Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[S:16][C:17]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=3F)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[S:16][C:17]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=3[NH2:30])=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ncc(C(=O)c3cccnc3F)s2)CC1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCCN(c2ncc(C(=O)c3cccnc3N)s2)CC1
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 100 %

Procedure:
A microwave vial was charged with tert-butyl-4-(5-(2-fluoronicotinoyl)thiazol-2-yl)-1,4-diazepane-1-carboxylate (300 mg, 0.75 mmol) and aqueous ammonium hydroxide (1 ml). The reaction mixture was stirred in the microwave at 110° C. for 25 minutes. The reaction mixture was concentrated in vacuo to afford the title compound (300 mg, 100%). The residue was used in the next step without any further purification. MS (ES+): 405
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[OH:1][CH:3]([CH2:4][NH:28][CH:25]([CH3:27])[CH3:26])[CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)[nH]c(=O)c2c1
Reactant: CC(C)N
Product: COc1ccc2nc(-c3ccc(OCC(O)CNC(C)C)cc3)[nH]c(=O)c2c1

Procedure:
This compound was prepared analogous to Example 4 from 2-[4-(1,2-epoxy-propoxy)-phenyl]-6-methoxy-3,4-dihydro-quinazolin-4-one and isopropylamine.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([O:10][C:11](=[O:24])[C:12](=[O:23])[CH2:13][C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[CH3:9].[NH4+].[Cl-]>C1COCC1>[CH2:8]([O:10][C:11](=[O:24])[C:12]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([OH:23])[CH2:13][C:14]([CH3:15])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:22])[CH3:9]
Reactant: Cl[Mg]C1CCCC1
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccccc1)C1CCCC1
Reaction time: 3 h

Procedure:
2.13 ml of a 2 M ethereal cyclopentyl magnesium chloride solution is added in drops at −70° C. to a solution of 1.0 g of 4-methyl-4-phenyl-2-oxopentanoic acid-ethyl ester in 20 ml of THF. After 3 hours at −70° C., the batch is poured into cold, saturated NH4Cl solution and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated by evaporation. Column chromatography on silica gel with ethyl acetate-cyclohexane yields 320 mg of the product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:31])=[C:16]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:33])[CH3:32])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:34]I.O>CN(C)C=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:31])=[C:16]([N:21]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[CH3:34])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:33])[CH3:32])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Reactant: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(C)c2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Sodium hydride (a 60% dispersion in liquid paraffin, 598.8 mg, 14.97 mmol) was washed twice with hexane and then suspended to N,N-dimethylformamide (10 ml). To this suspension was gradually added a solution of 3-(4-isopropylphenyl)-N-(4-methoxybenzyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (998.9 mg, 2.25 mmol) in N,N-dimethylformamide (30 ml) and the reaction mixture was stirred at 60° C. for 30 minutes. To this mixture was added methyl iodide (2.19 g, 15.45 mmol) and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was cooled down to room temperature and water was added to the solution. The product was extracted with ethyl acetate. The extracts were dried on magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 10:1) to obtain the title compound (69% yield) as an oily mixture of rotamers.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]1([N:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][C:27]([CH:36]=O)=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([N:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][C:27]([CH2:36][NH:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=4)[CH2:15][CH2:14]3)=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: O=[N+]([O-])c1ccc(N2CCN(CCNCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1
Yield: 68.5 %

Procedure:
Compound 55 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 1,5-diphenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCBr
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCCCCO)ccc12

Procedure:
Analogously to Example 1.4, 1.2 g (3.88 mmol) of ethyl 3-phenyl-3-(6-hydroxyindol-3-yl)propionate are reacted with 1.16 g (7.6 mmol) of 4-bromo-1-butanol in the presence of 2.1 g (15.2 mmol) of potassium carbonate in 30 ml of acetone, giving ethyl 3-phenyl-3-[6-(4-hydroxybutoxy)indol-3-yl]propionate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19]Br)[CH:6]=1.[Cl:22][C:23]1[CH:36]=[CH:35][C:26]([O:27][C@H:28]2[O:32][C:31](=[O:33])[NH:30][C@@H:29]2[CH3:34])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:30]2[C@H:29]([CH3:34])[C@@H:28]([O:27][C:26]3[CH:35]=[CH:36][C:23]([Cl:22])=[CH:24][CH:25]=3)[O:32][C:31]2=[O:33])[CH:6]=1
Reactant: C[C@H]1NC(=O)O[C@@H]1Oc1ccc(Cl)cc1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](Oc3ccc(Cl)cc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid methyl ester and (4R,5S)-5-(4-chloro-phenoxy)-4-methyl-oxazolidin-2-one.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[O:8])(=O)C.[OH-].[Na+].C1(C)C=CC=CC=1.C(O)(=O)C>CO>[SH:4][CH2:5][CH:6]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8]
Reactant: CCOC(=O)CCNC(=O)C(CSC(C)=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(O)CCNC(=O)C(CS)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the product from part (a) (1.02 g., 3.02 mmole) in methanol (6 ml.) is chilled (ice/methanol) and to it, under nitrogen, is added 1N sodium hydroxide (6.35 ml.) over 15 minutes. The mixture is stirred for 3 hours while warming to room temperature (TLC indicates incomplete reaction), and additional 1N sodium hydroxide (3.0 ml.) is added in one portion. After stirring for an additional 3 hours at room temperature, the mixture is concentrated to approximately 1/2 volume in vacuo, and the residue is partitioned between water (50 ml.) and ethyl acetate (30 ml.). The aqueous layer is washed with ethyl acetate (30 ml.), adjusted to a pH of about 2 with concentrated hydrochloric acid, and extracted again with ethyl acetate (3×20 ml.). These organic layers are pooled, washed with water and brine (30 ml. each), dried (Na2SO4), and concentrated in vacuo to yield 0.71 g. of (±)-3-[[2-(mercaptomethyl)-1-oxo- -phenylpropyl]amino]propanoic acid as a white solid; m.p. 76°-82°. TLC (silica gel, toluene/acetic acid; (4:1) Rf =0.37, minor spot at 0.07.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29]([O:31]C)=O)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[NH4+:35]>C1COCC1.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29](=[O:31])[NH2:35])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Yield: 43 %

Procedure:
A solution of the 9-[(3-phenoxyphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (100.0 mg, 0.24 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 24 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 41.0 mg (43%) of the 9-[(3-phenoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.5-6.7 (m, 13H), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). MS (ES) m/e 407, 409.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][CH:7]1[CH:10]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH:8]1[NH2:30])([CH3:4])[CH3:3].[NH2:43][C:44]1[N:49]=[C:48]([OH:50])[C:47]([N+:51]([O-:53])=[O:52])=[C:46](Cl)[N:45]=1.C(N(CC)CC)C.C(OCC)C>CN(C=O)C>[NH2:43][C:44]1[N:49]=[C:48]([OH:50])[C:47]([N+:51]([O-:53])=[O:52])=[C:46]([NH:30][CH:8]2[CH2:9][CH:10]([CH2:11][O:12][Si:13]([C:26]([CH3:27])([CH3:28])[CH3:29])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:45]=1
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(C)[Si](OCC1CC(N)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)[Si](OCC1CC(Nc2nc(N)nc(O)c2[N+](=O)[O-])C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 63.9 %

Procedure:
2-(((1,1-dimethylethyl)diphenylsilyl)oxy)-3-(((1,1- dimethylethyl)diphenyl-silyl)oxymethyl)-1-aminocyclobutane (588 mg, 0.99 mmol), the product of Step N, 189 mg (0.99 mmol) of 2-amino-6-chloro-4-hydroxy-5-nitropyrimidine (prepared as described by J. F. Constant, et al. in J. Heterocyclic Chem, 1035 (1985)) and triethylamine (220 μL, 1.50 mmol) were combined in 5 mL of anhydrous DMF. The reaction mixture was stirred in an oil bath at 50° C. under a nitrogen atmosphere for 2.5 h. Diethyl ether (200 mL) was added and the ether solution was washed with 2×50 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue (800 mg) was dissolved in methylene chloride and purified on a 1.0×45 cm silica gel column eluted @ 10 psi with 100 mL of methylene chloride, followed by 100 mL of 2% methanol in methylene chloride and finally 100 mL of 4% methanol in methylene chloride, to give 473 mg (64% yield) of the title compound; MS DCI-NH3M/Z: 748 (M+H)+ ; 1H NMR (CDCl3) δ 2.13-2.33 (m, 3H), 2.89 (s, 1H), 2.97 (s, 1H), 3.59-3.70 (m, 2H), 4.26 (t, 1H), 4.65 (m, 1H), 7.30-7.47 (m, 10H), 7.56-7.60 (m, 10H).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[N:7][CH:8]=1.Cl[S:11]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:13])=[O:12].[C:24]([O-])(O)=[O:25].[Na+]>N1C=CC=CC=1>[CH3:24][O:25][C:4]1[CH:3]=[CH:8][N:7]=[CH:6][C:5]=1[NH:9][S:11]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:13])=[O:12]
Reactant: COc1cncc(N)c1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1cnccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methoxypyridin-3-amine (1 eq) in pyridine (0.4 M) was added methyl 2-(chlorosulfonyl)benzoate (1 eq) and the mixture was stirred overnight at room temperature. The mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography to give afford the title compound. 1H NMR (400 MHz, DMSO-D6) δ 9.35-9.57 (m, 1H) 8.54-8.61 (m, 1H) 8.17-8.23 (m, 1H) 7.74-7.85 (m, 2H) 7.61-7.73 (m, 1H) 7.32-7.42 (m, 1H) 6.91-7.00 (m, 1H) 3.73 (s, 3H) 3.51 (s, 3H)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[SH-:12].[K+].O>C(O)C>[SH:12][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: [SH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc2ccc(S)nn12

Procedure:
A mixture of 6-chloro-2,3-dihydro-s-triazolo[4,3-b]-pyridazin-3-one [P. Francavilla and F. Lauria, J. Het. Chem., 8, 415 (1971) ] (1.70 g., 0.01 mole) and potassium hydrosulfide (1.44 g., 0.02 mole) in ethanol (30 ml.) was heated in a sealed tube for 8 hours at 140°. After cooling, water (50 ml.) was added to the reaction mixture and a small amount of insoluble material was removed by filtration. The filtrate being concentrated under reduced pressure, the concentrate was acidified to pH 2 with dil. HCl to afford yellow precipitate of 6-mercapto-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-one which was collected by filtration, washed with water (10 ml.) and dried in vacuo on P2O5. Yield 1.43 g. (84%). M.p. > 300° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:25])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].Cl[CH2:27][O:28][CH2:29][CH3:30].C(N(C(C)C)CC)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:27][O:28][CH2:29][CH3:30])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)C=C[C@]32O)C1
Reactant: CCOCCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC[C@@H]2C[C@@H](OC(C)=O)CC[C@@]21C

Procedure:
A solution of 9.20 g of 3β-acetoxy-14β-hydroxy-5β-androst-15-en-17-one (G. Groszek et al., Bull. Pol. Acad. Sci., Chem., 34, 1986, 313), 11 ml of ethyl chloromethyl ether, 54 ml of diisopropylethylamine in 750 ml of dichloromethane was heated at reflux for 24 hrs. The solution was then cooled and poured into 500 ml of aq. 8% citric acid solution. The lower layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by chromatography using cyclohexane/chloroform/acetone 80/10/10 as eluant to give 6.10 g of 3β-acetoxy-14β-ethoxymethoxy-5β-androst-15-en-17-one, as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:13][CH3:14])=[N:10][S:11][N:12]=2)=[CH:4][CH:3]=1.[Cu](C#N)[C:16]#[N:17].CN(C)C=O.[C-]#N.[Na+]>O>[C:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:13][CH3:14])=[N:10][S:11][N:12]=2)=[CH:4][CH:3]=1)#[N:17]
Reactant: N#C[Cu]C#N
Reactant: COc1nsnc1-c1ccc(Br)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nsnc1-c1ccc(C#N)cc1
Yield: 62.1 %

Procedure:
In a manner similar to L. Friedman and H. Shechter, J. O. C., 26, 2522 (1961), incorporated herein by reference, 1.15 g (0.0043 mole) of 4-(4-bromophenyl)-3-methoxy-1,2,5-thiadiazole, 0.46 g (0.0051 mole) of copper cyanide, 15 ml of N,N-dimethylformamide, and a solution of 66.5 g of sodium cyanide in 200 ml of water were reacted to produce 0.58 g of 4-(4-cyanophenyl)-3-methoxy-1,2,5-thiadiazole, Compound 30 of Table I. Compounds 8 and 44 were also prepared by this method.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1)=O.C(N(CC)C(C)C)(C)C.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C)C=O>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:9]1[CH2:10][CH2:11][O:12][CH:7]([CH2:6][NH2:5])[CH2:8]1
Reactant: Fc1cccc(CBr)c1
Reactant: O=C(NCC1CNCCO1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NCC1CN(Cc2cccc(F)c2)CCO1
Temperature: 20 °C
Reaction time: 24 h
Yield: 47.3 %

Procedure:
A mixture of Intermediate 19 (0.300 g) and N,N-diisopropylethylamine (0.372 ml) in N,N-dimethylformamide (5 ml) was treated with 3-fluorobenzyl bromide (0.295 g). The solution was stirred at 20° C. under nitrogen for 24 h. The mixture was partitioned between dichloromethane (10 ml) and saturated aqueous potassium carbonate (10 ml). The phases were separated and the organic phase applied to an ion exchange cartridge (10 g Isolute SCX, prewashed with methanol). The SCX cartridge was eluted with methanol (40 ml) followed by 10% 0.880 ammonia in methanol (40 ml) and the appropriate fractions were concentrated in vacuo. The residue was dissolved in methanol (2 ml) and treated with aqueous 2N sodium hydroxide (2 ml). The solution was stirred at 20° C. for 24 h. The mixture was partitioned between dichloromethane (15 ml) and water (20 ml). The aqueous extract was washed with dichloromethane (15 ml) and the combined organic extracts concentrated to give the title compound as a colourless gum (0.150 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[OH:18])=[O:9])=[CH:6][C:5]([N+:19]([O-:21])=[O:20])=[CH:4][N:3]=1.N1C=CC=CC=1>O>[N+:19]([C:5]1[CH:4]=[N:3][C:2]2[O:18][C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[NH:10][C:8](=[O:9])[C:7]=2[CH:6]=1)([O-:21])=[O:20]
Reactant: Cc1ccc(NC(=O)c2cc([N+](=O)[O-])cnc2Cl)c(O)c1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc2c(c1)Oc1ncc([N+](=O)[O-])cc1C(=O)N2
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
A mixture of 2-chloro-5-nitro-N-(3-hydroxytol-4-yl)-3-pyridinecarboxamide (6.3 g, 0.02 mol) and pyridine (100 ml) was heated under argon at 90° C. for 2.5 hours. The cooled solution was diluted with water and the yellow-orange precipitate collected and washed with water. The solid was then stirred in hot water (100 ml) for 45 min., filtered and washed with ethanol and ether to give 4.3 g of a tan-brown solid. Recrystallization from dimethylformamide/water afforded 3.76 g (69% of theory) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[C:11]3[CH:22]=[C:23]([C:25]([OH:27])=O)[S:24][C:10]=3[C:9]=2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:4][CH:3]=1.CN.C[CH2:37][N:38](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:15])[C:11]3[CH:22]=[C:23]([C:25]([NH:38][CH3:37])=[O:27])[S:24][C:10]=3[C:9]=2[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)N1CCOCC1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution (0.02 M) of 5-(4-chlorophenyl)-6-cyclohexyl-4-(2-morpholin-4-yl-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid in DCM at RT was treated with methylamine (2 N solution in THF, 1.5 eq.), DIEA (3 eq.) and HATU (2 eq.). The mixture was stirred at RT for 2 h, then it was diluted with DCM and washed sequentially with aqueous HCl (0.1 N), aqueous NaHCO3 (saturated solution) and dried. Evaporation of the solvent under reduced pressure gave a residue which was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 10 micron, 19×100 mm; flow: 20 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 50% A isocratic for 1 min then linear to 20% A in 9 min) to afford the title compound (74%) as a solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[N:11]#[C:12]Br.C(N(CC)CC)C>C(Cl)Cl>[O:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH:2]=[CH2:3])=[CH:5][CH:6]=1)[C:12]#[N:11]
Reactant: C=CCc1ccc(O)cc1
Reactant: N#CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCc1ccc(OC#N)cc1
Yield: 65.7 %

Procedure:
To a solution of 2.142 g (15.96 mmol) of 4-(2-propenyl)phenol (prepared as in Example 1) in 15 mL of methylene chloride was added 2.351 g (22.19 mmol) of cyanogen bromide (Aldrich). The mixture was cooled in an ice-salt bath and 3 mL (22 mmol) of triethylamine was added dropwise with stirring. The mixture was stirred for an additional 15 minutes. The solvent was removed under vacuum and the mixture was transferred to a separatory funnel with 25 mL of water and 75 mL of petroleum ether (30-60° C. boiling range). The aqueous and organic layers were separated. The organic layer was washed with three 50 mL portions 6N hydrochloric and one 50 mL portion of saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under vacuum to yield 1.668 g (66%) of crude 1-cyanato-4-(2-propenyl)benzene. The product was distilled to yield 1.307 g (51%) of 1-cyanato-4-(2-propenyl)benzene. The structure of the product was verified by IR and NMR spectroscopy. The product can be further purified by passing the product through a silica gel column using 1% toluene in petroleum ether as the solvent system.