Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1.[O:45]=[C:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]([CH2:56][C:57]2[CH:58]=[C:59]([CH:63]=[CH:64][CH:65]=2)[C:60](O)=[O:61])=[N:48][NH:47]1>CC(N(C)C)=O.O>[F:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:60]([C:59]3[CH:58]=[C:57]([CH:65]=[CH:64][CH:63]=3)[CH2:56][C:49]3[C:50]4[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:46](=[O:45])[NH:47][N:48]=3)=[O:61])[CH2:41][CH2:40]2)=[CH:37][CH:38]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.7 %

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (150 mg, 0.47 mmol), diisopropylethylamine (102 mg, 0.8 mmol) and 1-(4-fluorophenyl)piperazine (65 mg, 0.47 mmol) were added sequentially at ambient temperature to a stirred solution of 3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (A) (100 mg, 0.36 mmol) in dry dimethylacetamide (1 ml), the mixture was stirred at ambient temperature for 4 hours and allowed to stand at ambient temperature for 16 hours, then it was added dropwise to stirred cold water (10 ml). After 30 minutes, the resulting solid was collected by filtration, washed with water (2×1 ml) and hexane (1 ml), dried in vacuo and purified using preparative HPLC to give 4-{3-[4-(4-fluorophenyl)piperazin-1-ylcarbonyl]benzyl}-1(2H)-phthalazinone (21)(76 mg) as a cream solid; m/z (M+H)+. 443; HPLC Purity 90%; HPLC Retention time 4.00 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:12]#[N:13])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].[BH4-].[Na+].[H][H]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:12][NH2:13])[C:7]2([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1(C#N)CC12CCCC2
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C1(CN)CC12CCCC2
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 1-cyano-spiro[2.4]heptane-1-carboxylic acid methyl ester (3.45 g, 19.3 mmol) in methanol (240 mL) was added cobalt chloride hexahydrate (CoCl2—6H2O) (9.16 g, 38.5 mmol) to give a deep purple colored solution. Sodium borohydride (7.30 g, 193 mmol) was added portionwise over 10 minutes with caution to control the evolution of hydrogen and the exothermic reaction that ensued to give a black solution. The reaction mixture was stirred for 30 minutes under nitrogen after the addition was completed. The reaction was quenched carefully by the addition of 0.5N HCl (1.3 L). The solution was made alkaline (pH˜9) by the addition of concentrated ammonium hydroxide. The mixture was extracted with ethyl acetate (4×400 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to afford 3.07 g (87%) of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid methyl ester as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 0.74 (br d, 1H), 1.4–1.7 (m, 10H), 1.9 (m, 1H), 2.58 (d, J=13.8 Hz, 1H), 3.16 (d, J=13.8 Hz, 1H), 3.48 (s, 3H); MS (APCI) m/z 184 [M+H]+.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7](O)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].C[N:18]1CCOCC1.ClC(OCC(C)C)=O.N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH2:18])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of N-Boc-L-Nle-OH (0.5 g, 2.2 mmol) in anhydrous THF (15 mL) under Ar at -23° C. was added 4-methylmorpholine followed by iso-butyl chloroformate (0.21 mL, 2.2 mmol). The reaction mixture was then treated with gaseous NH3 for 1 h. Stirring was continued at -23° C. for an additional 2 h. The mixture was warmed to R.T. and then poured onto 10% aqueous citric acid (20 mL). The mixture was extracted with EA (3×50 mL). The combined organics were washed with sat. NaHCO3 (3×25 mL), sat. NaCl (2×25 mL), dried (MgSO4), filtered and concentrated to afford N-Boc-L-Nle-NH2 as a white solid (0.48 g, 91%): 1H NMR (CDCl3, 300 MHz) δ0.84-0.92 (m, 3 H), 1.22-1.31 (m, 4 H), 1.41 (s, 9 H), 1.49-1.59 (m, 1 H), 1.74-2.01 (m, 1 H), 4.03-4.1 (m, 1 H), 5.06 (d, 1 H), 5.75 (s, 1 H), 6.25 (s, 1 H) ppm.
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][C:11]1[C:12]([CH3:23])=[N:13][O:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:19]3[CH:20]=[CH:21][C:16]([C:15]4[O:14][N:13]=[C:12]([CH3:23])[C:11]=4[CH2:10][CH2:9][S:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:17][CH:18]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CCSCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCSCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 4-(2-benzylsulfanyl-ethyl)-5-(4-bromo-phenyl)-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([C:8]2([S:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]2)[CH:7]=1.[F:32][C:33]([F:39])([F:38])[S:34]([NH2:37])(=[O:36])=[O:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:32][C:33]([F:39])([F:38])[S:34]([NH:37][CH:11]1[CH2:12][CH2:13][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[C:28]([F:31])([F:30])[F:29])([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:9][CH2:10]1)(=[O:36])=[O:35]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)C1(c2cc(F)ccc2C(F)(F)F)CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(NC1CCC(c2cc(F)ccc2C(F)(F)F)(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)C(F)(F)F
Temperature: 60 °C

Procedure:
A 2 L 3-neck round bottom flask equipped with a nitrogen bubbler, thermocouple, stir bar, heating mantle and condenser was charged with 4-[5-fluoro-2-(trifluoromethyl)phenyl]-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexanol (94.7 g, 201 mmol) in THF (1 L). Trifluoromethanesulfonamide (45.0 g, 302 mmol) and triphenylphosphine (79 g, 302 mmol) were added, followed by DIAD (0.059 L, 302 mmol,) which was added dropwise over 20 min. The reaction was heated to 60° C. and stirred for 18 hrs at 60° C. The reaction was concentrated and dissolved in CH2Cl2 and purified by column chromatography on silica gel, eluting with ethyl acetate/heptanes to provide 1,1,1-trifluoro-N-(4-[5-fluoro-2-(trifluoromethyl)phenyl]-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl)methanesulfonamide.
Reaction SMILES: [Li]CCCC.[C:6](#[N:8])[CH3:7].C[O:10][C:11]([CH:13]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14]1)=O.C(#N)C.C(=O)=O>C1COCC1>[CH3:18][O:17][C:15]1([O:19][CH3:20])[CH2:16][CH:13]([C:11](=[O:10])[CH2:7][C:6]#[N:8])[CH2:14]1
Reactant: COC(=O)C1CC(OC)(OC)C1
Reactant: CC#N
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1(OC)CC(C(=O)CC#N)C1
Reaction time: 1 h

Procedure:
To 200 mL of THF at −78° C. was added n-BuLi (207.0 mL, 517.0 mmol, 2.5 M in hexanes). After the reaction temperature equilibrated (˜15 min), a solution of acetonitrile (27.0 mL, 517.0 mmol in 100 mL of THF) was added dropwise via addition funnel over a 20 min period. The resulting milky white slurry was allowed to stir one hr before a solution of 3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester (45.0 g, 258.6 mmol in 150 mL of THF) was added down the side of the flask over a 20 min period. After one hr, the reaction was warmed to −45° C. (acetonitrile/CO2), and allowed to stir for two hr. The reaction was quenched cold by the dropwise addition of 2 N HCl (˜260 mL), pH=7 and then diluted with EtOAc (1 L). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×600 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound (quantitative yield) as a yellow oil that was used with out further purification. Rf 0.32 (40% EtOAc/hexanes). m/z (APCI+) 182 (M−1).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[N:12]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.CS(O[CH2:33][CH2:34][CH3:35])(=O)=O.C(=O)(O)[O-].[Na+]>O.CN(C=O)C>[CH2:33]([NH:2][C@H:3]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[N:12]=2)=[O:10])[CH2:4]1)[CH2:34][CH3:35]
Reactant: CCCOS(C)(=O)=O
Reactant: C[C@H]1CN(C(=O)c2nn(C)c3ccccc23)C[C@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN[C@@H]1CN(C(=O)c2nn(C)c3ccccc23)C[C@@H]1C
Temperature: 70 °C
Reaction time: 5 h
Yield: 27.9 %

Procedure:
Into 2 ml of DMF were dissolved 200 mg (0.68 mmol) of cis-3-amino-4-methyl-1-(1-methylindazol-3-ylcarbonyl)pyrrolidine hydrochloride and 0.11 ml (0.81 mmol) of triethylamine, and 188 mg (1.36 mmol) of n-propyl methanesulfonate was added under ice cooling. Then, the mixture was stirred for 5 hours at room temperature, for 3 hours at 60° C. and further for 5 hours at 70° C. After addition of water, the solution was made alkaline with sodium bicarbonate, which was then extracted with methylene chloride. After washed with saturated saline solution and dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure to obtain crude oil. This was subjected to silica gel column chromatographic purification (methylene chloride:methanol=20:1) to obtain 57 mg (27.9%) of aimed compound (pale yellow oil).
Reaction SMILES: [CH2:1]([C@@H:8]([C@@H:13]([OH:15])[CH3:14])[C:9](OC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CC(O)C>[CH2:1]([C@@H:8]([C@@H:13]([OH:15])[CH3:14])[C:9]([NH:17][NH2:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)[C@H](C)O
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: C[C@H](O)[C@H](Cc1ccccc1)C(=O)NN
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A 0.70 g (3.36 mmol) of methyl (2S,3S)-2-benzyl-3-hydroxybutyrate (optical purity: 96%e.e.; anti/syn=98/2) was dissolved in 1 ml of 2-propanol, and 0.34 g (6.72 mmol) of hydrazine monohydrate was added thereto dropwise at room temperature. After the addition, the mixture was refluxed for 8 hours, and then stirred overnight to obtain a concentrate. The obtained concentrate was crystallized by using a mixed solvent of ethyl acetate and hexane to give 0.45 g (64%) of the title compound. Melting point: 167.1° C. Optical purity: >99.9%e.e. anti/syn>99/1
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][CH:5]([CH3:32])[CH2:6][C:7]1([CH:21]([C:29](C)=[CH2:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]1=[O:20].[BH4-].[Na+]>CCO>[OH:1][CH2:30][CH2:29][CH:21]([C:7]1([CH2:6][CH:5]([CH3:4])[CH3:32])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]1=[O:20])[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: O=[O+][O-]
Reactant: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCN(CCc2ccccc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CC1(C(CCO)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Ozone is bubbled through a solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-α-(propen-2-yl)-3-pyrrolidineacetate (555 mg, 1.39 mmol) and EtOH (12 mL) at -78° C. for 5 minutes. Nitrogen is then bubbled through the solution for 5 minutes. Sodium borohydride (79 mg, 2.1 mmol) is added and the mixture is allowed to warm slowly and to stir at room temperature overnight. The mixture is concentrated to near dryness, and aqueous workup (EtOAc, MgSO4) to give 511 mg (91%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](O)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:12][C:13]1[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=1.C(OP(C#N)(OCC)=O)C.C(N(CC)CC)C>COCCOC.CCOC(C)=O>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[NH:20][C:15]3[CH:14]=[C:13]([CH3:12])[CH:18]=[CH:17][C:16]=3[N:19]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Yield: 45.9 %

Procedure:
A mixture of 3-amino-6-bromo-pyrazine-2-carboxylic acid (2.5 g, 11.47 mmol), 4-methylbenzene-1,2-diamine (1.401 g, 11.47 mmol), diethoxyphosphoryl-formonitrile (2.058 g, 1.871 mL, 12.62 mmol) and triethylamine (2.321 g, 3.197 mL, 22.94 mmol) was heated in DME (75.00 mL) at 170° C. in the microwave for 1 hour. The reaction mixture was diluted with EtOAc, filtered and washed with water and brine, dried over MgSO4 and concentrated to a brown solid. The mixture was slurried in DCM and treated with diethyl ether/petroleum ether. The resultant solid was washed with ether and dried to afford the product as an orange/brown solid (1.6 g, 46% Yield). MS (ES+) 305.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:18]O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:10]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(Br)ccc1Sc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)ccc1Sc1ccccc1

Procedure:
478 g of 3-bromo-6-(phenylthio)-benzoic acid in 1.5 litres of methanol and 200 ml of concentrated sulphuric acid are heated under reflux for 8 hours. The solution is concentrated under reduced pressure, treated with water and extracted with water. The organic solution is washed with aqueous sodium bicarbonate solution, dried over magnesium sulphate and concentrated under reduced pressure. There is obtained methyl 3-bromo-6-(phenylthio)-benzoate as a yellow oil.
Reaction SMILES: [C:1]([O:9][C@:10]1([C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([C@@H:29]([OH:33])[CH2:30]2)[C@:26]2([CH3:27])[C:21](=[CH:22][C:23](=[O:34])[CH2:24][CH2:25]2)[C@@H:20]([CH3:35])[CH2:19]3)[CH2:16][CH2:15]1)[C:11](=[O:14])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([O:13][CH2:12][C:11](=[O:14])[C@:10]1([O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([C@@H:29]([OH:33])[CH2:30]2)[C@:26]2([CH3:27])[C:21](=[CH:22][C:23](=[O:34])[CH2:24][CH2:25]2)[C@@H:20]([CH3:35])[CH2:19]3)[CH2:16][CH2:15]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(OC(=O)c2ccccc2)C(=O)CO)[C@@]2(C)CCC(=O)C=C12
Product: CC(=O)OCC(=O)[C@@]1(OC(=O)c2ccccc2)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
Analogously to Example 9, 2.2 g of 17-benzoyloxy-11β,21-dihydroxy-6α-methyl-4-pregnene-3,20-dione is reacted with acetic anhydride and worked up as usual. The crude product is purified on 350 g of silica gel with a methylene chloride-acetone gradient (0-8% acetone), thus isolating 1.6 g of 21-acetoxy-17-benzoyloxy-11β-hydroxy-6α-methyl-4-pregnene-3,20-dione, mp 210° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]2[C:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[C@@H:22]([NH2:24])[CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:21][C:18]1[CH:19]=[CH:20][C:15]2[N:14]=[C:13]([CH:22]([NH:24][C:26]3[N:34]=[CH:33][N:32]=[C:31]4[C:27]=3[N:28]=[CH:29][NH:30]4)[CH3:23])[N:12]([CH:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:11]3)[C:16]=2[CH:17]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 45 %

Procedure:
A mixture of 3-[2-((S)-1-aminoethyl)-6-fluorobenzoimidazol-1-yl]azetidine-1-carboxylic acid tert-butyl ester (354 mg, 1.05 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (278 mg, 1.16 mmol) and DIPEA (0.41 mL, 3.18 mmol) in n-butanol (1.4 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford 377 as a white solid (214 mg, 71%). LCMS (Method K): RT 3.59 min [M+H]+ 453.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.43 (1H, s), 8.23 (1H, br s), 8.14 (1H, br s), 7.96 (1H, d, J=7.67 Hz), 7.68 (1H, dd, J=8.83, 5.02 Hz), 7.36 (1H, dd, J=9.41, 2.45 Hz), 7.11 (1H, td, J=9.29, 2.36 Hz), 5.79 (1H, br s), 5.70-5.60 (1H, m), 4.48-4.34 (2H, m), 4.31-4.19 (2H, m), 1.65 (3H, d, J=6.67 Hz), 1.44 (9H, s)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2>C(O)C.[Pd]>[CH2:11]([C:9]1[CH:10]=[CH:2][CH:3]=[C:4]2[C:8]=1[NH:7][N:6]=[CH:5]2)[CH3:12]
Reactant: CCc1cc(Br)cc2cn[nH]c12
Agent: [Pd]
Solvent: CCO
Product: CCc1cccc2cn[nH]c12
Yield: 131.8 %

Procedure:
To a solution of 5-bromo-7-ethyl-1H-indazole (900 mg, 4.00 mmol) in ethanol (16.0 mL) flushed with nitrogen was added palladium on carbon (128 mg, 1.2 mmol) and the mixture stirred under H2 at 1 atm. After 70 h the reaction was filtered over a pad of celite. The filtrate was collected and concentrated. The residue was dissolved in ethanol and 80 mg of palladium on carbon was added and stirred under H2 at 1 atm. After 3 h another 80 mg of palladium on carbon was added and stirred under H2 at 1 atm. After 16 h the reaction was filtered through a pad of celite. The filtrate was collected and concentrated. The yellow solid obtained was triturated with ether, filtered and dried under vacuum to give 7-ethyl-1H-indazole (771 mg, 5.27 mmol, 119%) as an off white solid. This was used directly without further purification. MS (M+H)+=146.8; 1H NMR (CDCl3) δ: 8.54 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.59 (d, J=7.1 Hz, 1H), 7.43 (t, J=7.1 Hz, 1H), 3.25 (q, J=7.4 Hz, 2H), 1.48 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>O1CCCC1>[C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:8]2[N:9]=[C:10]([NH:12][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:11][C:7]=2[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)NC1CCc2nc(N)sc2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NC1CCc2nc(NC(=O)c3ccccc3)sc2C1

Procedure:
To a solution of 4.2 g (0.02 Mol) of 6-acetylamino-2-amino-4,5,6,7-tetrahydro-benzthiazole in 100 ml of absolute tetrahydrofuran are added 2.2 g (0.022 Mol) of triethylamine and 3.1 (0.022 Mol) of benzoylchloride and the mixture is refluxed for 3 hours. The reaction mixture is mixed with water and extracted with ethyl acetate. The organic phase is concentrated by evaporation. The residue is recrystallized from methanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]I.Br[C:14]1[C:15](=[O:26])[NH:16][C:17](=[O:25])[C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:14]2[C:15](=[O:26])[NH:16][C:17](=[O:25])[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1NC(=O)C(c2ccccc2)=C1Br
Agent: C[Mg]I
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1ccccc1
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A solution of 4.9 g of indole in 50 ml of benzene was treated with 19 ml of a 3M solution of methylmagnesium iodide in diethyl ether and stirred under nitrogen for 15 minutes. 3.5 g of 3-bromo-4-phenyl-1H-pyrrole-2,5-dione were added and the mixture was stirred for 18 hours. The solvent was evaporated and the residue was dissolved in 250 ml of dichloromethane and 50 ml of 2M hydrochloric acid. The organic extracts were washed with water, dried and evaporated. The residue was purified on silica gel with ethyl acetate/petroleum ether. Trituration with dichloromethane and recrystallization from methanol yielded 1.40 g of 3-(3-indolyl)-4-phenyl-1H-pyrrole-2,5-dione, m.p. 256° C.
Reaction SMILES: [C:1]([C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>C(O)(=O)C.[Pd]>[CH2:1]([C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCCCCCCCCCC#Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1c[nH]cn1
Reaction time: 16 h
Yield: 89.7 %

Procedure:
Twenty percent Pd/C (1 g) was added to a solution of 4-(1-dodecynyl)-1-(triphenylmethyl) imidazole (2.39 g, 5 mmol) in glacial acetic acid (100 mL), along with 50 psi of hydrogen gas. Stirred for 16 hours and concentrated in vacuo. The residue was made basic with saturated Na2CO3, neutralized with 1N HCl, and extracted with ether. The ether layer was dried over MgSO4, filtered, and concentrated to give an oily white solid. Recrystallized from hexanes to give the title compound as a white solid (1.06 g, 90%); mp 69°-71° C.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22](O)=[O:23])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[NH:3]1.B.C1COCC1>C1COCC1>[OH:23][CH2:22][C:17]12[CH2:18][CH2:19][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:25])[NH:3][C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:21][CH2:20]1)[CH2:15][CH2:16]2
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc21
Agent: B
Solvent: C1CCOC1
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-(2,6-Dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid (3.2 g, 9.25 mmol) was dissolved in 100 mL of anhydrous THF and cooled to 0° C. Borane-THF (1.0 M in THF, 18.5 mL, 2 eq) was added and the reaction mixture was stirred at 0° C. for 10 min, then warmed to rt and stirred for 48 h. The reaction mixture was then carefully quenched with 10 mL of MeOH and then concentrated under reduced pressure. The resulting residue was dissolved in 20 mL of MeOH and concentrated under reduced pressure. This treatment was repeated four more times to afford the desired alcohol.
Reaction SMILES: [CH2:1]1[C:10]2[CH:5]([CH2:6][CH2:7][CH:8]3C=[CH:13][CH:12]=[CH:11][C:9]3=2)[NH:4][CH2:3][CH2:2]1.[CH3:15][OH:16]>>[OH:16][C:15]1[C:8]2[CH2:7][CH2:6][C@H:5]3[C@H:10]([CH2:1][CH2:2][CH2:3][N:4]3[CH2:12][CH2:11][C:9]3[CH:10]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: C1=CC2=C3CCCNC3CCC2C=C1
Reactant: CO
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCCN1CCc1ccccc1
Yield: 46 %

Procedure:
Cis-(−)-7-hydroxy4-phenethyl-1,2,3,4,4a,5,6, 10b)-octahydrobenzo[f]quinoline (hereinafter, “cis-(−)-25”) was prepared in 46% yield from 34 mg (0.11 mmole) of cis-(−-24 by the method described for trans-9 in Example 3. The melting point observed was 196° C. and [α]D (20° C.) was −6.0 (c 0.20, MeOH).