Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7](C(OCC)=O)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[CH:22]2.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[CH:22]2
Reactant: CCOC(=O)c1c(O)c2cc(-c3ccc4c(ccn4C)c3)c(Cl)cc2[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ccc2cc(-c3cc4c(O)cc(=O)[nH]c4cc3Cl)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
To a solution of ethyl 7-chloro-4-hydroxy-6-(1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydro-3-quinolinecarboxylate (Example 27) (50 mg, 0.126 mmol) in ethanol (5 mL) was added sodium hydroxide 1N (0.315 mL, 0.315 mmol). The reaction mixture was stirred at 80° C. for 2 h. Additional solution of 1N sodium hydroxide was added (1 mL) and the reaction mixture was stirred at 160° C. for another 30 nm under microwave irradiation. After cooling, the solvent was evaporated and the mixture was dissolved in water and acidified with 1N HCl. The resulting solid was filtered, dried then triturated in hot acetonitrile, filtered and dried to give the title compound 7-chloro-4-hydroxy-6-(1-methyl-1H-indol-5-yl)quinolin-2(1H)-one (16 mg, 0.049 mmol, 39.1% yield) as a cream solid. LCMS: (M+H)+=325; Rt=2.66 min. HRMS: calculated for C18H14ClN2O2 (M+H)+: 325.0744. found: 325.0739.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][CH2:11][C@H:10]([NH:19][C:20](=[O:39])[C@@H:21]([C@H:24]2[C@@H:29]([OH:30])[C@@H:28](/[CH:31]=[CH:32]/[C:33]([CH3:36])([CH3:35])[CH3:34])[O:27]C(C)(C)[O:25]2)[O:22][CH3:23])[C:9]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.Cl>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][CH2:11][C@H:10]([NH:19][C:20](=[O:39])[C@H:21]([O:22][CH3:23])[C@H:24]([OH:25])[C@@H:29]([OH:30])[C@H:28]([OH:27])/[CH:31]=[CH:32]/[C:33]([CH3:35])([CH3:36])[CH3:34])[C:9]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H](C(=O)N[C@H]1CSc2ccccc2N(Cc2ccccc2)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)N[C@H]1CSc2ccccc2N(Cc2ccccc2)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 17.5 %

Procedure:
101 mg of 9 (178 μmol) in 0.85 mL of THF and 1.78 mL of 1N hydrochloric acid are mixed together, with stirring and under argon, in a 20 mL round-bottomed flask. Stirring is continued for 5 hours at room temperature. The solution is then cooled to 0° C. It is neutralized to pH 7.0 with 1N sodium hydroxide. The resulting mixture is extracted twice with 5 mL of EtOAc. The organic phases are combined, dried over magnesium sulfate and filtered and then brought to dryness. 66 mg of crude product are obtained, which product, after purification on a preparative silica plate (eluent: 90/10 CH2Cl2/MeOH), gives 16.5 mg of expected product Example 3.
Reaction SMILES: [OH-].[K+:2].[CH3:3][O:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]([O:15]C)=[O:14])[CH:12]=1)=[O:6]>CO>[CH3:3][O:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:12]=1)[C:13]([O-:15])=[O:14])=[O:6].[K+:2]
Reactant: COC(=O)c1cncc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cncc(C(=O)[O-])c1
Temperature: 25 °C

Procedure:
A 162 ml portion of 0.1 M potassium hydroxide aqueous solution was added to a 50 ml methanol solution of 3.01 g of dimethylpyridine-3,5-dicarboxylate and stirred at room temperature for 3Hours. The reaction solution was washed with diethyl ether, and the aqueous layer was concentrated under a reduced pressure. The residue was mixed with ethanol and stirred at 50° C. for 15Hours. The insoluble matter was removed by filtration, and then the filtrate was concentrated under a reduced pressure to obtain 2.51 g of potassium 5-(methoxycarbonyl)nicotinate as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:29])[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:25]2[CH2:26][CH2:27][N:22]([C:20](=[O:21])[CH2:19][CH:18]([CH3:17])[CH3:29])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CC(C)CC(=O)N1CCC(=O)CC1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CC(=O)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-(3-methylbutyryl)piperidin-4-one (78.4 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}-3-methylbutan-1-one (114 mg, 66%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.36 min, m/z 403.46 (35), 401.44 (M++H, 100). HPLC tr=3.39 min (96.55%) 1H NMR (270 MHz, CDCl3) δ 0.92 (6H, d, J=6.4 Hz, 2CH3), 1.23 (2H, m, CH2), 1.46 (br s, NH), 1.82 (2H, br d, J=12.9 Hz, CH2), 2.05 (1H, hept, J=6.4 Hz, CHMe2), 2.19 (2H, m, CH2), 2.65 (2H, m, CH2), 2.99 (1H, m, CHNH), 3.77 (1H, m, ½CH2), 3.79 (2H, s, CH2NH), 4.40 (1H, br d, J=13.3 Hz, ½CH2), 6.81-6.87 (3H, m, ArH), 7.11 (1H, td, ArH), 7.19-7.25 (3H, m, ArH) and 7.38 (1H, dd, J=7.2, 1.5 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 22.80 (CH2), 22.90 (CH3), 25.93 (CH), 32.30, 33.15, 40.23, 42.24, 44.44, 45.65 (CH2), 53.87 (CH), 118.93, 119.62, 124.54, 127.94, 128.71, 129.83, 130.58, 131.79, 154.34, 156.37 (ArC), and 170.91 (C═O).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Cl>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:31][C:30]5[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=5[O:28][CH3:27])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: COc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1CN1CCn2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-methoxybenzyl chloride, to give the desired product as a white solid (54%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:10][CH2:11][CH:12]1[N:25]([CH3:26])[C:17]2=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]2[C:15](=[O:27])[N:14]([CH3:28])[CH2:13]1>>[CH3:26][N:25]1[C:17]2=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]2[C:15](=[O:27])[N:14]([CH3:28])[CH2:13][CH:12]1[CH2:11][CH2:10][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN1CC(CCCl)N(C)c2nc3ccccc3n2C1=O
Reactant: CNc1ccccc1
Product: CN1CC(CCN(C)c2ccccc2)N(C)c2nc3ccccc3n2C1=O
Temperature: 60 °C

Procedure:
To 15 mL of N-methylaniline was added 3.0 g (0.01 mol) of 2-(2-chloroethyl)-3,4-dihydro-1,4-dimethyl-1H-[1,3,5]triazepino[3,2-a]benzimidazol-5(2H)-one. The reaction was heated at 60° C. for 1.5 hr, then 100° C. for ~48 hr. The N-methylaniline was removed by distillation. The residue was dissolved in 100 mL of CH2Cl2, washed with 2×100 mL of 1N NaOH and dried over Na2SO4. The organic phase was filtered and concentrated by rotary evaporation. The residue was then heated to 100° C., 0.5 mm Hg to remove any residual starting amine. The crude syrup was crystallized from toluene/iso-octane to afford 2.0 g (55%) of white analytically pure crystals, mp 74°-90° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:24]/[O:25][CH3:26])/[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][OH:18])[CH2:15][S:16][C@H:11]12)=[O:8].[N-:27]=[C:28]=[O:29]>O1CCOCC1>[CH3:26][O:25]/[N:24]=[C:6](\[C:7]([NH:9][C@@H:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17][O:18][C:28]([NH2:27])=[O:29])[CH2:15][S:16][C@H:11]12)=[O:8])/[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=C=O
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Solvent: C1COCCO1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Yield: 77 %

Procedure:
A solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethyl-ceph-3-em-4-carboxylic acid (3.84 g) in dioxan (35 ml) was added to the above isocyanate solution at ca 25°. The reaction and work up was similar to that described in Example 8, except that the product was not triturated with ether, and yielded the title compound as a pale yellow solid, (3.28 g, 77%) m.p. (M802)179°; [α]D22 +54.4° (c.1.0, DMSO).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[C:3]=1[O:20][CH2:21][CH:22](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]2[N:9]([CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[CH:22]([CH3:23])[CH2:21][O:20][C:3]=2[C:2]=1[F:1]
Reactant: COC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)OS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(=CN1c2ccc(F)c(F)c2OCC1C)C(=O)OC
Temperature: 80 °C
Yield: 92.7 %

Procedure:
A mixture of 749 mg of the compound obtained in Example 7, 207 mg of potassium carbonate and 5 ml of anhydrous DMF was heated at 80° C. for 8 hours. The mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 455 mg of the titled compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[C@@H:15]12[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:19]([CH2:20][CH2:21]1)[CH2:18][NH:17][CH2:16]2.CCN(C(C)C)C(C)C>C(O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:17]3[CH2:16][C@H:15]4[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:19]([CH2:20][CH2:21]4)[CH2:18]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CN(c1ccc3nnc(C(F)(F)F)n3n1)C2
Yield: 68.8 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (312 mg, 1.40 mmol), (1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (312 mg, 1.47 mmol) and DIPEA (0.36 ml, 2.10 mmol) in ethanol (7.00 ml) was heated at 70° C. for 18 hours. On cooling a white precipitate formed which was collected by filtration, washed with ethanol (10 mL) and dried under vacuum to afford (1R,5S)-tert-butyl 3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (384 mg, 69%) as a white crystalline solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Cc2cccc(C(F)(F)F)c2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Cc3cccc(C(F)(F)F)c3)cc2=O)n1
Yield: 63 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(3-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionic acid (Intermediate 64) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(3-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionamide as a white solid (43.7 mg, 63%); ES+-HRMS m/e calcd for C27H32N5O3F3 [M+H+] 532.2530, found 532.2526. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.03-1.08 (m, 1H) 1.04 (br s, 3H) 1.06 (br s, 3H) 1.17-1.73 (m, 8H) 1.90 (br s, 1H) 2.15-2.31 (m, 1H) 3.88 (s, 2H) 3.99 (s, 2H) 4.66 (s, 1H) 5.47 (dd, J=10.7, 4.4 Hz, 1H) 6.37 (d, J=2.1 Hz, 1H) 6.72 (s, 1H) 7.51 (d, J=2.1 Hz, 1H) 7.54-7.72 (m, 3H) 7.75 (s, 1H) 7.98 (d, J=2.1 Hz, 1H) 10.77 (s, 1H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:11]=2N=N1.C1(C[C@H](N2CC3C(=CC=CC=3S(C)(=O)=O)C2=O)C(O)=O)CCCCC1.C1(C[C@H](N2CC3C(=C(S(C)(=O)=O)C=CC=3)C2=O)C(O)=O)CCCCC1.NC1C=NC=CN=1.[CH:85]1([CH2:91][C@H:92]([N:101]2[CH2:109][C:108]3[C:103](=[CH:104][CH:105]=[CH:106][CH:107]=3)[C:102]2=[O:110])[C:93]([NH:95][C:96]2[S:97][CH:98]=[CH:99][N:100]=2)=[O:94])[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]1>C(OCC)(=O)C.C(Cl)Cl>[CH:85]1([CH2:91][CH:92]([N:101]2[CH2:109][C:108]3[C:103](=[CH:104][CH:105]=[CH:106][CH:107]=3)[C:102]2=[O:110])[C:93]([NH:95][C:96]2[S:97][CH:98]=[CH:99][N:100]=2)=[O:94])[CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:11]1
Reactant: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CS(=O)(=O)c1cccc2c1C(=O)N([C@@H](CC1CCCCC1)C(=O)O)C2
Agent: CS(=O)(=O)c1cccc2c1CN([C@@H](CC1CCCCC1)C(=O)O)C2=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1nccs1)C(CC1CCCCCC1)N1Cc2ccccc2C1=O

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid and regio-isomeric (S)-3-cyclohexyl-2-(7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (200 mg; 0.55 mmol) and 2-aminopyrazine (88 mg; 0.91 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Biotage 40S; eluent: ethyl acetate/methylene chloride, gradient:20% to 60%) a crude mixture that was further purified by reverse phase HPLC (Rainin Dynamax SD-1 instrument) using a gradient of 10% acetonitrile/water/0.1% trifluoroacetic acid to 90% acetonitrile on a C18 column to give 21 mg of (S)-3-Cyclohexyl-2-(4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide: EI-HRMS m/e calcd for C22H24N4O4SNa (M++Na+) 465.1567, found 465.1570 and 13 mg of (S)-3-Cyclohexyl-2-(7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide: EI-HRMS m/e calcd for C22H24N4O4SNa (M++Na+) 465.1567, found 465.1568.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:3].[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCl>[CH2:15]([N:14]([CH3:13])[C:2]([O:4][CH2:5][C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C#CCOC(=O)Cl
Reactant: CNCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C#CCOC(=O)N(C)Cc1ccccc1
Temperature: 0 °C
Yield: 28.6 %

Procedure:
2.85 g (15 millimoles) of ethyl 4-(chlorocarbonyloxy)-2-butynoate obtained in the first step of Example VI-9 was dissolved in 20 ml of dichloromethane, and 9 ml of a dichloromethane solution containing 3.1 ml (24 millimoles) of N-methylbenzylamine was rapidly added under cooling with ice. The mixture was reacted for 1 hour under stirring and cooling with ice. The reaction mixture was poured into ice water, adjusted to pH 2 with dilute hydrochloride acid and subjected to extraction treatment. The dichloromethane extraction solution was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (with use of 30 g of silica gel). The desired fraction eluted by hexane-benzene (1:0→3:1), was collected and concentrated under reduced pressure, whereby 1.18 g (yield: 28.5%) of colorless oily ethyl 4-(N-benzyl-N-methylcarbamoyloxy)-2-butynoate was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)C>[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: COc1ccc(C=O)cc1O
Reactant: OC1Cc2ccccc2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C=O)cc1OC1Cc2ccccc2C1
Yield: 20.7 %

Procedure:
A solution of 3-hydroxy-4-methoxy-benzaldehyde (15.2 g, 100 mmol, 1 eq), 2-indanol (12.1 g, 90 mmol, 0.9 eq), and triphenylphosphine (26.2 g, 100 mmol, 1 eq) in dry THF (300 mL) was treated dropwise with diisopropylazodicarboxylate (19.6 mL, 100 mmol, 1 eq). The reaction mixture was stirred at reflux for 16 hours, then cooled and diluted with diethyl ether (500 mL). The solution was washed with water (2×150 mL), 1 M NaOH (4×125 mL), and saturated NaCl (sodium chloride) (2×100 mL), dried with CH2Cl2, then concentrated to provide a syrup, which solidified upon standing. The solid was suspended in diethyl ether (350 mL) and stirred overnight to break up all chunks. The solid was collected by vacuum filtration and recrystallized from ethanol/water (21.4 g). The ethereal filtrate was concentrated and purified by flash chromatography (silica gel, 7.5×36 cm Biotage KP-Sil column, eluted with 25% ethyl acetate in heptane) to yield an additional 5 g of product. 1H NMR (300 MHz, CDCl3) δ9.86 (s, 1H), 7.49-7.44 (m, 2H), 7.25-7.16 (m, 4H), 6.97 (d, J=8.7 Hz, 1H), 5.29-5.22 (m, 1H), 3.89 (s, 1H), 3.45 (dd, J=16.7, 6.6 Hz, 2H), 3.24 (dd, J=16.7, 3.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ190.9, 155.5, 147.9, 140.4, 130.0, 126.9, 126.8, 124.7, 112.1, 111.0, 78.9, 56.1, 39.7.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:20][C:21]([O:23]C)=[O:22])[CH:11](C(OC)=O)[C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1>CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:20][C:21]([OH:23])=[O:22])[CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1
Reactant: COC(=O)CC(c1ccc(F)cc1)C(C(=O)OC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC(CC(=O)O)c1ccc(F)cc1
Reaction time: 12 h
Yield: 92.5 %

Procedure:
An aqueous solution of sodium hydroxide (3N, 23 mL, 69 mmol) was added to a solution of 2-(4-fluorophenyl)-1,1,3-trimethoxy carbonyl propane (6.7 g, 21.5 mmol) in methanol (100 ml) at room temperature and the mixture was stirred for 12 hours. The resulting mixture was concentrated under reduced pressure, and then water (20 ml) and concentrated hydrochloric acid (10 ml) were added under ice cooling. The aqueous mixture was refluxed for 12 hours. The reaction mixture was extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was crystallized from ethyl acetate-hexane to obtain 4.5 g of 3-(4-fluorophenyl) glutaric acid (yield 93%). mp. 145–147° C.
Reaction SMILES: Cl.C(OC(=O)[C:6]1[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=1)C.CO[CH:17](OC)[CH2:18]CCCl>C(O)C.O>[NH:12]1[C:9]2[C:10](=[CH:11][CH:6]=[CH:7][CH:8]=2)[CH:18]=[CH:17]1
Reactant: CCOC(=O)c1ccc(NN)cc1
Reactant: COC(CCCCl)OC
Agent: Cl
Solvent: O
Solvent: CCO
Product: c1ccc2[nH]ccc2c1
Yield: 68.5 %

Procedure:
A solution of ethyl-p-hydrazinobenzoate hydrochloride (10 g, 46 mmol) and 4-chlorobutanal dimethyl acetal (7.8 g, 46 mmol) in ethanol/water (5:1, 500 ml) was heated at reflux for 2 h. The solvent was removed under vacuum and the residue chromatographed through silica-gel eluting with dichloromethane/ethanol/ammonia (40:8:1) to give the title-indole as an oil (3.69 g). The hydrogen maleate salt was prepared, mp 127° C.; (Found: C, 59.46; H, 5.96; N, 8.47. C13H16N2O2.C4H4O4 requires C, 59.68; H, 5.93; N, 8.54%), m/e 232 (M+), δ(360 MHz, D2O) 1.43 (3H, t, J=7.1 Hz, Me); 3.21 (2H, t, J=7.0 Hz, CH2); 3.37 (2H, t, J=7.0 Hz, CH2); 4.42 (2H, q, J=7.1 Hz, CH2); 6.23 (2H, s, maleate-H); 7.40 (1H, s, indole-H); 7.56 (1H, d, J=8.8 Hz, aromatic-H); 7.88 (1H, dd, J=1.6 and 8.8 Hz, aromatic-H); 8.38 (1H, d, J=1.6 Hz, aromatic-H).
Reaction SMILES: C([C:8]1([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH3:20])=[CH:14][CH:15]=2)[C:10](=[O:21])[CH:9]1C([O-])=O)C1C=CC=CC=1.C1CC=CCC=1>C(O)(=O)C>[CH2:32]1[O:31][C:28]2[CH:29]=[CH:30][C:25]([CH:8]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH3:20])=[CH:14][CH:15]=4)[C:10](=[O:21])[CH2:9]3)=[CH:26][C:27]=2[O:33]1
Reactant: CCCOc1ccc2c(c1)C(=O)C(C(=O)[O-])C2(Cc1ccccc1)c1ccc2c(c1)OCO2
Solvent: CC(=O)O
Solvent: C1=CCC=CC1
Product: CCCOc1ccc2c(c1)C(=O)CC2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of benzyl-(1RS,2SR)-(3,4-methylenedioxyphenyl)-5-prop-1-yloxy-3-oxo-indane-2-carboxylate (8.2 g, 18.4 mmol) in warm acetic acid (130 ml), was added under argon 10% Pd/C (4.1 g) followed by 1,4-cyclohexadiene (17.4 ml, 185 mmol). The reaction was exothermic and gas evolution was observed. The reaction was allowed to stir under argon at room temperature for 2 h. The mixture was filtered through a pad of celite and concentrated in vacuo. Flash chromatography of the residue (silica gel, 3:7 ethyl acetate:hexane) afforded the title compound as a pinkish solid (5.08 g, 93%).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C.O>CN(C=O)C>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[N:7]3[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(S)cc1
Reactant: Cc1cn2c(Cl)cccc2n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cn2c(Sc3ccc(N)cc3)cccc2n1
Yield: 67.9 %

Procedure:
A solution of 5-chloro-2-methylimidazo[1,2-a]pyridine (1.0 g) and 4-aminothiophenol (3.25 g) and triethylamine (1.7 ml) in DMF (10 ml) was stirred for 3 days at 90° C. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 2:1→ethyl acetate→ethanol:ethyl acetate 1:9), to give 5-(4-aminophenylthio)-2-methylimidazo[1,2-a]pyridine (1.04 g) as colorless crystals.