Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:9][C:10](=[O:27])[NH:11][C:12]1[S:16][C:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:14]([CH3:24])[C:13]=1[C:25]#[N:26])(=O)C1C=CC=CC=1.[OH-].[Na+]>CCO>[NH2:26][C:25]1[C:13]2[C:14]([CH3:24])=[C:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:16][C:12]=2[NH:11][C:10](=[O:27])[N:9]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)sc(NC(=O)NC(=O)c2ccccc2)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)OC(C)(C)C)sc2[nH]c(=O)nc(N)c12
Temperature: 25 °C
Yield: 63 %

Procedure:
To a suspension of tert-butyl 5-(3-benzoylureido)-4-cyano-3-methylthiophene-2-carboxylate (example 64a) (18 g, 60.52 mmol) in EtOH (200 mL) was added NaOH (75 mL, 2N). The suspension became clear, and the mixture was heated to reflux for 30 min. After cooling to rt, the reaction was filtered, and the filtrate was cooled to 0° C. in an ice/water bath. The solution was neutralized with 10% acetic acid. The precipitated solid was collected by filtration, and heated in EtOH at 80° C. under N2 for 20 min. After cooling to rt, the product was collected by filtration and washed with 10% EtOH in H2O to yield tert-Butyl 4-amino-5-methyl-2-oxo-1,2-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (10.73 g, 63%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ1.51 (s, 9H), 2.73 (s, 3H), 3.18 (s, 2H). MS 282.2 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][N:16]=[C:15]([C:18]3[C:19]([CH2:37][CH3:38])=[C:20]([CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH:21]=[CH:22][CH:23]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]([CH3:12])[CH3:11])#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:37]([C:19]1[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[N:14]=[C:13]([C:5]2[CH:6]=[CH:7][C:8]([CH2:9][CH:10]([CH3:11])[CH3:12])=[C:3]([CH:4]=2)[C:1]#[N:2])[S:17][N:16]=1)[CH3:38]
Reactant: CCc1c(-c2nsc(-c3ccc(CC(C)C)c(C#N)c3)n2)cccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1c(-c2nsc(-c3ccc(CC(C)C)c(C#N)c3)n2)cccc1C1CCNCC1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)-1-piperidinecarboxylate (D124) (0.089 g, 0.168 mmol) in Dichloromethane (DCM) (10 mL) at room temp was added TFA (0.388 mL, 5.04 mmol). This solution was stirred for 2 hr. This solution was condensed and dried in high vacuum to remove TFA to afford 5-{3-[2-ethyl-3-(4-piperidinyl)phenyl]-1,2,4-thiadiazol-5-yl}-2-(2-methylpropyl)benzonitrile (D125) (72 mg) as a brown oil residue, which was used directly in the next step. MS (ES): C26H30N4S requires 430.2. found 431.2 (M+H+).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:7]=[CH:8][C:9]=1[CH3:10].O>C(O)(=O)C>[Br:1][C:7]1[CH:8]=[C:9]([CH3:10])[C:4]([CH3:3])=[CH:5][C:6]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(C)c(C)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc(C)c(C)cc1Br
Reaction time: 0.25 h

Procedure:
Bromine (5.08 mL, 99.1 mmol) was added over 1 h to a stirred solution of N-(3,4-dimethylphenyl)acetamide 1-6 (13.5 g, 82.6 mmol) in acetic acid (200 mL) at approximately 15° C. After 15 minutes, water (400 mL) was added until no further precipitation was observed. The resultant solid was filtered, washed with water (until white) and dried in vacuo to afford 1-7 as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Br:9][CH:10]([CH2:14][CH2:15][Br:16])[C:11](Cl)=[O:12].Cl>ClCCl.C(N(CC)CC)C>[Br:9][CH:10]([CH2:14][CH2:15][Br:16])[C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)C(Br)CCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)C(Br)CCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-bromoaniline (1.73 g) in dichloromethane (40 ml), triethylamine (2.8 ml) and a solution of 2,4-dibromobutyryl chloride (3.2 g) in dichloromethane (10 ml) were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. After addition of 1 N hydrochloric acid to the reaction solution, the mixture was separated into two layers. The aqueous layer was subjected to extraction with chloroform. The organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of the title compound, which was used in the next reaction without being purified.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][NH:12][C:13](=[O:24])[C@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].[CH:25]1[CH2:29][CH:28]=[CH:27][CH:26]=1>ClCCl.ClCCl.CS(C)=O.C(N(CC)CC)C>[C:19]([O:18][C:17](=[O:23])[NH:16][C@H:14]([CH3:15])[C:13]([N:12]1[O:11][CH:27]2[CH2:28][CH:29]1[CH:25]=[CH:26]2)=[O:24])([CH3:20])([CH3:22])[CH3:21]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NO
Reactant: C1=CCC=C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1OC2C=CC1C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
At about −78° C. and under an atmosphere of nitrogen, oxalyl dichloride (30.43 g, 239.74 mmol, 4.00 equiv.) was added dropwise, over a period of 20 minutes, to stirred solution of dimethylsulfoxide (28.1 g, 359.66 mmol, 6.00 equiv.) in dichloromethane (200 mL). To this mixture was added dropwise, over a period of about 10 minutes, a solution of (R)-tert-butyl 1-(hydroxyamino)-1-oxopropan-2-ylcarbamate (12.24 g, 59.94 mmol, 1.00 equiv.) and cyclopenta-1,3-diene (4.15 g, 62.78 mmol, 1.05 equiv.) in a mixture of dichloromethane/dimethylsulfoxide (5:1) (60 mL). The resulting mixture was stirred for at about −78° C. for about 30 minutes, and then triethylamine (66.8 mL) was added. The resulting mixture was washed with 1M hydrochloric acid (2×200 mL), and extracted with dichloromethane (3×100 mL). After the organic layers were combined, the organic phase was washed with 10% sodium bicarbonate (2×200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:10)) to give the desired product as a white solid (8.6 g; yield=53%). 1H NMR (300 MHz, CDCl3) δ: 6.54 (s, 1H), 6.39 (m, 1H), 5.22-5.34 (m, 3H), 4.51 (m, 1H), 2.02 (d, J=8.4 Hz, 1H), 1.86 (d, J=8.7 Hz, 1H), 1.43 (s, 9H), 1.09 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.Cl[C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C(OCC)(=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:15]2[N:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])[N:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)c1cccnc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2ncccc2C(=O)O)n(-c2ccccc2)n1
Temperature: 150 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
To a solution of 3-methyl-1-phenyl-1H-pyrazol-5-amine (600 mg, 3.46 mmol) and 2-chloronicotinic acid (546 mg, 3.46 mmol) in DMF (6 mL), was added potassium carbonate (543 mg, 3.93 mmol) and copper (II) acetate (18 mg). The mixture was stirred at 150° C. for 18 h, and then cooled to rt, and diluted with ethyl acetate (2×) and water. The solution was adjusted to pH 2-3 using 1 N aqueous HCl. The mixture was extracted with EtOAc (3×5 mL), and then the combined organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by HPLC (20-90% acetonitrile in water) to afford the product (126 mg, 18%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.19 (s, 3H), 6.62 (s, 1H), 6.77 (m, 1H), 7.34 (m, 1H), 7.45 (m, 2H), 7.53 (m, 2H), 8.16 (d, 1H), 8.22 (d, 1H), 12.32 (s, 1H); ES-MS m/z 295.1 (MH+); HPLC RT (min) 2.17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:21][C:20](=[O:22])[N:19]([CH3:23])[N:18]=2)[CH2:13][CH2:12]1.O.O.Cl[Sn]Cl>CO>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[O:21][C:20](=[O:22])[N:19]([CH3:23])[N:18]=3)[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: Cn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)oc1=O
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Cn1nc(C2CCN(c3ccc(N)cc3F)CC2)oc1=O
Yield: 78.7 %

Procedure:
5-[1-(2-Fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadazol-2-one (5b, 1.23 g, 4 mmol) on reacting with CH3I (0.68 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at 0° C. for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (6d, 1.18 g, 92%). Nitro compound (6d, 1.29 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5[1-(4-amino-2-fluorophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7f, 920 mg, 83%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7f, 0.29 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-3-fluoro-4-[4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8f, 375 mg, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][S:22][CH2:23]Cl.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:21][S:22][CH3:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSCCl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (13 g) in dirnethylformamide (100 ml) was added 60% sodium hydride (2.5 g) under an argon atmosphere, and the mixture was stirred at room temperature for 30 minutes. Then, chloromethyl methyl sulfide (5.2 ml) was dropwise added with ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=20:1-10:1) and dried under reduced pressure to give the title compound (9.6 g).
Reaction SMILES: [CH3:1][C:2]([NH:25]C(=O)OCC1C=CC=CC=1)([CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1>C(O)C.[Pd]=O>[CH3:1][C:2]([CH3:24])([NH2:25])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: CC(C)(CCCCOCCCCc1ccc(N2CCOCC2)cc1)NC(=O)OCc1ccccc1
Agent: O=[Pd]
Solvent: CCO
Product: CC(C)(N)CCCCOCCCCc1ccc(N2CCOCC2)cc1
Yield: 90.3 %

Procedure:
A solution of the product of stage (ii) (4.60 g) in absolute ethanol (75 ml) was hydrogenated at room temperature and atmospheric pressure over a pre-reduced 10% palladium oxide on carbon catalyst (1 g, 50% paste in water) in absolute ethanol (25 ml). The catalyst was removed by filtration through `hyflo` and the solvent evaporated in vacuo at 40° to yield the title compound as a colourless oil (3.0 g). T.l.c. (T-ET-A 39:10:1) Rf 0.32.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[CH3:32][O:33][C:34](=[O:54])[CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38](OS(C(F)(F)F)(=O)=O)[CH:37]=1>>[CH3:32][O:33][C:34](=[O:54])[CH2:35][C:36]1[CH:37]=[C:38]([C:14]2[CH:15]=[CH:16][C:17]([C:19]([F:21])([F:20])[F:22])=[CH:18][C:13]=2[CH2:12][N:3]([C:4](=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:1][CH3:2])[CH:39]=[C:40]([C:42]([F:44])([F:43])[F:45])[CH:41]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)c1ccccc1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: N-ethyl-N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-benzamide and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:17]/[C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:18])=[CH:5][C:4]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1ccc(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 71 %

Procedure:
The title compound was prepared by condensing 4-methoxy-3-(thiophen-2-yl)-benzaldehyde (Ex-41A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 219–220° C., 71% yield. 1H-NMR (DMSO-D6) δ 13.36 (br s, 1H), 8.25–8.31 (m, 3H), 8.11 (d, J=8 Hz, 2H), 7.85–7.98 (m, 3H), 7.78–7.80 (m, 1H), 7.61 (d, J=5 Hz, 1H), 7.25 (d, J=9 Hz, 1H), 7.17 (dd, J=4, 6 Hz, 1H), 3.99 (s, 3H). HRMS m/z=calc. 365.0848, found 365.0833.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[Cl:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31].C(Cl)Cl.CO>C(#N)C>[Cl:26][CH2:27][CH2:28][CH2:29][C:30]([NH:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1)=[O:31]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: O=C(Cl)CCCCl
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=O)CCCCl)c4c(c23)C1=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
A solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 4 mL of acetonitrile was stirred at 20° C. 68 μL of 4-chlorobutyryl chloride were added. The mixture was magnetically stirred at 20° C. during 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 70 mg (yield: 53%) of the desired product (formula below) as an orange powder
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH:20]([CH3:22])[CH3:21])[N:11]([CH3:23])[C:10]2=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br-].[Br-].[Br-].C1([N+](CC)(CC)CC)C=CC=CC=1.C1([N+](CC)(CC)CC)C=CC=CC=1.C1([N+](CC)(CC)CC)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:24])[N:11]([CH3:23])[N:12]([CH:20]([CH3:21])[CH3:22])[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)N1C(c2ccncc2)C(c2ccc(Cl)c(Cl)c2)C(=O)N1C
Agent: CC[N+](CC)(CC)c1ccccc1
Agent: [Br-]
Solvent: ClCCl
Product: CC(C)n1c(-c2ccncc2)c(-c2ccc(Cl)c(Cl)c2)c(=O)n1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The solution of 4-(3,4-Dichloro-phenyl)-1-isopropyl-2-methyl-5-pyridin-4-yl-pyrazolidin-3-one 40 mg in dichloromethane 10 mL was treated with phenyltriethylammonium tribromide 0.1 g at room temperature, The reaction mixture was stirred at room temperature for 15 h. The reaction was quenched with sat. Na2SO3 25 mL at 0° C. The reaction mixture was extracted with dichloromethane, 3×25 mL. The combined organic phase was washed with brine, dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as light yellow solid 20 mg. MS (ES+): 362 (M+H)+.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].B(F)(F)F.[CH3:30]COCC>CO>[CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([O:25][CH3:30])=[O:24])[S:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOCC
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)O)c1
Agent: FB(F)F
Solvent: CO
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OC)c1
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 4-(hexadecylamino)-2-thiophenecarboxylic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice-cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield methyl 4-(hexadecylamino)-2-thiophenecarboxylate as a white solid.
Reaction SMILES: C[O-].[Na+].[Na].[OH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:16].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>CO>[O:21]1[CH2:20][CH:19]1[CH2:17][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:16]
Reactant: O=C1NCCc2c(O)cccc21
Reactant: ClCC1CO1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C1NCCc2c(OCC3CO3)cccc21
Reaction time: 2 h
Yield: 34 %

Procedure:
To a solution of sodium methoxide (made from 2.4 g (106 mmol) of sodium) in 360 ml of methanol was added 14.5 g (106 mmol) of 3,4-dihydro-5-hydroxy-1(2H)-isoquinolinone. Then 22.2 g of epichlorohydrin in 250 ml of methanol was added dropwise at 55°. After 18 hours an additional 5 g of epichlorohydrin was added and the mixture was stirred for two hours more. The reaction was cooled and concentrated. The residue was chromatographed (SiO2, chloroform/methanol 8:1) to provide 7.9 g (34%) of the desired product. An analytical sample was obtained by recrystallization from chloroform; mp 165°-166°.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)=[C:4]([NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[C:3]1=[O:36].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[C:4]([NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[C:3]1=[O:36]
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(C)c3ncccc23)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)Nc1c(-c2cccc(O)c2)c2cccnc2n(C)c1=O
Reaction time: 6 h
Yield: 65.2 %

Procedure:
To a solution of N-[1-methyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (1310 mg, 2.7 mmol) in methylene chloride (20 ml) was added dropwise boron tribromide (1.7 g, 6.75 mmol) at 0° C., and the mixture was stirred for 6 hours. The mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with methylene chloride. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, purified by silica gel column chromatography (3% methanol in chloroform), and crystallized from diethyl ether/hexane to give the title compound (830 mg, 1.76 mmol) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC1C=CC=CC=1Cl>[F:14][C:12]1[CH:11]=[CH:10][C:9]2[NH:15][C:4]3[C:3]([C:8]=2[CH:13]=1)=[C:2]([F:1])[CH:7]=[CH:6][CH:5]=3
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1ccccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: Fc1ccc2[nH]c3cccc(F)c3c2c1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A solution of 2′,5-difluoro-2-nitro-1,1′-biphenyl (1.400 g, 6.0 mmol) and triphenylphosphine (3.903 g, 14.9 mmol) in anhydrous 1,2-dichlorobenzene (5 mL) was heated to 175° C. in a microwave reactor for 4 hrs. The mixture was cooled to room temperature and purified by silica gel chromatography (5-50% methylene chloride/hexanes) to afford the product as a light brown solid (0.62 g, 51%). 1H NMR (CDCl3, 300 MHz) δ 8.12 (br s, 1H), 7.87 (dd, 1H, J=9.0, 2.4 Hz), 7.41-7.31 (m, 2H), 7.24-7.15 (m, 2H), 6.91 (dd, 1H, J=10.2, 8.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:20]([F:34])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.C(#N)C.Cl.[OH-].[Na+]>C(OCC)(=O)C.O>[NH2:1][C:2]1[C:3]([C:18]2[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[C:20]([F:34])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: Nc1ncc(C2CCC3(CC2)OCCO3)nc1-c1ccc(C(=O)NCc2ccccc2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Nc1ncc(C2CCC(=O)CC2)nc1-c1ccc(C(=O)NCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-(3-amino-6-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazin-2-yl)-N-benzyl-2-fluorobenzamide (170 mg, 0.368 mmol) was added acetonitrile (3 mL), water (2 mL) and then HCl 3M aqueous solution (0.613 mL, 1.838 mmol). The reaction was stirred at room temperature for 30 min followed by LCMS. To the reaction was added 200 mL of ethyl acetate, basified with excess 1M NaOH. The aqueous layer was extracted and the organic layer was washed with water (3×), filtered and concentrated to residue to give the desired product as free base. Assume quantitative yield (0.368 mmol). LCMS (m/z): 419.3 (MH+), 0.75 min.