Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:32])[C:13]=2[NH:17][C:18](=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=2)[C:8]1=[O:33])(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.CO>[Cl:32][C:12]1[C:13]([NH:17][C:18](=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:29])([F:30])[F:28])[CH:21]=2)=[C:14]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:33])[N:7]([CH2:6][CH2:5][OH:4])[CH:16]=[CH:15]2
Reactant: CC(=O)OCCn1ccc2c(NC(=O)Cc3ccc(F)c(C(F)(F)F)c3)c(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Cc1ccc(F)c(C(F)(F)F)c1)Nc1c(Cl)ccc2c(=O)n(CCO)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask was charged with 2-(6-chloro-5-(2-(4-fluoro-3-(trifluoromethyl)phenyl)acetamido)-1-oxoisoquinolin-2(1H)-yl)ethyl acetate (80.0 mg, 0.000165 mol), potassium carbonate (34.2 mg, 0.000248 mol), methanol and 2 drops of water and the reaction stirred for 20 minutes at room temperature. The reaction was then filtered over sodium sulfate and celite and washed with methanol. The solvent was removed and the residue purified by preparative HPLC (reverse phase) to obtain the product as a pale yellow solid. MS m/z=443.3 (M+H) 1H NMR (400 MHz; DMSO-d6) δ 10.18 (s, 1H), 8.15 (d, J=8.81 Hz, 1H), 7.82 (d, J=6.7 Hz, 1H), 7.77-7.74 (m, 1H), 7.59 (d, J=8.81 Hz, 1H), 7.52 (t, J=9.52 Hz, 1H), 7.46 (d, J=7.40 Hz, 1H), 6.40 (d, J=7.59 Hz, 1H), 4.88 (t, J=5.0 Hz, 1H), 4.00 (t, J=5.55 Hz, 2H), 3.89 (s, 2H), 3.65 (q, J=5.55 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3c(F)cccc3F)cc2)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3c(F)cccc3F)cc1)nn2C[C@H]1CCCN1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of tert-butyl (2R)-2-([4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)-pyrrolidine-1-carboxylate (280 mg, 0.54 mmol, 1.00 equiv) in dichloromethane (10 mL). Trifluoroacetic acid (2 mg, 0.02 mmol, 0.03 equiv) was added dropwise with stirring at 25° C. The resulting solution was stirred for 3 h at 25° C. and then concentrated under vacuum. The resulting solution was diluted with 50 mL of dichloromethane, washed with ethyl acetate and H2O, brine and concentrated under vacuum to give 200 mg (88%) of 3-[4-(2,6-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][N:12]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
NaH (37 mmol, 2 equiv.) was taken up in DMF (25 ml) and cooled to 0° C. 6-Nitro-1H-indole (18.5 mmol, 1 equiv.) was added in portions, and the mixture was stirred for 1 h at 25° C. The reaction mixture was cooled to 0° C. again, ethyl bromoacetate (22.22 mmol, 1.2 equiv.) was added dropwise, and the mixture was stirred for 2 h at 25° C. The reaction mixture was then poured into ice-water and extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with sat. NaCl solution (30 ml), dried over Na2SO4 and concentrated under reduced pressure. The product was crystallized from hexane and was used in the next step without being purified further. Yield: 57%
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:7])[CH2:5][CH3:6])[NH2:3].O=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:4](=[O:7])[CH2:5][CH3:6])[N:3]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCC(=O)N(C)N
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=NN(C)C(=O)CC)C(=O)OCC
Yield: 49 %

Procedure:
A solution of N-methylpropionohydrazide (18.78 g, 183.9 mmol) and diethyl ketomalonate: (56.1 mL, 368 mmol) in toluene (136 mL) was refluxed with a Dean-Stark trap for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 5 to 10% EtOAc in hexanes) to afford 23 g (49%) of the desired product.
Reaction SMILES: [OH:1][CH:2]([CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]1)[CH2:3][O:4][C:5]1[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:29]([Cl:35])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].N1C=CC=CC=1>C(Cl)(Cl)Cl>[ClH:35].[C:29]([O:1][CH:2]([CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:20]1)[CH2:3][O:4][C:5]1[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OC(COc1cccc2nc[nH]c12)CN1CCC(COc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC(COc1cccc2nc[nH]c12)CN1CCC(COc2ccccc2)CC1
Product: Cl

Procedure:
3.8 g. 4-[2-Hydroxy-3-(4-phenoxymethylpiperidino)-propoxy]-benzimidazole and 1.3 g. pivaloyl chloride are boiled under reflux for 2 hours in 25 ml. pyridine. After stripping off the solvent, the residue is taken up in 100 ml. chloroform. The chloroform solution is thoroughly washed with water, dried over anhydrous sodium sulphate and finally mixed with 50 ml. ethereal hydrochloric acid. After evaporation and recrystallization from ethanol, there is obtained 4-[2-pivaloyloxy-3-(4-phenoxymethylpiperidino)-propoxy]-benzimidazole hydrochloride; m.p. 132°-134° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@@H:8]3[CH2:9][C:10]([CH3:25])([CH3:24])[O:11][CH2:12]4)[CH2:4][CH2:3]1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C(Cl)Cl>[C:26]([O:21][C:16]1[CH:17]=[CH:18][C:19]2[CH2:20][C@H:7]3[N:6]([CH2:5][CH:2]4[CH2:4][CH2:3]4)[CH2:23][CH2:22][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][C:10]([CH3:25])([CH3:24])[O:11][CH2:12]4)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC1(C)C[C@H]2[C@H]3Cc4ccc(O)cc4[C@@]2(CCN3CC2CC2)CO1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@@H]1CC(C)(C)OC3

Procedure:
Equimolar amounts of 17-cyclopropylmethyl-7,7-dimethyl-3-hydroxy-6-oxamorphinan (XIV, prepared in Example 5), acetyl chloride and pyridine are mixed together in dry methylene chloride and heated at reflux temperature for 3 hours to produce the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:29][C:28]([N:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)=[N:27][N:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][N:26]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N2C[C@@H](CC[C@H]2c2nnc(N3CCNCC3)o2)N1OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 172.9 %

Procedure:
CF3COOH (5 mL) was slowly added at 0° C. to a solution of tert-butyl 4-(5-((2S,5R)-6-(benzyl-oxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)piperazine-1 carboxylate (723 mg, 1.5 mmol) in DCM (20 mL). The mixture was stirred at 0° C. for 3 hrs, then, the solvent was concentrated to afford (2S,5R)-6-(benzyloxy)-2-(5-(piperazin-1-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (997 mg) as a brown oil, which was used directly in the next step. ESI-MS (EI+, m/z): 385.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[C:20]([Cl:21])[C:15]=3[C:14](=[O:23])[N:13]([CH3:24])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>C(O)(=O)C>[Cl:21][C:20]1[C:15]2[C:14](=[O:23])[N:13]([CH3:24])[CH2:12][C:11]3[N:10]([CH:9]=[N:8][C:7]=3[C:5]3[O:6][C:2]([CH2:3][N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[CH:1][N:4]=3)[C:16]=2[CH:17]=[CH:18][C:19]=1[F:22]
Reactant: CCCNCCC
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1c-2ccc(F)c1Cl
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2c-3ccc(F)c2Cl)o1
Temperature: 25 °C
Reaction time: 53 h
Yield: 24.7 %

Procedure:
A solution of 3.49 g (0.010 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide in 200 ml of acetic acid was treated with 3.38 g (0.0151 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 53 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The red-brown residue was dissolved in 100 ml of THF, treated with 11.9 ml (0.087 mol) of dipropylamine and stirred at room temperature for 16 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the yellow-brown product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 17:3 as the eluent. There were obtained 1.1 g (25%) of 7-chloro-3-(5-dipropylaminomethyl-oxazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as a yellow foam. A sample was recrystallized from isopropyl ether; m.p. 110-112°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C:13](O)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:31][NH2:32]>C(Cl)Cl>[OH:31][NH:32][C:13](=[O:14])[CH2:12][CH:11]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)ON
Reactant: O=C(O)CC(CCCCc1ccccc1)Sc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(CC(CCCCc1ccccc1)Sc1ccccc1)NO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7-Phenyl-3-phenylsulfanylheptanoic acid (2 g; 6.5 mmol) is dissolved in CH2Cl2 (20 mL) and cooled to 0° C. Oxalyl chloride (1.1 mL, 13 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 20° C. for 2 hours. The reaction is then concentrated in vacuo and azeotroped with CH2Cl2. The resulting oil is dissolved in CH2Cl2 (20 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (1.7 g, 16 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (100 mL) and 1 N HCl (50 mL), the organic layer is then separated and washed with water (40 mL), dried (MgSO4) and concentrated in vacuo to yield 7-phenyl-3-phenylsulfanylheptanoic acid hydroxyamide.
Reaction SMILES: [OH-].[Na+].C=O.[CH3:5]CCCCC.[CH3:11][C:12]1[C:16]([CH3:18])([CH3:17])[CH:15]([CH2:19][CH:20]=[O:21])[CH2:14][CH:13]=1>CO.O>[CH3:18][C:16]1([CH3:17])[C:12]([CH3:11])=[CH:13][CH2:14][CH:15]1[C:19](=[CH2:5])[CH:20]=[O:21]
Reactant: CC1=CCC(CC=O)C1(C)C
Reactant: CCCCCC
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C(C=O)C1CC=C(C)C1(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 215.6 %

Procedure:
A 3 liter 3 neck round bottomed flask was charged with 50 g of sodium hydroxide (1.25 moles) in 250 g of methanol. 200 g of paraformaldehyde, 500 g of hexane and 2.5 g of BHA were added and the flask was cooled to 0° C. With fast agitation 500 g of campholenic aldehyde at a purity of 88.9% (2.92 moles) were added dropwise over 70 minutes keeping the temperature at 0°-5° C. The batch was stirred for 3 hours at 0° C. Then 50 ml of water was added and the layers are separated. The water layer was back extracted with 250 ml of hexane. The hexane extracts were combined and washed with 2×500 ml of 10% sodium hydroxide and 3×500 ml of water. The batch was dried and afforded 1163 g of crude 2-(2,2,3-trimethylcyclopent-3-en-1-yl)propenal in hexane. A second batch was prepared analogously affording 1169 g of crude product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7]2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH2:25][C:26]([N:1]1[CH2:6][CH2:5][C:4]2([C:10]3[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:7]2)[CH2:3][CH2:2]1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: c1ccc2c(c1)COC21CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCl)N1CCC2(CC1)OCc1ccccc12
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
3H-spiro[2-benzofuran-1,4′-piperidine] (5 g, 26 mmol) was dissolved in THF (100 mL) and cooled in ice. Then N-ethyldiisopropylamine (4.94 mL, 29 mmol) and chloroacetyl chloride (2.31 mL, 29 mmol) were added. The mixture was stirred at 20° C. for 15 min. The solid was filtered off and washed with THF. The filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica gel with heptane/AcOEt 70:30. One obtained light yellow crystals (6.5 g, 92%). MS: m/z=266 [M+H]+.
Reaction SMILES: [CH2:1]([P:5]([CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH2:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])[CH:2]([CH3:4])[CH3:3].[CH2:18]([Cl:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[Cl-:30].[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][CH2:6][P+:5]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH3:17])([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CP(CCCN(C)C)CCCN(C)C
Reactant: CCCCCCCCCCCCCl
Product: CCCCCCCCCCCC[P+](CCCN(C)C)(CCCN(C)C)CC(C)C
Product: [Cl-]
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A magnetically stirred mixture of 15.6 g (0.06 mole) of i-butyl bis-(dimethylaminopropyl) phosphine of Example 10 and 12.3 g (0.06 mole) of n-dodecyl chloride was heated under nitrogen to 130° C. and then kept there for 24 hours. The nmr spectrum of a sample of the heated mixture showed a substantial selective quaternarization of the t-phosphine moiety. Accordingly, the crude mixture was heated at 150° C. at 0.2 mm. to distill off the volatile unreacted compounds and to obtain the residual product, i.e. bis-(3-dimethylaminopropyl) dodecyl i-butyl phosphonium chloride. The product weighed 23 g, 82% of the calculated yield, and hardened to a wax like solid at room temperature. Nmr indicated that quaternarization occurred at the phosphine group.
Reaction SMILES: [F-:1].[Cs+].Cl[C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>CN(C)C=O>[F:1][C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: [F-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 110 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Cesium fluoride (499.02 g, 3.19 mol) was added into a flask equipped with a stirrer under a nitrogen gas stream, and was agitated for one hour at 110° C. Methyl 2-chloro-3-nitrobenzoate (229.00 g, 1.06 mol) and N,N-dimethylformamide (2000 ml) were added thereto, and the reaction mixture was agitated for one hour at 140° C. The reaction mixture was naturally cooled to room temperature, and then was filtered, and the filtrate was concentrated under reduced pressure. The concentration residue was poured into water and agitated for a while, and then a solid that precipitated was collected by filtration and dried under reduced pressure. As a result, 160.03 g (yield: 76%) of the indicated compound was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CN1CCOCC1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>O1CCCC1>[CH2:34]([O:33][C:31]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:32])[CH3:35]
Reactant: CCCCCCCCCCCCCCCC(=O)NCCCO
Reactant: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)NCCCOC(=O)OCC

Procedure:
3.14 g of N-(3-hydroxypropyl) hexadecanamide (10 mmoles) was suspended in 75 ml of tetrahydrofuran (THF) at 45° C. with stirring. 1.11 g of N-methylmorpholine (11 mmoles) and 1.19 g of ethyl chloroformate (11 mmoles) were added and the resulting mixture was stirred for a further 3 hours at ambient temperature. The mixture was then evaporated to dryness under vacuum. The residue was taken up with 50 ml of water and extracted 3 times with 30 ml of ethyl acetate; the organic phases were washed twice with 20 ml of water, recombined and evaporated to dryness. The residue was crystallized from 30 ml of tert-butylmethyl ether. The crystallizate was separated by filtration, washed twice with 5 ml of cold tert-butylmethyl ether and finally dried in a high degree of vacuum. The yield of the reaction was 92%.
Reaction SMILES: [CH:1]1(O)[CH2:5][CH2:4][CH:3]=[CH:2]1.[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:1]2[CH2:5][CH2:4][CH:3]=[CH:2]2)=[C:10]([Cl:17])[N:9]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: OC1C=CCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncn(C3C=CCC3)c2n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 40.6 %

Procedure:
Add to a stirred solution of 2-cyclopenten-1-ol (2c 2.60 g, 30.9 mmol), 2,6-dichloropurine (1, 7.00 g, 37.0 mmol) and triphenyl phosphine (9.70 g, 37.0 mmol) in dry THF (120 ml) at 0° C., diethyl azodicarboxylate (5.85 ml, 37.0 mmol) dropwise over a period of 15 min. under a nitrogen atmosphere. Stir the resulting solution for 60 hrs at room temperature. Concentrate the reaction mixture, charge the residue directly onto a silica gel column and elute with hexane:ethyl acetate (3:1) to give of 2,6-dichloro-9-cyclopent-2-enyl-9H-purine (3c) (3.20 g, 41%.)
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[F:26][C:27]([F:35])([F:34])[CH2:28][CH2:29][C:30]([NH:32][OH:33])=N>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:33][N:32]=[C:30]([CH2:29][CH2:28][C:27]([F:35])([F:34])[F:26])[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N=C(CCC(F)(F)F)NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(CCC(F)(F)F)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and 4,4,4-trifluoro-N-hydroxy-butyramidine following a procedure analogous to that described in Example 1. LC (method 8): tR=1.30 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][OH:34])[N:18]=[C:17]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:42].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:16]=[C:17]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[N:18]=[C:19]([O:30][CH2:31][CH2:32][C:33]([OH:42])=[O:34])[C:20]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCCO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Yield: 15.6 %

Procedure:
4-t-Butyl-N-[6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyl]-benzenesulfonamide (800 mg) was dissolved in dimethylformamide (40 ml). Pyridinium dichromate (2.63 g) was added to the solution, and the resultant mixture was stirred for 14 hours at room temperature. Ethyl acetate was added to the reaction mixture, followed by successive washing with 0.5N-HCl, water, and brine. The organic layer was dried over anhydrous sodium sulfate and, evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=25:1), to thereby obtain 128 mg (yield: 16%) of the title compound as a white powder.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28]C)=[O:27].O.[OH-].[Li+]>O1CCCC1.O>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([OH:28])=[O:27]
Reactant: COC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a solution of methyl 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate (2.80 g, 6.5 mmol) in tetrahydrofuran (30 mL) and water (10 mL) was added lithium hydroxide monohydrate (0.82 g, 19 mmol). The reaction mixture was stirred at ambient temperature for 16 h. Most of the tetrahydrofuran was removed in vacuo and the resultant solution was washed with diethyl ether (2×50 mL). The aqueous phase was rendered acidic to litmus by the addition of 1 M hydrochloric acid and extracted with ethyl acetate (3×50 mL). The combined organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether (50 mL) and the solid was collected by vacuum filtration, washed with diethyl ether (20 mL), air-dried and dried under high vacuum to afford 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (2.20 g, 81%) as a colorless solid: mp>250° C. (water); 1H NMR (300 MHz, DMSO-d6) 13.06 (br s, 1H), 7.89-7.82 (m, 2H), 7.66 (d, J=7.6 Hz, 1H), 7.55-7.47 (m, 1H), 7.29-7.16 (m, 2H), 7.07-6.96 (m, 2H), 6.49 (s, 1H), 6.42 (s, 1H), 5.17-4.72 (m, 4H), 4.55-4.45 (m, 2H), 3.06-2.88 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.2, 167.1, 161.2, 160.7, 142.0, 136.9, 132.2, 131.8, 131.2, 129.1, 128.8, 128.4, 127.3, 123.8, 123.2, 120.5, 120.0, 118.9, 109.3, 92.5, 79.7, 72.1, 57.0, 42.5; MS (ES+) m/z 414.0 (M+1).