Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:21]([O:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-hydroxypiperidine-1,4-dicarboxylate from step A (535 mg, 2.06 mmol) in DMF (8.2 mL) was carefully added sodium hydride (60% dispersion in mineral oil, 124 mg, 3.09 mmol). The mixture was stirred for 30 minutes at room temperature. Benzyl bromide (0.29 mL, 2.47 mmol) was added, and the reaction was stirred for another 30 minutes. Upon completion as monitored by TLC analysis, the reaction was quenched with 50 mL of 1:1 saturated aq. NH4Cl:water. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried with MgSO4, and concentrated under vacuum. Silica gel chromatography (5-10% ethyl acetate:hexanes) provided the title compound as a clear oil (359 mg, 54% yield). MS (ES+) [M+H]+=340.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[H][H]>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC/C=C/c1ccccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CCCCc1ccccc1OC
Yield: 99.2 %

Procedure:
To a solution of ethyl (4E)-5-(2-methoxyphenyl)-4-pentenoate (3.40 g, 14.5 mmol) in a mixture of EtOAc and MeOH (40.0/10.0 mL), Pd/C (palladium on carbon 10%, 0.700 g) was added in small portions to avoid fire. The reaction mixture was then stirred for overnight at room temperature under 300 psi of hydrogen. After the pressure was released, the mixture was filtered through Celite and the Celite was washed with EtOAc (3×50 mL). The filtrate was concentrated in vacuo to afford crude product as a light yellow oil (3.40 g 100%), which was used without further purification.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[CH:33]1[CH:38]=[C:37]([CH2:39]Br)[C:36]([Cl:41])=[CH:35][CH:34]=1.[H-].[Na+]>C(#N)C.O>[Cl:41][C:36]1[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=1[CH2:39][N:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:22][CH:21]=1)[C:24](=[O:32])[CH2:25][N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: Clc1ccccc1CBr
Reactant: O=C(CN1CCOCC1)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(CN1CCOCC1)N(Cc1ccccc1Cl)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 126.9 %

Procedure:
A mixture of 0.11 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-4-morpholineacetamide, 56 mg of O-chlorobenzyl bromide and 0.41 g of K2 CO3 in 5 ml of acetonitrile is heated at reflux for 18 hours. An additional 30 mg of O-chlorobenzyl bromide and 0.4 mmol of sodium hydride is added followed by heating for 24 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried with Na2SO4 and evaporated to give 0.18 g of a residue which is purified by chromatography on silica gel with 1:1 ethyl acetate-methylene chloride to give 80 mg of off white solid. MS(CI): 555 (M+H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25]O)[CH2:20][CH2:19]2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[CH3:32][C:33]1([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:42][CH:41]=2)[NH:37][C:36](=[O:38])[NH:35][C:34]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.Cl>CN(C)C=O.O>[F:30][C:2]([F:1])([F:31])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:37]3[C:33]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:42][CH:41]=4)([CH3:32])[C:34](=[O:39])[NH:35][C:36]3=[O:38])[CH2:20][CH2:19]2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(CCO)CC1
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(CCN2C(=O)NC(=O)C2(C)c2ccc(OC(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
2-(4-{4-[1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}piperazin-1-yl)ethanol (7.8 mg, 0.0170 mmol), 5-methyl-5-(4-(1-methylethoxy)phenyl)imidazolidine-2,4-dione (A11)(15.6 mg, 0.0631 mmol) and triphenylphosphine (15.8 mg, 0.0601 mmol) were dried with a vacuum pump, dissolved in N,N-dimethylformamide (284 μL), added DEAD (23 μL, 0.0167 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added water (1.0 mL) and 2N aqueous solution of hydrochloric acid (1.0 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (3.1 mg (yield 26%)) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]Cl.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:4][C:3]4[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=4[Cl:1])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: ClCc1cc(Cl)ccc1Cl
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3cc(Cl)ccc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 2,5-dichlorobenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (43% yield). 1H NMR (300 MHz, CDCl3) δ 7.96-8.04, 7.53, 7.16-7.33, 6.96, 3.75-3.84, 3.64, 3.56, 2.62-2.70, 1.53, 1.51, 0.70-0.83, 0.43-0.51, 0.06-0.13. MS (ES+) m/z 434 (M).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][Si](C=[N+]=[N-])(C)C>CO>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: COc1cc(C(=O)O)c(N)cc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(OC)c(Cl)cc1N
Yield: 46 %

Procedure:
A solution of 2-amino-4chloro-5-methoxybenzoic acid (3.0 g, 15.0 mmol; prepared according to the procedure of Denny, et al., J. Med. Chem. 34:217-222 (1991)) in 70 ml MeOH was treated with excess trimethylsilyl diazomethane. The solution was concentrated and the residue flash chromatographed on silica (9:1 hexane/EtOAc to give the title compound (46%): mp 63°-64° C.; 1H NMR (300 MHz, CDCl3) δ 6 3.83 (s, 3H), 3.90 (s, 3H), 5.48 (bs, 2H), 6.75 (s, 1H), 7.39 (s, 1H); MS (DCI/NH3) m/z 216 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1>>[F:33][C:34]1[CH:35]=[C:36]([O:40][C:2]2[N:7]=[C:6]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: Oc1cccc(F)c1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(Cl)n3)cc2)CCN1C(=O)OC(C)(C)C
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(Oc4cccc(F)c4)n3)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 3.3 h

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(6-chloro-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D107) and 3-fluorophenol using a procedure similar to that described for D125 in Description 125 although the reaction time was 3.3 h. MS (ES): MH+ 535.4.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][CH:22]([SH:24])[CH3:23].Cl>CN(C)C(=O)C>[CH:22]([S:24][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:23])[CH3:21]
Reactant: CC(C)S
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 90 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid in 6 ml N,N-dimethylacetamide were added 15.2 mol cesium carbonate and 10.1 mmol 2-propanethiol, and the mixture was stirred at 90° C. for 3 h. The reaction mixture was then cooled to room temperature and acidified to pH 1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light yellow liquid which was used in the next step without further purification (yield 99%). EI-MS (m/e): 274.1 (M+, 35%), 232.1 ([M-C3H6]+, 30%, 214.1 (M-C3H6—H2O)+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:16](=[O:18])[CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1
Reactant: O=C(O)Cc1cccc(OCc2ccccc2)c1
Reactant: c1ccoc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1cccc(OCc2ccccc2)c1)c1ccco1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
3-Benzyloxyphenylacetic acid (3.5 kg, 14.45 mol) was dissolved in CH2Cl2 (35 L), and furan (3.0 kg, 44 mol) and trifluoroacetic anhydride (4.55 kg, 21.65 mol) were added to the solution. The reaction was kept being stirred at room temperature for 2 days. The reaction was quenched with saturated NaHCO3 to pH=6.9, and the organic reagent in the mixture was evaporated. The residue was extracted with EtOAc, and the organic layer was washed with brine, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the 1-(furan-2-yl)-2-(3-benzyloxyphenyl)ethan-1-one as yellow oil: 4 kg (yield: 95%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:32])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([Cl:32])(=[O:17])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccccc1-c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccccc1-c1ccc(F)cc1

Procedure:
4′-Fluorobiphenyl sulfonic acid (3 g) was refluxed in thionyl chloride (30 mL) with a catalytic quantity of DMF (0.5 mL) for 4 hours. Toluene was added and the solvents evaporated under vacuum to give the title compound as an amorphous solid.
Reaction SMILES: [O:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:3]([OH:5])=[O:4].[BH4-].[Na+].Cl>O.C(O)CCCCCCCCC>[OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCCCCCCO
Solvent: O
Product: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a magnetically stirred suspension of α-oxo-2-nitrobenzenepropanoic acid (5.00 g) in water (75 ml) containing 1 drop of decyl alcohol was added sodium borohydride (2.50 g) in portions to maintain a temperature between 45 and 50°. The resulting solution was then left at room temperature for 21/2 hours. The solution was acidified with concentrated hydrochloric acid and seeded. Stirring and cooling gave crude product; yield 5.01 g, m.p. 84°-90°. Recrystallization from water gave titled product; yield 2.63 g (52%), m.p. 95°-98° with spectral data as above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:16][CH3:17])=[C:6]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:16]([CH3:17])=[O:26])=[C:6]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(F)cc1C(=O)Cn1cccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)c1ccc(F)cc1C(=O)Cn1cccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.5 %

Procedure:
To a stirred cooled solution of 1-[5-Fluoro-2-(methylthio)phenyl]-2-(pyrrol-1-yl)ethanone (22c) (1.76 g, 7.06 mmol) in dichloromethane (12 ml) was added dropwise in 30 minutes a solution of m-chloroperbenzoic acid (71.5% grade, 1.70 g, 7.06 mmol) in dichloromethane (10 ml). After stirring for 45 minutes at 0° C., the mixture was treated with a 5% solution of sodium carbonate in water (41 ml) and was stirred for 15 minutes at room temperature. The organic phase was separated and water was extracted with dichloromethane (3×10 ml). The organic layers were dried and evaporated, the residue was chromatographed (10% dichloromethane in ethyl acetate) to afford 1.02 g of 23c as white crystals that darkened rapidly (64% yield). 1H NMR (CDCl3) δ8.42-8.35 (m, 1H); 7.61-7.51 (m, 2H); 6.68-6.62 (m, 2H); 6.26-6.24 (m, 2H); 5.41-5.17 (q, 2H, J=31.32, 17.87 Hz); 2.77 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH3:21])[N:15]=3)[CH2:10][CH2:9]2)=[C:4]([F:22])[CH:3]=1.[N+:23]([C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1)([O-:25])=[O:24]>CC(O)=O.CO>[CH2:20]([N:16]1[N:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2](/[N:1]=[CH:31]/[C:29]4[O:30][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=4)=[CH:3][C:4]=3[F:22])[CH2:9][CH2:10]2)[O:18][C:17]1=[O:19])[CH3:21]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CCn1nc(C2CCN(c3ccc(N)cc3F)CC2)oc1=O
Solvent: CC(=O)O
Solvent: CO
Product: CCn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Yield: 87 %

Procedure:
5-[1-(4-Amino-2-fluorophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7 g, 0.30 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and re-crystallized in ethanol to obtain product 3-ethyl-5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9 g, 373 mg, 87%).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N+:27]([O-])=[CH:26][CH:25]=[CH:24]2)=[O:20])[CH3:17].[CH3:32][NH2:33].O1CCCC1>ClCCl>[CH3:32][NH:33][C:26]1[CH:25]=[CH:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH:22]=2)[N:27]=1
Reactant: CN
Reactant: CCOC(=O)c1ccc2c(ccc[n+]2[O-])c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2nc(NC)ccc2c1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
Trifluoromethanesulfonic anhydride (1.92 mL, 11.4 mmol) was added dropwise to a −70° C. solution of 6-(ethoxycarbonyl)quinoline 1-oxide (2.25 g, 10.4 mmol) in dichloromethane (150 mL). The mixture was stirred at −70° C. for 5 minutes. Then a solution of methylamine in tetrahydrofuran (31 mL, 62 mmol, 2 M) was added dropwise. The mixture was stirred at −70° C. for 5 minutes. The reaction was quenched with water (20 mL). The layers were separated and the aqueous was extracted with dichloromethane (3×30 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave the title compound (850 mg, 35%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.33 (d, 1H), 8.16-8.13 (m, 1H), 7.90-7.87 (d, 1H), 7.70-7.67 (d, 1H), 6.68 (d, 1H), 5.30 (br. s., 1H), 4.43-4.38 (q, 2H), 3.13-3.12 (d, 3H), 1.44-1.40 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=O.[CH2:12]([CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][NH2:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CCCCCCC>[CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([NH:22][CH2:21][CH:20]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:6]
Reactant: CCCCCCCCCCC(CN)CCCCCCCC
Reactant: CC(CC(=O)O)CC(C)(C)C
Solvent: CCCCCCC
Product: CCCCCCCCCCC(CCCCCCCC)CNC(=O)CC(C)CC(C)(C)C

Procedure:
3.6 g of 3,5,5-trimethylhexanoic acid and 6.8 g. of 2-octyldodecylamine were mixed together in the tube of a microwave machine (Maxidigest™ MX 350 from the company Prolabo; frequency 2450±50 MHz, modulable power 300 W). After irradiation for about 50 minutes at 170° C.±10° C., the reaction mixture was dissolved in heptane and then purified on silica. 7 g of the desired amide were obtained.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1>C1(C)C=CC=CC=1.O1CCCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:2]([NH:1][C:4]2[CH:9]=[CH:8][C:7]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)=[CH:6][CH:5]=2)=[O:3])[CH:20]=1
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Reactant: Nc1cccnc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cccnc3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(Pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was prepared by treatment of 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50, 2.50 g, 10.20 mmoles) in toluene/tetrahydrofuran (3:1) with pyridine-3-amine (51, 0.960 g, 10.20 mmoles). The reaction mixture was stirred at room temperature for 16 hours, then concentrated. Yield: 3.21 g (93%). LCMS (HP walk-on); 2.89 min., 340.6, M+H.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:32][C:33]([CH3:37])([CH3:36])[C:34]#[CH:35].C(#N)C>C(Cl)Cl.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>[CH3:32][C:33]([CH3:37])([CH3:36])[C:34]#[C:35][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: C#CC(C)(C)C
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: ClCCl
Product: COc1cnc2c(Oc3ccc(Nc4nnc(C#CC(C)(C)C)c5ccccc45)cc3)ccnc2c1
Temperature: 90 °C

Procedure:
A resealable pressure bottle, purged with argon, was charged with 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (120 mg, 0.28 mmol), bis(triphenylphosphine)palladium(ii) chloride (24 mg, 0.03 mmol), copper(I) iodide (6.4 mg, 0.03 mmol), 3,3-dimethyl-1-butyne (86 μl, 0.70 mmol), and ACN (2.8 mL, 0.1 M). To the mixture was added TEA (0.785 mL, 5.6 mmol). The reaction vessel was sealed and the mixture was heated to 90° C. for 16 h. The reaction mixture was cooled to RT, diluted with DCM and filtered over Celite. The filtrate was concentrated under reduced pressure to give a brown residue, which was purified by Gilson HPLC {5-65% (0.1% TFA in CH3CN) in H2O over 20 min}. The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with DCM. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 4-(3,3-dimethylbut-1-ynyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine MS [M+H]=476.1 Calc'd for C29H25N5O2: 475.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C@:4]([C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:13][C:14]1[N:18]=[C:17]([CH:19]([OH:21])[CH3:20])[NH:16][CH:15]=1)[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[S:42](Cl)([C:45]1[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=1)(=[O:44])=[O:43]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:41])[C@:4]([C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH2:13][C:14]1[N:18]=[C:17]([CH:19]([O:21][S:42]([C:45]2[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[CH3:20])[NH:16][CH:15]=1)[N:5]=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@](Cc1c[nH]c(C(C)O)n1)(N=Cc1ccccc1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)[C@](Cc1c[nH]c(C(C)OS(=O)(=O)c2ccc(C)cc2)n1)(N=Cc1ccccc1)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To the solution of compound 2·III from Step C is added 0.5 ml of pyridine and then 190.5 mg (1 mmole) of tosyl chloride. After 30 minutes at 25° C. the solution is washed three times with water, once with brine, and dried with K2CO3 and filtered. The filtrate is used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.Cl.[CH3:18][N:19](C)C=O>>[C:18]([C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1)#[N:19]
Reactant: CN(C)C=O
Reactant: O=c1c2cc(Br)ccc2ccn2cccc12
Agent: Cl
Product: N#Cc1ccc2ccn3cccc3c(=O)c2c1
Reaction time: 0.5 h

Procedure:
A stirred mixture of 1 gm. of 9-bromo-11H-pyrrolo[2,1-b][3]benzazepin-11-one, 1 gm. of cuprous cyanide and 5 ml. of dimethylformamide is heated to reflux for 5 hr. The mixture is then poured into a solution of 4 gm. of ferric chloride hydrate in 25 ml. of 2N hydrochloric acid. After stirring the resulting mixture at 60° for 30 min., it is extracted with 3 × 50 ml. of ethyl acetate, the organic extracts washed with 3 × 100 ml. of water and dried over Na2SO4. Evaporation of the dried solution yields 9-cyano-11H-pyrrolo[2,1-b][3]benzazepin-11-one, m.p. 213°-217° C.