Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[CH:19]=[CH:20][C:21](O)=O>>[Br:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1cccc(Br)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(Br)c3)nc2n(CC)c1=O
Yield: 51.1 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.0 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.52 g (11.1 mmol) of 3-bromocinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 2.01 g (yield 37%) of Compound 154 as pale green plates.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)[N:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)[N:5]=1
Reactant: O=C1NC[C@@H](Cn2ccc([N+](=O)[O-])n2)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccn(C[C@@H]2CNC(=O)O2)n1
Yield: 1.1 %

Procedure:
In a Parr shaker bottle was placed (S)-5-(3-nitro-pyrazol-1-ylmethyl)-oxazolidin-2-one (364 mg, 1.72 mmol), 10% palladium on carbon (200 mg) and ethanol (25 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 4 h. The reaction was then filtered through a pad of celite and washed with ethanol and concentrated in vacuo to afford (S)-5-(3-amino-pyrazol-1-ylmethyl)-oxazolidin-2-one (3.60 mg, 91%) as a yellow oil: LR-ES-MS m/z calculated for C7H10N4O2 [M]+ 182, observed 183 [M+H]+.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:29])[O:15][C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]2[CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:23]1([C:16]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:10]3[CH2:9][NH:8][CH2:13][CH2:12][N:11]3[C:14](=[O:29])[O:15]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of (1,1-dimethylethyl)tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (2.3 g, 5.5 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added an aqueous saturated sodium hydrogen carbonate solution (10 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to obtain the title compound (1.6 g, yield 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH2:11][Br:14])=[O:4]
Reactant: COC(=O)c1c(C)cc(Cl)nc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1c(CBr)cc(Cl)nc1Cl
Yield: 72.2 %

Procedure:
To a solution of 5.3 g (24.1 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester in CCl4 (92 ml) were added 3.1 g (26.5 mmol) N-Bromosuccinimide, 395 mg (2.4 mmol) AIBN and 1.45 ml (25.3 mmol) acetic acid. The mixture was irradiated with a 200 W Wolfram lamp at 60° C. for 24 h. Subsequently the mixture was filtered through celite and the filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 97:3) provided 5.2 g of a mixture of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester and 4-(bromomethyl)-2,6-dichloro-pyridine-3-carboxylic acid methylester which was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.Cl.O>[Fe].C(O)C>[Br:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)cnc1N
Yield: 50.4 %

Procedure:
A mixture of 2-amino-5-bromo-3-nitropyridine (62.2 g, 285 mmol), iron powder (171 g, 3.06 mol), concentrated hydrochloric acid (2.85 ml), water (60 ml) and ethanol (230 ml) was refluxed for 2 h, filtered whilst warm, the solids washed twice with ethanol (2×150 ml) and the combined ethanol solutions were evaporated to dryness. The crude solid was recrystallized from water, using decolourising charcoal, filtered whilst warm, the solids washed twice with warm ethanol (2×100 ml), the ethanol evaporated off and the precipitate was filtered off, washed with water (3×75 ml) and dried to afford the title compound (27 g, 50%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)COC)CC4)c[nH]c13)OCO2

Procedure:
Starting from trans-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A185) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>N1C=CC=CC=1.C(Cl)Cl>[C:32]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@@H:13]([O:15][C:16](=[O:17])[CH2:12][CH2:13][CH3:14])[CH3:14])=[N:20][N:19]=2)=[CH:22][C:23]=1[Cl:28])(=[O:33])[CH2:31][CH2:30][CH3:29]
Reactant: CCCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)c(Cl)c3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Oc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)OC(=O)CCC)o2)cc1Cl
Reaction time: 23 h

Procedure:
To a solution of 2-chloro-4-((1R,2S)-1-(5-(3-chloro-4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (example 37) (96.5 mg, 0.23 mmol) in pyridine (0.6 mL) and CH2Cl2 (4 mL) was added n-butyryl chloride (0.12 mL, 1.15 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (10 mL). The mixture was partitioned between H2O (25 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic extracts were washed with NaHCO3 (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange/brown viscous oil, which was purified by flash chromatography over silica gel (20-25% EtOAc in hexanes) to provide the title compound as an off white solid (116 mg, 90%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.11 (d, J=2.0 Hz, 1H), 8.03 (dd, J=2.2, 8.4 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 5.74 (d, J=9.0 Hz, 1H), 5.67 (dq, J=5.7, 6.5 Hz, 1H), 5.45 (dd, J=5.7, 8.6 Hz, 1H), 2.67 (t, J=7.4 Hz, 2H), 2.33-2.28 (m, 2H), 1.83-1.72 (m, 2H), 1.66-1.52 (m, 2H), 1.47 (d, J=6.5 Hz, 3H), 1.04 (t, J=7.4 Hz, 3H), 0.86 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[OH-].[K+].I[CH3:12]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CNc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2 g (11.6 mmol) 3-Bromoaniline is dissolved in 15 mL DMF and treated with 716 mg (1.1 eq.) KOH and 0.722 mL (1 eq.) iodomethane under continuous stirring at room temperature for 20 hours. The reaction mixture is extracted with ethyl acetate and water, the combined organic phases are washed with brine and dried with sodium sulfate and evaporated to dryness. The residue is column chromatographed (ethyl acetate/petroleum ether 2:5) to yield after evaporation the desired product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])C(=O)[NH:6]2.[OH-:14].[Na+].OO>>[NH2:6][C:7]1[C:3]([C:4]([OH:13])=[O:14])=[C:2]([CH3:1])[C:10]([CH3:11])=[CH:9][CH:8]=1
Reactant: Cc1ccc2c(c1C)C(=O)C(=O)N2
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Product: Cc1ccc(N)c(C(=O)O)c1C
Temperature: 85 °C
Reaction time: 2 h

Procedure:
An aqueous solution (80 ml) containing 4,5-dimethyl-1H-indole-2,3-dione (9.8 g, 0.056 mmol) and sodium hydroxide (8.1 g, 0.2 mol) was heated to 85° C., and then 10% aqueous hydrogen peroxide (43 ml) was slowly added. The obtained solution was stirred at 85° C. for 2 hours, cooled to room temperature, and filtered. The filtrate was adjusted to pH 1 using sulfuric acid, to obtain 6-amino-2,3-dimethylbenzoic acid as crystals.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]([CH3:43])[C:10](=[O:42])[NH:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23](C2CCCCO2)[N:22]=[C:21]3[C:33]([NH:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[O:34])[CH:15]=[N:16][CH:17]=1.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:8][N:9]([CH3:43])[C:10](=[O:42])[NH:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:33]([NH:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[O:34])[CH:15]=[N:16][CH:17]=1
Reactant: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C(=O)Nc2cccnc2)nn3C2CCCCO2)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)Nc1cncc(-c2ccc3[nH]nc(C(=O)Nc4cccnc4)c3c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.3 %

Procedure:
TFA (5 mL) was added to a solution of 5-(5-(3,3-dimethylureido)pyridin-3-yl)-N-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (CXXVI) (0.134 g, 0.27 mmol) and triethylsilane (0.110 mL, 0.69 mmol) in DCM (5 mL) and stirred 3 h at room temperature. The solvent was removed under vacuum. The residue was treated with water, sonicated briefly to disperse the solids, basified to pH 9.0 with 5 N NH4OH and sonicated again. The solids were filtered, washed with cold water and purified by column chromatography (100% DCM→5:95 MeOH[7N NH3]:DCM) to afford 5-(5-(3,3-dimethylureido)pyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide (1) as a white solid (35.8 mg, 0.09 mmol, 33% yield). 1H NMR (DMSO-d6) δ ppm 13.99 (s, 1H), 10.69 (s, 1H), 9.08 (d, J=1.2 Hz, 1H), 8.74 (d, J=1.8 Hz, 1H), 8.63 (s, 1H), 8.51 (d, J=1.5 Hz, 1H), 8.47 (s, 1H), 8.33-8.30 (m, 2H), 8.26 (m, 1H), 7.80 (s, 2H), 7.41 (dd, J=6.6, 3.6 Hz, 1H), 2.98 (s, 6H); ESIMS found for C21H19N7O2 m/z 402.3 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:13])[O:8][CH:7]([C:18]([F:21])([F:20])[F:19])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2.[CH3:27]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOCCOC>[CH2:14]([N:12]([CH3:13])[C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8]2)=[CH:3][C:2]=1[CH3:27])[CH:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(N(C)CC(C)C)cc2OC1C(F)(F)F
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(=O)C1=Cc2cc(C)c(N(C)CC(C)C)cc2OC1C(F)(F)F
Temperature: 115 °C
Yield: 45 %

Procedure:
A mixture of ethyl 6-chloro-7-[isobutyl(methyl)amino]-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 8c (0.50 g, 1.28 mmole), trimethylboroxine (0.38 g, 2.75 mmole), [(tBu3P)PdBr]2 (0.01 g), and Cs2CO3 (0.75 g, 2.31 mmole) in anhydrous diglyme (10.0 mL) was heated to 115° C. under a dry N2 atmosphere for 18 hrs. The contents were poured into water (40 ml) and extracted with EtOAc (2×40 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil which was subject to HPLC (reverse phase) and eluted with 50-85% ACN/water with 0.05% TFA to give yellow solid (0.21 g, 45%). No further purification was performed. GCMS m/z 371.0 (M+). LCMS m/z 372.0 (M+H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[C:6]([CH:15]2[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16]2)=[C:5]1[CH3:23])(=O)C.[OH-].[K+]>O.C(O)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][C:5]([CH3:23])=[C:6]2[CH:15]1[CH:20]2[CH2:19][CH2:18][N:17]([CH2:22][CH2:21]2)[CH2:16]1
Reactant: COc1ccc2c(c1)c(C1CN3CCC1CC3)c(C)n2C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2[nH]c(C)c(C3CN4CCC3CC4)c2c1

Procedure:
200 mg of 3-(1-Acetyl-5-methoxy-2-methyl-3-indolyl)quinuclidine are stirred on a steam bath for 16 hours with 100 mg of KOH in 7 ml of water and 14 ml of ethanol. The mixture is then worked up as is customary. 3-(5-methoxy-2-methyl-3-indolyl)quinuclidine is obtained; hydrochloride, m.p. 231.7°-234.0°.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>>[O:22]([CH2:21][CH2:20][CH2:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1cccc2nccn12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)(C)[Si](C)(C)OCCCc1cccc2nccn12
Yield: 64.8 %

Procedure:
Using 13.22 g (100 mmol) of 5-methylimidazo[1,2-a]pyridine, 50 ml (100 mmol) of a 2M lithium diisopropylamide solution (produced by Aldrich Company) and 23.92 g (100 mmol) of 1-bromo-2-t-butyldimethylsiloxyethane, the same procedure as in Reference Example 3 was followed, to yield 18.81 g (64.8%, yellow oily substance) of 5-(3-t-butyldimethylsiloxypropyl)imidazo[1,2-a]pyridine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]2[O:13][CH2:14][CH:15]([OH:16])[CH:11]2[O:10][CH2:9]1.[N+:17]([O:20][C@@H:21]([CH2:37][O:38][N+:39]([O-:41])=[O:40])[CH2:22][CH2:23][CH2:24][C:25](O[C@@H]1CO[C@@H]2[C@H](O)CO[C@H]12)=[O:26])([O-:19])=[O:18].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:17]([O:20][C@@H:21]([CH2:37][O:38][N+:39]([O-:41])=[O:40])[CH2:22][CH2:23][CH2:24][C:25]([O:16][C@H:15]1[CH2:14][O:13][C@@H:12]2[C@@H:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:9][O:10][C@H:11]12)=[O:26])([O-:19])=[O:18]
Reactant: O=C(CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: OC1COC2C(OC3CCCCO3)COC12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3S,3aR,6S,6aR)-6-(tetrahydro-2H-pyran-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol (0.64 g, 2.80 mmol) and (5R)-5,6-bis-nitrooxy-hexanoic acid (1.18 g, 4.95 mmol) (obtained as described in EXAMPLE 5) were dissolved in DCM (30 ml), EDAC (0.81 g, 4.20 mmol) and 4-dimethylaminopyridine (0.068 g, 0.56 mmol) were added. After stirring at room temperature for 12 hrs, the reaction mixture was washed with water. The organic layer was dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 10 to 80%), affording the title product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][C:32]([NH:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[O:33])[C:26]=1[CH3:43])=O.N1CCCCC1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][C:32]([NH:34][CH2:35][CH:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)=[O:33])[C:26]=1[CH3:43])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)NCC1CCN(C)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (400 mg, 1.12 mmol), 2-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-N-(1-methyl-piperidin-4-ylmethyl)-acetamide (295 mg, 1.2 q.) and piperidine (1.5 eq.) was stirred at rt for 96 hours. The reaction was concentrated and purified on a silica gel column to give the titled compound as a brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].O>CN(C=O)C>[Si:23]([O:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)=[O:4])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: O=C(CO)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
Step A To a solution of 2-hydroxy-1-(4-nitrophenyl)ethanone (1 g, 5.52 mmol) in DMF (25 ml) was added imidazole (564 mg, 8.28 mmol), followed by the addition of tert-butylchlorodimethylsilane (915 mg, 6.07 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was poured into H2O (25 mL) and extracted with ethyl acetate (3×25 mL). The organic layers were combined, washed with H2O (5×25 mL), brine (1×25 mL), dried over MgSO4 and concentrated in vacuo to give 2-(tert-butyldimethylsilyloxy)-1-(4-nitrophenyl)ethanone as a yellow solid (1.6 g, 98%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]1(=[O:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CCOCC.Cl>[F:9][C:2]([F:1])([F:8])[C:3](=[C:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]1=[O:25])[OH:5]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=C1C(=C(O)C(F)(F)F)CCc2ccccc21
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A 250 mL one neck round bottomed flask equipped with a reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL of ether. To this solution was added 48 mL of 25% sodium methoxide in methanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in ether (50 mL) was added over about 5 minutes The reaction mixture was stirred at room temperature for 14 hours and was diluted with 100 mL of 3N HCl. The phases were separated, and the organic layer was washed with 3N HCl and with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was taken up in 70 mL of boiling ethanol/water and cooled to room temperature, whereupon crystals of 3,4-dihydro-2-[2,2,2-trifluoro-1-hydroxyethylidene]-1(2H)-naphthalenone formed which were isolated by filtration and air dried to give 32 g (81%) of pure 3,4-dihydro-2-[2,2,2-trifluoro-1-hydroxyethylidene]-1(2H)-naphthalenone: mp 48°-49° C.; 1H NMR (CDCl3) δ 2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H); 19F NMR (CDCl3) δ-72.0. EI GC-MS M+ =242.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12]([NH2:18])=[C:11]3[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.CO.N#N>CCOC(C)=O.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH2:13][CH:12]([NH2:18])[CH:11]3[C:19]([F:22])([F:20])[F:21])=[CH:6][CH:7]=1
Reactant: Nc1cnc2ccc(-c3ccc(F)cc3)cc2c1C(F)(F)F
Agent: [Pd+2]
Agent: N#N
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1CNc2ccc(-c3ccc(F)cc3)cc2C1C(F)(F)F
Reaction time: 16 h
Yield: 15.4 %

Procedure:
To a solution of 147B (400 mg, 1.3 mmol) in EtOAc (5 mL)-MeOH (15 mL) was bubbled with N2 for 15 min, then palladium hydroxide (20 weight % palladium on carbon) (200 mg) was added. The resulting suspension was subjected to hydrogenation under 80 psi of pressure for 16 h., then filtered. The filtrate was concentrated. The residue was chromatographed (silica gel) eluting with 20% EtOAc in hexane (100 mL), 50% EtOAc in hexane (100 mL), 100% ETOAc (100 mL), 5% MeOH in EtOAc (150 mL) to give title compound (62 mg, 15% yield) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1.[OH:14][CH:15]([CH3:19])[C:16](=[O:18])[CH3:17].N1C=CC=CC=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:19][CH:15]([O:14][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:12][CH:11]=1)[C:16](=[O:18])[CH3:17]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(=O)C(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)OC(C)C(C)=O)cc1

Procedure:
A mixture of terphthalic acid monomethyl ester (1.0 g, 5 mmol), 3-hydroxy-butane-2-one (0.531 g, 6.8 mmol), 4-dimethylamino pyridine (1.27 g, 10 mmol), pyridine (0.79 g, 10 mmol) and EDCl.HCl (1.6 g, 8 mmol) was stirred in dry DMF (10 mL) over night under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL×2) and with brine, then dried over anhydrous sodium sulphate and concentrated. the obtained residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound.