Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[NH2:30][C@H:31]([C:39]([CH2:41][F:42])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.Cl>C1COCC1.CN(C=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:30][C@H:31]([C:39]([CH2:41][F:42])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)CF
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)CF)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of Z-PheOH (0.207 g, 0.69 mmol) in THF (4 mL), cooled to -20° C., were added NMM (76 uL, 0.69 mmol) and IBCF (90 uL, 0.69 mmol). After 10 minutes, a chilled (-10° C.) solution of PheCH2F hydrochloride (0.15 g, 0.69 mmol) in DMF (1 mL) was added, followed by NMM (76 uL, 0.69 mmol). The mixture was stirred for 30 minutes. 1M HCl (5 mL) was added. The solution was extracted with ethyl acetate (30 mL), washed with saturated aqueous NaHCO3 (6 mL), brine (4 mL), dried over MgSO4, filtered, and evaporated to dryness. The residue was crystallized from ethyl acetate/hexane, yielding 0.22 (53%) of Z-Phe-PheCH2F.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[Cl:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].NC1C(Cl)=CC(CO)=C(OC)C=1>O1CCCC1>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[Cl:12]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Agent: COc1cc(N)c(Cl)cc1CO
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Nc1ccc(CO)cc1Cl

Procedure:
Obtained as a light brown solid (76%) starting from commercially available methyl 4-amino-3-chlorobenzoate (4 g; 0.021 mol) and lithium aluminium hydride (1.09 g; 0.028 mol) in 144 ml tetrahydrofuran following the experimental procedure as described for intermediate 38.
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[CH:5]=[CH:4][N:3]=[N:2]1.[ClH:19]>CO>[ClH:19].[N:1]1([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2ccnn2)C1
Agent: Cl
Solvent: CO
Product: c1cn(C2CCCNC2)nn1
Temperature: 30 °C
Reaction time: 5 h

Procedure:
A 100-mL round-bottomed flask was charged with a solution of tert-butyl 3-(1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (2.8 g, 11.11 mmol, 1.00 equiv) in MeOH (50 mL). To this mixture was added conc. HCl (10 mL). The resulting solution was stirred at 30° C. for 5 hours in an oil bath. Upon completion, the resulting mixture was cooled down to room temperature and concentrated on a rotary evaporator affording 3-(1H-1,2,3-triazol-1-yl)piperidine hydrochloride as pale yellow solid (3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: CC(=O)NN
Reactant: Fc1cc2c(cc1Br)CCC(=S)N2
Solvent: CCCCO
Product: Cc1nnc2n1-c1cc(F)c(Br)cc1CC2
Temperature: 120 °C

Procedure:
To a stirred solution of 6-bromo-7-fluoro-3,4-dihydroquinoline-2(1H)-thione (122-4; 7.0 g, 0.026 mol) in n-butanol (30 mL) was added acetic hydrazide (4.81 g, 0.065 mol). Reaction mass was warmed at 120° C. for 16 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.88-7.86 (d, J=7.6 Hz, 1H), 7.70-7.67 (d, J=10 Hz, 1H), 3.0-2.94 (m, 4H), 2.67 (s, 3H). MS (M+1): 284.2.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:7][CH:6]([C:20](O)=[O:21])[CH2:5]1)(=[O:3])[CH3:2].O[N:24]=[C:25]([NH2:30])[CH2:26][CH2:27][O:28][CH3:29]>>[F:18][CH:17]([F:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH:8]2[CH2:7][CH:6]([C:20]3[O:21][N:30]=[C:25]([CH2:26][CH2:27][O:28][CH3:29])[N:24]=3)[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9]2)=[CH:15][CH:14]=1
Reactant: COCCC(N)=NO
Reactant: CC(=O)N1CC(C(=O)O)CC(c2ccc(CC(F)F)cc2)C1
Product: COCCc1noc(C2CC(c3ccc(CC(F)F)cc3)CN(C(C)=O)C2)n1

Procedure:
According to General Method 6A, 153 mg (0.270 mmol, purity 50%) of the compound from Example 59A and 41.3 mg (0.297 mmol, purity 85%) of N′-hydroxy-3-methoxypropanimidamide were reacted Yield: 46.6 mg (32% of theory, purity 72%)
Reaction SMILES: [CH2:1]([C:15]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[C:18]([NH2:19])=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:16]=1)[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:5]([NH2:6])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=O>C(O)C.C(O)=O>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=[N:19][C:18]1[C:20]([CH:22]([CH3:24])[CH3:23])=[CH:21][C:15]([CH2:1][C:2]2[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]([N:6]=[CH:34][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=2)=[CH:16][C:17]=1[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)c1cc(Cc2cc(C(C)C)c(N)c(C(C)C)c2)cc(C(C)C)c1N
Reactant: O=Cc1ccccn1
Solvent: CCO
Solvent: O=CO
Product: CC(C)c1cc(Cc2cc(C(C)C)c(N=Cc3ccccn3)c(C(C)C)c2)cc(C(C)C)c1N=Cc1ccccn1
Temperature: 45 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a suspension of 2b (1.60 g, 4.37 mmol) in absolute ethanol (10 ml) was added 2-pyridinecarboxaldehyde (1.24 ml, 13.11 mmol, 3 eq.) and two drops of formic acid. The mixture was stirred at 45° C. overnight. On cooling to room temperature the suspension was filtered, washed with cold ethanol and dried under reduced pressure to afford 18a as a yellow solid (1.68 g, 49%).
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:19][CH:18]=1
Reactant: COc1ccc(NN=C(Cl)C(C)=O)cc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(NN=C(Sc2ccc(Cl)cc2)C(C)=O)cc1
Yield: 76.9 %

Procedure:
A suspension of 31.7 g (0.139 mol) of 1-chloro-1-[(4-methoxyphenyl)hydrazono]-2-propanone in 400 ml of ethanol was treated with 23.4 g (0.161 mole) of 4-chlorothiophenol followed by 23.4 ml of triethylamine. The suspension was heated at reflux for 2 hours and cooled. The resultant suspension was filtered and the precipitate was washed with 1 portion of cold ethanol. The solids were dried in vacuo to yield 35.77 g of 1-[(4-chlorophenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, mp 111.5°-113.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:24][C@@H:25]2[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26]2)=[N:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H](O)C1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Temperature: 100 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (75 mg, 0.226 mmol), was added (1S,3R)-3-aminocyclopentanol (68.6 mg, 0.678 mmol), NMP (0.75 ml) and triethylamine (0.158 ml, 1.130 mmol). The crude reaction mixture was stirred at 100° C. for 18 hr, and the reaction progress followed by LCMS. The crude reaction mixture was cooled, filtered, and purified by prep LC. The product fractions were collected, 50 mL of 1 M NaOH and 50 mL of EtOAc were added. The aqueous layer was removed, the organic layer was washed with 50 mL of saturated salt solution, dried over sodium sulfate, and reduced to constant mass. 28 mg of the desired compound was obtained. LCMS (m/z): 413.1 (MH+), retention time=0.67 min.; 1H NMR (400 MHz, CHLOROFORM-d, 25° C.) δ ppm 1.71 (d, J=14.09 Hz, 1H) 1.75-1.91 (m, 2H) 1.97-2.05 (m, 1H) 2.10-2.16 (m, 1H) 2.61 (br. s., 1H) 4.03-4.18 (m, 1H) 4.39 (tt, J=4.84, 2.59 Hz, 1H) 4.55 (d, J=5.09 Hz, 2H) 5.19 (br. s., 2H) 6.41 (d, J=8.22 Hz, 1H) 6.55 (s, 1H) 6.90-7.02 (m, 2H) 7.05-7.18 (m, 2H) 7.24-7.34 (m, 1H) 7.43-7.55 (m, 1H) 8.07 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:8])=[O:7].C([Li])CCC.CN(C)[C:22](=[O:24])[CH3:23]>O1CCCC1>[N:9]1([S:6]([C:2]2[S:1][C:5]([C:22](=[O:24])[CH3:23])=[CH:4][CH:3]=2)(=[O:8])=[O:7])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(=O)N(C)C
Reactant: O=S(=O)(c1cccs1)N1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)N2CCCCC2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
1-(Thiophen-2-ylsulfonyl)piperidine (5 g, 21.6 mmol) was taken up in anhydrous tetrahydrofuran (90 mL) and the solution, which was kept under a nitrogen atmosphere, was cooled down to −78° C. n-Butyllithium (2.5 M in hexanes, 12.96 mL, 32.4 mmol) was added to the reaction dropwise with a syringe. The reaction was stirred at −78° C. for 10 min and allowed to warm up to −30° C. and stirred for 30 min. The reaction was cooled back down to −78° C. and N,N-dimethylacetamide (4.01 mL, 43.2 mmol) diluted with anhydrous tetrahydrofuran (10 mL) was added slowly to the reaction. The reaction was stirred for 15 min and then allowed to warm up to room temperature over 1 h. The mixture was quenched with acetic acid (10 mL) and diluted with ethyl acetate and a saturated solution of sodium bicarbonate. The layers were separated and the organic layer washed with water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 10 to 40% ethyl acetate in hexanes to afford an off-white solid (1.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[CH:9]=[C:8]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(N2CCCCC2)cc1Br
Temperature: 110 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of 2-bromo-4-fluorobenzaldehyde (300 mg, 1.48 mmol) in 3.0 mL of N,N-dimethylformamide was added potassium carbonate (204 mg, 1.48 mmol), piperidine (154 μL, 1.55 mmol) at room temperature. After being stirred at 110° C. overnight, the reaction mixture was diluted with a 2:1 solution of ethyl acetate and hexane. The solution was washed with water, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25) to obtain the title compound (355 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14](OCC)(=[O:20])[C:15](OCC)=[O:16]>>[O:16]=[C:15]1[C:14](=[O:20])[NH:1][C:2]2[C:12](=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=2)[NH:13]1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of ethyl 3,4-diaminobenzoate (5 g, 27.75 mmol, 1.00 equiv) in diethyl oxalate (100 mL). The resulting solution was stirred overnight at 140° C. in an oil bath. Then the resulting solution was cooled to room temperature. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 3.5 g (54%) of ethyl 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate as a brown solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[C:7](O)(=O)[C:8]([CH3:11])([CH3:10])[CH3:9].P(Cl)(Cl)(Cl)=O.Cl>O1CCOCC1>[C:8]([C:11]1[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]=1)([CH3:10])([CH3:9])[CH3:7]
Reactant: CC(C)(C)C(=O)O
Reactant: CNC(=S)NN
Agent: Cl
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1nnc(C(C)(C)C)s1
Yield: 80 %

Procedure:
To a solution of 91.6 g of 4-methylthiosemicarbazide and 102.3 g of pivalic acid in 400 ml of dioxane at 90° is added slowly 160.5 g of phosphorus oxychloride at such a rate that the reaction temperature is maintained at 85°-90° C. without external heating. When the addition is complete, the mixture is heated at 85°-90° C until HCl evolution ceases (several hours), is cooled and the supernatant liquid decanted from the solid mass in the flask. The mass is broken up, slurried with 700 ml of water and made basic (pH 8-9) by the slow addition of sodium hydroxide pellets. The resulting precipitate is filtered, washed with water, air dried and recrystallized from hexane to give 119.4 g (80% yield) of 2-tert.butyl-5-methylamino-1,3,4-thiadiazole, m.p. 79°-81°.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:9][C:10](=[O:32])[NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:23][CH2:22]2)=[O:20])[CH2:15][CH2:14]1)(C)(C)C.OS(O)(=O)=O>C(Cl)Cl.[OH-].[Na+]>[NH2:7][CH:8]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:9][C:10]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:23][CH2:22]2)=[O:20])[CH2:15][CH2:14]1)=[O:32]
Reactant: CC(C)C(=O)N1CCN(C(=O)[C@H]2CC[C@H](CNC(=O)CC(NC(=O)OC(C)(C)C)c3ccccc3)CC2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)[C@H]2CC[C@H](CNC(=O)CC(N)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2-{[trans-4-(4-Isobutyryl-piperazine-1-carbonyl)-cyclohexylmethyl]-carbamoyl}-1-phenyl-ethyl)-carbamic acid tert-butyl ester (0.65 g, 1.21 mmol) in DCM (20 mL), H2SO4 (0.16 mL, 3.02 mmol) was added and the reaction was left stirring at room temperature for 18 hours. The mixture was diluted with 20 mL of NaOH 2N solution and the aqueous phase was concentrated under reduced pressure to give a white solid. The titled compound was extracted with EtOH. The solvent was removed under reduced pressure affording 0.13 g of the titled compound (24% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].[NH2:16][C:17]1[CH:18]=[C:19]([CH2:23][CH:24]([O:30][CH:31]([CH3:33])[CH3:32])[C:25]([O:27]CC)=[O:26])[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH2:9][CH2:8][OH:7])[C:6]([NH:16][C:17]1[CH:18]=[C:19]([CH2:23][CH:24]([O:30][CH:31]([CH3:33])[CH3:32])[C:25]([OH:27])=[O:26])[CH:20]=[CH:21][CH:22]=1)=[O:10]
Reactant: O=C1OCCC1Oc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cc1cccc(N)c1)OC(C)C
Solvent: Cc1ccccc1
Product: CC(C)OC(Cc1cccc(NC(=O)C(CCO)Oc2ccc(Cl)cc2Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
20 mg of 3-(2,4-Dichlorophenoxy)dihydrofuran-2-one and 30 mg of ethyl 3-(3-aminophenyl)-2-isopropoxypropanoate were dissolved in 1 ml of toluene, and the solution was heated under reflux for 8 hours. After removing the solvent under a stream of nitrogen, the residue was dissolved in 0.6 ml of ethanol, and 0.12 ml of 5N sodium hydroxide was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with 2 ml of water and 0.14 ml of 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was collected, and the solvent was removed under a stream of nitrogen. The residue was purified by HPLC using a reverse-phase column and a water-acetonitrile-trifluoroacetic acid elution solvent, to give 6.8 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)(C)(C)C>>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:16]2[CH:17]=[CH:18][C:13]([C:12](=[O:20])[NH:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)=[CH:14][N:15]=2)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Cl)nc2)c1
Agent: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1I
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cn2)CC1

Procedure:
4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester was prepared from N-(3-tert-butyl-phenyl)-6-chloro-nicotinamide and 1-Boc-piperazine following a procedure similar to the one described in the synthesis of 4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester above. The product was obtained after silica gel column purification with 10-30% EtOAc in hexanes gradient. HRMS m/z calcd for C25H34N4O3 [M+H]+: 439.2704. Found: 439.2704.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([N:11]1[CH2:16][CH2:15][C:14](=[N:17][OH:18])[C:13](=[N:19][OH:20])[C:12]1=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>>[CH2:4]([N:11]1[CH2:16][CH2:15][C:14]2=[N+:17]([O-:18])[O:20][N:19]=[C:13]2[C:12]1=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1C(=NO)C(=NO)CCN1Cc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Product: O=C1c2no[n+]([O-])c2CCN1Cc1ccccc1
Yield: 88.4 %

Procedure:
80 ml of 14% strength sodium hypochlorite solution are rapidly added dropwise at 0° C. to a solution of 3.0 g (12 mmol) of 1-benzylpiperidine-2,3,4-trione-3,4-dioxime in 80 ml of 10% strength sodium hydroxide solution. The deposited precipitate is immediately filtered off with suction, washed with water and dried in vacuo. 2.6 g (87%) of 5-benzyl-6,7-dihydro[1,2,5]oxadiazolo[3,4-c]pyridin-4(5H)-one-1-oxide, m.p. 118°-120° C., are obtained, 1H-NMR (DMSO): δ=2.95 (t), 3.65 (t), 4.70 (t), 7.35 (s), 13C-NMR (DMSO): δ=18.0 (t), 44.8 (t), 49.2 (t), 111.9 (s), 127.4 (d), 127.7 (d), 128.5 (d), 136.2 (s), 149.6 (s), 155.7 (s).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>[C].[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2
Reactant: CCOC(=O)c1cc2c(C)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(C)ccc(O)c2[nH]1
Temperature: 25 °C
Yield: 6.5 %

Procedure:
A mixture of ethyl 7-benzyloxy-4-methyl-1H-indole-2-carboxylate (15.0 g, 485 mmol), ammonium formate (30.6 g, 485 mmol), 10% palladium-carbon (2.00 g) and ethanol (450 ml) was heated under reflux for 0.5 hour. The reaction mixture was cooled to room temperature, after which the insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate/toluene to obtain ethyl 7-hydroxy-4-methyl-1H-indole-2-carboxylate (6.96 g). M.p. 211-212° C.
Reaction SMILES: CC[C@@]12[C@](O)(CC)CC[C@H]1[C@@H]1CCC3[C@@H]([C@H]1CC2)CCC(=O)C=3.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][CH2:34]O)[CH:29]=[CH:30][CH:31]=1.P(Br)(Br)[Br:37]>C1C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][CH2:34][Br:37])[CH:29]=[CH:30][CH:31]=1
Reactant: BrP(Br)Br
Reactant: COc1cccc(CCCO)c1
Agent: CC[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Solvent: c1ccccc1
Product: COc1cccc(CCCBr)c1

Procedure:
Referring now to FIG. 1, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, 13β,17α-diethyl-17β-hydroxygon-4-en-3-one, is illustrated. 3-(m-Methoxyphenyl)propanol (I) is heated with phosphorus tribromide in benzene after dropwise addition in the cold to form 3-(m-methoxyphenyl)propyl bromide (II). This halogen compound (II) dissolved in tetrahydrofuran is condensed with sodium acetylide in liquid ammonia to obtain 5-(m-methoxyphenyl)-1-pentyne (III). Compound III is allowed to stand under nitrogen with water, 30% formalin, acetic acid, diethylamine, dioxan, and cuprous chloride a 70°C for about 12 hours, whereby there is obtained 1-diethylamino-6-(m-methoxyphenyl)-2-hexyne (IV), which is in turn hydrated in the presence of a mercury salt and sulfuric acid to form 1-diethylamino-6-(m-methoxyphenyl)-3-hexanone (V). The ketamine (V) may eliminate diethylamine on distillation to give the vinyl ketone 6-m-methoxyphenyl)-1-hexen-3-one (VI). Either the ketamine (V) or the ketone (VI), or mixtures thereof, is then reacted with 2-ethyl-1,3-cyclopentanedione (VII) under Michael condensation conditions, e.g. refluxing in methanolic potassium hydroxide to form 2-ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione (VIII).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].CI.[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)Cl>[Br:1][C:2]1[C:3]([O:12][CH3:15])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(O)c(Br)cc1F
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1cc([N+](=O)[O-])c(F)cc1Br
Yield: 94.5 %

Procedure:
A stirred solution of 30.0 g (0.127 mole) of 2-bromo-4-fluoro-5-nitrophenol, 26.9 g (0.19 mole) of methyl iodide, and 26.3 g (0.19 mole) of potassium carbonate in 200 mL of acetone was heated at reflux for five hours. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give a residue. The residue was dissolved in methylene chloride and passed through a column of silica gel. The elute was concentrated under reduced pressure to give 30 g of 4-bromo-2-fluoro-5-methoxynitrobenzene; m.p. 74°-76° C.