Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=[O:3].CCN(C(C)C)C(C)C.[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH2:56]>ClCCCl.CN(C1C=CN=CC=1)C>[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH:56][C:2]([C@:4]12[CH2:39][CH2:38][C@@H:37]([CH:40]([CH3:42])[CH3:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C@@H:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)=[O:3]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)Cl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)CCN
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)NCCN(C)C)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a flask containing methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(chlorocarbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (77 mg, 0.13 mmol) in DCE (2 mL) was added Hunig's base (0.068 mL, 0.390 mmol), DMAP (1 mg, 8.19 mmol), and N,N-dimethylethylenediamine (0.029 mL, 0.260 mmol). The mixture was stirred for two hours at rt. The reaction was quenched with 5 mL of water and was extracted with dichloromethane (3×5 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure and was purified by Biotage flash chromatography using a 0-10% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)ethylcarbamoyl)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a white foam (37 mg, 44% yield). LCMS: m/e 647.7 (M+H)+, 3.09 min (method 3).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11]CC)=[O:10])[CH2:4][C:3]1=[O:20].[OH-].[Li+]>C(O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([OH:11])=[O:10])[CH2:4][C:3]1=[O:20]
Reactant: CCOC(=O)C(c1ccccc1)N1CCN(C)C(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(C(C(=O)O)c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.1 %

Procedure:
Ethyl 2-(4-methyl-3-oxopiperazin-1-yl)-2-phenylacetate (250 mg, 0.90 mmol) was dissolved in ethanol (8.6 ml) and water (4.3 ml). Lithium hydroxide (28.2 mg, 1.18 mmol) was added and the reaction was stirred at room temperature for three days. A second portion of lithium hydroxide (4.33 mg, 0.18 mmol) was added and the reaction was stirred at room temperature for 24 hours. EtOH was evaporated and 1N HCl was added to the aqueous solution till pH 7. The water was evaporated and the residue was suspended in acetonitrile and filtered on a buckner funnel washing with acetonitrile to obtain 170 mg of desired compound as a white solid. The compound was used in the next step without any further purification.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[O:29][C:28]([Si](C(C)C)(C(C)C)C(C)C)=[N:27][CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH3:8][C:6]1[CH:7]=[C:2]([C:25]2[O:29][CH:28]=[N:27][CH:26]=2)[C:3]2[N:4]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:5]=1
Reactant: CCOC(=O)c1cnc2c(Br)cc(C)cn12
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cnc2c(-c3cnco3)cc(C)cn12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A mixture of ethyl 8-bromo-6-methylimidazo[1,2-a]pyridine-3-carboxylate (1478 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (2018 mg), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (426 mg) and potassium carbonate (1443 mg) in DME/water (12/3 mL) was stirred with microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (10 mL), and 1N hydrochloric acid (10 mL) was added thereto. The mixture was stirred at room temperature for 2 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (1075 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:32]1([NH2:39])[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[NH:33]1>O1CCOCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:36]4[N:35]=[C:34]([NH2:38])[N:33]=[C:32]([NH2:39])[CH:37]=4)=[CH:18][CH:19]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: NC1=NC=CC(N)(Cl)N1
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4ccc(Cl)c(C(F)(F)F)c4)[nH]3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 46.3 %

Procedure:
4-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (1.3 g, 3.66 mmol) was dissolved in 18 mL of anhydrous dioxane in a 10-20 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (1.19 g, 3.66 mmol, 1.0 eq) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 4-chloro-2,4-diaminopyrimidine (0.530 g, 3.66 mmol) was added. The vial was capped and microwaved at 200° C. for 25 min. Then the reaction mixture was diluted with ca. 10 mL of MeOH, transferred into a round-bottom flask and concentrated in vacuo to ca. 20 mL. The resulting reddish solution was loaded on a short pad of silica gel and eluted first with 100% ethyl acetate to remove the unreacted starting material and then with 20% MeOH in EtOAc to elute the product. The product was further purified by ISCO system (80 g pre-packed column, 40 min method, 0% to 10% MeOH gradient in ethyl acetate). Solvent was removed in vacuo to give the title product as an off-white solid (0.785 g). Yield 46.3%.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([Sn](Cl)(Cl)CCCC)[CH2:28]CC.C(=O)C.C1([SiH3])C=CC=CC=1>C1COCC1>[CH2:27]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=1)=[O:16])[CH3:28]
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2Nc2ccccc2)cc1
Agent: CC=O
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CCN(c1ccccc1)c1ccccc1NC(=O)c1ccc(C(=O)OC)cc1
Reaction time: 0.25 h
Yield: 530 %

Procedure:
To a stirring solution of compound 112 (1.00 g, 2.89 mmol) in THF was added dibutyltin dichloride (0.175 g, 0.577 mmol) and acetaldehyde (1.182 g, 26.8 mmol) and the reaction mixture was stirred 15 minutes. Phenylsilane (0.375 g, 3.46 mmol) was added and the reaction mixture was stirred at room temperature 60 h then solvent evaporated. The resulting crude product was purified by Isco (80 g column, 10%-50%) to afford title compound 113 (1.145 g, 100%) as a yellowish oil. LRMS (ESI): (calc) 374.16. (found) 375.4 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([O:14][C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:13]=[C:12]([O:14][C:15]([F:16])([F:17])[F:18])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(OC(F)(F)F)cc1N
Yield: 94.1 %

Procedure:
Methyl 2-nitro-4-trifluoromethoxybenzoate (10 g) and 5% palladium on activated carbon (0.5 g) in methanol was hydrogenated for 20 hours at ambient temperature. The mixture was filtered and the filtrate evaporated to give methyl 2-amino-4-trifluoromethoxybenzoate (8.35 g) as a brown oil, NMR (CDCl3) 3.9(s,3H), 5.9(brs,2H), 6.55(m,2H), 7.9(d,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([CH3:34])[CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=1.C1C(=O)N([Br:42])C(=O)C1>>[Br:42][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@H:23]([CH3:34])[CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CN(C)C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CN(C)C(=O)OC(C)(C)C)cc1
Yield: 43 %

Procedure:
Following General Procedure I, (S)-tert-butyl 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propyl(methyl)carbamate (1.0 g, 2.0 mmol was reacted with NBS (446 mg, 2.5 mmol) to afford the desired product (500 mg, 43%) as a yellow solid: ESI MS m/z 557 [C27H29BrN2O4S+H]+.
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][CH3:13].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4]=2[CH2:12][CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCc1oc2ccccc2c1C(Cl)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CCc1oc2ccccc2c1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1

Procedure:
Using 3-[chloro(cyclohexyl)methyl]-2-ethyl-1-benzofuran (300 mg) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (270 mg) synthesized in Example 2(2) and in the same manner as in Example A22(4), the title object compound (287 mg, 57%) was obtained as a white solid.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:10][C:11](=[O:43])[C@H:12]([OH:42])[CH2:13][C@H:14]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]2[N:36]=[N:37][N:38]([OH:39])[C:34]=2[CH:33]=1)=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:18][CH:17]=1)[CH3:9].[F:44][C:45]([F:50])([F:49])CCO>>[F:44][C:45]([F:50])([F:49])[CH2:9][CH2:8][O:10][C:11](=[O:43])[C@H:12]([OH:42])[CH2:13][C@H:14]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]2[N:36]=[N:37][N:38]([OH:39])[C:34]=2[CH:33]=1)=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:18][CH:17]=1
Reactant: OCCC(F)(F)F
Reactant: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCCC(F)(F)F)c1ccc2nnn(O)c2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
4.0 M HCl in 1,4-dioxane (196 μL, 786 μmol) was added to a solution of (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl)amino]pentanoic acid ethyl ester (50.0 mg, 98.2 μmol) in 3,3,3-trifluoropropan-1-ol (336 mg, 3.0 mmol), and the resulting mixture was stirred at 70° C. for 3 hours. The mixture was concentrated in vacuo to yield a white solid, which was purified by preparative HPLC (C18 column chromatography using 40-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (18 mg, purity 100%). MS m/z [M+H]+ calc'd for C27H24ClF3N4O5, 577.14. found 577.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1.O.[Na]>C1COCC1>[NH2:7][C:8]1[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Nc1ncccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncccc1CO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Lithium aluminum hydride (12.4 g, 326.7 mmol) was portionwisely added to a suspension of 2-amino-3-carboxypyridine (30.0 g, 217.2 mmol) in THF (350 mL) at 0° C. Once the addition was completed, the reaction mixture was stirred at room temperature for 15 minutes and then at reflux overnight. The mixture was then cooled to 0° C. and hydrolyzed by the successive addition of water (18 mL), a solution of sodium hydroxyde (18 mL) and water (30 mL) again. The resulting white suspension was filtered on Clarcel® and the cake was washed with THF (200 mL) and a mixture of CHCl3/MeOH (250 mL, 9:1). After concentration to dryness of the filtrate, the title product was obtained as a yellow solid (24.2 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:42])([CH3:41])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:40])([C@@:17]4([CH3:39])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36](O)=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].C(NC(C)C)(C)C.[CH2:50]([NH2:55])[CH2:51][CH:52]([CH3:54])[CH3:53].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CCOC(C)=O>[CH2:50]([NH:55][C:36]([C@:20]12[CH2:32][CH2:31][C@@H:30]([C:33]([CH3:35])=[CH2:34])[C@@H:21]1[C@@H:22]1[C@@:17]([CH3:39])([CH2:18][CH2:19]2)[C@@:16]2([CH3:40])[C@@H:25]([C@:26]3([CH3:29])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:42])([CH3:41])[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)=[CH:28][CH2:27]3)[CH2:24][CH2:23]1)=[O:37])[CH2:51][CH:52]([CH3:54])[CH3:53]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (358.0 mg, 0.625 mmol) in THF (10 mL) was added N,N-diisopropylamine (0.327 mL, 1.875 mmol), isoamylamine (0.110 mL, 0.937 mmol) and HATU (356 mg, 0.937 mmol). The reaction mixture was stirred at 25° C. After 16 h, the reaction mixture was diluted with EtOAc (50 mL), washed with 1N HCl (5 mL), 5% NaHCO3, brine, dried over MgSO4, filtered and concentrated to a foam product. The residue was absorpted on to 4 g of silica gel, loaded on to a silica gel column (40 g cartridge) and eluted with 0% B to 50% B for 240 mL then 50% B (solvent: A=hexanes, B=5:1 hex:EtOAc) to afford the title compound as a white solid (229 mg, 0.342 mmol, 54.8% yield). LCMS: m/e 642.6 (M−H)+, 3.24 min (method 5); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.9 (2H, m, J=8.2 Hz), 7.2 (2H, m, J=8.5 Hz), 5.6 (1H, t, J=5.6 Hz), 5.3 (1H, dd, J=6.3, 2.0 Hz), 4.8 (1H, d, J=2.1 Hz), 4.6-4.6 (1H, m), 3.9 (3H, s), 3.3-3.4 (1H, m), 3.2-3.3 (2H, m), 2.5-2.6 (1H, m), 2.1 (1H, dd, J=17.1, 6.4 Hz), 2.0-2.1 (1H, m), 1.9-2.0 (1H, m), 1.8 (2H, dd, J=11.7, 7.5 Hz), 1.7 (3H, s), 1.6-1.7 (2H, m), 1.6 (1H, s), 1.6 (1H, dd, J=13.3, 2.6 Hz), 1.4-1.5 (11H, m), 1.2-1.3 (2H, m), 1.1 (1H, dd, J=12.5, 4.6 Hz), 1.0 (6H, s), 1.0 (3H, s), 1.0 (3H, s), 0.9 (3H, s), 0.9 (6H, d, J=2.4 Hz); 13C NMR(CHLOROFORM-d) δ ppm 14.4, 15.6, 16.2, 19.3, 19.5, 20.7, 21.1, 22.2, 22.3, 25.5, 25.7, 29.2, 30.6, 33.4, 33.6, 36.0, 37.2, 37.7, 38.2, 38.5, 40.3, 41.5, 42.2, 46.5, 49.3, 49.9, 51.7, 52.6, 55.4, 65.6, 109.0, 123.9, 127.6, 128.2, 129.8, 145.9, 148.5, 150.8, 167.0, 175.6.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br.Br[CH2:16][CH2:17][CH2:18][NH2:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:19][CH2:18][CH2:17][CH2:16][N:5]1[CH2:4][CH2:3][C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6]1
Reactant: NCCCBr
Reactant: CC1(c2ccccc2)CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(c2ccccc2)CCN(CCCN)CC1
Yield: 18.2 %

Procedure:
4-Methyl-4-phenylpiperidine (1.00 g, 5.70 mmol, 1.00 equiv), 3-bromopropylamine hydrobromide (1.87 g, 8.55 mmol, 1.00 equiv) and potassium carbonate (1.97 g, 14.2 mmol, 2.5 equiv) were stirred in refluxing dioxane (20 mL) for 36 hours. After removal of the solvent, water (50 mL) was added and the pH was adjusted to 11-12 by addition of 1 N aqueous NaOH. The mixture was extracted with CH2Cl2 (150 mL+3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, CHCl3-MeOH-NH3 (2 M in MeOH) 100:20:10) to give 241 mg (18%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: N[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].N(OCCCC)=O.C(Br)(Br)[Br:24]>>[Br:24][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: BrC(Br)Br
Reactant: CCCCn1cnc(C(=O)OCC)c1N
Agent: CCCCON=O
Product: CCCCn1cnc(C(=O)OCC)c1Br
Yield: 46 %

Procedure:
To a solution of ethyl 5-amino-1-n-butyl-1H-imidazole-4-carboxylate (0.05 g, 0.24 mmol) in bromoform (5 mL) was added butyl nitrite (0.10 mL, 0.71 mmol). The reaction mixture was stirred at reflux for 5 h. After an aqueous work up, extracting with ethyl acetate, the combined organic extracts were washed with brine and dried (Na2SO4). After removing the solvent under reduced pressure, flash column chromatography (1:1 ether/hexane) of the residue gave the title compound as an oil (0.03 g, 46%). 1H NMR (250 MHz, CDCl3)δ 7.50 (b, 1H), 4.41 (q, 2H), 3.95 (t, 2H), 1.70 (quintet, 2H), 1.40 (m, 5H), 1.00 (t, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=1)[C:12]([O:14][CH3:15])=[O:13])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pt](=O)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[CH2:8][CH:9]1[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccnc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Reaction time: 0.75 h
Yield: 105.5 %

Procedure:
Methyl 2-(3,5-di-tert-butylbenzyl)isonicotinate (3.538 g, 10.42 mmol) was dissolved in acetic acid (30 mL) and platinum(IV) oxide (0.118 g, 0.52 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 5 h 45 min. The catalyst was filtered off and washed with MeOH and the eluate evaporated. DCM and 10% K2CO3 were added and the phases separated. The organic layer was washed with brine, passed through a phase separator and evaporated to yield crude methyl 2-(3,5-di-tert-butylbenzyl)piperidine-4-carboxylate (3.80 g, 106%) as a beige oil. MS m/z 346 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[C@@H:10]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[C:34]([O:38][C:39]([NH:41][C:42]([CH3:47])([C:44](O)=[O:45])[CH3:43])=[O:40])([CH3:37])([CH3:36])[CH3:35].Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl.O>[C:34]([O:38][C:39]([NH:41][C:42]([CH3:47])([CH3:43])[C:44]([NH:11][C@H:10]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Crude D-tryptophan benzyl ester (1.0 g, 3.40 mmol), 1-hydroxybenztriazole hydrate (0.63 g, 4.1 mmol) and t-butoxycarbonyl-α-methylalanine (0.84 g, 4.11 mmol) were stirred together at room temperature in chloroform (20 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980 mg, 5.11 mmol) was added to this mixture in a single portion. The reaction mixture was stirred at room temperature for 4 hours and worked up by pouring into water (50 mL). The chloroform layer was separated and washed with 5% aqueous citric acid solution (25 mL) and 5% aqueous sodium bicarbonate solution (25 mL). The chloroform layer was dried over magnesium sulfate, filtered and evaporated under vacuum to afford a thick oily foam. Chromatography on silica gel using ethyl acetate/hexanes (2:3 v/v) afforded a yellow foam (0.822 g 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].O=[C:11]([CH2:19][CH3:20])[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:19][CH3:20])[CH:16]([CH3:18])[CH3:17]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCC(=O)C(=O)OCC(C)C
Product: CCC(Nc1ccc(Cl)c(Cl)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl 2-oxobutanoate (prepared by following General Procedure AO above using 2-oxobutyric acid (Aldrich) and iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.3 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).