Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[N:17]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1.Cl.Cl.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CN=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>CO>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1/[CH:1]=[CH:23]/[C:20]1[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=1
Reactant: Cc1nc2ccccc2n1-c1ccccn1
Reactant: O=Cc1ccncc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccn1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccncc1

Procedure:
Free base of the titled compound was prepared from 2-methyl-1-(2-pyridyl)-1H-benzimidazole and pyridine4-carboxaldehyde according to the preparation of (E)-1-(2-pyridyl)-2-[2-(2-pyridyl)ethenyl]-1H-benzimidazole dihydrochloride Example 44). The free base and oxalic acid were dissolved into MeOH. Concentration and recrystalization from ethyl MeOH/Et2O/n-hexane yielded the titled compound. MW: 388.39; mp: 203.6-205.3° C. (decomposed); 1H-NMR (DMSO) δ: 8.81-8.75 (1H, m), 8.62-8.55 (2H, m), 8.20 (1H, dt, J=1.9,7.7 Hz), 7.88 (1H, d, J=16.0 Hz), 7.81-7.74 (2H, m), 7.69-7.60 (3H, m), 7.52-7.46 (1H, m), 7.47 (1H, d, J=16.0 Hz) 7.40-7.28 (2H, m).
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(O)=O.[CH2:27]([NH:34][C:35]([C:37]1[S:41][C:40]([N:42]2[CH2:46][CH2:45][N:44]([CH2:47][C:48]([OH:50])=O)[C:43]2=[O:51])=[N:39][C:38]=1[CH3:52])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[F:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH2:59])=[CH:56][CH:55]=1>>[CH2:27]([NH:34][C:35]([C:37]1[S:41][C:40]([N:42]2[CH2:46][CH2:45][N:44]([CH2:47][C:48]([NH:59][CH2:58][C:57]3[CH:60]=[CH:61][C:54]([F:53])=[CH:55][CH:56]=3)=[O:50])[C:43]2=[O:51])=[N:39][C:38]=1[CH3:52])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(N2CCN(CC(=O)O)C2=O)sc1C(=O)NCc1ccccc1
Agent: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 75 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 2-(3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)acetic acid to react with 4-fluorobenzylamine, the title compound was obtained as a colorless solid in 75% yield: mp 232-234° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.64 (t, J=5.9 Hz, 1H), 8.52 (t, J=5.9 Hz, 1H), 7.37-7.12 (m, 9H), 4.38 (d, J=5.9 Hz, 2H), 4.29 (d, J=5.9 Hz, 2H), 4.05-3.98 (m, 2H), 3.93 (s, 2H), 3.65-3.57 (m, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.4, 161.7, 161.1 (d, JC-F=242.0 Hz), 157.3, 155.4, 150.8, 139.6, 135.3 (d, JC-F=2.9 Hz), 129.1 (d, JC-F=8.1 Hz), 128.2, 127.2, 126.6, 117.8, 115.0 (d, JC-F=21.3 Hz), 46.2, 42.8, 42.5, 42.0, 41.3, 17.0; MS (ES+) m/z 482.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2([CH3:10])[C:7]([CH2:9][CH:3]1[CH2:4][CH2:5]2)=[O:8].C([N-]C(C)C)(C)C.[Li+].[C:20](=[O:22])=[O:21].C(OCC)C>C1(C)C=CC=CC=1>[CH3:10][C@@:6]12[C:2]([CH3:11])([CH3:1])[C@@H:3]([CH2:4][CH2:5]1)[CH:9]([C:20]([OH:22])=[O:21])[C:7]2=[O:8]
Reactant: O=C=O
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Following the procedure of W. W. Shumway et al. J. Org. Chem. 2001, 66, 5832-5839, L-(−)-camphor (15 g, 98.5 mmol) was dissolved in toluene (62 mL), cooled to −78 degrees, and lithium diisopropylamide (1.8 M solution in heptane/tetrahydrofuran/ethylbenzene; 98.5 mL, 197 mmol, 2 equiv.) was added via an addition funnel over 15 min. The resulting solution was stirred at −78 degrees for 30 min, warmed to room temperature, and carefully poured over an excess of pulverized dry ice (300 g). Toluene (30 mL) was added and the solution was allowed to warm to room temperature. Diethyl ether (100 mL) was added and the solution was extracted with water (3×150 mL). The organic layer was discarded. The aqueous layer was acidified with 2M HCl to pH 1, salted with solid sodium chloride, and extracted with ether (3×150 mL). The combined organic extracts were dried (sodium sulfate), filtered, and evaporated to give (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carboxylic acid (16.0 g, 83%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[NH2:15]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:12]([O:11][CH3:10])[CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(N)cc1OC
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(OC)c3)n2)cc1OC

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3,4-dimethoxyaniline were reacted to yield N2,N4-bis(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.90 (d, 1H, J=1.8 Hz), 7.13 (d, 2H, J=4.8 Hz), 7.08 (d, 1H, J=8.7 Hz), 6.94 (d, 2H, J=10.5 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.76 (d, 1H, J=8.7 Hz), 6.70 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H); 19F NMR (CDCl3): 6-47433; LCMS: ret. time: 19.64 min.; purity: 95%; MS (m/e): 401 (MH+).
Reaction SMILES: [CH:1]1([CH:6]=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](N(CC)CC)C.[CH3:15][C:16](=[O:19])[CH:17]=[CH2:18]>C(O)C.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[CH:1]1([C:6](=[O:7])[CH2:18][CH2:17][C:16](=[O:19])[CH3:15])[CH2:8][CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCCC1
Reactant: CCN(CC)CC
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCO
Product: CC(=O)CCC(=O)C1CCCCC1
Temperature: 85 °C
Yield: 107.5 %

Procedure:
To a solution of cyclopentanecarbaldehyde (2.00 g, 20.38 mmol) in ethanol (7.2 mL) was added triethylamine (5.68 mL, 40.8 mmol), but-3-en-2-one (1.69 mL, 26.7 mmol), and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium bromide (1.03 g, 4.08 mmol). The reaction mixture was heated at 85° C. for 72 hours after which it was concentrated. The resulting residue was extracted with ethyl acetate (3×50 mL) and the organic layers were dried (sodium sulfate), filtered and concentrated to an orange residue which was used in the next step without further purification. The crude product, 1-cyclohexylpentane-1,4-dione (3.68 g, 21.9 mmol) was isolated as an orange oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 2.91 (m, 1H), 2.68-2.78 (m, 4H), 2.19 (s, 3H), 1.70-1.87 (m, 4H), 1.54-1.69 (m, 4H).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][C:5]=1[OH:11])([O-])=O.C([Cl:15])(=O)C>>[Cl:15][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1O
Reactant: CC(=O)Cl
Product: [O-][n+]1ccc(Cl)c(O)c1

Procedure:
The starting material was prepared by reaction of 4-nitro-3-hydroxy pyridine-N-oxide with acetyl chloride under reflux for 1 hour. The crude product was purified by rapid chromatography on silica gel using CH2Cl2 /MeOH 7:3 v/v as eluant to give 4-chloro-3-hydroxypyridine-N-oxide. Reduction of this compound with Raney nickel and hydrogen at ambient temperature for 2 hours in MeOH gave 4-chloro-3-hydroxypyridine. This compound was reacted with NaH in DMSO at 50°, the reaction mixture cooled and treated with 4-nitrobenzyl bromide for 1 hour. The reaction mixture was worked up with water and ether and the product treated with HCl/ether to give 4-chloro-3-(4-nitrobenzyloxy)pyridine hydrochloride. Reaction of the free base with excess methyl iodide at ambient temperature for 24 hours gave 4-chloro-1-methyl-3-(4-nitrobenzyloxy)pyridinium iodide. n.m.r. in d6DMSO-4.3(s, 3H); 5.6(s, 2H); 7.7(d, 2H); 8.3(d, 2H); 8.4(d, 1H); 8.7(d, 1H); 9.15(s, 1H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:43])[N:24]([CH2:32][CH2:33][O:34][CH2:35][CH:36]2[CH2:40][O:39]C(C)(C)[O:37]2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH:20]=[C:19]([Cl:44])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.O.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[Cl:44][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH2:32][CH2:33][O:34][CH2:35][CH:36]([OH:37])[CH2:40][OH:39])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])=[O:43]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCOCC2COC(C)(C)O2)c2ccccc2F)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCOCC(O)CO)c1ccccc1F
Reaction time: 3 h

Procedure:
A solution of (2-{3-chloro-5-[[2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-ethyl]-(2-fluoro-phenyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.035 g) and water (0.010 ml) in mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stored at room temperature for 3 h and then the solvent removed under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.022 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[N:23][CH:24]=1.[ClH:36].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:36].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:31](=[O:32])[C:28]4[CH:27]=[CH:26][C:25]([C:22]5[CH:21]=[CH:20][C:19]([C:18]([F:35])([F:17])[F:34])=[CH:24][N:23]=5)=[CH:30][CH:29]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cn4)cc3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-[5-(trifluoromethyl)-2-pyridyl]benzenecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [OH-].[Li+].[CH3:3][S:4]([O:7][C:8]1[C:9]([O:20][CH3:21])=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13](C(=O)C)[N:12]=[CH:11]2)(=[O:6])=[O:5].O>O1CCCC1.CO>[CH3:3][S:4]([O:7][C:8]1[C:9]([O:20][CH3:21])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)(=[O:5])=[O:6]
Reactant: COc1c(OS(C)(=O)=O)ccc2c1cnn2C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1c(OS(C)(=O)=O)ccc2[nH]ncc12
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 2M-aqueous lithium hydroxide solution (0.352 ml, 0.704 mmol) was added to a solution of 1-acetyl-4-methoxy-1H-indazol-5-yl methanesulfonate (100 mg, 0.352 mmol) in a mixture of tetrahydrofuran (1.0 ml) and methanol (1.0 ml) at room temperature. After 1 hour, the resulting mixture was poured into water (10 ml) and extracted with ethyl acetate (20 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-methoxy-1H-indazol-5-yl methanesulfonate (80 mg, 94%).
Reaction SMILES: [CH2:1]([O:4][C:5](Cl)=[O:6])[CH2:2]Cl.Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[C:12]([F:18])[CH:11]=1.C(N(CC)CC)C.CC(C)([O-])C.[K+]>C1COCC1.C(Cl)Cl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:2][CH2:1][O:4][C:5]2=[O:6])=[C:12]([F:18])[CH:11]=1
Reactant: O=C(Cl)OCCCl
Reactant: NCc1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCCN1Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-chloroethyl chloridocarbonate (114 μL, 1.1 mmol) was added to a mixture of 1-(4-bromo-2-fluorophenyl)methanamine hydrochloride (0.240 g, 1.0 mmol) and triethylamine (293 μL, 2.1 mmol). The mixture was stirred at RT for 3 h, and then 1M of potassium tert-butoxide in THF (1.2 mL) was added. The mixture was stirred overnight at RT, diluted with methylene chloride, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product which was directly used in next step without further purification. LCMS: (M+H)=275.9/273.9.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.O[O:20][S:21]([O-:23])=O.[K+].[CH3:25]O>O>[CH3:25][S:21]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1)(=[O:23])=[O:20]
Reactant: CSc1nccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-(methylthio)-4-[4-(trifluoromethyl)phenyl]pyrimidine (2.24 g, 8.4 mmol) in methanol (85 mL) and water (85 mL) at 0° C. was added oxone™ (15.25 g, 24.8 mmol). The reaction was stirred at 0° C. for 1 h and then at room temperature for 18 h. The reaction mixture was diluted with water (200 mL) and extracted with chloroform (2×250 mL). The organic solution was dried (Na2SO4) filtered and evaporated to afford the title compound as a white solid (2.235 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)=[O:25])[N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2cccs2)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 5-Thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1.5/1) afforded the title compound. 1H NMR (400 MHz, CDCl3): 7.32-7.36 (m, 1H), 7.22-7.26 (m, 1H), 7.08 (s, 1H), 7.02-7.08 (dd, 1H), 6.96-7.2 (m, 2H), 6.86-6.92 (m, 2H), 4.3-4.4 (q, 2H), 3.52-3.58 (m, 4H), 3.05-3.25 (m, 4H), 1.3-1.42 (m, 3H). 13C NMR (400 MHz, CDCl3): 164, 130, 126.8, 126.4, 120, 118.2, 115.4, 62.3, 54, 50.5, 42, 44.5, 14.6.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([Li])CCC.[F:11][CH:12]([F:33])[C:13]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15](Cl)[C:14]=1[C:29]([O:31][CH3:32])=[O:30].[Li].N1C=CC=N1>O1CCCC1.O>[F:22][C:19]([F:20])([F:21])[C:17]1[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[C:14]([C:29]([O:31][CH3:32])=[O:30])=[C:13]([CH:12]([F:11])[F:33])[N:18]=1
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1-n1cccn1
Reaction time: 0.75 h
Yield: 43.6 %

Procedure:
To a solution of 0.94 g (0.014 mol) of pyrazole in 25 ml of anhydrous tetrahydrofuran was added 0.9 g (0.014 mol) of n-butyllithium. This cloudy solution was then transferred to a solution of 5 g (0.014 mol) of product of Example 103 in 25 ml of anhydrous THF. The solution turned red upon addition of the pyrazole lithium salt. After 45 minutes at room temperature the reaction was complete. The mixture was poured into 100 ml of water and extracted with two 75 ml portions of ether. The combined ether layers were washed with two 100 ml portions of water, dried (CaSO4), filtered and concentrated to 4.1 g of oil which was about 80% product. Trituration with petroleum ether gave 2.4 g (45%) of pure product; mp 42°-52° C. Recrystallization from cyclohexane afforded an analytical sample; mp 48.5°-50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:25][C@@H:26]([OH:30])[C:27]([OH:29])=[O:28])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([OH:24])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:31](O)[CH2:32][CH3:33].Cl.O1CCOC[CH2:37]1>>[CH2:33]([O:28][C:27](=[O:29])[C@H:26]([OH:30])[CH2:25][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[O:23][N:22]=[C:21]([OH:24])[CH:20]=1)=[O:18])[CH2:32][CH2:31][CH3:37]
Reactant: C1COCCO1
Reactant: O=C(NN(Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O)c1cc(O)no1
Reactant: CCCO
Agent: Cl
Product: CCCCOC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
(R)-3-[N-(3′-Chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-propionic acid (60 mg, 0.1 mmol) was dissolved in 1-propanol (4 mL, 50 mmol) and 4 M HCl in dioxane (700 mL, 3 mmol) was added. The mixture was stirred at room temperature until the reaction was complete (˜3 hours), then evaporated under reduced pressure and purified (Interchim reverse phase chromatography column, 30-95% MeCN in water with 5% TFA). The clean fractions were combined and lyophilized, then purified by preparative HPLC to yield the title compound (43 mg, purity 95%). MS m/z [M+H]+ calc'd for C24H26ClN3O6, 488.15. found 488.4.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH:47]1([C:52](Cl)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1.C(N(CC)CC)C>O1CCCC1>[CH:47]1([C:52]([NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CCCC1

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added cyclopentanecarbonyl chloride (0.060 mL, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). Completion of the reaction necessitated the addition of 2 more equivalents of reagents and a total reaction time of 48 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 699 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:15])[O:3]1.Cl.[N:17]1([C:23](=[O:36])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:27][CH:26]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>CCO>[OH:13][CH:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:15])[O:3][CH:2]([CH3:1])[CH2:11]2)[CH2:14][N:20]1[CH2:19][CH2:18][N:17]([C:23](=[O:36])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][CH:30]=2)[CH2:22][CH2:21]1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: CC1Cc2cc(C3CO3)ccc2C(=O)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1Cc2cc(C(O)CN3CCN(C(=O)Cc4ccc(-n5cnnn5)cc4)CC3)ccc2C(=O)O1

Procedure:
A sealed tube containing 3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (72 mg, 35 mmol), 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride (109 mg, 0.35 mmol), DIEA (0.2 mL) and EtOH (3 mL) was heated to 80 C for 12 hours. The excess solvent was removed and the crude product purified via MPLC (35% EtOAc/Hex-60% EtOAc/Hex) to give 6-[1-hydroxy-2-(4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-3-methyl-3,4-dihydro-1H-isochromen-1-one. LC-MS (IE, m/z): 477 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:20]=[CH:21][N:22]=2)[CH:5]=[C:6]([C:17]([OH:19])=O)[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[N+:66]([CH:69]([C:71]1([OH:75])[CH2:74][NH:73][CH2:72]1)[CH3:70])([O-:68])=[O:67]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:4]([CH:20]=[CH:21][N:22]=2)[CH:5]=[C:6]([C:17]([N:73]2[CH2:74][C:71]([CH:69]([N+:66]([O-:68])=[O:67])[CH3:70])([OH:75])[CH2:72]2)=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16]
Reactant: CC([N+](=O)[O-])C1(O)CNC1
Reactant: O=C(O)c1cn2ccnc2c(Cl)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC([N+](=O)[O-])C1(O)CN(C(=O)c2cn3ccnc3c(Cl)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A solution of 8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (150 mg, 0.35 mmol) (prepared using procedures similar to those described in US 2006030610 and US 2005054701), N,N-diisopropylethylamine (300 μL, 1.74 mmol), PyBOP (180 mg, 0.35 mmol) and 3-(1-nitroethyl)azetidin-3-ol hydrochloride (76 mg, 0.42 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was then partitioned between 5% aqueous lithium chloride, and ethyl acetate. The aqueous portion was extracted twice using ethyl acetate. The combined organic portion was washed with 20% aqueous citric acid, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by column chromatography. Eluting with 5% methanol in dichloromethane, the isolated product was concentrated in vacuo to afford 195 mg, 0.35 mmol (100%) of 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-(1-nitro ethyl)azetidin-3-ol as a yellow foam. 1H NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 7.23 (br s, 1H), 6.55-6.51 (m, 1H), 6.02 (br s, 1H), 4.79 (q, 1H), 4.45-3.96 (4H), 1.56 (d, 3H). MS (EI) for C20H19ClFI6O4: 560 (MH+).