Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]C(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:29][C:28]([C:30](OC)=[O:31])=[N:27][N:26]=1>C1COCC1>[C:8]1([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:30]([C:28]2[S:29][C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)=[N:26][N:27]=2)=[O:31])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCCCCCc1ccccc1
Reactant: COC(=O)c1nnc(-c2ccccn2)s1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C(CCCCCCc1ccccc1)c1nnc(-c2ccccn2)s1
Reaction time: 0.5 h
Yield: 7.3 %

Procedure:
A solution of 6-bromohexylbenzene (31 pt, 0.2 mmol) in THF (1 mL) was treated dropwise with 1.7 M t-BuLi (235 μL, 0.4 mmol) at −78° C. After stirring for 30 min, the resulting alkyllithium reagent was added to a cooled solution of methyl 5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxylate (S43, 44 mg, 0.2 mmol) in THF (0.5 mL) at −78° C. The reaction mixture was stirred for 3 h at −78° C. before it was quenched with the addition of MeOH. The mixture was extracted with EtOAc, washed with water, saturated aqueous NaHCO3 and saturated aqueous NaCl, and dried over Na2SO4. Evaporation in vacuo yielded the crude product which was purified by flash chromatography (SiO2, 3×14 cm, 15% EtOAc-hexanes) to provide the title compound (5.1 mg, 7%) as white solid: 1H NMR (CDCl3, 600 MHz) δ 8.69 (m, 1H), 8.41 (dd, 1H, J=0.8, 7.9 Hz), 7.89 (m, 1H), 7.45 (m, 1H), 7.27 (m, 2H), 7.17 (m, 3H), 3.27 (t, 2H, J=7.4 Hz) 2.61 (t, 2H, J=7.7 Hz), 1.81 (m, 2H), 1.65 (m, 2H), 1.45 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 194.1, 174.9, 169.6, 150.3, 148.6, 142.8, 137.5, 128.5, 128.4, 126.3, 125.7, 121.7, 39.4, 36.0, 31.4, 29.9, 29.1, 24.0; IR (film) νmax 2927, 2854, 1734, 1685, 1647, 1584, 1406, 1009, 785, 742, 698 cm−1; HRMS-ESI-TOF m/z 352.1474 ([M+H]+, C20H21N3OS requires 352.1478).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[C:18]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[NH:32][C:33](=[O:41])[C@:34]([OH:40])([CH3:39])[C:35]([F:38])([F:37])[F:36].[CH2:42]([CH2:44][NH2:45])[OH:43]>CN(C=O)C.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29](=[O:31])[NH:45][CH2:44][CH2:42][OH:43])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH:17]=[CH:16][C:15]=1[NH:32][C:33](=[O:41])[C@:34]([OH:40])([CH3:39])[C:35]([F:37])([F:36])[F:38]
Reactant: NCCO
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(C(=O)O)cc2)cc1Cl)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(C(=O)NCCO)cc2)cc1Cl)C(F)(F)F
Reaction time: 17 h

Procedure:
A solution of 1,1′-carbonyldiimidazole (0.169 g) and (R)-N-[2-chloro4-(4-carboxyphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 121) (0.30 g) in DMF (1 ml)/ethyl acetate (9 ml) was heated at 50° C. for 30 minutes. Ethanolamine (0.055 ml) was added and the mixture was heated and stirred a further 17 hours. The mixture was cooled, diluted with ethyl acetate (50 ml), washed with dilute aqueous hydrochloric acid (25 ml), water (25 ml), saturated aqueous sodium hydrogen carbonate solution (25 ml) and brine, then dried. Volatile material was removed by evaporation and the residue was purified by chromatography, eluting with 2.5% ethanol/ethyl acetate to give the title compound (0.25 g) as a solid. NMR (CDCl3+DMSO-δ6):1.58 (s, 3H), 3.44 (m, 2H), 3.62 (m, 2H), 4.26 (t, 1H), 7.05 (s, 1H), 7.76 (dd, 1H), 7.83-8.01 (m, 6H), 8.56 (d, 1H), 9.73 (brs, 1H); MS (ESP−): 495.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([C:28](=[O:29])[CH2:27][C:24]5[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccc(F)cc1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of the product from Example 54F (30 mg, 0.115 mmol) and 2-(4-fluorophenyl)acetic acid (21.3 mg, 0.138 mmol) was added a solution of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (33.1 mg, 0.173 mmol) in dichloromethane (1.0 mL). To the resulting solution was added hydroxybenzotriazole hydrate (26.5 mg, 0.173 mmol) and diisopropylethylamine (0.040 mL, 0.230 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was partitioned between water and ethyl acetate, and the organic extract was dried over Na2SO4. The mixture was filtered and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in hexanes. The title compound was obtained as a colorless solid (16 mg, 35%). 1H NMR (300 MHz, CDCl3) δ ppm 0.85-1.03 (m, 4 H), 1.78-2.06 (m, 3 H), 2.11-2.48 (m, 3 H), 2.63-3.27 (m, 3 H), 3.61-4.00 (m, 4 H), 4.55-4.85 (m, 1 H), 5.25-5.40 (m, 1 H), 6.96-7.06 (m, 2 H), 7.15-7.25 (m, 2 H), 7.93 (d, J=1.36 Hz, 1 H), 8.01 (d, J=1.36 Hz, 1 H); MS (ESI) m/z 397 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH3:30])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: Cc1ccccc1/C=C/C(=O)O
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3ccccc3C)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-o-tolyl-acrylic acid.
Reaction SMILES: [O:1]1[CH2:5][C@H:4](O)[C@H:3]([OH:7])[CH2:2]1.I([O-])(=O)(=O)=O.[Na+].C(=O)([O-])[O-].[K+].[K+].C(OP([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(OCC)=O)C>CCCCCC.C(OCC)(=O)C>[OH:7][CH:3]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:4][CH2:5][O:1][CH2:2]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O[C@@H]1COC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1=CCOCC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
To an aqueous solution (400 mL) of (3R,4S)-tetrahydrofuran-3,4-diol (100 g) was added sodium periodate (225 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. An aqueous solution (50 mL) of potassium carbonate (13.2 g) was added at room temperature, and an aqueous solution (100 mL) of ethyl diethylphosphonoacetate (322 g) was added dropwise over 2 hr. Then, an aqueous solution (800 mL) of potassium carbonate (384 g) was added dropwise over 2 hr. The reaction mixture was stirred at room temperature for 24 hr, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was distilled under reduced pressure (110-130° C./3-4 mmHg). The obtained crude product was subjected to silica gel column chromatography (hexane/ethyl acetate=1:1) to give the title compound (66.5 g, 40%) as a colorless liquid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.Br[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:21]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[CH:3]([CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)[C:4](=[O:34])[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]1=2)([CH3:23])[CH3:22]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3ccc4ccccc4c3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL DMF at 0° C. is added dropwise over 5 min 1.45 mL (0.72 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, and then a solution of 160 mg (0.72 mmol, 1.1 equiv) of 2-bromomethylnaphthalene in 3 mL DMF is added. The resulting solution is stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 2/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 310 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.80-7.70 (m, 3H), 7.45-6.93 (m, 16H), 6.84 (dd, 1H, J=1.2, 8.3), 5.04 (m, 1H), 4.35 (d, 1H, J=16.3), 4.13 (d, 1H, J=16.3), 3.85 (s, 3H), 3.68 (m, 2H), 3.48 (dd, 1H, J=4.6, 13.7), 1.09 (d, 6H, J=6.8); low resolution MS (FAB)m/e 598 (MH+), 597 (M+), 433.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To a stirred suspension of 222 gms of 1-(4'-chloro[1,1']-biphenyl-4-yl)ethanone in 1500 ml of methanol add in a portionwise fashion, 21 gms of sodium borohydride. Reflux and stir the mixture on a steam bath for 2 hours and stir at room temperature overnight. Concentrate the mixture to 500 ml, dilute with water, cool and filter the product to yield 238 gms of 1-(4'-chloro[1,1']biphenyl-4-yl)ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[N:3]=1.[Cl:11]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH2:10][Cl:11])=[CH2:9])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1cccc(Br)n1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C=C(CCl)c1cccc(Br)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
A mixture of 3.60 g of 2-bromo-6-isopropenylpyridine, 2.91 g of N-chlorosuccinimide and 8 ml of benzene was stirred at 80° C. for 5 hours. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane then n-hexane - ethyl acetate 20:1) to obtain 1.50 g of the objective compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:15]2[O:22][CH:21]=[C:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O>N1C=CC=CC=1.C(Cl)Cl>[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:10])=[O:11])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:15]2[O:22][CH:21]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:25][CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCNCC4)coc23)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCN(C(=O)OCc5ccccc5)CC4)coc23)c(F)c1
Yield: 51 %

Procedure:
N-[2-Fluoro-4-(methylsulfonyl)phenyl]-7-(piperidin-4-yl)furo[3,2-d]pyrimidine-4-amine hydrochloride (9.0 mg, 0.021 mmol) was dissolved in pyridine (0.4 mL), and a 0.25 mol/L solution of benzyl chloroformate in anhydrous methylene chloride (0.1 mL) was added dropwise slowly under ice-cooling, and then the resultant mixture was stirred for 15 minutes under ice-cooling, and water was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel preparative thin layer chromatography (chloroform:methanol=20:1) to give the titled compound (5.6 mg, 51%) as a yellow oily substance.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH:27]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:28][C:29]([OH:31])=[O:30]>C[O-].[Na+].CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][CH:27]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)CC(CN)CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)CC(=O)O
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmole) and 3-(aminomethyl)-5-methylhexanoic acid (249 mg, 1.6 mmole, AK Scientific) in 0.5 M sodium methoxide in methanol (2.5 ml) was refluxed for two days before it was cooled to room temperature, concentrated and dissolved in water, extracted with dichloromethane. The remaining aqueous layer was acidified with 1N hydrochloric chloride, extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and ethyl acetate to give the title compound as a white solid (35 mg). LC-MS ESI+: 448 (M+1)+; ESI−: 446 (M-1)−.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])=[N:5][C:6]([S:10][CH3:11])=[N:7][C:8]=1[Cl:9].[C:21](C1NC=CN=1)(C1NC=CN=1)=[O:22]>C(Cl)Cl>[Cl:9][C:8]1[N:7]=[C:6]([S:10][CH3:11])[N:5]=[C:4]2[N:12]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[C:21](=[O:22])[NH:1][CH2:2][C:3]=12
Reactant: CSc1nc(Cl)c(CN)c(Nc2c(F)cccc2F)n1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 81.3 %

Procedure:
To the solution of 5-(aminomethyl)-6-chloro-N-(2,6-difluorophenyl)-2-(methylthio)-4-pyrimidinamine (0.317 g) in CH2Cl2 (5 mL) was added the mixture of carbonyl diimidazole (0.178 g) in CH2Cl2 (5 mL). The resultant mixture was stirred for about 3 hours at r.t., mixed with CH2Cl2 (10 mL) and washed with HCl (1 N, 2×10 mL) and H2O (20 mL). The organic layers were collected, dried over Na2SO4, filtered and concentrated to provide the title compound (0.279 g, 81%). LC-MS m/z 343 (M+H)+, 1.75 min (ret. time); 1H-NMR (400 MHz, CDCl3) δ 7.44-7.40 (m, 1H), 7.07-7.03 (m, 2H), 5.84 (br, 1H), 4.62 (s, 2H), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:27]#N)[CH2:14][CH2:13][N:12]([CH:15]3[C:25]4=[C:26]5[C:21](=[CH:22][CH:23]=[CH:24]4)[CH:20]=[CH:19][CH:18]=[C:17]5[CH2:16]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(OCC)C>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH:15]1([N:12]2[CH2:11][CH2:10][C:9]3([N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:32](=[O:33])[CH2:27]3)[CH2:14][CH2:13]2)[C:25]2=[C:26]3[C:21](=[CH:22][CH:23]=[CH:24]2)[CH:20]=[CH:19][CH:18]=[C:17]3[CH2:16]1
Reactant: N#CC1(Nc2ccc(Cl)cc2)CCN(C2Cc3cccc4cccc2c34)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: O=C1CC2(CCN(C3Cc4cccc5cccc3c45)CC2)N1c1ccc(Cl)cc1

Procedure:
Reaction of (RS)-4-(4-chloro-phenylamino)-1-(acenaphthen-1-yl)-piperidine-4-carbonitrile in accordance with the general method of example 1 and treatment of the base with fumaric acid in diethyl ether yielded the title compound, pale brown solid, m.p. 196° C. and MS: m/e=403.3 (M+H+).
Reaction SMILES: [C:1](=O)(O)[O-:2].[Na+].[CH2:6]([O:8][C:9]([C:11]1[N:12]=[CH:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16](Cl)[C:15]=12)=[O:10])C>>[CH3:6][O:8][C:9]([C:11]1[N:12]=[CH:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([O:2][CH3:1])[C:15]=12)=[O:10]
Reactant: CCOC(=O)c1ncn2c1c(Cl)nc1ccccc12
Reactant: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ncn2c1c(OC)nc1ccccc12
Yield: 58.9 %

Procedure:
To a methanolic solution (250 ml) of 4-chloroimidazo [1,5-a]quinoxaline 3-carboxylic acid ethyl ester (4 g) was added sodium bicarbonate (10 g) with stirring. The mixture was heated on steam bath for 2 hours. After removal of solvent under vacuum, the residue was taken up in water, then extracted with chloroform several times. The combined chloroform extracts were washed with water, dried by magnesium sulfate and evaporated to give the product as an off-white solid (2.2 g, 55% yield). Recrystallized from acetonitrile, m.p. 189°-191° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Brc1ccc(Br)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 74.2 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 1,4-dibromobenzene (11.8 g, 50 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.02 g (74%) of the product 4-(3-bromo-phenyl)-1H-indole as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:6]([NH:7][C:8](=[O:35])/[C:9](=[N:23]\[O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[C:10]2[N:11]=[C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][CH:14]=2)[C:5](=[O:36])[NH:4]1.[CH2:37]([O:44][CH2:45][C@H:46]1[CH2:48][O:47]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:37]([O:44][CH2:45][C@H:46]([OH:47])[CH2:48][NH:1][CH2:2][C@@H:3]1[C@H:6]([NH:7][C:8](=[O:35])/[C:9](=[N:23]\[O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[C:10]2[N:11]=[C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][CH:14]=2)[C:5](=[O:36])[NH:4]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN)cs1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNC[C@@H](O)COCc2ccccc2)cs1
Yield: 48 %

Procedure:
Prepared in analogous manner to example 63 step 1, using tert-butyl 2-(((Z)-(2-(((2R,3S)-2-(aminomethyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (200 mg, 0.38 mmol), (R)-2-((benzyloxy)methyl)oxirane (623 mg, 3.8 mmol), DCM (2 mL). The crude residue was purified via silica gel chromatography (MeOH-DCM, 4-10%) to afford the title compound (126 mg, 48%). LCMS: m/z=691.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][C:25]1([CH3:31])[O:29][C:28](=[O:30])[N:27]=[CH:26]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[CH2:26][C:25]([CH3:31])([CH3:24])[O:29][C:28]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC1(C)C=NC(=O)O1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3)CC2)c(C)c1
Yield: 38.2 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (842 mg) described in Preparation Example 77 and 5,5-dimethyloxazolin-2-one (345 mg) described in Preparation Example 43, the title compound (312 mg) was obtained.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=1>CN(C)C=O>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: OCc1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccc2)n1

Procedure:
2.9 ml benzyl alcohol was dissolved in 10 ml N,N-dimethylformamide and 0.7 g sodium hydride (purity 95%) was slowly added. After gas evolution has ceased, 6 g 2,6-dibromopyridine was added and the mixture heated to reflux for 3 hours. After cooling, the reaction mixture was filtered through a silica gel column using hexane/ethyl acetate 1/1. The solvent was removed in vacuo and the crude product purified by flash silica gel column chromatography. The title compound was obtained as a colourless oil.
Reaction SMILES: C([O:8][C:9]1[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:20]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:19][C:10]=1[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:22]=[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:20]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:19][C:10]=1[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12]
Reactant: CCOC(=O)CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1O
Reaction time: 1 h
Yield: 88 %

Procedure:
In 50 ml of ethanol was dissolved 4.83 g of ethyl 2-(2-benzyloxy-4-methylsulfonylamino-5-phenoxybenzoyl)acetate. Thereto was added 200 mg of 5% palladium-carbon. The mixture was subjected to hydrogenation for 1 hour at 40° C. at atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration. The filtrate was subjected to distillation under reduced pressure to remove the solvent. The residue was mixed with diisopropyl ether. The resulting crystal was collected by filtration and recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to obtain 3.46 g (yield: 88%) of ethyl 2-(2-hydroxy-4-methylsulfonylamino-5-phenoxybenzoyl)acetate having a melting point of 111.5°-112.5° C.