Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:10][C:9]=1[C:19]([O:21]C)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:10][C:9]=1[C:19]([NH2:2])=[O:21])[CH3:5]
Reactant: [NH4+]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N=NN(C)C
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1cc(-c2ccccc2)sc1C(N)=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 8 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (80 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]-5-phenylthiophene-2-carboxylate (2.2 g) in THF (15 mL) for 5 min followed by catalytic amount of PEG-400 and the mixture was stirred at rt for 36 h. The solution was poured into ice cooled water and extracted with chloroform. The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (94:6) as eluents to give the product. The crude product was recrystallized from chloroform-hexane to give the product as a yellow color solid (170 mg, 8%), mp 220-222° C. IR (neat) νmax, 3343, 2922, 2855, 1642, 1595, 1221, 1023, 880, 841 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.30 (1H, br s), 7.64-7.66 (2H, m), 7.53 (1H, s), 7.30-7.41 (3H, m), 6.34 (1H, br s), 3.59 (3H, s), 3.20 (3H, s); 13C NMR (100 MHz, CDCl3): δ 164.7, 151.1, 146.7, 133.9, 128.9, 128.5, 125.8, 125.4, 114.7, 43.6, 36.5; LC-MS (positive ion mode): m/z 297 (M+Na)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:21]=1)[CH2:10][O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])([O:3][CH3:4])=[O:2].[Br:22]Br>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:21]=1)[CH2:10][O:11][CH:12]([Br:22])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc(COCC(=O)c2ccccc2)c1
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1cccc(COC(Br)C(=O)c2ccccc2)c1

Procedure:
g 20 of 5-carbomethoxy-2-benzyloxy-acetophenone, m.p.=86°-88° C. dissolved in methylene chloride (ml 200) were reacted with bromine (9.8 g) at 10° C. for 15 minutes. After treatment with 10% sodium sulphite and water, the organic phase was evaporated to dryness. The residue, crystallized from isopropyl ether, gave 5-carbomethoxy-2-benzyloxy-ω-bromo-acetophenone (17 g), m.p.=84°-86° C., which was dissolved in dimethylformamide (85 ml) and reacted with anhydrous potassium acetate (5.6 g) at 50° C. for 2 hours. After cooling, and dilution with water, the precipitate was filtered and washed with cold methanol so obtaining 5-carbomethoxy-2-benzyloxy-ω-acetoxy-acetophenone (12.9 g), m.p.=86°-87° C., which was dissolved in tetrahydrofuran (40 ml) and ethanol (20 ml); few drops of concentrated HCl were added and then the solution was hydrogenated at atmospheric pressure and room temperature in the presence of 5% Pd/C (2.5 g) to the theoretical hydrogen consumption. The mixture was filtered to remove the catalyst and the organic solution was evaporated to dryness so obtaining crude 5-carbomethoxy-2-hydroxy-ω-acetoxy-acetophenone (9.2 g), which was dissolved in dioxane (20 ml) and pyridine (10 ml) and reacted with trans-cinnamoyl-chloride (9.4 g) at room temperature for 8 hours. The reaction mixture was diluted with water and acidified to pH 4. The precipitate was filtered, dried and dissolved in methyl-ethyl-ketone (100 ml); anhydrous K2CO3 (9.3 g) was added and the mixture was vigorously stirred under reflux for 5 hours.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[CH3:11][O:12][C:13](=[O:34])[CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:34])[CH2:14][C:2]1[O:1][C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1Cc2ccccc2O1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc2ccccc2o1
Reaction time: 5 h

Procedure:
A solution of 2-coumaranone (5.0 g, 37 mmol) and methyl(triphenylphosphoranylideneacetate) (13.5 g. 40 mmol) in toluene (70 mL) was heated to reflux for 25 hours. More toluene was added (10 mL), and after a further 5 hours, more methyl(triphenylphosphoranylideneacetate) (0.5 g, 1.5 mmol). After another 19 hours, a further 1.0 g (3.0 mmol) was added, and after a further 21 hours, the solvent was removed in vacuo. Column chromatography (heptane:ethyl acetate 4:1) gave the product as a brown oil, 28 mmol, 75%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[CH2:5][O:6][C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:9][NH2:10])[CH3:2].C(N(CC)CC)C.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>C(Cl)Cl>[CH2:24]([O:23][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][O:6][C:7]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:9][NH:10][C:36]([CH:33]1[CH2:35][CH2:34]1)=[O:37])[CH3:25]
Reactant: CCOC(COC(CCN)(c1ccccc1)c1ccccc1)OCC
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(COC(CCNC(=O)C1CC1)(c1ccccc1)c1ccccc1)OCC
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows. The solution of 3.4 g of 2-(3-amino-1,1-diphenylpropoxy)-acetaldehye diethyl acetal, 1.5 g of triethylamine and 35 ml of methylene chloride is stirred and cooled in an ice bath during the dropwise addition of the solution of 1.05 g of cyclopropane carboxylic acid chloride in 15 ml of methylene chloride. Upon stirring subsequently for 1/2 hour at 0°-5° C, the solution is washed successively with 2N aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated, to yield the 2-(3-cyclopropylcarbonylamino-1,1-diphenylpropoxy)-acetaldehyde diethyl acetal.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O.[H][H]>C(O)C.[Pd]>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:16]=[CH:15][CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A stirred solution of 4-(3-nitrobenzyl)morpholine (1.0 g, Reference Example 33) in ethanol (25 mL) was treated with 5% Pd/C (15 mg), then placed under a blanket of hydrogen. After stirring at room temperature for a further 2 hours the reaction mixture was filtered through celite and then evaporated. The residue was subjected to column chromatography on silica eluting with ethyl acetate to give the title compound (700 mg) as a light brown oil, Rf 0.08 (ethyl acetate). 1H NMR [(CDCl3]: δ 7.09 (t, 1H), 6.73–6.67 (m, 2H), 6.58 (d, 1H), 3.84–3.45 (t and bs overlapping, 6H), 3.41 (s, 2H) and 2.45 (t, 4H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[O:30][N:29]=1.CC#N>CCOC(C)=O>[F:19][C:2]([F:1])([F:18])[C:3]1[N:4]([CH2:27][C:28]2[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=3)[O:30][N:29]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:14])([F:15])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc2c(cc(C(F)(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 75 °C
Reaction time: 18 h
Yield: 61.7 %

Procedure:
A mixture of 2,4-bis(trifluoromethyl)-1H-indole-5-carbonitrile (0.050 g, 0.18 mmol), Cs2CO3 (0.064 g, 0.20 mmoL), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.052 g, 0.20 mmoL) and CH3CN (4 mL) was stirred at 75° C. for 18 h. The mixture was diluted with EtOAc (25 mL) and washed with water (15 mL) and brine (15 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 0-30% EtOAc in hexanes) to afford the title compound (0.056 g, 62%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J=8.8 Hz, 1H), 8.29 (d, J=8.8 Hz, 1H) 8.23 (s, 1H), 8.09-8.06 (m, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.48 (s, 1H), 6.03 (s, 2H); MS m/z 527 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[N:28][NH:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=[N+]([O-])c1cccc(NN=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A solution of 4,4′-dichlorobenzophenone (0.38 g, 1.5 mmol) was added to a solution of 3-nitrophenylhydrazine hydrochloride (0.43 g, 2.25 mmol), concentrated sulfuric acid (0.3 mL) in 10 mL of methanol at 50° C. It was stirred at 50° C. for additional 2 h. The reaction mixture was concentrated to ¼ of its original volume and diluted with 20 mL of water. The precipitates were separated by filtration and washed with 3% aqueous NaHCO3 and water. The crude product was recrystallized from ethanol to give 0.46 g (81% yield) of the desired compound as a yellow needle, mp 170-172° C. 1H NMR (300 MHz, d6-DMSO): δ7.35 [d, 2H, J=7.7 Hz, Ar—H], 7.37-7.49 [m, 5H, Ar—H], 7.58 [d, 1H, J=8.4 Hz, Ar—H], 7.64 [d, 2H, J=8.4 Hz, Ar—H], 7.69 [d, 1H, J=8.4 Hz, Ar—H], 8.02 [s, 1H, Ar—H], 9.63 [s, 1H, NH].
Reaction SMILES: [C:1]1([C:7]2[C:11]([N+]([O-])=O)=[N:10][O:9][N+:8]=2[O-:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18].C(N(CC)CC)C>CO>[C:1]1([C:7]2[C:11]([S:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])=[N:10][O:9][N+:8]=2[O-:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CS
Reactant: O=[N+]([O-])c1no[n+]([O-])c1-c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CSc1no[n+]([O-])c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4.6 g of 3-phenyl-4-nitrofuroxan, 2.4 g of methyl thioglycolate and 2.2 g of triethylamine in 50 ml of methanol is stirred under a nitrogen atmosphere. In the course of this, the mixture warms to about 40° C. After 1 hour, it is poured into ice-water, whereupon a solid separates after stirring briefly, which is filtered off with suction and recrystallised from isopropanol.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[S:16][CH:17]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[CH:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[S:16][CH:17]=1)=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a cold (−50° C.) suspension of methyltriphenylphosphonium bromide (1.2 g, 3.3 mmol) in tetrahydrofuran (5 mL) was added a solution of sodium bis(trimethylsilyl)-amide (3.4 mL, 3.4 mmol), and the resulting mixture was stirred for 1 h at room temperature. The resulting cloudy yellow solution was re-cooled to −30° C., and 1,1-dimethylethyl 4-(4-formyl-2-thiazolyl)-1-piperidinecarboxylate (0.5 g, 1.68 mmol) was added. The resulting slightly yellow solution was stirred at room temperature for 3 h, then diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and purified by column chromatography on silica gel using 15-30% ethyl acetate in hexanes as eluant to give 471 mg of the title compound as a colorless oil.
Reaction SMILES: B(F)(F)[F:2].N[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([Br:16])[CH:12]=[CH:11]2.C(ON=O)(C)(C)C>C1COCC1.C(COC)OC>[Br:16][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[C:6]([F:2])[CH:7]=[CH:8][CH:9]=2)[CH:14]=1
Reactant: FB(F)F
Reactant: Nc1cccc2ccc(Br)cc12
Agent: CC(C)(C)ON=O
Solvent: COCCOC
Solvent: C1CCOC1
Product: Fc1cccc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of BF3-etherate (0.86 ml, 1.25 M in THF, 6.5 mmol) in 12 ml dimethoxyethane was added at −5° C. a solution of 8-amino-2-bromo-naphthalene (1.20 g, 5.4 mmol) in dimethoxyethane (12 ml) over a periode of 35 min. After 1 hour a solution of tert-butylnitrite (0.62 ml, 5.4 mmol) in dimethoxyethane (24 ml) was added and the mixture was stirred for two hours at r.t. and the solvent was removed under reduced pressure. Chlorbenzene (120 ml) was added and the reaction mixture was refluxed for 50 min and the mixture was concentrated. The solid was diluted in methylene chloride and washed with NaHCO3. The organic phase was dried over MgSO4, filtered and reduced to give the crude product. Chromatography on silica gel (hexane) afforded 721 mg (59%) of the product as a brown oil. MS: m/e=242 (M+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>CN(C)C=O>[CH:35]1([CH2:38][N:14]2[C:15]3[C:20](=[CH:19][C:18]([C:22]([N:24]4[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]4)=[O:23])=[CH:17][CH:16]=3)[CH:21]=[C:13]2[C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[O:12])[CH2:37][CH2:36]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC5(CC4)OCCO5)cc3c2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC4(CC2)OCCO4)n3CC2CC2)CC1
Yield: 76 %

Procedure:
The title compound was synthesized in analogy to example 51, from (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 196), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (76%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1Cl
Yield: 94.6 %

Procedure:
0.2 g (0.00105 mol) of 1-benzyl-4-hydroxypiperidine and 0.26 ml (0.00184 mol) of triethylamine were dissolved in 10 ml of toluene and treated with 0.11 ml (0.00084 mol) of 2-chloro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.262 g (95%) of 1-benzyl-piperidin-4-yl 2-chloro-benzoate was obtained as white crystals; m.p. 143°-144°.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1.C(N(CC)CC)C.[O:17](S(C(F)(F)F)(=O)=O)[S:18]([C:21]([F:24])([F:23])[F:22])(=O)=[O:19]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[S:18]([O:1][C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1)(=[O:19])=[O:17]
Reactant: CC1(C)OC(=O)C=C1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)C=C1OS(=O)(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a −78° C. stirred solution of 4-hydroxy-5,5-dimethyl-5H-furan-2-one (250 mg, 1.95 mmol) in 18 mL of anhydrous CH2Cl2, was added triethylamine (0.40 mL, 2.9 mmol) and Tf2O (0.49 mL, 2.9 mmol). The reaction was stirred at −78° C. for 30 minutes, and quenched with saturated NH4Cl solution (10 mL). The mixture was warmed up to room temperature and separated. The aqueous layer was extracted with CH2Cl2 (2×20 mL). All organic layers were combined, dried over Na2SO4 and evaporated to brown oil, which was purified by plugging through a short pad of silica gel column with EtOAc/hexanes (1/3). Evaporation of solvents gave 2,2-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate as a light brown oil (450 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:26]([C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:36]4[CH:37]=[CH:38][C:33]([O:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:34][CH:35]=4)=[O:41])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(Oc5ccccc5)cc4)cc3)cc2C1=O
Yield: 98 %

Procedure:
The compound of example 49 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 4-phenoxy phenyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1I.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][N:12]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: Cc1nccc(Cl)c1I
Reactant: C#Cc1ccc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nccc(Cl)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 1.0 g (4.0 mmol) 4-chloro-3-iodo-2-methyl-pyridine and 513 mg (4.3 mmol) 2-amino-5-ethynyl-pyridine using 75 mg (0.40 mmol) CuI, 276 mg (0.40 mmol) PdCl2(PPh3)2 and 5.4 mL (39.5 mmol) triethylamine in 40 mL dry DMF. After completion of the reaction the solvent is removed under vacuum and the product is purified by chromatography on silica gel using a DCM/MeOH gradient (100:0 to 90:10). Yield: 617 mg (64%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:5]=1[O:17][CH3:18].[Cl:19]OC(C)(C)C.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[Br:1][CH2:2][CH2:3][C:4]1[C:5]([O:17][CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([Cl:19])[CH:16]=1
Reactant: CCOC(=O)COc1ccc(CCBr)c(OC)c1
Reactant: CC(C)(C)OCl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1cc(OC)c(CCBr)cc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl 2-[4-(2-bromoethyl)-3-methoxyphenoxy]acetate (640 mg) in dichloromethane (4 ml) was added tert-butyl hypochlorite (251 μl) at room temperature, and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of sodium sulfite (504 mg) in water (2 ml) and the resulting mixture was stirred for 30 minutes at room temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=7/1) gave ethyl 2-[4-(2-bromoethyl)-2-chloro-5-methoxyphenoxy]acetate (685 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[C:41]1[NH:42][C:43]([C:46]2[CH:51]=[CH:50][C:49](B3OC(C)(C)C(C)(C)O3)=[C:48]([C:61]([O:63][CH3:64])=[O:62])[CH:47]=2)=[CH:44][N:45]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)(O)[O-].[Na+]>O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][O:27][C:25]([C:20]1[C:21]([C:49]2[C:48]([C:61]([O:63][CH3:64])=[O:62])=[CH:47][C:46]([C:43]3[NH:42][C:41]([CH:37]4[CH2:38][CH2:39][CH2:40][N:36]4[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])=[N:45][CH:44]=3)=[CH:51][CH:50]=2)=[CH:22][CH:23]=[C:18]([C:15]2[NH:14][C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:17][CH:16]=2)[CH:19]=1)=[O:26]
Reactant: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1Br
Reactant: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1-c1ccc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)cc1C(=O)OC
Temperature: 80 °C
Yield: 34.8 %

Procedure:
To the solution of 2-[5-(4-bromo-3-methoxycarbonyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (158 mg, 0.35 mmol) and 2-{5-[3-Methoxycarbonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (166 mg, 0.33 mmol) in 1,2-dimethoxyether (3 ml) and water (1 ml) was added sodium bicarbonate (91 mg, 1.1 mmol), followed by Pd(PPh3)4 (15 mg) and PdCl2(dppf)CH2Cl2 (15 mg). The mixture was heated at 80° C. for 7 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (EtOAc) gave 4,4′-Bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-2,2′-dicarboxylic acid dimethyl ester (85 mg). m/z: 741.0 (M+H)+, 370.9 (M+2H)+/2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH2:24][C:25]#[CH:26])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[CH2:24]([O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1)[C:25]#[CH:26]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: C#CCOc1ccc2ccc(N)nc2n1
Solvent: O
Solvent: CCO
Product: C#CCOc1ccc2ccc(NC(=O)c3ccc(OC)cc3)nc2n1
Temperature: 4 °C
Yield: 60.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (11.5 g), N,N'-carbonyldiimidazole (12 g) and 2-amino-7-propargyloxy-1,8-naphthyridine (10 g). The product produced by precipitation in water (15.3 g; m.p. 140° C.) is dissolved in boiling ethanol (190 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (3×20 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-(7-propargyloxy-1,8-naphthyridin-2-yl)-4-methoxybenzamide (10.1 g) is produced, m.p. 140° C.