, 0.33 mmol) in THF (1 mL) is added dropwise, and the mixture heated at 80° C. (oil bath temperature) for 16 hours. After extractive work-up, preparative thin layer chromatography (hexanes) furnishes the title compound as a clear oil (60 mg, 51%). NMR (CDCl3, 400 MHz) H-1: 7.19 (1H, d, J=8.4 Hz), 6.58 (1H, dd, J=2.4, 8.4 Hz), 6.60 (s, 1H, J=2.4 Hz), 3.99 (sext, 1H, J=6.8 Hz), 3.85 (3H, s), 3.75 (3H, s), 2.81 (2H, q, J=7.4 Hz), 2.58 (2H, br q, J=6.8 Hz), 1.6–1.9 (m, 4H), 1.44 (3H, d, J=6.4 Hz), 1.28 (t, 3H, J=7.6 Hz), 1.19 (3H, t, J=7.6 Hz), 1.06 (t, 3H, J=7.2 Hz). C-13: 161.10, 157.86, 153.49, 151.79, 151.67, 144.47, 131.68, 121.18, 104.78, 98, 60, 55.44, 55.33, 40.87, 29.65, 27.54, 27.08, 20.56, 12.43, 12.09, 11.51. MS: 414.2 (+1, positive mode) and 412.2 (M−1, negative mode).
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([O:12][C:13]2[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)=[O:17])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 63.6 %

Procedure:
To a solution of 4-fluoro-3-nitroaniline (1.0 g, 6.40 mmol) and 3-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide (1.80 g, 6.40 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.32 g, 9.60 mmol), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off and washed with ethyl acetate (150 mL). The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (1.70 g, 64%) as a red-orange powder.