Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:8][C@H:7]([O:30][C@H:31]2[C@H:44]([O:45][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:43]([CH2:54][O:55][C:56](=[O:63])[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[O:42][C@H:33]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@H:32]2[O:64][C:65](=[O:72])[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C@H:6]1[O:73][C:74](=[O:81])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)C=C>CO.ClCCCl.[Pd](Cl)Cl>[C:74]([O:73][C@H:6]1[C@@H:5]([OH:4])[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:8][C@@H:7]1[O:30][C@H:31]1[C@H:44]([O:45][C:46](=[O:53])[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@@H:43]([CH2:54][O:55][C:56](=[O:63])[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[O:42][C@H:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:32]1[O:64][C:65](=[O:72])[C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)(=[O:81])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: C=CCO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](O[C@@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OCc3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl[Pd]Cl
Solvent: ClCCCl
Solvent: CO
Product: O=C(OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OCc3ccccc3)O[C@H](COC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A solution of the allyl ether 49 (688 mg, 0.627 mmol) in MeOH (6 mL) and 1,2-dichloroethane (6 mL) (0.05 M) was treated with solid palladium chloride (25 mg). The mixture was stirred at 70° C. (external oil bath) for 2 h. TLC indicated complete conversion. The mixture was evaporated onto silica and purified by column chromatography (silica 2.7×17 cm, gradient elution with hexane-EtOAc 200:20, 200:40, 200:50, 210:70, 200:100) to give the alcohol 50 as a colourless gum (0.539 mg, 81%). 1H NMR (CDCl3, 400 MHz) δ 8.18-8.03 (m, 8H, Ph), 7.85-7.81 (m, 4H, Ph), 7.68-7.25 (m, 23H, Ph), 5.97 (dd or t, 1H, JH3(I)H4(I)=9.8, JH4(I)-H5(I)=9.8, H4I), 5.68 (dd, 1H, J JH1(I)-H2(I)=2.0, JH2(I)-H3(I)=2.9, H2I), 5.60 (dd or t, 1H, J JH3(II)-H4(II)=9.8, J JH4(II)-H5(II)=9.8, H4II), 5.28 (br s, 1H, H1II), 5.15 (d, 1H, J JH1(II)-H2(II)=2.0, H1I), 5.05 (dd, 1H, JH1(II)-H2(II)=2.0, JH2(II)-H3(II)=2.9, H2II), 4.77 (d, 1H, Jgem=11.7, CH2), 4.65-4.56 (m, 4H, CH2, H6Ieq, H3I and H6II), 4.44 (dd, 1H, Jgem=12.7, JH5(I)-H6(I)ax=4.9, H6Iax), 4.34 (m, 1H, H5II), 4.32 (dd, 1H, Jgem=10.7, JH5(II)-H6(II)=2.9, H6II), 4.28 (ddd, 1H, JH5(I)-H6(I)ax=4.9, JH5(I)-H6(I)eq=2.9, H5I), 4.17 (dd, 1H, H3II).
Reaction SMILES: [CH3:1][C:2]12[CH2:29][CH:5]([C:6]3([CH3:28])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=4)=[O:17])[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[CH2:30](O)[CH2:31][OH:32].CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]12[CH2:29][CH:5]([C:6]3([CH3:28])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]4([C:18]5[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=5)[O:32][CH2:31][CH2:30][O:17]4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: OCCO
Reactant: COC(=O)c1ccc(C(=O)c2ccc3c(c2)C2(C)C4(C)CCC(C4)C2(C)O3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C2(c3ccc4c(c3)C3(C)C5(C)CCC(C5)C3(C)O4)OCCO2)cc1

Procedure:
2 g (5.12 mmol) of the ketone obtained in Example 8, in 20 ml of benzene, were treated with 0.5 ml of ethylene glycol and 10 mg of TsOH. The reaction mixture was heated at reflux for 24 hours and was then neutralized with a saturated sodium bicarbonate solution. After extraction with ethyl ether, the organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated to yield, after chromatography on silica in a hexane/EtOAc (90/10) mixture and triturating in hexane, 910 mg (41%) of the expected compound, melting at 136°-137° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:25][C:15]2[NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][C:22]=3[C:14]=2[CH2:13]1.Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]1[CH2:25][C:15]2[N:16]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[N:29]=3)[C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][C:22]=3[C:14]=2[CH2:13]1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)C3
Reactant: Fc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)n2)CC(N2C(=O)c3ccccc3C2=O)C1
Yield: 88.4 %

Procedure:
Dissolve (±)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile (6.88 g, 21.0 mmol) and 2-bromomethyl-6-fluoro-pyridine (3.99 g, 21.0 mmol) in DMF (80 mL). Add cesium carbonate (7.51 g, 23.1 mmol, 1.10 equivalents) and stir the reaction mixture at room temperature under nitrogen for 48 h. Dilute the reaction with ethyl acetate, wash with water (3×), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a semi-solid (8.10 g). Purify the crude product on a 120 g silica gel column eluting with 0 to 100% ethyl acetate/hexanes to obtain 6.7 g of a tan/brown solid. Suspend the product in ether (100 mL) at room temperature overnight. Filter the solid, rinse with ether, and dry under high vacuum to obtain the title compound as a tan solid (5.70 g, 62%). LCMS 437.1 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[CH3:20][O:21][C:22]1[C:27]2[N:28]=[C:29]([CH2:31][O:32][CH3:33])[NH:30][C:26]=2[C:25]([C:34](OC)=[O:35])=[CH:24][CH:23]=1>O1CCCC1.CCCCCC>[CH3:20][O:21][C:22]1[C:27]2[N:28]=[C:29]([CH2:31][O:32][CH3:33])[NH:30][C:26]=2[C:25]([C:34](=[O:35])[CH2:19][C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: COCc1nc2c(OC)ccc(C(=O)OC)c2[nH]1
Reactant: Cc1ccncc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCc1nc2c(OC)ccc(C(=O)Cc3ccncc3)c2[nH]1
Temperature: -78 °C
Yield: 25.1 %

Procedure:
A solution of diisopropylamine (1.51 g) in tetrahydrofuran (15 ml), under nitrogen, cooled to −10° C. was treated with butyl lithium in hexane (6 ml, 2.5 M). The solution was cooled to −78° C. then treated dropwise with a solution of 4-picoline (1.40 g) in tetrahydrofuran (10 ml) followed by a solution of methyl 7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate [1,25 g, Reference Example 3(a)] in tetrahydrofuran (15 ml). The brown solution was allowed to warm to room temperature and the resulting yellow suspension was filtered. The insoluble material was washed with a little tetrahydrofuran then air dried. The yellow solid (2.3 g) was dissolved in water (75 ml) and the solution extracted three times with dichloromethane (25 ml). The combined extracts were dried over magnesium sulphate and then evaporated. The resulting yellow solid (1.53 g) was subjected to flash chromatography on silica eluting initially with a mixture of methanol and dichloromethane (5:95, v/v) to give 1-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-2-(4-pyridyl)ethanone (0.39 g) recrystallised from toluene as a yellow solid, m.p. 218-220° C. with decomposition. [Elemental analysis:—C, 66.58; H, 5.53; N, 13.76%. Calculated:—C, 66.45; H, 5.50; N, 13.5%]; then eluting with a mixture of methanol and dichloromethane (1:9, v/v) to give 1,3-bis-(4-pyridyl)-2-(7-methoxy-2-methoxymethyl-3H-benzimidazol-4-yl)-propan-2-ol (0.4 g) recrystallised from methanol as a white solid, m.p. 210° C. with decomposition. [Elemental analysis:—C, 68.40; H, 5.94; N, 13.85%. Calculated:—C, 68.30; H, 5.98; N, 14.00%].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[CH2:13]([N:20]=[C:21]=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(N(C)C)=O>[CH2:13]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1ccc2c(=O)[nH]ccc2c1
Solvent: CC(=O)N(C)C
Product: O=C(NCc1ccccc1)Nc1ccc2c(=O)[nH]ccc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
6-Amino-2H-isoquinolin-1-one (0.2 mmol, 39 mg) and benzyl isocyanate (0.2 mmol, 27 mg) were dissolved in 1 mL DMA. The mixture was allowed to stir at 60° C. overnight. The product was obtained by HPLC purification. MS (M+1) 294.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C[C@H]1CCCN(CC(=O)c2ccc(C#N)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C[C@H]1CCCN(CC(O)c2ccc(C#N)cc2)C1
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a mixture of (R)-ethyl 2-(1-(2-(4-cyanophenyl)-2-oxoethyl)piperidin-3-yl)acetate (1 g, 3.18 mmol) in MeOH was added sodium borohydride (0.120 g, 3.18 mmol). The reaction mixture was stirred for 1 hour. The reaction was quenched with water. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated. The resulting solids were purified on a silica gel cartridge using an EtOAc/hexanes gradient to give 575 mg of ethyl 2-((3R)-1-(2-(4-cyanophenyl)-2-hydroxyethyl)piperidin-3-yl)acetate.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(=O)O)cc1-c1ccccc1
Yield: 84 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-phenylbenzyl)oxy]-1H-pyrazole-4-carboxylate (0.25 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux for 1 hr. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-phenylbenzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (0.20 g, yield 83%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 181-182° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:18][CH2:19][CH3:20])=[C:6]([CH:12]2[CH2:16][NH:15][C:14](=[O:17])[CH2:13]2)[C:7](F)=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[C-:21]#[N:22].[Na+].O>CS(C)=O>[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([C:21]#[N:22])=[C:6]([CH:12]2[CH2:13][C:14](=[O:17])[NH:15][CH2:16]2)[C:5]=1[O:18][CH2:19][CH3:20])(=[O:3])[CH3:2]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C1CNC(=O)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1C1CNC(=O)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A racemic mixture of 4-(3-acetyl-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one (0.20 g, 0.67 mmol) (from Example 345, Step 5) and sodium cyanide (0.057 g, 1.2 mmol) in dimethyl sulfoxide (1.5 mL) was stirred at 80° C. for 3 h. The reaction mixture was poured into water (35 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. The crude material was purified by flash column chromatography using ether (containing 10% methanol) in hexanes (0%-100%) to give the desired product (0.15 g, 71%) as a mixture of enantiomers. LCMS for C15H16ClN2O3 (M+H)+: m/z=307.1; Found: 307.0. The mixture of enantiomers was separated by chiral HPLC to give the individual enantiomers as peak 1 and peak 2 (RT=5.00 min and 10.4 min; Phenomenex Lux Cellulose C-2, 21.2×250 mm, 5 micron particle size, eluting with 60% ethanol in hexanes at 18 mL/min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[NH4+:38]>>[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]2[NH:38][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:15]=2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [NH4+]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Product: CCOC(=O)c1nc(-c2ccc(OCc3ccccc3)cc2)[nH]c1-c1ccc(F)cc1

Procedure:
Ethyl 3-(4-fluorophenyl)-2-hydroxyimino-3-oxopropionate, 4-benzyloxybenzaldehyde and ammonium acetate are reacted and treated in the same manner as in Example 22 to give ethyl 2-(4-benzyloxy-phenyl)-5-(4-fluorophenyl)imidazole-4-carboxylate. Ethyl 2-(4-benzyloxyphenyl)-5-(4-fluorophenyl)imidazole-4-carboxylate is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(4-benzyloxyphenyl)-5-(4-fluorophenyl)-imidazole-4-carboxylic acid. 2-(4-Benzyloxyphenyl)-5-(4-fluorophenyl) imidazole-4-carboxylic acid is reacted and treated in the same manner as in Example 1 to give 2-(4-benzyloxyphenyl)-5-(4-fluorophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]#N.N([O-])=[O:15].[Na+].[OH-:18].[Na+]>OS(O)(=O)=O.O>[CH3:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]([OH:15])=[O:18]
Reactant: O=N[O-]
Reactant: Cc1cc2nccn2c(C)c1C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc2nccn2c(C)c1C(=O)O
Temperature: 120 °C
Yield: 90 %

Procedure:
The above-prepared nitrile (500 mg, 2.9 mmol) was dissolved in a mixture of H2SO4 (conc. 4 ml) and H2O (1 ml). The mixture was heated at 120° C. for 16 h. It was then cooled to 90° C. and NaNO2 (1.4 g, 20 mmol) was added in small portions over 10 min. The reaction was heated at 90° C. for and additional 1 h and then cooled to rt and poured into an ice-water mixture (˜20 ml). The chilled mixture was basified to PH=12 using 10N NaOH. The aqueous mixture was then washed with CH2Cl2 (15 ml×2) to remove impurities. It was then acidified to PH=2. After being concentrated under high vacuum to dryness, the residue was extracted with CH2Cl2/CH3OH (4/1, 30 ml×3). The combined extracts were concentrated to give 5,7-dimethyl-imidazo[1,2-a]pyridine-6-carboxylic acid (500 mg, 90% containing impurities) as a beige solid. 1H NMR (CDCl3) δ 2.56 (s, 3H), 2.83 (s, 3H), 7.74 (s, 1H), 8.08 (d, 1H, J=1.8 Hz), 8.22 (d, 1H, J=1.8 Hz).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=1.[F:22][C:23]1[CH:31]=[C:30]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:28])=[C:30]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[CH:31]=1
Reactant: O=C(O)c1ccc(F)cc1-n1nccn1
Reactant: CN(C)c1cc(N2CC3CNCC3C2)nc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cc(N2CC3CN(C(=O)c4ccc(F)cc4-n4nccn4)CC3C2)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
A mixture of [6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine (50 mg, 0.17 mmol), 4-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (37.8 mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF (4.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (42.0 mg, 51.6%). MS (ESI) mass calcd. for C22H22F4N8O, 490.46; m/z found [M+H]+. 1H NMR (CDCl3): 7.90-7.65 (m, 3H), 7.57-7.35 (m, 1H), 7.18-7.02 (m, 1H), 5.23-5.05 (m, 1H), 4.02-3.20 (m, 7H), 3.16-2.84 (m, 9H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([C:29]1[O:33][C:32]([C:34]2[C:38]([CH:39]=O)=[C:37]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)[N:36]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=3[Cl:55])[N:35]=2)=[N:31][N:30]=1)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([C:29]1[O:33][C:32]([C:34]2[C:38]([CH:39]=[C:1]([Br:5])[Br:2])=[C:37]([C:41]3[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=3)[N:36]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=3[Cl:55])[N:35]=2)=[N:31][N:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1nnc(-c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C=O)o1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1nnc(-c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C=C(Br)Br)o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
To a solution of carbontetrabromide (313 mg, 0.94 mmol) in methylene chloride (15 ml) at 0° C. was added triphenylphosphine (248 mg, 0.95 mmol). The reaction mixture was stirred at 0° C. for 10 minutes and then 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbaldehyde (300 mg, 0.63 mmol) in methylenechloride (10 ml) was added slowly. The reaction temperature was warmed slowly to room temperature and stirred overnight. The resulting solution was quenched with saturated ammonium chloride and extracted organic layer with ethyl ether (50 ml twice). After evaporation, crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to recover starting material (110 mg, 37%) and produce 2-tert-butyl-5-(5-(4-chlorophenyl)-4-(2,2-dibromovinyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole (230 mg, 58% yield) as white solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCSc1ccncc1
Yield: 83.7 %

Procedure:
To a solution of 700 mg (2.90 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 1.62 ml (11.6 mmol) of triethylamine in 30 ml of methylene chloride was added 1.55 ml (3.48 mmol) of oleoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.05 g of the desired compound (83.7%, colorless powder), mp: 50.0°-50.5° C.
Reaction SMILES: [C:1]1([C:6](Cl)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1>C1C=CC=CC=1>[C:1]1([C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=3)=[CH:12][CH:11]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)c2cccs2)cc1
Yield: 51.9 %

Procedure:
A mixture of 1.1 g of 2-thenoyl chloride, 1.0 g of 6-(p-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone and 10 ml of benzene was treated in the same manner as described in Example 1 to effect reaction whereby 800 mg of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([CH2:31][NH:32][CH2:33][CH2:34][CH3:35])[CH:25]=2)[CH:18]=1)[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:37]#[C:38]Br>C(O)C>[CH2:1]([O:8][C:9](=[O:36])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:25]=[C:26]3[C:27](=[CH:28][CH:29]=2)[N:30]=[C:38]([NH2:37])[N:32]([CH2:33][CH2:34][CH3:35])[CH2:31]3)[CH:18]=1)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCc1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1N
Reactant: N#CBr
Solvent: CCO
Product: CCCN1Cc2cc(Oc3cccc(N(C(=O)OCc4ccccc4)C4CCCCC4)c3)ccc2N=C1N

Procedure:
A mixture of [3-(4-amino-3-propylaminomethyl-phenoxy)-phenyl]-cyclohexyl-carbamic acid benzyl ester (0.0018 mol) and cyanogen bromide (0.00234 mol) in ethanol (60 mL) was stirred and refluxed for 3 hours and then was cooled. The ethanol solvent was evaporated. The residue was triturated under diisopropyl ether and ethanol, filtered off, and dried to yield the title compound as a solid.