Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:30]=[C:31]([CH3:49])[C:32](=[C:34]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:33]=1)([CH3:28])([CH3:27])[CH3:26].Cl>C(OCC)C>[C:25]([C:29]1[CH:30]=[C:31]([CH3:49])[CH:32]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[CH:33]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 1.42 g of fluorene (8.52 mmol) was dissolved in 60 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 5.6 ml of n-butyl lithium/hexane solution (1.58M: 8.85 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, 2.99 g of 3-tert-butyl-1-methyl-6,6-di(4-chloro-phenyl)fulvene (8.08 mmol) was added and stirred under reflux for several days. The reaction mixture was gradually added dropwise to 30 ml of a hydrochloric acid aqueous solution (1N) set in an ice bath, and stirred briefly. Therein, diethyl ether was added to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution, water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a red solid. The solid was purified with a column chromatography using 180 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. Thereafter, the remaining product was re-crystallized using hexane and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 1.69 g (3.16 mmol) as a pale yellow solid (yield: 39%).
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:3].[B-](F)(F)(F)F.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[N:33]=[N:34][N:35]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45](O)=[O:46])=[CH:39][CH:38]=3)[CH:36]=2)=[N:24]1.CCN(C(C)C)C(C)C.CNC>CN(C=O)C.C1COCC1>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[N:33]=[N:34][N:35]([C:37]3[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][C:45]([N:2]([CH3:3])[CH3:1])=[O:46])=[CH:41][CH:42]=3)[CH:36]=2)=[N:24]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)CCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
TBTU (188 mg; 0.58 mmol; 1.3 eq.) was added to a cooled (0° C.) solution of 3-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}propanoic acid (150 mg; 0.45 mmol; 1.0 eq.) and DIEA (176 μl; 1.03 mmol; 2.3 eq.) in DMF (3 mL). After 10 min, dimethylamine (270 μl of a 2.00 M in THF; 0.54 mmol; 1.20 eq.) was added and the reaction mixture was stirred overnight at RT. The resulting solid was filtered off and purified by preparative HPLC to afford the title compound as a brown solid. 1H NMR (300 Mz, DMSO-d6) δ: 13.34 (brs, 1H), 9.26 (s, 1H), 8.36 (d, J=8.1 Hz, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.62-7.59 (m, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.46-7.41 (m, 1H), 7.28-7.23 (m, 1H), 2.96 (s, 3H), 2.93-2.88 (m, 2H), 2.83 (s, 3H), 2.70-2.65 (m, 2H). HPLC (Condition A): Rt 3.23 min (purity 92.2%). MS (ESI+): 361.3, MS (ESI−): 359.3.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>C(#N)C>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClC[C@@H]1CO1
Solvent: CC#N
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and ferric chloride (12.6 g. 0.30 mol) were added to 100 mL of acetonitrile. The mixture was stirred at 25° C. for 30 minutes. (S)-epichlorohydrin (18.6 g, 0.2 mol) was then added and stirred at 60° C. for 8 hours. Filtered and the solvent was evaporated to provide 55 g of colorless oil in 94% yield. HPLC: 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:7][C:6]2=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl.Cl[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>O1CCCC1.C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:7][C:6]2=1
Reactant: ClCc1ccccn1
Reactant: COc1ccc2[nH]c3c(c2c1)CC(NC(=O)C(C)C)CC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c(n2Cc2ccccn2)CCC(NC(=O)C(C)C)C1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Dissolve N-(6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (200 mg, 0.70 mmol) in anhydrous tetrahydrofuran (6 mL) under nitrogen. Add dropwise potassium bis(trimethylsilyl)amide (3.2 mL, 1.6 mmol, 0.5M in toluene) and stir 30 min. Add slowly 2-(chloromethyl)pyridine hydrochloride (131 mg, 0.80 mmol) in THF/DMF (0.4 mL/1.3 mL) and stir at ambient temperature for 18 h. Quench with saturated ammonium chloride solution (0.5 mL) and partition between ethyl acetate and water. Separate the two phases and wash the aqueous phase with ethyl acetate (2×). Dry the combined organic portions (MgSO4), filter, and concentrate in vacuo to obtain a residue. Purify the material by silica gel chromatography, eluting with 50% ethyl acetate/dichloromethane with a gradient up to 80% ethyl acetate/dichloromethane to obtain 199 mg (75%) of a light yellow solid. MS (ES): m/z 378 (M+1); 1H NMR(DMSO-d6): δ 8.50 (dd, 1H, J=4.8, 0.9 Hz), 7.82 (d, 1H, J=7.5 Hz), 7.65 (dt, 1H, J=7.6, 1.6 Hz), 7.22 (m, 2H), 6.89 (d, 1H, J=2.2 Hz), 6.77 (d, 1H, J=7.9 Hz), 6.63 (dd, 1H, J=8.6, 2.4 Hz), 5.32 (s, 2H), 3.97 (m, 1H), 3.72 (s, 3H), 2.91 (dd, 1H, J=15.0, 5.3 Hz), 2.85-2.76 (m, 1H), 2.74-2.64 (m, 1H), 2.45 (m, 1H), 2.37 (m, 1H), 1.94 (m, 1H), 1.77 (m, 1H), 0.99 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.Cl[C:21]([O:23][CH2:24][CH2:25]Cl)=[O:22]>C(#N)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:25][CH2:24][O:23][C:21]2=[O:22])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(N)ccc1Br
Reactant: O=C(Cl)OCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(N2CCOC2=O)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
To a stirred solution of 4-Bromo-3-methoxy-aniline (10.0 g) in acetonitrile (176 mL) was added Hünig Base (25 mL) and 2-chloroethyl chloroformate (10.6 g). The mixture was stirred at room temperature for 0.5 h. The solvent was removed in vacuum. The residue was dissolved in tetrahydrofurane (250 mL), and potassium tert-butoxide (16.2 g) was added. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuum. The residue was dissolved in ethyl acetate and the mixture was washed with water and with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave a compound that was crystallized from ethanol. Yield: 7.7 g of the title compound. The mother liquor was concentrated in vacuum and aminophase-silica-gel chromatography gave a solid that was recrystallized from ethanol to give further 2.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=2[N:3]=1.C(O[CH:17]1[O:29][C@H:28]([CH3:30])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C>>[Cl:1][C:2]1[N:6]([C@@H:17]2[O:29][C@H:28]([CH3:30])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:5]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=2[N:3]=1
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: COc1ccc2[nH]c(Cl)nc2c1
Product: COc1ccc2c(c1)nc(Cl)n2[C@@H]1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 65 %

Procedure:
2-Chloro-5-methoxy-1H-benzimidazole (0.661 g, 3.6 mmol) was coupled to 1,2,3-tri-O-acetyl-5deoxy-D-ribofuranose according to General Procedure II. The crude product was purified by flash chromatography (9:1 methylene chloride/ether) to yield the title compound (0.900 g, 65%) as a ˜1:1 mix of regioisomers (1H NMR); MS (AP): m/z 405 (M+Na); 1H NMR (DMSO-d6) δ: 7.65-7.54 (two d, 1H), 7.21 (s, 1H), 6.97 (m, 1H), 6.18-6.11 (two d, 1H), 5.70-5.59 (m, 1H), 5.21 (q, 1H), 4.27 (m, 1H), 3.83 (two s, 3H), 2.16 (s, 3H), 2.05 (s, 3H), 1.51 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:20])[C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[NH2:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33]>ClCCl>[C:6]([N:8]([CH3:20])[C@H:9]([C:17]([NH:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: CN(C)CCCN
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN(C)CCCNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
N-t-Butyloxycarbonyl-N-methylphenylalanine (2.79 g) and NMM (1.01 g) were dissolved in dichloromethane (20 ml) and the stirred solution cooled to -20° IBCF (1.37 g) was then added and the mixture stirred for 5 minutes before the addition of NH2CH2CH2CH2NMe2 (1.02 g). The solution was stirred for 1 hour at -20° and then at room temperature for 12 hours. The mixture was evaporated, and the residue dissolved in ethyl acetate (50 ml) and an aqueous solution of sodium bicarbonate (saturated, 50 ml). The ethyl acetate layer was washed with aqueous sodium bicarbonate (saturated, 50 ml), water (2×50 ml) and 10% aqueous citric acid (2×50 ml). The citric acid extracts were combined, made basic with saturated sodium bicarbonate solution, and extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were combined, dried (Na2SO4) and evaporated to yield the title compound as an oil Rf1E 0.24, Rf3A 0.37.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)=[N:6][CH:7]=1.C(N(CC)C1C=CC=CC=1)C.[N+:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([O-:30])=[O:29]>O1CCOCC1>[NH2:16][C:11]1[N:10]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[C:34]3[CH:33]=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:39][CH:38]=3)=[CH:3][CH:4]=2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(Nc2ccc(N)cn2)nc(N)n1
Solvent: CCN(CC)c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cn2)nc(N)n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a suspension of 10 (500 mg, 2.31 mmol) and N,N-diethylaniline (1 ml, 1.5 eq) in 1,4-dioxane (20 ml) at 0° C. was added dropwise a solution of p-nitrobenzoylchloride (429 mg, 12.31 mmol). The reaction mixture was stirred at 20° C. for 2 h. TLC and mass spectrum showed still presence of 10. Therefore more p-nitrobenzoylchloride (43 mg, 0.1 eq ) was added and stirred for 20 h. The resulting precipitate was filtered and washed with more 1,4-dioxane. The collected solid was stirred in aqueous NH3, filtered washed with water and dried to give essentially pure 11 (821 mg, 97%); mp (MeOH)>300° C.; 1H NMR [(CD3)2SO] δ 10.58 (s, 1 H, NH), 9.56 (s, 1 H, NH), 8.65 (d, J=2.5 Hz, 1 H, H-2′), 8.38 (d, J=8.9 Hz, 2 H, H-3,5), 8.20 (d, J=9.2 Hz, 2 H, H-2,6), 8.17 (d, J=9.1 Hz, 1 H, H-5′), 8.02 (dd, J=9.0, 2.6 Hz, 1H, H-4′), 6.45 (s, 1 H, H-5″), 6.15 (s, 2 H, NH2), 2.12 (s, 3 H, CH3); HRMS (FAB+) (M+1) m/z calc. for C17H16N7O3 (M+1) m/z, 366.1315, found 366.1314; Anal. calc. for C17H15N7O3: C, 55.9; H, 4.1; N, 26.8, found C, 55.6; H, 4.2; N, 26.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[NH:9][C:10]([CH3:18])=[C:11]3[C:16]=2[CH:15]=[N:14][NH:13][C:12]3=[O:17])[CH:7]=1.C(N(CC)CC)C.ClCCl.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39]>O1CCCC1>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[O:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[CH:7][C:6]=1[C:8]1[NH:9][C:10]([CH3:18])=[C:11]2[C:16]=1[CH:15]=[N:14][NH:13][C:12]2=[O:17]
Reactant: Cc1[nH]c(-c2cc(N)ccc2Oc2ccc(F)cc2F)c2cn[nH]c(=O)c12
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2[nH]c(C)c3c(=O)[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
To a solution of Example 78c (40.5 mg, 0.110 mmol) and triethylamine (0.077 mL, 0.55 mmol) in the mixture of dichloromethane (2 mL) and tetrahydrofuran (2 mL) was added ethanesulfonyl chloride (0.038 mL, 0.40 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 6 hours and concentrated. The residue was diluted with dioxane (2 mL) and 1M sodium hydroxide (1.1 mL), and heated at 50° C. for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with water and ethyl acetate, adjusted the pH to 7 by addition of 1M HCl and separated. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1-5% methanol in dichloromethane) to afford the title compound (20 mg, 40%). 1 H NMR (300 MHz, DMSO-d6) δ 12.45 (s, 1 H) 11.45 (s, 1 H) 9.81 (s, 1 H) 8.04 (s, 1 H) 7.36-7.50 (m, 2 H) 7.13-7.27 (m, 2 H) 7.02-7.12 (m, 1 H) 6.88 (d, J=8.73 Hz, 1 H) 3.13 (q, J=7.14 Hz, 2 H) 2.63 (s, 3 H) 1.23 (t, J=7.34 Hz, 3 H). MS (ESI+) m/z 461 (M+H)+.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[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.ClC(OCC(C)C)=O.[NH:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36]>C(Cl)Cl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([N:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -35 °C
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
A solution of Boc-Phe-OH (5.48 g) and NMM (2.09 g) in methylene chloride (50 ml) was cooled to -20° C. To this solution was added dropwise isobutyl chloroformate (2.82 g) maintaining the temperature between -22° C. to -20° C. in 7 minutes. After stirring the mixture for 20 minutes at the same temperature, the solution was cooled to -35° C. and HNMeBzl (2.50 g) was added dropwise to the solution. The reaction mixture was stirred for 2 hours during which period the temperature was gradually raised to -2° C. The solution was washed successively with water (twice), diluted sodium hydrogencarbonate solution (twice), water 0.5N hydrochloric acid (twice), and sodium chloride solution, and dried over magnesium sulfate. After evaporation, the solidified residue was pulverized in hot diisopropyl ether (10 ml), and after cooling, n-hexane (30 ml) was added to the mixture. The crystalline solid was filtered, washed with n-hexane (5 ml×2), and dried to give Boc-Phe-NMeBzl (6.49 g).
Reaction SMILES: N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(OC)=O)=CC=2)=CC3)CC1.CN(C)CC[C:45]([NH:47][C@:48]12[CH2:82][CH2:81][C@@H:80]([C:83]([CH3:85])=[CH2:84])[C@@H:49]1[C@@H:50]1[C@@:63]([CH3:66])([CH2:64][CH2:65]2)[C@@:62]2([CH3:67])[C@@H:53]([C@:54]3([CH3:79])[C@@H:59]([CH2:60][CH2:61]2)[C:58]([CH3:69])([CH3:68])[C:57]([C:70]2[CH:78]=[CH:77][C:73]([C:74]([OH:76])=[O:75])=[CH:72][CH:71]=2)=[CH:56][CH2:55]3)[CH2:52][CH2:51]1)=[O:46].[CH3:87][N:88]1[CH:92]=[CH:91][N:90]=[C:89]1[CH2:93][CH2:94]C(O)=O>>[CH3:66][C@:63]12[C@@:62]3([CH3:67])[C@@H:53]([C@:54]4([CH3:79])[C@@H:59]([CH2:60][CH2:61]3)[C:58]([CH3:69])([CH3:68])[C:57]([C:70]3[CH:71]=[CH:72][C:73]([C:74]([OH:76])=[O:75])=[CH:77][CH:78]=3)=[CH:56][CH2:55]4)[CH2:52][CH2:51][C@@H:50]1[C@H:49]1[C@H:80]([C:83]([CH3:85])=[CH2:84])[CH2:81][CH2:82][C@:48]1([NH:47][C:45](=[O:46])[CH2:94][CH2:93][C:89]1[N:88]([CH3:87])[CH:92]=[CH:91][N:90]=1)[CH2:65][CH2:64]2
Reactant: Cn1ccnc1CCC(=O)O
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(N)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
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCc3nccn3C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-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 following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-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)benzoic acid, except 3-(1-methyl-1H-imidazol-2-yl)propanoic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 666.4 (M+H)+, 4.15 min (method 8). 1H NMR (500 MHz, METHANOL-d4) δ=7.95 (d, J=8.5 Hz, 2H), 7.53-7.46 (m, 2H), 7.25 (d, J=8.2 Hz, 2H), 5.33 (dd, J=1.8, 6.1 Hz, 1H), 4.79 (d, J=1.5 Hz, 1H), 4.66 (s, 1H), 3.91 (s, 3H), 3.30-3.18 (m, 2H), 2.84-2.79 (m, 2H), 2.73 (dt, J=5.2, 11.1 Hz, 1H), 2.64 (d, J=12.5 Hz, 1H), 2.35 (dd, J=8.2, 12.2 Hz, 1H), 2.18 (dd, J=6.4, 17.4 Hz, 1H), 1.96 (dt, J=3.2, 12.1 Hz, 1H), 1.91-1.78 (m, 2H), 1.77 (s, 1H), 1.74 (s, 3H), 1.71-1.66 (m, 1H), 1.60 (br. s., 2H), 1.46-1.26 (m, 7H), 1.22-1.13 (m, 1H), 1.11 (s, 3H), 1.07 (s, 3H), 1.05 (s, 4H), 0.99 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[N:51]([C:52]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:50]=[N:49][N:48]=2)=[CH:37][CH:36]=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1[N:14]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[N:51]([C:52]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)([C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[N:50]=[N:49][N:48]=3)=[CH:39][CH:40]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(=O)c2cc(C=CC(=O)OCC)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(C=CC(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
To a suspension of 1.75 g of ethyl 3-(2-butyl-1,4-dihydro-4-oxo-6-quinazolinyl)-2-propenoate in 25 ml of dry tetrahydrofuran at room temperature is rapidly added 6.70 g of a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran. After stirring for 20 minutes at room temperature 3.899 g of 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole is rapidly added in one portion and the reaction mixture heated at reflux for 48 hours. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and the organic layer washed with 5% HCl, water and brine. The organic layer is dried with MgSO4 and concentrated in vacuo to a residue which is purified by column chromatography on silica gel by eluting with 1:4 ethyl acetate-hexanes to give 1.732 g of the desired product as a solid. FAB mass spec 799 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1N.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>O>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[OH:13]
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1O
Temperature: 0 °C

Procedure:
2-methyl-5-nitroaniline (40 g) was dissolved in refluxing 10% sulphuric acid (600 ml), cooled to 0° C. whereupon the salt separates out. With continuous stirring, sodium nitrite solid (18 g) was added in small portions. The diazitization was complete when a positive starch/KI test was observed. This diazonium solution was added at once to a vigorously refluxing solution of water (800 ml) and concentrated sulphuric acid (400 ml). Refluxing was continued until all gassing had ceased. A solid had precipitated out and, upon cooling to ambient temperature, was collected and dried to give crude 2-methyl-5-nitrophenol. This crude phenol (36.8 g) in dimethylformamide (200 ml) along with anhydrous K2CO3 (35 g) and 2-bromopropane (50 ml) was stirred and warmed to 60° C. for 12 hours. After cooling, the solvent was removed, the residue treated with water and the product extracted with ether. This ether solution was washed with 2N KOH, water, dried (MgSO4) and evaporated to give 1-(1-methylethoxy)-2-methyl-5-nitrobenzene, bp. 80°-85° C./0.15 mm., 34.5 g. This nitrobenzene (34.5 g) in methanol (250 ml) was reduced on a parr hydrogenator using Raney nickel. After removal of the catalyst and solvent, the product, 3-(1-methylethoxy)-4-methyl-benzenamine, bp. 80°-85° C./0.05 mm., 25 g. was obtained. This amine (10 g) in methylene chloride (50 ml) and crushed ice (50 g) was stirred whilst thiophosgene (6.5 ml) in methylene chloride (25 ml) was added dropwise. The reaction was stirred overnight at ambient temperature. After separating the organic layer, the methylene chloride solution was washed with water, dried and evaporated to leave a pale yellow oil, bp. 80°-85° C./0.04 mm of 5-isothiocyanato-1-(methylethoxy)-2-methylbenzene, 12,4 g. Ethyl 3-amino-4,4,4-trifluoro-2-butenoate (11 g) was added portionwise to a stirred suspension of sodium hydride (2.5 g, 60%) in tetrahydrofuran (50 ml) at 15° C. When complete, the reaction was chilled to -70° C. (acetone/ dry ice), whereupon the above isothiocyanate (12.4 g.) in THF (25 ml) was added at once. The temperature rose to -50° C. before cooling to -70° C. After stirring to ambient temperature and leaving overnight a solid had precipitated out. The solvent was removed, water added, washed with ether and acidified. A pale yellow solid had precipitated out. This was collected on a filter, washed with water, dried and recrystallized from IPA to give 2,3 dihydro-3-[3-(1-methylethoxy)-4-methylphenyl]- 2-thioxo-6-(trifluoromethyl)-4(1H)-pyrimidinone, mp. 227°-228°.