Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([N:18]4[CH2:21][CH:20]([OH:22])[CH2:19]4)[CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:23])=[CH:5][CH:4]=1.CCN(CC)CC.S(=O)(=O)=O.N1C=CC=CC=1.CO>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([N:18]4[CH2:21][C:20](=[O:22])[CH2:19]4)[CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:23])=[CH:24][CH:25]=1
Reactant: COc1ccc(Cn2c(=O)ccc3ncc(N4CC(O)C4)cc32)cc1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)ccc3ncc(N4CC(=O)C4)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a mixture of 1-(4-methoxybenzyl)-7-(3-hydroxyazetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-6) (2.637 g, 7.81 mmol, 1.0 eq) in DMSO (30 mL) was added Et3N (9 mL, 64.82 mmol, 8.3 eq) and a solution of pyridine sulfur trioxide (8.71 g, 54.7 mmol, 7.0 eq) in DMSO (30 mL) sequentially. The resulting mixture was stirred at RT for 1 h. The reaction was complete based on TLC analysis. The mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1:1 to 1:3 petroether/ethyl acetate and then 80:1DCM/MeOH) to afford the desired product 1-(4-methoxybenzyl)-7-(3-oxoazetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-7) (2.6 g, 99% yield) as a pale solid. HNMR (300 MHz, DMSO-d6) δ: 7.93 (s, 1H), 7.82 (d, J=9.6 Hz, 1H), 7.21 (d, J=9 Hz, 2H), 6.84 (m, 3H), 6.60 (d, J=9.6 Hz, 1H), 5.37 (s, 2H), 4.79 (s, 4H), 3.65 (s, 3H); ESI-MS m/z: 336.1 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:18]=[C:17]([NH:19][C:20]3[C:25]([CH3:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=3)[CH:16]=[CH:15][C:14]=2[NH2:28])[CH:8]=[CH:9][CH:10]=1.Cl.O.[OH-].[Na+]>COCCO.O1CCOCC1>[CH3:26][C:25]1[CH:24]=[N:23][C:22]2[NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([CH:6]=3)[CH2:11][CH2:12][C:13]3[CH:18]=[C:17]([NH:19][C:20]=1[N:21]=2)[CH:16]=[CH:15][C:14]=3[NH2:28]
Reactant: Cc1cnc(Cl)nc1Nc1ccc(N)c(CCc2cccc(N)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: COCCO
Product: Cc1cnc2nc1Nc1ccc(N)c(c1)CCc1cccc(c1)N2
Yield: 42 %

Procedure:
To a solution of 2-[2-(3-aminophenyl)ethyl]-N(4)-(2-chloro-5-methylpyrimidin-4-yl)benzene-1,4-diamine trihydrochloride (0.16 g, 0.45 mmol) in 2-methoxyethanol (2 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (110 μL). The resultant mixture was heated at 150° C. in the microwave for 15 min. After cooling, water and NaOH (12 N) were added to neutralize the mixture to pH=7. The aqueous layer was extracted with EtOAc four times. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product as an off-white powder (60 mg, 48%). LCMS for C19H20N5 (M+H)+: m/z=318.2.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.II.C1(OC)C=CC=CC=1.C[O:22][B:23](OC)[O:24]C>C1COCC1.C(OCC)C>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([B:23]([OH:24])[OH:22])[CH:8]=[CH:7][CH:6]=1
Reactant: COB(OC)OC
Reactant: COc1cccc(Br)c1
Agent: II
Agent: [Mg]
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(B(O)O)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Magnesium turnings (10.4 g, 428 mmol) were placed in a three-necked flask equipped with one condenser and one addition funnel and the flask was flame-dried under a stream of nitrogen. Rubber septa were used to enclose the vessel and the reaction was run under a stream of nitrogen. A solution of 3-bromoanisole (40 g, 214 mmol) in THF (400 mL) was placed in the addition funnel. The magnesium turnings were covered with THF and warmed to 65° C. A crystal of iodine and then a few mL of the anisole solution were added to the turnings. A few minutes later the amber color disappeared. The anisole solution was then slowly dripped into the reaction vessel. After all of the anisole was added, the reaction was maintained at 65° C. for 2 h. After cooling to ambient temperature, the Grignard solution was poured into a solution of trimethylborate (24.96 g, 240 mmol) in diethylether (250 mL) and stirred for 1 h. The solution was quenched with 1N HCl and extracted with ether. The ether was removed by rotary evaporation leaving the boronic acid as an white solid (27.59 g, 181.51 mmol).
Reaction SMILES: C(O[C:4]1(O[Si](C)(C)C)[CH2:6][CH2:5]1)C.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1.O.[BH3-]C#N.[Na+]>C1COCC1.C(O)(=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:20][CH2:21][N:22]([CH:4]3[CH2:5][CH2:6]3)[CH2:23][CH2:24]2)=[N:17][CH:18]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Brc1ccc(N2CCNCC2)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(N2CCN(C3CC3)CC2)nc1
Temperature: 25 °C

Procedure:
[(1-Ethoxy-cyclopropyl)oxy]trimethylsilane (26 mL, 129.3 mmol) was added to a solution of 1-(5-bromopyridin-2-yl)-piperazine (15 g, 62.0 mmol) in THF (120 mL). Water (24 mL), acetic acid (11 mL), and 1 M NaCNBH3 in THF (90 mL, 90 mmol) were added to the reaction mixture, which was then heated at reflux temperature for 3 hours. The resulting solution was cooled to rt and evaporated to dryness in vacuo. The residue was dissolved in a mixture of dichloromethane (200 mL) and water (50 mL) and 4 N sodium hydroxide (20 mL) was added to pH 8-9. The organic phase was isolated and the aqueous phase was extracted with further dichloromethane (100 mL). The combined organic phases were evaporated to dryness in vacuo and the residue was purified on a silica gel column (gradient: from 5% ethyl acetate in heptane to 100% ethyl acetate over 40 min.). This afforded 13.1 g (75%) of 1-(5-bromopyridin-2-yl)-4-cyclopropylpiperazine.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:22][S:23][CH3:24])[C:17]([F:21])=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CN(C=O)C>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:30][CH:29]=1
Reactant: CSCc1c(F)ccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCc1c(F)ccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.46 g (7.01 mmol) of potassium cyanide were added to 1.55 g (3.50 mmol) of the compound from Example 66A in 32 ml of DMF. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were dried over sodium sulfate, the solid was filtered off, and the solvents were removed. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.00 g (77% of theory) of the target compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Br:24][C:25]1[C:26]([CH3:32])=[N:27][C:28](F)=[CH:29][CH:30]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:27][C:26]=1[CH3:32]
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Reactant: Cc1nc(F)ccc1Br
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ccc(Br)c(C)n4)cc3n2C)c1
Yield: 14.1 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (3.12 g, 10 mmol), 3-bromo-6-fluoro-2-methylpyridine (2.09 g, 11 mmol), copper iodide (0.19 g, 1.0 mmol), 1,10-phenanthroline (0.18 g, 1.0 mmol), cesium carbonate (9.77 g, 30 mmol) and DMF (50 mL) to obtain the title compound (0.68 g, 14%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH:26]=[O:27])=[C:10]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N+:28]([CH:30](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:31])#[C-:29].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:26]3[O:27][CH:29]=[N:28][C:30]=3[CH3:31])=[C:10]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)CCc1c(C=O)nc2c(cnn2CC)c1-c1cncc(C)c1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCn1ncc2c(-c3cncc(C)c3)c(CCC(=O)O)c(-c3ocnc3C)nc21
Yield: 31.2 %

Procedure:
A mixture of ethyl 3-[1-ethyl-6-formyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (30 mg), 1-[(1-isocyanoethyl)sulfonyl]-4-methylbenzene (17.6 mg), potassium carbonate (17 mg) in MeOH (1 ml) was refluxed for 1.5 hours. After cooling, the mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified to pH3-4 by adding 1N HCl and extracted with CHCl3. The organic layer was washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography eluting with a mixture of MeOH and CHCl3 (1:10). Crystallization from EtOAc-n-hexane gave 3-[1-ethyl-6-(4-methyl-1,3-oxazol-5-yl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoic acid (10 mg) as a colorless crystal.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1.C(N(CC)CC)C>CN(C)C=O.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.[Cu]I>[F:9][C:4]1[C:3]([C:1]#[C:2][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: C#Cc1cccnc1F
Reactant: O=[N+]([O-])c1cc(F)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(F)ccc1C#Cc1cccnc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
Into a round bottom flask was added 3-ethynyl-2-fluoropyridine (0.3 g, 0.002 mol), 4-fluoro-1-iodo-2-nitrobenzene (0.675 g, 0.00253 mol), bis(triphenylphosphine)palladium(II) chloride (0.09 g, 0.1 mmol), copper(I) iodide (0.04 g, 0.2 mmol), and triethylamine (0.52 mL, 3.7 mmol) in N,N-dimethylformamide (4 mL). The reaction was stirred at room temperature for 2 hours. The reaction was extracted with ethyl acetate, and the combined organic extracts were washed with brine (3×), dried over MgSO4, and purified by column chromatography on silica gel (10% ethyl acetate 90% hexanes), to give 0.443 g of product. 1H NMR (400 MHz, CDCl3): δ 8.44-8.50 (m, 1H), 7.99-8.02 (m, 1H), 7.79-7.90 (m, 1H), 7.78-7.82 (m, 1H), 7.37-7.42 (m, 1H), 7.23-7.29 (m, 1H). MS [M+H]=261.0.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[CH2:28][O:29][C:30]1[CH:31]=[C:32](CN)[CH:33]=[CH:34][CH:35]=1>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH2:28][C@@H:24]5[CH2:25][CH2:26][CH2:27][N:23]5[CH3:22])[CH:35]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: CN1CCC[C@H]1COc1cccc(CN)c1
Product: CN1CCC[C@H]1COc1cccc(Cn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)c1

Procedure:
The title compound was synthesised using the same method as described for Example 20c using the reagents 5-(4-Chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.176 g, 0.55 mmol) and 1-(3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}phenyl)methanamine (0.10 g, 0.45 mmol). Purification by prep-HPLC gave the product as a solid. Yield: 0.22 g (41%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.58-7.64 (m, 2H), 7.38-7.46 (m, 3H), 7.21-7.27 (m, 1H), 6.82-6.94 (m, 3H), 5.17 (s, 2H), 3.90-3.99 (m, 1H), 3.79-3.87 (m, 1H), 3.03-3.13 (m, 1H), 2.54-2.66 (m, 1H), 2.43 (s, 3H), 2.22-2.32 (m, 1H), 1.92-2.06 (m, 1H), 1.64-1.88 (m, 3H). MS (ESI+) 466.12 (M+1H+).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4]1.[CH:15]([N:18](C(C)C)CC)(C)C.CS(Cl)(=O)=O.CN>ClCCl.CS(C)=O.C(Cl)(Cl)Cl>[CH3:15][NH:18][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4]1
Reactant: OCC1CCOC(c2ccccc2)O1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CNCC1CCOC(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a solution of 4-hydroxymethyl-2-phenyl-1,3-dioxane (0.80 g, 4.12 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (1.702 ml, 10.30 mmol) and the solution was cooled in an ice bath. Methanesulfonyl chloride (0.414 ml, 5.35 mmol) was added and the solution was allowed to warm to RT. After 1 h, it was washed with 2M aq HCl, saturated aq NaHCO3, dried and concentrated to a syrup (1.15 g). A solution of (0.9 g, 3.30 mmol) of this material in DMSO (8 mL) containing 40% aq methylamine (2.85 ml, 33.0 mmol) was stoppered and heated at ˜75-80° C. for 24 h. The solution was cooled, chloroform was added and washed twice with water, dried and concentrated. Chromatography afforded title compound (0.465 g, 2.24 mmol, 68%) as a syrup. 1H NMR (CDCl3) δ 7.50-7.47 (2H, m), 7.39-7.30 (3H, m), 5.52 (1H, s), 4.31-4.25 (1H, m), 4.09-3.93 (2H, m), 2.80 (1H, dd, J=12.3, 8.0 Hz), 2.67 (1H, dd, J=12.3, 3.4 Hz), 2.45 (3H, s), 1.96-1.83 (2H, m), 1.49 (1H, dd, J=13.2, 1.2 Hz); 13C NMR δ 139.0, 129.2, 128.6, 126.5, 101.6, 76.8, 67.2, 57.0, 36.8, 29.5.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH3:21][NH:22][CH3:23]>O.CN(C=O)C>[CH3:21][N:22]([CH3:23])[C:7]1[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CNC
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(N(C)C)cc(C(F)(F)F)nc1C(F)(F)F
Reaction time: 3 h

Procedure:
A mixture of 7.67 g (0.024 mol) of product of Example 19 and 5.4 g (0.048 mol) of 40% solution of dimethylamine in H2O and 50 ml of DMF was stirred for three hours. The temperature rose to 48° C. and dropped back down to room temperature. The reaction mixture was poured into H2O, extracted with ether, washed with diluted HCl, dried (MgSO4) and concentrated in vacuo to 6.63 g of solid which was recrystallized in hot hexane affording 6.01 g (75.8%) of product as a white solid; mp 63.5°-65° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:17](=[O:18])[NH:16][N:15]=[N:14]1)([CH3:3])[CH3:2].[CH:19](I)([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH:19]([CH3:21])[CH3:20])[N:15]=[N:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1-n1nn[nH]c1=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1-n1nnn(C(C)C)c1=O
Reaction time: 2 h
Yield: 52 %

Procedure:
14.3 g of 1-(2,6-diisopropylphenyl)-5-oxo-2-tetrazoline, 12.8 g of isopropyl iodide and 10.4 g of pulverised potassium carbonate are dissolved in 140 ml of dimethylformamide and stirred for 2 hours at +60° C. The resulting suspension is poured onto water and extracted three times with ether. The combined ethereal phases are washed with water and saturated sodium chloride solution, dried over Na2SO4 and concentrated by evaporation. In order to remove the 1-(2,6-diisopropylphenyl)-5-isopropoxy-tetrazole formed as by-product, the mixture is chromatographed on silica gel with the eluant CH2Cl2 /cyclohexane (3:1). In this manner 8.7 g of 1-(2,6-diisopropylphenyl)-4-isopropyl-5-oxo-2-tetrazoline having a melting point of 60°-62° C. are obtained.
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C:10]2([F:18])[F:17])[CH:2]=1.Cl.Cl[Si](C)(C)C.Cl[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27].CCO>N1C=CC=CC=1.O>[CH2:29]([O:28][C:26]([NH:8][C:7]1[CH:1]=[CH:2][N:3]([C@H:9]2[C:10]([F:17])([F:18])[C@H:11]([OH:16])[C@@H:12]([CH2:14][OH:15])[O:13]2)[C:4](=[O:5])[N:6]=1)=[O:27])[CH:30]=[CH2:31]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: C=CCOC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: C=CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of gemcitabine hydrochloride (1.2 g, 4 mmol) in 12 mL pyridine, chlorotrimethylsilane (2.54 mL, 20 mmol) was added at 0° C.; after stirring for 2 h, allyl chloroformate (0.43 mL, 4 mmol) was added at 0° C. The reaction mixture was allowed to warm to RT, and heated at 45° C. overnight, then cooled to 30-35° C. when 12 mL of absolute EtOH was added. The reaction mixture was reheated at 45° C. for 0.5 h, and following the addition of 6 mL of H2O, was heated at 45° C. for 5 h, then cooled to RT and concentrated in vacuo. The residue was partitioned between EtOAc and water; The organic layer was separated, and the aqueous layer was again extracted with EtOAc. The organic extracts were combined and washed with saturated aqueous CuSO4 solution, saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (5:1→10:1 EtOAc/Hexane) afforded 1 (white solid, 70% yield): 1H NMR (400 MHz, DMSO-d6) δ11.00 (s, 1H), 8.26-8.28 (d, 1H), 7.13-7.15 (d, 1H), 6.34-6.37 (d, 1H), 6.18-6.22 (t, 1H), 5.95-6.02 (m, 1H), 5.38-5.43 (d, 1H), 5.34 (t, 1H), 5.27-5.30 (d, 1H), 4.67-4.69 (d, 2H), 4.20-4.25 (m, 1H), 3.90-3.95 (m, 1H), 3.82-3.86 (m, 1H), 3.66-3.72 (m, 1H); MS (HR-ESI): m/z 346.0857 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[C:27]([OH:33])(=[O:32])[CH2:28][CH2:29][C:30]#[CH:31].C(N(CC)CC)C>COCCOC.[Cu](I)I.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:31]#[C:30][CH2:29][CH2:28][C:27]([OH:33])=[O:32])=[CH:20][CH:19]=1)=[O:26])[CH3:9]
Reactant: C#CCCC(=O)O
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cc1noc(-c2ccc(C#CCCC(=O)O)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.200 g, 0.46 mmol), 4-pentynoic acid (0.054 g, 0.55 mmol), copper iodide (spatula tip), triethylamine (0.12 mL, 0.84 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.053 g, 0.05 mmol) were combined in DME (5 mL), and the reaction was purged with N2 for 15 minutes and then stirred at 80° C. overnight. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound. Mass spec. data (M+H)=453.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.Cl.C1C2C(=CC=CC=2)C=CC=1OC1CCNCC1.[Cl:39][CH2:40][CH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)=[O:43].ClCCCC(C1C=CC=CC=1)=O>>[ClH:39].[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:40][CH2:41][C:42]([C:44]2[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=2)=[O:43])[CH2:17][CH2:16]1
Reactant: COc1cccc2c(OC3CCNCC3)cccc12
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(CCCCl)c1ccccc1
Agent: c1ccc2cc(OC3CCNCC3)ccc2c1
Product: COc1cccc2c(OC3CCN(CCC(=O)c4ccc(Cl)cc4)CC3)cccc12

Procedure:
When in the procedure of Example 13, 4-(5-methoxy-1-naphthalenyloxy)piperidine hydrochloride is substituted for 4-(2-naphthalenyloxy)piperidine hydrochloride and 3-chloro-1-(4-chlorophenyl)-1-propanone substituted for 4-chloro-1-phenyl-1-butanone, 3-[4-(5-methoxy-1-naphthalenyloxy)-1-piperidyl]-1-(4-chlorophenyl)-1-propanone hydrochloride is produced.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(-n2cccc2)cc1
Product: CN(C(=O)Oc1ccc(-n2cccc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-pyrrol-1-yl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (27%, off-white crystals). HPLC-MS m/z=293.2 (M+1), Rt: 4.51 min.
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[N:7]([CH3:17])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:18][C@@H:19]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)[C@H:20]([OH:32])[CH2:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[CH:25]=1>C(Cl)Cl.O1CCCC1>[CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:18][C@@H:19]([CH2:33][C:34]3[CH:35]=[C:36]([F:41])[CH:37]=[C:38]([F:40])[CH:39]=3)[C@H:20]([OH:32])[CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[CH:25]=3)=[O:16])[CH:12]=2)[N:7]([CH3:17])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCc1cn(C)c2ccc(C(=O)O)cc12
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCc1cn(C)c2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 40 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
To a mixture of 3-Butyl-1-methyl-1H-indole-5-carboxylic acid (0.15 g) in methylene chloride (5 mL) and tetrahydrofuran (10 mL) was added 1,1-carbonyldiimidazole (0.105 g). The mixture was stirred at 40° C. at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.2 g) in methylene chloride (5 mL) was added. The mixture was stirred at 40° C. for 18 h then poured into methylene chloride (50 mL). The mixture was washed with water then brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 85:10:5 (methylene chloride: hexanes: methanol) as eluent to give 0.102 g of the title compound: MS (ESI+) for C33H39F2N3O2 m/z 547.9 (M+H)+.