Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=O)(C)(C)C.Cl>C1COCC1>[NH2:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]2)[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
(R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (C1) (5.17 g, 14.3 mmol) was dissolved in THF (47.8 ml) and, while stirring at RT, 37% HCl (4.71 ml, 57.4 mmol) was added dropwise. The reaction was stirred at RT for 15 hours overnight. The solvent was evaporated, and the residue was dissolved in DCM/MeOH (9/1; 10 ml) and about 3 g of SiO2 was added. The solvent was evaporated, and the solid was loaded on a silica gel column and eluted with DCM/MeOH/NH4OH (9/1/0.1) to obtain (R)-quinuclidin-3-yl 2-amino-2-phenylacetate (2.23 g; 60% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:17](=[O:18])[NH:16][CH2:15][CH2:14][C:13]=1[C:12]=23)=[O:4].IC1N[C:22]2[CH:23]=[CH:24]C=C3C(=O)N[CH2:30][CH2:29][C:28]=1[C:27]=23.C(N(CC)CC)C.C(O)CCCCCCC>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].CN(C=O)C>[CH2:1]([O:2][C:3]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:17](=[O:18])[NH:16][CH2:15][CH2:14][C:13]=1[C:12]=23)=[O:4])[CH2:24][CH2:23][CH2:22][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C1NCCc2c(I)[nH]c3cccc1c23
Reactant: COC(=O)c1[nH]c2cccc3c2c1CCNC3=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCCCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCOC(=O)c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
Following a procedure similar to that described for Example MM (Compound 42), 2-iodo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (330 mg, 1.06 mmol), triethylamine (342 mg, 3.38 mmol), and palladium tetrakis(triphenylphosphine) (61 mg, 0.05 mmol) were reacted in 20 mL 1:1 n-octanol:DMF in a sealed tube under a carbon monoxide atmosphere to yield 6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carboxylic acid octyl ester, 250 mg (58%), as a white solid: m.p. 170-171° C.; 1H NMR (300 MHz, d6-DMSO) δ 0.85 (t, J=7.2 Hz, 3H), 1.27 (m, 8H), 1.42 (m, 2H), 1.73 (m, 2H), 3.25 (m, 2H), 3.42 (m, 2H), 4.30 (t, J=6.6 Hz, 3H), 7.38 (app t, J=7.5 Hz, 1H), 7.62 (dd, J=8.1, 0.9 Hz, 1H), 7.74 (dd, J=7.5, 0.9 Hz, 1H), 8.17 (br t, 1H), 11.86 (br s, 1H). MS (FAB, MH+) 343. Anal. (C20H26N2O3) C, H, N.
Reaction SMILES: [C:1]1(C=O)[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[C:3](C=O)[CH:2]=1.S([O-])([O-])(=O)=O.[Mg+2].Cl.C(NO)(C)(C)C.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1cc(C=O)c2cccccc1-2
Agent: CC(C)(C)NO
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: c1ccc2cccc-2cc1
Temperature: 95 °C
Yield: 225.1 %

Procedure:
1,3-Azulenedicarboxaldehyde (600 mg) is dissolved in 6.5 ml of pyridine. Magnesium sulfate (1200 mg) and N-tert-butylhydroxylamine hydrochloride (1638 mg) is added to the solution. The mixture is heated with stirring to 95° C. under nitrogen and is stirred for 13 hours. Upon cooling to rt, the reaction mixture is poured into a separator funnel containing 60 ml of CHCl3 and 60 ml of sat aq. NaHCO3. The aqueous layer is separated and washed with three 30 ml portions of CHCl3. The combined organic layers are dried over anhydrous MgSO4, filtered, and evaporated to give the bis-nitrone 34 (940 mg, 89% yield) as dark green crystals. Oxidation potential equals 0.72 V vs SCE. 1H NMR (CDCl3): 10.35 (s, 1H), 8.65 (d, 2H, J=10 Hz) 8.11 (s, 2H), 7.68 (t, 1H, J=10 Hz), 7.32 (t, 2H, J=10 Hz), 1.67 (s, 18H). 13C NMR (CDCl3): 139.9, 135.0, 134.2, 125.8, 125.6, 123.2, 120.5, 69.8, 28.4. IR (thin film): 3052, 2972, 1644, 1564, 1452, 1404, 1356, 1261, 1196, 1124, 1052, and 892 cm−1.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1.C1C2C(=CC=CC=2)C=CC=1.[N:32]1C=C[CH:35]=[CH:34][CH:33]=1>>[N:32]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: c1ccccc1
Reactant: c1ccncc1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Solvent: c1ccc2ccccc2c1
Product: c1ccc2ncccc2c1

Procedure:
As the aromatic, low-boiling solvent, use may be made of any solvents having a boiling point of not more than 250° C., which includes benzene, toluene, xylene, pyridine, raw naphthalene oil, gas light oil, tar light oil and a mixture thereof. The reason why the boiling point of the solvent is limited to not more than 250° C. is based on the facts that such a solvent is easy to be recovered from the solution after the removal of the insoluble matter and that high molecular weight components corresponding to high heat-reactive pyridine insoluble matter in the pitch can efficiently be removed because this solvent exhibits an adequate dissolving power to the pitch. That is, the aromatic solvent having a boiling point of more than 250° C. is generally high in the dissolving power, so that if the pitch is dissolved in the latter solvent such as anthracene oil, only the quinoline insoluble matter such as free carbon, inorganic matter and the like naturally contained in the pitch is substantially separated and removed and consequently the obtained pitch still contains high molecular weight components corresponding to the pyridine insoluble matter. When such a pitch is subjected to a heat treatment, the high molecular weight components having a rich heat reactivity are polycondensed to form mesophase as a secondary quinoline insoluble matter, so that it is difficult to produce a precursor pitch of homogeneous phase suitable for the production of carbon fibers. For this reason, the use of the aromatic solvent having a boiling point of more than 250° C. such as anthracene oil, quinoline and derivatives thereof is not favorable to the invention.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][C:16]([NH:19]C(=O)OC(C)(C)C)([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>CCO>[NH2:19][C:16]([CH3:17])([CH3:18])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:27][O:28][CH2:29][CH3:30]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)N
Yield: 84.5 %

Procedure:
Tert-butyl 2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylcarbamate (1.26 g, 3.05 mmol) was dissolved in 10 mL of EtOH and treated with 10 mL of 2 M HCl in EtOH. After heating at reflux for 2 h, the reaction mixture was cooled and concentrated under reduced pressure. The resulting yellow solid was dissolved in 50 mL of H2O and extracted with CHCl3 (20 mL). The organic layer was discarded and the aqueous portion was made basic (pH ˜12) by addition of concentrated NH4OH solution. This was then extracted with CHCl3 (4×20 mL) and the combined organic portions were dried with Na2SO4 and concentrated to give 1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-4-amine (808 mg) as a light brown powder.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:20]3[CH2:24][CH2:23][NH:22][C:21]3=[O:25])[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)CN3CCNC3=O)CC2)ccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), imidazolidin-2-one (64 mg, 0.73 mmol, 1.10 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.4 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-imidazolidin-2-one (22): HPLC retention time, 1.33 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 352.8, found, 353.5.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][C:7]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: Cc1ccc(CN=[N+]=[N-])cc1S(C)(=O)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CN)cc1S(C)(=O)=O
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 4-(1-azidomethyl)-1-methyl-2-(methylsulfonyl)benzene (5.0 g, 22.17 mmol), THF (40 mL), triphenylphosphine (6.4 g, 24.3 mmol) and water (1.6 mL, 34.2 mmol) at 0° C., and the reaction mixture was stirred at room temperature over night. The solvents were removed and the residue was dissolved in MTBE and 20% HCl in dioxane was added dropwise at 0° C. and the resulting salt was collected and washed with EtOAc. The salt was then neutralized with 6N aq. NaOH and extracted with CH2Cl2. The organic layers were concentrated under reduced pressure to get the title compound as a very thick oil. 1H NMR (400 MHz, CDCl3): 7.98 (s, 1H), 7.50 (d, 1H, J=8.0 Hz), 7.32 (d, 1H, J=8.0 Hz), 3.93 (s, 2H), 3.08 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diphenyl(piperidin-4-yl)methanol (J. Med. Chem. 1989, 32(1), 105-118) (0.42 g, 1.57 mmol) in methylene chloride (15 mL) was added trifluoroacetic acid (3 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to yield the trifluoroacetic acid salt of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.35 (tt, J=7.33, 1.65 Hz, 4H), 7.26 (m, 4H), 7.15 (dt, J=6.36, 1.57 Hz, 2H), 3.15 (m, 4H), 2.43 (t, 4H); MS (DCI) m/z 250 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=O)CC(OCC)=O.[Br:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[C:18](Cl)=[N:19][CH:20]=1>CN(C=O)C>[Br:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([CH3:3])=[N:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH 55% in oil (300 mg, 6.87 mmol) in 6 ml DMF was added dropwise diethyl malonate (Aldrich, Buchs, Switzerland, 1.0 g, 6.24 mmol). The reaction mixture was stirred for 20 min at rt before adding 5-bromo-2-chloro-3-nitropyridine (Matrix, Columbia, USA, 1.19 g, 5.0 mmol). The reaction mixture was stirred for 30 min at rt and for 1 h at 40° C. The reaction mixture was quenched with 10% aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine (4×), dried over Na2SO4, filtered and evaporated. The residue was stirred in concentrated HCl (20 ml) for 13 h at 100° C. After cooling, the reaction mixture was basified with 10 M aqueous NaOH and extracted with EtOAc (2×). The organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dry loaded on silica gel and purified by MPLC (heptane/EtOAc 0% to 15%) to give the title compound as a yellow solid. (HPLC: tR 2.84 (Method A).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([N:14]([CH3:16])[CH3:15])=[N:10][N+:11]([O-:13])=[O:12])=[CH:5][N:6]=1.[OH-].[Na+].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([S:20]([CH3:19])(=[O:22])=[O:21])[C:9]([N:14]([CH3:16])[CH3:15])=[N:10][N+:11]([O-:13])=[O:12])=[CH:5][N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(C)C(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)S(C)(=O)=O
Yield: 41.1 %

Procedure:
To a solution of 1-(2-chloro-5-thiazolylmethyl)-3,3- dimethyl-2-nitroguanidine (0.300 g) in an aqueous NaOH solution (NaOH (0.319 g) and water (10 ml)) were added CH2Cl2 (10 ml) and 4-dimethylaminopyridine (0.013 g). To the mixture was added methanesulphonyl chloride (0.391 g) dropwise at room temperature under stirring. After stirring for 30 minutes, the mixture was partitioned. The organic layer was dried over MgSO, and concentrated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with hexane-AcOEt (1:1) to afford 0.160 g of 1-(2-chloro-5-thiazolylmethyl)-3,3-dimethyl-l-methanesulphonyl-2-nitroguanidine (Compound No. 28) as a pale yellow crystal, m.p. 82°-86° C.
Reaction SMILES: [CH:1]1([CH:4]([OH:16])[CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[N:28]1([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:45])([F:44])[F:43])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[CH:1]1([CH:4]([OH:16])[CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:31]3[CH2:32][CH2:33][N:28]([C:34](=[O:35])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]([F:45])([F:43])[F:44])[CH2:29][CH2:30]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCC(O)C1CC1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCC(O)C1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 80 °C
Yield: 31.9 %

Procedure:
To a solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide (58 mg, 0.24 mmol) in 10 mL of DMF was added 1,8-diazabicylco[5.4.0]undec-7-ene (0.109 g), piperazin-1-yl-(2-trifluoromethylphenyl)methanone (86.7 mg, 0.33 mmol) and Bu4NI (4 mg, 0.01 mmol). The mixture was heated at 80° C. overnight. Water was added and the mixture was extracted with ethyl acetate (2×15 mL). The organic extract was washed with diluted HCl, followed by bicarbonate solution and brine, then dried over Na2SO4 and concentrated. The residue was dissolved in small amount of dichloromethane and purified by column chromatography eluted with ethyl acetate to yield the product as a white solid (35.5 mg, 32% yield). 1H NMR (300 MHz, CDCl3) δ 8.24, 8.02, 7.73, 7.58, 7.34, 6.98, 4.04, 3.85, 3.52, 3.33, 3.10, 2.60-2.41, 0.95, 0.52, 0.32. MS (ES+) m/z 464.3 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.[O:40]1[CH2:44][CH:43](O)[CH:42]([OH:46])[CH2:41]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[O:33]=[C:31]1[O:30][N:29]=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:15][C:12]3[C:13](=[O:14])[N:8]([CH:5]4[CH2:6][CH2:7][C:2]5([O:46][CH:42]6[CH2:41][O:40][CH2:44][CH:43]6[O:1]5)[CH2:3][CH2:4]4)[C:9]4[N:10]([N:37]=[CH:38][N:39]=4)[C:11]=3[CH2:34][CH2:35][CH3:36])=[CH:21][CH:20]=2)[NH:32]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: OC1COCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OC2COCC2O3)c2ncnn12
Yield: 65.9 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.30 g), tetrahydrofuran-3,4-diol (0.11 g), 4-methylbenzenesulfonic acid (0.011 g) and toluene (20 mL) was heated under reflux for 6 hr using a Dean-Stark trap. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized (ethyl acetate-hexane) to give the title compound as a colorless solid (0.23 g, 68%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:52]=[CH:51][C:8]([CH2:9][CH2:10][NH:11][CH2:12][C@:13]23[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:14]2[C@@H:15]2[C@@:28]([CH3:31])([CH2:29][CH2:30]3)[C@@:27]3([CH3:32])[C@@H:18]([C@:19]4([CH3:44])[C@@H:24]([CH2:25][CH2:26]3)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]3[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=3)=[CH:21][CH2:20]4)[CH2:17][CH2:16]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+].O>O1CCOCC1.CO>[C:3]([C:5]1[CH:52]=[CH:51][C:8]([CH2:9][CH2:10][NH:11][CH2:12][C@:13]23[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:14]2[C@@H:15]2[C@@:28]([CH3:31])([CH2:29][CH2:30]3)[C@@:27]3([CH3:32])[C@@H:18]([C@:19]4([CH3:44])[C@@H:24]([CH2:25][CH2:26]3)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]3[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=3)=[CH:21][CH2:20]4)[CH2:17][CH2:16]2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCc3ccc(C(=O)OC)cc3)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: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CNCCc3ccc(C(=O)O)cc3)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
Temperature: 50 °C
Reaction time: 12 h
Yield: 22.4 %

Procedure:
To the solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((4-(methoxycarbonyl)phenethylamino)methyl)-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 (5 mg) in dioxane (2 ml) and MeOH (2 ml), 3 mg of lithium hydroxide was added followed by 0.5 ml of water. The resulting clear solution was stirred at 50° C. for 12 h. The solvent was removed in vacuo and yellow solid was obtained. The crude material was purified by prep. HPLC to afford the title compound as a white solid (1.1 mg, 22.0%). LCMS: m/e 692.5 (MH+), 2.28 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 6.50 (d, J=8.3 Hz, 2H), 6.38 (d, J=8.3 Hz, 2H), 5.91 (d, J=8.3 Hz, 2H), 5.68 (d, J=8.3 Hz, 2H), 3.75-3.81 (m, 1H), 3.22 (s, 1H), 3.11 (s, 1H), 1.79-1.91 (m, 2H), 1.66-1.75 (m, 1H), 1.51-1.66 (m, 2H), 1.33 (s, 1H), 0.84-1.02 (m, 1H), 0.44-0.68 (m, 2H), 0.10-0.33 (m, 8H), 0.12-0.10 (m, 6H), 0.34-0.12 (m, 6H), 0.42-0.34 (m, 6H), 0.46 (s, 3H), 0.49 (s, 3H), 0.57 (s, 3H), 0.59 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1.CO.Cl>O1CCCC1>[OH:14][CH:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([CH3:3])([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:13]1
Reactant: CC1(COc2ccc([N+](=O)[O-])cc2)CC(=O)c2ccccc2O1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(COc2ccc([N+](=O)[O-])cc2)CC(O)c2ccccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
120 mg of sodium borohydride were added gradually to a mixture of 1 g of 2-methyl-2-(4-nitrophenoxymethyl)-4-oxochroman (prepared as described in Preparation 1), 10 ml of methanol and 10 ml of tetrahydrofuran, in an ice bath. The resulting reaction mixture was stirred for 30 minutes in the ice bath, after which it was stirred for a further 30 minutes at room temperature. At the end of this time, dilute aqueous hydrochloric acid was added to the reaction mixture to acidify it, and then the mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, and then the organic solvent was removed by distillation under reduced pressure. The residue was subjected to silica gel column chromatography eluted with a 10:1 by volume mixture of benzene and ethyl acetate, to afford 710 mg of the title compound as a pale yellow oily substance.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][OH:22])[CH:10]([C:23]([O:25][CH3:26])=[O:24])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.O>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][O:22][C:28]2=[O:30])[CH:10]([C:23]([O:25][CH3:26])=[O:24])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1Nc1ccccc1CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N1C(=O)OCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 1-Boc-4-(2-hydroxymethylphenylamino)-3-piperidine carboxylate from Step 2 above (4.1 g, 11.3 mmol) was stirred in THF (40 mL) in an ice bath and treated with triphosgene (1.11 g, 3.74 mmol) followed by triethylamine (4.7 mL, 3.41 g, 33.7 mmol). The mixture was stirred at ambient temperature for 18 h, then treated with an additional 0.47 g of triphosgene and 1.9 mL of triethylamine, and stirred an additional 4.5 h. Water was added and the mixture was extracted with ethyl acetate. The combined ethyl acetate layers were washed with 2N HCl then with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with CHCl3 followed by 1:99 MeOH:CHCl3. The combined product fractions were evaporated to dryness in vacuo to give methyl 1-Boc-4-(3,1-benzoxazin-2-one-1-yl)-3-piperidine carboxylate.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)C.CO>ClCCl>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: c1ccc(C2CC(c3csc(C4CCNCC4)n3)=NO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Step A) (0.815 g, 1.97 mmol) in dichloromethane (50 mL) was added a solution of hydrogen chloride and diethyl ether (2 M, 10 mL, 20 mmol). The reaction mixture was stirred at room temperature for 1 h to give a gummy precipitate. Methanol was added to dissolve the precipitate, and the reaction mixture was stirred for an additional 1 h. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, the organic layer was dried (MgSO4) and concentrated to give the title compound as a clear oil (0.31 g), which solidified on standing.