Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](/[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])\[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C\C=C\C(=O)O)c2ccccc2OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
As in Example 115, (E,E)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid (3.4 g) and 4-nitrophenol (1.8 g) in 25 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.27 g). The mixture was stirred at room temperature for 2 hours. After the usual work up, the ester was crystallized from 2-propanol to yield 3.0 g of (E,E)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester, mp 149°-150° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Br:7][C:8]1[CH:13]=[C:12]([C:14]2[C:23]3[C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[O:26][C:22]=3[C:21]([Br:31])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:11]=[C:10]([Br:32])[C:9]=1[OH:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:6][O:5][C:3](=[O:4])[CH2:2][O:33][C:9]1[C:8]([Br:7])=[CH:13][C:12]([C:14]2[C:23]3[C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[O:26][C:22]=3[C:21]([Br:31])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)=[CH:11][C:10]=1[Br:32]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3oc4ccccc4c23)cc1Br
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3oc4ccccc4c23)cc1Br
Reaction time: 21 h
Yield: 54.6 %

Procedure:
Methyl bromoacetate (0.554 mL, 5.8 mmol) was added to a stirred, room temperature suspension of 2, 6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]furan-11yl)-phenol (1.6 g, 2.92 mmol), potassium carbonate (0.81 g, 5.8 mmol) and dimethylformamide (7 mL). After 21 h, the reaction mixture was added to water and filtered. The solid was taken up in THF and silica gel was added. The solvent was removed. The adsorbate was flash chromatographed (9:1 petroleum ether:ethyl acetate as eluent) to provide the title compound as a white solid (0.987 g, 55%): mp 188-189° C.: NMR (DMSO-d6); δ8.37 (d, J=8 Hz, 1 H), 7.91 (s, 2 H), 7.84 (d, J=8 Hz, 1 H), 7.80 (ddd, J=8, 7, 1 Hz, 1 H), 7.70 (d, J=8 Hz, 1 H), 7.64-7.58 (m, 2 H), 7.31 (t, J=8 Hz, 1 H), 6.92 (d, J=8, 1 H), 4.88 (s, 2 H), 3.80 (s, 3 H); MS (EI): [M+], 3 bromine isotope pattern, 616 (30%), 618 (100%) 620 (100%) 622 (30%); Anal. Calc. for C25H15Br3O4: C, 48.50, H, 2.44, N, 0.00. Found: C, 48.53, H, 2.29, N, 0.00.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3]C)=[O:2].C(O)(=[O:32])C>O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[C:22]([C:23]([OH:24])=[O:32])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][CH:16]=1)([OH:3])=[O:2]
Reactant: CC(=O)O
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 1.03 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole in 10 mL of anhydrous acetic acid at 25° was added a solution of 0.62 g of chromium trioxide in 10 mL of water. The mixture was stirred at 25° for 15 minutes and then poured into water. The precipitated solids were recovered by filtration and then dissolved in 50 mL of 1.0N aqueous sodium hydroxide solution. The alkaline solution was allowed to stand at 25° overnight and then was acidified to pH 3 with 10% aqueous hydrochloric acid. The precipitated solid was recovered by filtration and recrystallized from ethyl acetate to afford 0.10 g of 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxylic acid (m.p. 186°-187° (decomp.)). NMR (DMSO-d6) δ 12.97 (br s, 2H); 7.68 (d, 1H); 7.53 (t, 1H); 7.41 (t, 1H); 7.34 (d, 1H); 7.28 (d, 2H); 7.02 (d, 2H); 5.61 (s, 2H); 2.60 (t, 2H); 1.53 (quint., 2H); 1.27 (sext., 2H); 0.81 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH2:14])[CH:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:5]2.[CH2:23]([C:25]1[CH:30]=[C:29]([CH2:31]OS(C)(=O)=O)[CH:28]=[CH:27][N:26]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:23]([C:25]1[CH:30]=[C:29]([CH2:31][NH:14][CH2:13][CH2:12][N:7]2[CH:6]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH:28]=[CH:27][N:26]=1)[CH3:24]
Reactant: NCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Reactant: CCc1cc(COS(C)(=O)=O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)ccn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
67 mg of 2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 180-b), 47 mg of 2-ethyl-4-[(methyl sulfonyl oxy)methyl]pyridine, and 30 mg of potassium carbonate were added to acetonitrile (2 ml), followed by stirring at 60° C. for 2 hours. After concentration, it was purified by PLC (chloroform:methanol=10:1) to obtain 26 mg (yield 28%) of a title compound as a yellow oily substance.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)[OH:7])[CH2:5][CH2:4]1.I[CH3:20]>O1CCCC1>[CH:3]1([CH:6]([O:7][CH3:20])[C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:4][CH2:5]1
Reactant: CI
Reactant: COc1cccc2cc(C(O)C3CC3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2cc(C(OC)C3CC3)oc12
Reaction time: 0.08 h

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.52 g) in tetrahydrofuran (60 ml) under an atmosphere of nitrogen was added slowly a solution of cyclopropyl-(7-methoxybenzofuran-2-yl)-methanol (1.88 g) in tetrahydrofuran (15 ml). After stirring for 5 minutes, iodomethane (1.6 ml) was added and the mixture concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml), the organic layer washed with water (100 ml), separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with dichloromethane afforded the title compound as a yellow gum (1.62 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.CO>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Solvent: CO
Product: Nc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6-bromo-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine (1.6 g, 5 mmol) in methanol (45 ml) ammonium sulfide (8.5 ml, 25 mmol, 20% solution in water) was added slowly. The mixture was stirred at room temperature for 30 minutes and then heated and refluxed for 5 h. The reaction mixture was concentrated and cooled to 0° C. The precipitate was filtered off, washed with cold methanol and dried to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]O)[CH:2]=1.[BrH:9]>CCOC(C)=O>[BrH:9].[Br:9][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1cccnc1
Agent: Br
Solvent: CCOC(C)=O
Product: BrCc1cccnc1
Yield: 122.9 %

Procedure:
To 3-pyridylcarbinol (2 g, 18.3 mmol) was added 47-49% hydrobromic acid (2 mL, 13.7 mmol). The solution was refluxed for 3 hours. The solution was diluted with EtOAc and extracted thrice with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give a solid. The solid was recrystallized in ethanol to afford the title compound as a white solid (2.13 g, 45.8%). ES (+) MS m/e=173 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]([CH3:15])=[CH2:14])=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH2:12][C:13]([CH3:15])([CH3:14])[O:11][C:4]=2[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=C(C)Cc1c(Cl)ccc([N+](=O)[O-])c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CC1(C)Cc2c(Cl)ccc([N+](=O)[O-])c2O1
Yield: 84.1 %

Procedure:
A mixture of 20.0 g (0.088 mole) of 3-chloro-2-(2-methyl-2-propen-1-yl)-6-nitrophenol and 0.35 g (0.002 mole) of p-toluenesulfonic acid in 100 mL of xylene was heated at reflux for approximately 16 hours. The solvent was evaporated under reduced pressure, leaving a residue which was passed through a column of silica gel, eluting with methylene chloride. The product-containing fractions were combined, washed with an aqueous solution of sodium hydroxide, dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure, yielding 16.85 g of 4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:12]=2)=[N:8][C:7]=1[CH3:26])=[O:5])C.[OH-].[Na+]>O1CCCC1.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:13]2[C:14]([CH3:16])=[CH:15][C:11]([C:9]3[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:26])[N:8]=3)=[N:12]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1sc(-c2cc(C)n(CCc3ccc(F)cc3)n2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C)n(CCc3ccc(F)cc3)n2)sc1C(=O)O
Yield: 70.7 %

Procedure:
A mixture of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-5-methyl-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid ethyl ester (0.32 g, 0.86 mmol), NaOH (0.17 g, 4.29 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was heated to reflux for 16 hr. The solvent was removed in vacuo and the residue was neutralized with 5% HCl to pH 5-6. The resulting solid was filtered and dried to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-5-methyl-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid as a white solid (0.21 g, 70% yield). This material was used without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1cn2ccnc2c(NCc2ccncc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(-c2cn3ccnc3c(NCc3ccncc3)n2)c1
Temperature: 25 °C

Procedure:
A mixture of (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-pyridin-4-ylmethyl-amine 4 (1.0 equiv.), 3-aminophenyl boronic acid (1.1 equiv.), Pd (PPh3)4 (0.10 equiv.), and K3PO4 (2.20 equiv.) in 4:1 1,4-dioxane:water is heated to 90° C. for 24 hr. The mixture is cooled to RT and partitioned between EtOAc and sat. NaHCO3. The aqueous phase is extracted with EtOAc and combined extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (EtOAc) to yield [6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-pyridin-4-ylmethyl-amine 5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[CH2:21][O:20]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]([OH:20])[CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]c(-c3ccc(OCC4CO4)cc3)nc2c1
Reactant: C1COCCN1
Product: OC(COc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1)CN1CCOCC1

Procedure:
The title compound was prepared from 6-bromo-2-[4-(oxiran-2-ylmethoxy)phenyl]-3H-imidazo[4,5-b]pyridine and morpholine.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]2[NH:11][CH:12]=[CH:13][C:4]=12.C([O-])([O-])=O.[Na+].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([N:6]1[CH:7]=[C:8]([CH:9]=[O:10])[C:3]([NH:2][CH3:1])=[C:4]2[CH:13]=[CH:12][N:11]=[C:5]12)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CNc1c(C=O)cnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1c(C=O)cn(Cc2ccccc2)c2nccc1-2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution of 4-methylamino-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.5 g, 2.86 mmol) in DMF is added Na2CO3 (900 mg, 8.6 mmol) and benzyl bromide (0.5 ml, 4.3 mmol). The reaction is stirred at room temperature for 12 hours. The reaction mixture is partitioned in 100 ml water and 100 ml ethyl acetate, extracted with ethyl acetate three times. The organic phase is combined and washed with brine, dried over Na2SO4. The crude product is purified by silica gel flash chromatography, eluted with 5% methanol in ethyl acetate to give the title compound as yellow solid. 1H NMR 400 MHz (DMSO-d6) δ 9.70 (s, 1H), 9.20 (q, 1H, J=5.2 Hz), 8.59 (s, 1H), 7.46 (m, 2H), 7.35 (m, 3H), 7.28 (d, 1H, J=2.8 Hz), 7.22 (d, 1H, J=2.4 Hz), 5.65 (s, 2H), 3.31 (d, 2H, J=2.4 Hz). MS m/z 266.2 (M+1).
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[CH2:12][C@H:11]([O:13]C2CCCCO2)[C@H:10]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][C:25](=[O:31])[CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@H:9]1/[CH:32]=[CH:33]/[C@@H:34]([O:40]C1CCCCO1)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CO>[OH:7][C@@H:8]1[CH2:12][C@H:11]([OH:13])[C@H:10]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][C:25](=[O:31])[CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@H:9]1/[CH:32]=[CH:33]/[C@@H:34]([OH:40])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCC(=O)COC(C)=O)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: CO
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCC(=O)COC(C)=O)[C@@H](O)C[C@H]1O
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A solution of the acetate of Example 25 (36 mg, 0.055 mmol) and PPTs (2 mg) in MeOH (1.0 mL) was stirred at 45° C. for 4 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was diluted with EtOAc and washed with 1N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 50%-100% EtOAc/hex) afforded 18 mg of the named compound.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([O:16][CH2:17][C@@H:18]2[CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)[CH:12]=[N:13][C:14]=1[Cl:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:9]1[CH:10]=[C:11]([O:16][CH2:17][C@@H:18]2[CH2:21][CH2:20][NH:19]2)[CH:12]=[N:13][C:14]=1[Cl:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C(=O)c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(OC[C@@H]2CCN2)cnc1Cl
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
5-benzoyl-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 107a is dissolved in CH2Cl2 (10 mL). The mixture is cooled to 0° C., TFA (10 mL) is added and the reaction is stirred for 45 minutes as it warms to room temperature. The mixture is concentrated in vacuo and taken up in a minimum amount of H2O. The aqueous mixture is basified with 15% NaOH and extracted with CH2Cl2 (200 mL), which is dried (MgSO4) and concentrated. The residue is chromatographed (silica gel) to afford the free amine. The isolated free amine is taken up in a minimum amount of Et2O, cooled to 0° C., and treated with HCl in EtOH to afford the hydrochloride salt.
Reaction SMILES: C([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:8])[OH:7])=O.Cl.O.[CH3:25]O>>[CH3:25][O:22][C:20](=[O:21])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:8])[OH:7])[NH2:3]
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: Cl
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O

Procedure:
deformylating formyl-α-L-aspartyl-L-phenylalanine in the presence of hydrogen chloride, methanol and water. Then, adding methanol and hydrogen chloride directly to the resulting solution to obtain the chloride salt of α-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:52])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[N:26]=[CH:25][N:24](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:23]=4)[CH:20]=3)[N:15](C3CCCCO3)[N:14]=2)[CH:8]=1)=[O:5]>Cl.O1CCOCC1>[NH:24]1[CH:25]=[N:26][C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:1])[CH3:52])[CH:12]=[CH:11][CH:10]=2)=[N:23]1
Reactant: CN(C)CC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
2-(Dimethylamino)-N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)acetamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature for 3 hours. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and purified by preparatory HPLC. (0.023 g, 13% yield over 2 steps): 1H NMR (CD3OD) δ 8.7 (d, 1H), 8.32 (br s, 1H), 8.17 (t, 1H), 8.05 (dd, 1H), 7.7 (t, 2H), 7.6 (dd, 1H), 7.4 (t, 1H), 3.18 (s, 2H), 2.38 (s, 6H); ES-MS (m/z) 362 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH:10]2[O:15][CH2:16][C:17]([O:20][CH3:21])([O:18][CH3:19])[CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH:13]=[O:14])[CH:10]2[O:15][CH2:16][C:17]([O:20][CH3:21])([O:18][CH3:19])[CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1(OC)COC2C(CO)CN(C(=O)OC(C)(C)C)C21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC1(OC)COC2C(C=O)CN(C(=O)OC(C)(C)C)C21
Reaction time: 0.67 h
Yield: 78.9 %

Procedure:
To a solution of the alcohol 1g (370 mg, 1.22 mmol) dissolved in dry DCM (10 mL) was added Dess Martin periodinane (673 mg, 1.59 mmol). The reaction was stirred for 40 minutes and then quenched by addition of 10 mL of 10% Na2S2O3: NaHCO3(sat) 1:1. The solution was diluted with DCM (50 mL) and extracted with a 1:1 mixture of 10% Na2S2O3: NaHCO3(sat) (50 mL). The organic phase was dried with Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (heptane: ethyl acetate (2:1) which gave the title compound (290 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:4](=[O:6])[C:3]4[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=4[Cl:1])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2,5-dichlorobenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (56% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.38-7.30, 6.97, 4.12-3.23, 1.50, 0.80-0.67, 0.51-0.38, 0.16-0.06. MS (ES+) m/z 448.2 (M+1).
Reaction SMILES: [S:1]([N:11]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH:23](=[N:25]/[S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])\[CH3:24]>C1COCC1>[CH3:29][C:28]([CH3:31])([S@@:26]([NH:25][C@@H:23]([C:12]1[N:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])[CH:15]=[CH:14][C:13]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:24])=[O:27])[CH3:30]
Reactant: C/C=N/[S@@](=O)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)OC(C)(C)C)c2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)OC(C)(C)C)c2[C@@H](C)N[S@@](=O)C(C)(C)C)cc1
Reaction time: 0.75 h
Yield: 43.1 %

Procedure:
To a solution of tert-butyl 1-tosyl-1H-pyrrole-3-carboxylate (,287a 1.67 g, 5.20 mmol) in 40 mL of THF at −78° C. was added LDA(Aldrich) (1.7 M solution in heptane/THF/ethylbenzene, 3.67 mL, 6.24 mmol) slowly dropwise. After 45 min, a solution of (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide (Prepared according to PCT Int. Appl., WO2005103020; 0.765 g, 5.20 mmol) in THF was added slowly dropwise via syringe over several min. After 15 min, the acetone/dry ice bath was removed and the reaction was quenched by dropwise addition of saturated aq. NH4Cl and Et2O. The organic layer was washed with saturated aq. NH4Cl once, saturated aq. NaCl once and the organics were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g ISCO redisep gold column) using 0-50% EtOAc/hexanes. The product-containing fractions were concentrated to afford tert-butyl 2-((R)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)-1-tosyl-1H-pyrrole-3-carboxylate (287b; 1.05 g, 2.24 mmol, 43% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.73 (2H, d, J=8.2 Hz), 7.28-7.34 (3H, m), 6.58 (1H, d, J=3.3 Hz), 5.95 (1H, d, J=9.2 Hz), 5.14 (1H, br. s.), 2.43 (3H, s), 1.50-1.54 (12H, m), 0.96 (9H, s). m/z (ESI, +ve) 469.1 (MA-1)11.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21]CC)=[O:20])[CH:13]=[N:14]2)C1C=CC=CC=1.[Li+].[OH-]>C1COCC1.O>[CH3:1][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[CH:13]=[N:14]2
Reactant: CCOC(=O)c1cnc2cccc(OCc3ccccc3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2ncc(C(=O)O)cc12

Procedure:
A solution of ethyl 5-methoxyquinoline-3-carboxylate (2.31 g, 10 mmol) prepared in stage B of example 2 and LiOH (0.4 g, 20 mmol) in THF (20 mL) and water (0.5 mL) was refluxed for 2 hours. After cooling, the solvents were evaporated under vacuum. The solid residue was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:10][CH2:11][Cl:12]>>[Cl:12][CH2:11][CH2:10][N:5]1[CH2:6][CH2:7][C:2]([CH3:1])([OH:8])[CH2:3][CH2:4]1
Reactant: ClCCBr
Reactant: CC1(O)CCNCC1
Product: CC1(O)CCN(CCCl)CC1

Procedure:
4-methylpiperidin-4-ol (made via literature methods) and 1-bromo-2-chloroethane are reacted using the procedure for Example OO to afford 1-(2-chloroethyl)-4-methylpiperidin-4-ol.