Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[N:13]([CH:25]=[N:26][N:27]=2)[C:14](SC)=[N:15][C:16]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[C:28]1([CH2:34][C@H:35]([NH2:38])[CH2:36][NH2:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C=O)C>[NH2:38][C@@H:35]([CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:36][NH:37][C:14]1[N:13]2[CH:25]=[N:26][N:27]=[C:12]2[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:15]=1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c2nncn12
Reactant: NC[C@@H](N)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: N[C@H](CNc1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c2nncn12)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8-(2-naphthyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine (350 mg, 1 mmol), K3CO3 (100 mg) and (2S)-3-phenylpropane-1,2-diamine (150 mg, 1 mmol) were combined in dry DMF (ca. 5 mL) and the mixture was stirred at room temperature for 48 h. To the reaction solution was added water (ca. 10 mL) at RT and a precipitate formed. The suspension was stirred at RT for 1 h. The solid was filtered off and washed with water (3×10 ml) and dried under vacuum at 50° C. overnight; MS (m/z) 472.3 (M+H)+; C29H25N7 requir. 471.56.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=1[NH2:9].[I:15][Cl:16].Cl>CO>[ClH:16].[I:15][C:12]1[CH:11]=[C:10]([CH3:14])[C:8]([NH2:9])=[C:7]([CH3:6])[CH:13]=1
Reactant: ClI
Reactant: Cc1cccc(C)c1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(I)cc(C)c1N
Reaction time: 3 h

Procedure:
To a suspension of sodium bicarbonate (126 g, 1.5 moles) and 2,6-dimethylaniline (61.5 mL, 500 mmoles) in methanol (700 mL) was added iodine monochloride (1.0 M in dichloromethane, 550 mL, 550 mmoles) at room temperature over 1 h. After addition was complete, stirring was continued for 3 h. The reaction was filtered to remove excess sodium bicarbonate and the solvent removed in vacuo. The residue was re-dissolved in diethyl ether (1.5 L) and treated with hydrochloric acid (2M in ether, 375 mL, 750 mmoles). The resulting suspension was stored in the freezer (−15° C.) overnight. The solid was filtered and washed with diethyl ether until it became colorless, to give 126.5 g (89%) as a grey-green powder. 1H-NMR (DMSO-d6) δ 2.33 (s, 6H), 7.48 (s, 2H), 9.05 (bs, 3H); 13C-NMR (DMSO-d6) δ 17.4, 91.5, 133.1, 131.2, 136.9.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:32])([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:33]([O-])=O)C1C=CC=CC=1>[H][H].[Pd]>[CH3:1][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:32])([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:17])=[CH:11][C:10]=1[NH2:33]
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CNC(=O)OC(C)(C)C)C(=O)N2CCCC2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Product: CNc1ccc(C(C)(CNC(=O)OC(C)(C)C)C(=O)N2CCCC2)cc1N

Procedure:
Prepared analogously to Example 1f from 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-tert.butyloxycarbonylamino-1-pyrrolidino-propan-1-one and hydrogen/palladium on activated charcoal.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:18])=[O:17])[N:8]=1.[NH3:22]>C(O)C>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:18])=[O:17])[N:8]=1
Reactant: NC(=O)CCCCn1ccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CCO
Product: NC(=O)CCCCn1ccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1 h

Procedure:
To a solution of 5-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1-yl)valeramide (0.5 g.) in 6 M ammonia in ethyl alcohol (6 ml.) was added mercuric oxide (0.56 g.) over 5 minutes. The mixture was stirred for 1 hour and filtered. The filtrate was evaporated in vacuo to an oil which was dissolved in EtOAc. Addition of petroleum ether (b.p. 60°-80°) gave 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeramide as a crystalline solid, m.p. 128°-132°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.C([Li:21])CCC>C1C=CC=CC=1.CCCCCC>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Li:21])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [Li]CCCC
Reactant: CCCCCCCCOc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: [Li]c1ccc(OCCCCCCCC)cc1

Procedure:
31.38 g (110.0 mmol) of 1-bromo-4-octyloxybenzene in 80 ml of benzene and 81 ml (130.0 mmol) of a 1.6-molar n-butyllithium solution in hexane are stirred at room temperature under argon for 4 hours. The 4-octyloxyphenyllithium formed as a white precipitate is filtered off under argon, washed twice with 20 ml of n-hexane, dried in vacuo and slowly added dropwise as a solution in 60 ml of tetrahydrofuran at 0° C. under argon to a solution of 11.51 g (100.0 mmol) of 2,6-difluoropyridine in 80 ml of tetrahydrofuran. After a reaction time of 1 hour at 0° C., sodium chloride solution is added, the mixture is taken up in ether, the organic phase is washed with sodium chloride solution, dried over sodium sulfate, filtered, the solvent is removed from the filtrate, and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate), giving 4.00 g of 2-fluoro-6-(4-octyloxyphenyl)pyridine. ##STR17##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[ClH:12]>O>[Cl:12][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: Cl
Solvent: O
Product: Oc1ccc(CCCCl)cc1
Yield: 90 %

Procedure:
3-(4-Hydroxyphenyl)-1-propanol (0.97 g, 0.006374 mol) and concentrated HCl (20 ml) were heated at 100° C. for 14 h. After being cooled, the reaction mixture was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated in vacuo to give a raw product. Purification by flash chromatography (heptane/ethyl acetate 9:1) gave a pure product (0.98 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][CH:11]=[O:12].C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:3]([CH2:8][CH2:9][NH:10][CH:11]=[O:12])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(CCNC=O)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc(CCNC=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of N-[2-(5-amino-1-methylpyrazol-4-yl)ethyl]formamide (2.7 g, 16 mmol) and triethylamine (2.5 ml, 17.6 mmol) in methylene chloride (50 ml) was added triphenylmethyl chloride (5.2 g, 17.6 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with successively 10% aqueous citric acid solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give N-[2-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)ethyl]formamide (4.7 g) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]3C(=O)CCC[C:8]3=[N:7][C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18]>CS(C)=O>[N:4]1([C:5](=[O:16])[C:6]2[NH:7][CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:18])[CH3:17]
Reactant: Cn1c(=O)c2nc3n(c2n(C)c1=O)C(=O)CCC3
Solvent: CS(C)=O
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of 2.4 μmol flavin N6 -aminohexyl-adenine dinucleotide, prepared as described in part A of Example 1 above, in 200 μl dimethylsulfoxide under argon gas was added 0.9 mg 1,3-dimethyl-1,6,7,8-tetrahydropyrido[1,2-e]purine-2,4,9(3H)-trione (3.62 μmol), prepared according to the method of Cook et al, Res. Comm. in Chem. Pathol. and Pharm. 13:497 (1976), followed after 4 hours by addition of a further 1.8 mg (7.3 μmol) of the same. After stirring overnight, the solvent was evaporated under vacuum (0.1 mm Hg) and the residue chromatographed on a 2.5×90 cm LH-20 Sephadex (Pharmacia Fine Chemicals, Uppsala, Sweden) column and eluted with 0.3 M triethylammonium bicarbonate buffer (pH 7.8). The crude product eluted between 210 and 246 ml of the effluent, was collected, applied to a 20×20 cm×1000μ silica gel plate and eluted with an 8:2 ethanol: 1 M triethylammonium bicarbonate buffer (pH 7.8) mixture. The band containing the desired product (Rf =0.77) was scraped from the plate, extracted with 1 M triethylammonium bicarbonate buffer (pH 7.8), filtered and concentrated. Final purification by rechromatography on LH-20 Sephadex eluted with the buffer at 0.3 M gave 1.26 μmoles of the labeled conjugate, as determined by absorbance measurement at 450 nm, which was a yield of 53%.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]([F:16])([F:15])[CH2:13][NH2:14]>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:14][CH2:13][C:12]([F:16])([F:15])[F:11]
Reactant: NCC(F)(F)F
Reactant: O=Cc1cccc(Cl)c1Cl
Product: FC(F)(F)CNCc1cccc(Cl)c1Cl

Procedure:
Amine 27 was prepared according to the reaction sequence described for Amine 3, but using instead 2,3-dichlorobenzaldehyde as the starting aldehyde and 2,2,2-trifluoroethylamine as the starting amine. The title compound was isolated as a colorless oil.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[CH3:16][C:17]([CH3:29])([CH3:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26]N)=[N:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:16][C:17]([CH3:29])([CH3:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[N:11]3)=[CH:6][NH:7]2)=[N:24][CH:25]=1
Reactant: CC(C)(C)COc1ccc(NN)nc1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)COc1ccc(-n2[nH]cc(-n3ccnn3)c2=O)nc1

Procedure:
171 mg (0.8 mmol) of the compound from Example 3A and 455 mg (purity 35%, 0.8 mmol) of the compound from Example 12A are initially introduced into 7 ml ethanol. 31 mg (0.2 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is stirred under reflux for 64 h. Thereafter, it is concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions are combined, the solvent is removed and the residue is dried under a high vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([F:16])([F:15])[CH2:6][NH:7][CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH3:2].[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([F:15])([F:16])[CH2:6][N:7]([C:21]1[C:22]([N+:26]([O-:28])=[O:27])=[CH:23][N:24]=[C:19]([Cl:18])[N:20]=1)[CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)CNCCc1cccs1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(CCc1cccs1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.3 %

Procedure:
A solution of 0.98 g (0.0037 mole) of 2,2-difluoro-3-(2-thiophen-2-yl-ethylamino)-propionic acid ethyl ester in 1 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 0.72 g (0.0037 mole) of 2,4-dichloro-5-nitro-pyrimidine, 1.3 g (0.15 mole) of sodium bicarbonate and 10 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 1.53 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2-thiophen-2-yl-ethyl)-amino]-2,2-difluoro-propionic acid ethyl ester (IV-269) as a yellow thick oil. This material was used directly in the next step without further purification.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH2:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1)C.Cl>CN(C)C=O.O>[NH:15]1[C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13]([CH2:12][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:14]1
Reactant: CN(C)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1c[nH]c2ccccc12)c1ccccc1
Reaction time: 0.5 h
Yield: 131.9 %

Procedure:
NaCN (1.4 g, 29 mmol) was provided in absolute dimethylformamide (10 ml) in argon. At a bath temperature of 35° C. benzaldehyde (3 ml, 29 mmol) dissolved in absolute dimethylformamide (10 ml) was added in drops within 1.5 h and stirred for a further 0.5 h at this temperature. Gramine (10.1 g, 58 mmol) dissolved in absolute dimethylformamide (30 ml) was added in drops to this reaction solution within 2 h at an inside temperature of 70° C. The mixture was stirred a further 1 h at this temperature. For work up the vessel contents were placed in water (150 ml). The aqueous phase was acidified with 2N HCl to separate non-converted gramine as, a water-soluble hydrochloride. The aqueous phase was then extracted with chloroform (3×50 ml). The combined extracts were washed with NaHCO3 solution (50 ml) and dried over Na2SO4. The volatile constituents were then completely removed in a vacuum. The residue (9 g) obtained after distilling off the solvent was purified by column chromatography [silica gel 60 (300 g); cyclohexane/ethyl acetate 6:1 (1500 ml)].
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1.[NH2:25][OH:26].C[O-].[Na+]>CO>[OH:26][NH:25][C:3](=[O:2])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: NO
Reactant: COC(=O)C=Cc1cccc(NC(=O)CCCc2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/c1cccc(NC(=O)CCCc2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(Method G6) To a mixture of 3-[3-(4-phenyl-butyrylamino)-phenyl]acrylic acid methyl ester (3d) (0.323 g, 1.0 mmol) and hydroxylamine (0.278 g, 4.0 mmol) in methanol (7 ml) a 3.43 N solution of sodium methylate (1.75 ml, 6.0 mmol) in methanol was added. The resulting mixture was stirred at ambient temperature for 7 hours, diluted with saturated NaH2PO4 (50 ml) and extracted with ethyl acetate (3×25 ml). The organic layer was washed with saturated NaCl and dried (Na2SO4). The solvent was evaporated and the residue was crystallized from acetonitrile affording the title compound as reddish crystals (0.122 g, 38%). M.p. 152-153° C. (from acetonitrile). 1H NMR (DMSO-d6, HMDSO) δ: 1.69-2.11 (m, 2H); 2.35 (t, 2H, J=7.4 Hz); 2.64 (t, 2H, J=7.0 Hz); 6.45 (d, 1H, J=15.6 Hz); 7.12-7.66 (m, 9H); 7.94 (s, 1H); 9.07 (br s, 1H); 9.98 (s, 1H); 10.81 (br s, 1H). HPLC analysis on Symmetry C18 column: impurities <1% (column size 3.9×150 mm; mobile phase acetonitrile −0.1 M phosphate buffer (pH 2.5), 40:60; detector UV 254 nm; flow rate 1.0 ml/min; sample concentration 0.5 mg/ml). Anal. Calcd for C19H20N2O3, %: C, 70.35; H, 6.21; N, 8.64. Found, %: C, 70.21; H, 6.20; N, 8.61.
Reaction SMILES: [C@H:1]12[CH2:55][C@H:4]([N:5]([CH2:7][CH2:8][NH:9][C@:10]34[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:11]3[C@@H:12]3[C@@:25]([CH3:28])([CH2:26][CH2:27]4)[C@@:24]4([CH3:29])[C@@H:15]([C@:16]5([CH3:48])[C@@H:21]([CH2:22][CH2:23]4)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]4[CH2:37][CH2:36][C@H:35]([C:38]([O:40]CC6C=CC=CC=6)=[O:39])[CH2:34][CH:33]=4)=[CH:18][CH2:17]5)[CH2:14][CH2:13]3)[CH2:6]1)[CH2:3][O:2]2.[OH-].[Li+]>C1COCC1.CO>[C@H:1]12[CH2:55][C@H:4]([N:5]([CH2:7][CH2:8][NH:9][C@:10]34[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:11]3[C@@H:12]3[C@@:25]([CH3:28])([CH2:26][CH2:27]4)[C@@:24]4([CH3:29])[C@@H:15]([C@:16]5([CH3:48])[C@@H:21]([CH2:22][CH2:23]4)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]4[CH2:37][CH2:36][C@H:35]([C:38]([OH:40])=[O:39])[CH2:34][CH:33]=4)=[CH:18][CH2:17]5)[CH2:14][CH2:13]3)[CH2:6]1)[CH2:3][O:2]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@@H](C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 80 %

Procedure:
To a solution of (S)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)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)cyclohex-3-enecarboxylate in THF (1.5 mL) and MeOH (0.5 mL) was added 1N lithium hydroxide (0.115 mL, 0.115 mmol). The reaction was stirred at 75° C. After 3 h the reaction mixture was concentrated and the crude material was dissolved in THF (2 mL)/H2O (150 μL) and purified by reverse phase prep-HPLC using prep-HPLC method 15 and dried under vacuum to give (S)-4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13 aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)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)cyclohex-3-enecarboxylic acid (21 mg, 0.023 mmol, 80% yield) as a white solid. LC/MS: m/e 659.5 (M+H)+, 34.14 min (method 8). 1H NMR (400 MHz, 1:1 CDCl3:METHANOL-d4) δ 5.33 (br. s., 1H), 5.17 (d, J=4.6 Hz, 1H), 4.78 (s, 1H), 4.70 (br. s., 1H), 4.52 (s, 1H), 4.03 (d, J=8.6 Hz, 1H), 3.75 (br. s., 1H), 3.72 (d, J=8.6 Hz, 1H), 3.18-3.09 (m, 2H), 3.09-2.92 (m, 4H), 2.79-2.64 (m, 2H), 2.53-2.42 (m, 1H), 2.31-2.23 (m, 2H), 2.16 (br. s., 2H), 2.04-1.93 (m, 8H), 1.81-1.73 (m, 2H), 1.72 (s, 3H), 1.69-1.63 (m, 1H), 1.61-1.33 (m, 12H), 1.30 (dd, J=12.2, 3.4 Hz, 1H), 1.24 (br. s., 1H), 1.20-1.14 (m, 1H), 1.12-1.09 (m, 3H), 1.05 (s, 3H), 0.97 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H)
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:3].[ClH:22].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:28].[ClH:22].[OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])[CH3:3]
Reactant: C[C@H](O)[C@@H](CCc1ccccc1O)n1cnc(C(N)=O)c1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](O)[C@@H](CCc1ccccc1OCCCN(C)C)n1cnc(C(N)=O)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-hydroxyphenyl)-3-pentyl]imidazole-4-carboxamide (20 mg), 3-(dimethylamino)propyl chloride hydrochloride (32.7 mg) and potassium carbonate (38 mg) in N,N-dimethylformamide (3 ml) was stirred overnight at 60° C. The mixture was evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, triethylamine, and methanol (20:1:4) and the product was treated with HCl in EtOAc to give a pale brown oil of 1-{(2S,3R)-2-hydroxy-5-[2-(3-dimethylaminopropoxy)phenyl]-3-pentyl}imidazole-4-carboxamide dihydrochloride (5) (21.2 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[C:9]([C:11]#[N:12])[N:10]=1)=[O:5])C.[OH-].[K+:22]>C(O)C>[K+:22].[C:11]([C:9]1[N:10]=[C:6]([C:4]([O-:5])=[O:3])[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[CH:8]=1)#[N:12]
Reactant: CCOC(=O)c1nc(C#N)cn1COCC[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid ethyl ester (0.4 g, 1.3 mmol) (as prepared in the previous step) in ethanol (3 mL) was added a solution of 6M KOH (0.2 mL) and the reaction was stirred for 10 min and then concentrated to give 0.40 g (100%) of the title compound as a yellow solid. 1H-NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 5.92 (s, 2H), 3.62 (m, 2H), 0.94 (m, 2H), 0.00 (s, 9H). Mass spectrum (ESI-neg, m/z) Calcd. for C11H17N3O3Si, 266.1 (M−H), found 266.0.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([O:11][CH2:10][CH2:9][O:8][C:7]1[CH:12]=[CH:13][C:4]([Br:3])=[CH:5][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCCOCc2ccccc2)cc1

Procedure:
Sodium hydride (60% in mineral oil, 0.500 g) was added to a solution of 2-(4-bromophenoxy)ethanol (2.25 g) in N,N-dimethylformamide (15 mL) at room temperature with stirring. After being stirred for 20 minutes, benzyl bromide (1.42 mL) was added at that temperature, and the mixture was stirred for additional 13 hrs. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to afford 1-(2-benzyloxyethoxy)-4-bromobenzene (2.51 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[OH2:15].[OH2:16].[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:1]=[CH:1]/[C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[S:11]([NH2:14])(=[O:16])=[O:15])=[C:3]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:4]=1
Reactant: O
Reactant: Cc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(/C=C/c2ccc(N)cc2S(N)(=O)=O)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
In a round bottom flask under nitrogen was placed 5-nNitro-2-[(E)-2-(4-nitro-2-(aminosulfonyl)phenyl)ethenyl]benzenesulfonamide (Example 51, 0.38 g, 0.887 mmol) and 40 mL of ethyl acetate added. To this mixture was added tin chloride dihydrate (1.00 g, 4.44 mmol) and a reflux condenser was attached. The solution was heated in an oil bath to 80 C. and stirred for 16 hours. After cooling to room temperature the solution was diluted with ethyl acetate (250 mL) and washed with saturated sodium bicarbonate. The whole mixture was filtered thru Celite and the aqueous layer discarded. The organics were then washed with brine, dried (MgSO4) and concentrated on a rotovap to dryness. The crude material was then recrystallized from 10% methanol/dichloromethane and dried under vacuum to afford 100 mg of the title compound as a dark yellow solid (31%): 1HNMR (DMSO-d6) δ7.58 (d, J=8.5 Hz, 2H), 7.49 (s, 2H), 7.31 (br s, 4H), 7.15 (d, J=2 Hz, 2H), 6.75 (dd, J=8.5 Hz, 2 Hz, 2H), 5.65 (br s, 4H).