Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([CH2:33]C(=O)C)(=[O:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:31][C:30](=[O:32])[CH3:33])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: BrCCCCCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(=O)CCCCCCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 6.9 %

Procedure:
A mixture of 0.5 g of 6-(3,4-dibenzyloxyphenyl)hexyl bromide, 0.12 g of acetylacetone, 0.15 g of potassium carbonate, 0.02 g of sodium iodide, and 5 ml of ethanol was refluxed for 20 hours. To the reaction mixture was added 15 ml of water and the product was extracted with 20 ml of ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide a sticky product. The product was applied to silica gel (45 ml) column chromatography and eluted with a mixture of toluene and ethyl acetate (30:1) to provide 33 mg of 9-(3,4-dibenzyloxyphenyl)-2-nonanone as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH2:6][C:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:17]([N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[C:18]#[CH:19]>>[OH:13][C:7]1([CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([C:19]#[C:18][CH2:17][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])[CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Reactant: OC1(CCc2cccc(Br)c2)CCCCC1
Product: O=C1c2ccccc2C(=O)N1CC#Cc1cccc(CCC2(O)CCCCC2)c1

Procedure:
Coupling of 1-(3-bromophenethyl)cyclohexanol with 2-(prop-2-ynyl)isoindoline-1,3-dione following the method described in Example 12 gives 2-(3-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)prop-2-ynyl)isoindoline-1,3-dione.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Yield: 78.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 3-methoxyaniline (107 mg, 0.87 mmol) to provide 193 (107 mg, 78% yield) as a white solid. LC-MS (M+H=318, obsd.=318).
Reaction SMILES: F[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([I:11])[CH:5]=[CH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[I:11][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[O:10][CH2:9][CH2:8][C:7]=12
Reactant: OCCc1c(I)ccnc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Ic1ccnc2c1CCO2

Procedure:
To a solution of 2-(2-fluoro-4-iodopyridin-3-yl)ethanol (3.13 g, 11.7 mmol) in 1,4-dioxane (100 mL), K3PO4 (10.0 g, 47.1 mmol) was added. The mixture was heated under reflux for 36 h. The reaction mixture was then filtered, the filter cake was washed with EtOAc, and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in DCM (100 mL), washed with brine (2×100 mL), dried over Na2SO4 and concentrated. The resulting residue of the crude sub-title compound (2.55 g) was used in the next step directly without further purification. LCMS calc. for C7H7INO (M+H)+: m/z=247.9. found 248.0.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20](=O)[C:21](OCC)=[O:22])C.CC(C)([O-])C.[K+]>O>[OH:22][C:21]1[C:20](=[O:19])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1ccccc1)Nc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=C1C(O)=C(c2ccccc2)C(=O)N1c1ccccc1
Reaction time: 3 h

Procedure:
After the addition of anhydride THF (20 ml) to compound 5a (1.55 g, 7.34 mmol), the temperature was adjusted to 0° C. Diethyloxalate (1.45 g, 9.50 mmol) and potassium t-butoxide (1.35 g, 11.9 mmol) were added thereto and the agitation for 3 hours was carried out. After the identification of the reaction progress with TLC, the solution was poured into the distilled water and acidified with 1N HCL aqueous solution. Three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4, solvents were removed and then, the suspension was carried out by HX.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[NH4+].[H][H]>[Pd].C(O)C>[C:5]1([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: CCOC(=O)NNc1ccc(-c2ccc(Br)cc2)nn1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)NNc1ccc(-c2ccccc2)nn1

Procedure:
A mixture of 15.57 g. of ethyl 3-[6-(p-bromophenyl)-3-pyridazinyl]carbazate, 1.5 g. of 10% palladium on carbon catalyst, 200 ml. of ethanol and 60 ml. of ammonium hydroxide is shaken under 40 lb. of hydrogen pressure for 4 hours with external heating of bottle by means of a heated jacket. The reaction mixture is filtered and the filtrate concentrated to a solid which is washed with water to give 10.1 g. of cream colored crystals. Recrystallization by dissolving in ethanol and diluting with petroleum ether gave white crystals, m.p. 158°-160° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([CH:19]1[CH2:21][CH2:20]1)[C@@H:6]([OH:18])[C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])=[N+:2]=[N-:3].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CCOC(C)=O.O>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:9][CH2:8][C@@H:7]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[C@H:6]([OH:18])[C@@H:5]([CH:19]2[CH2:20][CH2:21]2)[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)[C@H](O)[C@H](CN=[N+]=[N-])C1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)[C@H](CN=[N+]=[N-])C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of tert-butyl [(1R,2R,3S)-4-azido-3-cyclopropyl-2-hydroxy-1-(hydroxymethyl)butyl]carbamate (0.435 g, 1.45 mmol) in anhydrous pyridine (5 mL) was added 4-dimethylaminopyridine (0.055 g, 0.20 mmol) and para-toluenesulfonyl chloride (0.55 g, 2.8 mmol). After stirring at ambient temperature for 2 h, the reaction mixture was diluted with EtOAc (40 mL) and H2O (3 mL). The layers were separated, the organic layer was washed with H2O (3×3 mL) and the combined aqueous phases were extracted with EtOAc (3 mL). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (40 g silica gel column, eluting with 0-30% EtOAc/hexanes) to afford the sub-title compound (506 mg, 77%). LCMS (ESI) calc. for C15H23N4O4S [M+H-Boc+H]+ m/z=355.2. found 355.1
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][O:24]C(=O)C)[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=O)C>CO.C(=O)([O-])[O-].[K+].[K+].O>[C:29]([O:28][C@H:14]1[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C@:20]1([CH2:23][OH:24])[C:7]([CH2:6][C@@H:5]([OH:4])[CH2:22][CH2:21]1)=[CH:8][CH2:9]3)(=[O:31])[CH3:30]
Reactant: CC(=O)OC[C@]12CC[C@H](OC(C)=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(CO)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-androstene-3β,17β,19-triol triacetate in methanol and potassium carbonate in water is combined and stirred at room temperature for a period of about 2 hours. The solution is poured onto water and the solid which forms is collected by filtration. Crystallization of this solid from an acetone solution yields 5-androstene-3β,17β,19-triol 17-acetate.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:6]([CH2:20][CH2:21][OH:22])[S:7]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][C:11]=2[CH3:19])(=[O:9])=[O:8])[CH2:5][CH2:4]1.Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]([N:30]2[CH2:35][CH2:34][C:33]3([CH2:40][CH2:39][N:38]([C:41]4[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=4)[CH2:37][CH2:36]3)[CH2:32][CH2:31]2)[CH:25]=1.O>O1CCCC1.C(OCC)(=O)C>[CH:3]1([N:6]([CH2:20][CH2:21][O:22][C:24]2[CH:25]=[C:26]([N:30]3[CH2:31][CH2:32][C:33]4([CH2:36][CH2:37][N:38]([C:41]5[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=5)[CH2:39][CH2:40]4)[CH2:34][CH2:35]3)[N:27]=[CH:28][N:29]=2)[S:7]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][C:11]=2[CH3:19])(=[O:9])=[O:8])[CH2:4][CH2:5]1
Reactant: COc1cc(C)c(S(=O)(=O)N(CCO)C2CC2)c(C)c1
Reactant: Clc1cc(N2CCC3(CCN(c4ccncc4)CC3)CC2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(CCOc2cc(N3CCC4(CCN(c5ccncc5)CC4)CC3)ncn2)C2CC2)c(C)c1
Reaction time: 8 h
Yield: 7 %

Procedure:
To a suspension of sodium hydride (7.28 mmol, 10 equiv.) in tetrahydrofuran (10 ml) there was added, at 0° C., N-cyclopropyl-N-(2-hydroxyethyl)-4-methoxy-2,6-dimethylphenylsulfonamide (C-10) (0.8 mmol, 1.1 equiv.), followed by 3-(6-chloro-pyrimidin-4-yl)-9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane (0.73 mmol, 1 equiv.). The reaction mixture was stirrred overnight at room temperature; water was then added and the mixture was diluted with ethyl acetate. The organic phase was extracted with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (Alox-neutral). Yield: 7%. Rt=3.4 min; m/z=607.5 [MH]+
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].[OH:13][CH:14]1[CH2:17][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[CH2:15]1>ClCCl>[CH3:11][S:8]([O:13][CH:14]1[CH2:15][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[CH2:17]1)(=[O:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(O)C2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC(OS(C)(=O)=O)C2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.76 mL (5.49 mmol) of triethylamine and then 0.43 mL (5.49 mmol) of mesyl chloride are added to a solution of 1.52 g (4.99 mmol) of tert-butyl 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate, obtained in step 6.1., in 45 mL of dichloromethane. The reaction medium is stirred at room temperature for 1 hour 30 minutes. After evaporating off the solvent, water is added to the reaction medium, the aqueous phase is separated out and extracted several times with dichloromethane, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, 1.90 g of product are obtained in the form of a brown oil, which is used without further purification in the following step.
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][C:11]2[NH:12][C:13](=[O:19])[N:14]([O:17][CH3:18])[C:15](=[O:16])[C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[CH3:18][O:17][N:14]1[C:15](=[O:16])[C:10]2[CH2:9][NH:8][CH2:21][CH2:20][C:11]=2[NH:12][C:13]1=[O:19]
Reactant: COn1c(=O)[nH]c2c(c1=O)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: COn1c(=O)[nH]c2c(c1=O)CNCC2

Procedure:
6-(tert-Butoxycarbonyl)-3-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione (1.0 g) was suspended in 4 N hydrochloric acid in ethyl acetate (10 ml) and the resultant mixture was stirred at room temperature for 3 hours. The reaction solution was distilled away under reduced pressure. To the residue, methanol was added and the solvent was distilled away under reduced pressure. This was repeated three times to obtain the titled compound (790 mg) as a white powder. The resultant compound was used in a next reaction without further purifying.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1)[C:16]#[N:17].N>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:22]=2)[CH:20]=1)[C:16]#[N:17]
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1cc(Cl)cc(C#N)c1
Agent: N
Product: N#Cc1cc(Cl)cc(-c2cc(-c3cncc(F)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and the product of Example 66A (82 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 8.00 (s, 1H), 8.22 (ddd, J=9.5, 2.7, 1.7 Hz, 1H), 8.26 (dd, J=2.0, 1.4 Hz, 1H), 8.33 (t, J=1.7 Hz, 1H), 8.40 (t, J=1.5 Hz, 1H), 8.79 (d, J=2.7 Hz, 1H), 8.98 (t, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 300 (M+H)+, 302 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12]Br)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][NH:15][CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:15]([CH3:16])[CH3:14])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNC
Reactant: COC(=O)c1ccc(CBr)c(Br)c1
Product: COC(=O)c1ccc(CN(C)C)c(Br)c1
Yield: 70 %

Procedure:
By following essentially the procedure of Example 137, Part B, the title compound was prepared from methyl 3-bromo-4-bromomethylbenzoate (Example 137, Part A) and dimethylamine (40%), in 70% yield. The flash chromatography was carried out by eluting with a gradient of hexanes(100-80%)/EtOAc(0-20%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4].[C:27](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[CH3:27])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Temperature: 60 °C
Yield: 100 %

Procedure:
To 2-(4-Fluoro-phenyl)-5-iodo-6-methanesulfonylamino-furo[2,3-b]pyridine-3-carboxylic acid methylamide (9 mg, 0.018 mmol) and potassium carbonate (25.4 mg, 0.184 mmol) in acetone (0.1 ml) is added iodomethane (0.115 ml, 1.840 mmol). After heating at 60° C. for 1 day, the reaction mixture is filtered and concentrated to dryness to afford 2-(4-Fluoro-phenyl)-5-iodo-6-(methanesulfonyl-methyl-amino)-furo[2,3-b]pyridine-3-carboxylic acid methylamide (9.3 mg, 0.018 mmol, 100% yield). MS (ESI) m/z 503.9 (M+1). 1H NMR (400 MHz, CD3CN) δ ppm 8.60 (s, 1H), 7.95 (m, 2H), 7.23-7.18 (m, 2H), 6.79 (br s, 1H), 3.14 (s, 3H), 2.80-2.79 (d, 3H).
Reaction SMILES: N12CCN(CC1)CC2.OO.[N:11]12[CH2:18][CH2:17][N+:14]([O-:19])([CH2:15][CH2:16]1)[CH2:13][CH2:12]2.[F:20][B-:21]([F:24])([F:23])[F:22].[Na+].[F:26][B-:27]([F:30])([F:29])[F:28].[H+].[F:32]F>C(#N)C>[N:11]12[CH2:18][CH2:17][N+:14]([O-:19])([CH2:15][CH2:16]1)[CH2:13][CH2:12]2.[F:20][B-:21]([F:24])([F:23])[F:22].[F:26][B-:27]([F:30])([F:29])[F:28].[OH:19][N+:14]12[CH2:17][CH2:18][N+:11]([F:32])([CH2:16][CH2:15]1)[CH2:12][CH2:13]2
Reactant: FF
Agent: C1CN2CCN1CC2
Agent: F[B-](F)(F)F
Agent: OO
Solvent: CC#N
Product: O[N+]12CC[N+](F)(CC1)CC2
Yield: 38 %

Procedure:
1,4-Diazabicyclo[2.2.2]octane N-oxide was prepared by the reaction of 1,4-diazabicyclo[2.2.2]octane with hydrogen peroxide as described by Farkas in J. Chem. Eng. Data (1968) 13,278. A solution of 1,4-diazabicyclo[2.2.2]octane N-oxide (1.28 g, 10 mmole), sodium tetrafluoroborate (1.1 g, 10 mmole), and tetrafluoroboric acid (50% solution, 1.83 g, 10 mmole) in acetonitrile (250 mL) was cooled to -35° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 14 mmole). The reaction was evaporated, the remaining solid washed with acetone and dried to afford 1.23 grams of 1-hydroxyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate) (38% yield); m.p. 336-8° C.; 1H NMR (D2O): d 5.0 (m, 6H), 4.6 (m, 6H); 13C NMR (D2O): d 61.6 (d, J=15.5 Hz), 62.3 (d, J=6.2 Hz); 19F (D2O): d 41 (1F), -150 (8 F); 15(D2): d -207.5 (d, J=84 Hz), -275.9. Anal. Calcd for C6H13B2F9N2O: C, 22.40; H 4.07; N, 8.70; B, 6.72. Found: C, 22.69; H, 4.25; N, 8.80; B, 6.39.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[C:16]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:10][C@H:9]1[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]2[C:16]3[C:15]([O:14][C@@H:11]4[CH2:12][CH2:13][NH:8][C@H:9]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH2:10]4)=[N:20][CH:19]=[N:18][C:17]=3[O:21][C:22]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@@H]4CCN(C(=O)OC(C)(C)C)[C@H](CCC(=O)O)C4)c23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@@H]4CCN[C@H](CCC(=O)O)C4)c23)cc1

Procedure:
Stir 34 mg of 3-[(2R,4R)-1-(tert-butoxycarbonyl)-4-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-2-yl]propanoic acid in approx. 0.1 ml of a 3:2 mixture of trifluoroacetic acid and dichloromethane at RT for 30 min. Then remove the volatile components under reduced pressure and dry the residue under high vacuum. Take up the residue in acetonitrile/water and neutralize with 1N sodium hydroxide solution (pH approx. 7). Filter off the precipitated colourless solid with suction, wash twice with water and twice with acetonitrile and dry under high vacuum. 20 mg (71.3% of theory) of the target compound are obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[NH:12][C:11]([O:22][CH3:23])=[N:10][C:9]=1[CH2:24][O:25][CH3:26])=[O:7])#[N:2].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:29]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[N:12]([C:28]([O:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:29])[C:11]([O:22][CH3:23])=[N:10][C:9]=1[CH2:24][O:25][CH3:26])=[O:7])#[N:2]
Reactant: COCC1=C(C(=O)OCCC#N)C(c2ccc(F)c(F)c2)NC(OC)=N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCC1=C(C(=O)OCCC#N)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Yield: 67.3 %

Procedure:
To a well stirred solution of (+)-5-(2-cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine (0.82 g, 2.24 mmol) and 4-(N,N-dimethylamino)pyridine (0.329 g, 2.69 mmol) in CH2Cl2 (200 mL) was added a powder of 4-nitrophenyl chloroformate (0.543 g, 2.69 mmol) at room temperature. The solvent was evaporated and the residue was purified by column chromatography on silica gel using dichloromethane/hexane (20%-50%) as the eluent to give (+)-5-(2-cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl] pyrimidine (0.80 g, 67%) as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)(=[O:18])=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:25][C:21]1[CH:20]=[C:19]([S:16]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)(=[O:17])=[O:18])[CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCCCCCNc2nc(Cl)ncc2Br)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(S(=O)(=O)NCCCCCNc2nc(Cl)ncc2Br)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 300 mg (0.63 mmol) of N-[5-(5-bromo-2-chloro-pyrimidin-4-ylamino)-pentyl]-3-nitro-benzenesulfonamide in 6 ml of ethanol is mixed with 600 mg of tin(II) chloride and stirred for 30 minutes at 70° C. After cooling, the reaction mixture is carefully added to ice water and made basic with saturated NaHCO3 solution. It is extracted with ethyl acetate (3×). The combined organic phases are dried (Na2SO4), filtered, and concentrated by evaporation. The remaining residue is purified by chromatography (ethyl acetate/hexane 4:1). 112 mg (0.25 mmol, corresponding to 40% of theory) of the product is obtained.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O[C:16]([CH3:27])([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:17]>CS(O)(=O)=O>[CH3:17][C:16]1([CH3:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(O)CCCc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1(C)CCCc2ccccc21
Temperature: 105 °C
Yield: 89.9 %

Procedure:
A mixture of P2O5 (55.3 g, 0.390 mol) in 400 ml of methanesulfonic acid was heated to 105° C. under argon until all of the solid had dissolved. The resulting solution was cooled to room temperature and 2-hydroxy-2-methyl-5-phenylpentane (63.0 g, 0.354 mol) added slowly with stirring. After 4 hours the reaction was quenched by carefully pouring the solution onto 1 L of ice. The resulting mixture was extracted with Et2O (4×125 ml) and the combined organic layers washed with water, saturated aqueous NaHCO3, water, and saturated aqueous NaCl before being dried over MgSO4. Concentration of the solution under reduced pressure, followed by distillation afforded 51.0 g (90%) of the product as a clear colorless oil, bp. 65°-67° C./1.1 mmHg. 1H NMR (CDCl3): δ7.32 (1H, d, J=7.4 Hz), 7.16-7.05 (3H, m), 2.77 (2H, t, J =6.3 Hz), 1.80 (2H, m), 1.66 (2H, m), 1.28 (6H, s).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[S:18][C:17]([CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1.[OH-].[Na+].O>CS(C)=O>[OH:25][CH:19]([C:17]1[S:18][C:14]([CH2:13][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:15][CH:16]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Oc1ccnc2ccccc12
Reactant: CCCCCC(O)c1ccc(CBr)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(O)c1ccc(COc2ccnc3ccccc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a well-stirred solution of 4-hydroxyquinoline (2 g, 0.014 mol) and 5-bromomethyl-2-(1-hydroxyhexyl)thiophene (3.82 g, 0.014 mol) in DMSO (50 ml) was added a 2N solution of sodium hydroxide (8 ml, 0.016 mol). The mixture became warm immediately. This clear solution was stirred overnight at room temperature, and then was poured into water (200 ml). The aqueous solution was extracted thoroughly with ethyl acetate (4×30 ml). The organic extract was washed with water and brine, and then dried over MgSO4. All volatiles were removed, and the crude product was purified chromatographically (silica gel; 15% ethyl acetate in hexane) to yield 2.1 g (44%) of the pure product.