Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][O:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:26][OH:27]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][O:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=[N:26][OH:27])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: NO
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=O
Agent: Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=NO

Procedure:
By the general method described in Part F of Example 30, 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one was reacted with hydroxylamine hydrochloride to provide 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one oxime in about a 3.5 to 1 mixture of E and Z isomers as a white solid after recrystallization from a mixture of toluene and methanol, mp 220-223° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: Cc1cccc(CCN)c1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cccc(CCNc2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)c1
Temperature: 160 °C
Yield: 35.1 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(3-methylphenyl)ethanamine (300 mg, 2.22 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (125 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.03 (s, 3H), 2.79-2.82 (m, 2H), 3.49-3.51 (m, 2H), 5.35 (s, 2H), 5.99 (s, 2H), 6.28 (s, 1H), 6.92-7.10 (m, 4H), 7.41 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Cl-].[NH4+]>ClCCl>[Br:8][C:4]1[N:3]=[C:2]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Br)n2)CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-dibromopyridine (34 g) in dichloromethane (740 ml) is added dropwise, at −78° C. under argon, n-butyllithium (1.6 M in tetrahydrofuran, 100 ml). The reaction mixture is stirred at −78° C. for 20 minutes and then tert-butyl 4-oxopiperidine-1-carboxylate is added. The mixture is stirred at room temperature for 20 minutes. The reaction mixture is subsequently admixed with saturated ammonium chloride solution at 30° C. and the aqueous phase is removed. After the aqueous phase has been extracted with dichloromethane, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives tert-butyl 4-(6-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (60 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[OH:12])=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1nccc2ccc(Br)cc12
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: Brc1ccc2ccnc(OCc3ccccc3)c2c1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
To a 25 mL round-bottom flask containing 7-bromoisoquinolin-1-ol (500 mg, 2.23 mmol) was added TEA (0.467 mL, 3.35 mmol) and benzyl bromide (0.319 mL, 2.68 mmol) in DMF (10 mL) to give a brown solution. The reaction was heated to 80° C. overnight. After cooling to RT, the reaction mixture was concentrated in vacuo, and taken up in DCM and water. The aqueous layer was extracted with DCM (2×), and the combined organics fractions were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purify by flash column chromatography (10-30-50% EtOAc/Heptanes), providing the title compound (640 mg, 2.037 mmol, 91% yield). M+1=316.0. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.62 (d, J=2.01 Hz, 1H), 7.73 (dd, J=2.13, 8.41 Hz, 1H), 7.39 (d, J=8.28 Hz, 1H), 7.28-7.36 (m, 5H), 7.11 (d, J=7.53 Hz, 1H), 6.46 (d, J=7.28 Hz, 1H), 5.23 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:11]([O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)no1
Temperature: 50 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
A mixture of methyl 3-hydroxyisoxazole-5-carboxylate (5.0 g, 34.9 mmol), benzyl bromide (6.84 g, 40 mmol) and potassium carbonate (8.3 g, 60 mmol) in N,N-dimethylformamide (100 mL) was stirred at 50° C. for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 95:5 to 50:50). Solvent was removed to obtain a solid (1.68 g, 21%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:10][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(F)cc1OCc1ccccc1
Temperature: 90 °C

Procedure:
A mixture of the product from step (i) (3.0 g), potassium carbonate (4.42 g) and benzyl bromide (3.90 ml) in DMF (40 ml) was heated at 90° C. for 14 h. The mixture was partitioned between water/ethyl acetate, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 5:1, yield 6.3 g.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]C)=[O:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][C:11]1[O:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][C:7]=1[CH2:6][O:5][C:4]1[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=1[CH2:2][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1COc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.98 g), methyl 2-(4-hydroxyphenyl)acetate (0.51 g), anhydrous potassium carbonate (0.52 g), and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained oil, tetrahydrofuran (6 mL), and methanol (6 mL) was added a 1N aqueous sodium hydroxide solution (6 mL) and the mixture was stirred at room temperature for 2 hrs. Dilute hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (1.00 g, 76%) of 2-[4-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 173-174° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[S:44]1[CH:48]=[CH:47][CH:46]=[C:45]1[CH2:49][C:50](O)=[O:51]>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:50](=[O:51])[CH2:49][C:45]3[S:44][CH:48]=[CH:47][CH:46]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1cccs1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1cccs1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2-thiopheneacetic acid (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyo)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-thiophen-2-yl-acetamide (0.7 g, 78%) as a white solid: mp 171-173° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.24 min. (99%); 1H NMR (DMSO-d6) δ 2.02-2.09 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.77 (s, 2H), 4.72 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 6.95-6.97 (m, 2H), 7.35-7.38 (m, 1H), 7.65-7.69 (m, 1H), 7.78-7.84 (m, 2H), 8.70 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 36.35, 37.87, 48.84, 121.91, 124.90, 126.22, 126.60, 127.13, 131.52, 133.21, 134.68, 137.33, 138.97, 166.89, 167.42, 169.61, 169.78, 172.73; Anal. Calcd. for C20H17N3O5S: C, 58.39; H, 4.16; N, 10.21; S, 7.79. Found: C, 58.41; H, 4.01; N, 10.07; S, 7.62.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23].CNCCNC.CC(O)(C)C.[Na+].[I-:38]>C(Cl)Cl.[Cu]I>[I:38][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23]
Reactant: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: FC(F)(F)c1nc2ccc(I)cc2c(C(F)(F)F)c1-c1ccccc1

Procedure:
A mixture of 6-bromo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (273 mg, 0.650 mmol, Intermediate 8, step c), CuI (14 mg, 0.074 mmol), N,N′-dimethylethylenediamine (0.0158 mL, 0.147 mmol), t-BuOH (0.65 mL), and NaI (200 mg, 1.33 mmol) was microwaved at 150° C. for 30 min (Biotage). The reaction was diluted with DCM (10 mL), filtered through Celite® and a 0.45 um filter, and concentrated. The residue was flash chromatographed with a heptane to 20% EtOAc/heptane gradient to afford the title compound as a light yellow oil that crystallized upon standing.
Reaction SMILES: CCCCCC.[H-].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.[CH:19]([N:22]=[C:23]=[S:24])([CH3:21])[CH3:20]>C1COCC1>[CH:19]([NH:22][C:23]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=2)[CH:13]=[CH:14]1)=[S:24])([CH3:21])[CH3:20]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CC(C)N=C=S
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)NC(=S)n1ccc2cc(Cl)ccc21
Reaction time: 1 h
Yield: 61.7 %

Procedure:
A stirred slurry of hexane washed potassium hydride (0.87 g, 21.8 mmol) in 50 mL of dry THF was treated portionwise with 5-chloroindole (3.3 g, 21.8 mmol). The mixture was heated at reflux until a clear solution was obtained. A solution of isopropyl isothiocyanate (2.2 g, 21.8 mmol) in 5 mL THF was slowly added and stirring was continued for 1 hour. The solvent was evaporated and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The amber solids were recrystallized from EtOH to provide 3.4 g of the title compound as a tan solid, m.p. 135° C. (62% of theory).
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18](Br)[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O>C(Cl)Cl>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1c2cccc3c2C(CCC3Br)C1c1ccccc1
Reactant: C1COCCN1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)N1c2cccc3c2C(CCC3N2CCOCC2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A portion (600 mg) of the compound obtained in Example 132 was dissolved in anhydrous methylene chloride (10 ml) and to the solution was added morpholine (0.25 ml). The mixture was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:19-1:3) to yield 560 mg (92%) of the titled compound.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](I)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]#[CH:25]>C(#N)C.C(N(CC)CC)C>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:25]#[C:24][CH2:23][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH:15]=3)=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(I)ncc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Reaction time: 0.75 h
Yield: 74.4 %

Procedure:
A suspension of N-(1-adamantylmethyl)-5-chloro-2-iodoisonicotinamide (Example2(i)) (0.43 g) and tert-butyl prop-2-ynylcarbamate, (0.31 g) in anhydrous acetonitrile (5 ml) and triethylamine (5 ml) was purged with nitrogen for 5 minutes and the copper (I) iodide (0.004 g) and bis-triphenyphosphine palladium dichloride (0.014 g) were added. The mixture was stirred under nitrogen for 0.75 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel eluting with acetone:dichloromethane (1:19) to afford the sub-titled compound (0.34 g) as a yellow foam.
Reaction SMILES: [C@@H:1]12[O:11][CH2:10][C@@H:8]([O:9]1)[C:6](O)=[C:4](O)[C@@H:2]2[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([O:3][C@@H:2]2[CH:4]=[CH:6][C@H:8]3[CH2:10][O:11][C@@H:1]2[O:9]3)=[O:38])=[CH:35][CH:34]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: OC1=C(O)[C@H](O)[C@@H]2OC[C@H]1O2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O[C@@H]2C=C[C@H]3CO[C@@H]2O3)cc1
Yield: 78.5 %

Procedure:
1.28 g (10.0 mmol) of 1,6-anhydro-β-D-threo-hex-3-enopyranose, 5.25 g (20.0 mmol) of triphenyl phosphine, and 3.04 g (20.0 mmol) of 4-methoxybenzoic acid were added to 16 ml of dry THF, and a solution obtained by dissolving 3.48 g (20.0 mmol) of diethylazodicarboxylate in 16 ml of dry THF was gradually dropped in the above mixture in a nitrogen-sealed ice-water bath. The resultant solution was stirred at room temperature for 41 hours. The solvent was distilled from the reaction solution at a reduced pressure. Triphenyl phosphine oxide as a byproduct was eliminated from the residue using a silica gel column (eluent: chloroform). The solvent was distilled from the resultant eluate at a reduced pressure, and the residue was purified using a silica gel column (hexane:ethyl acetate=5:1) to obtain 2.06 g (yield: 78.5%) of 1,6-anhydro-3,4-dideoxy-2-O-(4-methoxybenzoyl)-β-D-eryt hro-hex-3-enopyranose. This product was recrystallized from a solvent mixture of hexane and diethyl ether.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C[O-].[Na+].[CH3:21][O:22][CH2:23]CCOS(C1C=CC(C)=CC=1)(=O)=O>CO.O>[CH3:21][O:22][CH2:23][CH2:16][CH2:15][S:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([OH:5])=[O:7])[CH2:13][CH2:12]1
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCSC1CCN(C(=O)O)CC1
Reaction time: 0.25 h

Procedure:
Amine preparation: A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.82 g) and potassium thioacetate (2.31 g) was heated to 60° C. in DMF (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (1.80 g). To a solution of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (607 mg) in dry MeOH (5 mL) was added a solution of sodium methoxide in MeOH (25% wt, 0.59 mL). After stirring for 15 min, toluene-4-sulfonic acid 3-methoxy-propyl ester (described elsewhere, 571 mg) was added in MeOH. After 24 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to yield 4-(3-methoxy-propylsulfanyl)-piperidine-1-carboxylic acid tent-butyl ester. Treatment with mCPBA (as described above) yielded 4-(3-methoxy-propane-1-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]1[CH2:22][N:21]([S:28]([CH2:31][CH:32]([CH:36]([CH3:38])[CH3:37])[C:33]([OH:35])=O)(=[O:30])=[O:29])[CH2:20][CH2:19][C:18]2=1.[Si]([O:46][NH2:47])(C(C)(C)C)(C)C.O>ClCCl>[OH:46][NH:47][C:33](=[O:35])[CH:32]([CH2:31][S:28]([N:21]1[CH2:20][CH2:19][C:18]2[C:17]3[C:25](=[CH:26][CH:27]=[C:15]([O:14][CH3:13])[CH:16]=3)[NH:24][C:23]=2[CH2:22]1)(=[O:29])=[O:30])[CH:36]([CH3:38])[CH3:37]
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)O)C(C)C)C3
Reactant: CC(C)(C)[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)NO)C(C)C)C3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.7 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (104 mg) was added to a slurry of 2-(6-methoxy-1,3,4,9-tetrahydro-β-carboline-2-sulfonylmethyl)-3-methylbutyric acid (172 mg) in dichloromethane (10 ml). The mixture was stirred for 5 minutes before addition of O-(t-butyldimethylsilyl)hydroxylamine (80 mg), then for 1.5 h. The mixture was poured into water (10 ml) and extracted with dichloromethane (3×15 ml). The combined organics were washed with water (2×50 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in dichloromethane (10 ml) and 1.0N hydrogen chloride in ether (2.5 ml) was added. The mixture was stirred at room temperature for 2 h. It was evaporated under reduced pressure and the residue chromatographed (SiO2, 5% methanol in dichloromethane) to give the title compound (37 mg, 21%) as a pale orange solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26](Cl)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26]([N:4]3[CH2:5][CH2:6][N:1]([CH2:7][C:8]#[N:9])[CH2:2][CH2:3]3)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: N#CCN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of piperazin-1-yl-acetonitrile (0.32 g, 2.3 mmol) and Et3N (350 mg, 3.4 mmol) is added 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (615 mg, 2.3 mmol) at 0° C. The reaction is warmed to room temperature and stirred 4 h. The reaction is diluted with CH2Cl2, washed with 1 N HCl, NaHCO3 and dried over MgSO4. The solution is concentrated and the residue is triturated with PE, triturated with Et2O, and pumped to yield [4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-1-yl]-acetonitrile which can be used without further purification. 1H NMR (300 MHz, CDCl3) δ7.89-7.84 (m, 3H), 7.48 (dd, 1H), 4.36 (s, 2H), 3.92 (s, 2H), 3.64-3.61 (m, 2H), 3.57-3.54 (m, 2H); MS (Ion Spray) 444 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:16]O>>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cncc(Br)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a suspension of 5-bromonicotinic acid (20 g, 99.0 mmol) in anhydrous MeOH (100 mL), was carefully added conc. H2SO4 (12 mL) via a syringe. After the addition the reaction mixture was heated to reflux overnight, then cooled to room temperature and concentrated on rotary evaporator. Ice-water (200 mL) was added and a white solid crashed out. The solid was collected by filtration, dissolved in EtOAc (300 mL), washed with aq. NaHCO3, water and brine, dried over MgSO4, filtered and evaporated to give 18 g of 5-Bromo-nicotinic acid methyl ester as a white powder. Yield 84%. 1H NMR (400 MHz, DMSO): 3.88 (s, 3H); 0.74 (s, 3H), 8.43 (s, 1H,), 8.96 (s, 1H), 9.02 (s, 1H). MS (M+H, 217).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[C:21]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:23])[CH3:22]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC(C)=O)C(=O)OCC

Procedure:
Alternatively, diethyl 2-aminomalonate hydrochloride (21.4 g, 100 mmol) and triethylamine (56 mL, 400 mmol, 4.0 eq.) were dissolved in dichloromethane (500 mL) and stirred with acetic anhydride (9.5 mL, 100 mmol, 1.0 eq.) at 0° C. and overnight at r.t. The mixture was washed with brine (2×200 mL) and dried over MgSO4. The organic phase was filtered through a short silica gel column I (6×6 cm, dichloromethane). The product 1 was isolated as a white crystalline solid. Yield: 22.08 g (100%); 99% purity (GC).