Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[N:2]1.[CH:9](=[C:16]([C:19]#[N:20])[C:17]#[N:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1>CCO>[NH2:20][C:19]1[N:2]2[N:1]=[CH:5][CH:4]=[C:3]2[C:6]([C:7]#[N:8])=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]=1[C:17]#[N:18]
Reactant: N#CC(C#N)=Cc1ccccc1
Reactant: N#CCc1cc[nH]n1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)c(C#N)c2ccnn2c1N
Yield: 14.3 %

Procedure:
To a stirred solution of (1H-Pyrazol-3-yl)-acetonitrile (100 mg, 0.93 mM) in absolute EtOH (4.7 mL) at 25° C. was added benzylidene malononitrile (144 mg, 0.93 mM) and piperidine (0.009 mL, 0.09 mM). The mixture then refluxed for 1.0 hr. The solvent evaporated. Chromatography done on silica gel (60×2.5 cm) with CH2Cl2 afforded 7-Amino-5-phenyl-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile (34.6 mg, 14%) LCMS: MH+=260; HRMS: m/z 260.0938 (MH+), Calcd. C15H9N5: m/z 260.0936; δC (DMSO) CH: 99.0, 128.5, 128.5, 128.8, 128.8, 129.8, 145.4; C: 75.4, 86.9, 115.5, 116.0, 134.8, 138.9, 148.1, 149.4.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([OH:27])[CH2:24][C@@H:23]1[C@H:28]1[O:32][C:31]([CH3:34])([CH3:33])[N:30]([C:35](=[O:37])[CH3:36])[C@H:29]1[CH2:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH3:47][O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[O:48][CH3:47])[CH2:24][C@@H:23]1[C@H:28]1[O:32][C:31]([CH3:33])([CH3:34])[N:30]([C:35](=[O:37])[CH3:36])[C@H:29]1[CH2:38][C:39]1[CH:40]=[C:41]([F:46])[CH:42]=[C:43]([F:45])[CH:44]=1)=[O:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: COc1ccccc1O
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1O[C@@H]1C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Reaction time: 18 h
Yield: 52.4 %

Procedure:
Add dropwise diisopropyl azodicarboxylate (0.065 mL, 0.327 mmol) to a solution of (2R,4S)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.099 g, 0.218 mmol), 2-methoxy phenol (0.036 mL, 0.327 mmol) and triphenylphosphine (0.086 g, 0.327 mmol) in tetrahydrofuran (1.5 mL). Stir 18 hours. Purify reaction mixture on silica gel with ethyl acetate/hexane mixtures to give the desired compound as a foam (0.064 g, 53%). MS(ES): m/z=561 [M+H].
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:21][CH:18]1[CH2:19][CH2:20][N:15]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
A mixture of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (3.15 g, 15.8 mmol), 4-piperidinol (1.0 g, 9.88 mmol), and acetic acid (0.8 mL) in methylene chloride (30 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (3.35 g, 15.8 mmol) was added and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the residue was dissolved in methylene chloride and washed with 1N HCl. The aqueous phase was extracted with ether (3×10 mL) and adjusted to pH 9-10 with 1N NaOH. The basic aqueous mixture was extracted with methylene chloride (3×10 mL). The combined organic extracts were concentrated in vacuo to afford 1,1-dimethylethyl 4-hydroxy-1,4′-bipiperidine-1′-carboxylate (1.1 g, 39% yield). This material was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[NH2:1][C:2]1[C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C1COCCN1
Product: Nc1ncc(Br)nc1N1CCOCC1

Procedure:
2-Amino-3,5-dibromopyrazine is reacted with morpholine at 130° C. under pressure yielding 2-amino-3-morpholino-5-bromopyrazine.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([C:43]([OH:45])=O)[CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[CH:35]=1)=[O:5])C.[CH:46]1([NH2:50])[CH2:49][CH2:48][CH2:47]1>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[CH:33]=[C:32]([C:43](=[O:45])[NH:50][CH:46]3[CH2:49][CH2:48][CH2:47]3)[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: NC1CCC1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NC3CCC3)cc(-c3cccc(F)c3)c2)c1CCC(=O)O

Procedure:
The title compound was prepared according to the general procedure described in Steps 7 and 8 of Method C starting from 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid and cyclobutylamine (6% yield after two steps).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][C:8]1[CH2:14][CH:13]2[N:10]([C:11](=[O:17])[CH:12]2[CH2:15][CH3:16])[C:9]=1[C:18]([O:20]CC1C=CC([N+]([O-])=O)=CC=1)=[O:19].[H][H]>O1CCOCC1.P([O-])([O-])([O-])=O.[Pt]=O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][C:8]1[CH2:14][CH:13]2[N:10]([C:11](=[O:17])[CH:12]2[CH2:15][CH3:16])[C:9]=1[C:18]([OH:20])=[O:19]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ncccn3)CC12
Reactant: [H][H]
Agent: O=[Pt]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCC1C(=O)N2C(C(=O)O)=C(Sc3ncccn3)CC12
Reaction time: 4 h
Yield: 38.8 %

Procedure:
63.4 mg of p-nitrobenzyl 3-(2-pyrimidinylthio)6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2carboxylate obtained in Example 26 was dissolved in a mixture of 3.2 ml of dioxane and 1.2 ml of a 0.1 M phosphate buffer (pH 6.86). Then, 70 mg of platinum oxide was added, and the reaction was performed at room temperature for 4 hours in a Paar reducing apparatus (hydrogen pressure 4 kg/cm2). The catalyst was removed by filtration. The filtrate and the wash liquid were combined, and after adjusting the pH of the mixture to 7.2, concentrated under reduced pressure to about 2/3 of the initial amount. Sodium chloride (2 g) was added to the concentrated solution, and water was added to adjust the total amount to 70 ml. The resulting solution was applied to a column of Diaion HP-20AG (1.1×20 cm), and eluted with 300 ml in total of an aqueous solution of acetone with the concentration of acetone varying gradually from 0 to 50% (v/v) by a concentration gradient method. The fractions were screened by high-speed liquid chromatography, and fractions having an ultraviolet absorption at λmax 300 nm were collected and lyophilized to afford 16.8 mg of the desired product (yield 39%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH:5]([CH2:12][N+:13]([O-])=O)[CH2:6][C:7](OCC)=[O:8]>[Ni].C(O)C>[F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH:5]1[CH2:12][NH:13][C:7](=[O:8])[CH2:6]1
Reactant: CCOC(=O)CC(CCC(F)(F)F)C[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: O=C1CC(CCC(F)(F)F)CN1
Yield: 97.4 %

Procedure:
A mixture of crude ethyl 6,6,6-trifluoro-3-(nitromethyl)hexanoate a7 (50 g), Raney Nickel (570 mg, 9.7 mmol, 0.05 eq) and Vanadium metavanadate (227 mg, 2 mmol, 0.01 eq) in ethanol (1 l) is placed in an autoclave under hydrogen pressure (50 bars) at 50° C. for 40 h. After cooling, filtration over celite and condensation under vacuum, 4-(3,3,3-trifluoropropyl)pyrrolidin-2-one a8 (34.3 g) is isolated.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[O:4][N:3]=1.[CH3:36][Mg]I>>[OH:17][C:8]([CH3:36])([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]3)=[CH:28][CH:29]=2)=[CH:20][CH:19]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CC(=O)CCc1ccccc1
Reactant: C[Mg]I
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CC(C)(O)CCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 36, Step 1, using 1-{4′-[3-methyl-4-(2-oxo-4-phenyl-butyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and methylmagnesium iodide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[C:14]([C:17](=O)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[C:25]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([NH:32][NH2:33])=[O:31])=[CH:28][CH:27]=2)=[N:24][N:23]=[N:22]1>Cl.CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:33][NH:32][C:30](=[O:31])[C:29]3[CH:34]=[CH:35][C:26]([C:25]4[NH:24][N:23]=[N:22][N:21]=4)=[CH:27][CH:28]=3)[CH3:18])[C:13]([CH3:20])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=NN(c2ccc(C(C)(C)C)cc2)C(=O)C1=C(C)NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Yield: 12.9 %

Procedure:
A DMF solution (1 ml) of 27.2 mg (0.10 mmol) of 1-(1-(4-tert-butylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 20.4 mg (0.10 mmol) of 4-(1H-tetrazol-5-yl)-benzoic hydrazide synthesized by the method disclosed in WO03/037328 was heated at 60° C. for 6 hours with one drop of concentrated hydrochloric acid, and the precipitated solid was washed with water and collected by filtration. The solid was mixed with 1M aqueous sodium hydroxide and filtered. 1M Hydrochloric acid was added to the filtrate, and the precipitated solid was collected by filtration to obtain 5.9 mg of the desired product as a brown solid (yield 12%).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:20]=[C:21]([F:24])[C:22]=1O.C(N(CC)CC)C>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:20]=[C:21]([F:24])[C:22]=1[O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)Cc1cc(F)c(O)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
Trifluoromethanesulphonic anhydride (0.854 mL, 5.21 mmol) was added dropwise to a stirred solution of methyl 2-(3,5-difluoro-4-hydroxyphenyl)acetate (Intermediate 24-3; 0.702 g, 3.47 mmol) in DCM (15.06 mL) cooled to 0° C., over a period of 5 minutes under nitrogen. Triethylamine (1.452 mL, 10.42 mmol) was added dropwise over 5 minutes (keeping internal temperature between 5-10° C.) and the resulting solution stirred at room temperature for 4 hours under nitrogen. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (100 mL), saturated NaHCO3 (100 mL), and water (100 mL). The organic layer was dried by passing through a phase seperating cartridge and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(3,5-difluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (0.930 g, 80%) as a straw yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[N:11]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:3]=[C:4]([CH3:10])[CH:5]=[C:6]2[CH:9]=[N:11][NH:8][C:7]=12
Reactant: Cc1cc(C)c(N)c(Br)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2cn[nH]c2c(Br)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-bromo-4,6-dimethylpyridin-3-amine [104829-98-3] (4.00 g, 19.9 mmol) in acetic acid (300 mL) was treated with a solution of sodium nitrite (1.37 g, 19.9 mmol) in water (2.5 mL). The reaction mixture was stirred at RT for 15 min and was then allowed to stand at ambient temperature for 24 h. An additional solution of sodium nitrite (500 mg, 7.25 mmol) in water (1 mL) was added to the mixture which was allowed to stand at RT for 16 h. Acetic acid was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHCO3. The precipitate was filtered off, washed and discarded. The combined filtrates were washed with water and brine, then dried (Phase separator) and concentrated under vacuum to give 7-bromo-5-methyl-1H-pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 212 [M+H]+, tR (HPLC conditions k): 2.49 min.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=2[N:3]=1.[CH:33]([N:36]=[C:37]=[O:38])([CH3:35])[CH3:34]>C1COCC1>[CH:33]([NH:36][C:37]([N:20]1[CH2:19][CH2:18][C:17]([CH2:16][CH2:15][N:14]2[CH:12]3[CH2:11][CH2:10][CH:9]2[CH2:8][CH:7]([N:6]2[C:5]4[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=4[N:3]=[C:2]2[CH3:1])[CH2:13]3)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21]1)=[O:38])([CH3:35])[CH3:34]
Reactant: CC(C)N=C=O
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)NC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (20 mg, 0.047 mmol) in THF (2 mL) was added isopropyl isocyanate (4.3 mg, 0.047 mmol). The resulting mixture was stirred at ambient temperature overnight. After evaporation of the solvent, the residue was purified on silical gel, eluting with a gradient of 10-30% methanol in ethyl acetate to afford N-isopropyl-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboxamide as white solid (15 mg, 63%). 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=7.2 Hz, 1H), 7.43-7.38 (m, 2H), 7.34-7.24 (m, 4H), 7.22-7.15 (m, 2H), 4.67 (br, 1H), 4.24 (d, J=7.3 Hz, 1H), 3.99 (m, 1H), 3.62-3.58 (m, 2H), 3.30 (br, 2H), 3.23-3.16 (m, 2H), 2.62 (s, 3H), 2.42 (br, 2H), 2.25-2.20 (m, 2H), 1.98-1.83 (m, 9H), 1.68 (br, 2H), 1.17 (d, J=6.4 Hz, 6H). HRMS m/z (M+H)+ calcd: 514.3546, obsd: 514.3530.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:20])[O:19][CH2:18][CH:17]=[CH:16][CH2:15][O:14]1>C(Cl)Cl>[CH3:12][C:13]1([CH3:20])[O:19][CH2:18][CH:17]2[CH:16]([O:9]2)[CH2:15][O:14]1
Reactant: CC1(C)OCC=CCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)OCC2OC2CO1
Yield: 80 %

Procedure:
To a suspension of m-chloroperbenzoic acid (74% pure; 78.15 g; 0.33 mole) in methylene chloride (600 ml), was added a solution of 2,2-dimethyl-4,7-dihydro-1,3-dioxepin (II) (41.0 g, 0.32 mole) in methylene chloride (200 ml) during 30 min at room temperature. The mixture was refluxed for 8 hrs and then cooled in ice for 1 hr. The precipitated solid was filtered off and the organic filtrate was washed with 10% aqueous sodium sulfite (2×100 ml), saturated aqueous sodium bicarbonate (3×500 ml), 5% aqueous sodium hydroxide (2×250 ml) and brine (2×200 ml) and dried (MgSO4). Removal of the solvent followed by vacuum distillation of the residual oil gave the epoxide product (III) as a colorless liquid. 36.94 g (80% yield). b.p. 90°-92°/11 mm.
Reaction SMILES: C1C(=O)N([O:8][C:9]([O:11][CH2:12][CH:13]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=O)C(=O)C1.[NH2:26][C@H:27]([C:32]([OH:34])=[O:33])[CH2:28][C:29]([OH:31])=[O:30].C([O-])([O-])=O.[Na+].[Na+].Cl>O.O1CCOCC1>[C:9]([NH:26][C@H:27]([C:32]([OH:34])=[O:33])[CH2:28][C:29]([OH:31])=[O:30])([O:11][CH2:12][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[C:25]1=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:8]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Forty-five g (0.134M, 0.96 eq) of Fmoc-Osu was added to 20 g (0.15M, 1 eq) of aspartic acid and 20 g of Na2CO3 dissolved in 400 mL of water and 200 mL of dioxane. The mixture was stirred for 2 hrs while the pH was maintained at about 9 by the addition of small amounts of Na2 CO3. Then the cloudy white mixture was poured into 500 mL of ice water containing 40 mL of conc HCl. The white solid was extracted with 500 mL EtOAc and this was mixed with 500 mL of hexane. The mixture was chilled overnight and stirred the next day to give 38 g of Fmoc-aspartic acid as crystals (71% yield) upon filtration and air drying. 10 g (0.28M) of this product was dissolved in 200 mL of methanol and 20 mL of conc H2 SO4 was added. The solution was allowed to stand overnight. The mixture was poured into 1 L of water and filtered. The resulting white solid was dried and redissolved in EtOAc. Slow addition of hexane and chilling gave 9 g (83% yield) of product as white needles, mp 78°-80°. [a]d =-13.9°.
Reaction SMILES: [Si]([C:8]1[O:9][C:10]2[C:30]([O:31][CH:32]([CH3:34])[CH3:33])=[C:29]([O:35][CH3:36])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:21][O:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:24][CH3:25])[C:17]=1[O:22][CH3:23])[C:13]([C:12]1[C:11]2[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:31][CH:32]([CH3:34])[CH3:33])[C:10]=2[O:9][CH:8]=1)=[O:26]
Reactant: COc1cc(C(=O)c2c([Si](C)(C)C(C)(C)C)oc3c(OC(C)C)c(OC)ccc23)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2coc3c(OC(C)C)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-t-butyldimethylsilyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy-7-isopropoxy-benzofuran (0.066 mmol) in tetrahydrofuran (1 mL) was added tetrabutylammoniumfluoride (76.5 μl, 0.076 mmol, 1M solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for 20 minutes (monitored by tlc), diluted with ethyl acetate (10 mL) and washed with 1M hydrochloric acid (5 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The crude product was purified by flash chromatography (silica gel, eluent=hexane/diethyl ether; 7:3) to afford the title compound as a light yellow paste (23 mg) that was used directly in the next step; 1H NMR (300 MHz, CDCl3) δ 8.00 (s, 1H, C2H), 7.78 (d, 1H, J=8.60 Hz), 7.15 (s, 2H, benzoyl Hs), 7.04 (d, 1H, J=8.61 Hz), 4.73 (m, 1H), 3.93 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.90 (s, 6H, 2×OMe), 1.37 (d, 6H, J=6.14 Hz).
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)([O-])=O>Cl.C(OCC)C>[NH2:8][C:11]1[CH:12]=[CH:13][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: Nc1ccc(C(=O)N2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A solution of tin chloride dihydrate (5.44 g, 24.1 mmol) in concentrated hydrochloric acid (32 ml) was added slowly to a cooled, stirred solution of (4-nitro-phenyl)-(4-phenyl-piperazin-1-yl)-methanone (1.0 g, 3.2 mmol) in anhydrous diethyl ether (32 ml). The resulting mixture was stirred for 1 hour at room temperature, then cooled and quenched carefully with 10M sodium hydroxide (aq.) until slightly basic (˜pH 9). The aqueous mixture was extracted with ethyl acetate (100 ml) and the organic extracts dried over magnesium sulfate then concentrated in vacuo to the title compound as a cream solid (667 mg, 73% yield). HPLC retention time 6.2 min. Mass spectrum (ES+) m/z 282 (M+H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[I:11](O)(=O)(=O)=O.II>C(O)(=O)C.O.S(=O)(=O)(O)O>[I:11][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:10])=[N:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Nc1ncccc1[N+](=O)[O-]
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(I)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
To a solution of 3-nitropyridin-2-amine (1.2 g, 8.63 mmol) in acetic acid (5 ml), water (1 ml) and sulfuric acid (0.2 ml) was added periodic acid (0.4 g, 1.72 mmol, 0.2 eq.) and the mixture was stirred at 90° C. for 15 min. Iodine (0.87 g, 3.45 mmol, 0.4 eq.) was added portionwise and the mixture was heated at 90° C. for 1 h. The mixture was quenched by the addition of water and extracted with ethylacetate (3×150 ml). The combined organic layer was washed with water, aqueous sodium thiosulfate, brine and dried over sodium sulphate. The solvent was distilled off to give the product in 57% yield (1.3 g). 1H NMR (300 MHz, DMSO-d6): δ 8.58 (d, 1H), 8.54 (d, 1H) 8.04 (br s, 2H); LC-MS (ESI); Calculated mass: 265.01: Observed mass: 265.9 [M+H]+ (rt: 1.36 min).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=1.[C:21](=[O:23])=[O:22]>O1CCCC1>[Cl:20][C:16]1[N:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=1[C:21]([OH:23])=[O:22]
Reactant: Clc1cccc(Cl)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine 3.76 g in tetrahydrofuran 25 ml is dropped at −78° C. n-butyllithium (23.2 ml). The mixture is stirred at 0° C. for 10 minutes and thereto is added 2,6-dichloropyridine 5.0 g in tetrahydrofuran 25 ml at −78° C. over a period of 20 minutes. The mixture is stirred at −78° C. for 3 hours. The reaction mixture is poured into powdered dry ice and is left at room temperature overnight. After removal of the solvent the residue is dissolved in a mixture of ethyl acetate and a 10% aqueous sodium hydroxide solution, and the water layer is separated and made acid with concentrated hydrochloric acid. The resulting colorless precipitate is filtered and washed with cold water to give 2,6-dichloronicotinic acid 4.50 g. mp 148-150° C., MS(ESI): 190(M−H)−