Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=2)=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:21]O>>[C:1]1([CH3:15])[CH:2]=[CH:3][C:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]([O:14][CH3:21])=[O:13])[CH:8]=2)=[CH:5][CH:6]=1
Reactant: CO
Reactant: Cc1ccc(-c2cc(C(=O)O)n[nH]2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(-c2ccc(C)cc2)[nH]n1
Yield: 84 %

Procedure:
5-p-Tolyl-1H-pyrazole-3-carboxylic acid (250 mg, 1.24 mmol) and sulfuric acid (120 μL, 1.48 mmol) in methanol (5 mL) were heated to reflux for 16 hrs. The solvent was evaporated and the residue was resuspended in CH2Cl2. The residue was filtrated and the filtrate was washed with water and brine and dried over Na2SO4. Solvent was evaporated and the white solid was combined with the precipitate collected previously. Methyl 5-p-tolyl-1H-pyrazole-3-carboxylate (224 mg, 84%) was obtained as a white solid. 1H-NMR (400 MHz, CDCl3): (ppm)=7.56 (d, J=7.6 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.02 (s, 1H), 3.91 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:4]=1[NH2:5].B(Br)(Br)Br>C(Cl)(Cl)Cl>[CH3:13][S:10]([C:7]1[CH:8]=[CH:9][C:3]([OH:2])=[C:4]([NH2:5])[CH:6]=1)(=[O:11])=[O:12]
Reactant: COc1ccc(S(C)(=O)=O)cc1N
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(O)c(N)c1
Reaction time: 0.33 h

Procedure:
The title compound was prepared by reacting 2-methoxy-5-methylsulfonyl aniline (5.0 g, 24.8 mmol) with boron tribromide (26 mmol, 26 mL, 1M in dichloromethane) in chloroform (30 m L) at 0° C. After 20 minutes, the reaction was quenched with sodium bicarbonate and the ph of the aqueous phase was adjusted to pH 7 and extracted with ethyl acetate. Concentration under reduced pressure gave 690 mg of product as an orange solid (15%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[N+:16]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni].O.[H][H]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH2:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1cccc(F)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(F)c1N
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of the N-tert-Butyloxycarbonyl-3-fluoro-2-nitro aniline (950 mg, 2.5 mmol) in MeOH was added catalytic amount of Raney Nickel in water, hydrogen was applied at 40 psi and the mixture was stirred overnight. The mixture was filtered over Celite and the solvent was evaporated to give the desired product in 66% yield (550 mg). MS (ESI)=226 (MH+)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:16]=[C:15]([CH3:17])[S:14][C:13]=2[CH3:18])=[C:4](Cl)[N:3]=1.Cl.[OH-:21].[Na+]>C(O)(=O)C>[CH3:18][C:13]1[S:14][C:15]([CH3:17])=[CH:16][C:12]=1[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:21])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Cc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(C)s1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Cn2cnc3c(=O)[nH]c(N)nc32)c(C)s1

Procedure:
A mixture of 2-amino-9-[(2,5-dimethyl-3-thienyl)methyl]-6-chloropurine (3.8 g, 0.0129 mol) and 2N HCl was heated on a steambath for 3.0 hours and then heated under reflux for another hour. At the end of this time 1N NaOH solution was added to the solution till basic and the mixture was heated for another five minutes. The mixture was then acidified with acetic acid, cooled, and filtered to give 3.6 g, of the product. An analytical sample was obtained by chromatography over silica gel using 10% methanol/chloroform as eluting solvent, mp >300° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13]CC)=O.[CH2:16]([O:18][C:19](=[O:23])[CH2:20][C:21]#[N:22])[CH3:17].C([O-])(O)=O.[Na+]>O1CCOCC1>[OH:13][C:11]1[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]=2[N:1]=[C:21]([CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:23])[N:22]=1
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1nc(O)c2c3c(sc2n1)CCCC3
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (8.0 g, 0.0355 mol) and ethyl-2-cyanoacetate (8.03 g, 0.0710 mol) was dissolved in dioxane (250 ml). It was cooled to 0° C. To this reaction mixture, HCl gas was purged up to saturation (for 20 min, initially reaction mass becomes turbid and then becomes clears). Then reaction mass was stirred for 18 h at room temperature. After completion of the reaction it was cooled to 0° C. and basified with saturated NaHCO3 (pH=8). Further it was extracted with ethyl acetate (250 ml×3). Combined organic extracts were washed with water followed with brine. Separated organic layer was dried over anhy. Na2SO4, filtered and concentrated to get 9 g crude product. It was purified by column chromatography by using 100-200 mesh silica gel and 1-2% MeOH: DCM solvent system to give ethyl 2-(4-hydroxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetate as yellow solid. Yield—(9.0 g, 86.71%); 1H-NMR: (400 MHz, CDCl3); δ=4.25-4.20 (q, 2H), 3.77 (s, 2H), 3.00-2.97 (m, 2H), 2.76-2.74 (m, 2H), 1.88-1.81 (m, 4H), 1.29-1.25 (t, 3H); LC-MS [M+H]=292.9.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:25])[CH:6]=[C:7]([CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]([Cl:37])=[CH:34][CH2:35]Cl>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([O:25][CH2:35][CH:34]=[C:33]([Cl:37])[Cl:32])[CH:6]=[C:7]([CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=1)[CH3:2]
Reactant: ClCC=C(Cl)Cl
Reactant: CCc1cc(O)cc(C)c1OCCCOc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(C)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 0.7 g of 3-ethyl-5-methyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]phenol and 0.27 g of potassium carbonate, to which a solution of 0.34 g of 1,1,3-trichloropropene dissolved in 5 ml of N,N-dimethylformamide was added dropwise, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice-water, and extracted twice with 100 ml of diethyl ether. The combined diethyl ether was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude produce was subjected to silica gel chromatography, which afforded 0.6 g of 3-ethyl-5-methyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]-1-(3,3-di-chloro-2-propenyloxy)benzene (65% yield), nD23.0 1.5188.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.N([O-])=O.[Na+].O.O.O.[C:21]([O-])(=[O:23])C.[Na+].C=O.Cl.NO.[Na].S([O-])([O-])=O.C([O-])(=O)C.[Na+]>O.C1(C)C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[CH:21]=[O:23]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: CC(=O)[O-]
Agent: C=O
Agent: Cl
Agent: NO
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
3-Amino-4-chlorobenzotrifluoride (A.E. Porai-Kosic et al., Zh. Prikl. Khim. 28, 969, 1955; Chem. Abstr. 50, 4880, 1956) (222 g) is slowly added to a stirred solution of 260 ml hydrochloric acid in 2330 ml water. The resultant suspension of the hydrochloride is cooled, treated with 450 g of ice and diazotized at 0°-5° C. with a solution of 80 g of sodium nitrite in 110 ml of water, added dropwise. The mixture is stirred for 1 hour at 0°-5° C. and treated with a cooled solution of 100 g of sodium acetate trihydrate in 150 ml water. The undissolved substance is separated (distillation recovers 70.8 g starting 3-amino-4-chlorobenzotrifluoride) and the solution of the diazonium salt is added while stirring at 10°-20° C. to a solution of formaldoxime (prepared by boiling a mixture of 57.5 g paraformaldehyde, 131.5 g of hydroxylamine hydrochloride, 255 g of sodium acetate trihydrate and 850 ml of water for 15 minutes) and a solution of 32.5 g cupric sulfate pentahydrate, 5 g sodium of sulfite and 800 g of sodium acetate in 300 ml water with the addition of 300 ml of toluene. The mixture is stirred for 2 hours, 1100 ml of hydrochloric acid added and the mixture refluxed for 2 hours. It is then distilled with steam and the distillate extracted with benzene. The extract is washed with a 5% sodium hydrogen carbonate solution and evaporated. The residue is dissolved in 200 ml ether and the solution stirred for 2 hours with 450 ml of 40% sodium hydrogen sulfite solution. After standing overnight, the precipitated addition product is filtered with suction, washed with ether, and suspended in 1 liter of water, then, 200 ml of hydrochloric acid are added and the mixture refluxed for 2 hours. After cooling, it is extracted with benzene, the extract dried with magnesium sulfate, evaporated and the residue processed by distillation. There are obtained 49.1 g (31% per conversion) of 2-chloro-5-trifluoromethylbenzaldehyde, b.p. 93°-96° C./2.1 kPa.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][C:13]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+].Cl>C1COCC1>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1=Cc2cc(C#Cc3ccccc3)ccc2OCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(C#Cc3ccccc3)ccc2OCC1
Yield: 94.7 %

Procedure:
To methyl 7-phenylethynyl-2,3-dihydro-1-benzooxepine-4-carboxylate (463 mg, 1.52 mmol) were added methanol (10 ml), THF (10 ml) and a 1 N aqueous solution of sodium hydroxide (4.56 ml), and the resulting mixture was stirred at room temperature for 24 hours. After addition of 1 N hydrochloric acid (4.56 ml), the reaction mixture was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was successively washed with water and diisopropyl ether, and was then dried under reduced pressure to obtain 7-phenylethynyl-2,3-dihydro-1-benzooxepine-4-carboxylic acid (417 mg, 1.44 mmol, 94%).
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[C:17](Cl)([CH3:20])([CH3:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:17]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:15]4[C:4]([CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12]2)=[CH:5][CH:6]=[C:7]3[CH:8]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)Cl
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1cc2ccc3cccc4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.4 %

Procedure:
A mixed solution of 100 g of pyrene, 55.4 g of t-butylchloride and 400 ml of dichloromethane was cooled to 0° C. under an argon gas stream and then 70.4 g of aluminum chloride was added. This mixed solution was stirred at room temperature for 5 hours and poured into 500 g of ice, followed by stirring at room temperature for 30 minutes. After the mixed solution was suction-filtered, the filtrate was extracted twice with 300 ml of dichloromethane. The organic layer was washed with 300 ml of water, dried over magnesium sulfate and then evaporated. To the concentrated residue, 300 ml of methanol was added, followed by stirring at 80° C. and further filtration. Furthermore, 300 ml of methanol was added, followed by stirring at 80° C. and further filtration. To 59.1 g of the crude product obtained by vacuum drying among 110.7 g of the crude product, 150 ml of methanol was added. The resulting solution was stirred at 85° C. for one hour, filtered and then vacuum-dried to obtain 50.3 g (content: 83%) of 2-t-butylpyrene.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:26])([F:25])[C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[N:11]=[C:10]([NH2:24])[CH:9]=1.[N+:27]([O-])([OH:29])=[O:28].[OH-].[Na+]>>[N+:27]([C:9]1[C:10]([NH2:24])=[N:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:22])([F:21])[F:23])=[CH:13][C:8]=1[C:7]([F:6])([F:25])[F:26])([O-:29])=[O:28]
Reactant: Nc1cc(C(F)(F)F)cc(-c2ccccc2C(F)(F)F)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(-c2ccccc2C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sulfuric acid (10 mL) was placed in a 100 mL two-necked round-bottomed flask fitted with a magnetic stir bar and an internal thermometer and cooled to 0° C. 4-Trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (720 mg, 2.35 mmol, prepared as described in STEP C above) was added portion wise so that the internal temperature did not exceed 5° C. The resulting mixture was stirred at 0° C. for 1 h. Nitric acid (106 μL, 2.35 mmol) was added slowly, keeping the internal temperature below 10° C. The mixture was stirred an additional 2 h at 0° C., poured over ice water (100 mL), treated with 6 M aqueous NaOH to pH 10, and extracted twice with EtOAc (100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min) to yield 3-nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine as a bright yellow solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C13H7N3O2F6: 352.0 (M+H). Measured: 352.0.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]#[N:25])=[CH:13][CH:12]=2)[C:8]2[CH:26]=[C:27]([N:30]([CH3:40])[C:31]([NH:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:32])[CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[Cl-].[NH4+].[N-:43]=[N+:44]=[N-:45].[Na+]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]3[NH:45][N:44]=[N:43][N:25]=3)=[CH:13][CH:12]=2)[C:8]2[CH:26]=[C:27]([N:30]([CH3:40])[C:31]([NH:33][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)=[O:32])[CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2ccc(N(C)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccc(Cl)cc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CCCCc1nc2ccc(N(C)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccc(Cl)cc2-c2nnn[nH]2)cc1

Procedure:
Prepared in analogous manner to Example 59 from 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-methyl-amino)-benzimidazol-1-yl)-methyl]-4-chloro-2-cyano-biphenyl and ammonium chloride/sodium azide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[F-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[C:20]1[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][N:21]=1>C(OCC)(=O)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:20]2[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:5][CH:4]=1
Reactant: Oc1cccnc1Br
Reactant: COc1ccc(CS)cc1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ncccc2O)cc1
Temperature: 150 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
4-Methoxy-α-toluenethiol (9.4 mL), potassium fluoride (3.34 g) and potassium carbonate (10.3 g) were added to a DMF (100 mL) solution of 2-bromo-3-hydroxypyridine (10 g, 57.5 mmol), and stirred at 150° C. for 3 days. The reaction liquid was diluted with ethyl acetate, and washed three times with distilled water. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate and hexane to obtain the intended compound (6.2 g, 43%) as a white solid.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=2)[CH2:4]1>Cl>[ClH:1].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=2)[CH2:4]1
Reactant: COC(=O)Cc1ccc2c(c1)CC(N)C2
Agent: Cl
Product: NC1Cc2ccc(CC(=O)O)cc2C1

Procedure:
3.6 g of methyl 2-aminoindane-5-acetatehydrochloride are refluxed for 3 hours in 160 ml of semiconcentrated hydrochloric acid. The hydrochloric acid is distilled off and the remaining product is triturated with a little ethanol, suction filtered and dried in vacuo.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:45])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:44])[CH2:9][CH2:10][C@@:11]3([C:27]([C@@H:29]4[CH2:33][CH2:32][C@H:31]([CH2:34][N:35]5[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]5)[CH2:30]4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:47])[CH3:46].N1C=CC=CC=1.[CH3:54][C:55]1([CH3:62])[CH2:59][C:58](=[O:60])[O:57][C:56]1=[O:61]>C(OCC)(=O)C>[C:56]([C:55]([CH3:62])([CH3:54])[CH2:59][C:58]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:45])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:44])[CH2:9][CH2:10][C@@:11]3([C:27]([C@@H:29]4[CH2:33][CH2:32][C@H:31]([CH2:34][N:35]5[CH2:36][CH2:37][CH:38]([C:41]([OH:43])=[O:42])[CH2:39][CH2:40]5)[CH2:30]4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:47])[CH3:46])=[O:60])([OH:61])=[O:57]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)[C@@H]3CC[C@H](CN4CCC(C(=O)O)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)[C@@H]3CC[C@H](CN4CCC(C(=O)O)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of 1-(((1S,3R)-3-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)cyclopentyl)methyl)piperidine-4-carboxylic acid (0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) were added and the contents were refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml), the organic layer was washed with 5% aqueous HCl, then water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 11H); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: 778 (100%), [M+1].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)([O-:3])=[O:2].Cl.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH2:29])[N:23]=2)=[CH:17][CH:16]=1.C(N(CC)C1C=CC=CC=1)C>O=P(Cl)(Cl)Cl>[NH2:29][C:24]1[N:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)=[O:12])=[CH:16][CH:17]=2)[CH:27]=[C:26]([CH3:28])[N:25]=1
Reactant: Cc1cc(Nc2ccc(N)cc2)nc(N)n1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cn1
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc([N+](=O)[O-])cn3)cc2)nc(N)n1
Temperature: 20 °C
Reaction time: 72 h
Yield: 33.9 %

Procedure:
5-Nitropyridine-2-carboxylic acid 18 (1.06 g, 6.31 mmol) was refluxed in POCl3 (10 mL) for 1 h. (clear solution obtained), cooled to 20° C. and excess POCl3 was removed under vacuum. The resulting residue was dissolved in 1,4-dioxane ((20 mL) and added slowly to a suspension of 17 (1.44 g, 5.72 mmol) and N,N-diethylaniline (2.0 mL, 12.62 mmol) in 1,4-dioane (20 mL). The reaction mixture was stirred at 20° C. for 3 days. The resulting white precipitate was filtered and washed with more 1,4-dioxane. The solid was stirred in aqueous NH3 (20 mL) and the resulting red precipitate was filtered, washed with water and recrystallized from MeOH to give 20 (708 mg, 31%); mp (MeOH)>290° C.; 1H NMR ([(CD3)2SO] δ 10.74 (1 H, NH), 9.43 (dd, J=2.6, 0.5 Hz, 1 H, H-6), 8.96 (s, 1 H, NH), 8.81 (dd, J=8.6, 2.6 Hz, 1 H, H-4), 8.38 (dd, J=8.6, 0.6 Hz, 1 H, H-3), 7.81 (d, J=9.0 Hz, 2 H, H-2′ H-6′), 7.70 (d, J=9.1 Hz, 2 H, H-3′,5′), 6.09 (s, 2 H, NH2), 5.87 (s, 1 H, H-5″), 2.09 (s, 3 H, CH3); HRMS (FAB+) calc. for C17H16N7O3 (M+1) m/z 366.1315, found 366.1314; Anal. calc. for C17H15N7O3.0.25 MeOH: C, 55.5; H, 4.4: N, 26.3; found, C, 55.7; H, 4.5; N, 26.2%.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8]CC(=N)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:17].C(#[N:20])C>>[ClH:17].[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][NH2:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC#N
Reactant: CCOC(=N)COc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: NOc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 71.2 g of ethyl 4-nitrophenoxyethaneimidoate (0.32 mol) (compound VII) in 925 ml of acetonitrile are added slowly, at 20° C., 35 ml of 37% hydrochloric acid (0.38 mol). The reaction medium is stirred at 20° C. for 2 hours and then filtered, and the O-(4-nitrophenyl)hydroxylamine hydrochloride thus formed is dried at 30° C. in a vacuum oven. With stirring, this hydrochloride is dissolved in a mixture formed from 800 ml of dichloromethane and of a sodium hydroxide solution (16.8 g in 500 ml) and the phases are then allowed to separate by settling. The organic phase is separated out and washed with 500 ml of water. This organic phase is evaporated on a rotary evaporator and the solid obtained is then dried in a vacuum oven.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>C(Cl)Cl>[CH:20]1([NH:26][C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:3])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CC(C)C[C@H](CC(=O)NC1CCCCC1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of benzyl (2R)-2-carboxymethyl-4-methylvalerate (527 mg) and cyclohexylamine (238 mg) in methylene chloride (10 ml) was added WSCD.HCl (460 mg) at room temperature. After being stirred overnight, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with 5% HCl, water, saturated sodium bicarbonate and water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with n-hexane to give benzyl (2R)-2-(cyclohexylcarbamoylmethyl)-4-methylvalerate (410 mg).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][N:15]([CH3:37])[C:16](=[O:36])[C@@H:17]([N:24]2[CH2:29][CH2:28][CH:27]([NH:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33])[CH2:26][CH2:25]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.FC(F)(F)C1C=C(CCN(C)C(=O)[C@H](OS(C)(=O)=O)C2C=CC=CC=2)C=C(C(F)(F)F)C=1>>[F:38][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][N:15]([CH3:37])[C:16](=[O:36])[CH:17]([N:24]2[CH2:29][CH2:28][CH:27]([NH:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33])[CH2:26][CH2:25]2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)[C@H](c1ccccc1)N1CCC(NC(CO)CO)CC1
Agent: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)[C@H](OS(C)(=O)=O)c1ccccc1
Product: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(c1ccccc1)N1CCC(NC(CO)CO)CC1

Procedure:
(S)—N-[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide is obtaine is obtained analogously starting from (R)-N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide (prepared from D-(−)-mandelic acid).