Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1.[Cl-].[Na+]>O.CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:32][CH2:33][C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[NH:36][CH:35]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3cc(OCCc4c[nH]c5ccccc45)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (500 mg, 1.51 mmol), cesium carbonate (980 mg, 3.02 mmol), 3-(2-bromoethyl)indole (375 mg, 1.66 mmol), and DMF (10 mL) were combined and stirred at ambient temperature overnight followed by heating at 80° C. for 4 hours. The reaction mixture was cooled to ambient temperature and poured into 200 mL of water containing 20 g of sodium chloride. The resulting precipitate was filtered, dissolved in dichloromethane, and purified by flash column chromatography on silica gel, eluting with a gradient of 0-8% methanol in dichloromethane. Clean fractions were combined and concentrated. The solid was slurried in hot acetonitrile, filtered, and dried under reduced pressure to yield 305 mg of 1-(4-amino-2-ethoxymethyl-7-[2-(1H-indol-3-yl)ethoxy]-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as an off-white solid, mp 220.0-222.0° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])/[C:2](=[C:4](\[CH:6]=O)/[Cl:5])/[Cl:3].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>C1C=CC=CC=1>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:6]2[O:9][C:1](=[O:8])[C:2]([Cl:3])=[C:4]2[Cl:5])=[CH:11]1
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Reactant: c1ccc2[nH]ccc2c1
Solvent: c1ccccc1
Product: O=C1OC(c2c[nH]c3ccccc23)C(Cl)=C1Cl
Temperature: 25 °C
Yield: 16.5 %

Procedure:
A stirred mixture of 20.3 g (0.12 mole) of mucochloric acid, 14.1 g (0.12 mole) of indole and 125 ml of benzene was heated for approximately twenty hours at reflux temperature. The reaction mixture was cooled to ambient temperature and a dark brown solid which had separated was collected by filtration. This solid was purified by two successive recrystallizations from benzene at approximately 60° C., with the aid of decolorizing charcoal. After the second recrystallization, the purified product was dried at 60° C. in vacuo to obtain 5.3 g of the known 5-(3-indolyl)-3,4-dichloro-2(5H)-furanone (Formula VI: R=R1 =Y=H), a pale green-colored solid, which first melted at 174° C., then turned black and finally decomposed at 182° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][O:18][C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH2:3]1.[OH-].[Na+]>CO>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][O:18][C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:3]1
Reactant: CCCc1c(OCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O
Yield: 16.5 %

Procedure:
A mixture of 150 mg (0.277 mmol) of the titled product of Example 60, 3 ml of methanol, and 3 ml of 1N sodium hydroxide was stirred at reflux for one hour. The reaction mixture was permitted to cool and then partitioned between ethyl acetate and 3N hydrochloric acid. The aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and the solvent removed under reduced pressure. Crystallization of the residue from ethyl acetate gave 24 mg of the title compound as a solid, m.p. 159.5°-161.5° C.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33]C(=O)C)[CH2:20][C:21](OC)=[O:22])[CH2:14][C:15](OC)=[O:16])(=O)C.C1COCC1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[C:13](=[C:19](\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][SH:33])/[CH2:20][CH2:21][OH:22])/[CH2:14][CH2:15][OH:16]
Reactant: COC(=O)CC(CCCCCCCCSC(C)=O)=C(CCCCCCCCSC(C)=O)CC(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCC/C(CCCCCCCCS)=C(\CCO)CCCCCCCCS
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
To a flamed-dried 20 mL vial fitted with a screw-cap septa was added Dimethyl 3,4-bis(8-(acetylthio)octyl)hex-3-enedioate (1 equiv, 0.36 mmol, 196 mg) and THF (4.5 mL). DIBAl-H (12 equiv, 4.3 mmol, 2.9 mL of a nominally 1.5 M solution in toluene) was added dropwise at rt. The reaction was stirred at rt for 2 h and quenched by the careful addition of 2N HCl (3 mL). The solution was transferred to a sepratory funnel and diluted with sat. aq. NH4Cl (15 mL) and Et2O (15 mL). The layers were separated and the aqueous layer extracted with Et2O (2×15 mL). The combined organic layers were washed with brine (20 mL), dried with Na2SO4, concentrated in vacuo, and purified by flash column chromatography (40% EtOAc/Hex) to afford (Z)-3,4-bis(8-mercaptooctyl)hex-3-ene-1,6-diol (82.8 mg, 0.205 mmol, 57%). TLC Rf=0.41 (50% EtOAc/Hex); Mp=67.4-68.2° C.; 1HNMR (600 MHz): δ 3.64 (t, 4H, J=6.9 Hz), 2.54 (q, 4H, J=7.4 Hz), 2.35 (t, 4H, J=7.0 Hz), 2.08-2.02 (4H), 1.68 (bs, 2H), 1.62 (quint., 4H, J=7.4 Hz), 1.42-1.27 (22H); 13CNMR (150 MHz): δ 132.4, 61.3, 34.6, 34.0, 31.7, 29.7, 29.5, 29.2, 29.0, 28.3, 24.6; FTIR: 3402, 3349, 2923, 2850, 1465, 1348, 1028, 721 cm−1; HRMS-ESI: calc. for C22H44NaO2S2 (M+Na)+: 427.2680. found: 427.2679.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[N+:7]=1[O-:14].OS(O)(=O)=O.[OH-].[Na+]>>[Br:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:2])[CH:9]=[C:8]([CH2:12][CH3:13])[N+:7]=1[O-:14]
Reactant: CCc1cccc(Br)[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc([N+](=O)[O-])cc(Br)[n+]1[O-]
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
With ice bath cooling HNO3 (100%, 25 ml) was added dropwise to 2-bromo-6-ethyl-pyridine 1-oxide (example 5a) (20.0 g, 99 mmol), followed by H2SO4 (98%, 17 ml). The mixture was stirred at 90° C. for 90 min and then cooled to rt. Crushed ice (500 g) was added and the pH was adjusted to pH 12 with 28% aqueous NaOH solution. After extraction with AcOEt (4×250 ml) the combined organic phases were dried (Na2CO3) and evaporated to give 15.9 g (65%) of a yellow solid mass which was directly used in the next step
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]([CH3:11])[CH3:10])[C:3]=1[NH2:12].[CH:13](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:12]=[CH:13][N:8]2[CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)Nc1ncnc(Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)n1cnc2c(Cl)ncnc21
Temperature: 115 °C

Procedure:
Compound 52A (268 mg, 1.44 mmol), triethyl orthoformate (2.4 ml, 14.36 mmol) and para-toluenesulfonic acid (27.3 mg, 0.144 mmol) were combined and heated at 115° C. overnight. Precipitation occurred upon cooling to room temperature. The precipitate was collected via filtration, rinsed with diethyl ether and dried under reduced pressure to yield the title compound 52B: 1H NMR (300 MHz, DMSO-d6) δ ppm 8.81 (1H, s), 8.78 (1H, s), 4.89 (1H, m), 1.58 (6H, d).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]([C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[CH:13][N:12]=1)[CH2:2][CH3:3].[N+:23]([O-])([OH:25])=[O:24].S(=O)(=O)(O)O>>[N+:23]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([C:11]2[NH:16][C:15](=[O:17])[C:14]([C:18]3[NH:22][N:21]=[N:20][N:19]=3)=[CH:13][N:12]=2)[CH:7]=1)([O-:25])=[O:24]
Reactant: CCCOc1ccccc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCOc1ccc([N+](=O)[O-])cc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
2-(2-n-Propoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one (1.03 g., 3.46 mmoles) was added over a period of 20 minutes to a cooled (5°) mixture of 70% nitric acid (1.7 ml., 26.9 mmoles) and concentrated sulfuric acid (2 ml.). The mixture was allowed to stand at room temperature for 2 hours. The mixture was poured onto ice-water (200 ml.). The precipitate was recrystallized from 2-methoxyethanol to give the title compound (0.73 g., 61.3%), m.p. 251°-252° (decomp).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1.Cl.[N:31](OCCC(C)C)=[O:32].C(N(CC)CC)C>O1CCOCC1.O>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[N:31][OH:32])[C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(C)CCON=O
Reactant: CC(=O)Cc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)C(=NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g of 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)propan-2-one are introduced into 4 ml of HCl 5% in dioxane, then 0.6 g of isopentyl nitrite is added dropwise thereto. After 1 hour's stirring at room temperature, 0.8 ml of triethylamine is added. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phase and purification over silica gel, 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-propane-1,2-dione 1-oxime is obtained. 1H-NMR (CDCl3) 300 MHz: 2.30 (m, 2H), 2.51 (s, 3H), 4.16 (t, 2H), 4.30 (t, 2H), 4.58 (d, 2H), 6.11 (t, 1H), 6.84 (s, 2H), 6.98 (d, 2H), 7.34 (d, 2H), 8.30 (s, 1H)
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O>>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([CH2:39][C:35]6[O:34][CH:38]=[CH:37][N:36]=6)[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: O=Cc1ncco1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(Cc4ncco4)C3)ccc1-2
Yield: 44 %

Procedure:
Following the procedure for 423, a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and oxazole-2-carbaldehyde were reacted. The crude product was purified by flash chromatography (SiO2, 0-6% 2N NH3/MeOH in DCM) to give an oil. The oil was triturated with ether, the resulting solid filtered off and washed with ether to give 481 as a cream solid (81 mg, 44%). LCMS: RT=3.21 min, [M+H]+=449. 1H NMR δ (ppm) (CDCl3): 8.30 (1 H, d, J=8.18 Hz), 7.89 (1 H, s), 7.62 (1 H, d, J=0.84 Hz), 7.08 (1 H, dd, J=8.21, 1.86 Hz), 7.06 (1 H, d, J=0.83 Hz), 6.96 (1 H, d, J=1.83 Hz), 5.93-5.84 (1 H, m), 4.38 (2 H, t, J=5.06 Hz), 3.87 (2 H, t, J=7.32 Hz), 3.80 (2H, s), 3.78-3.69 (1 H, m), 3.41-3.34 (4 H, m), 1.60 (6 H, d, J=6.63 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13]Cl.[CH3:21][NH:22][CH2:23][CH2:24][OH:25].[I-].[K+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>CN1CCCC1.O>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][N:22]([CH3:21])[CH2:23][CH2:24][OH:25]
Reactant: CNCCO
Reactant: ClCCCC(Oc1cc(Cl)ccc1Cl)c1ccccc1
Agent: CN1CCCC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [I-]
Solvent: O
Product: CN(CCO)CCCC(Oc1cc(Cl)ccc1Cl)c1ccccc1
Reaction time: 4 h

Procedure:
A solution of the product from step (b) (0.20 g, 0.61 mmol), 2-(methylamino)ethanol (0.137 g,) 1.83 mmol) and potassium iodide (0.051 g, 0.31 mmol) in N-methylpyrrolidine was heated to 100° C. in a sealed vessel and stirred for 4 h. The reaction was cooled and poured into water (50 ml) and the mixture extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with water (3×30 ml), dried (magnesium sulphate) and evaporated. The residue was dissolved in methanol and treated with one equivalent of fumaric acid, stirred for ten minutes, then the solvent was removed in vacuo. The solid residue was triturated with ethyl acetate and the white solid obtained filtered off and dried to give the title compound (0.155 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14](OC)=[O:15])[CH2:11][CH:10]([C:18](OC)=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CC(C(=O)OC)CN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCC1CC(CO)CN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To dimethyl 1-benzylpiperidine-3,5-dicarboxylate (1.5 g, 5.15 mmol) in dry THF (30 mL) was added a solution of lithium aluminum hydride in THF (2M, 3.87 mL, 7.73 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. then warmed to 23° C. and stirred for 1.5 hour. A solution of methanol (0.5 mL) and (0.25 mL) was added followed by a 15% solution of NaOH (0.250 mL). The mixture was stirred for 1 hour at 23° C. then filtered. The organic material was extracted with ethyl acetate (3×20 mL) and the combined extracts were dried (MgSO4) and concentrated in vacuo to afford 0.91 g (75% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.26-7.35 (5H, m), 3.59 (2H, s), 3.44-3.55 (4 H, m), 3.06 (2 H, dt, J=10.6, 1.8 Hz), 1.88-1.98 (2 H, m), 1.79-1.86 (1 H, m), 1.68 (3 H, m). LCMS (+ESI, M+H+) m/z: 236.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)([CH2:13][CH2:14][O:15]C2CCCCO2)[CH2:10][C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([N:8]1[CH2:12][C:11]([CH2:13][CH2:14][OH:15])([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[CH2:10][C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(CCOC2CCCCO2)(c2ccc3ccccc3c2)CN1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1CC(CCO)(c2ccc3ccccc3c2)CN1Cc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
1-Benzyl-4-naphthalen-2-yl-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]pyrrolidin-2-one (003F145) (1.1620g, 2.71 mmol) was dissolved in methanol (2.7 mL) and treated with p-toluenesulfonic acid (0.0515 g, 0.27 mmol, 0.1 eq.). The solution was allowed to stir at 20° C. for 4 hours. The residue was chromatographed on silica gel with a gradient from 50% ethyl acetate in hexane to 5% methanol in dichloromethane to give the 0.6161 g (66%) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[C:31]([O:41][CH:42]2[O:44][C@H:43]2[CH3:45])=[CH:30][CH:29]=1>CO>[CH2:1]([N:8]([CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:10]1)[CH2:45][CH:43]([OH:44])[CH2:42][O:41][C:31]1[C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:39][C:40]=2[CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1ccc(S(=O)(=O)N2CCC(NCc3ccccc3)C2)cc1
Reactant: C[C@@H]1OC1Oc1cccc2[nH]c3ccccc3c12
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(N(Cc3ccccc3)CC(O)COc3cccc4[nH]c5ccccc5c34)C2)cc1
Yield: 111.5 %

Procedure:
To a solution of benzyl-[1-(4-butoxy-benzenesulfonyl)-pyrrolidin-3-yl]-amine (0.16 g, 0.4 mmol) in methanol (2 ml) was added (2S)-3-(9H-carbazol-4-yloxy)-methyl oxirane (0.12 g, 0.5 mmol) and the mixture was stirred at reflux for 3 days. The methanol was then evaporated, and the residue was washed with a mixture of ether and hexanes to give 0.28 g of an off-white solid; m.p. 73-76° C.; MS (ES) m/z 628.2 (MH+); HRMS (EI) Calcd. for C36H41N3O5S (M+): 627.2767, Found: 627.2808.
Reaction SMILES: [CH3:1][C@H:2]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C:3]([OH:5])=O.Cl.[NH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:10]([O:9][C:7](=[O:8])[NH:6][CH:2]([C:3](=[O:5])[NH:18][CH2:19][C:20](=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCC(=O)c1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(NC(=O)OCc1ccccc1)C(=O)NCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of commercially available N-α-CBZ-L-alanine (2.11 g, 9.5 mmol) in dichloromethane (50 mL) was added 2-aminoacetophenone hydrochloride (1.62 g, 9.5 mmol). The resulting solution was cooled to 0° C. and N-methylmorpholine (1.15 g, 11 mmol), 1-hydroxybenzotriazole (2.55 g, 18.9 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.35 g, 12.3 mmol), in that order, were added under an Argon atmosphere. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched by addition of saturated aqueous NaHCO3 solution; the separated organic phase was washed with 2N citric acid, saturated NaHCO3 solution and brine, then dried over MgSO4 overnight. After filtration and concentration, the residue was purified by column chromatography on silica gel (eluent, EtOAc:hexane-1:1) to yield the title compound, [1-(2-oxo-2-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=2)=[N:13][CH:14]=1.[CH3:29][C:30]1[C:34]([CH3:35])=[C:33]([NH:36][C:37](=O)[O:38]C2C=CC=CC=2)[O:32][N:31]=1.CC1C(C)=C(N)ON=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[CH:22]=[C:23]2[CH2:24][CH2:25][N:26]([C:37]([NH:36][C:33]3[O:32][N:31]=[C:30]([CH3:29])[C:34]=3[CH3:35])=[O:38])[CH2:27][CH2:28]2)=[N:13][CH:14]=1
Reactant: Cc1noc(NC(=O)Oc2ccccc2)c1C
Reactant: Brc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cc1noc(N)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1noc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(Br)cn4)c3)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
5-Bromo-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine trifluoroacetate (0.584 mmol, from Step 5), in acetonitrile (1.75 mL) was treated with phenyl 3,4-dimethylisoxazol-5-ylcarbamate (100 mg, 0.467 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3,4-dimethylisoxazol-5-amine) and diisopropylethylamine (0.305 mL, 1.75 mmol) and stirred at room temperature. After 2 h, the reaction was concentrated and the residue was purified by flash chromatography on silica gel (0-6% ethanol (containing 11% aq NH4OH):dichloromethane) to afford a clear oil which was evaporated from isopropyl ether/dichloromethane and evaporated again from diethyl ether/dichloromethane to give the title compound (0.200 g, 96% yield) as a white foam. MS (APCI) M+1=483.1; 1H NMR (400 MHz, CDCl3) δ ppm 1.89 (s, 3H) 2.20 (s, 3H) 2.43-2.49 (m, 2H) 2.56-2.62 (m, 2H) 3.45-3.52 (m, 2H) 3.56-3.62 (m, 2H) 6.41 (br. s, 1H) 6.61 (br. s, 1H) 6.86 (dd, J=8.68, 0.49 Hz, 1H) 6.95-7.02 (m, 2H) 7.04-7.09 (m, 1H) 7.37 (t, J=7.90 Hz, 1H) 7.79 (dd, J=8.58, 2.53 Hz, 1H) 8.22-8.24 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)(=[O:7])=[O:6].Br[C:18]1[N:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[N:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[CH:20][CH:19]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(NCCO)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(=O)(=O)NCCO)cc3)nc2)CC1
Yield: 26.6 %

Procedure:
The title compound (70 mg, 27%) was prepared as a white solid from (4-{[(2-hydroxyethyl)amino]sulfonyl}phenyl)boronic acid (130 mg, 0.55 mmol), 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 81, Step 1, 197 mg, 0.55 mmol), Pd(PPh3)2Cl2 (100 mg, 0.14 mmol), 2M Na2CO3 (2 mL) and DME (4 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.36 (d, 1H, J=2.9 Hz), 8.05 (d, 2H, J=8.6 Hz), 7.91 (d, 2H, J=8.6 Hz), 7.69 (d, 1H, J=8.8 Hz), 7.26 (dd, 1H, Ja=8.8 Hz, Jb=2.9 Hz), 5.11 (t, 1H, J=6.0 Hz), 4.96-4.83 (m, 1H), 4.20 (bs, 2H), 3.89 (d, 2H, J=6.2 Hz), 3.70-3.61 (m, 2H), 3.13-2.99 (m, 2H), 2.83-2.70 (m, 2H), 2.07-1.92 (m, 1H), 1.89-1.79 (m, 2H), 1.70 (bs, 1H), 1.37-1.17 (m, 8H); LRMS (ESI), m/z 478 (M+H).