Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[CH2:16]1OCCOCCOCCOCCOCCO[CH2:17]1.[OH-].[K+].BrCCBr>C(Cl)Cl>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH2:17][CH2:16]2)=[O:8])=[CH:10][CH:11]=1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: BrCCBr
Product: O=C(c1ccc(F)cc1)C1(n2cncn2)CC1
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of 2-(1H-1,2,4-triazol-1-yl)-4'-fluoroacetophenone (10.24 g, 50 mMole) in methylene chloride (70 ml) was added 18-Crown-6 ether (1 g) (trade mark for 1,4,7,10,13,16-hexaoxacyclooctadecane) and potassium hydroxide (6.1 g, 109 mMole) with stirring. Ten minutes later 1,2-dibromoethane was added (10.3 g, 55 mMole in one batch. Stirring was continued for 18 hours. The mixture was poured into saturated saline solution (100 ml) and the organic phase was separated, washed with water (3×30 ml) and dried over anhydrous magnesium sulphate. Evaporation gave an oil, weight 13.7 g. Purification was carried out by flash column chromatography under slight pressure (2 p.s.i.) on a Merck "Kieselgel 60" (trade mark) 230-400 mesh fractions after collection and evaporation gave a solid, the pure title compound, 2.9 g, m.p. 73°-75° (25% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[C:24]([NH:29][CH2:30][C:31]([NH2:33])=[O:32])=[N:25][CH:26]=[CH:27][CH:28]=1.[N-]1C=CN=C1>O1CCCC1.C(#N)C>[NH2:33][C:31](=[O:32])[CH2:30][NH:29][C:24]1[C:23]([NH:22][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: NC(=O)CNc1ncccc1N
Reactant: O=C(O)c1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Solvent: CC#N
Product: NC(=O)CNc1ncccc1NC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19.2 %

Procedure:
While bubbling nitrogen through a solution of picolinic acid (1.23 g, 0.01 mole) in 100 ml of tetrahydrofuran, solid 1,1'-carbonyldiimidazole (1.62 g, 0.01 mole) was added in portions. The reaction mixture was allowed to stir at room temperature for 5 hours. Then, a solution of 2-[(3-amino-2-pyridinyl)amino]acetamide (1.66 g, 0.01 mole) in acetonitrile was added in portions to the imidazolide solution and the reaction mixture was allowed to stir at room temperature overnight. The solvents were evaporated. The residue completely solidified upon standing. The solid was washed with methylene chloride and the solid was filtered off. The solid was recrystallized from ethyl acetate to give several crops of crystals, which were combined and recrystallized from ethyl acetate to give 0.52 g of title compound, mp 188°-90° C. with decomposition.
Reaction SMILES: [CH:1]([NH-:4])([CH3:3])[CH3:2].[OH:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([C:16]([O-:18])=[O:17])[C:12]2=[O:15])=[CH:8][CH:7]=1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1C=CC=CC=1>[CH:1]([NH-:4])([CH3:3])[CH3:2].[N:28]1([CH2:27][CH2:26][O:5][C:6]2[CH:14]=[C:13]3[C:9]([C:10]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:11]([C:16]([O-:18])=[O:17])[C:12]3=[O:15])=[CH:8][CH:7]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: O=C([O-])C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CC(C)[NH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C([O-])C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylate isopropyl amide (7.0 g, 22.78 mmol) was dissolved in tetrahydrofuran:benzene (150 ml:50 ml). Then, hydroxyethylmorpholine (3.59 g, 27.33 mmol) and triphenyl phosphine (7.17 g, 27.33 mmol) were added thereto. When the temperature was adjusted to 0° C., diisopropyl azodicarboxylate (5.53 g, 27.33 mmol) was added dropwise to the mixture followed by stirring for 2 hours at room temperature. The mixture was washed with brine and extracted with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography to obtain 6-(2-morpholine-4-yl ethoxy)-1-oxo-3-phenyl-1H-indene-2-carboxylate isopropyl amide (9.5 g, yield 99%).
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21](OC(C)(C)C)=[O:22]>C(Cl)Cl>[N:21]([S:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22]
Reactant: CC(C)(C)ON=O
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=NSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
Triphenylmethyl mercaptan (0.050 g, 0.18 mmol) was dissolved in anhydrous methylene chloride and cooled to 0° C. Tert-butyl nitrite (0.186 g, 1.80 mmol) was added and the resulting mixture was stirred at 0° C. for 30 min. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. The solvent and excess of tert-butyl nitrite were evaporated to give the title compound as a green solid (0.054 g, 98%). 1H NMR (CDCl3) δ: 7.13-7.18 (m, 4H), 7.25-7.39 (m, 11⌴H).
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH3:7])[C:3]#[C:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>C1COCC1>[CH3:16][S:17]([O:6][CH2:5][C:4]#[C:3][C:2]([OH:8])([CH3:7])[CH3:1])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(O)C#CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(O)C#CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methylpent-2-yne-1,4-diol (Synthesis 2001. 1013.) (1.00 g) in THF (40 mL) were added triethylamine (1.85 mL) and methanesulfonyl chloride (0.69 mL). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.57 g).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH2:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>O1CCCC1.O>[C:6]([C@@H:2]([NH:1][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH:3]([CH3:5])[CH3:4])(=[O:7])[NH2:8]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)[C@H](N)C(N)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](NCCCS(=O)(=O)O)C(N)=O
Temperature: 25 °C

Procedure:
To a solution of L-valinamide (1.57 g, 13.5 mmol) in tetrahydrofuran (20 mL) was slowly added 1,3-propane sultone (1.61 g, 12.9 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was dissolved in water (60 mL) and treated with ion exchange resin Dowex Marathon C (strongly acidic, 15 g). The mixture was stirred for 15 minutes. The resin was removed by filtration. The filtrate was poured into EtOH (250 mL). The solid product, after the completion of the precipitation, was collected by filtration, and dried in vacuo, to afford compound EQ (1.6 g, 51%). 1H NMR (D2O, 500 MHz) δ ppm 3.63 (d, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.05 (m, 4H), 0.93 (d, 3H), 0.88 (d, 3H). 13C NMR (D2O, 125 MHz) δ ppm 170.24, 65.92, 48.16, 46.31, 29.59, 21.31, 18.02, 17.07. [α]D=+10.5° (c=0.0027 in water), ES-MS 237 (M−1).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:5]1)[CH2:2][CH3:3].[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([NH:24][NH:25][CH:26]([CH3:28])[CH3:27])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([NH:24][N:25]([CH:26]([CH3:28])[CH3:27])[C:15](=[O:17])/[CH:14]=[CH:13]/[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH2:1][CH2:2][CH3:3])[CH:5]=1)=[O:23]
Reactant: CCCn1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCn1cc(/C=C/C(=O)N(NC(=O)c2cccc(F)c2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-propyl-1H-indol-3-yl)acrylic acid (160.0 mg, 0.70 mmol), 3-fluoro-N′-isopropylbenzohydrazide (206.0 mg, 1.05 mmol) and HATU (399.2 mg, 1.05 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.18 ml, 1.05 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) for refinement and dried so that white (E)-3-fluoro-N′-isopropyl-N′-(3-(1-propyl-1H-indol-3-yl)acryloyl)benzohydrazide was obtained (136.0 mg, 47.7%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][C@H:57]1[N:62]([CH2:63][CH2:64][C@@H:65]([NH:74][C:75]2[CH:80]=[CH:79][C:78]([S:81]([NH2:84])(=[O:83])=[O:82])=[CH:77][C:76]=2[S:85]([C:88]([F:91])([F:90])[F:89])(=[O:87])=[O:86])[CH2:66][S:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:61][CH2:60][O:59][CH2:58]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:84][S:81]([C:78]3[CH:79]=[CH:80][C:75]([NH:74][C@H:65]([CH2:64][CH2:63][N:62]4[CH2:61][CH2:60][O:59][CH2:58][C@H:57]4[CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:53])[CH3:54])([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:66][S:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[C:76]([S:85]([C:88]([F:89])([F:90])[F:91])(=[O:86])=[O:87])[CH:77]=3)(=[O:83])=[O:82])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](OC[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOC[C@H]4CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 253 %

Procedure:
To a solution of (R)-4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 183 mg, 0.34 mmol) in DCM (3 ml) were added sequentially DMAP (125 mg, 1.02 mmol), 4-((R)-4-((S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 105, 280 mg, 0.34 mmol) and EDC (131 mg, 0.68 mmol). The resulting solution was stirred at room temperature overnight. Evaporation of the volatiles under reduced pressure gave a residue which was purified by column chromatography (ISCO, 27 g silica gel column, eluting with 0→20% EtOAc/hexanes) to give 4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((R)-4-((S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide (EXAMPLE 24, STEP 1,153 mg) which was used in the preparation of EXAMPLE 24, STEP 2 without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:38])[C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])C(=O)C(F)(F)F)=[CH:15][C:14]=3[O:36][CH3:37])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])[C:6]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:38])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])=[CH:15][C:14]=3[O:36][CH3:37])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])[C:6]=2[CH:49]=1
Reactant: COc1cc(N(CCOc2ccccc2C)C(=O)C(F)(F)F)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(NCCOc2ccccc2C)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.9 %

Procedure:
To a solution of 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-[2-methoxy-4-{N-[2-(2-methylphenoxy)ethyl]-N-trifluoroacetylamino}-benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.45 g) in methanol (20 ml) is added a solution of potassium carbonate (0.11 g) in water (5 ml), and the mixture is stirred at room temperature for 12 hours. The mixture is evaporated to remove the solvent, and thereto is added water. The mixture is extracted with ethyl acetate, and the extract is dried, evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=80:1→50:1→30:1), and recrystallized from acetone/n-hexane to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-[2-methoxy-4-[2-(2-methylphenoxy)ethylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.12 g) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[CH2:12]CC#N)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:17]([OH:20])(=[O:19])[CH3:18]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[CH2:12][CH2:18][C:17]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)CCC#N)cc1OC
Reactant: CC(=O)O
Agent: Cl
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC
Temperature: 25 °C

Procedure:
A stirred solution of 4-(3',4'-dimethoxyphenyl)-4-oxobutyronitrile (111) (2.26 g, 0.01 mol) in acetic acid (15 ml) and hydrochloric acid (12N, 40 ml) was heated at reflux for 1.5 hours and cooled to room temperature. The solvent was removed under reduced pressure to give a brown solid. Recrystallization from water gave 112 as light tan crystals (1.57 g, 66%). 1H NMR (CDCl3) 2.80 (t, J=7.5 Hz, 2H), 3.30 (t, J=7.5 Hz, 2H), 3.94 (s, 3H), 3.96 (s, 3H), 6.89 (d, 1H, J=9 Hz), 7.55 (d, 1H, J=1 Hz) and 7.64 (dd, 1H, 1 and 9 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:24])=[CH:3][CH2:4][CH:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:23].[OH-:25].[Na+]>O>[C:11]1([N:8]([C:9](=[O:10])[CH:5]([CH2:4][CH:3]=[C:2]([CH3:24])[CH3:1])[C:6]([OH:23])=[O:25])[NH:7][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [OH-]
Reactant: CC(C)=CCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Agent: [Na+]
Solvent: O
Product: CC(C)=CCC(C(=O)O)C(=O)N(Nc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
64 gm (0.2 mol) of 4-(3-methyl-2-butenyl)-1,2-diphenyl-3,5-dioxo-pyrazolidine were dissolved in an aqueous sodium hydroxide solution obtained by dissolving 16 gm (0.4 mol) of sodium hydroxide pellets in 640 ml of water. The solution was heated for 7 hours. The reaction mixture was then cooled to room temperature and washed twice with ether. The ether extract contained a little hydrazobenzene. The aqueous alkaline solution was then made acid to Congo red with 10% hydrochloric acid and quickly extracted with ethyl ether. The organic phase was evaporated to dryness, leaving (3-methyl-2-butenyl)propanedioic acid mono(1,2-diphenyl hydrazide) as an oily residue which was dissolved in a dilute ammonium hydroxide solution obtained by diluting 40 ml of an aqueous 32% ammonium hydroxide solution with 600 ml of water. To this solution was added a solution of 11 gm of calcium chloride in 40 ml of water. The calcium salt of (3-methyl-2-butenyl)propanedioic acid mono(1,2-phenylhydrazide)dihydrate which precipitated upon stirring was suction filtered off and dried for 8 hours at 50° C. and 15 mmHg. The salt was obtained as a white solid. Yield: 54.06 gm (72% of theory), M.p. 166° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)CCC.[F:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[N:49]=[C:48]([C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[C:52](Br)[CH:51]=3)[O:47][N:46]=2)=[N:43][CH:44]=1>O1CCCC1>[F:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[N:49]=[C:48]([C:50]3[CH:51]=[C:52]([C:6]4[N:7]=[CH:8][N:9]([C:11]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:10]=4)[CH:53]=[C:54]([F:56])[CH:55]=3)[O:47][N:46]=2)=[N:43][CH:44]=1
Reactant: Fc1ccc(-c2noc(-c3cc(F)cc(Br)c3)n2)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: C1CCOC1
Product: Fc1ccc(-c2noc(-c3cc(F)cc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)c3)n2)nc1
Temperature: 100 °C
Yield: 23.5 %

Procedure:
To the solution of 4-Tributylstannyl-1-trityl-1H-imidazole (106 mg, 0.18 mmol) in tetrahydrofuran (5 ml) added 3-(5-Fluoro-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (50.0 mg, 0.15 mmol) and tetrakis(triphenylphoshine)palladium (O) (17.1 mg, 0.01 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 100° C. under argon overnight. The reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was purified on silica gel using 30% ethyl acetate in hexanes to isolate 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(1-trityl-1H-imidazol-4-yl)phenyl)-1,2,4-oxadiazole (20.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([O:26][CH2:27][CH2:28]Br)(=[O:25])[CH3:24].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(#N)C.C(O)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[C:23]([O:26][CH2:27][CH2:28][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:25])[CH3:24]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)OCCBr
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CC(=O)OCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (3,5 g, 25 mmol), 2-bromoethyl acetate (4 g, 26.5 mmol) in acetonitrile (50 ml) was heated at reflux for 4 hours. After cooling to room temperature, the inorganic salts were filtered and washed with DCM (dichloromethane 50 ml). The organic solvent was removed on a rotary evaporator to give an oil. The oily product was purified on a flash chromatography column (60 g of SiO2 ; eluted with MEOH 2%-4% in DCM). The pure product thus obtained weighed 4.43 g. This oil was dissolved in ethanol and treated with a solution of fumaric acid (1,2 g) in ethanol. The salt crystallized out at room temperature to yield 3.44 g (57%), m.p.=154-155° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:25][N:26](CC)CC.ClC(OCC(C)C)=O.Cl.CN>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:21]([NH:26][CH3:25])=[O:23])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of t-boc-gly-phe 7a (5.3 g, 1.6×10-2 mole) in dry THF (80 ml) under argon at -10° C. is added in turn Et3N (2.5 ml, 1.8×10-2 mole) and isobutyl chloroformate (2.4 ml, 1.8×10-2 mole). The resulting mixture is stirred at -10° C. for 10 minutes before a freshly neutrallized mixture of methylamine hydrochloride (3.3 g, 4.9×10-2 mole), Et3N (6.9 ml, 4.9×10-2 mole), THF (80 ml), and H2O (40 ml) is added in one portion. The cooling bath is then removed and the mixture allowed to warm to room temperature. After stirring overnight the reaction is quenched into saturated aqueous NaHCO3. The aqueous alkaline mixture is extracted with Et2O (3 times) and CH2Cl2 (2 times). The ethereal extracts are combined and subsequently washed with saturated aqueous NaCl as are the CH2Cl2 extracts. The ethereal and CH2Cl2 extracts are then combined and dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate gives a yellowish foam which when triturated with Et2O affords 8a as a colorless solid which crystallizes from aqueous ethanol as colorless matted needles, 4.1 g (74%), m.p. 158°-160° C. In a similar fashion, t-boc-gly-phe-leu-NHEt is prepared from 7a and leucine ethylamide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][N:33]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:32](=[O:36])[CH:31]=2)=[CH:26][CH:25]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 50.2 %

Procedure:
The compound was prepared from tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.548 mmol) and 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (129 mg, 0.548 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (143 mg, 50%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=8.0 Hz, 1H), 7.43-7.29 (m, 6H), 7.01 (d, J=7.9 Hz, 1H), 6.05-6.02 (m, 2H), 5.02 (s, 2H), 4.64 (br s, 2H), 3.84 (br s, 2H), 3.63 (s, 3H), 2.82 (br s, 2H), 1.50 (s, 9H).