Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH:11]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.Cl.[NH2:20][OH:21]>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8](/[CH:11]=[N:20]/[OH:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NO
Reactant: Cc1c(C=O)ccc(C#N)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1c(/C=N/O)ccc(C#N)c1Cl
Temperature: 70 °C
Reaction time: 4 h

Procedure:
2-chloro-4-formyl-3-methylbenzonitrile (5.0 g, 27.8 mmol) was dissolved in dry THF (60 ml). Pyridine (6.7 ml, 84.0 mmol) and hydroxylamine hydrochloride (3.87 g, 55.7 mmol) were added to the solution. The mixture was heated to 70° C. and stirred for 4 h. THF was evaporated and ice water (50 ml) was added. The mixture was stirred for 1 h and the precipitate was filtered off and washed twice with cold water. After drying (5.3 g) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 2.48 (s, 3H), 7.79 (m, 2H), 8.45 (s, 1H), 11.93 (s, 1H).
Reaction SMILES: O.Cl(O)(=O)(=O)=O.[CH2:7]([N:14]1[CH2:22][CH2:21][C:17]2([C:19](=[O:20])C2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-:24].[Na+].[Na+]>O1CCCC1>[CH2:7]([N:14]1[CH2:22][CH2:21][C:17]([CH2:19][OH:20])([OH:24])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CC12CCN(Cc1ccccc1)CC2
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: OCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
100 ml water and 10 ml perchloric acid were added to 100 ml solution of 6.8 g of this 6-benzyl-1-oxo-6-azaspiro[2.5]octane in tetrahydrofuran, and the mixture was stirred at room temperature for 7 hr. The mixture was ice-cooled, and aqueous sodium carbonate was added thereto to adjust the pH thereof to 7, and then the mixture was evaporated. Ethyl acetate was added to the residue, and the insoluble mattters were removed by filtration. The filtrate was evaporated, and then purified by silica gel column chromatography to give 4 g of 1-benzyl-4-(hydroxymethyl)-4-piperidinol.
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[C:12]([F:18])=[N:13][CH:14]=[CH:15][C:16]=1I.[O:19]=[C:20]([CH2:25][CH3:26])[C:21]([O:23][CH3:24])=[O:22].O.C1COCC1>CCCCCC.C1COCC1>[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[C:12]([F:18])=[N:13][CH:14]=[CH:15][C:16]=1[C:20]([OH:19])([CH2:25][CH3:26])[C:21]([O:23][CH3:24])=[O:22]
Reactant: Fc1nccc(I)c1C1OCCO1
Reactant: CCC(=O)C(=O)OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)(C(=O)OC)c1ccnc(F)c1C1OCCO1

Procedure:
6.9 ml (11 mmol) of 1.6M butyllithium in hexane are added dropwise to a solution, stirred at −78° C. under an argon atmosphere, of 3.1 g (11 mmol) of 3-(1,3-dioxolan-2-yl)-2-fluoro-4-iodopyridine in 100 ml of THF. The reaction mixture is then stirred for 10 minutes at −78° C. before the dropwise addition of a solution of 1.5 g (13 mmol) of methyl 2-oxo-butyrate in 20 ml of THF. The mixture is stirred for 3 hours at −78° C., hydrolysed with a mixture of water/THF, and decanted. The aqueous phase is extracted 3 times with 50 ml of ethyl acetate each time, and the combined organic phases are dried over magnesium sulphate and then concentrated. The expected product is obtained by purification of the residue by chromatography over silica (eluant:dichloromethane/acetone 95/5).
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)COCC(O)(C1C=CC=CC=1)C[CH2:11][N:12](C)[C:13](=[O:18])[C:14]([F:17])([F:16])[F:15].C[OH:37]>N>[CH3:11][NH2:12].[C:13]([OH:18])([C:14]([F:17])([F:16])[F:15])=[O:37]
Reactant: CN(CCC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)C(=O)C(F)(F)F
Reactant: CO
Agent: N
Product: CN
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-(3,5-bis(trifluoromethyl)benzyloxy)-3-hydroxy-3-phenylbutyl)-2,2,2-trifluoro-N-methylacetamide (7.5 mg, 0.015 mmol) was dissolved in excess ammonia in methanol (2 M, 2 ml) and stirred at room temperature for 1 hour. The solution was concentrated, and the residue was purified by preparative HPLC and to give mono-methyl amine as a TFA salt. 1H NMR (500 MHz, MeOH) δ ppm 7.69 (s, 2H) 7.68 (s, 1H) 7.31–7.38 (m, 2 H) 7.19–7.25 (m, 2 H) 7.14 (t, J=6.71 Hz, 1 H) 4.49–4.56 (m, 2 H) 3.60–3.64 (m, 1 H) 3.53–3.57 (m, 1 H) 2.77–2.84 (m, 1 H) 2.66–2.74 (m, 1 H) 2.42–2.47 (m, 3 H) 2.16–2.24 (m, 1 H) 2.06 (ddd, J=13.89, 7.93, 5.65 Hz, 1 H); 13C NMR (126 MHz, MeOH) δ ppm 144.34 (s) 143.23 (s) 132.78 (q, JCCF=33.94 Hz) 129.56 (s) 128.83 (s) 128.61 (s) 126.65 (s) 124.90 (q, JCF=271.28 Hz) 122.31 (s) 79.55 (s) 77.00 (s) 72.87 (s) 46.94 (s) 35.46 (s) 33.81 (s); HRMS [ESI, MH+] m/z calcd for C20H22NO2F6 422.1555, found 422.1552.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:13]=[C:12](I)[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.C(#N)C.C(N(CC)CC)C.[CH2:28]([NH:31][C:32](=[O:45])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[C:29]#[CH:30]>CN(C=O)C.[Cu](I)I>[C@@H:1]1([N:9]2[CH:13]=[C:12]([C:30]#[C:29][CH2:28][NH:31][C:32](=[O:45])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:42])([F:43])[F:41])[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: C#CCNC(=O)CCCCCNC(=O)C(F)(F)F
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CCCCCNC(=O)C(F)(F)F)NCC#Cc1cc([N+](=O)[O-])n([C@H]2C[C@H](O)[C@@H](CO)O2)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
1-(2-Deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (354 mg, 1 mmol, containing α-anomer) was azeotroped twice with anhydrous acetonitrile in a 50 mL flask, followed by addition of copper iodide (31 mg, 160 μmol) and tetrakistriphenylphosphine palladium (0) (58 mg, 50 μmol). After these materials were dissolved in anhydrous DMF (5 mL), triethylamine (210 μL, 1.5 mmol) was added while stirring at room temperature and further stirred at room temperature under light-shielding conditions. To this mixture, a solution of N-(2-propynyl)-6-trifluoroacetamidohexanamide (396 mg, 1.5 mmol) in DMF (4 mL) was added dropwise and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (5-10% CH3OH in CH2Cl2) and C18-HPLC (39-41% CH3CN in H2O, 15 minutes) to give the desired product as an amorphous substance (408 mg, yield 83%).
Reaction SMILES: [C:1]1([C:3]([CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:15])O)=[CH:4][C:5](=[CH:7][CH:8]=1)O)[OH:2].C1C=CC=CC=1.C1(C)C=CC=CC=1>C1CCCCC1>[O:2]1[C:1]2[C:3](=[CH:4][CH:5]=[CH:7][CH:8]=2)[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][OH:15]
Reactant: Oc1ccc(O)c(CCCCC(O)O)c1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: C1CCCCC1
Product: OCCC1CCc2ccccc2O1

Procedure:
The hydroquinonepentanediol compound (19) is refluxed in a nonpolar organic solvent (for example, benzene, toluene, or cyclohexane) in the presence of an alkyl or phenylsulfonic acid (for example, p-toluenesulfonic acid) to cause an intramolecular dehydrocondensation, and then cyclization, whereby the chroman ethanol compound (110) is obtained while retaining the chirality. Accordingly, the configuration of the chiral central carbon atom stemming from the starting mevalonolactone (12) is introduced into the 2-position of the chroman ring. The purification is carried out by silica gel column chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[C:12]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]1.O>CN(C)C(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)C1(n2cc([N+](=O)[O-])cn2)CCC1
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (8.2 g) in N,N-dimethylacetamide (70 mL) was added sodium hydride (60% in mineral oil, 3.2 g) in an ice bath, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added ethyl 1-bromocyclobutanecarboxylate (15 g) in an ice bath, and the mixture was stirred at room temperature for 10 hr. Water was poured into the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.C[Si](N[Si](C)(C)C)(C)C.C1C(=O)N([Br:33])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:33][CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[S:9][C:10]=1[C:14]([OH:16])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1sc(-c2ccc(Cl)cc2)nc1CBr
Yield: 72 %

Procedure:
Following the procedure described in Part D of Example 1, 1.00 g of commercially available of 2-(4-chlorophenyl)-4-methylthiazole-5-carboxylic acid, 0.502 mL of HMDS, 0.702 g of NBS and 32 mg of AIBN in 3.40 mL of CCl4 afforded the title compound (0.940 g, 72% yield) as a yellow/orange solid: 1H NMR (500 MHz, DMSO-d6) δ 11.06 (1H, br. s.), 8.02 (2H, d, J=8.25 Hz), 7.61 (2H, d, J=8.80 Hz), 5.01 (2H, s); HPLC retention time: 3.591 min; LCMS (ES): m/z 334 [M+H]+.
Reaction SMILES: CON(C)[C:4](=[O:14])[CH2:5][CH2:6][C:7]([CH3:13])([CH3:12])[C:8]([O:10][CH3:11])=[O:9].[F:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[C:21]([F:23])[CH:22]=1>C1COCC1>[F:16][C:17]1[CH:18]=[C:19]([C:4](=[O:14])[CH2:5][CH2:6][C:7]([CH3:12])([CH3:13])[C:8]([O:10][CH3:11])=[O:9])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: COC(=O)C(C)(C)CCC(=O)N(C)OC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CCC(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 5-[methoxy(methyl)amino]-2,2-dimethyl-5-oxopentanoate from Step C (4.68 g, 21.6 mmol) in THF (46.8 mL), cooled to 0° C., was added 3,5-difluorophenyl magnesium bromide (65 mL, 0.5 M in THF, 32.3 mmol) over 30 minutes. The reaction was allowed to stir at ambient temperature for 2 h, after which time no additional reaction progress was observed. Additional 3,5-difluorophenyl magnesium bromide (50 mL, 0.5 M in THF, 25.0 mmol) was added over 30 minutes. After 3 h at 0° C., the reaction was quenched by the rapid addition of a cold (0° C.) solution of EtOH (71 mL) and cone. HCl (5.0 mL). The reaction was then diluted with water (200 mL) and diethyl ether (400 mL). The organics were washed with water (200 mL×3) and brine (100 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. This residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:hexanes—50:50 to 100:0, to give the title compound. MS: m/z=239 (M−31(MeO−)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.Cl.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][C:27]([F:26])([F:36])[F:37])=[CH:30][CH:31]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6.1 mmol of 2-(4-((6-fluoro-2-quinoxalinyl)oxy)phenoxy)propionyl chloride in 15 ml of methylene chloride was added dropwise to an ice-cooled solution of 1.43 g (6.7 mmol) of 4-(trifluoromethoxy)aniline hydrochloride and 1.54 g (15 mmol) of triethylamine in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 3 hours and then poured into a dilute aqueous HCl solution. The organic layer was separated, washed with a saturated NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual solid was taken up in boiling methanol, treated with charcoal and filtered through celite. The filtrate was allowed to cool to give 1.14 g (38 percent of theoretical) of the above-named product as colorless crystals which melted at 140.5°-142° C. The structure of the compound was confirmed by its IR and NMR spectrum. (Compound 8)
Reaction SMILES: C([N:8]1[C@@H:17]2[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CCO>[N:11]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:12]2[C@H:17]([CH2:16][CH2:15][CH2:14][CH2:13]2)[NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)[C@H]2CCCC[C@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN[C@H]2CCCC[C@H]21
Yield: 95.7 %

Procedure:
Pearlman's catalyst (0.24 g) was added to an EtOH (25 ml) solution of (4aS,8aR) -tert-butyl 4-benzyldecahydroquinoxaline-1-carboxylate (2.4 g, 7.26 mmol). This suspension was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was filtered through celite, and the residue was washed with EtOH. Then, the filtrate was concentrated under reduced pressure to obtain (4aS,8aR)-tert-butyl decahydroquinoxaline-1-carboxylate (1.67 g, yield: 96%) in a colorless oil form.
Reaction SMILES: [CH2:1]([NH:4][C@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[Cl:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[CH2:1]([N:4]([C@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)[C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH2:15][Cl:14])[CH:2]=[CH2:3]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: C=CCN[C@@H]1CCc2ccccc21
Solvent: ClCCl
Product: C=CCN(C(=O)C(C)(C)CCl)[C@@H]1CCc2ccccc21
Reaction time: 14 h

Procedure:
To the DCM solution of (1R) —N-allylindan-1-amine (prepared in Step A), cooled to −20° C., was added 3-chloro-2,2-dimethylpropanoyl chloride (872 mg, 5.63 mmol). After allowing the reaction to sit at −20° C. for 14 hours LCMS analysis indicated a complete consumption of secondary amine. The reaction mixture was then concentrated in vacuo to a reasonable volume of DCM. This DCM solution was then applied to a silica gel column for purification, eluting with a gradient of 10-50% EtOAc in hexanes to give the title compound. MS: m/z=314 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[CH3:49][O:50][C:51]1[CH:61]=[CH:60][C:54]([O:55][CH2:56][CH2:57]CO)=[CH:53][CH:52]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:57][CH2:56][O:55][C:54]2[CH:60]=[CH:61][C:51]([O:50][CH3:49])=[CH:52][CH:53]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccc(OCCCO)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OCCCOC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-methoxyphenoxy)-1-propanol (73 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (118 mg, yield 80%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C:12]1[CH:25]=[CH:24][C:15]2[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][O:18][C:14]=2[CH:13]=1>CCO.O>[NH2:3][C:12]1[CH:25]=[CH:24][C:15]2[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][O:18][C:14]=2[CH:13]=1
Reactant: CCOC(=O)c1coc2cc(N3C(=O)c4ccccc4C3=O)ccc12
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1coc2cc(N)ccc12
Reaction time: 2 h

Procedure:
A mixture of ethyl 6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-benzofuran-3-carboxylate (4.7 g, 14.0 mmol) in 200 mL of EtOH was added NH2NH2H2O (6.3 mL, 107.1 mmol, 85% in water) dropwise and the mixture was stired for 2 h at room temperature. The solvent was removed under vacuum and the residue was dissolved in water. The mixture was extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified with silca gel column chromatograph to give ethyl 6-amino-1-benzofuran-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.[O-]S([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=[CH:18][N+:19]=1[O-:31]
Reactant: CCOC(=O)c1cccnc1-c1ccc(F)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc[n+]([O-])c1-c1ccc(F)cc1F
Temperature: 30 °C

Procedure:
To a nitrogen purged, 12 L, 5-necked flask, fitted with an overhead stirrer, a thermocouple and a condenser, was charged ethyl 2-(2,4-difluorophenyl)nicotinate, 3 (144 g, 548 mmoles, 1.0 eq), and 4 L of CH2Cl2. With stirring, mCPBA was added over 5 minutes, and the temperature was gradually increased from 22 to 38° C. in 45 minutes (completeness of reaction determined by HPLC). The reaction was cooled to room temperature and the contents slowly poured into 3 L of water. Na2SO3 was added slowly (exotherm from 20 to 33° C.) until the peroxide test (starch/I2 paper) indicated no peroxides remained in the mixture. The aqueous layer was separated and the organic layer was washed with saturated NaHCO3 (˜3 L). The organic layer was dried with MgSO4, filtered, and concentrated to a brown thick oil. The oil was then treated with MTBE (2 L) and stirred to give a white precipitate, which was collected by filtration, washed with MTBE and dried under vacuum to give the title Compound 4.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(S(C)(=O)=O)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (34.2 mg, 0.059 mmol) and triethylamine (0.025 mL, 0.178 mmol) in DCM (0.5 mL) was added methanesulfonyl chloride (6.9 μL, 0.089 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (14.7 mg, 41.6%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.6 Hz, 6H), 1.82-1.93 (m, 2H), 2.02-2.08 (m, 2H), 2.77 (t, J=5.7 Hz, 2H), 2.84-2.93 (m, 2H), 2.98 (s, 3H), 3.24-3.32 (m, 2H), 3.45 (t, J=5.9 Hz, 2H), 4.10-4.18 (m, 3H), 4.50-4.55 (m, 1H), 5.67 (br s, 1H), 6.99-7.04 (m, 1H), 7.26-7.35 (m, 2H); ESI-MS m/z [M+H]+ 482.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[CH2:17][OH:18])=[CH:4][CH:3]=1.[F:19][C:20]1[C:25]([F:26])=[C:24](O)[CH:23]=[CH:22][C:21]=1[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[C:9]2[CH2:17][O:18][C:24]2[CH:23]=[CH:22][C:21]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:20]([F:19])[C:25]=2[F:26])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Reactant: OCc1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Product: O=C(O)CCc1ccc(OCc2c(C(F)(F)F)ccn2-c2ccc(Cl)cc2)c(F)c1F

Procedure:
The title compound was prepared by reacting the product prepared in Step D of Example 1 and ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate, according to the procedures described in Example 1, Steps E and F.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][NH:10][C:11](=[O:21])[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[N+:18]([O-:20])=[O:19])[N:6]=[N:5]1.[O:22](S(C1C=CC(C)=CC=1)(=O)=O)[S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=O)=[O:24]>C(Cl)Cl>[CH3:30][C:29]1[CH:31]=[CH:32][C:26]([S:23]([O:1][CH2:2][CH2:3][N:4]2[CH:8]=[C:7]([CH2:9][NH:10][C:11](=[O:21])[CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[N+:18]([O-:20])=[O:19])[N:6]=[N:5]2)(=[O:24])=[O:22])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C(Cn1ccnc1[N+](=O)[O-])NCc1cn(CCO)nn1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCn2cc(CNC(=O)Cn3ccnc3[N+](=O)[O-])nn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.1 %

Procedure:
To a round bottom flask was added the alcohol 20 (106 mg, 0.359 mmol), TEA (36.3 mg, 0.359 mmol) and DCM (10 mL). Ts2O (117 mg, 0.359 mmol) was added in one portion. The reaction was stirred at RT for 4 hrs. The reaction was then concentrated to dryness and purified on a silica gel cartridge using EtOAc:Hex as the eluent to afford 55 mg (34% yield) of 21 as a white solid. Mass Spec (lo-res): Calc'd for C17H19N7O6S: 449.11. found: 450.1 (M+H).