Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][C:11]([CH2:18][NH2:19])([CH2:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH3:29][C:30]1[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].O>C(Cl)Cl>[CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][C:11]([CH2:18][NH:19][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:40])[F:41])=[N:38][C:30]=3[CH3:29])([CH2:14][CH:15]3[CH2:16][CH2:17]3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Reactant: NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
To a stirred solution of C-(4-cyclopropylmethanesulfonyl-1-cyclopropylmethyl-cyclohexyl)-methylamine (200 mg; 0.701 mmol) and N-ethyldiisopropylamine (0.15 ml; 0.841 mmol) in DCM (5 ml) was added 2-methyl-6-(trifluoromethyl)nicotinoyl chloride (172 mg; 0.771 mmol). The mixture was stirred for 90 minutes. Water (4 ml) and DCM (4 ml) were added and the mixture was stirred vigorously for 5 minutes then passed through a PTFE separation frit. The organic phase was collected and evaporated in vacuo to give an oil. The crude product was chromatographed on silica eluted with 15% EtOAc in DCM to give a yellow oil, which still contained impurities. The oil was rechromatographed on silica eluted with 20% EtOAc in DCM to give a yellow oil. The oil was crystallised from EtOAC using hexane to give a white solid (170 mg). 1H NMR(500 MHz, CDCl3): δ 7.82 (1H, d, J7.8), 7.55 (1H, d, J 7.9), 5.90 (1H, t, J 6.0), 3.61 (2H, d, J 6.4), 2.98-2.88 (3H, m), 2.72 (3H, s), 2.07-1.85 (6H, m), 1.43-1.37 (2H, m), 1.24 (2H, d, J 6.6), 1.20-1.12 (1H, m), 0.77-0.69 (3H, m), 0.54-0.50 (2H, m), 0.42-0.40 (2H, m), 0.06-0.04 (2H, m). MS (m/e)=473. MPt=148-151° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH:41]([CH3:43])[CH3:42])=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH:41]([CH3:42])[CH3:43])=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)C)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)C)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
Piperidine (0.030 g, 0.353 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.101 g, 0.529 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-isopropoxybenzoic acid (0.066 g, 0.176 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:6) to obtain the titled compound (0.030 g, 0.068 mmol, 39%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][C:20]([CH3:30])([C:26]([O:28][CH3:29])=[O:27])[CH2:21]2.O>N1C=CC=CC=1>[CH3:30][C:20]1([C:26]([O:28][CH3:29])=[O:27])[CH2:21][C:22]2[C:18](=[CH:17][CH:25]=[CH:24][C:23]=2[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH2:19]1
Reactant: COC(=O)C1(C)Cc2cccc(O)c2C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C1(C)Cc2cccc(OS(=O)(=O)C(F)(F)F)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At −15° C., 1.5 ml (8.7 mmol) of trifluoromethanesulfonic anhydride were slowly added dropwise to a solution of 897 mg (4.35 mmol) of methyl 4-hydroxy-2-methyl-2,3-dihydro-1H-indene-2-carboxylate in 20 ml of pyridine. After warming to room temperature, the reaction mixture was stirred for another 2 h. 20 ml of water were then added and, after phase separation, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by flash chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 1100 mg (3.25 mmol, 75% of theory) of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28]CN(CC)CC.COS(OC)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH3:28])=[CH:15][CH:14]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: CNc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 46 %

Procedure:
A solution of (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methyl-pentanoic acid amide (Example 48, 400 mg, 1 mmol), Et3N (0.16 mL, 1.1 mmol), dimethylsulfate (139 mg, 1.1 mmol) in 25 mL of toluene was stirred at rt for 18 h. The reaction was concentrated, then taken into EtOAc and washed with H2O, brine, dried over K2CO3 and concentrated to give a crude mixture of starting material and product. The material was further purified by flash chromatography (SiO2, 35% EtOAc/hexanes) to afford the title compound, 195 mg, in 46% yield. MS (ESI), (M+H)+424.1; 1H NMR (CDCl3) δ7.65 (d, 2H, J=8.0), 7.58 (d, 2H, J=8.2), 7.47 (d, 2H, J=8.0), 7.31 (d, 2H, J=8.5), 6.24 (br s, 1H), 5.16 (br s, 1H), 4.50(dd, 2H, J=50, 17), 4.27 (t, 1H, J=10), 2.44 (s, 3H), 1.74-1.83 (m, 1H), 1.25-1.33 (m, 1H), 0.93-1.01 (m, 1H), 0.74 (d, 3H, J=7.0), 0.63 (d, 3H, J=7.0).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([O-:3])=[O:2].[N+](=[CH2:23])=[N-]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([C:9]1[C:14]([C:15]([O:17][CH3:23])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cccnc1C(=O)c1cccc([N+](=O)[O-])c1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)c1cccnc1C(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
2-(3-Nitrobenzoyl)-3-carboxypyridine was dissolved in 20 ml of methylene chloride and the solution was cooled in an ice/water bath. Diazomethane (25 ml, 0.33M) was added to the solution and stirred for 2 hours. The solvent was removed and the residue chromatographed (methylene chloride) yielding 0.26 g of 2-(3-nitrobenzoyl)-3-methoxycarbonylpyridine.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][NH:17][CH2:16]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][N:17]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:16]1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CC1CNCC(C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CC(C)CC(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol), 3,5-dimethylpiperidine (0.20 ml, 1.48 mmol), and DIPEA (0.26 ml, 1.48 mmol) were dissolved in acetonitrile (12 ml) and stirred at room temperature for 16 hours. Acetonitrile was evaporated and the crude was purified by flash chromatography (Petroleum ether/EtOAc=95/5) to obtain ethyl 2-(3,5-dimethylpiperidin-1-yl)-2-phenylacetate (203 mg, 59.7% yield) as colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:45][CH:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CN1CCC(N)CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CN1CCC(Nc2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 1-methyl-piperidin-4-ylamine according to conditions described in general procedure C. Mp: 128-129° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.41-1.84 (m, 4 H), 2.09 (s, 3 H), 2.66 (bs, 2 H), 3.26-3.80 (m, 3 H), 3.27 (t, J=4.7 Hz, 4 H), 3.76 (t, J=4.7 Hz, 4H), 6.32 (s, 1 H), 7.05 (d, J=12.4 Hz, 2 H), 7.27 (d, J=8.4 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.47 (s, 1 H), 7.55-7.60 (m, 3 H), 7.82 (d, J=8.0 Hz, 1 H), 8.00 (d, J=7.7 Hz, 1 H), 8.23 (bs, 1 H), 10.45 (s, 1 H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH:14]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]#[N:25])=[CH:23][C:18]=2[CH2:17][CH2:16][O:15]1.C(N(CC)CC)C>ClCCl>[O:11]=[CH:12][CH2:13][CH:14]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]#[N:25])=[CH:23][C:18]=2[CH2:17][CH2:16][O:15]1
Reactant: N#Cc1ccc2c(c1)CCOC2CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#Cc1ccc2c(c1)CCOC2CC=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dimethylsulfoxide (0.35 mL, 5 mmol) and oxalyl chloride (2M in dichloromethane) (2.2 mL, 4.4 mmol) were stirred in dichloromethane (30 mL) under nitrogen at −78° C. After 10 min, 1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile (0.48 g, 2.4 mmol) in dichloromethane (50 mL) was added dropwise and the solution stirred at −78° C. for 1 h, before triethylamine (2.5 mL, 18 mmol) was added slowly. The reaction was allowed to warm to room temperature and after 2 h the reaction was quenched by addition of water. Removal of the solvent in vacuo yielded the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[O:12][C:4]2([CH:9]3CC[CH:5]2[CH2:6][CH2:7][CH2:8]3)[O:3][CH2:2]1.[O:13]=[O+][O-].C1(P([C:29]2[CH:34]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:2]1[O:3][C:4]2([CH2:5][CH:6]3[C:7](=[O:13])[CH:8]([CH2:34][CH2:29]3)[CH2:9]2)[O:12][CH2:1]1
Reactant: C1CC2CCC(C1)C21OCCO1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: O=C1C2CCC1CC1(C2)OCCO1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a solution of 3-methylenyl bicyclo[3,2,1]octan-8-one ethylene ketal (0.21 g, 1.15 mmol, 1.0 eq.) in CH2Cl2 (2 mL) at −78° C. was bubbled O3 until the reaction stayed blue (about 3 min). The O3 bubbling was stopped and the reaction mixture was stirred for 5 min at −78° C. The reaction was quenched by addition of triphenylphosphine (0.43 g, 1.4 eq.) and stirring at −78° C. for 10 minutes. The reaction mixture was allowed to warm at room temperature, stirred for 40 minutes and concentrated. The residue was purified by silica gel chromatography (10% to 15% EtOAc-hexanes) to give bicyclo[3,2,1]octane-3,8-dione 8-ethylene ketal as a colorless oil (0.08 g, 40%).
Reaction SMILES: [C:1]1(=[O:10])[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[C:3](=[O:9])[O:2]1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.[CH3:35][OH:36]>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:35][O:36][C:3]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[C:1]([OH:10])=[O:2])=[O:9]
Reactant: O=C1OC(=O)C2CCCC12
Reactant: CO
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@@H]1CCC[C@@H]1C(=O)O
Temperature: -55 °C
Reaction time: 36 h
Yield: 100 %

Procedure:
(1S,2R)-2-(Methoxycarbonyl)cyclopentanecarboxylic acid was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. Tetrahydro-cyclopenta[c]furan-1,3-dione (5.0 g, 35.7 mmol) was dissolved in a 1:1 mixture of toluene and carbon tetrachloride (720 mL). The mixture was cooled to −55° C. under a nitrogen atmosphere, and then quinine (12.7 g, 39.3 mmol) was added. A solution of methanol (4.33 mL, 107 mmol) in toluene-carbon tetrachloride (1:1, 30 mL) was slowly added via an addition funnel. The suspension was stirred at −55° C. for 36 h, and then allowed to warm to 25° C. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (400 mL), washed with 1.0 M aqueous hydrochloric acid solution (2×400 mL) and saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, (1S,2R)-2-(methoxycarbonyl)cyclopentanecarboxylic acid (6.2 g, 35.7 mmol, quantitative), as a clear oil. 1H NMR (400 MHz, CD3OD) δ: 1.67 (1H, m), 1.84 (1H, m), 1.99 (4H, m), 3.08 (2H, m), 3.63 (3H, s).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][C@@H:4]2[CH3:23].[OH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]2[C@H:31]3[C@H:42]([CH2:43][CH2:44][C@:26]12[CH3:27])[C@:39]1([CH2:40][OH:41])[C:34](=[CH:35][C:36](=[O:46])[CH2:37][C@@H:38]1[CH3:45])[CH2:33][C@H:32]3[CH3:47].O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CC(=O)C[C@@H]1C)CC3>>[CH3:23][C@@H:4]1[C@@:3]2([CH:2]=[O:1])[C:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:21])=[CH:7][C:6](=[O:22])[CH2:5]1.[CH3:45][C@@H:38]1[C@@:39]2([CH:40]=[O:41])[C:34]([CH2:33][C@@H:32]([CH3:47])[C@@H:31]3[C@@H:42]2[CH2:43][CH2:44][C@@:26]2([CH3:27])[C@H:28]3[CH2:29][CH2:30][C:25]2=[O:24])=[CH:35][C:36](=[O:46])[CH2:37]1
Reactant: C[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Reactant: C[C@@H]1CC2=CC(=O)C[C@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Product: C[C@@H]1CC2=CC(=O)C[C@H](C)[C@]2(C=O)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Product: C[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C=O

Procedure:
Substituting 17β,19-dihydroxy-1α,17α-dimethyl-4-androsten-3-one, 19-hydroxy-1α-methyl-4-androstene-3,17-dione, 17β,19-dihydroxy-1α,7α-dimethyl-4-androsten-3-one and 17β,19-dihydroxy-1α,6α,17α-trimethyl-4-androsten-3-one for the 17β,19-dihydroxy-1α-methyl-4-androsten-3-one above results in the preparation of 17β-hydroxy-1α,17α-dimethyl-4-androstene-3,19-dione, 1α-methyl-4-androstene-3,17,19-trione, 1α,7α-dimethyl-4-androstene-3,17,19-trione and 17β-hydroxy-1α,6α,17α-trimethyl-4-androstene-3,19-dione, respectively.
Reaction SMILES: [CH:1](O)=O.[CH3:4][C:5]([S:22][S:23][CH3:24])([CH3:21])[CH2:6][NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[C:13]([CH2:19][OH:20])[CH:12]=1.[OH-].[Na+]>C=O>[CH3:1][N:7]([CH2:6][C:5]([CH3:4])([S:22][S:23][CH3:24])[CH3:21])[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][OH:20])[N:14]=[C:15]([CH2:17][OH:18])[CH:16]=1
Reactant: O=CO
Reactant: CSSC(C)(C)CNCCOc1cc(CO)nc(CO)c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CSSC(C)(C)CN(C)CCOc1cc(CO)nc(CO)c1
Temperature: 100 °C

Procedure:
365 μl of formic acid are added to a suspension, cooled to 0° C., of 322 mg of 4-[2-(2-methyl-2-(methyldisulphanyl)propylamino)ethoxy]-2,6-bis(hydroxymethyl)pyridine in 262 μl of formaldehyde. The mixture is heated at 100° C. for 1¼ hours. After returning to ambient temperature, the mixture is hydrolysed and then a 5N aqueous sodium hydroxide solution is added until a pH=12 is obtained. The aqueous phase is extracted 3× with AcOEt and the combined organic phases are dried over MgSO4 and concentrated under RP. 310 mg of 4-{2-[methyl(2-methyl-2-(methyldisulphanyl)propyl)amino]ethoxy}-2,6-bis(hydroxymethyl)pyridine are thus obtained.
Reaction SMILES: Cl.[N:2]1[C:7]2[CH2:8][NH:9][CH2:10][C:6]=2[CH:5]=[N:4][CH:3]=1.C[Al](C)C.C[Al](C)C.C1N2CCN(CC2)C1.[CH3:27][N:28]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:29]1[N:34]=[C:33]([NH2:35])[N:32]=[C:31]([C:36]2[N:40]=[C:39](C(Cl)(Cl)Cl)[O:38][N:37]=2)[N:30]=1>C1COCC1>[CH3:27][N:28]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:29]1[N:34]=[C:33]([NH2:35])[N:32]=[C:31]([C:36]2[N:40]=[C:39]([N:9]3[CH2:10][C:6]4[CH:5]=[N:4][CH:3]=[N:2][C:7]=4[CH2:8]3)[O:38][N:37]=2)[N:30]=1
Reactant: c1ncc2c(n1)CNC2
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C(Cl)(Cl)Cl)n2)n1
Agent: C1CN2CCN1CC2
Agent: C[Al](C)C
Agent: Cl
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3Cc4cncnc4C3)n2)n1
Yield: 8.3 %

Procedure:
To a solution of 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride salt (38 mg, 0.231 mmol) in anhydrous THF (3 mL) was added DABAL-Me3 (bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]-octane) (57 mg, 0.231 mmol) at room temperature. The solution was heated under nitrogen at 40 C for 3 h and N-methyl-N-phenyl-6-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-[1,3,5]triazine-2,4-diamine (Intermediate 60, 60 mg, 0.155 mmol) was added. The resulting reaction mixture was heated at 80 C for 5 h and then quenched with water (2 mL) drop-wise. The solution was extracted into EtOAc (3×25 mL) and the combined organics washed with a 1M aq. solution of HCl (20 mL), brine (20 mL), dried over magnesium sulfate, evaporated to dryness and purified by preparative HPLC-MS (Method B) to afford the title compound as a white solid (5 mg, 8%).
Reaction SMILES: [C:1]([N:4]1[CH2:11][S:10][CH2:9][C@@H:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:12][O:13][C:14](=[O:25])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[NH2:16].C(N1CSC[C@@H]1C(O)=O)(=O)C.COC(=O)[C@H](CC1C=CC(O)=CC=1)N.[H-].[Na+].[Cl:53][C:54]1[N:59]=[C:58](Cl)[CH:57]=[CH:56][N:55]=1>CN(C=O)C.O>[C:1]([N:4]1[CH2:11][S:10][CH2:9][C@@H:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:12][O:13][C:14](=[O:25])[C@H:15]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][C:56]2[CH:57]=[CH:58][N:59]=[C:54]([Cl:53])[N:55]=2)=[CH:22][CH:23]=1)[NH2:16]
Reactant: Clc1ccnc(Cl)n1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CC(=O)N1CSC[C@@H]1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](N)Cc1ccc(Oc2ccnc(Cl)n2)cc1
Yield: 65.8 %

Procedure:
A solution of N-acetyl-D-thioproline-L-tyrosine methyl ester (1.76 g, 5 mmol), [prepared from N-acetyl-D-thioproline and tyrosine methyl ester by a similar method to the preparation of Intermediate 5] in DMF (10 ml) was added to a suspension of sodium hydride (60% in mineral oil, 210 mg, 5.25 mmol) in DMF (5 ml) at room temperature. After 10 min a solution of 2,4-dichloropyrimidine (782 mg, 5.25 mmol) in DMF (5 ml) was added. After 1 h water (1 ml) was added and the solvent evaporated in vacuo. The residue was dissolved in EtOAc (200 ml) and washed with water (3×50 ml) and brine (30 ml), dried (Na2SO4) and evaporated in vacuo. Chromatography (SiO2, MeOH/DCM 5:95) gave the title compound as a white foam (1.59 g, 68%). δH (DMSO-d6, 400K) 8.56 (1 H, d, J 5.7 Hz, PyrH), 7.9 (1 H, br d, CONH),7.32 (2 H, d,J 8.7 Hz, ArH), 7.15 (2 H, d, J 8.7 Hz, ArH), 6.99 (1 H, d, J 5.7 Hz, PyrH), 4.83 (1 H, dd, J 7.4, 3.9 Hz, CHαthiopro), 4.77 (1 H, d, J 9.2 Hz, NCHHBS), 4.64 (1 H,dt, J 8.5, 5.6 Hz, CHαtyr),4.39 (1 H, d, J 9.2 Hz, NCHAHBS), 3.67 (3 H, s, CO2Me), 3.26 (1 H, dd, J 11.6, 7.4 Hz, CHCHAHBS), 3.19 (1 H, dd, J 14.0, 5.7 Hz, CHCHAHBAr), 3.09-3.00 (2 H, m, CHCHAHBS+CHCHAHBAr) and 2.00 (3 H, s,COCH3); m/z (ESI, 15 V) 465 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.[Fe](Cl)(Cl)Cl>[C:1]([NH:4][CH:5]([CH2:10][N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: Cl[Fe](Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(CN1CCN(C)CC1)NC(C)=O
Temperature: 20 °C
Reaction time: 66 h

Procedure:
To a solution of 8.57 g of methyl 2-acetamidoacrylate in 500 mL of dichloromethane stirred under inert atmosphere, about 6.65 mL of N-methylpiperazine are added, then 0.97 g of iron trichloride are added, and the mixture is stirred at a temperature of about 20° C. for 66 hours. Then, 300 mL of an aqueous solution of sodium sulfate are dropped to the reaction medium while stirring the reaction mixture and the mixture filtered through Celite. After separation of the phase by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated in a vacuum oven under reduced pressure (2 kPa) at a temperature of about 40° C. in order to obtain an orange-colored liquid. The aqueous phase is extracted with 3 times 150 mL of dichloromethane and all of the organic extracts are collected, dried over sodium sulfate, then concentrated under reduced pressure (2 kPa) at a temperature of about 20° C. in order to obtain an yellow oil. Both of the organic extracts as described above are combined and purified by chromatography under argon pressure (50 kPa), on a column of silica gel (particle size 40-63 μm; diameter 5 cm; height 25 cm), eluting with successive mixtures of 20% dichloromethane/methanol/aqueous ammonia (99/1/0, 97/3/0, 90/10/0.25, 80/20/0.25 by volume). The fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 30° C. About 3.3 g of methyl 2-(acetylamino)-3-(4-methyl-piperazinyl)propanoate are obtained in the form of a yellow liquid. [Infrared spectrum CCl4 3437; 3318; 2941; 2798; 1749; 1685; 1499; 1458; 1374; 1286; 1204; 1168 and 1014 cm−1]
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[CH3:23][CH:24]1[O:29][CH:28]([CH3:30])[CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:22][O:21][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]3[CH2:25][CH:24]([CH3:23])[O:29][CH:28]([CH3:30])[CH2:27]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20]
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Reactant: CC1CNCC(C)O1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(NC(=O)CCCCCN2CC(C)OC(C)C2)c2nccc(C)c2c1
Yield: 55.1 %

Procedure:
A mixture of 5.5 g (0.015 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 1.85 ml (0.018 mole) of 2,6-dimethylmorpholine in 90 ml of benzene was heated under reflux for 24 hr. Triethylamine (2 ml) was added and the mixture was heated under reflux for an additional 2 hr, allowed to cool, and filtered. The filtrate was washed with water, dried and concentrated. TLC(silica gel--ethyl acetate) demonstrated a mixture of the unchanged bromo compound, Rf(silica--ethyl acetate)=0.63, and the product, Rf=0.08. A solution of the residue, 1.3 ml (0.01 mole) of 2,6-dimethylmorpholine, and 1.5 ml of triethylamine in 80 ml of benzene was heated under reflux for 40 hr, allowed to cool, filtered, washed with water, dried and concentrated. The residue was chromatographed over 200 g of silica gel with 1 liter each of the following solutions of methanol in ethyl acetate: 1.5%, 2%, 3% to afford 3.7 g of crude product. Recrystallization from hexane afforded 3.3 g of the title compound, mp 87°-90°. The NMR spectrum confirmed the presence of hexane.