Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]([CH2:19]O)[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(C)(=O)=O.[CH2:27]([N:29](CC)CC)C.[C-]#N.[NH4+].[NH4+].[NH4+].[NH4+].[C-]#N.[C-]#N.[C-]#N>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([CH2:19][C:27]#[N:29])[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CO)CCOCc1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CC#N)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3-Benzyloxy-1-hydroxymethyl-propyl)-carbamic acid tert-butyl ester (7.4 g, 25 mmole) was dissolved in 100 ml DCM. Mesyl chloride (4.3 g, 37.5 mmole) and triethylamine (5.0 g, 50 mmole) were added. The reaction was stirred at room temperature for 20 minutes. 100 ml DCM and 100 ml water were added. The organic layer washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was dissolved in 200 ml toluene. Tetraammonium cyanide (10 g, 37.5 mmole) was added and the reaction was stirred at room temperature overnight. The organic layer washed with water (2×100 ml), brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by column (EtOAc/hexane from 100/0 to 30/70 in 45 minutes). Yield, 6.4 g, 84%. 1H NMR (CDCl3 400 MHz δ 7.29-7.38 (m, 5H), 5.20 (d, J=5.9 Hz, 1H), 4.50 (m, 2H), 3.91 (m, 1H), 3.54-3.66 (m, 2H), 2.60-2.77 (m, 2H), 1.89-1.99 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Product: CC[C@H](COC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 150–152° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (d, J=2.2 Hz, 1 H), 7.12 (s, 1 H), 7.10 (d, J=1.8 Hz, 1 H), 4.95–4.90 (m, 1 H), 4.34 (t, J=8.1 Hz, 2 H), 3.67 (dd, J=10.6, 5.8 Hz, 1 H), 3.55 (dd, J=10.6, 3.5 Hz, 1 H), 3.35 (s, 3 H), 3.12 (t, J=8.1 Hz, 2 H), 1.92–1.72 (m, 2 H), 0.93 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2BrCl2 (M+H)+: 446.0038; found m/z 446.0008.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:12])=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])c(OC(C)C)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)c(OC(C)C)c1

Procedure:
5-Methyl-1-(1-methylethoxy)-2-nitrobenzene, 17.7 g (91 mmol), is dissolved in methanol, palladium on charcoal is added and the mixture is exposed to hydrogen gas until the required amount of hydrogen is absorbed. The mixture is worked up in the usual manner to give 15 g of 4-methyl-2-(1-methylethoxy)benzenamine.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=O)[CH:7]=[C:8]([F:10])[CH:9]=1)=O.C([O-])(=O)C.[NH4+:28].O>C(O)(=O)C>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[NH:28][C:3](=[O:2])[C:5]3[N:6]([CH:7]=[C:8]([F:10])[CH:9]=3)[CH:11]=2)=[CH:15][CH:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1cc(F)cn1CC(=O)c1ccc(C(C)(C)C)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Temperature: 25 °C

Procedure:
A solution of 52.4 mg (0.165 mmol) 1-[2-(4-tert-butyl-phenyl)-2-oxo-ethyl]-4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester and 382 mg (4.95 mmol) ammonium acetate in 0.5 ml acetic acid is stirred for 18 hours at 110° C. The reaction mixture is allowed to cool to room temperature and excess water is added. The resulting precipitate is filtered off, washed with water and dried. It is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(4-tert-butyl-phenyl)-7-fluoro-2H-pyrrolo[1,2-a]pyrazin-1-one as light brown crystals; HPLC/MS 2.88 min (B), [M+H] 285; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 10.97 (s, 1H), 7.61 (s, 1H), 7.58 (d, J=8.5, 2H), 7.48 (m, 3H), 6.75 (d, J=1.6, 1H), 1.31 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C:3]([O:5][CH2:6][CH2:7][O:8][C:9](OC1C=CC(S(C)(=O)=O)=CC=1)=[O:10])=[O:4].[CH2:23]1[CH2:28][CH2:27][C:26]([CH2:33][NH2:34])([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24]1.C(=O)(O)[O-].[K+]>C(#N)C.C(OCC)C>[CH3:1][CH:2]([CH3:22])[C:3]([O:5][CH2:6][CH2:7][O:8][C:9]([NH:34][CH2:33][C:26]1([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24][CH2:23][CH2:28][CH2:27]1)=[O:10])=[O:4]
Reactant: CC(C)C(=O)OCCOC(=O)Oc1ccc(S(C)(=O)=O)cc1
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)C(=O)OCCOC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A 50 mL, single-neck, round-bottomed flask equipped with a magnetic stir bar and a nitrogen inlet was charged with sulfone D3 (300 mg, 1 mmol) and gabapentin (171 mg, 1 mmol) in acetonitrile (1 mL). To the resulting slurry, saturated aqueous potassium bicarbonate (1 mL) was slowly added over a period of two minutes. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into a separatory funnel, diluted with diethyl ether (20 mL), washed with 5% aqueous sulfuric acid (10 mL), water (10 mL), and brine (100 mL). The organic phase was dried over sodium sulfate and evaporated under vacuum to give a viscous oil. The crude product was purified by column chromatography using ethyl acetate and hexane to give the title compound E4 as a viscous oil (250 mg, 75% yield). 1H NMR (CDCl3, 400 MHz): δ 1.16 (d, J=6.8 Hz, 6H), 1.35-1.55 (m, 10H), 1.46 (d, J=5.2 Hz, 3H), 2.32 (s, 2H), 2.52 (m, 1H), 3.23 (d, J=6.8 Hz, 2H), 5.27 (t, J=6.4 Hz, 1H, —NH) 6.76 (q, J=5.6 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C@H:10]([OH:21])[CH2:9]1)=O)(C)(C)C.[ClH:22]>CCOC(C)=O>[ClH:22].[CH3:20][C:16]1[CH:15]=[C:14]([C@@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[OH:21])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc([C@@H]2CCNC[C@H]2O)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of trans -N-t-butoxycarbonyl-4-(3-methylphenyl)-3 hydroxypiperidine, (0.20 g, 0.12 mmol) in EtOAc (50 ml) at 0° C. was bubbled HCl gas until saturated. The reaction was stirred at 0° C. for 10 min and then the solvent evaporated in vacuo to afford the product as a white foam.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]2[N:12]=[CH:13][CH:14]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])O.[Na+].[CH3:20][NH2:21]>C(O)C>[CH2:1]([C:5]1[CH:10]=[C:9]([NH:21][CH3:20])[N:8]2[N:12]=[CH:13][CH:14]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(Cl)n2nccc2n1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCc1cc(NC)n2nccc2n1
Temperature: 120 °C

Procedure:
5-n-Butyl-7-chloropyrazolo[1,5-a]pyrimidine (the compound prepared in step (2) of Reference Example 1; 8.60 g), sodium hydrogen carbonate (3.44 g) and 40% methylamine (3.18 g) were added to 50 ml of ethanol and heated at 120° C. for 2 hours. After completion of the reaction, ethanol was distilled off under reduced pressure. After addition of some water, the residue was extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:2) to provide 2.33 g of 5-n-butyl-7-methylaminopyrazolo[1,5-a]pyrimidine as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]1[O:12][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[O:7][CH2:10]1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)cc1

Procedure:
A mixture of 100 g 4-bromobenzaldehyde, 40 ml ethylene glycol, 800 ml of toluene and a catalytic amount of p-toluenesulfonic acid was refluxed for 2 hours, removing water with a Dean-Stark trap. The mixture was then cooled and poured into cold dilute potassium carbonate solution, extracted three times with ether and dried (MgSO4). Solvent was removed under reduced pressure, giving 118 g of 4-bromobenzaldehyde ethylene ketal (23) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:26][C:25]1[CH:27]=[CH:28][C:22]([O:21][CH3:20])=[CH:23][C:24]=1[N+:29]([O-:31])=[O:30])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(NC(=O)CNC(=O)OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
N-(Benzyloxycarbonyl)glycine (2.72 g, 13.13 mmol) was dissolved in CH2Cl2 and an excess of thionyl chloride at room temperature. After 2 h, the reaction was evaporated under vacuum and the residue was stripped with toluene twice and dried under vacuum. The white solid was taken into CH2Cl2 and 4-methoxy-2-nitroaniline (2.1819 g, 12.98 mmol) was added as a solid, followed by triethylamine (2.0 mL, 1.455 g, 14.38 mmol). The reaction was stirred at RT for 24 h, then was evaporated under vacuum. The residue was dissolved in EtOAc and washed with aqueous 1N NaHCO3. The EtOAc layer was dried (MgSO4) and concentrated under vacuum. Thin layer chromatography analysis (1:1:1 hexanes/Et2O/CH2Cl2) showed good conversion to the acylated material. The crude material was dissolved in 2:1:1 hexanes/Et2O/CH2Cl2 initially, with the addition of enough Et2O/CH2Cl2 and sonication/heating to dissolve all the solid material. Silica gel chromatography (2:1:1 hexanes/Et2O/CH2Cl2 (2 L), then 1:1:1 hexanes/Et2O/CH2Cl2 (1.5 L), then Et2O/CH2Cl2) gave the title compound (3.3387 g, 72%): 1H NMR (250 MHz, CDCl3) δ 3.85 (s, 3H), 4.06 (d, 2H), 5.18 (s, 2H), 5.61 (t, 1H), 7.2-7.4 (m, 6H), 7.65 (d, 1H), 8.63 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13]O)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.Cl[Cu]>[CH3:1][O:2][C:3](=[O:15])[C:4]([NH:5][C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])=[CH2:13]
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: Cl[Cu]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of N-Boc-serine methyl ester (Compound 1e, 2.19 g, 10 mmol) and EDCl (2.01 g, 10.5 mmol) in DCM (70 mL) was added CuCl (1.04 g, 10.5 mmol). The reaction mixture was stirred at room temperature for 72 h. Upon removal of the solvent, the residue was diluted with EtOAc, washed sequentially with water and brine and then dried over MgSO4. The crude product was purified by flash column chromatography (eluent: EtOAc:hexane ˜1:4) to yield compound if as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:18]O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Product: O=Cc1ccc(OCCC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
By the method of example 12, 4-hydroxybenzaldehyde was condensed with 3,3,3-triphenylpropanol to provide 4-(3,3,3-triphenylpropoxy)benzaldehyde, a white solid, mp 127°-130° C. after recrystallization from hexane (58% yield). This material (4.0 g, 10.2 mmol) was suspended in ethanol (100 mL), and sodium borohydride (0.2 g, 5.0 mmol) was added. After 3 hr, aqueous 1N HCl was added dropwise until gas evolution ceased. Precipitated boric acid was removed by filtration, and the filtrate concentrated to a gummy residue. This was partitioned between water and ether, and the ether solution dried (MgSO4), filtered, and concentrated. The residue was kept under high vacuum overnight to remove solvent, leaving 4-(3,3,3-triphenylpropoxy)benzyl alchohol as an amorphous solid (3.9 g, 97%). This material (3.9 g, 9.9 mmol) was dissolved in benzene (80 mL), and thionyl chloride (1.0 mL, 14 mmol) was added, followed by five drops of DMF at 5-minute intervals. The mixture was heated briefly to reflux, cooled, and concentrated to an oil which solidified on standing. Trituration of the solid with cold methanol provided 4-(3,3,3-triphenylpropoxy)benzyl chloride as a white powder, mp 91°-95° C. (83%). 1H NMR (CDCl3) δ 7.19-7.35 (m, 17H), 6.66 (d, J=8.7 Hz, 2H), 4.51 (s, 2H), 3.72 (t, J=7.8 Hz, 2H), 3.12 (t, J=7.8 Hz, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[CH:12]=[CH:11][C:10]=1[NH:22][C:23]([N:25]1[CH2:29][C@@H:28]([C:30]([F:33])([F:32])[F:31])[C@H:27]([CH2:34][NH2:35])[CH2:26]1)=[O:24].[Cl:36][C:37]1[S:41][C:40]([C:42](O)=[O:43])=[CH:39][CH:38]=1>>[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[CH:12]=[CH:11][C:10]=1[NH:22][C:23]([N:25]1[CH2:29][C@@H:28]([C:30]([F:31])([F:32])[F:33])[C@H:27]([CH2:34][NH:35][C:42]([C:40]2[S:41][C:37]([Cl:36])=[CH:38][CH:39]=2)=[O:43])[CH2:26]1)=[O:24]
Reactant: NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1C(F)(F)F
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1C(F)(F)F)c1ccc(Cl)s1

Procedure:
77.3 Using general method E, (3R,4S)-3-aminomethyl-4-trifluoromethyl-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide trifluoro acetate was coupled with 5-chlorothiophene-2-carboxylic acid to give (3R,4S)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-trifluoromethyl-pyrrolidine-1-carboxy-lic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 443.0 ([M+H]+)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc(Cl)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
A solution of 1,3,5-trichloronitrobenzene (800 mg) and 1-t-butoxycarbonyl-piperazine (790 mg) in toluene (20 ml) was stirred at 80° C. under N2 for 15 hours. The reaction mixture was cooled to room temperature, partitioned between water and ethyl acetate, the organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was subjected to silica gel chromatography (cyclohexane:ethyl acetate 8:2) to afford 4-(3,5-dichloro-2-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.37 g). 1H NMR (400 MHz, CDCl3) 1.5 (s, 9H), 2.9 (m, 4H), 3.5 (m, 4H), 7.0 (d, J=2 Hz, 1H), 7.16 (d, J=2 Hz, 1H); Retention Time HPLC 2.33 min; MS (ES+) 276/278 (M-BOC), 317/319 (M-isoprene).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)[CH3:2].[NH4+].O[N:29]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:29])=[O:15])=[CH:9]2)[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Temperature: 0 °C
Yield: 81.9 %

Procedure:
To an ice-cooled and stirred mixture of 7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (0.54 g) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole ammonium salt (0.33 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.42 g). After stirred at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate and brine, dried (MgSO4), filtered, and concentrated to give a light yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (441 mg, 82%) as pale yellow crystals. MS 376 (MH+).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:2].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>>[CH2:1]([NH:3][CH:4]1[CH2:8][CH2:7][N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:5]1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCNC1CCNC1
Product: CCNC1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
The compound was prepared from 3-ethylamino-pyrolidine (TCI-US) and 4-fluoro-nitrobenzene (Aldrich) following the procedure used in Example 1. MS (m+H)+: 236.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:9]1([CH2:15][CH2:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[O:3]=[C:2]1[NH:4][C:5](=[O:6])[CH:7]=[CH:8][N:1]1[C:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:21]
Reactant: O=C=NCCCCc1ccccc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(NCCCCc1ccccc1)n1ccc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
Uracil (0.10 g, 0.89 mmol) was dissolved in dry pyridine (4.4 mL). DMAP (0.12 g, 0.96 mmol) was added and the reaction mixture was stirred under nitrogen atmosphere at room temperature for 30 min. 4-Phenyl butyl isocyanate (0.27 mL, 1.60 mmol, 1.8 equiv) was then added and the resulting mixture was stirred for 12 hrs. The solvent was evaporated under reduced pressure and the crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc from 50:50 to 30:70) to afford the title compound (0.10 g, 59%) as white powder. 1H NMR (400 MHz, CDCl3): δ 1.59-1.82 (m, 4H), 2.66 (t, J=7.2 Hz, 2H), 3.29-3.60 (m, 2H), 5.89 (d, J=8.5 Hz, 1H), 7.11-7.22 (m, 3H), 723-734 (m, 2H), 8.41 (d, J=8, 5 Hz, 1H), 8.66 (s, 1H), 9.06 (t, J=5.7 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 28.69, 28.92, 35.56, 41.23, 77.16, 104.01, 126.06, 128.53, 139.08, 141.95, 149.84, 151.51, 162.30 MS (ESI) m/z: 310 [M-N]−.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][CH:13]=[C:14]4[C@@H:19]5[CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23][C@:18]5([C:26]([OH:28])=[O:27])[CH2:17][CH2:16][C@@:15]4([CH3:29])[C@:10]3([CH3:30])[CH2:9][CH2:8][C@H:7]1[C:6]([CH3:32])([CH3:31])[C@@H:5]([OH:33])[CH2:4][CH2:3]2.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:33][C@H:5]1[CH2:4][CH2:3][C@@:2]2([CH3:1])[CH:7]([CH2:8][CH2:9][C@:10]3([CH3:30])[CH:11]2[CH2:12][CH:13]=[C:14]2[C@@:15]3([CH3:29])[CH2:16][CH2:17][C@:18]3([C:26]([O:28][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:27])[CH:19]2[CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]3)[C:6]1([CH3:32])[CH3:31]
Reactant: CC1(C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]2C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)C(=CCC4[C@@]5(C)CC[C@H](O)C(C)(C)C5CC[C@]43C)C2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.1 %

Procedure:
A mixture of oleanolic acid (1a, 6.0 g, 13.1 mmol), benzyl bromide (2.8 g, 16.4 mmol), K2CO3 (2.7 g, 19.7 mmol) and DMF (120 mL) was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica, 30% EtOAc in hexanes) to provide the sub-title compound (6.6 g, 92%) as a white solid.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][NH2:10])=[O:8])=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C=O)C>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:26]1([S:32]([NH:10][NH:9][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:2][CH:3]=2)=[O:8])(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NNS(=O)(=O)c1ccccc1)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Biphenyl-4-carboxylic acid hydrazide (0.5 g, 2.36 mmol) was suspended in THF (26 mL). N,N-diisopropylethylamine (1.64 mL, 9.44 mmol) was added, and the reaction was cooled to 0° C. Phenylsulfonyl chloride (0.33 mL, 2.59 mmol) was added followed by DMAP (5 mg, 0.04 mmol). The reaction was allowed to warm to room temperature. The solution was orange after it stirred for 1 hour; DMF (5 mL) was added, and the solution became clear. After 3 hours of stirring, the solution was diluted with EtOAc (150 mL). It was then washed with saturated sodium bicarbonate and brine and dried over Na2SO4. The reaction was then concentrated down and triturated with CH2Cl2. The desired product was isolated (0.19 g, 22.7%). MS: 351.1 (M)−1 for C19H16N2O3S); mp 216-219° C. TLC: SiO2, Rf=0.55 (1:1 hexane/EtOAc). Analysis C19H16N2O3S.0.25 H2O: (calc) C, 63.94; H, 4.66; N, 7.85. (found) C, 63.76; H, 4.64; N, 7.76. HPLC: (30% H2O/70% CH3CN/0.1% TFA), RT=3.731 min. Purity: 94.16%. IR (KBr, cm−1) 3337, 3035, 2811, 1655, 1340, 1156. 1H NMR (400 MHz, DMSO) δ 7.26-8.00 (m, 14H), 10.01 (s, 1H, 10.71 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[N:10]([CH:11]=1)[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2].[Cl:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>O>[CH2:1]([C:3]1[CH:4]=[C:5]2[N:10]([C:11]=1[C:20]([C:19]1[CH:23]=[CH:24][C:16]([CH2:15][CH2:14][CH2:13][Cl:12])=[CH:17][CH:18]=1)=[O:21])[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc2ccccn2c1
Reactant: O=C(Cl)c1ccc(CCCCl)cc1
Solvent: O
Product: CCc1cc2ccccn2c1C(=O)c1ccc(CCCCl)cc1
Temperature: 50 °C
Yield: 94.9 %

Procedure:
A mixture of 8 g (55 mmoles) of 2-ethyl-indolizine and 13.1 g (60 mmoles) of 4-(3-chloropropyl)benzoyl chloride was heated to 50° C. for 18 hours. It was taken up in water, extracted with dichloromethane, washed with a sodium carbonate solution; the organic phase was then dried over sodium sulphate and concentrated to dryness. It was purified by flash chromatography over alumina (eluent: cyclohexane/methylene chloride, 50/50). In this manner, 17 g of the desired compound was obtained in the form of an oil. Yield: 94%.